diff --git "a/train.tsv" "b/train.tsv"
new file mode 100644--- /dev/null
+++ "b/train.tsv"
@@ -0,0 +1,122468 @@
+Background	O
+Chemotherapy	O
+-	O
+induced	O
+cardiomyopathy	O
+(	O
+CICM	O
+)	O
+and	O
+heart	O
+failure	O
+are	O
+major	O
+complications	O
+of	O
+cancer	O
+therapeutics	O
+and	O
+can	O
+result	O
+in	O
+significant	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+There	O
+is	O
+limited	O
+data	O
+on	O
+the	O
+incidence	B-EPI
+and	O
+risk	O
+factors	O
+of	O
+CICM	O
+in	O
+African	O
+American	O
+and	O
+Afro	O
+-	O
+Caribbean	O
+patients	O
+.	O
+
+Methods	O
+We	O
+performed	O
+a	O
+retrospective	O
+chart	O
+review	O
+to	O
+evaluate	O
+the	O
+baseline	O
+characteristics	O
+that	O
+may	O
+predispose	O
+to	O
+CICM	O
+.	O
+
+Patients	O
+were	O
+African	O
+American	O
+and	O
+Afro	O
+-	O
+Caribbean	O
+ethnicity	O
+.	O
+
+Data	O
+was	O
+collected	O
+between	O
+2014	O
+to	O
+2018	O
+.	O
+
+Patients	O
+had	O
+transthoracic	O
+echocardiogram	O
+(	O
+TTE	O
+)	O
+or	O
+multigated	O
+acquisition	O
+scan	O
+(	O
+MUGA	O
+)	O
+prior	O
+to	O
+cancer	O
+therapy	O
+and	O
+every	O
+3	O
+months	O
+thereafter	O
+,	O
+until	O
+the	O
+end	O
+of	O
+the	O
+regimen	O
+.	O
+
+CICM	O
+was	O
+defined	O
+as	O
+a	O
+≥16	O
+%	O
+reduction	O
+in	O
+LVEF	B-LOC
+or	O
+≥10	O
+%	O
+reduction	O
+in	O
+LVEF	B-LOC
+to	O
+a	O
+value	O
+<	B-STAT
+50	I-STAT
+%	I-STAT
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+230	O
+patients	O
+were	O
+studied	O
+,	O
+with	O
+a	O
+mean	O
+age	O
+of	O
+54±12	O
+years	O
+with	O
+91	O
+%	O
+were	O
+females	O
+,	O
+BMI	O
+30±4	O
+,	O
+81	O
+%	O
+were	O
+taking	O
+anthracyclines	O
+,	O
+87	O
+%	O
+were	O
+on	O
+Trastuzumab	B-LOC
+while	O
+5	O
+%	O
+were	O
+receiving	O
+both	O
+medications	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+comorbidities	O
+was	O
+as	O
+follows	O
+:	O
+hypertension	O
+8	O
+%	O
+,	O
+diabetes	O
+mellitus	O
+8	O
+%	O
+,	O
+ESRD	O
+8	O
+%	O
+,	O
+dyslipidemia	O
+8	O
+%	O
+,	O
+CAD	O
+7	B-STAT
+%	I-STAT
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+CICM	O
+was	O
+7	O
+%	O
+overall	O
+,	O
+while	O
+it	O
+was	O
+6	O
+%	O
+and	O
+8	O
+%	O
+for	O
+patients	O
+taking	O
+Anthracyclines	O
+and	O
+Trastuzumab	B-LOC
+,	O
+respectively	O
+.	O
+
+CICM	O
+was	O
+associated	O
+with	O
+dyslipidemia	O
+(	O
+r=	O
+.22	O
+,	O
+p=	O
+.001	O
+)	O
+,	O
+hypertension	O
+(	O
+r=	O
+.12	O
+,	O
+p=	O
+.05	O
+)	O
+,	O
+baseline	O
+ejection	O
+fraction	O
+(	O
+r=	O
+-.21	O
+,	O
+p=	O
+.001	O
+)	O
+and	O
+concomitant	O
+use	O
+of	O
+radiation	O
+therapy	O
+(	O
+r=	O
+.147	O
+,	O
+p=	O
+.02	O
+)	O
+,	O
+but	O
+not	O
+with	O
+age	O
+,	O
+gender	O
+,	O
+beta	O
+blocker	O
+use	O
+,	O
+angiotensin	O
+converting	O
+enzyme	O
+inhibitor	O
+use	O
+,	O
+number	O
+of	O
+chemotherapy	O
+cycles	O
+or	O
+stage	O
+of	O
+the	O
+malignancy	O
+.	O
+
+On	O
+multivariate	O
+analysis	O
+CICM	O
+was	O
+independently	O
+associated	O
+with	O
+baseline	O
+ejection	O
+fraction	O
+(	O
+β=	O
+-.193	O
+,	O
+P=	O
+.003	O
+)	O
+and	O
+dyslipidemia	O
+(	O
+β=	O
+-.20	O
+,	O
+P=	O
+.003	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+incidence	B-EPI
+of	O
+CICM	O
+in	O
+African	O
+Americans	O
+and	O
+Afro	O
+-	O
+Caribbean	O
+is	O
+higher	O
+than	O
+reported	O
+in	O
+the	O
+general	O
+population	O
+.	O
+
+Dyslipidemia	O
+and	O
+baseline	O
+ejection	O
+fraction	O
+were	O
+seen	O
+as	O
+the	O
+major	O
+risk	O
+factors	O
+associated	O
+with	O
+the	O
+higher	O
+incidence	B-EPI
+of	O
+CICM	O
+.	O
+
+Background	O
+Cardiac	O
+rupture	O
+is	O
+a	O
+disastrous	O
+but	O
+uncommon	O
+complication	O
+of	O
+acute	O
+ST	B-LOC
+-	O
+elevation	O
+myocardial	O
+infarction	O
+(	O
+STEMI	O
+)	O
+.	O
+
+The	O
+incidence	B-EPI
+,	O
+risk	O
+factors	O
+and	O
+in	O
+-	O
+hospital	O
+outcomes	O
+related	O
+to	O
+cardiac	O
+rupture	O
+in	O
+the	O
+current	O
+era	O
+are	O
+unknown	O
+.	O
+
+Methods	O
+This	O
+study	O
+consecutively	O
+collected	O
+all	O
+acute	O
+STEMI	O
+patients	O
+admitted	O
+to	O
+a	O
+single	O
+tertiary	O
+center	O
+in	O
+China	B-LOC
+from	O
+January	O
+2004	O
+to	O
+December	O
+2015	O
+.	O
+
+Characteristics	O
+of	O
+each	O
+cardiac	O
+rupture	O
+were	O
+collected	O
+and	O
+analyzed	O
+.	O
+
+Results	O
+Among	O
+4190	O
+patients	O
+,	O
+75	B-STAT
+(	O
+1.8	O
+%	O
+)	O
+patients	O
+had	O
+cardiac	O
+rupture	O
+,	O
+including	O
+33	O
+at	O
+the	O
+ventricular	O
+septum	O
+and	O
+42	O
+at	O
+the	O
+left	O
+ventricle	O
+free	O
+wall	O
+(	O
+LVFW	O
+)	O
+.	O
+
+Patients	O
+with	O
+cardiac	O
+rupture	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+female	O
+,	O
+with	O
+more	O
+advanced	O
+age	O
+,	O
+lower	O
+rate	O
+of	O
+primary	O
+percutaneous	O
+coronary	O
+intervention	O
+(	O
+PPCI	O
+)	O
+,	O
+and	O
+higher	O
+in	O
+-	O
+hospital	O
+mortality	O
+.	O
+
+Compared	O
+with	O
+survivors	O
+,	O
+the	O
+death	O
+cases	O
+were	O
+older	O
+,	O
+had	O
+a	O
+higher	O
+white	O
+blood	O
+cell	O
+count	O
+,	O
+higher	O
+rate	O
+of	O
+delayed	O
+admission	O
+(	O
+>	O
+12	O
+h	O
+from	O
+symptom	O
+onset	O
+to	O
+door	O
+)	O
+,	O
+earlier	O
+occurrence	B-EPI
+of	O
+cardiac	O
+rupture	O
+,	O
+higher	O
+percentage	O
+of	O
+LVFW	O
+rupture	O
+and	O
+lower	O
+rate	O
+of	O
+surgical	O
+repair	O
+.	O
+
+Logistic	O
+regression	O
+analysis	O
+showed	O
+that	O
+surgical	O
+repair	O
+served	O
+as	O
+the	O
+most	O
+valuable	O
+factor	O
+affecting	O
+survival	O
+.	O
+
+Moreover	O
+,	O
+elevated	O
+white	O
+blood	O
+cell	O
+count	O
+and	O
+advanced	O
+age	O
+might	O
+be	O
+related	O
+to	O
+an	O
+increased	O
+in	O
+-	O
+hospital	O
+death	O
+due	O
+to	O
+cardiac	O
+rupture	O
+.	O
+
+Conclusions	O
+In	O
+this	O
+contemporary	O
+cohort	O
+,	O
+female	O
+sex	O
+,	O
+advanced	O
+age	O
+and	O
+low	O
+rate	O
+of	O
+PPCI	O
+post	O
+-	O
+STEMI	O
+are	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+cardiac	O
+rupture	O
+.	O
+
+Advanced	O
+age	O
+and	O
+elevated	O
+white	O
+blood	O
+cell	O
+count	O
+might	O
+be	O
+related	O
+to	O
+an	O
+increased	O
+in	O
+-	O
+hospital	O
+mortality	O
+after	O
+cardiac	O
+rupture	O
+,	O
+whereas	O
+surgical	O
+repair	O
+served	O
+as	O
+the	O
+most	O
+valuable	O
+factor	O
+affecting	O
+survival	O
+.	O
+
+Background	O
+Nonarteritic	O
+anterior	O
+ischemic	O
+optic	O
+neuropathy	O
+(	O
+NAION	O
+)	O
+in	O
+young	O
+patients	O
+(	O
+age	O
+≤50	O
+)	O
+accounts	O
+for	O
+a	O
+minority	O
+of	O
+all	O
+cases	O
+of	O
+NAION	O
+and	O
+is	O
+more	O
+highly	O
+associated	O
+with	O
+crowding	O
+of	O
+the	O
+optic	O
+nerves	O
+and	O
+bilateral	O
+involvement	O
+than	O
+NAION	O
+in	O
+older	O
+patients	O
+.	O
+
+Optic	O
+disc	O
+drusen	O
+(	O
+ODD	O
+)	O
+are	O
+likewise	O
+associated	O
+with	O
+crowded	O
+optic	O
+nerves	O
+and	O
+are	O
+located	O
+in	O
+the	O
+prelaminar	O
+optic	O
+nerve	O
+head	O
+where	O
+they	O
+could	O
+contribute	O
+to	O
+NAION	O
+pathogenesis	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+prevalence	B-EPI
+of	O
+ODD	O
+in	O
+the	O
+eyes	O
+of	O
+young	O
+NAION	O
+patients	O
+using	O
+modern	O
+imaging	O
+methods	O
+and	O
+to	O
+compare	O
+it	O
+to	O
+the	O
+baseline	O
+1.8%-2.0	B-STAT
+%	I-STAT
+prevalence	B-EPI
+of	O
+ODD	O
+in	O
+the	O
+general	O
+population	O
+.	O
+
+Methods	O
+In	O
+this	O
+retrospective	O
+study	O
+,	O
+all	O
+young	O
+NAION	O
+patients	O
+(	O
+ages	O
+18	O
+-	O
+50	O
+years	O
+,	O
+inclusive	O
+)	O
+seen	O
+in	O
+2	O
+tertiary	O
+care	O
+neuro	O
+-	O
+ophthalmology	O
+clinics	O
+(	O
+in	O
+London	B-LOC
+,	O
+Canada	B-LOC
+and	O
+Copenhagen	B-LOC
+,	O
+Denmark	B-LOC
+)	O
+in	O
+the	O
+ten	O
+-	O
+year	O
+interval	O
+between	O
+April	O
+1	O
+,	O
+2009	O
+,	O
+and	O
+March	O
+31	O
+,	O
+2019	O
+,	O
+were	O
+identified	O
+and	O
+their	O
+medical	O
+charts	O
+reviewed	O
+.	O
+
+Patients	O
+were	O
+included	O
+in	O
+the	O
+study	O
+if	O
+ODD	O
+were	O
+diagnosed	O
+by	O
+any	O
+method	O
+(	O
+including	O
+ophthalmoscopy	O
+,	O
+ultrasound	O
+[	O
+US	B-LOC
+]	O
+,	O
+fundus	O
+autofluorescence	O
+[	O
+FAF	O
+]	O
+,	O
+computed	O
+tomography	O
+[	O
+CT	O
+]	O
+,	O
+or	O
+any	O
+optical	O
+coherence	O
+tomography	O
+[	O
+OCT	O
+]	O
+method	O
+)	O
+,	O
+or	O
+if	O
+ODD	O
+were	O
+excluded	O
+by	O
+enhanced	O
+-	O
+depth	O
+imaging	O
+OCT	O
+(	O
+EDI	O
+-	O
+OCT	O
+)	O
+using	O
+the	O
+ODD	O
+Studies	O
+(	O
+ODDS	O
+)	O
+Consortium	O
+protocol	O
+.	O
+
+The	O
+presence	O
+or	O
+absence	O
+of	O
+ODD	O
+was	O
+recorded	O
+for	O
+each	O
+eye	O
+.	O
+
+Results	O
+There	O
+were	O
+37	O
+eligible	O
+patients	O
+(	O
+74	O
+eyes	O
+)	O
+.	O
+
+Mean	O
+age	O
+of	O
+NAION	O
+onset	O
+was	O
+38.5	O
+±	O
+10.0	O
+years	O
+,	O
+and	O
+23	O
+patients	O
+(	O
+62	O
+%	O
+)	O
+were	O
+men	O
+.	O
+
+Patients	O
+had	O
+undergone	O
+the	O
+following	O
+methods	O
+of	O
+ODD	O
+detection	O
+:	O
+ophthalmoscopy	O
+(	O
+37	O
+patients	O
+)	O
+,	O
+EDI	O
+-	O
+OCT	O
+(	O
+36	O
+patients	O
+)	O
+,	O
+FAF	O
+(	O
+31	O
+patients	O
+)	O
+,	O
+US	B-LOC
+(	O
+9	O
+patients	O
+)	O
+,	O
+and	O
+CT	O
+orbits	O
+(	O
+8	O
+patients	O
+)	O
+.	O
+
+We	O
+found	O
+a	O
+prevalence	B-EPI
+of	O
+ODD	O
+of	O
+56.7	O
+%	O
+in	O
+NAION	O
+-	O
+affected	O
+patients	O
+and	O
+53.3	O
+%	O
+in	O
+NAION	O
+-	O
+affected	O
+eyes	O
+.	O
+
+Only	O
+35.9	O
+%	O
+of	O
+ODD	O
+were	O
+visible	O
+on	O
+ophthalmoscopy	O
+.	O
+
+Twenty	O
+of	O
+21	O
+ODD	O
+patients	O
+(	O
+95.2	O
+%	O
+)	O
+had	O
+bilateral	O
+ODD	O
+.	O
+
+Age	O
+of	O
+onset	O
+and	O
+sex	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+ODD	O
+-	O
+positive	O
+group	O
+and	O
+the	O
+ODD	O
+-	O
+negative	O
+group	O
+.	O
+
+EDI	O
+-	O
+OCT	O
+outperformed	O
+any	O
+combination	O
+of	O
+ophthalmoscopy	O
+,	O
+US	B-LOC
+,	O
+FAF	O
+,	O
+and	O
+CT	O
+at	O
+detecting	O
+ODD	O
+.	O
+
+Conclusion	O
+ODD	O
+were	O
+found	O
+with	O
+much	O
+higher	O
+prevalence	B-EPI
+in	O
+young	O
+patients	O
+with	O
+NAION	O
+than	O
+in	O
+the	O
+general	O
+population	O
+and	O
+were	O
+usually	O
+bilateral	O
+and	O
+buried	O
+.	O
+
+ODD	O
+may	O
+contribute	O
+to	O
+NAION	O
+pathogenesis	O
+by	O
+exacerbating	O
+an	O
+underlying	O
+compartment	O
+syndrome	O
+in	O
+the	O
+crowded	O
+	O
+disc	O
+at	O
+risk	O
+.	O
+	O
+
+EDI	O
+-	O
+OCT	O
+may	O
+be	O
+the	O
+best	O
+imaging	O
+modality	O
+for	O
+ODD	O
+detection	O
+in	O
+future	O
+studies	O
+.	O
+
+Background	O
+Pseudohypoparathyroidism	O
+(	O
+PHP	O
+,	O
+OMIM	O
+#	O
+103580	O
+)	O
+is	O
+a	O
+very	O
+rare	O
+disease	O
+(	O
+incidence	B-EPI
+0.3	B-STAT
+-	I-STAT
+1/100,000	I-STAT
+)	O
+.	O
+
+Heterozygous	O
+inactivating	O
+mutations	O
+involving	O
+the	O
+maternal	O
+GNAS	O
+exons	O
+1	B-STAT
+-	I-STAT
+13	I-STAT
+that	O
+encodes	O
+the	O
+alpha	O
+subunit	O
+of	O
+the	O
+stimulatory	O
+G	O
+protein	O
+(	O
+Gsα	O
+)	O
+cause	O
+inactivating	O
+parathyroid	O
+hormone	O
+(	O
+PTH)/PTHrP	O
+signalling	O
+disorder	O
+type	O
+2	O
+(	O
+iPPSD2	O
+or	O
+PHP	O
+type	O
+1A	O
+)	O
+,	O
+which	O
+is	O
+characterized	O
+by	O
+Albright	O
+hereditary	O
+osteodystrophy	O
+and	O
+resistance	O
+to	O
+multiple	O
+hormones	O
+that	O
+act	O
+through	O
+the	O
+Gsα	O
+signalling	O
+pathway	O
+(	O
+including	O
+PTH	O
+,	O
+thyroid	O
+-	O
+stimulating	O
+hormone	O
+,	O
+and	O
+α	O
+-	O
+melanocyte	O
+-	O
+stimulating	O
+hormone	O
+)	O
+.	O
+
+To	O
+date	O
+,	O
+little	O
+information	O
+is	O
+available	O
+on	O
+craniofacial	O
+features	O
+in	O
+patients	O
+with	O
+PHP	O
+.	O
+
+The	O
+small	O
+number	O
+of	O
+patients	O
+studied	O
+in	O
+previous	O
+reports	O
+as	O
+well	O
+as	O
+the	O
+lack	O
+of	O
+molecular	O
+characterization	O
+of	O
+the	O
+patients	O
+may	O
+have	O
+precluded	O
+the	O
+detection	O
+of	O
+specific	O
+orofacial	O
+manifestations	O
+in	O
+the	O
+different	O
+PHP	O
+subtypes	O
+.	O
+
+Materials	O
+/	O
+methods	O
+We	O
+conducted	O
+a	O
+systematic	O
+analysis	O
+of	O
+dental	O
+and	O
+craniofacial	O
+features	O
+in	O
+19	O
+patients	O
+with	O
+iPPSD2	O
+and	O
+maternal	O
+GNAS	O
+inactivating	O
+mutations	O
+to	O
+assess	O
+the	O
+frequency	O
+and	O
+specificity	O
+of	O
+the	O
+anomalies	O
+.	O
+
+Results	O
+Facial	O
+examinations	O
+showed	O
+reduced	O
+vertical	O
+,	O
+sagittal	O
+,	O
+and	O
+transverse	O
+development	O
+of	O
+the	O
+mid	O
+-	O
+facial	O
+structures	O
+.	O
+
+Intraoral	O
+and	O
+radiographic	O
+examinations	O
+revealed	O
+that	O
+89	O
+per	O
+cent	O
+of	O
+the	O
+patients	O
+had	O
+at	O
+least	O
+one	O
+dental	O
+anomaly	O
+,	O
+including	O
+tooth	O
+submergence	O
+leading	O
+to	O
+severe	O
+infraocclusion	O
+in	O
+83	O
+per	O
+cent	O
+of	O
+cases	O
+.	O
+
+Craniofacial	O
+analysis	O
+of	O
+lateral	O
+cephalometric	O
+radiographs	O
+also	O
+showed	O
+a	O
+significant	O
+alteration	O
+in	O
+the	O
+development	O
+of	O
+the	O
+cranial	O
+base	O
+and	O
+maxillary	O
+and	O
+mandibular	O
+structures	O
+in	O
+these	O
+patients	O
+.	O
+
+Conclusions	O
+Patients	O
+with	O
+iPPSD2	O
+and	O
+maternal	O
+GNAS	O
+mutations	O
+had	O
+specific	O
+craniofacial	O
+alterations	O
+and	O
+dental	O
+abnormalities	O
+.	O
+
+These	O
+specific	O
+defects	O
+should	O
+be	O
+assessed	O
+in	O
+order	O
+to	O
+provide	O
+appropriate	O
+dental	O
+and	O
+orthodontic	O
+care	O
+to	O
+these	O
+patients	O
+.	O
+
+(	O
+clinical	O
+trial	O
+registration	O
+:	O
+1920371	O
+v	O
+0	O
+,	O
+French	O
+Nationale	O
+Data	O
+Processing	O
+and	O
+Liberties	O
+Commission	O
+-	O
+CNIL	O
+)	O
+.	O
+
+Objective	O
+The	O
+aim	O
+of	O
+the	O
+current	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+risk	O
+and	O
+also	O
+the	O
+types	O
+of	O
+ictal	O
+injuries	O
+in	O
+three	O
+groups	O
+of	O
+people	O
+with	O
+seizures	O
+[	O
+i.e.	O
+,	O
+IGE	O
+vs.	O
+TLE	O
+vs.	O
+FS	O
+]	O
+.	O
+
+Methods	O
+This	O
+was	O
+a	O
+retrospective	O
+study	O
+.	O
+
+All	O
+patients	O
+with	O
+an	O
+electro	O
+-	O
+clinical	O
+diagnosis	O
+of	O
+IGE	O
+,	O
+TLE	O
+,	O
+or	O
+FS	O
+were	O
+recruited	O
+at	O
+the	O
+outpatient	O
+epilepsy	O
+clinic	O
+at	O
+Shiraz	O
+University	O
+of	O
+Medical	O
+Sciences	O
+,	O
+Shiraz	B-LOC
+,	O
+Iran	B-LOC
+,	O
+from	O
+2008	O
+until	O
+2020	O
+.	O
+
+Age	O
+,	O
+sex	O
+,	O
+age	O
+at	O
+seizure	O
+onset	O
+,	O
+seizure	O
+type(s	O
+)	O
+,	O
+and	O
+occurrence	B-EPI
+of	O
+ictal	O
+injury	O
+at	O
+any	O
+time	O
+since	O
+the	O
+onset	O
+of	O
+the	O
+seizures	O
+and	O
+its	O
+characteristics	O
+were	O
+registered	O
+routinely	O
+for	O
+all	O
+patients	O
+at	O
+the	O
+time	O
+of	O
+the	O
+first	O
+visit	O
+.	O
+
+Results	O
+One	O
+thousand	O
+and	O
+one	O
+hundred	O
+seventy	O
+-	O
+four	O
+patients	O
+were	O
+studied	O
+(	O
+481	O
+patients	O
+with	O
+IGE	O
+,	O
+402	O
+people	O
+with	O
+TLE	O
+,	O
+and	O
+291	O
+persons	O
+with	O
+FS	O
+)	O
+.	O
+
+While	O
+the	O
+groups	O
+differed	O
+in	O
+their	O
+demographic	O
+and	O
+clinical	O
+characteristics	O
+,	O
+the	O
+rates	O
+of	O
+ictal	O
+injury	O
+did	O
+not	O
+differ	O
+significantly	O
+between	O
+the	O
+groups	O
+.	O
+
+Tongue	O
+injury	O
+was	O
+more	O
+frequently	O
+reported	O
+by	O
+patients	O
+with	O
+TLE	O
+compared	O
+with	O
+that	O
+by	O
+people	O
+with	O
+IGE	O
+or	O
+FS	O
+.	O
+
+Other	O
+types	O
+/	O
+locations	O
+of	O
+ictal	O
+injury	O
+were	O
+more	O
+or	O
+less	O
+reported	O
+by	O
+all	O
+three	O
+groups	O
+of	O
+the	O
+patients	O
+.	O
+
+Conclusion	O
+Ictal	O
+injuries	O
+may	O
+happen	O
+with	O
+more	O
+or	O
+less	O
+similar	O
+rates	O
+among	O
+people	O
+with	O
+epilepsy	O
+(	O
+IGE	O
+and	O
+TLE	O
+)	O
+and	O
+those	O
+with	O
+FS	O
+.	O
+
+Ictal	O
+injury	O
+(	O
+rate	O
+,	O
+type	O
+,	O
+or	O
+location	O
+)	O
+should	O
+not	O
+be	O
+used	O
+as	O
+a	O
+marker	O
+for	O
+any	O
+specific	O
+diagnosis	O
+among	O
+people	O
+with	O
+seizures	O
+.	O
+
+Inherited	O
+retinal	O
+diseases	O
+(	O
+IRDs	O
+)	O
+,	O
+which	O
+are	O
+among	O
+the	O
+most	O
+common	O
+genetic	O
+diseases	O
+in	O
+humans	O
+,	O
+define	O
+a	O
+clinically	O
+and	O
+genetically	O
+heterogeneous	O
+group	O
+of	O
+disorders	O
+.	O
+
+Over	O
+80	O
+forms	O
+of	O
+syndromic	O
+IRDs	O
+have	O
+been	O
+described	O
+.	O
+
+Approximately	O
+200	O
+genes	O
+are	O
+associated	O
+with	O
+these	O
+syndromes	O
+.	O
+
+The	O
+majority	O
+of	O
+syndromic	O
+IRDs	O
+are	O
+recessively	O
+inherited	O
+and	O
+rare	O
+.	O
+
+Many	O
+,	O
+although	O
+not	O
+all	O
+,	O
+syndromic	O
+IRDs	O
+can	O
+be	O
+classified	O
+into	O
+one	O
+of	O
+two	O
+major	O
+disease	O
+groups	O
+:	O
+inborn	O
+errors	O
+of	O
+metabolism	O
+and	O
+ciliopathies	O
+.	O
+
+Besides	O
+the	O
+retina	O
+,	O
+the	O
+systems	O
+and	O
+organs	O
+most	O
+commonly	O
+involved	O
+in	O
+syndromic	O
+IRDs	O
+are	O
+the	O
+central	O
+nervous	O
+system	O
+,	O
+ophthalmic	O
+extra	O
+-	O
+retinal	O
+tissues	O
+,	O
+ear	O
+,	O
+skeleton	O
+,	O
+kidney	O
+and	O
+the	O
+cardiovascular	O
+system	O
+.	O
+
+Due	O
+to	O
+the	O
+high	O
+degree	O
+of	O
+phenotypic	O
+variability	O
+and	O
+phenotypic	O
+overlap	O
+found	O
+in	O
+syndromic	O
+IRDs	O
+,	O
+correct	O
+diagnosis	O
+based	O
+on	O
+phenotypic	O
+features	O
+alone	O
+may	O
+be	O
+challenging	O
+and	O
+sometimes	O
+misleading	O
+.	O
+
+Therefore	O
+,	O
+genetic	O
+testing	O
+has	O
+become	O
+the	O
+benchmark	O
+for	O
+the	O
+diagnosis	O
+and	O
+management	O
+of	O
+patients	O
+with	O
+these	O
+conditions	O
+,	O
+as	O
+it	O
+complements	O
+the	O
+clinical	O
+findings	O
+and	O
+facilitates	O
+an	O
+accurate	O
+clinical	O
+diagnosis	O
+and	O
+treatment	O
+.	O
+
+Background	O
+Metabolic	O
+syndrome	O
+(	O
+MetS	O
+)	O
+is	O
+a	O
+major	O
+risk	O
+factor	O
+for	O
+cardiovascular	O
+diseases	O
+.	O
+
+The	O
+objective	O
+of	O
+the	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+updated	O
+prevalence	B-EPI
+of	O
+MetS	O
+and	O
+provide	O
+a	O
+comprehensive	O
+illustration	O
+of	O
+the	O
+possible	O
+temporal	O
+changes	O
+in	O
+MetS	O
+prevalence	B-EPI
+in	O
+China	B-LOC
+from	O
+2011	O
+to	O
+2015	O
+.	O
+
+Methods	O
+The	O
+data	O
+for	O
+this	O
+study	O
+are	O
+from	O
+the	O
+2011	O
+and	O
+2015	O
+waves	O
+of	O
+the	O
+China	O
+Health	O
+and	O
+Retirement	O
+Longitudinal	O
+Study	O
+(	O
+CHARLS	O
+)	O
+.	O
+
+CHARLS	O
+is	O
+a	O
+nationally	O
+representative	O
+survey	O
+targeting	O
+populations	O
+aged	O
+45	O
+and	O
+above	O
+from	O
+28	O
+provinces	O
+in	O
+mainland	O
+China	B-LOC
+.	O
+
+A	O
+total	O
+of	O
+11,847	O
+and	O
+13,013	O
+participants	O
+were	O
+eligible	O
+for	O
+data	O
+analysis	O
+at	O
+the	O
+two	O
+time	O
+points	O
+.	O
+
+Results	O
+The	O
+estimated	B-EPI
+prevalence	I-EPI
+of	O
+MetS	O
+in	O
+2015	O
+was	O
+20.41	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+19.02	B-STAT
+-	O
+21.8	O
+%	O
+)	O
+by	O
+the	O
+National	O
+Cholesterol	O
+Education	O
+Program	O
+(	O
+NCEP	O
+)	O
+Expert	O
+Panel	O
+on	O
+Detection	O
+,	O
+Evaluation	O
+,	O
+and	O
+Treatment	O
+of	O
+High	O
+Blood	O
+Cholesterol	O
+in	O
+Adults	O
+(	O
+ATP	O
+III	O
+)	O
+criteria	O
+,	O
+34.77	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+33.12	O
+-	O
+36.42	O
+%	O
+)	O
+by	O
+the	O
+International	O
+Diabetes	O
+Federation	O
+(	O
+IDF	O
+)	O
+criteria	O
+,	O
+39.68	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+37.88	O
+-	O
+41.47	O
+%	O
+)	O
+by	O
+the	O
+revised	O
+ATP	O
+III	O
+criteria	O
+,	O
+and	O
+25.55	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+24.19	O
+-	O
+26.91	O
+%	O
+)	O
+by	O
+the	O
+Chinese	O
+Diabetes	O
+Society	O
+(	O
+CDS	O
+)	O
+criteria	O
+.	O
+
+The	O
+prevalence	B-EPI
+was	O
+higher	O
+among	O
+women	O
+and	O
+elderly	O
+adults	O
+and	O
+in	O
+urban	O
+and	O
+northern	O
+populations	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+trends	O
+in	O
+the	O
+prevalence	B-EPI
+decreased	O
+significantly	O
+between	O
+2011	O
+and	O
+2015	O
+by	O
+the	O
+ATP	O
+III	O
+,	O
+revised	O
+ATP	O
+III	O
+and	O
+CDS	O
+criteria	O
+.	O
+
+However	O
+,	O
+trends	O
+increased	O
+significantly	O
+from	O
+2011	O
+to	O
+2015	O
+by	O
+the	O
+IDF	O
+criteria	O
+.	O
+
+Conclusions	O
+A	O
+higher	O
+prevalence	B-EPI
+of	O
+MetS	O
+is	O
+found	O
+in	O
+those	O
+who	O
+reported	O
+being	O
+middle	O
+aged	O
+and	O
+elderly	O
+,	O
+women	O
+,	O
+residing	O
+in	O
+northern	O
+China	B-LOC
+or	O
+living	O
+in	O
+urban	O
+areas	O
+.	O
+
+Additionally	O
+,	O
+temporal	O
+changes	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+MetS	O
+varied	O
+according	O
+to	O
+different	O
+criteria	O
+.	O
+
+Increased	O
+attention	O
+to	O
+the	O
+causes	O
+associated	O
+with	O
+populations	O
+who	O
+have	O
+higher	O
+levels	O
+of	O
+MetS	O
+is	O
+warranted	O
+.	O
+
+Background	O
+Hypertension	O
+is	O
+prevalent	B-EPI
+in	O
+35%-46	O
+%	O
+of	O
+the	O
+general	O
+population	O
+;	O
+1	O
+%	O
+of	O
+them	O
+experience	O
+accelerated	O
+hypertension	O
+.	O
+
+Among	O
+patients	O
+with	O
+accelerated	O
+hypertension	O
+,	O
+acute	O
+worsening	O
+of	O
+renal	O
+functions	O
+occur	O
+in	O
+22%-55	O
+%	O
+.	O
+
+Morbidity	O
+and	O
+mortality	O
+rates	O
+are	O
+high	O
+.	O
+
+Partial	O
+renal	O
+recovery	O
+is	O
+seen	O
+in	O
+some	O
+,	O
+while	O
+others	O
+rapidly	O
+progress	O
+to	O
+end	O
+-	O
+stage	O
+renal	O
+disease	O
+.	O
+
+Methods	O
+Patients	O
+who	O
+presented	O
+with	O
+accelerated	O
+hypertension	O
+,	O
+renal	O
+dysfunction	O
+,	O
+and	O
+had	O
+undergone	O
+renal	O
+biopsy	O
+were	O
+evaluated	O
+and	O
+their	O
+clinical	O
+profile	O
+was	O
+analyzed	O
+.	O
+
+Those	O
+who	O
+became	O
+dialysis	O
+dependent	O
+were	O
+excluded	O
+from	O
+further	O
+follow	O
+-	O
+up	O
+.	O
+
+Study	O
+outcome	O
+were	O
+blood	O
+pressure	O
+control	O
+,	O
+renal	O
+functions	O
+,	O
+requirement	O
+of	O
+renal	O
+replacement	O
+and	O
+mortality	O
+.	O
+
+Results	O
+Of	O
+the	O
+30	O
+patients	O
+evaluated	O
+,	O
+age	O
+at	O
+presentation	O
+was	O
+41.2	O
+±	O
+15.46	O
+years	O
+and	O
+26	B-STAT
+(	O
+86.7	O
+%	O
+)	O
+were	O
+males	O
+,	O
+10	B-STAT
+(	O
+33	O
+%	O
+)	O
+had	O
+presented	O
+with	O
+nonspecific	O
+complaints	O
+.	O
+
+Mean	O
+duration	O
+of	O
+hypertension	O
+and	O
+blood	O
+pressure	O
+were	O
+21.93	O
+months	O
+and	O
+196	B-STAT
+±	I-STAT
+20.8/129	I-STAT
+±	O
+12.4	O
+mmHg	O
+,	O
+respectively	O
+.	O
+
+Glomerulonephritis	O
+and	O
+hypertensive	O
+nephrosclerosis	O
+had	O
+similar	O
+characteristics	O
+except	O
+proteinuria	O
+(	O
+P	O
+=	O
+0.04	O
+)	O
+.	O
+
+Average	O
+follow	O
+-	O
+up	O
+(	O
+n	O
+=	O
+25	O
+)	O
+duration	O
+was	O
+3.69	O
+years	O
+(	O
+range	O
+:	O
+0.05	O
+-	O
+9.6	O
+)	O
+.	O
+
+At	O
+the	O
+end	O
+of	O
+study	O
+,	O
+6	O
+were	O
+dialysis	O
+dependent	O
+,	O
+while	O
+in	O
+others	O
+,	O
+mean	O
+e	O
+-	O
+GFR	O
+was	O
+23.96	O
+ml	O
+/	O
+min/1.73	O
+m	O
+2	O
+.	O
+
+Poor	O
+renal	O
+prognosis	O
+was	O
+predicted	O
+by	O
+glomerulonephritis	O
+(	O
+relative	O
+risk-4.6	O
+)	O
+and	O
+degree	O
+of	O
+interstitial	O
+fibrosis	O
+.	O
+
+Five	O
+-	O
+year	O
+patient	O
+and	O
+renal	O
+survival	O
+were	O
+94.4	O
+%	O
+and	O
+71.9	O
+%	O
+,	O
+respectively	O
+.	O
+
+Conclusion	O
+Accelerated	O
+hypertension	O
+occurs	B-EPI
+among	O
+patients	O
+with	O
+both	O
+primary	O
+and	O
+secondary	O
+hypertension	O
+.	O
+
+It	O
+leaves	O
+permanent	O
+renal	O
+sequelae	O
+.	O
+
+Though	O
+some	O
+patients	O
+recover	O
+renal	O
+function	O
+partially	O
+,	O
+further	O
+progression	O
+is	O
+rapid	O
+,	O
+especially	O
+among	O
+those	O
+with	O
+chronic	O
+glomerulonephritis	O
+.	O
+
+Background	O
+An	O
+isolated	O
+coronary	O
+sinus	O
+(	O
+CS	O
+)	O
+atrial	O
+septal	O
+defect	O
+(	O
+ASD	O
+)	O
+is	O
+defined	O
+as	O
+a	O
+CS	O
+unroofed	O
+in	O
+the	O
+terminal	O
+portion	O
+without	O
+a	O
+persistent	O
+left	O
+superior	O
+vena	O
+cava	O
+or	O
+other	O
+anomalies	O
+.	O
+
+This	O
+defect	O
+is	O
+rare	O
+and	O
+part	O
+of	O
+the	O
+wide	O
+spectrum	O
+of	O
+unroofed	O
+CS	O
+syndrome	O
+(	O
+URCS	O
+)	O
+.	O
+
+Recently	O
+,	O
+several	O
+reports	O
+have	O
+described	O
+this	O
+finding	O
+.	O
+
+The	O
+database	O
+of	O
+New	O
+Tokyo	O
+Hospital	O
+was	O
+searched	O
+to	O
+determine	O
+the	O
+incidence	B-EPI
+of	O
+this	O
+defect	O
+.	O
+
+Additionally	O
+,	O
+to	O
+raise	O
+awareness	O
+of	O
+this	O
+condition	O
+,	O
+the	O
+findings	O
+from	O
+five	O
+patients	O
+with	O
+CS	O
+ASD	O
+who	O
+underwent	O
+surgical	O
+repair	O
+at	O
+New	O
+Tokyo	O
+Hospital	O
+are	O
+discussed	O
+.	O
+
+Case	O
+presentation	O
+The	O
+patients	O
+were	O
+three	O
+women	O
+and	O
+two	O
+men	O
+with	O
+an	O
+age	O
+range	O
+of	O
+63	O
+-	O
+77	O
+years	O
+.	O
+
+All	O
+patients	O
+underwent	O
+transthoracic	O
+echocardiography	O
+and	O
+computed	O
+tomography	O
+,	O
+and	O
+one	O
+underwent	O
+magnetic	O
+resonance	O
+imaging	O
+.	O
+
+In	O
+two	O
+patients	O
+,	O
+the	O
+defect	O
+was	O
+found	O
+unexpectedly	O
+intraoperatively	O
+;	O
+left	O
+-	O
+to	O
+-	O
+right	O
+shunting	O
+was	O
+apparent	O
+in	O
+the	O
+other	O
+three	O
+patients	O
+preoperatively	O
+.	O
+
+The	O
+pulmonary	O
+-	O
+to	O
+-	O
+systemic	O
+blood	O
+flow	O
+ratio	O
+ranged	O
+from	O
+1.42	O
+to	O
+3.1	O
+following	O
+cardiac	O
+catheterization	O
+,	O
+and	O
+oxygen	O
+saturation	O
+step	O
+-	O
+up	O
+was	O
+seen	O
+on	O
+the	O
+right	O
+side	O
+of	O
+the	O
+heart	O
+.	O
+
+Valvular	O
+regurgitation	O
+was	O
+seen	O
+in	O
+4/5	B-STAT
+patients	O
+with	O
+different	O
+combinations	O
+and	O
+degrees	O
+of	O
+mitral	O
+,	O
+tricuspid	O
+,	O
+and	O
+aortic	O
+valve	O
+involvement	O
+.	O
+
+Right	O
+atrial	O
+and	O
+ventricular	O
+dilation	O
+were	O
+seen	O
+in	O
+4/5	B-STAT
+patients	O
+;	O
+three	O
+patients	O
+had	O
+left	O
+atrial	O
+dilation	O
+.	O
+
+Three	O
+patients	O
+experienced	O
+atrial	O
+fibrillation	O
+,	O
+and	O
+one	O
+of	O
+these	O
+also	O
+experienced	O
+paroxysmal	O
+ventricular	O
+contractions	O
+.	O
+
+All	O
+patients	O
+underwent	O
+surgical	O
+repair	O
+,	O
+and	O
+some	O
+underwent	O
+multiple	O
+procedures	O
+.	O
+
+One	O
+patient	O
+who	O
+had	O
+previously	O
+undergone	O
+kidney	O
+transplantation	O
+died	O
+approximately	O
+1	O
+year	O
+postoperatively	O
+;	O
+the	O
+remaining	O
+four	O
+patients	O
+are	O
+currently	O
+experiencing	O
+good	O
+activities	O
+of	O
+daily	O
+living	O
+without	O
+symptoms	O
+.	O
+
+Conclusions	O
+CS	O
+ASD	O
+(	O
+Kirklin	O
+and	O
+Barratt	O
+-	O
+Boyes	O
+type	O
+IV	O
+URCS	O
+)	O
+comprised	O
+1.3	O
+%	O
+of	O
+adult	O
+congenital	O
+heart	O
+surgeries	O
+and	O
+0.07	B-STAT
+%	I-STAT
+of	O
+adult	O
+open	O
+-	O
+heart	O
+surgeries	O
+at	O
+New	O
+Tokyo	O
+Hospital	O
+from	O
+1999	O
+to	O
+2019	O
+.	O
+
+At	O
+New	O
+Tokyo	O
+Hospital	O
+,	O
+cardiac	O
+surgery	O
+is	O
+performed	O
+mainly	O
+for	O
+patients	O
+with	O
+acquired	O
+cardiac	O
+disease	O
+,	O
+and	O
+CS	O
+ASD	O
+is	O
+rare	O
+.	O
+
+Early	O
+diagnosis	O
+is	O
+important	O
+,	O
+as	O
+well	O
+as	O
+early	O
+surgical	O
+repair	O
+in	O
+symptomatic	O
+patients	O
+,	O
+especially	O
+those	O
+with	O
+blood	O
+access	O
+shunts	O
+,	O
+which	O
+may	O
+overload	O
+the	O
+heart	O
+.	O
+
+The	O
+case	O
+of	O
+a	O
+poor	O
+prognosis	O
+in	O
+this	O
+series	O
+is	O
+noteworthy	O
+,	O
+as	O
+similar	O
+cases	O
+have	O
+not	O
+been	O
+reported	O
+previously	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+a	O
+growing	O
+body	O
+of	O
+research	O
+has	O
+shown	O
+sex	O
+differences	O
+in	O
+the	O
+prevalence	B-EPI
+and	O
+symptomatology	O
+of	O
+psychopathologies	O
+,	O
+such	O
+as	O
+depression	O
+,	O
+anxiety	O
+,	O
+and	O
+fear	O
+-	O
+related	O
+disorders	O
+,	O
+all	O
+of	O
+which	O
+show	O
+high	O
+incidence	B-EPI
+rates	O
+in	O
+early	O
+life	O
+.	O
+
+This	O
+has	O
+highlighted	O
+the	O
+importance	O
+of	O
+including	O
+female	O
+subjects	O
+in	O
+animal	O
+studies	O
+,	O
+as	O
+well	O
+as	O
+delineating	O
+sex	O
+differences	O
+in	O
+neural	O
+processing	O
+across	O
+development	O
+.	O
+
+Of	O
+particular	O
+interest	O
+is	O
+the	O
+corticolimbic	O
+system	O
+,	O
+comprising	O
+the	O
+hippocampus	O
+,	O
+amygdala	O
+,	O
+and	O
+medial	O
+prefrontal	O
+cortex	O
+.	O
+
+In	O
+rodents	O
+,	O
+these	O
+corticolimbic	O
+regions	O
+undergo	O
+dynamic	O
+changes	O
+in	O
+early	O
+life	O
+,	O
+and	O
+disruption	O
+to	O
+their	O
+normative	O
+development	O
+is	O
+believed	O
+to	O
+underlie	O
+the	O
+age	O
+and	O
+sex	O
+-	O
+dependent	O
+effects	O
+of	O
+stress	O
+on	O
+affective	O
+processing	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+consolidate	O
+research	O
+on	O
+sex	O
+differences	O
+in	O
+the	O
+hippocampus	O
+,	O
+amygdala	O
+,	O
+and	O
+medial	O
+prefrontal	O
+cortex	O
+across	O
+early	O
+development	O
+.	O
+
+First	O
+,	O
+we	O
+briefly	O
+introduce	O
+current	O
+principles	O
+on	O
+sexual	O
+differentiation	O
+of	O
+the	O
+rodent	O
+brain	O
+.	O
+
+We	O
+then	O
+showcase	O
+corticolimbic	O
+regional	O
+sex	O
+differences	O
+in	O
+volume	O
+,	O
+morphology	O
+,	O
+synaptic	O
+organization	O
+,	O
+cell	O
+proliferation	O
+,	O
+microglia	O
+,	O
+and	O
+GABAergic	O
+signaling	O
+,	O
+and	O
+explain	O
+how	O
+these	O
+differences	O
+are	O
+influenced	O
+by	O
+perinatal	O
+and	O
+pubertal	O
+gonadal	O
+hormones	O
+.	O
+
+In	O
+compiling	O
+this	O
+research	O
+,	O
+we	O
+outline	O
+evidence	O
+of	O
+what	O
+and	O
+when	O
+sex	O
+differences	O
+emerge	O
+in	O
+the	O
+developing	O
+corticolimbic	O
+system	O
+,	O
+and	O
+illustrate	O
+how	O
+temporal	O
+dynamics	O
+of	O
+its	O
+maturational	O
+trajectory	O
+may	O
+differ	O
+in	O
+male	O
+and	O
+female	O
+rodents	O
+.	O
+
+This	O
+will	O
+help	O
+provide	O
+insight	O
+into	O
+potential	O
+neural	O
+mechanisms	O
+underlying	O
+sex	O
+-	O
+specific	O
+critical	O
+windows	O
+for	O
+stress	O
+susceptibility	O
+and	O
+behavioral	O
+emergence	O
+.	O
+
+Background	O
+Pathogenic	O
+intestinal	O
+protozoa	O
+are	O
+considered	O
+as	O
+a	O
+serious	O
+public	O
+health	O
+problem	O
+in	O
+developing	O
+countries	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+elucidate	O
+the	O
+overall	B-EPI
+prevalence	I-EPI
+and	O
+spatial	O
+distribution	O
+of	O
+three	O
+common	O
+human	O
+pathogenic	O
+intestinal	O
+protozoan	O
+infections	O
+in	O
+Iran	B-LOC
+.	O
+
+Methods	O
+Six	O
+English	O
+and	O
+Persian	O
+databases	O
+were	O
+explored	O
+for	O
+published	O
+papers	O
+on	O
+the	O
+prevalence	B-EPI
+of	O
+Entamoeba	O
+histolytica	O
+/	O
+dispar	O
+,	O
+Giardia	O
+lamblia	O
+,	O
+and	O
+Cryptosporidium	O
+spp	O
+.	O
+
+in	O
+the	O
+general	O
+population	O
+of	O
+Iran	B-LOC
+from	O
+2000	O
+to	O
+2015	O
+.	O
+
+All	O
+eligible	O
+data	O
+were	O
+collected	O
+using	O
+a	O
+pre	O
+-	O
+designed	O
+data	O
+extraction	O
+form	O
+,	O
+and	O
+the	O
+overall	B-EPI
+prevalence	I-EPI
+was	O
+estimated	O
+using	O
+a	O
+random	O
+-	O
+effects	O
+meta	O
+-	O
+analysis	O
+model	O
+.	O
+
+We	O
+used	O
+ArcMap	O
+for	O
+mapping	O
+the	O
+prevalence	B-EPI
+of	O
+the	O
+studied	O
+protozoa	O
+and	O
+clustering	O
+analysis	O
+.	O
+
+Results	O
+Altogether	O
+,	O
+118	O
+eligible	O
+papers	O
+from	O
+24	O
+provinces	O
+of	O
+Iran	B-LOC
+were	O
+included	O
+and	O
+analyzed	O
+.	O
+
+The	O
+weighted	B-EPI
+prevalence	I-EPI
+of	O
+E.	O
+histolytica	O
+/	O
+dispar	O
+,	O
+G.	O
+lamblia	O
+,	O
+and	O
+Cryptosporidium	O
+spp	O
+.	O
+
+infection	O
+among	O
+Iranian	O
+general	O
+population	O
+were	O
+calculated	O
+1.3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+1.1	O
+-	O
+1.5	O
+%	O
+)	O
+,	O
+10.6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+9.6	O
+-	O
+11.5	O
+%	O
+)	O
+and	O
+2	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+1.5	O
+-	O
+2.5	O
+%	O
+)	O
+,	O
+respectively	O
+.	O
+
+Conclusion	O
+Our	O
+findings	O
+indicated	O
+human	O
+intestinal	O
+protozoan	O
+infections	O
+caused	O
+by	O
+E.	O
+histolytica	O
+/	O
+dispar	O
+,	O
+G.	O
+lamblia	O
+,	O
+and	O
+Cryptosporidium	O
+spp	O
+.	O
+
+have	O
+still	O
+public	O
+health	O
+importance	O
+in	O
+some	O
+parts	O
+of	O
+Iran	B-LOC
+.	O
+
+Background	O
+Down	O
+syndrome	O
+is	O
+the	O
+most	O
+common	O
+chromosomal	O
+disorder	O
+at	O
+birth	O
+and	O
+is	O
+often	O
+accompanied	O
+by	O
+structural	O
+birth	O
+defects	O
+.	O
+
+Current	O
+data	O
+on	O
+major	O
+structural	O
+defects	O
+in	O
+this	O
+population	O
+are	O
+limited	O
+.	O
+
+Methods	O
+States	O
+and	O
+territorial	O
+population	O
+-	O
+based	O
+surveillance	O
+programs	O
+submitted	O
+data	O
+on	O
+identified	O
+cases	O
+of	O
+Down	O
+syndrome	O
+and	O
+identified	O
+structural	O
+birth	O
+defects	O
+during	O
+2013	O
+-	O
+2017	O
+.	O
+
+We	O
+estimated	B-EPI
+prevalence	I-EPI
+by	O
+program	O
+type	O
+and	O
+maternal	O
+and	O
+infant	O
+characteristics	O
+.	O
+
+Among	O
+programs	O
+with	O
+active	O
+case	O
+ascertainment	O
+,	O
+we	O
+estimated	O
+the	O
+prevalence	B-EPI
+of	O
+birth	O
+defects	O
+by	O
+organ	O
+system	O
+and	O
+for	O
+specific	O
+defects	O
+by	O
+maternal	O
+age	O
+(	O
+<	O
+35	O
+,	O
+≥35	O
+)	O
+and	O
+infant	O
+sex	O
+.	O
+
+Results	O
+We	O
+identified	O
+13,376	O
+cases	O
+of	O
+Down	O
+syndrome	O
+.	O
+
+Prevalence	B-EPI
+among	O
+all	O
+programs	O
+was	O
+12.7	B-STAT
+per	I-STAT
+10,000	I-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+Among	O
+these	O
+children	O
+,	O
+75	O
+%	O
+had	O
+at	O
+least	O
+one	O
+reported	O
+co	O
+-	O
+occurring	O
+birth	O
+defect	O
+diagnosis	O
+code	O
+.	O
+
+Among	O
+6,210	O
+cases	O
+identified	O
+by	O
+active	O
+programs	O
+,	O
+66	O
+%	O
+had	O
+a	O
+cardiovascular	O
+defect	O
+with	O
+septal	O
+defects	O
+being	O
+the	O
+most	O
+common	O
+:	O
+atrial	O
+(	O
+32.5	O
+%	O
+)	O
+,	O
+ventricular	O
+(	O
+20.6	O
+%	O
+)	O
+,	O
+and	O
+atrioventricular	O
+(	O
+17.4	O
+%	O
+)	O
+.	O
+
+Defect	O
+prevalence	B-EPI
+differed	O
+by	O
+infant	O
+sex	O
+more	O
+frequently	O
+than	O
+by	O
+maternal	O
+age	O
+.	O
+
+For	O
+example	O
+,	O
+atrioventricular	O
+septal	O
+defects	O
+were	O
+more	O
+common	O
+in	O
+female	O
+children	O
+(	O
+20.1	O
+%	O
+vs.	O
+15.1	O
+%	O
+)	O
+while	O
+limb	O
+deficiencies	O
+were	O
+more	O
+prevalent	B-EPI
+in	O
+male	O
+children	O
+(	O
+0.4	B-STAT
+%	I-STAT
+vs.	O
+0.1	B-STAT
+%	I-STAT
+)	O
+.	O
+
+Conclusions	O
+Our	O
+study	O
+provides	O
+updated	O
+prevalence	B-EPI
+estimates	O
+for	O
+structural	O
+defects	O
+,	O
+including	O
+rare	O
+defects	O
+,	O
+among	O
+children	O
+with	O
+Down	O
+syndrome	O
+using	O
+one	O
+of	O
+the	O
+largest	O
+and	O
+most	O
+recent	O
+cohorts	O
+to	O
+date	O
+.	O
+
+These	O
+data	O
+may	O
+aid	O
+clinical	O
+care	O
+and	O
+surveillance	O
+.	O
+
+Georgia	B-LOC
+uses	O
+post	O
+-	O
+analytical	O
+tools	O
+through	O
+Collaborative	O
+Laboratory	O
+Integrated	O
+Reports	O
+(	O
+CLIR	O
+)	O
+to	O
+triage	O
+abnormal	O
+newborn	O
+screening	O
+(	O
+NBS	O
+)	O
+results	O
+for	O
+follow	O
+-	O
+up	O
+.	O
+
+Condition	O
+specific	O
+tools	O
+are	O
+used	O
+to	O
+assign	O
+each	O
+case	O
+a	O
+risk	O
+level	O
+,	O
+which	O
+is	O
+used	O
+to	O
+guide	O
+follow	O
+-	O
+up	O
+recommendations	O
+.	O
+
+Follow	O
+-	O
+up	O
+recommendations	O
+include	O
+assessment	O
+by	O
+the	O
+child	O
+'s	O
+primary	O
+care	O
+provider	O
+as	O
+well	O
+as	O
+testing	O
+,	O
+either	O
+a	O
+repeat	O
+NBS	O
+or	O
+confirmatory	O
+testing	O
+.	O
+
+Triaging	O
+abnormal	O
+cases	O
+using	O
+these	O
+tools	O
+has	O
+been	O
+advantageous	O
+in	O
+managing	O
+the	O
+workflow	O
+for	O
+the	O
+follow	O
+-	O
+up	O
+team	O
+,	O
+as	O
+well	O
+as	O
+prioritizing	O
+cases	O
+that	O
+appropriately	O
+require	O
+more	O
+attention	O
+and	O
+resources	O
+.	O
+
+The	O
+initial	O
+goal	O
+in	O
+utilizing	O
+these	O
+tools	O
+was	O
+to	O
+reduce	O
+the	O
+amount	O
+of	O
+confirmatory	O
+testing	O
+,	O
+particularly	O
+for	O
+disorders	O
+where	O
+there	O
+are	O
+many	O
+false	O
+positives	O
+.	O
+
+We	O
+assessed	O
+the	O
+performance	O
+of	O
+these	O
+tools	O
+retrospectively	O
+for	O
+three	O
+of	O
+the	O
+most	O
+commonly	O
+detected	O
+conditions	O
+by	O
+tandem	O
+mass	O
+spectrometry	O
+in	O
+Georgia	B-LOC
+:	O
+phenylketonuria	O
+,	O
+medium	O
+chain	O
+acyl	O
+-	O
+CoA	O
+dehydrogenase	O
+deficiency	O
+and	O
+very	O
+long	O
+chain	O
+dehydrogenase	O
+deficiency	O
+.	O
+
+The	O
+post	O
+-	O
+analytical	O
+tools	O
+appropriately	O
+assigned	O
+all	O
+true	O
+positive	O
+cases	O
+to	O
+the	O
+higher	O
+levels	O
+of	O
+follow	O
+-	O
+up	O
+testing	O
+and	O
+reduced	O
+the	O
+level	O
+of	O
+intervention	O
+for	O
+a	O
+significant	O
+number	O
+of	O
+cases	O
+as	O
+well	O
+.	O
+
+Based	O
+on	O
+the	O
+experience	O
+gained	O
+from	O
+our	O
+utilization	O
+of	O
+the	O
+tools	O
+in	O
+the	O
+follow	O
+-	O
+up	O
+program	O
+,	O
+we	O
+are	O
+well	O
+situated	O
+to	O
+move	O
+forward	O
+with	O
+using	O
+the	O
+tools	O
+in	O
+a	O
+more	O
+prospective	O
+manner	O
+,	O
+and	O
+reduce	O
+the	O
+number	O
+of	O
+cases	O
+that	O
+will	O
+be	O
+reported	O
+,	O
+rather	O
+than	O
+just	O
+assigning	O
+resources	O
+appropriately	O
+at	O
+follow	O
+-	O
+up	O
+.	O
+
+Post	O
+-	O
+analytical	O
+tools	O
+are	O
+an	O
+improvement	O
+over	O
+trying	O
+to	O
+capture	O
+the	O
+variation	O
+in	O
+the	O
+newborn	O
+population	O
+using	O
+multiple	O
+cutoffs	O
+.	O
+
+It	O
+also	O
+easily	O
+identifies	O
+significant	O
+abnormalities	O
+that	O
+are	O
+unrelated	O
+to	O
+inherited	O
+disease	O
+,	O
+such	O
+as	O
+large	O
+amino	O
+acid	O
+elevations	O
+due	O
+to	O
+total	O
+parenteral	O
+nutrition	O
+.	O
+
+Aim	O
+:	O
+Sentinel	O
+lymph	O
+node	O
+biopsy	O
+(	O
+SLNB	O
+)	O
+is	O
+the	O
+accepted	O
+approach	O
+to	O
+stage	O
+the	O
+clinically	O
+negative	O
+axilla	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+lymphedema	O
+(	O
+LE	O
+)	O
+after	O
+SLNB	O
+is	O
+about	O
+5	B-STAT
+%	I-STAT
+.	O
+
+We	O
+hypothesize	O
+that	O
+patients	O
+undergoing	O
+axillary	O
+excision	O
+of	O
+>	O
+5	O
+lymph	O
+nodes	O
+(	O
+LNs	O
+)	O
+are	O
+at	O
+increased	O
+risk	O
+of	O
+developing	O
+LE	O
+.	O
+
+Methods	O
+and	O
+Results	O
+:	O
+A	O
+single	O
+institution	O
+prospective	O
+breast	O
+cancer	O
+database	O
+was	O
+retrospectively	O
+reviewed	O
+from	O
+January	O
+2013	O
+to	O
+December	O
+2017	O
+,	O
+to	O
+identify	O
+patients	O
+who	O
+underwent	O
+SLNB	O
+and	O
+were	O
+diagnosed	O
+with	O
+LE	O
+.	O
+
+Inclusion	O
+criteria	O
+was	O
+(	O
+1	O
+)	O
+de	O
+novo	O
+breast	O
+cancer	O
+,	O
+(	O
+2	O
+)	O
+SLNB	O
+in	O
+clinically	O
+node	O
+negative	O
+patients	O
+,	O
+and	O
+(	O
+3	O
+)	O
+no	O
+preoperative	O
+diagnosis	O
+LE	O
+of	O
+an	O
+extremity	O
+.	O
+
+Exclusion	O
+criteria	O
+was	O
+history	O
+of	O
+axillary	O
+lymph	O
+node	O
+dissection	O
+.	O
+
+Age	O
+,	O
+body	O
+mass	O
+index	O
+,	O
+tumor	O
+-	O
+node	O
+-	O
+metastasis	O
+status	O
+,	O
+surgery	O
+type	O
+,	O
+neoadjuvant	O
+or	O
+adjuvant	O
+chemotherapy	O
+,	O
+radiotherapy	O
+,	O
+and	O
+hormone	O
+therapy	O
+were	O
+analyzed	O
+.	O
+
+Of	O
+the	O
+3325	O
+patients	O
+identified	O
+,	O
+2940	O
+patients	O
+met	O
+the	O
+inclusion	O
+criteria	O
+and	O
+were	O
+included	O
+in	O
+the	O
+final	O
+analysis	O
+.	O
+
+Median	O
+follow	O
+-	O
+up	O
+time	O
+was	O
+24	O
+months	O
+.	O
+
+Forty	O
+-	O
+seven	O
+(	O
+2	O
+%	O
+)	O
+patients	O
+were	O
+diagnosed	O
+with	O
+LE	O
+,	O
+and	O
+nine	O
+patients	O
+(	O
+19	O
+%	O
+)	O
+had	O
+>	O
+5	O
+LNs	O
+excised	O
+.	O
+
+LE	O
+was	O
+diagnosed	O
+in	O
+3.7	O
+%	O
+of	O
+patients	O
+who	O
+had	O
+>	O
+5	O
+LNs	O
+excised	O
+versus	O
+1.4	O
+%	O
+of	O
+patients	O
+with	O
+≤5	O
+LNs	O
+excised	O
+.	O
+
+Incidence	B-EPI
+of	O
+LE	O
+was	O
+higher	O
+in	O
+patients	O
+with	O
+>	O
+5	O
+LNs	O
+excision	O
+(	O
+p	O
+=	O
+0.006	O
+)	O
+.	O
+
+Conclusion	O
+:	O
+Our	O
+study	O
+showed	O
+that	O
+patients	O
+have	O
+a	O
+higher	O
+likelihood	O
+of	O
+developing	O
+LE	O
+when	O
+>	O
+5	O
+LNs	O
+are	O
+excised	O
+.	O
+
+Background	O
+In	O
+South	B-LOC
+Korea	I-LOC
+,	O
+the	O
+number	O
+of	O
+Q	O
+fever	O
+cases	O
+has	O
+rapidly	O
+increased	O
+since	O
+2015	O
+.	O
+
+Therefore	O
+,	O
+this	O
+study	O
+aimed	O
+to	O
+characterize	O
+the	O
+epidemiological	O
+and	O
+clinical	O
+features	O
+of	O
+Q	O
+fever	O
+in	O
+South	B-LOC
+Korea	I-LOC
+between	O
+2011	O
+and	O
+2017	O
+.	O
+
+Methods	O
+/	O
+principal	O
+findings	O
+We	O
+analyzed	O
+the	O
+epidemiological	O
+investigations	O
+and	O
+reviewed	O
+the	O
+medical	O
+records	O
+from	O
+all	O
+hospitals	O
+that	O
+had	O
+reported	O
+at	O
+least	O
+one	O
+case	O
+of	O
+Q	O
+fever	O
+from	O
+2011	O
+to	O
+2017	O
+.	O
+
+We	O
+also	O
+conducted	O
+an	O
+online	O
+survey	O
+to	O
+investigate	O
+physicians	O
+'	O
+awareness	O
+regarding	O
+how	O
+to	O
+appropriately	O
+diagnose	O
+and	O
+manage	O
+Q	O
+fever	O
+.	O
+
+The	O
+nationwide	B-EPI
+incidence	I-EPI
+rate	O
+of	O
+Q	O
+fever	O
+was	O
+annually	O
+0.07	B-STAT
+cases	I-STAT
+per	I-STAT
+100,000	I-STAT
+persons	I-STAT
+.	O
+
+However	O
+,	O
+there	O
+has	O
+been	O
+a	O
+sharp	O
+increase	O
+in	O
+its	O
+incidence	B-EPI
+,	O
+reaching	O
+up	O
+to	O
+0.19	B-STAT
+cases	I-STAT
+per	I-STAT
+100,000	I-STAT
+persons	I-STAT
+in	O
+2017	O
+.	O
+
+Q	O
+fever	O
+sporadically	O
+occurred	O
+across	O
+the	O
+country	O
+,	O
+with	O
+the	O
+highest	O
+incidences	B-EPI
+in	O
+Chungbuk	O
+(	O
+0.53	B-STAT
+cases	I-STAT
+per	I-STAT
+100,000	B-STAT
+persons	I-STAT
+per	I-STAT
+year	I-STAT
+)	I-STAT
+and	O
+Chungnam	O
+(	O
+0.27	B-STAT
+cases	I-STAT
+per	I-STAT
+100,000	B-STAT
+persons	I-STAT
+per	I-STAT
+year	I-STAT
+)	I-STAT
+areas	O
+.	O
+
+Patients	O
+with	O
+acute	O
+Q	O
+fever	O
+primarily	O
+presented	O
+with	O
+mild	O
+illnesses	O
+such	O
+as	O
+hepatitis	O
+(	O
+64.5	O
+%	O
+)	O
+and	O
+isolated	O
+febrile	O
+illness	O
+(	O
+24.0	O
+%	O
+)	O
+,	O
+whereas	O
+those	O
+with	O
+chronic	O
+Q	O
+fever	O
+were	O
+likely	O
+to	O
+undergo	O
+surgery	O
+(	O
+41.2	O
+%	O
+)	O
+and	O
+had	O
+a	O
+high	O
+mortality	O
+rate	O
+(	O
+23.5	O
+%	O
+)	O
+.	O
+
+Follow	O
+-	O
+up	O
+for	O
+6	O
+months	O
+after	O
+acute	O
+Q	O
+fever	O
+was	O
+performed	O
+by	O
+24.0	O
+%	O
+of	O
+the	O
+physician	O
+respondents	O
+,	O
+and	O
+only	O
+22.3	O
+%	O
+of	O
+them	O
+reported	O
+that	O
+clinical	O
+and	O
+serological	O
+evaluations	O
+were	O
+required	O
+after	O
+acute	O
+Q	O
+fever	O
+diagnosis	O
+.	O
+
+Conclusions	O
+Q	O
+fever	O
+is	O
+becoming	O
+an	O
+endemic	O
+disease	O
+in	O
+the	O
+midwestern	O
+area	O
+of	O
+South	B-LOC
+Korea	I-LOC
+.	O
+
+Given	O
+the	O
+clinical	O
+severity	O
+and	O
+mortality	O
+of	O
+chronic	O
+Q	O
+fever	O
+,	O
+physicians	O
+should	O
+be	O
+made	O
+aware	O
+of	O
+appropriate	O
+diagnosis	O
+and	O
+management	O
+strategies	O
+for	O
+Q	O
+fever	O
+.	O
+
+Dyslipidemia	O
+is	O
+a	O
+major	O
+cause	O
+of	O
+cardiovascular	O
+diseases	O
+which	O
+represent	O
+a	O
+leading	O
+cause	O
+of	O
+death	O
+in	O
+humans	O
+.	O
+
+Diverse	O
+immune	O
+cells	O
+are	O
+known	O
+to	O
+be	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+cardiovascular	O
+diseases	O
+such	O
+as	O
+atherosclerosis	O
+.	O
+
+Conversely	O
+,	O
+dyslipidemia	O
+is	O
+known	O
+to	O
+be	O
+tightly	O
+associated	O
+with	O
+immune	O
+disorders	O
+in	O
+humans	O
+,	O
+as	O
+evidenced	O
+by	O
+a	O
+higher	O
+incidence	B-EPI
+of	O
+atherosclerosis	O
+in	O
+patients	O
+with	O
+autoimmune	O
+diseases	O
+including	O
+psoriasis	O
+,	O
+rheumatoid	O
+arthritis	O
+,	O
+and	O
+systemic	O
+lupus	O
+erythematosus	O
+.	O
+
+Given	O
+that	O
+the	O
+dyslipidemia	O
+-	O
+related	O
+autoimmune	O
+diseases	O
+are	O
+caused	O
+by	O
+autoreactive	O
+T	O
+cells	O
+and	O
+B	O
+cells	O
+,	O
+dyslipidemia	O
+seems	O
+to	O
+directly	O
+or	O
+indirectly	O
+regulate	O
+the	O
+adaptive	O
+immunity	O
+.	O
+
+Indeed	O
+,	O
+accumulating	O
+evidence	O
+has	O
+unveiled	O
+that	O
+proatherogenic	O
+factors	O
+can	O
+impact	O
+the	O
+differentiation	O
+and	O
+function	O
+of	O
+CD4	O
++	O
+T	O
+cells	O
+,	O
+CD8	O
++	O
+T	O
+cells	O
+,	O
+and	O
+B	O
+cells	O
+.	O
+
+This	O
+review	O
+discusses	O
+an	O
+updated	O
+overview	O
+on	O
+the	O
+regulation	O
+of	O
+adaptive	O
+immunity	O
+by	O
+dyslipidemia	O
+and	O
+proposes	O
+a	O
+potential	O
+therapeutic	O
+strategy	O
+for	O
+immune	O
+disorders	O
+by	O
+targeting	O
+lipid	O
+metabolism	O
+.	O
+
+Neuroendocrine	O
+tumors	O
+(	O
+NETs	O
+)	O
+are	O
+rare	O
+neoplasms	O
+,	O
+with	O
+an	O
+estimated	O
+annual	B-EPI
+incidence	I-EPI
+of	O
+6.9/100	B-STAT
+000	O
+.	O
+
+They	O
+arise	O
+from	O
+cells	O
+of	O
+the	O
+diffuse	O
+endocrine	O
+system	O
+,	O
+which	O
+are	O
+mainly	O
+dispersed	O
+throughout	O
+the	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+,	O
+pancreatic	O
+,	O
+and	O
+respiratory	O
+tracts	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+GI	O
+-	O
+NETs	O
+has	O
+recently	O
+begun	O
+to	O
+show	O
+a	O
+steady	O
+increase	O
+.	O
+
+According	O
+to	O
+the	O
+Surveillance	O
+,	O
+Epidemiology	O
+,	O
+and	O
+End	O
+Results	O
+database	O
+,	O
+53	O
+%	O
+of	O
+patients	O
+with	O
+NETs	O
+present	O
+with	O
+localized	O
+disease	O
+,	O
+20	O
+%	O
+with	O
+locoregional	O
+disease	O
+,	O
+and	O
+27	O
+%	O
+with	O
+distant	O
+metastases	O
+at	O
+the	O
+time	O
+of	O
+diagnosis	O
+.	O
+
+Surgery	O
+is	O
+the	O
+mainstay	O
+for	O
+the	O
+treatment	O
+of	O
+locoregional	O
+GI	O
+-	O
+NETs	O
+.	O
+
+Endoscopic	O
+resection	O
+is	O
+an	O
+option	O
+for	O
+well	O
+-	O
+differentiated	O
+early	O
+GI	O
+-	O
+NETs	O
+,	O
+which	O
+are	O
+thought	O
+to	O
+very	O
+rarely	O
+metastasize	O
+to	O
+lymph	O
+nodes	O
+.	O
+
+A	O
+lesion	O
+that	O
+is	O
+technically	O
+difficult	O
+to	O
+resect	O
+via	O
+endoscopy	O
+is	O
+an	O
+indication	O
+for	O
+local	O
+resection	O
+(	O
+partial	O
+resection	O
+without	O
+lymph	O
+node	O
+dissection	O
+)	O
+.	O
+
+GI	O
+-	O
+NETs	O
+with	O
+possible	O
+lymph	O
+node	O
+metastasis	O
+is	O
+an	O
+indication	O
+for	O
+enterectomy	O
+with	O
+lymph	O
+node	O
+dissection	O
+.	O
+
+For	O
+NETs	O
+with	O
+metastatic	O
+lesions	O
+,	O
+cytoreduction	O
+surgery	O
+can	O
+control	O
+hormonal	O
+hypersecretion	O
+and	O
+alleviate	O
+symptoms	O
+;	O
+therefore	O
+,	O
+cytoreduction	O
+surgery	O
+is	O
+recommended	O
+.	O
+
+The	O
+indications	O
+for	O
+surgery	O
+vary	O
+and	O
+are	O
+based	O
+on	O
+the	O
+organ	O
+where	O
+the	O
+NET	O
+arose	O
+;	O
+therefore	O
+,	O
+an	O
+understanding	O
+of	O
+the	O
+patient	O
+'s	O
+clinical	O
+state	O
+and	O
+individualized	O
+treatment	O
+that	O
+is	O
+based	O
+on	O
+the	O
+characteristics	O
+of	O
+the	O
+patient	O
+'s	O
+GI	O
+-	O
+NET	O
+is	O
+needed	O
+.	O
+
+This	O
+review	O
+summarizes	O
+surgical	O
+treatments	O
+of	O
+GI	O
+-	O
+NETs	O
+in	O
+each	O
+organ	O
+.	O
+
+Background	O
+Tuberculosis	O
+osteomyelitis	O
+is	O
+rarely	O
+seen	O
+in	O
+the	O
+diaphyseal	O
+bones	O
+.	O
+
+It	O
+may	O
+be	O
+confused	O
+with	O
+Brodie	O
+'s	O
+abscess	O
+due	O
+to	O
+similar	O
+clinical	O
+,	O
+radiological	O
+and	O
+laboratory	O
+findings	O
+.	O
+
+Late	O
+diagnosis	O
+of	O
+the	O
+disease	O
+causes	O
+bone	O
+destruction	O
+.	O
+
+Tuberculosis	O
+osteomyelitis	O
+of	O
+the	O
+bone	O
+is	O
+a	O
+rare	O
+condition	O
+caused	O
+by	O
+the	O
+Mycobacterium	O
+tuberculosis	O
+.	O
+
+Its	O
+incidence	B-EPI
+has	O
+increased	O
+in	O
+Western	O
+countries	O
+in	O
+recent	O
+years	O
+due	O
+to	O
+HIV	O
+infection	O
+,	O
+increasing	O
+elderly	O
+population	O
+and	O
+emerging	O
+resistant	O
+strains	O
+.	O
+
+The	O
+slow	O
+progress	O
+of	O
+tuberculous	O
+osteomyelitis	O
+,	O
+due	O
+to	O
+lack	O
+of	O
+significant	O
+elevations	O
+in	O
+the	O
+laboratory	O
+values	O
+and	O
+changes	O
+in	O
+the	O
+radiographic	O
+appearance	O
+,	O
+often	O
+leads	O
+to	O
+confusion	O
+with	O
+the	O
+subtypes	O
+of	O
+subacute	O
+osteomyelitis	O
+,	O
+defined	O
+as	O
+Brodie	O
+'s	O
+abscess	O
+.	O
+
+These	O
+two	O
+low	O
+-	O
+virulence	O
+clinical	O
+cases	O
+often	O
+lead	O
+to	O
+delays	O
+in	O
+diagnosis	O
+and	O
+progressive	O
+bone	O
+destruction	O
+.	O
+
+Case	O
+presentation	O
+We	O
+report	O
+a	O
+65	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+presented	O
+to	O
+our	O
+clinic	O
+with	O
+pain	O
+,	O
+swelling	O
+and	O
+sensitivity	O
+in	O
+the	O
+left	O
+leg	O
+.	O
+
+Diagnosed	O
+with	O
+infection	O
+in	O
+the	O
+tibia	O
+,	O
+the	O
+patient	O
+had	O
+undergone	O
+antibiotherapy	O
+.	O
+
+However	O
+,	O
+the	O
+patient	O
+'s	O
+symptoms	O
+were	O
+not	O
+resolved	O
+and	O
+we	O
+performed	O
+bone	O
+curettage	O
+and	O
+cementation	O
+.	O
+
+M.	O
+tuberculosis	O
+-specific	O
+DNA	O
+was	O
+detected	O
+by	O
+real	O
+-	O
+time	O
+polymerase	O
+chain	O
+reaction	O
+and	O
+the	O
+M.	O
+tuberculosis	O
+complex	O
+was	O
+produced	O
+from	O
+the	O
+perioperative	O
+samples	O
+.	O
+
+Conclusion	O
+In	O
+conclusion	O
+,	O
+histopathological	O
+examination	O
+and	O
+polymerase	O
+chain	O
+reaction	O
+are	O
+essential	O
+before	O
+surgery	O
+of	O
+subacute	O
+and	O
+chronic	O
+osteomyelitis	O
+with	O
+atypical	O
+clinical	O
+,	O
+laboratory	O
+and	O
+radiological	O
+findings	O
+for	O
+early	O
+diagnosis	O
+and	O
+accurate	O
+treatment	O
+.	O
+
+Background	O
+Many	O
+studies	O
+reported	O
+high	O
+prevalence	B-EPI
+of	O
+antiphospholipid	O
+antibodies	O
+(	O
+aPL	O
+)	O
+in	O
+patients	O
+with	O
+COVID-19	O
+raising	O
+questions	O
+about	O
+its	O
+true	O
+prevalence	B-EPI
+and	O
+its	O
+clinical	O
+impact	O
+on	O
+the	O
+disease	O
+course	O
+.	O
+
+Methods	O
+We	O
+conducted	O
+a	O
+meta	O
+-	O
+analysis	O
+and	O
+a	O
+systematic	O
+review	O
+to	O
+examine	O
+the	O
+prevalence	B-EPI
+of	O
+aPL	O
+and	O
+its	O
+clinical	O
+impact	O
+in	O
+patients	O
+with	O
+COVID-19	O
+.	O
+
+Results	O
+21	O
+studies	O
+with	O
+a	O
+total	O
+of	O
+1159	O
+patients	O
+were	O
+included	O
+in	O
+our	O
+meta	O
+-	O
+analysis	O
+.	O
+
+Among	O
+patients	O
+hospitalised	O
+with	O
+COVID-19	O
+,	O
+the	O
+pooled	B-EPI
+prevalence	I-EPI
+rate	O
+of	O
+one	O
+or	O
+more	O
+aPL	O
+(	O
+IgM	O
+or	O
+IgG	O
+or	O
+IgA	O
+of	O
+anticardiolipin	O
+(	O
+aCL	O
+)	O
+or	O
+anti	O
+-	O
+ß2	O
+glycoprotein	O
+(	O
+anti	O
+-	O
+ß2	O
+GPI	O
+)	O
+or	O
+antiphosphatidylserine	O
+/	O
+prothrombin	O
+,	O
+or	O
+lupus	O
+anticoagulant	O
+(	O
+LA	B-LOC
+)	O
+)	O
+was	O
+46.8	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+36.1	O
+%	O
+to	O
+57.8	O
+%	O
+)	O
+.	O
+
+The	O
+most	O
+frequent	O
+type	O
+of	O
+aPL	O
+found	O
+was	O
+LA	B-LOC
+,	O
+with	O
+pooled	B-EPI
+prevalence	I-EPI
+rate	O
+of	O
+50.7	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+34.8	O
+%	O
+to	O
+66.5	O
+%	O
+)	O
+.	O
+
+Critically	O
+ill	O
+patients	O
+with	O
+COVID-19	O
+had	O
+significantly	O
+higher	O
+prevalence	B-EPI
+of	O
+aCL	O
+(	O
+IgM	O
+or	O
+IgG	O
+)	O
+(	O
+28.8	O
+%	O
+vs	O
+7.10	O
+%	O
+,	O
+p<0.0001	O
+)	O
+and	O
+anti	O
+-	O
+ß2	O
+GPI	O
+(	O
+IgM	O
+or	O
+IgG	O
+)	O
+(	O
+12.0	O
+%	O
+vs	O
+5.8	O
+%	O
+,	O
+p<0.0001	O
+)	O
+as	O
+compared	O
+with	O
+non	O
+-	O
+critically	O
+ill	O
+patients	O
+.	O
+
+However	O
+,	O
+there	O
+was	O
+no	O
+association	O
+between	O
+aPL	O
+positivity	O
+and	O
+mean	O
+levels	O
+of	O
+C	O
+reactive	O
+protein	O
+(	O
+mean	O
+difference	O
+was	O
+32	B-STAT
+(	O
+95	O
+%	O
+CI	O
+-15	O
+to	O
+79	O
+)	O
+,	O
+p=0.18	O
+)	O
+,	O
+D	O
+-	O
+dimer	O
+(	O
+mean	O
+difference	O
+was	O
+34	B-STAT
+(	O
+95	O
+%	O
+CI	O
+-194	O
+to	O
+273	O
+)	O
+,	O
+p=0.77	O
+)	O
+,	O
+mortality	O
+(	O
+1.46	O
+(	O
+95	O
+%	O
+CI	O
+0.29	O
+to	O
+7.29	O
+)	O
+,	O
+p=0.65	O
+)	O
+,	O
+invasive	O
+ventilation	O
+(	O
+1.22	O
+(	O
+95	O
+%	O
+CI	O
+0.51	O
+to	O
+2.91	O
+)	O
+,	O
+p=0.65	O
+)	O
+and	O
+venous	O
+thromboembolism	O
+(	O
+1.38	O
+(	O
+95	O
+%	O
+CI	O
+0.57	O
+to	O
+3.37	O
+)	O
+,	O
+p=0.48	O
+)	O
+.	O
+
+Conclusions	O
+aPLs	O
+were	O
+detected	O
+in	O
+nearly	O
+half	O
+of	O
+patients	O
+with	O
+COVID-19	O
+,	O
+and	O
+higher	O
+prevalence	B-EPI
+of	O
+aPL	O
+was	O
+found	O
+in	O
+severe	O
+disease	O
+.	O
+
+However	O
+,	O
+there	O
+was	O
+no	O
+association	O
+between	O
+aPL	O
+positivity	O
+and	O
+disease	O
+outcomes	O
+including	O
+thrombosis	O
+,	O
+invasive	O
+ventilation	O
+and	O
+mortality	O
+.	O
+
+However	O
+,	O
+further	O
+studies	O
+are	O
+required	O
+to	O
+identify	O
+the	O
+clinical	O
+and	O
+pathological	O
+role	O
+of	O
+aPL	O
+in	O
+COVID-19	O
+.	O
+
+The	O
+increasing	O
+prevalence	B-EPI
+of	O
+AF	O
+in	O
+a	O
+growing	O
+population	O
+of	O
+adults	O
+with	O
+congenital	O
+heart	O
+disease	O
+(	O
+CHD	O
+)	O
+poses	O
+new	O
+challenges	O
+to	O
+clinicians	O
+involved	O
+in	O
+the	O
+management	O
+of	O
+these	O
+patients	O
+.	O
+
+Distinctive	O
+underlying	O
+anatomies	O
+,	O
+unique	O
+physiological	O
+aspects	O
+,	O
+a	O
+high	O
+diversity	O
+of	O
+corrective	O
+surgeries	O
+and	O
+associated	O
+comorbidities	O
+can	O
+complicate	O
+clinical	O
+decision	O
+-	O
+making	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+the	O
+authors	O
+provide	O
+an	O
+overview	O
+of	O
+the	O
+current	O
+knowledge	O
+on	O
+epidemiology	O
+and	O
+pathophysiology	O
+,	O
+with	O
+a	O
+special	O
+focus	O
+on	O
+the	O
+differences	O
+to	O
+the	O
+non	O
+-	O
+CHD	O
+population	O
+and	O
+the	O
+clinical	O
+impact	O
+of	O
+AF	O
+in	O
+adults	O
+with	O
+CHD	O
+.	O
+
+Acute	O
+and	O
+long	O
+-	O
+term	O
+management	O
+strategies	O
+are	O
+summarised	O
+,	O
+including	O
+the	O
+use	O
+of	O
+antiarrhythmic	O
+drugs	O
+,	O
+catheter	O
+or	O
+surgical	O
+ablation	O
+and	O
+prophylaxis	O
+of	O
+thromboembolism	O
+.	O
+
+Finally	O
+,	O
+gaps	O
+of	O
+knowledge	O
+and	O
+potential	O
+areas	O
+of	O
+future	O
+research	O
+are	O
+highlighted	O
+.	O
+
+Background	O
+Cobalamin	O
+(	O
+cbl	O
+)	O
+C	O
+is	O
+a	O
+treatable	O
+rare	O
+hereditary	O
+disorder	O
+of	O
+cbl	O
+metabolism	O
+with	O
+autosomal	O
+recessive	O
+inheritance	O
+.	O
+
+It	O
+is	O
+the	O
+most	O
+common	O
+organic	O
+acidemia	O
+,	O
+manifested	O
+as	O
+methylmalonic	O
+academia	O
+combined	O
+with	O
+homocysteinemia	O
+.	O
+
+Early	O
+screening	O
+and	O
+diagnosis	O
+are	O
+important	O
+.	O
+
+The	O
+mutation	O
+spectrum	O
+of	O
+the	O
+MMACHC	O
+gene	O
+causing	O
+cblC	O
+varies	O
+among	O
+populations	O
+.	O
+
+The	O
+mutation	O
+spectrum	O
+in	O
+Chinese	O
+population	O
+is	O
+notably	O
+different	O
+from	O
+that	O
+in	O
+other	O
+populations	O
+.	O
+
+Methods	O
+A	O
+PCR	O
+followed	O
+by	O
+high	O
+-	O
+resolution	O
+melting	O
+curve	O
+analysis	O
+(	O
+PCR	O
+-	O
+HRM	O
+)	O
+method	O
+covering	O
+all	O
+coding	O
+exons	O
+of	O
+MMACHC	O
+gene	O
+was	O
+designed	O
+to	O
+verify	O
+14	O
+pathogenic	O
+MMACHC	O
+gene	O
+variants	O
+found	O
+in	O
+patients	O
+with	O
+cblC	O
+,	O
+including	O
+all	O
+common	O
+mutations	O
+in	O
+Chinese	O
+patients	O
+with	O
+cblC.	O
+
+Result	O
+By	O
+PCR	O
+-	O
+HRM	O
+analysis	O
+,	O
+14	O
+pathogenic	O
+variants	O
+of	O
+MMACHC	O
+showed	O
+distinctly	O
+different	O
+melting	O
+curves	O
+,	O
+which	O
+were	O
+consistent	O
+with	O
+Sanger	O
+sequencing	O
+.	O
+
+The	O
+homozygous	O
+type	O
+of	O
+the	O
+most	O
+common	O
+mutation	O
+c.609	O
+G	O
+>	O
+A	O
+(	O
+p.	O
+Trp203Ter	O
+)	O
+can	O
+also	O
+be	O
+analyzed	O
+by	O
+specially	O
+designed	O
+PCR	O
+-	O
+HRM	O
+.	O
+
+Conclusion	O
+The	O
+established	O
+PCR	O
+-	O
+HRM	O
+method	O
+for	O
+screening	O
+common	O
+pathogenic	O
+MMACHC	O
+variants	O
+in	O
+Chinese	O
+patients	O
+with	O
+cblC	O
+has	O
+the	O
+advantages	O
+of	O
+high	O
+accuracy	O
+,	O
+high	O
+throughput	O
+,	O
+low	O
+cost	O
+,	O
+and	O
+high	O
+speed	O
+.	O
+
+It	O
+is	O
+suitable	O
+for	O
+the	O
+large	O
+-	O
+sample	O
+screening	O
+of	O
+suspected	O
+children	O
+with	O
+methylmalonic	O
+acidemia	O
+and	O
+carriers	O
+in	O
+population	O
+.	O
+
+Purpose	O
+Kabuki	O
+syndrome	O
+(	O
+KS	O
+)	O
+(	O
+OMIM	O
+147920	O
+and	O
+300867	O
+)	O
+is	O
+a	O
+rare	O
+genetic	O
+disorder	O
+characterized	O
+by	O
+specific	O
+facial	O
+features	O
+,	O
+intellectual	O
+disability	O
+,	O
+and	O
+various	O
+malformations	O
+.	O
+
+Immunopathological	O
+manifestations	O
+seem	O
+prevalent	B-EPI
+and	O
+increase	O
+the	O
+morbimortality	O
+.	O
+
+To	O
+assess	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+the	O
+manifestations	O
+,	O
+we	O
+measured	O
+the	O
+prevalence	B-EPI
+of	O
+immunopathological	O
+manifestations	O
+as	O
+well	O
+as	O
+genotype	O
+-	O
+phenotype	O
+correlations	O
+in	O
+KS	B-LOC
+individuals	O
+from	O
+a	O
+registry	O
+.	O
+
+Methods	O
+Data	O
+were	O
+for	O
+177	O
+KS	O
+individuals	O
+with	O
+KDM6A	O
+or	O
+KMT2D	O
+pathogenic	O
+variants	O
+.	O
+
+Questionnaires	O
+to	O
+clinicians	O
+were	O
+used	O
+to	O
+assess	O
+the	O
+presence	O
+of	O
+immunodeficiency	O
+and	O
+autoimmune	O
+diseases	O
+both	O
+on	O
+a	O
+clinical	O
+and	O
+biological	O
+basis	O
+.	O
+
+Results	O
+Overall	O
+,	O
+44.1	O
+%	O
+(	O
+78/177	O
+)	O
+and	O
+58.2	O
+%	O
+(	O
+46/79	O
+)	O
+of	O
+KS	B-LOC
+individuals	O
+exhibited	O
+infection	O
+susceptibility	O
+and	O
+hypogammaglobulinemia	O
+,	O
+respectively	O
+;	O
+13.6	O
+%	O
+(	O
+24/177	O
+)	O
+had	O
+autoimmune	O
+disease	O
+(	O
+AID	O
+;	O
+25.6	O
+%	O
+[	O
+11/43	O
+]	O
+in	O
+adults	O
+)	O
+,	O
+5.6	O
+%	O
+(	O
+10/177	O
+)	O
+with	O
+≥2	O
+AID	O
+manifestations	O
+.	O
+
+The	O
+most	O
+frequent	O
+AID	O
+manifestations	O
+were	O
+immune	O
+thrombocytopenic	O
+purpura	O
+(	O
+7.3	O
+%	O
+[	O
+13/177	O
+]	O
+)	O
+and	O
+autoimmune	O
+hemolytic	O
+anemia	O
+(	O
+4.0	O
+%	O
+[	O
+7/177	O
+]	O
+)	O
+.	O
+
+Among	O
+nonhematological	O
+manifestations	O
+,	O
+vitiligo	O
+was	O
+frequent	O
+.	O
+
+Immune	O
+thrombocytopenic	O
+purpura	O
+was	O
+frequent	O
+with	O
+missense	O
+versus	O
+other	O
+types	O
+of	O
+variants	O
+(	O
+p	O
+=	O
+0.027	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+high	O
+prevalence	B-EPI
+of	O
+immunopathological	O
+manifestations	O
+in	O
+KS	B-LOC
+demonstrates	O
+the	O
+importance	O
+of	O
+systematic	O
+screening	O
+and	O
+efficient	O
+preventive	O
+management	O
+of	O
+these	O
+treatable	O
+and	O
+sometimes	O
+life	O
+-	O
+threatening	O
+conditions	O
+.	O
+
+Mandatory	O
+folic	O
+acid	O
+fortification	O
+in	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+corresponded	O
+with	O
+a	O
+decline	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+spina	O
+bifida	O
+(	O
+SB	O
+)	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+describe	O
+the	O
+epidemiologic	O
+characteristics	O
+of	O
+isolated	O
+versus	O
+non	O
+-	O
+isolated	O
+SB	O
+cases	O
+in	O
+both	O
+pre-	O
+and	O
+post	O
+-	O
+fortification	O
+periods	O
+.	O
+
+SB	O
+cases	O
+in	O
+the	O
+Slone	O
+Epidemiology	O
+Center	O
+Birth	O
+Defects	O
+Study	O
+from	O
+1976	O
+to	O
+2011	O
+without	O
+chromosomal	O
+anomalies	O
+and	O
+syndromes	O
+were	O
+included	O
+.	O
+
+A	O
+maternal	O
+interview	O
+,	O
+conducted	O
+within	O
+6	O
+months	O
+of	O
+delivery	O
+,	O
+collected	O
+information	O
+on	O
+demographics	O
+,	O
+reproductive	O
+history	O
+,	O
+diet	O
+,	O
+and	O
+supplement	O
+use	O
+.	O
+
+Daily	O
+folic	O
+acid	O
+intake	O
+in	O
+the	O
+periconceptional	O
+period	O
+was	O
+calculated	O
+using	O
+both	O
+dietary	O
+and	O
+supplement	O
+information	O
+and	O
+categorized	O
+as	O
+low	O
+intake	O
+(	O
+<	O
+400	O
+µg	O
+/	O
+day	O
+)	O
+or	O
+high	O
+intake	O
+(	O
+≥400	O
+µg	O
+/	O
+day	O
+)	O
+.	O
+
+SB	O
+cases	O
+(	O
+n	O
+=	O
+1170	O
+)	O
+were	O
+classified	O
+as	O
+isolated	O
+(	O
+80.4	O
+%	O
+)	O
+or	O
+non	O
+-	O
+isolated	O
+(	O
+19.1	O
+%	O
+)	O
+.	O
+
+Non	O
+-	O
+isolated	O
+cases	O
+were	O
+further	O
+divided	O
+into	O
+subgroups	O
+based	O
+on	O
+accompanying	O
+major	O
+malformations	O
+(	O
+midline	O
+,	O
+renal	O
+,	O
+genital	O
+,	O
+heart	O
+,	O
+laterality	O
+)	O
+.	O
+
+Compared	O
+to	O
+non	O
+-	O
+isolated	O
+cases	O
+,	O
+isolated	O
+cases	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+white	O
+,	O
+non	O
+-	O
+Hispanic	O
+and	O
+have	O
+more	O
+than	O
+12	O
+years	O
+of	O
+education	O
+.	O
+
+Cases	O
+in	O
+the	O
+renal	O
+,	O
+genital	O
+,	O
+and	O
+heart	O
+subgroups	O
+had	O
+the	O
+lowest	O
+proportions	O
+of	O
+mothers	O
+with	O
+a	O
+high	O
+folic	O
+acid	O
+intake	O
+.	O
+
+The	O
+change	O
+from	O
+pre-	O
+to	O
+post	O
+-	O
+fortification	O
+was	O
+associated	O
+with	O
+a	O
+decrease	O
+in	O
+the	O
+proportion	O
+of	O
+isolated	O
+cases	O
+from	O
+83	O
+%	O
+to	O
+72	O
+%	O
+,	O
+though	O
+in	O
+both	O
+periods	O
+isolated	O
+cases	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+female	O
+and	O
+their	O
+mothers	O
+were	O
+more	O
+likely	O
+to	O
+have	O
+high	O
+folic	O
+acid	O
+intake	O
+.	O
+
+These	O
+findings	O
+highlight	O
+the	O
+importance	O
+of	O
+separating	O
+isolated	O
+and	O
+non	O
+-	O
+isolated	O
+cases	O
+in	O
+etiologic	O
+research	O
+of	O
+SB	O
+.	O
+
+Wilson	O
+'s	O
+disease	O
+or	O
+hepatolenticular	O
+degeneration	O
+Abstract	O
+.	O
+
+Wilson	O
+'s	O
+disease	O
+,	O
+or	O
+hepatolenticular	O
+degeneration	O
+,	O
+is	O
+a	O
+rare	O
+inherited	O
+disorder	O
+of	O
+copper	O
+metabolism	O
+.	O
+
+The	O
+most	O
+common	O
+clinical	O
+presentations	O
+are	O
+liver	O
+disease	O
+and	O
+/	O
+or	O
+neuro	O
+-	O
+psychiatric	O
+manifestations	O
+.	O
+
+Pathophysiologically	O
+,	O
+Wilson	O
+'s	O
+disease	O
+is	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+ATP7B	O
+gene	O
+,	O
+which	O
+lead	O
+to	O
+defective	O
+biliary	O
+excretion	O
+of	O
+copper	O
+and	O
+subsequent	O
+accumulation	O
+of	O
+copper	O
+in	O
+the	O
+liver	O
+and	O
+in	O
+other	O
+organs	O
+.	O
+
+Its	O
+prevalence	B-EPI
+is	O
+approximately	B-STAT
+1:30	I-STAT
+000	I-STAT
+,	I-STAT
+however	O
+its	O
+penetrance	O
+,	O
+clinical	O
+presentation	O
+and	O
+disease	O
+severity	O
+vary	O
+widely	O
+,	O
+ranging	O
+from	O
+asymptomatic	O
+elevation	O
+of	O
+liver	O
+enzymes	O
+to	O
+cirrhosis	O
+or	O
+acute	O
+liver	O
+failure	O
+with	O
+or	O
+without	O
+neuro	O
+-	O
+psychiatric	O
+symptoms	O
+.	O
+
+For	O
+this	O
+reason	O
+,	O
+Wilson	O
+'s	O
+disease	O
+should	O
+be	O
+suspected	O
+and	O
+ruled	O
+out	O
+in	O
+cases	O
+of	O
+indeterminate	O
+liver	O
+disease	O
+or	O
+neuropsychiatric	O
+disturbances	O
+.	O
+
+The	O
+diagnostic	O
+algorithms	O
+are	O
+complex	O
+and	O
+involve	O
+clinical	O
+tests	O
+,	O
+ophthalmologic	O
+examination	O
+(	O
+Kayser	O
+-	O
+Fleischer	O
+rings	O
+in	O
+split	O
+-	O
+lamp	O
+examination	O
+)	O
+,	O
+blood	O
+and	O
+urine	O
+tests	O
+,	O
+genetic	O
+testing	O
+,	O
+imaging	O
+and	O
+histology	O
+.	O
+
+In	O
+compensated	O
+liver	O
+disease	O
+,	O
+treatment	O
+of	O
+Wilson	O
+'s	O
+disease	O
+by	O
+copper	O
+depletion	O
+(	O
+chelators	O
+,	O
+zinc	O
+)	O
+is	O
+usually	O
+effective	O
+.	O
+
+In	O
+case	O
+of	O
+liver	O
+failure	O
+liver	O
+transplantation	O
+may	O
+be	O
+needed	O
+,	O
+which	O
+corrects	O
+the	O
+underlying	O
+error	O
+of	O
+copper	O
+metabolism	O
+.	O
+
+New	O
+drugs	O
+with	O
+improved	O
+efficacy	O
+and	O
+tolerability	O
+are	O
+in	O
+clinical	O
+development	O
+.	O
+
+Background	O
+PURPOSE	O
+:	O
+Although	O
+many	O
+studies	O
+have	O
+investigated	O
+the	O
+relationship	O
+between	O
+transient	O
+global	O
+amnesia	O
+(	O
+TGA	O
+)	O
+and	O
+migraine	O
+,	O
+to	O
+date	O
+,	O
+no	O
+meta	O
+-	O
+analysis	O
+has	O
+confirmed	O
+the	O
+existence	O
+and	O
+size	O
+of	O
+their	O
+association	O
+.	O
+
+Methodology	O
+Literature	O
+search	O
+involved	O
+MEDLINE	O
+,	O
+EMBASE	O
+,	O
+CENTRAL	O
+and	O
+PsycINFO	B-LOC
+.	O
+
+Observational	O
+controlled	O
+studies	O
+including	O
+TGA	O
+patients	O
+(	O
+Caplan	O
+,	O
+Hodges	O
+and	O
+Warlow	O
+)	O
+were	O
+retrieved	O
+.	O
+
+Quality	O
+evaluation	O
+was	O
+based	O
+on	O
+the	O
+Newcastle	B-LOC
+-	O
+Ottawa	B-LOC
+scale	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+migraine	O
+was	O
+compared	O
+in	O
+TGA	O
+patients	O
+vs.	O
+healthy	O
+controls	O
+(	O
+HC	O
+)	O
+,	O
+as	O
+well	O
+as	O
+in	O
+TGA	O
+against	O
+TIA	O
+individuals	O
+.	O
+
+Data	O
+from	O
+case	O
+-	O
+control	O
+,	O
+cross	O
+-	O
+sectional	O
+and	O
+cohort	O
+studies	O
+were	O
+pooled	O
+separately	O
+.	O
+
+Results	O
+Literature	O
+search	O
+yielded	O
+1178	O
+articles	O
+,	O
+12	O
+of	O
+which	O
+were	O
+included	O
+in	O
+the	O
+present	O
+meta	O
+-	O
+analysis	O
+.	O
+
+Results	O
+from	O
+case	O
+-	O
+control	O
+(	O
+ten	O
+)	O
+,	O
+cohort	O
+(	O
+one	O
+)	O
+and	O
+cross	O
+-	O
+sectional	O
+(	O
+one	O
+)	O
+studies	O
+were	O
+compatible	O
+with	O
+an	O
+association	O
+between	O
+TGA	O
+and	O
+migraine	O
+.	O
+
+The	O
+nationwide	O
+inpatient	O
+cross	O
+-	O
+sectional	O
+study	O
+was	O
+of	O
+lesser	O
+value	O
+due	O
+to	O
+its	O
+inpatient	O
+orientation	O
+.	O
+
+The	O
+high	O
+-	O
+quality	O
+,	O
+population	O
+-	O
+based	O
+,	O
+retrospective	O
+cohort	O
+(	O
+158,301	B-STAT
+participants	I-STAT
+per	I-STAT
+group	I-STAT
+)	I-STAT
+determined	O
+a	O
+higher	O
+relative	O
+-	O
+risk	O
+(	O
+RR	O
+)	O
+of	O
+TGA	O
+for	O
+migraine	O
+vs.	O
+non	O
+-	O
+migraine	O
+individuals	O
+[	O
+RR	O
+=	O
+2.48	O
+,	O
+95%confidence	O
+-	O
+interval	O
+(	O
+95	O
+%	O
+CI	O
+)	O
+=	O
+(	O
+1.32	O
+,	O
+4.87	O
+)	O
+]	O
+.	O
+
+Sensitivity	O
+testing	O
+based	O
+on	O
+stricter	O
+diagnostic	O
+criteria	O
+strengthened	O
+the	O
+estimated	O
+association	O
+[	O
+RR	O
+=	O
+3.84	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+(	O
+1.57	O
+,	O
+9.38	O
+)	O
+]	O
+.	O
+
+Additionally	O
+,	O
+pooled	O
+data	O
+from	O
+eight	O
+case	O
+-	O
+control	O
+studies	O
+(	O
+700	O
+TGA	O
+,	O
+746	O
+HC	O
+)	O
+yielded	O
+similar	O
+results	O
+[	O
+Odds	O
+-	O
+Ratio	O
+,	O
+OR	O
+=	O
+2.51	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+(	O
+1.85	O
+,	O
+3.41	O
+)	O
+]	O
+,	O
+with	O
+the	O
+association	O
+mainly	O
+driven	O
+by	O
+the	O
+three	O
+high	O
+-	O
+quality	O
+studies	O
+,	O
+rather	O
+than	O
+the	O
+five	O
+articles	O
+of	O
+moderate	O
+quality	O
+.	O
+
+Finally	O
+,	O
+pooled	O
+findings	O
+from	O
+four	O
+case	O
+-	O
+control	O
+studies	O
+of	O
+moderate	O
+-	O
+quality	O
+revealed	O
+a	O
+higher	O
+prevalence	B-EPI
+of	O
+migraine	O
+among	O
+TGA	O
+compared	O
+to	O
+TIA	O
+patients	O
+[	O
+OR	O
+=	O
+1.82	O
+,	O
+95	O
+%	O
+CI	O
+=	O
+(	O
+1.22	O
+,	O
+2.73	O
+)	O
+]	O
+.	O
+
+Conclusions	O
+A	O
+significant	O
+association	O
+between	O
+TGA	O
+and	O
+migraine	O
+was	O
+established	O
+.	O
+
+The	O
+underlying	O
+connecting	O
+mechanism	O
+remains	O
+undetermined	O
+,	O
+yet	O
+.	O
+
+Short	O
+-	O
+term	O
+VEEG	O
+represents	O
+an	O
+affordable	O
+option	O
+in	O
+limited	O
+resources	O
+environments	O
+.	O
+
+There	O
+are	O
+few	O
+reports	O
+on	O
+its	O
+use	O
+.	O
+
+Its	O
+diagnostic	O
+yield	O
+is	O
+variable	O
+(	O
+7	B-STAT
+-	O
+57	O
+%	O
+)	O
+and	O
+can	O
+be	O
+related	O
+to	O
+the	O
+differences	O
+in	O
+recording	O
+time	O
+.	O
+
+The	O
+present	O
+study	O
+analyzes	O
+possible	O
+predictive	O
+factors	O
+to	O
+support	O
+the	O
+indication	O
+of	O
+a	O
+short	O
+-	O
+term	O
+VEEG	O
+.	O
+
+We	O
+analyzed	O
+short	O
+-	O
+term	O
+VEEG	O
+studies	O
+(	O
+<	O
+24	O
+h	O
+)	O
+throughout	O
+a	O
+period	O
+of	O
+5	O
+years	O
+(	O
+2013	O
+-	O
+2017	O
+)	O
+.	O
+
+The	O
+patients	O
+were	O
+clustered	O
+according	O
+to	O
+the	O
+date	O
+of	O
+last	O
+epileptic	O
+seizure	O
+and	O
+the	O
+frequency	O
+of	O
+epileptic	O
+events	O
+per	O
+month	O
+and	O
+subcategorized	O
+depending	O
+on	O
+the	O
+frequency	O
+found	O
+.	O
+
+Chi	O
+square	O
+univariate	O
+analysis	O
+was	O
+performed	O
+looking	O
+for	O
+predictive	O
+variables	O
+to	O
+obtain	O
+an	O
+epileptic	O
+short	O
+-	O
+term	O
+EEG	O
+.	O
+
+A	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+was	O
+performed	O
+with	O
+statistically	O
+significant	O
+variables	O
+.	O
+
+A	O
+total	O
+of	O
+1092	O
+VEEG	O
+were	O
+analyzed	O
+from	O
+832	O
+patients	O
+.	O
+
+34.5	B-STAT
+%	I-STAT
+were	O
+reported	O
+as	O
+epileptic	O
+VEEG	O
+.	O
+
+In	O
+the	O
+multivariate	O
+analysis	O
+,	O
+3	O
+predictors	O
+of	O
+epileptic	O
+short	O
+-	O
+term	O
+VEEG	O
+were	O
+identified	O
+:	O
+The	O
+use	O
+of	O
+2	O
+or	O
+more	O
+antiepileptic	O
+drugs	O
+(	O
+AEDs	O
+)	O
+(	O
+OR	O
+1.67	O
+,	O
+CI	O
+1.23	O
+-	O
+2.25	O
+,	O
+p	O
+=	O
+0.001	O
+)	O
+,	O
+the	O
+presence	O
+of	O
+an	O
+epileptic	O
+event	O
+in	O
+the	O
+last	O
+month	O
+(	O
+OR	O
+1.53	O
+,	O
+CI	O
+1.07	O
+-	O
+2.17	O
+,	O
+p	O
+=	O
+0.018	O
+)	O
+and	O
+daily	O
+seizures	O
+(	O
+OR	O
+1.84	O
+,	O
+CI	O
+1.21	O
+-	O
+2.78	O
+,	O
+p	O
+=	O
+0.004	O
+)	O
+.	O
+
+Six	O
+-	O
+month	O
+seizure	O
+free	O
+subjects	O
+predict	O
+a	O
+non	O
+-	O
+epileptic	O
+VEEG	O
+(	O
+OR	O
+0.58	O
+,	O
+CI	O
+0.30	O
+-	O
+0.89	O
+,	O
+p	O
+=	O
+0.013	O
+)	O
+.	O
+
+The	O
+Wiskott	O
+-	O
+Aldrich	O
+syndrome	O
+(	O
+WAS	O
+)	O
+is	O
+an	O
+X	O
+-	O
+linked	O
+disorder	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+WAS	O
+gene	O
+resulting	O
+in	O
+congenital	O
+thrombocytopenia	O
+,	O
+eczema	O
+,	O
+recurrent	O
+infections	O
+and	O
+an	O
+increased	O
+incidence	B-EPI
+of	O
+autoimmune	O
+diseases	O
+and	O
+malignancies	O
+.	O
+
+Without	O
+curative	O
+therapies	O
+,	O
+affected	O
+patients	O
+have	O
+diminished	O
+life	O
+expectancy	O
+and	O
+reduced	O
+quality	O
+of	O
+life	O
+.	O
+
+Since	O
+WAS	O
+protein	O
+(	O
+WASP	O
+)	O
+is	O
+constitutively	O
+expressed	O
+only	O
+in	O
+hematopoietic	O
+stem	O
+cell	O
+-	O
+derived	O
+lineages	O
+,	O
+hematopoietic	O
+stem	O
+cell	O
+transplantation	O
+(	O
+HSCT	O
+)	O
+and	O
+gene	O
+therapy	O
+(	O
+GT	O
+)	O
+are	O
+well	O
+suited	O
+to	O
+correct	O
+the	O
+hematologic	O
+and	O
+immunologic	O
+defects	O
+.	O
+
+Advances	O
+in	O
+high	O
+-	O
+resolution	O
+HLA	O
+typing	O
+,	O
+new	O
+techniques	O
+to	O
+prevent	O
+GvHD	O
+allowing	O
+the	O
+use	O
+of	O
+haploidentical	O
+donors	O
+,	O
+and	O
+the	O
+introduction	O
+of	O
+reduced	O
+intensity	O
+conditioning	O
+regimens	O
+with	O
+myeloablative	O
+features	O
+have	O
+increased	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+to	O
+over	O
+90	B-STAT
+%	I-STAT
+.	O
+
+The	O
+development	O
+of	O
+GT	O
+for	O
+WAS	O
+has	O
+provided	O
+basic	O
+knowledge	O
+into	O
+vector	O
+selection	O
+and	O
+random	O
+integration	O
+of	O
+various	O
+viral	O
+vectors	O
+into	O
+the	O
+genome	O
+,	O
+with	O
+the	O
+possibility	O
+of	O
+inducing	O
+leukemogenesis	O
+.	O
+
+After	O
+trials	O
+and	O
+errors	O
+,	O
+inactivating	O
+lentiviral	O
+vectors	O
+carrying	O
+the	O
+WAS	O
+gene	O
+were	O
+successfully	O
+evaluated	O
+in	O
+clinical	O
+trials	O
+,	O
+demonstrating	O
+cure	O
+of	O
+the	O
+disease	O
+except	O
+for	O
+insufficient	O
+resolution	O
+of	O
+the	O
+platelet	O
+defect	O
+.	O
+
+Thus	O
+,	O
+50	O
+years	O
+of	O
+clinical	O
+evaluation	O
+,	O
+genetic	O
+exploration	O
+and	O
+extensive	O
+clinical	O
+trials	O
+,	O
+a	O
+lethal	O
+syndrome	O
+has	O
+turned	O
+into	O
+a	O
+curable	O
+disorder	O
+.	O
+
+Background	O
+Repeated	O
+inflammation	O
+of	O
+the	O
+pancreas	O
+can	O
+cause	O
+pancreatitis	O
+or	O
+diabetes	O
+.	O
+
+It	O
+is	O
+well	O
+recognized	O
+that	O
+the	O
+organic	O
+acidemias	O
+may	O
+be	O
+complicated	O
+by	O
+pancreatitis	O
+but	O
+less	O
+recognized	O
+are	O
+other	O
+metabolic	O
+disorders	O
+in	O
+which	O
+pancreatitis	O
+can	O
+occur	O
+.	O
+
+This	O
+study	O
+shows	O
+that	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+of	O
+patients	O
+with	O
+various	O
+metabolic	O
+disorders	O
+in	O
+Korea	B-LOC
+revealed	O
+several	O
+with	O
+episodes	O
+of	O
+isolated	O
+pancreatitis	O
+or	O
+diabetes	O
+concomitantly	O
+with	O
+pancreatitis	O
+.	O
+
+Results	O
+and	O
+discussion	O
+In	O
+this	O
+study	O
+,	O
+two	O
+patients	O
+with	O
+methylmalonic	O
+aciduria	O
+(	O
+MMA	O
+)	O
+,	O
+two	O
+with	O
+propionic	O
+acidemia	O
+(	O
+PPA	O
+)	O
+,	O
+one	O
+with	O
+fatty	O
+acid	O
+oxidation	O
+disorder	O
+(	O
+FAOD	O
+)	O
+,	O
+and	O
+one	O
+with	O
+hyperornithinemia	O
+,	O
+gyrate	O
+atrophy	O
+,	O
+and	O
+juvenile	O
+onset	O
+diabetes	O
+mellitus	O
+(	O
+DM	O
+)	O
+were	O
+clinically	O
+followed	O
+for	O
+up	O
+to	O
+10	O
+-	O
+21	O
+years	O
+.	O
+
+Two	O
+Korean	O
+siblings	O
+with	O
+MMA	O
+showed	O
+recurrent	O
+pancreatitis	O
+from	O
+the	O
+age	O
+of	O
+15	O
+and	O
+19	O
+,	O
+respectively	O
+.	O
+
+The	O
+frequency	O
+of	O
+admission	O
+due	O
+to	O
+pancreatitis	O
+was	O
+up	O
+to	O
+11	O
+times	O
+.	O
+
+One	O
+patient	O
+with	O
+MMA	O
+developed	O
+diabetes	O
+mellitus	O
+at	O
+the	O
+age	O
+of	O
+20	O
+.	O
+
+The	O
+other	O
+patient	O
+with	O
+MMA	O
+developed	O
+recurrent	O
+pancreatitis	O
+at	O
+4	O
+years	O
+and	O
+diabetes	O
+at	O
+8	O
+years	O
+of	O
+age	O
+.	O
+
+One	O
+of	O
+the	O
+patients	O
+with	O
+PPA	O
+presented	O
+with	O
+diabetic	O
+ketoacidosis	O
+.	O
+
+The	O
+other	O
+PPA	O
+patient	O
+died	O
+of	O
+cardiac	O
+arrest	O
+at	O
+age	O
+10	O
+.	O
+
+The	O
+patient	O
+with	O
+FAOD	O
+presented	O
+with	O
+pancreatitis	O
+at	O
+10	O
+years	O
+and	O
+died	O
+at	O
+the	O
+age	O
+of	O
+15	O
+years	O
+due	O
+to	O
+cardiac	O
+arrest	O
+.	O
+
+A	O
+35	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+hyperornithinemia	O
+/	O
+gyrate	O
+atrophy	O
+was	O
+diagnosed	O
+with	O
+juvenile	O
+onset	O
+diabetes	O
+at	O
+the	O
+age	O
+of	O
+7	O
+years	O
+.	O
+
+No	O
+pancreatitis	O
+occurred	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+Conclusions	O
+We	O
+conclude	O
+that	O
+various	O
+metabolic	O
+disorders	O
+can	O
+trigger	O
+acute	O
+or	O
+chronic	O
+pancreatitis	O
+.	O
+
+Proper	O
+and	O
+prompt	O
+multidisciplinary	O
+management	O
+of	O
+metabolic	O
+derangement	O
+is	O
+crucial	O
+for	O
+preventing	O
+pancreatic	O
+damage	O
+.	O
+
+Further	O
+clinical	O
+and	O
+investigational	O
+studies	O
+are	O
+required	O
+to	O
+elucidate	O
+the	O
+pathogenesis	O
+of	O
+pancreatitis	O
+and	O
+diabetes	O
+mellitus	O
+in	O
+patients	O
+with	O
+inborn	O
+errors	O
+in	O
+metabolism	O
+.	O
+
+Background	O
+Reported	O
+birth	O
+prevalences	B-EPI
+of	O
+congenital	O
+limb	O
+defects	O
+(	O
+CLD	O
+)	O
+vary	O
+between	O
+countries	O
+:	O
+from	O
+13/10,000	B-STAT
+in	O
+Finland	B-LOC
+for	O
+the	O
+period	O
+1964	O
+-	O
+1977	O
+to	I-STAT
+30.4/10,000	I-STAT
+births	I-STAT
+in	O
+Scotland	B-LOC
+from	O
+1964	O
+-	O
+1968	O
+.	O
+
+Epidemiological	O
+studies	O
+permit	O
+the	O
+timely	O
+detection	O
+of	O
+trends	O
+in	O
+CLD	O
+and	O
+of	O
+associations	O
+with	O
+other	O
+birth	O
+defects	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+describe	O
+the	O
+birth	O
+prevalence	B-EPI
+of	O
+CLD	O
+in	O
+the	O
+northern	O
+Netherlands	B-LOC
+.	O
+
+Methods	O
+In	O
+a	O
+population	O
+-	O
+based	O
+,	O
+epidemiological	O
+study	O
+we	O
+investigated	O
+the	O
+birth	O
+prevalences	B-EPI
+of	O
+CLD	O
+for	O
+1981	O
+-	O
+2010	O
+.	O
+
+Data	O
+were	O
+collected	O
+by	O
+the	O
+European	O
+Surveillance	O
+of	O
+Congenital	O
+Anomalies	O
+in	O
+the	O
+northern	O
+Netherlands	B-LOC
+(	O
+EUROCAT	O
+-	O
+NNL	O
+)	O
+.	O
+
+We	O
+excluded	O
+malpositions	O
+,	O
+club	O
+foot	O
+,	O
+and	O
+dislocation	O
+/	O
+dysplasia	O
+of	O
+hips	O
+or	O
+knees	O
+.	O
+
+Trends	O
+were	O
+analysed	O
+for	O
+the	O
+19	O
+-	O
+year	O
+period	O
+1992	O
+-	O
+2010	O
+using	O
+χ²	O
+tests	O
+,	O
+as	O
+well	O
+as	O
+CLD	O
+association	O
+with	O
+anomalies	O
+affecting	O
+other	O
+organs	O
+.	O
+
+Results	O
+The	O
+birth	O
+prevalence	B-EPI
+of	O
+CLD	O
+was	O
+21.1/10,000	B-STAT
+births	I-STAT
+for	O
+1981	O
+-	O
+2010	O
+.	O
+
+There	O
+was	O
+an	O
+overall	O
+decrease	O
+in	O
+non	O
+-	O
+syndromic	O
+limb	O
+defects	O
+(	O
+P	O
+=	O
+0.023	O
+)	O
+caused	O
+by	O
+a	O
+decrease	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+non	O
+-	O
+syndromic	O
+syndactyly	O
+(	O
+P	O
+<	O
+0.01	O
+)	O
+in	O
+1992	O
+-	O
+2010	O
+.	O
+
+Of	O
+1,048	O
+children	O
+with	O
+CLD	O
+,	O
+55	O
+%	O
+were	O
+males	O
+,	O
+57	O
+%	O
+had	O
+isolated	O
+defects	O
+,	O
+13	O
+%	O
+had	O
+multiple	O
+congenital	O
+anomalies	O
+(	O
+MCA	O
+)	O
+,	O
+and	O
+30	O
+%	O
+had	O
+a	O
+recognised	O
+syndrome	O
+.	O
+
+The	O
+upper	O
+:	O
+lower	O
+limb	O
+ratio	O
+was	O
+2:1	O
+,	O
+and	O
+the	O
+left	O
+:	O
+right	O
+side	O
+ratio	O
+was	O
+1.2:1	O
+.	O
+
+Cardiovascular	O
+and	O
+urinary	O
+tract	O
+anomalies	O
+were	O
+common	O
+in	O
+combination	O
+with	O
+CLD	O
+(	O
+37	O
+%	O
+and	O
+25	O
+%	O
+of	O
+cases	O
+with	O
+MCA	O
+)	O
+.	O
+
+Digestive	O
+-	O
+tract	O
+anomalies	O
+were	O
+significantly	O
+associated	O
+with	O
+CLD	O
+(	O
+P	O
+=	O
+0.016	O
+)	O
+.	O
+
+Conclusions	O
+The	O
+birth	O
+prevalence	B-EPI
+of	O
+CLD	O
+in	O
+the	O
+northern	O
+Netherlands	B-LOC
+was	O
+21.1/10,000	B-STAT
+births	I-STAT
+.	O
+
+The	O
+birth	O
+prevalence	B-EPI
+of	O
+non	O
+-	O
+syndromic	O
+syndactyly	O
+dropped	O
+from	O
+5.2/10,000	B-STAT
+to	I-STAT
+1.1/10,000	I-STAT
+in	O
+1992	O
+-	O
+2010	O
+.	O
+
+This	O
+study	O
+is	O
+to	O
+describe	O
+current	O
+incidence	B-EPI
+of	O
+childhood	O
+clear	O
+cell	O
+sarcoma	O
+of	O
+kidney	O
+(	O
+CCSK	O
+)	O
+and	O
+to	O
+investigate	O
+the	O
+present	O
+survival	O
+of	O
+this	O
+cancer	O
+.	O
+
+Surveillance	O
+,	O
+Epidemiology	O
+,	O
+and	O
+End	O
+Result	O
+(	O
+SEER	O
+)	O
+data	O
+was	O
+used	O
+to	O
+identify	O
+children	O
+with	O
+CCSK	O
+and	O
+Wilms	O
+tumor	O
+(	O
+WT	O
+)	O
+aged	O
+0	O
+-	O
+19	O
+years	O
+in	O
+the	O
+US	B-LOC
+.	O
+
+Age	O
+-	O
+adjusted	O
+incidences	B-EPI
+were	O
+estimated	O
+over	O
+the	O
+decades	O
+.	O
+
+Age-	O
+and	O
+sex	O
+-	O
+specific	O
+epidemiology	O
+was	O
+also	O
+presented	O
+.	O
+
+Propensity	O
+score	O
+matching	O
+was	O
+used	O
+to	O
+balance	O
+features	O
+of	O
+CCSK	O
+and	O
+WT	O
+cases	O
+.	O
+
+Log	O
+rank	O
+test	O
+was	O
+used	O
+to	O
+compare	O
+survivals	O
+and	O
+Cox	O
+regression	O
+was	O
+used	O
+to	O
+evaluate	O
+independent	O
+effects	O
+of	O
+factors	O
+.	O
+
+The	O
+present	O
+age	O
+-	O
+adjusted	O
+incidence	B-EPI
+of	O
+childhood	O
+CCSK	O
+was	O
+0.205	B-STAT
+per	I-STAT
+million	I-STAT
+,	I-STAT
+which	O
+remained	O
+stable	O
+for	O
+years	O
+and	O
+ranked	O
+third	O
+in	O
+all	O
+pediatric	O
+renal	O
+tumors	O
+.	O
+
+The	O
+incidence	B-EPI
+rate	O
+ratios	O
+for	O
+boy	O
+and	O
+age	O
+under	O
+4	O
+were	O
+3	O
+and	O
+21	O
+,	O
+respectively	O
+.	O
+
+The	O
+current	O
+5	O
+-	O
+year	O
+overall	O
+survival	O
+(	O
+OS	O
+)	O
+rate	O
+for	O
+CCSK	O
+was	O
+87	O
+%	O
+,	O
+which	O
+is	O
+not	O
+evidently	O
+inferior	O
+to	O
+that	O
+for	O
+WT	O
+(	O
+90	O
+%	O
+)	O
+;	O
+however	O
+the	O
+outcome	O
+of	O
+CCSK	O
+was	O
+significantly	O
+poorer	O
+if	O
+both	O
+groups	O
+were	O
+well	O
+-	O
+balanced	O
+(	O
+OS	O
+rate	O
+was	O
+86	B-STAT
+vs.	O
+95	O
+%	O
+)	O
+.	O
+
+Early	O
+year	O
+of	O
+diagnosis	O
+and	O
+distant	O
+metastasis	O
+were	O
+independent	O
+survival	O
+factors	O
+.	O
+
+In	O
+conclusion	O
+,	O
+occurrence	B-EPI
+of	O
+CCSK	O
+remains	O
+stable	O
+over	O
+the	O
+years	O
+,	O
+with	O
+an	O
+age	O
+-	O
+adjusted	O
+incidence	B-EPI
+of	O
+0.205	B-STAT
+per	I-STAT
+million	I-STAT
+.	O
+
+Boy	O
+and	O
+age	O
+under	O
+4	O
+are	O
+risk	O
+factors	O
+for	O
+tumor	O
+development	O
+.	O
+
+CCSK	O
+currently	O
+has	O
+a	O
+favorable	O
+outcome	O
+but	O
+its	O
+nature	O
+may	O
+be	O
+more	O
+aggressive	O
+than	O
+common	O
+kidney	O
+tumor	O
+,	O
+which	O
+in	O
+turn	O
+proves	O
+efficacy	O
+of	O
+modern	O
+treatment	O
+.	O
+
+Background	O
+Pierre	O
+Robin	O
+sequence	O
+(	O
+PRS	O
+)	O
+is	O
+a	O
+rare	O
+congenital	O
+anomaly	O
+.	O
+
+Respiratory	O
+disorders	O
+and	O
+feeding	O
+difficulties	O
+represent	O
+the	O
+main	O
+burden	O
+.	O
+
+Objective	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+epidemiology	O
+of	O
+PRS	O
+using	O
+a	O
+cohort	O
+of	O
+cases	O
+from	O
+EUROCAT	O
+,	O
+the	O
+European	O
+network	O
+of	O
+population	O
+-	O
+based	O
+registries	O
+of	O
+congenital	O
+anomalies	O
+.	O
+
+Methods	O
+We	O
+analysed	O
+cases	O
+of	O
+PRS	O
+born	O
+in	O
+the	O
+period	O
+1998	O
+-	O
+2017	O
+collected	O
+by	O
+29	O
+population	O
+-	O
+based	O
+congenital	O
+anomaly	O
+registries	O
+in	O
+17	O
+different	O
+countries	O
+.	O
+
+We	O
+calculated	O
+prevalence	B-EPI
+estimates	O
+,	O
+prenatal	O
+detection	O
+rate	O
+,	O
+survival	O
+up	O
+to	O
+1	O
+week	O
+,	O
+and	O
+proportions	O
+of	O
+associated	O
+anomalies	O
+.	O
+
+The	O
+effect	O
+of	O
+maternal	O
+age	O
+was	O
+tested	O
+using	O
+a	O
+Poisson	O
+regression	O
+model	O
+.	O
+
+Results	O
+Out	O
+of	O
+11	O
+669	O
+155	O
+surveyed	O
+births	O
+,	O
+a	O
+total	O
+of	O
+1294	O
+cases	O
+of	O
+PRS	O
+were	O
+identified	O
+.	O
+
+The	O
+estimate	O
+of	O
+the	O
+overall	B-EPI
+prevalence	I-EPI
+was	O
+12.0	B-STAT
+per	I-STAT
+100	I-STAT
+000	I-STAT
+births	I-STAT
+(	O
+95	O
+%	O
+CI	O
+9.9	O
+,	O
+14.5	O
+)	O
+.	O
+
+There	O
+was	O
+a	O
+total	O
+of	O
+882	B-STAT
+(	O
+68.2	O
+%	O
+)	O
+isolated	O
+cases	O
+,	O
+and	O
+the	O
+prevalence	B-EPI
+was	O
+7.8	B-STAT
+per	I-STAT
+100	I-STAT
+000	I-STAT
+births	I-STAT
+(	O
+95	O
+%	O
+CI	O
+6.7	O
+,	O
+9.2	O
+)	O
+.	O
+
+A	O
+total	O
+of	O
+250	O
+cases	O
+(	O
+19.3	O
+%	O
+)	O
+were	O
+associated	O
+with	O
+other	O
+structural	O
+congenital	O
+anomalies	O
+,	O
+77	O
+cases	O
+(	O
+6.0	O
+%	O
+)	O
+were	O
+associated	O
+with	O
+chromosomal	O
+anomalies	O
+and	O
+77	B-STAT
+(	O
+6.0	O
+%	O
+)	O
+with	O
+genetic	O
+syndromes	O
+.	O
+
+The	O
+prenatal	O
+detection	O
+rate	O
+in	O
+isolated	O
+cases	O
+was	O
+12.0	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+9.8	O
+,	O
+14.5	O
+)	O
+and	O
+increased	B-STAT
+to	O
+16.0	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+12.7	O
+,	O
+19.7	O
+)	O
+in	O
+the	O
+sub	O
+-	O
+period	O
+2008	O
+-	O
+2017	O
+.	O
+
+The	O
+prevalence	B-EPI
+rate	O
+ratio	O
+of	O
+non	O
+-	O
+chromosomal	O
+cases	O
+with	O
+maternal	O
+age	O
+≥35	O
+was	O
+higher	O
+than	O
+in	O
+cases	O
+with	O
+maternal	O
+age	O
+<	O
+25	O
+for	O
+total	O
+(	O
+PRR	O
+1.26	O
+,	O
+95	O
+%	O
+CI	O
+1.05	O
+,	O
+1.51	O
+)	O
+and	O
+isolated	O
+cases	O
+(	O
+PRR	O
+1.33	O
+,	O
+95	O
+%	O
+CI	O
+1.00	O
+,	O
+1.64	O
+)	O
+.	O
+
+Survival	O
+of	O
+chromosomal	O
+cases	O
+(	O
+94.2	O
+%	O
+)	O
+and	O
+multiple	O
+anomaly	O
+cases	O
+(	O
+95.3	O
+%	O
+)	O
+were	O
+lower	O
+than	O
+survival	O
+of	O
+isolated	O
+cases	O
+(	O
+99.4	O
+%	O
+)	O
+.	O
+
+Conclusions	O
+This	O
+epidemiological	O
+study	O
+using	O
+a	O
+large	O
+series	O
+of	O
+cases	O
+of	O
+PRS	O
+provides	O
+insights	O
+into	O
+the	O
+epidemiological	O
+profile	O
+of	O
+PRS	O
+in	O
+Europe	B-LOC
+.	O
+
+We	O
+observed	O
+an	O
+association	O
+with	O
+higher	O
+maternal	O
+age	O
+,	O
+but	O
+further	O
+investigations	O
+are	O
+needed	O
+to	O
+test	O
+potential	O
+risk	O
+factors	O
+for	O
+PRS	O
+.	O
+
+Constitutional	O
+ring	O
+chromosomes	O
+can	O
+be	O
+found	O
+for	O
+all	O
+human	O
+chromosomes	O
+and	O
+are	O
+very	O
+rare	O
+chromosomal	O
+abnormalities	O
+.	O
+
+A	O
+complete	O
+ring	O
+chromosome	O
+without	O
+loss	O
+of	O
+genetic	O
+material	O
+results	O
+from	O
+fusion	O
+of	O
+subtelomeric	O
+regions	O
+or	O
+telomere	O
+-	O
+telomere	O
+fusion	O
+.	O
+
+In	O
+cases	O
+of	O
+complete	O
+ring	O
+chromosome	O
+,	O
+an	O
+increased	O
+incidence	B-EPI
+of	O
+severe	O
+growth	O
+failure	O
+with	O
+no	O
+or	O
+only	O
+minor	O
+anomalies	O
+has	O
+been	O
+observed	O
+and	O
+attributed	O
+to	O
+ring	O
+syndrome	O
+.	O
+
+Ring	O
+syndrome	O
+is	O
+thought	O
+to	O
+be	O
+caused	O
+by	O
+	O
+dynamic	O
+mosaicism	O
+	O
+due	O
+to	O
+ring	O
+instability	O
+.	O
+
+We	O
+report	O
+a	O
+6	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+with	O
+de	O
+novo	O
+ring	O
+chromosome	O
+4	O
+and	O
+typical	O
+characteristics	O
+of	O
+the	O
+ring	O
+syndrome	O
+,	O
+namely	O
+,	O
+proportionate	O
+severe	O
+growth	O
+failure	O
+,	O
+microcephaly	O
+,	O
+and	O
+minor	O
+anomalies	O
+.	O
+
+Cytogenetic	O
+studies	O
+showed	O
+complete	O
+ring	O
+chromosome	O
+4	O
+with	O
+mitotic	O
+instability	O
+.	O
+
+Microarray	O
+gave	O
+normal	O
+results	O
+,	O
+thus	O
+excluding	O
+the	O
+loss	O
+of	O
+detectable	O
+genetic	O
+material	O
+.	O
+
+The	O
+literature	O
+of	O
+complete	O
+ring	O
+chromosome	O
+4	O
+is	O
+reviewed	O
+.	O
+
+Our	O
+case	O
+report	O
+supports	O
+the	O
+theory	O
+of	O
+ring	O
+syndrome	O
+.	O
+
+No	O
+studies	O
+about	O
+the	O
+effects	O
+and	O
+possible	O
+side	O
+effects	O
+of	O
+growth	O
+hormone	O
+therapy	O
+on	O
+patients	O
+with	O
+ring	O
+chromosomes	O
+have	O
+yet	O
+been	O
+published	O
+.	O
+
+We	O
+suggest	O
+that	O
+cytogenetic	O
+monitoring	O
+of	O
+the	O
+rate	O
+of	O
+secondary	O
+aberrations	O
+in	O
+patients	O
+with	O
+ring	O
+chromosome	O
+undergoing	O
+growth	O
+hormone	O
+therapy	O
+might	O
+be	O
+feasible	O
+.	O
+
+Since	O
+the	O
+diagnosis	O
+would	O
+have	O
+been	O
+missed	O
+by	O
+molecular	O
+karyotyping	O
+,	O
+our	O
+case	O
+report	O
+underlines	O
+the	O
+continuing	O
+role	O
+of	O
+classical	O
+cytogenetics	O
+for	O
+the	O
+evaluation	O
+of	O
+structural	O
+chromosomal	O
+abnormalities	O
+in	O
+patients	O
+with	O
+mental	O
+and/or	O
+physical	O
+anomalies	O
+.	O
+
+Standard	O
+karyotyping	O
+is	O
+still	O
+indispensable	O
+and	O
+should	O
+have	O
+an	O
+ongoing	O
+role	O
+as	O
+first	O
+-	O
+tier	O
+analysis	O
+together	O
+with	O
+molecular	O
+karyotyping	O
+.	O
+
+©	O
+2017	O
+Wiley	O
+Periodicals	O
+,	O
+Inc.	O
+
+Congenital	O
+adrenal	O
+hyperplasia	O
+is	O
+the	O
+most	O
+common	O
+cause	O
+of	O
+ambiguous	O
+genitalia	O
+worldwide	B-LOC
+,	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+1	O
+in	O
+15,000	O
+live	O
+births	O
+.	O
+
+The	O
+most	O
+frequently	O
+-	O
+occurring	O
+subtype	O
+,	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+,	O
+results	O
+in	O
+diminished	O
+production	O
+of	O
+aldosterone	O
+and	O
+cortisol	O
+as	O
+well	O
+as	O
+increased	O
+androgen	O
+secretion	O
+.	O
+
+Previous	O
+studies	O
+have	O
+reported	O
+a	O
+relationship	O
+between	O
+ovarian	O
+cyst	O
+formation	O
+and	O
+adrenal	O
+androgen	O
+excess	O
+;	O
+nevertheless	O
+,	O
+neonatal	O
+large	O
+ovarian	O
+cysts	O
+have	O
+rarely	O
+been	O
+reported	O
+in	O
+newborns	O
+with	O
+congenital	O
+adrenal	O
+hyperplasia	O
+.	O
+
+Herein	O
+,	O
+we	O
+present	O
+the	O
+unique	O
+case	O
+of	O
+a	O
+neonate	O
+with	O
+classical	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+who	O
+underwent	O
+surgery	O
+for	O
+a	O
+huge	O
+unilateral	O
+solitary	O
+ovarian	O
+follicular	O
+cyst	O
+on	O
+the	O
+seventh	O
+postnatal	O
+day	O
+.	O
+
+Possible	O
+mechanisms	O
+by	O
+which	O
+androgen	O
+excess	O
+may	O
+cause	O
+ovarian	O
+cyst	O
+formation	O
+are	O
+also	O
+discussed	O
+.	O
+
+Objectives	O
+In	O
+this	O
+international	O
+study	O
+,	O
+we	O
+aimed	O
+to	O
+investigate	O
+the	O
+opinions	O
+of	O
+physicians	O
+dealing	O
+with	O
+patients	O
+with	O
+functional	O
+seizures	O
+(	O
+FS	O
+)	O
+worldwide	B-LOC
+on	O
+working	O
+restrictions	O
+and	O
+disability	O
+benefits	O
+eligibility	O
+.	O
+
+Methods	O
+International	O
+online	O
+survey	O
+of	O
+neurologists	O
+/	O
+mental	O
+health	O
+professionals	O
+from	O
+Argentina	B-LOC
+,	O
+Venezuela	B-LOC
+,	O
+Colombia	B-LOC
+,	O
+Italy	B-LOC
+,	O
+France	B-LOC
+,	O
+Iran	B-LOC
+,	O
+Iraq	B-LOC
+,	O
+United	B-LOC
+Arab	I-LOC
+Emirates	I-LOC
+(	O
+UAE	O
+)	O
+,	O
+Qatar	B-LOC
+,	O
+Saudi	B-LOC
+Arabia	I-LOC
+,	O
+Georgia	B-LOC
+,	O
+and	O
+Russia	B-LOC
+.	O
+
+Results	O
+Six	O
+hundred	O
+and	O
+twenty	O
+-	O
+seven	O
+physicians	O
+from	O
+12	O
+countries	O
+participated	O
+in	O
+the	O
+study	O
+.	O
+
+Working	O
+as	O
+a	O
+neurologist	O
+was	O
+a	O
+predictor	O
+to	O
+think	O
+that	O
+patients	O
+with	O
+FS	O
+should	O
+not	O
+be	O
+counseled	O
+to	O
+avoid	O
+performing	O
+all	O
+jobs	O
+or	O
+professions	O
+as	O
+long	O
+as	O
+they	O
+have	O
+active	O
+disease	O
+(	O
+OR	O
+:	O
+0.46	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0.30	O
+to	O
+0.68	O
+;	O
+p	O
+<	O
+0.001	O
+)	O
+.	O
+
+Having	O
+managed	O
+more	O
+than	O
+200	O
+patients	O
+was	O
+associated	O
+with	O
+the	O
+opinion	O
+that	O
+patients	O
+should	O
+not	O
+be	O
+counseled	O
+to	O
+avoid	O
+performing	O
+any	O
+type	O
+of	O
+work	O
+(	O
+OR	O
+:	O
+2.17	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.02	O
+to	O
+4.59	O
+;	O
+p	O
+=	O
+0.043	O
+)	O
+.	O
+
+Working	O
+as	O
+a	O
+psychiatrist	O
+/	O
+psychologist	O
+was	O
+associated	O
+with	O
+the	O
+idea	O
+that	O
+patients	O
+with	O
+FS	O
+should	O
+be	O
+qualified	O
+for	O
+disability	O
+benefits	O
+(	O
+OR	O
+:	O
+1.97	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.21	O
+-	O
+3.21	O
+;	O
+p	O
+=	O
+0.006	O
+)	O
+,	O
+and	O
+receive	O
+these	O
+benefits	O
+lifelong	O
+(	O
+OR	O
+:	O
+0.43	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+0.22	O
+-	O
+0.84	O
+;	O
+p	O
+=	O
+0.014	O
+)	O
+.	O
+
+Conclusion	O
+Neurologists	O
+and	O
+mental	O
+health	O
+professionals	O
+have	O
+different	O
+attitudes	O
+and	O
+opinions	O
+toward	O
+working	O
+restrictions	O
+and	O
+disability	O
+benefits	O
+for	O
+patients	O
+with	O
+FS	O
+.	O
+
+Further	O
+studies	O
+should	O
+investigate	O
+the	O
+reasons	O
+for	O
+these	O
+differences	O
+,	O
+and	O
+propose	O
+solutions	O
+to	O
+avoid	O
+discrimination	O
+and	O
+unequal	O
+access	O
+to	O
+employment	O
+and	O
+disability	O
+benefits	O
+.	O
+
+Exstrophy	O
+of	O
+the	O
+bladder	O
+is	O
+a	O
+rare	O
+congenital	O
+anomaly	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+about	O
+1	B-STAT
+per	I-STAT
+50,000	I-STAT
+newborns	I-STAT
+.	O
+
+The	O
+malignant	O
+potential	O
+of	O
+the	O
+exstrophied	O
+bladder	O
+mucosa	O
+is	O
+well	O
+known	O
+;	O
+95	O
+%	O
+are	O
+adenocarcinomas	O
+,	O
+and	O
+3	O
+%	O
+to	O
+5	O
+%	O
+are	O
+squamous	O
+cell	O
+carcinomas	O
+.	O
+
+Most	O
+of	O
+the	O
+malignant	O
+tumors	O
+(	O
+60	O
+%	O
+)	O
+associated	O
+with	O
+an	O
+exstrophy	O
+of	O
+the	O
+bladder	O
+occur	O
+during	O
+the	O
+fourth	O
+and	O
+fifth	O
+decades	O
+of	O
+life	O
+.	O
+
+Of	O
+the	O
+remaining	O
+,	O
+about	O
+20	O
+%	O
+each	O
+occur	O
+after	O
+60	O
+years	O
+and	O
+before	O
+40	O
+years	O
+.	O
+
+Here	O
+we	O
+present	O
+a	O
+case	O
+in	O
+which	O
+squamous	O
+cell	O
+carcinoma	O
+developed	O
+in	O
+an	O
+unrepaired	O
+exstrophy	O
+of	O
+the	O
+bladder	O
+.	O
+
+We	O
+present	O
+the	O
+management	O
+of	O
+the	O
+case	O
+and	O
+a	O
+brief	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+Pallister	O
+-	O
+Hall	O
+syndrome	O
+(	O
+PHS	O
+)	O
+is	O
+an	O
+extremely	O
+rare	O
+syndrome	O
+of	O
+unknown	B-STAT
+prevalence	B-EPI
+with	O
+autosomal	O
+dominant	O
+inheritance	O
+due	O
+to	O
+GLI3	O
+gene	O
+mutations	O
+classically	O
+characterized	O
+by	O
+the	O
+presence	O
+of	O
+a	O
+hypothalamic	O
+hamartoma	O
+and	O
+polydactyly	O
+.	O
+
+Additional	O
+diagnostic	O
+criteria	O
+include	O
+bifid	O
+epiglottis	O
+,	O
+imperforate	O
+anus	O
+,	O
+small	O
+nails	O
+,	O
+hypopituitarism	O
+,	O
+growth	O
+hormone	O
+deficiency	O
+,	O
+and	O
+genital	O
+hypoplasia	O
+.	O
+
+It	O
+is	O
+typically	O
+diagnosed	O
+in	O
+infancy	O
+and	O
+early	O
+childhood	O
+,	O
+presenting	O
+with	O
+seizures	O
+and/or	O
+precocious	O
+puberty	O
+due	O
+to	O
+the	O
+hypothalamic	O
+hamartoma	O
+,	O
+and	O
+with	O
+limb	O
+anomalies	O
+due	O
+to	O
+central	O
+polydactyly	O
+.	O
+
+Our	O
+patient	O
+had	O
+presented	O
+with	O
+polysyndactyly	O
+at	O
+birth	O
+.	O
+
+However	O
+,	O
+as	O
+this	O
+is	O
+not	O
+uncommon	O
+in	O
+infants	O
+and	O
+is	O
+usually	O
+as	O
+part	O
+of	O
+the	O
+sporadic	O
+,	O
+isolated	O
+form	O
+of	O
+polydactyly	O
+,	O
+no	O
+further	O
+work	O
+up	O
+was	O
+done	O
+.	O
+
+He	O
+then	O
+presented	O
+at	O
+age	O
+16	O
+years	O
+with	O
+a	O
+headache	O
+and	O
+subjective	O
+visual	O
+changes	O
+,	O
+with	O
+brain	O
+imaging	O
+revealing	O
+a	O
+hypothalamic	O
+hamartoma	O
+.	O
+
+He	O
+did	O
+not	O
+have	O
+a	O
+history	O
+of	O
+seizures	O
+or	O
+central	O
+precocious	O
+puberty	O
+.	O
+
+Genotyping	O
+revealed	O
+a	O
+pathogenic	O
+variant	O
+affecting	O
+the	O
+GLI3	O
+gene	O
+.	O
+
+We	O
+encourage	O
+all	O
+clinicians	O
+to	O
+consider	O
+PHS	O
+or	O
+an	O
+associated	O
+syndrome	O
+with	O
+a	O
+clinical	O
+finding	O
+of	O
+polydactyly	O
+.	O
+
+Further	O
+,	O
+as	O
+the	O
+natural	O
+history	O
+continues	O
+to	O
+reveal	O
+itself	O
+,	O
+this	O
+patient	O
+'s	O
+presentation	O
+provides	O
+important	O
+new	O
+data	O
+to	O
+the	O
+broad	O
+phenotypic	O
+spectrum	O
+of	O
+PHS	O
+.	O
+
+The	O
+genetic	O
+basis	O
+of	O
+Japanese	O
+autosomal	O
+recessive	O
+retinitis	O
+pigmentosa	O
+(	O
+ARRP	O
+)	O
+remains	O
+largely	O
+unknown	O
+.	O
+
+Herein	O
+,	O
+we	O
+applied	O
+a	O
+2	O
+-	O
+step	O
+genome	O
+-	O
+wide	O
+association	O
+study	O
+(	O
+GWAS	O
+)	O
+in	O
+640	O
+Japanese	O
+patients	O
+.	O
+
+Meta	O
+-	O
+GWAS	O
+identified	O
+three	O
+independent	O
+peaks	O
+at	O
+P	O
+<	O
+5.0	O
+×	O
+10	O
+-8	O
+,	O
+all	O
+within	O
+the	O
+major	O
+ARRP	O
+gene	O
+EYS	O
+.	O
+
+Two	O
+of	O
+the	O
+three	O
+were	O
+each	O
+in	O
+linkage	O
+disequilibrium	O
+with	O
+a	O
+different	O
+low	O
+frequency	O
+variant	O
+(	O
+allele	O
+frequency	O
+<	O
+0.05	O
+)	O
+;	O
+a	O
+known	O
+founder	O
+Mendelian	O
+mutation	O
+(	O
+c.4957dupA	O
+,	O
+p.	O
+S1653Kfs*2	O
+)	O
+and	O
+a	O
+non	O
+-	O
+synonymous	O
+variant	O
+(	O
+c.2528	O
+G	O
+>	O
+A	O
+,	O
+p.	O
+G843E	O
+)	O
+of	O
+unknown	O
+significance	O
+.	O
+
+mRNA	O
+harboring	O
+c.2528	O
+G	O
+>	O
+A	O
+failed	O
+to	O
+restore	O
+rhodopsin	O
+mislocalization	O
+induced	O
+by	O
+morpholino	O
+-	O
+mediated	O
+knockdown	O
+of	O
+eys	O
+in	O
+zebrafish	O
+,	O
+consistent	O
+with	O
+the	O
+variant	O
+being	O
+pathogenic	O
+.	O
+
+c.2528	O
+G	O
+>	O
+A	O
+solved	O
+an	O
+additional	O
+7.0	O
+%	O
+of	O
+Japanese	O
+ARRP	O
+cases	O
+.	O
+
+The	O
+third	O
+peak	O
+was	O
+in	O
+linkage	O
+disequilibrium	O
+with	O
+a	O
+common	O
+non	O
+-	O
+synonymous	O
+variant	O
+(	O
+c.7666	O
+A	O
+>	O
+T	O
+,	O
+p.	O
+S2556C	O
+)	O
+,	O
+possibly	O
+representing	O
+an	O
+unreported	O
+disease	O
+-	O
+susceptibility	O
+signal	O
+.	O
+
+GWAS	O
+successfully	O
+unraveled	O
+genetic	O
+causes	O
+of	O
+a	O
+rare	O
+monogenic	O
+disorder	O
+and	O
+identified	O
+a	O
+high	O
+frequency	O
+variant	O
+potentially	O
+linked	O
+to	O
+development	O
+of	O
+local	O
+genome	O
+therapeutics	O
+.	O
+
+West	B-LOC
+Nile	I-LOC
+virus	O
+(	O
+WNV	O
+)	O
+is	O
+a	O
+zoonotic	O
+mosquito	O
+-	O
+borne	O
+flavivirus	O
+that	O
+is	O
+harbored	O
+and	O
+amplified	O
+by	O
+wild	O
+birds	O
+via	O
+the	O
+enzootic	O
+transmission	O
+cycle	O
+.	O
+
+Wide	O
+range	O
+of	O
+hosts	O
+are	O
+found	O
+to	O
+be	O
+susceptible	O
+to	O
+WNV	O
+infection	O
+including	O
+mammals	O
+,	O
+amphibians	O
+and	O
+reptiles	O
+across	O
+the	O
+world	O
+.	O
+
+Several	O
+studies	O
+have	O
+demonstrated	O
+that	O
+WNV	O
+was	O
+present	O
+in	O
+the	O
+Malaysian	O
+Orang	O
+Asli	O
+and	O
+captive	O
+birds	O
+.	O
+
+However	O
+,	O
+no	O
+data	O
+are	O
+available	O
+on	O
+the	O
+WNV	O
+prevalence	B-EPI
+in	O
+wild	O
+birds	O
+found	O
+in	O
+Malaysia	B-LOC
+.	O
+
+Therefore	O
+this	O
+study	O
+was	O
+conducted	O
+to	O
+determine	O
+the	O
+serological	O
+and	O
+molecular	O
+prevalence	B-EPI
+of	O
+WNV	O
+in	O
+wild	O
+birds	O
+in	O
+selected	O
+areas	O
+in	O
+the	B-LOC
+West	I-LOC
+Coast	I-LOC
+of	O
+Peninsular	O
+Malaysia	B-LOC
+.	O
+
+Two	O
+types	O
+of	O
+wild	O
+birds	O
+were	O
+screened	O
+,	O
+namely	O
+migratory	O
+and	O
+resident	O
+birds	O
+in	O
+order	O
+to	O
+explore	O
+any	O
+possibility	O
+of	O
+WNV	O
+transmission	O
+from	O
+the	O
+migratory	O
+birds	O
+to	O
+the	O
+resident	O
+birds	O
+.	O
+
+Thus	O
+,	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+was	O
+conducted	O
+at	O
+the	O
+migratory	O
+birds	O
+sanctuary	O
+located	O
+in	O
+Kuala	B-LOC
+Gula	I-LOC
+,	O
+Perak	B-LOC
+and	O
+Kapar	B-LOC
+,	O
+Selangor	B-LOC
+by	O
+catching	O
+163	O
+migratory	O
+birds	O
+,	O
+and	O
+97	O
+resident	O
+birds	O
+from	O
+Kuala	B-LOC
+Gula	I-LOC
+and	O
+Parit	O
+Buntar	O
+,	O
+Perak	B-LOC
+at	O
+different	O
+time	O
+between	O
+2016	O
+and	O
+2017	O
+(	O
+Total	O
+,	O
+n	O
+=	O
+260	O
+)	O
+.	O
+
+Blood	O
+and	O
+oropharyngeal	O
+swabs	O
+were	O
+collected	O
+for	O
+serological	O
+and	O
+molecular	O
+analysis	O
+,	O
+respectively	O
+.	O
+
+Serum	O
+were	O
+screened	O
+for	O
+WNV	O
+antibodies	O
+using	O
+a	O
+commercial	O
+competitive	O
+ELISA	O
+(	O
+c	O
+-	O
+ELISA	O
+)	O
+(	O
+ID	O
+Screen	O
+®	O
+West	O
+Nile	O
+Competition	O
+Multi	O
+-	O
+species	O
+ELISA	O
+,	O
+ID	O
+VET	O
+,	O
+Montpellier	B-LOC
+,	O
+France	B-LOC
+)	O
+and	O
+cross	O
+-	O
+reactivity	O
+towards	O
+Japanese	O
+Encephalitis	O
+virus	O
+(	O
+JEV	O
+)	O
+was	O
+also	O
+carried	O
+out	O
+using	O
+the	O
+JEV	O
+-	O
+double	O
+antigen	O
+sandwich	O
+(	O
+DAS	O
+)	O
+ELISA	O
+.	O
+
+Oropharyngeal	O
+swabs	O
+were	O
+subjected	O
+to	O
+one	O
+-	O
+step	O
+RT	O
+-	O
+PCR	O
+to	O
+detect	O
+WNV	O
+RNA	O
+,	O
+in	O
+which	O
+positive	O
+reactions	O
+were	O
+subsequently	O
+sequenced	O
+.	O
+
+WNV	O
+seropositive	O
+rate	O
+of	O
+18.71	O
+%	O
+(	O
+29/155	O
+)	O
+at	O
+95	O
+%	O
+CI	O
+(	O
+0.131	O
+to	O
+0.260	O
+)	O
+and	O
+molecular	O
+prevalence	B-EPI
+of	O
+15.2	O
+%	O
+(	O
+16/105	O
+)	O
+at	O
+95	O
+%	O
+CI	O
+(	O
+0.092	O
+to	O
+0.239	O
+)	O
+were	O
+demonstrated	O
+in	O
+migratory	O
+and	O
+resident	O
+wild	O
+birds	O
+found	O
+in	O
+West	B-LOC
+Coast	I-LOC
+Malaysia	B-LOC
+.	O
+
+Phylogenetic	O
+analyses	O
+of	O
+the	O
+16	O
+WNV	O
+isolates	O
+found	O
+in	O
+this	O
+study	O
+revealed	O
+that	O
+the	O
+local	O
+strains	O
+have	O
+99	O
+%	O
+similarity	O
+to	O
+the	O
+strains	O
+from	O
+South	B-LOC
+Africa	I-LOC
+and	O
+were	O
+clustered	O
+under	O
+lineage	O
+2	O
+.	O
+
+Evidence	O
+of	O
+WNV	O
+infection	O
+in	O
+resident	O
+and	O
+migratory	O
+birds	O
+were	O
+demonstrated	O
+in	O
+this	O
+study	O
+.	O
+
+As	O
+a	O
+summary	O
+,	O
+intervention	O
+between	O
+migratory	O
+birds	O
+,	O
+resident	O
+birds	O
+and	O
+mosquitoes	O
+might	O
+cause	O
+the	O
+introduction	O
+and	O
+maintenance	O
+of	O
+WNV	O
+in	O
+Malaysia	B-LOC
+,	O
+however	O
+the	O
+assumption	O
+could	O
+be	O
+further	O
+proven	O
+by	O
+studying	O
+the	O
+infection	O
+dynamics	O
+in	O
+the	O
+mosquitoes	O
+present	O
+in	O
+the	O
+studied	O
+areas	O
+.	O
+
+Craniosynostosis	O
+is	O
+a	O
+heterogeneous	O
+condition	O
+caused	O
+by	O
+the	O
+premature	O
+fusion	O
+of	O
+cranial	O
+sutures	O
+,	O
+occurring	O
+mostly	O
+as	O
+an	O
+isolated	O
+anomaly	O
+.	O
+
+Pathogenesis	O
+of	O
+non	O
+-	O
+syndromic	O
+forms	O
+of	O
+craniosynostosis	O
+is	O
+largely	O
+unknown	O
+.	O
+
+In	O
+about	O
+15	O
+-	O
+30	O
+%	O
+of	O
+cases	O
+craniosynostosis	O
+occurs	B-EPI
+in	O
+association	O
+with	O
+other	O
+physical	O
+anomalies	O
+and	O
+it	O
+is	O
+referred	O
+to	O
+as	O
+syndromic	O
+craniosynostosis	O
+.	O
+
+Syndromic	O
+forms	O
+of	O
+craniosynostosis	O
+arise	O
+from	O
+mutations	O
+in	O
+genes	O
+belonging	O
+to	O
+the	O
+Fibroblast	O
+Growth	O
+Factor	O
+Receptor	O
+(	O
+FGFR	O
+)	O
+family	O
+and	O
+the	O
+interconnected	O
+molecular	O
+pathways	O
+in	O
+most	O
+cases	O
+.	O
+
+However	O
+it	O
+can	O
+occur	O
+in	O
+association	O
+with	O
+other	O
+gene	O
+variants	O
+and	O
+with	O
+a	O
+variety	O
+of	O
+chromosome	O
+abnormalities	O
+as	O
+well	O
+,	O
+usually	O
+in	O
+association	O
+with	O
+intellectual	O
+disability	O
+(	O
+ID	O
+)	O
+and	O
+additional	O
+physical	O
+anomalies	O
+.	O
+
+Evaluating	O
+the	O
+molecular	O
+properties	O
+of	O
+the	O
+genes	O
+undergoing	O
+intragenic	O
+mutations	O
+or	O
+copy	O
+number	O
+variations	O
+(	O
+CNVs	O
+)	O
+along	O
+with	O
+prevalence	B-EPI
+of	O
+craniosynostosis	O
+in	O
+different	O
+conditions	O
+and	O
+animal	O
+models	O
+if	O
+available	O
+,	O
+we	O
+made	O
+an	O
+attempt	O
+to	O
+define	O
+two	O
+distinct	O
+groups	O
+of	O
+unusual	O
+syndromic	O
+craniosynostosis	O
+,	O
+which	O
+can	O
+reflect	O
+direct	O
+effects	O
+of	O
+emerging	O
+new	O
+candidate	O
+genes	O
+with	O
+roles	O
+in	O
+suture	O
+homeostasis	O
+or	O
+a	O
+non	O
+-	O
+specific	O
+phenotypic	O
+manifestation	O
+of	O
+pleiotropic	O
+genes	O
+,	O
+respectively	O
+.	O
+
+RASopathies	O
+and	O
+9p23p22.3	O
+deletions	O
+are	O
+reviewed	O
+as	O
+examples	O
+of	O
+conditions	O
+in	O
+the	O
+first	O
+group	O
+.	O
+
+In	O
+particular	O
+,	O
+we	O
+found	O
+that	O
+craniosynostosis	O
+is	O
+a	O
+relatively	O
+common	O
+component	O
+manifestation	O
+of	O
+cardio	O
+-	O
+facio	O
+-	O
+cutaneous	O
+(	O
+CFC	O
+)	O
+syndrome	O
+.	O
+
+Chromatinopathies	O
+and	O
+neurocristopathies	O
+are	O
+presented	O
+as	O
+examples	O
+of	O
+conditions	O
+in	O
+the	O
+second	O
+group	O
+.	O
+
+We	O
+observed	O
+that	O
+craniosynostosis	O
+is	O
+uncommon	O
+on	O
+average	O
+in	O
+these	O
+conditions	O
+.	O
+
+It	O
+was	O
+randomly	O
+associated	O
+with	O
+Kabuki	O
+,	O
+Koolen	O
+-	O
+de	O
+Vries	O
+/	O
+KANSL1	O
+haploinsufficiency	O
+and	O
+Mowat	O
+-	O
+Wilson	O
+syndromes	O
+and	O
+in	O
+KAT6B	B-LOC
+-	O
+related	O
+disorders	O
+.	O
+
+As	O
+an	O
+exception	O
+,	O
+trigonocephaly	O
+in	O
+Bohring	O
+-	O
+Opitz	O
+syndrome	O
+reflects	O
+specific	O
+molecular	O
+properties	O
+of	O
+the	O
+chromatin	O
+modifier	O
+ASXL1	O
+gene	O
+.	O
+
+Surveillance	O
+for	O
+craniosynostosis	O
+in	O
+syndromic	O
+forms	O
+of	O
+intellectual	O
+disability	O
+,	O
+as	O
+well	O
+as	O
+ascertainment	O
+of	O
+genomic	O
+CNVs	O
+by	O
+array	O
+-	O
+CGH	O
+in	O
+apparently	O
+non	O
+-	O
+syndromic	O
+craniosynostosis	O
+is	O
+recommended	O
+,	O
+to	O
+allow	O
+for	O
+improvement	O
+of	O
+both	O
+the	O
+clinical	O
+outcome	O
+of	O
+patients	O
+and	O
+the	O
+accurate	O
+individual	O
+diagnosis	O
+.	O
+
+Background	O
+:	O
+Osteogenesis	O
+imperfecta	O
+(	O
+OI	O
+)	O
+is	O
+a	O
+rare	O
+disease	O
+characterized	O
+by	O
+increased	O
+bone	O
+fragility	O
+and	O
+susceptibility	O
+for	O
+fractures	O
+.	O
+
+Only	O
+few	O
+studies	O
+have	O
+compared	O
+the	O
+management	O
+for	O
+femoral	O
+fractures	O
+in	O
+children	O
+with	O
+OI	O
+.	O
+
+Nevertheless	O
+,	O
+no	O
+cohort	O
+studies	O
+have	O
+described	O
+the	O
+treatment	O
+for	O
+femoral	O
+fractures	O
+in	O
+adults	O
+with	O
+OI	O
+in	O
+Taiwan	B-LOC
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+investigate	O
+and	O
+compare	O
+the	O
+incidence	B-EPI
+of	O
+union	O
+and	O
+non	O
+-	O
+union	O
+femoral	O
+fractures	O
+and	O
+the	O
+best	O
+treatment	O
+options	O
+to	O
+avoid	O
+non	O
+-	O
+union	O
+fractures	O
+.	O
+
+Methods	O
+:	O
+We	O
+enrolled	O
+72	O
+patients	O
+with	O
+OI	O
+who	O
+were	O
+older	O
+than	O
+18	O
+years	O
+at	O
+MacKay	O
+Memorial	O
+Hospital	O
+between	O
+January	O
+2010	O
+and	O
+December	O
+2018	O
+.	O
+
+Femoral	O
+fracture	O
+incidence	B-EPI
+,	O
+non	O
+-	O
+union	O
+rate	O
+,	O
+and	O
+treatment	O
+modality	O
+were	O
+analyzed	O
+.	O
+
+Results	O
+:	O
+Of	O
+72	O
+patients	O
+with	O
+OI	O
+,	O
+11	O
+patients	O
+had	O
+femoral	O
+fractures	O
+and	O
+4	O
+patients	O
+of	O
+them	O
+had	O
+>	O
+1	O
+femoral	O
+fracture	O
+.	O
+
+The	O
+incidence	B-EPI
+for	O
+all	O
+types	O
+of	O
+femoral	O
+fractures	O
+was	O
+651	B-STAT
+fractures	I-STAT
+per	I-STAT
+100,000	I-STAT
+person	I-STAT
+-	O
+years	O
+annually	O
+.	O
+
+In	O
+15	O
+total	O
+fractures	O
+,	O
+4	O
+fractures	O
+resulted	O
+in	O
+non	O
+-	O
+union	O
+,	O
+and	O
+patients	O
+with	O
+type	O
+4	O
+OI	O
+mostly	O
+had	O
+shaft	O
+fractures	O
+.	O
+
+The	O
+best	O
+outcomes	O
+for	O
+non	O
+-	O
+union	O
+shaft	O
+fracture	O
+is	O
+achieved	O
+by	O
+surgical	O
+treatment	O
+.	O
+
+Conclusion	O
+:	O
+Adults	O
+with	O
+OI	O
+tended	O
+to	O
+develop	O
+femoral	O
+fractures	O
+and	O
+non	O
+-	O
+unions	O
+.	O
+
+Adults	O
+with	O
+type	O
+4	O
+OI	O
+were	O
+particularly	O
+at	O
+high	O
+risk	O
+for	O
+non	O
+-	O
+unions	O
+in	O
+shaft	O
+fractures	O
+with	O
+conservative	O
+treatment	O
+.	O
+
+Background	O
+A	O
+systematic	O
+review	O
+and	O
+meta	O
+-	O
+analysis	O
+were	O
+made	O
+of	O
+the	O
+incidence	B-EPI
+of	O
+recurrences	O
+in	O
+patients	O
+with	O
+proliferative	O
+verrucous	O
+leukoplakia	O
+(	O
+PVL	O
+)	O
+subjected	O
+to	O
+different	O
+types	O
+of	O
+treatment	O
+.	O
+
+Methods	O
+The	O
+study	O
+was	O
+carried	O
+out	O
+following	O
+the	O
+Preferred	O
+Reporting	O
+Items	O
+for	O
+Systematic	O
+Reviews	O
+and	O
+Meta	O
+-	O
+Analyses	O
+(	O
+PRISMA	O
+)	O
+statement	O
+guidelines	O
+.	O
+
+A	O
+literature	O
+search	O
+was	O
+made	O
+in	O
+the	O
+Medline	O
+(	O
+PubMed	O
+)	O
+,	O
+EMBASE	O
+,	O
+and	O
+Web	O
+of	O
+Science	O
+databases	O
+,	O
+together	O
+with	O
+a	O
+manual	O
+search	O
+,	O
+covering	O
+the	O
+period	O
+from	O
+1985	O
+to	O
+January	O
+2020	O
+,	O
+with	O
+no	O
+language	O
+restrictions	O
+.	O
+
+Studies	O
+were	O
+included	O
+if	O
+they	O
+described	O
+treatments	O
+applied	O
+to	O
+at	O
+least	O
+10	O
+patients	O
+with	O
+the	O
+corresponding	O
+outcomes	O
+.	O
+
+Methodological	O
+quality	O
+was	O
+evaluated	O
+using	O
+Jadad	B-LOC
+scale	O
+and	O
+Newcastle	B-LOC
+-	O
+Ottawa	B-LOC
+tool	O
+.	O
+
+Global	O
+incidence	B-EPI
+was	O
+calculated	O
+by	O
+random	O
+effects	O
+meta	O
+-	O
+analysis	O
+using	O
+the	O
+Comprehensive	O
+Meta	O
+-	O
+analysis	O
+version	O
+3.0	O
+software	O
+.	O
+
+Publication	O
+bias	O
+was	O
+assessed	O
+using	O
+funnel	O
+plots	O
+and	O
+the	O
+Duval	O
+and	O
+Tweedie	O
+trim	O
+and	O
+fill	O
+method	O
+.	O
+
+Results	O
+Of	O
+the	O
+922	O
+identified	O
+articles	O
+,	O
+12	O
+were	O
+found	O
+to	O
+meet	O
+the	O
+inclusion	O
+criteria	O
+.	O
+
+Most	O
+of	O
+them	O
+presented	O
+moderate	O
+or	O
+low	O
+risk	O
+of	O
+bias	O
+.	O
+
+A	O
+total	O
+of	O
+397	O
+patients	O
+were	O
+analyzed	O
+.	O
+
+The	O
+mean	O
+age	O
+was	O
+62.34	O
+years	O
+and	O
+248	O
+were	O
+women	O
+(	O
+62.5	O
+%	O
+)	O
+.	O
+
+The	O
+mean	O
+follow	O
+-	O
+up	O
+was	O
+79.3	O
+months	O
+.	O
+
+The	O
+most	O
+frequent	O
+treatment	O
+was	O
+surgical	O
+removal	O
+with	O
+a	O
+cold	O
+scalpel	O
+or	O
+laser	O
+(	O
+339	O
+patients	O
+)	O
+.	O
+
+A	O
+total	O
+of	O
+232	O
+subjects	O
+presented	O
+lesion	O
+recurrence	O
+.	O
+
+The	O
+combination	O
+of	O
+proportions	O
+global	O
+effect	O
+meta	O
+-	O
+analysis	O
+yielded	O
+a	O
+recurrence	O
+rate	O
+of	O
+67.2	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+48.3	O
+-	O
+81.8	O
+)	O
+,	O
+with	O
+the	O
+absence	O
+of	O
+publication	O
+bias	O
+.	O
+
+Conclusions	O
+There	O
+is	O
+not	O
+enough	O
+scientific	O
+evidence	O
+to	O
+conclude	O
+that	O
+any	O
+treatment	O
+strategy	O
+is	O
+able	O
+to	O
+reduce	O
+the	O
+recurrence	O
+in	O
+PVL	O
+.	O
+
+Coronavirus	O
+2019	O
+disease	O
+(	O
+COVID-19	O
+)	O
+is	O
+associated	O
+with	O
+coagulation	O
+dysfunction	O
+that	O
+predisposes	O
+patients	O
+to	O
+an	O
+increased	O
+risk	O
+for	O
+both	O
+arterial	O
+(	O
+ATE	O
+)	O
+and	O
+venous	O
+thromboembolism	O
+(	O
+VTE	O
+)	O
+and	O
+consequent	O
+poor	O
+prognosis	O
+;	O
+in	O
+particular	O
+,	O
+the	O
+incidence	B-EPI
+of	O
+ATE	O
+and	O
+VTE	O
+in	O
+critically	O
+ill	O
+COVID-19	O
+patients	O
+can	O
+reach	O
+5	O
+%	O
+and	O
+31	O
+%	O
+,	O
+respectively	O
+.	O
+
+The	O
+mechanism	O
+of	O
+thrombosis	O
+in	O
+COVID-19	O
+patients	O
+is	O
+complex	O
+and	O
+still	O
+not	O
+completely	O
+clear	O
+.	O
+
+Recent	O
+literature	O
+suggests	O
+a	O
+link	O
+between	O
+the	O
+presence	O
+of	O
+antiphospholipid	O
+antibodies	O
+(	O
+aPLs	O
+)	O
+and	O
+thromboembolism	O
+in	O
+COVID-19	O
+patients	O
+.	O
+
+However	O
+,	O
+it	O
+remains	O
+uncertain	O
+whether	O
+aPLs	O
+are	O
+an	O
+epiphenomenon	O
+or	O
+are	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+the	O
+disease	O
+.	O
+
+Background	O
+:	O
+Twenty	O
+-	O
+one	O
+-	O
+hydroxylase	O
+-	O
+deficient	O
+non	O
+-	O
+classic	O
+adrenal	O
+hyperplasia	O
+(	O
+NC	O
+-	O
+CAH	O
+)	O
+is	O
+a	O
+very	O
+common	O
+autosomal	O
+recessive	O
+syndrome	O
+with	O
+prevalence	B-EPI
+between	O
+1:1,000	B-STAT
+and	O
+1:2,000	B-STAT
+individuals	I-STAT
+and	I-STAT
+the	O
+frequency	O
+varies	O
+according	O
+to	O
+ethnicity	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+polycystic	O
+ovary	O
+syndrome	O
+has	O
+a	O
+familial	O
+basis	O
+and	O
+it	O
+is	O
+inherited	O
+under	O
+a	O
+complex	O
+hereditary	O
+trait	O
+.	O
+
+This	O
+syndrome	O
+affects	O
+6	B-STAT
+to	O
+10	O
+%	O
+of	O
+women	O
+in	O
+reproductive	O
+age	O
+and	O
+it	O
+is	O
+the	O
+most	O
+common	O
+endocrine	O
+disorder	O
+in	O
+young	O
+women	O
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+investigate	O
+,	O
+through	O
+a	O
+systematic	O
+review	O
+,	O
+the	O
+distinct	O
+characteristics	O
+and	O
+common	O
+findings	O
+of	O
+these	O
+syndromes	O
+.	O
+
+Methods	O
+:	O
+The	O
+search	O
+period	O
+covered	O
+January	O
+1970	O
+to	O
+November	O
+2018	O
+,	O
+using	O
+the	O
+scientific	O
+databases	O
+PubMed	O
+.	O
+
+Inclusion	O
+criteria	O
+were	O
+adult	O
+women	O
+patients	O
+with	O
+PCOS	O
+or	O
+NC	O
+-	O
+CAH	O
+.	O
+
+Search	O
+terms	O
+were	O
+	O
+polycystic	O
+ovary	O
+syndrome	O
+,	O
+	O
+	O
+PCOS	O
+,	O
+	O
+	O
+non	O
+-	O
+classical	O
+adrenal	O
+hyperplasia	O
+,	O
+	O
+	O
+NC	O
+-	O
+CAH	O
+,	O
+	O
+	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+.	O
+	O
+
+From	O
+an	O
+initial	O
+16,255	O
+titles	O
+,	O
+the	O
+evaluations	O
+led	O
+to	O
+the	O
+final	O
+inclusion	O
+of	O
+97	O
+papers	O
+.	O
+
+Results	O
+:	O
+The	O
+clinical	O
+features	O
+of	O
+NC	B-LOC
+-	O
+CAH	O
+are	O
+hirsutism	O
+and	O
+ovulatory	O
+and	O
+menstrual	O
+dysfunction	O
+therefore	O
+;	O
+differentiation	O
+between	O
+these	O
+two	O
+syndromes	O
+is	O
+difficult	O
+based	O
+on	O
+clinical	O
+grounds	O
+only	O
+.	O
+
+Additionally	O
+,	O
+NC	B-LOC
+-	O
+CAH	O
+and	O
+PCOS	O
+are	O
+both	O
+associated	O
+with	O
+obesity	O
+,	O
+insulin	O
+resistance	O
+,	O
+and	O
+dyslipidaemia	O
+.	O
+
+Reproductive	O
+abnormalities	O
+are	O
+also	O
+common	O
+between	O
+these	O
+hyperandrogenemic	O
+disorders	O
+since	O
+in	O
+patients	O
+with	O
+NC	B-LOC
+-	O
+CAH	O
+polycystic	O
+ovarian	O
+morphology	O
+and	O
+subfertility	O
+are	O
+present	O
+as	O
+they	O
+are	O
+in	O
+women	O
+with	O
+PCOS	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+PCOS	O
+,	O
+is	O
+confirmed	O
+once	O
+other	O
+disorders	O
+that	O
+mimic	O
+PCOS	O
+have	O
+been	O
+excluded	O
+e.g.	O
+,	O
+conditions	O
+that	O
+are	O
+related	O
+to	O
+oligoovulation	O
+or	O
+anovulation	O
+and/or	O
+hyperandrogenism	O
+,	O
+such	O
+as	O
+hyperprolactinaemia	O
+,	O
+thyroid	O
+disorders	O
+,	O
+non	O
+-	O
+classic	O
+congenital	O
+adrenal	O
+hyperplasia	O
+,	O
+and	O
+androgen	O
+-	O
+producing	O
+neoplasms	O
+.	O
+
+Conclusions	O
+:	O
+The	O
+screening	O
+tool	O
+to	O
+distinguish	O
+non	O
+-	O
+classic	O
+adrenal	O
+hyperplasia	O
+from	O
+PCOS	O
+is	O
+the	O
+measurement	O
+of	O
+17	O
+-	O
+hydroxyprogesterone	O
+levels	O
+.	O
+
+The	O
+basal	O
+levels	O
+of	O
+17	O
+-	O
+hydroxyprogesterone	O
+may	O
+overlap	O
+,	O
+but	O
+ACTH	O
+stimulation	O
+testing	O
+can	O
+distinguish	O
+the	O
+two	O
+entities	O
+.	O
+
+In	O
+this	O
+review	O
+these	O
+two	O
+common	O
+endocrine	O
+disorders	O
+are	O
+discussed	O
+in	O
+an	O
+effort	O
+to	O
+unveil	O
+their	O
+commonalities	O
+and	O
+to	O
+illuminate	O
+their	O
+shadowed	O
+distinctive	O
+characteristics	O
+.	O
+
+AIM	O
+:	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+develop	O
+an	O
+algorithm	O
+to	O
+prompt	O
+early	O
+clinical	O
+suspicion	O
+of	O
+mucopolysaccharidosis	O
+type	O
+I	O
+(	O
+MPS	O
+I	O
+)	O
+.	O
+
+METHODS	O
+:	O
+An	O
+international	O
+working	O
+group	O
+was	O
+established	O
+in	O
+2016	O
+that	O
+comprised	O
+11	O
+experts	O
+in	O
+paediatrics	O
+,	O
+rare	O
+diseases	O
+and	O
+inherited	O
+metabolic	O
+diseases	O
+.	O
+
+They	O
+reviewed	O
+real	O
+-	O
+world	O
+clinical	O
+cases	O
+,	O
+selected	O
+key	O
+signs	O
+or	O
+symptoms	O
+based	O
+on	O
+their	O
+prevalence	B-EPI
+and	O
+specificity	O
+and	O
+reached	O
+consensus	O
+about	O
+the	O
+algorithm	O
+.	O
+
+The	O
+algorithm	O
+was	O
+retrospectively	O
+tested	O
+.	O
+
+RESULTS	O
+:	O
+An	O
+algorithm	O
+was	O
+developed	O
+.	O
+
+In	O
+patients	O
+under	O
+two	O
+years	O
+of	O
+age	O
+,	O
+kyphosis	O
+or	O
+gibbus	O
+deformity	O
+were	O
+the	O
+key	O
+symptoms	O
+that	O
+raised	O
+clinical	O
+suspicion	O
+of	O
+MPS	O
+I	O
+and	O
+in	O
+those	O
+over	O
+two	O
+years	O
+they	O
+were	O
+kyphosis	O
+or	O
+gibbus	O
+deformity	O
+,	O
+or	O
+joint	O
+stiffness	O
+or	O
+contractures	O
+without	O
+inflammation	O
+.	O
+
+The	O
+algorithm	O
+was	O
+tested	O
+on	O
+35	O
+cases	O
+,	O
+comprising	O
+16	O
+Hurler	O
+,	O
+10	O
+Hurler	O
+-	O
+Scheie	O
+,	O
+and	O
+nine	O
+Scheie	O
+patients	O
+.	O
+
+Of	O
+these	O
+35	O
+cases	O
+,	O
+32	B-STAT
+(	O
+91	O
+%	O
+)	O
+-	O
+16	O
+Hurler	O
+,	O
+nine	O
+Hurler	O
+-	O
+Scheie	O
+and	O
+seven	O
+Scheie	O
+patients	O
+-	O
+would	O
+have	O
+been	O
+referred	O
+earlier	O
+if	O
+the	O
+algorithm	O
+had	O
+been	O
+used	O
+.	O
+
+CONCLUSION	O
+:	O
+The	O
+expert	O
+panel	O
+developed	O
+and	O
+tested	O
+an	O
+algorithm	O
+that	O
+helps	O
+raise	O
+clinical	O
+suspicion	O
+of	O
+MPS	O
+I	O
+and	O
+would	O
+lead	O
+to	O
+a	O
+more	O
+prompt	O
+final	O
+diagnosis	O
+and	O
+allow	O
+earlier	O
+treatment	O
+.	O
+
+Urea	O
+cycle	O
+disorders	O
+(	O
+UCDs	O
+)	O
+are	O
+rare	O
+inherited	O
+metabolic	O
+conditions	O
+that	O
+impair	O
+the	O
+effectiveness	O
+of	O
+the	O
+urea	O
+cycle	O
+responsible	O
+for	O
+removing	O
+excess	O
+ammonia	O
+from	O
+the	O
+body	O
+.	O
+
+The	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+UCDs	O
+is	O
+1:35	B-STAT
+000	I-STAT
+births	I-STAT
+,	I-STAT
+or	O
+approximately	O
+113	O
+new	O
+patients	O
+with	O
+UCD	O
+per	O
+year	O
+.	O
+
+This	O
+review	O
+summarizes	O
+neuropsychological	O
+outcomes	O
+among	O
+patients	O
+with	O
+the	O
+eight	O
+UCDs	O
+in	O
+reports	O
+published	O
+since	O
+1980	O
+.	O
+
+Rates	O
+of	O
+intellectual	O
+disabilities	O
+published	O
+before	O
+(	O
+and	O
+including	O
+)	O
+2000	O
+and	O
+after	O
+2000	O
+were	O
+pooled	O
+and	O
+compared	O
+for	O
+each	O
+UCD	O
+.	O
+
+Since	O
+diagnoses	O
+for	O
+UCDs	O
+tended	O
+to	O
+occur	O
+earlier	O
+and	O
+better	O
+treatments	O
+became	O
+more	O
+readily	O
+available	O
+after	O
+the	O
+turn	O
+of	O
+the	O
+century	O
+,	O
+this	O
+assessment	O
+will	O
+characterize	O
+the	O
+extent	O
+that	O
+current	O
+management	O
+strategies	O
+have	O
+improved	O
+neuropsychological	O
+outcomes	O
+.	O
+
+The	O
+pooled	O
+sample	O
+included	O
+data	O
+on	O
+cognitive	O
+abilities	O
+of	O
+1649	O
+individuals	O
+reported	O
+in	O
+58	O
+citations	O
+.	O
+
+A	O
+total	O
+of	O
+556	O
+patients	O
+(	O
+34	O
+%	O
+)	O
+functioned	O
+in	O
+the	O
+range	O
+of	O
+intellectual	O
+disabilities	O
+.	O
+
+The	O
+decline	O
+in	O
+the	O
+proportion	O
+of	O
+intellectual	O
+disabilities	O
+in	O
+six	O
+disorders	O
+,	O
+ranged	O
+from	O
+7	O
+%	O
+to	O
+41	O
+%	I-STAT
+.	O
+
+Results	O
+from	O
+various	O
+studies	O
+differed	O
+and	O
+the	O
+cohorts	O
+varied	O
+with	O
+respect	O
+to	O
+age	O
+at	O
+symptom	O
+onset	O
+,	O
+age	O
+at	O
+diagnosis	O
+and	O
+treatment	O
+initiation	O
+,	O
+current	O
+age	O
+,	O
+severity	O
+of	O
+the	O
+metabolic	O
+deficiency	O
+,	O
+management	O
+strategies	O
+,	O
+and	O
+ethnic	O
+origins	O
+.	O
+
+The	O
+proportion	O
+of	O
+cases	O
+with	O
+intellectual	O
+disabilities	O
+ranged	O
+from	O
+9	O
+%	O
+to	O
+65	O
+%	O
+after	O
+2000	O
+in	O
+the	O
+seven	O
+UCDs	O
+associated	O
+with	O
+cognitive	O
+deficits	O
+.	O
+
+Positive	O
+outcomes	O
+from	O
+some	O
+studies	O
+suggest	O
+that	O
+it	O
+is	O
+possible	O
+to	O
+prevent	O
+or	O
+reverse	O
+the	O
+adverse	O
+impact	O
+of	O
+UCDs	O
+on	O
+neuropsychological	O
+functioning	O
+.	O
+
+It	O
+is	O
+time	O
+to	O
+	O
+raise	O
+the	O
+bar	O
+	O
+in	O
+terms	O
+of	O
+expectations	O
+for	O
+treatment	O
+effectiveness	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+autoimmune	O
+polyglandular	O
+syndrome	O
+(	O
+APS	O
+)	O
+types	O
+1/2	B-STAT
+is	O
+difficult	O
+due	O
+to	O
+their	O
+rarity	O
+and	O
+nonspecific	O
+clinical	O
+manifestations	O
+.	O
+
+APS-1	O
+development	O
+can	O
+be	O
+identified	O
+with	O
+assays	O
+for	O
+autoantibodies	O
+against	O
+cytokines	O
+,	O
+and	O
+APS-2	O
+development	O
+with	O
+organ	O
+-	O
+specific	O
+antibodies	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+a	O
+microarray	O
+-	O
+based	O
+multiplex	O
+assay	O
+was	O
+proposed	O
+for	O
+simultaneous	O
+detection	O
+of	O
+both	O
+organ	O
+-	O
+specific	O
+(	O
+anti-21	O
+-	O
+OH	O
+,	O
+anti	O
+-	O
+GAD-65	O
+,	O
+anti	O
+-	O
+IA2	O
+,	O
+anti	O
+-	O
+ICA	O
+,	O
+anti	O
+-	O
+TG	O
+,	O
+and	O
+anti	O
+-	O
+TPO	O
+)	O
+and	O
+APS-1	O
+-	O
+specific	O
+(	O
+anti	O
+-	O
+IFN	O
+-	O
+ω	O
+,	O
+anti	O
+-	O
+IFN	O
+-	O
+α-2a	O
+,	O
+and	O
+anti	O
+-	O
+IL-22	O
+)	O
+autoantibodies	O
+.	O
+
+Herein	O
+,	O
+206	O
+serum	O
+samples	O
+from	O
+adult	O
+patients	O
+with	O
+APS-1	O
+,	O
+APS-2	B-LOC
+,	O
+isolated	O
+autoimmune	O
+endocrine	O
+pathologies	O
+or	O
+non	O
+-	O
+autoimmune	O
+endocrine	O
+pathologies	O
+and	O
+from	O
+healthy	O
+donors	O
+were	O
+analyzed	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+autoantibodies	O
+differed	O
+among	O
+the	O
+groups	O
+of	O
+healthy	O
+donors	O
+and	O
+patients	O
+with	O
+non-	O
+,	O
+mono-	O
+and	O
+multi	O
+-	O
+endocrine	O
+diseases	O
+.	O
+
+APS-1	O
+patients	O
+were	O
+characterized	O
+by	O
+the	O
+presence	O
+of	O
+at	O
+least	O
+two	O
+specific	O
+autoantibodies	O
+(	O
+specificity	O
+99.5	O
+%	O
+,	O
+sensitivity	O
+100	O
+%	O
+)	O
+.	O
+
+Furthermore	O
+,	O
+in	O
+16	O
+of	O
+the	O
+18	O
+patients	O
+,	O
+the	O
+APS-1	O
+assay	O
+revealed	O
+triple	O
+positivity	O
+for	O
+autoantibodies	O
+against	O
+IFN	O
+-	O
+ω	O
+,	O
+IFN	O
+-	O
+α-2a	O
+and	O
+IL-22	O
+(	O
+specificity	O
+100	O
+%	O
+,	O
+sensitivity	O
+88.9	O
+%	O
+)	O
+.	O
+
+No	O
+anti	O
+-	O
+cytokine	O
+autoantibodies	O
+were	O
+found	O
+in	O
+the	O
+group	O
+of	O
+patients	O
+with	O
+non	O
+-	O
+APS-1	O
+polyendocrine	O
+autoimmunity	O
+.	O
+
+The	O
+accuracy	O
+of	O
+the	O
+microarray	O
+-	O
+based	O
+assay	O
+compared	O
+to	O
+ELISA	O
+for	O
+organ	O
+-	O
+specific	O
+autoantibodies	O
+was	O
+88.8	B-STAT
+-	I-STAT
+97.6	I-STAT
+%	I-STAT
+.	O
+
+This	O
+multiplex	O
+assay	O
+can	O
+be	O
+part	O
+of	O
+the	O
+strategy	O
+for	O
+diagnosing	O
+and	O
+predicting	O
+the	O
+development	O
+of	O
+APS	O
+.	O
+
+We	O
+have	O
+studied	O
+36	O
+patients	O
+with	O
+HPRT	O
+deficiency	O
+,	O
+25	O
+with	O
+Lesch	O
+-	O
+Nyhan	O
+syndrome	O
+and	O
+11	O
+with	O
+partial	O
+HPRT	O
+deficiency	O
+(	O
+grades	O
+1	B-STAT
+to	I-STAT
+3	I-STAT
+)	O
+.	O
+
+Patients	O
+diagnosed	O
+with	O
+HPRT	O
+deficiency	O
+have	O
+increased	O
+50	O
+%	O
+since	O
+2000	O
+.	O
+
+The	O
+most	O
+relevant	O
+recent	O
+advances	O
+have	O
+been	O
+made	O
+in	O
+molecular	O
+diagnosis	O
+.	O
+
+Nevertheless	O
+,	O
+enzyme	O
+determinations	O
+are	O
+still	O
+essential	O
+for	O
+the	O
+diagnosis	O
+of	O
+HPRT	O
+deficiency	O
+.	O
+
+Therapy	O
+for	O
+the	O
+neurological	O
+manifestations	O
+of	O
+HPRT	O
+deficiency	O
+has	O
+not	O
+advanced	O
+.	O
+
+Allopurinol	O
+remains	O
+the	O
+drug	O
+of	O
+choice	O
+to	O
+diminish	O
+uric	O
+acid	O
+overproduction	O
+,	O
+but	O
+the	O
+optimal	O
+allopurinol	O
+dose	O
+must	O
+be	O
+established	O
+in	O
+each	O
+patient	O
+to	O
+prevent	O
+xanthine	O
+or	O
+uric	O
+acid	O
+urolithiasis	O
+,	O
+a	O
+process	O
+aided	O
+by	O
+sequential	O
+determination	O
+of	O
+urinary	O
+oxypurines	O
+and	O
+uric	O
+acid	O
+.	O
+
+Introduction	O
+Obstructive	O
+sleep	O
+apnea	O
+is	O
+highly	O
+prevalent	B-EPI
+in	O
+non	O
+-	O
+syndromic	O
+Pierre	O
+Robin	O
+sequence	O
+patients	O
+.	O
+
+Studies	O
+have	O
+found	O
+a	O
+probable	O
+relationship	O
+between	O
+obstructive	O
+sleep	O
+apnea	O
+and	O
+nasal	O
+obstruction	O
+and	O
+between	O
+obstructive	O
+sleep	O
+apnea	O
+and	O
+enuresis	O
+.	O
+
+Assessment	O
+of	O
+the	O
+relationship	O
+between	O
+these	O
+variables	O
+in	O
+non	O
+-	O
+syndromic	O
+Pierre	O
+Robin	O
+sequence	O
+patients	O
+is	O
+scarce	O
+.	O
+
+Objective	O
+The	O
+present	O
+study	O
+aims	O
+to	O
+evaluate	O
+the	O
+relationship	O
+between	O
+symptoms	O
+of	O
+obstructive	O
+sleep	O
+apnea	O
+,	O
+nasal	O
+obstruction	O
+and	O
+enuresis	O
+,	O
+determining	O
+the	O
+prevalence	B-EPI
+of	O
+symptoms	O
+suggestive	O
+of	O
+these	O
+conditions	O
+,	O
+in	O
+schoolchildren	O
+with	O
+non	O
+-	O
+syndromic	O
+Pierre	O
+Robin	O
+sequence	O
+,	O
+and	O
+describe	O
+the	O
+prevalence	B-EPI
+of	O
+excessive	O
+daytime	O
+sleepiness	O
+habitual	O
+snoring	O
+and	O
+voiding	O
+dysfunction	O
+symptoms	O
+associated	O
+with	O
+enuresis	O
+.	O
+
+Methods	O
+This	O
+was	O
+a	O
+prospective	O
+analytical	O
+cross	O
+-	O
+sectional	O
+study	O
+developed	O
+at	O
+a	O
+reference	O
+center	O
+.	O
+
+Anthropometric	O
+measurements	O
+and	O
+a	O
+structured	O
+clinical	O
+interview	O
+were	O
+carried	O
+out	O
+in	O
+a	O
+sample	O
+of	O
+48	O
+patients	O
+.	O
+
+The	O
+instruments	O
+	O
+sleep	O
+disorders	O
+scale	O
+in	O
+children	O
+	O
+	O
+nasal	O
+congestion	O
+index	O
+questionnaire	O
+	O
+(	O
+CQ-5	O
+)	O
+,	O
+and	O
+the	O
+	O
+voiding	O
+dysfunction	O
+symptom	O
+score	O
+questionnaire	O
+	O
+were	O
+used	O
+.	O
+
+Statistical	O
+analysis	O
+was	O
+performed	O
+for	O
+p	O
+<	O
+0.05	O
+.	O
+
+Results	O
+Positive	O
+	O
+sleep	O
+disorders	O
+scale	O
+in	O
+children	O
+	O
+scores	O
+for	O
+obstructive	O
+sleep	O
+apnea	O
+and	O
+CQ-5	O
+for	O
+nasal	O
+obstruction	O
+were	O
+observed	O
+in	O
+38.78	O
+%	O
+and	O
+16.33	O
+%	O
+,	O
+respectively	O
+.	O
+
+Enuresis	O
+was	O
+reported	O
+in	O
+16.33	O
+%	O
+of	O
+children	O
+,	O
+being	O
+characterized	O
+as	O
+primary	O
+in	O
+71.43	O
+%	O
+and	O
+polysymptomatic	O
+in	O
+55.55	O
+%	O
+;	O
+according	O
+to	O
+the	O
+	O
+voiding	O
+dysfunction	O
+symptom	O
+score	O
+questionnaire	O
+	O
+.	O
+
+There	O
+was	O
+a	O
+significant	O
+relationship	O
+between	O
+nasal	O
+obstruction	O
+and	O
+obstructive	O
+sleep	O
+apnea	O
+symptoms	O
+(	O
+p	O
+<	O
+0.05	O
+)	O
+,	O
+but	O
+no	O
+significance	O
+was	O
+found	O
+between	O
+obstructive	O
+sleep	O
+apnea	O
+symptoms	O
+and	O
+enuresis	O
+,	O
+and	O
+between	O
+nasal	O
+obstruction	O
+and	O
+enuresis	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+excessive	O
+daytime	O
+sleepiness	O
+was	O
+12.24	O
+%	O
+and	O
+of	O
+habitual	O
+snoring	O
+,	O
+48.98	B-STAT
+%	I-STAT
+.	O
+
+A	O
+family	O
+history	O
+of	O
+enuresis	O
+,	O
+younger	O
+age	O
+in	O
+years	O
+and	O
+a	O
+positive	O
+	O
+voiding	O
+dysfunction	O
+symptom	O
+score	O
+questionnaire	O
+	O
+score	O
+were	O
+associated	O
+with	O
+a	O
+higher	O
+prevalence	B-EPI
+of	O
+enuresis	O
+(	O
+p	O
+<	O
+0.05	O
+)	O
+.	O
+
+Conclusion	O
+Children	O
+with	O
+non	O
+-	O
+syndromic	O
+Pierre	O
+Robin	O
+sequence	O
+are	O
+at	O
+high	O
+risk	O
+for	O
+obstructive	O
+sleep	O
+apnea	O
+symptoms	O
+and	O
+habitual	O
+snoring	O
+,	O
+with	O
+a	O
+correlation	O
+being	O
+observed	O
+between	O
+nasal	O
+obstruction	O
+and	O
+obstructive	O
+sleep	O
+apnea	O
+symptoms	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+study	O
+showed	O
+that	O
+non	O
+-	O
+syndromic	O
+Pierre	O
+Robin	O
+sequence	O
+,	O
+obstructive	O
+sleep	O
+apnea	O
+and	O
+nasal	O
+obstruction	O
+symptoms	O
+were	O
+not	O
+risk	O
+factors	O
+for	O
+enuresis	O
+in	O
+these	O
+patients	O
+.	O
+
+Hepatocellular	O
+carcinoma	O
+(	O
+HCC	O
+)	O
+is	O
+the	O
+most	O
+common	O
+primary	O
+cancer	O
+of	O
+the	O
+liver	O
+with	O
+high	O
+morbidity	O
+and	O
+mortality	O
+rates	O
+worldwide	B-LOC
+.	O
+
+Since	O
+1963	O
+,	O
+when	O
+alpha	O
+-	O
+fetoprotein	O
+(	O
+AFP	O
+)	O
+was	O
+discovered	O
+as	O
+a	O
+first	O
+HCC	O
+serum	O
+biomarker	O
+,	O
+several	O
+other	O
+protein	O
+biomarkers	O
+have	O
+been	O
+identified	O
+and	O
+introduced	O
+into	O
+clinical	O
+practice	O
+.	O
+
+However	O
+,	O
+insufficient	O
+specificity	O
+and	O
+sensitivity	O
+of	O
+these	O
+biomarkers	O
+dictate	O
+the	O
+necessity	O
+of	O
+novel	O
+biomarker	O
+discovery	O
+.	O
+
+Remarkable	O
+advancements	O
+in	O
+integrated	O
+multiomics	O
+technologies	O
+for	O
+the	O
+identification	O
+of	O
+gene	O
+expression	O
+and	O
+protein	O
+or	O
+metabolite	O
+distribution	O
+patterns	O
+can	O
+facilitate	O
+rising	O
+to	O
+this	O
+challenge	O
+.	O
+
+Current	O
+multiomics	O
+technologies	O
+lead	O
+to	O
+the	O
+accumulation	O
+of	O
+a	O
+huge	O
+amount	O
+of	O
+data	O
+,	O
+which	O
+requires	O
+clustering	O
+and	O
+finding	O
+correlations	O
+between	O
+various	O
+datasets	O
+and	O
+developing	O
+predictive	O
+models	O
+for	O
+data	O
+filtering	O
+,	O
+pre	O
+-	O
+processing	O
+,	O
+and	O
+reducing	O
+dimensionality	O
+.	O
+
+Artificial	O
+intelligence	O
+(	O
+AI	O
+)	O
+technologies	O
+have	O
+an	O
+enormous	O
+potential	O
+to	O
+overcome	O
+accelerated	O
+data	O
+growth	O
+,	O
+complexity	O
+,	O
+and	O
+heterogeneity	O
+within	O
+and	O
+across	O
+data	O
+sources	O
+.	O
+
+Our	O
+review	O
+focuses	O
+on	O
+the	O
+recent	O
+progress	O
+in	O
+integrative	O
+proteomic	O
+profiling	O
+strategies	O
+and	O
+their	O
+usage	O
+in	O
+combination	O
+with	O
+machine	O
+learning	O
+and	O
+deep	O
+learning	O
+technologies	O
+for	O
+the	O
+discovery	O
+of	O
+novel	O
+biomarker	O
+candidates	O
+for	O
+HCC	O
+early	O
+diagnosis	O
+and	O
+prognosis	O
+.	O
+
+We	O
+discuss	O
+conventional	O
+and	O
+promising	O
+proteomic	O
+biomarkers	O
+of	O
+HCC	O
+such	O
+as	O
+AFP	O
+,	O
+lens	O
+culinaris	O
+agglutinin	O
+(	O
+LCA)-reactive	O
+L3	O
+glycoform	O
+of	O
+AFP	O
+(	O
+AFP	O
+-	O
+L3	O
+)	O
+,	O
+des	O
+-	O
+gamma	O
+-	O
+carboxyprothrombin	O
+(	O
+DCP	O
+)	O
+,	O
+osteopontin	O
+(	O
+OPN	O
+)	O
+,	O
+glypican-3	O
+(	O
+GPC3	O
+)	O
+,	O
+dickkopf-1	O
+(	O
+DKK1	O
+)	O
+,	O
+midkine	O
+(	O
+MDK	O
+)	O
+,	O
+and	O
+squamous	O
+cell	O
+carcinoma	O
+antigen	O
+(	O
+SCCA	O
+)	O
+and	O
+highlight	O
+their	O
+functional	O
+significance	O
+including	O
+the	O
+involvement	O
+in	O
+cell	O
+signaling	O
+such	O
+as	O
+Wnt	O
+/	O
+β	O
+-	O
+catenin	O
+,	O
+PI3K	O
+/	O
+Akt	O
+,	O
+integrin	O
+αvβ3	O
+/	O
+NF	O
+-	O
+κB	O
+/	O
+HIF-1α	O
+,	O
+JAK	O
+/	O
+STAT3	O
+and	O
+MAPK	O
+/	O
+ERK	O
+-	O
+mediated	O
+pathways	O
+dysregulated	O
+in	O
+HCC	O
+.	O
+
+We	O
+show	O
+that	O
+currently	O
+available	O
+computational	O
+platforms	O
+for	O
+big	O
+data	O
+analysis	O
+and	O
+AI	O
+technologies	O
+can	O
+both	O
+enhance	O
+proteomic	O
+profiling	O
+and	O
+improve	O
+imaging	O
+techniques	O
+to	O
+enhance	O
+the	O
+translational	O
+application	O
+of	O
+proteomics	O
+data	O
+into	O
+precision	O
+medicine	O
+.	O
+
+Congenital	O
+hypothyroidism	O
+(	O
+CH	O
+)	O
+is	O
+a	O
+thyroid	O
+hormone	O
+deficiency	O
+syndrome	O
+in	O
+newborns	O
+resulting	O
+from	O
+incomplete	O
+thyroid	O
+development	O
+and	O
+decreased	O
+thyroid	O
+hormone	O
+biosynthesis	O
+or	O
+thyroid	O
+-	O
+stimulating	O
+hormone	O
+secretion	O
+.	O
+
+Without	O
+early	O
+treatment	O
+,	O
+newborns	O
+with	O
+CH	O
+have	O
+irreversible	O
+neurological	O
+deficits	O
+and	O
+long	O
+-	O
+term	O
+metabolic	O
+complications	O
+.	O
+
+Therefore	O
+,	O
+several	O
+countries	O
+have	O
+implemented	O
+widespread	O
+newborn	O
+screening	O
+to	O
+identify	O
+and	O
+treat	O
+CH	O
+in	O
+newborns	O
+.	O
+
+Although	O
+newborn	O
+screening	O
+has	O
+improved	O
+diagnosis	O
+and	O
+treatment	O
+outcomes	O
+for	O
+CH	O
+,	O
+several	O
+questions	O
+remain	O
+concerning	O
+the	O
+etiology	O
+and	O
+increased	O
+incidence	B-EPI
+of	O
+CH	O
+in	O
+different	O
+populations	O
+.	O
+
+Moreover	O
+,	O
+the	O
+increase	O
+in	O
+the	O
+number	O
+of	O
+preterm	O
+,	O
+low	O
+-	O
+birth	O
+-	O
+weight	O
+newborns	O
+and	O
+of	O
+newborns	O
+admitted	O
+to	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+presenting	O
+with	O
+CH	O
+requires	O
+additional	O
+research	O
+to	O
+detect	O
+and	O
+treat	O
+all	O
+forms	O
+of	O
+CH	O
+.	O
+
+Introduction	O
+Children	O
+account	O
+for	O
+a	O
+relatively	O
+small	O
+proportion	O
+of	O
+laboratory	O
+-	O
+confirmed	O
+SARS	O
+-	O
+CoV-2	O
+infections	O
+.	O
+
+In	O
+children	O
+,	O
+COVID-19	O
+usually	O
+has	O
+a	O
+relatively	O
+mild	O
+course	O
+.	O
+
+However	O
+,	O
+in	O
+rare	O
+cases	O
+,	O
+severe	O
+disorders	O
+can	O
+be	O
+observed	O
+,	O
+and	O
+clinical	O
+manifestations	O
+may	O
+differ	O
+from	O
+adults	O
+.	O
+
+Purpose	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+analyse	O
+the	O
+frequency	O
+,	O
+clinical	O
+picture	O
+and	O
+outcome	O
+of	O
+COVID-19	O
+in	O
+children	O
+based	O
+on	O
+the	O
+experience	O
+from	O
+the	O
+tertiary	O
+care	O
+centre	O
+and	O
+regional	O
+sanitary	O
+-	O
+epidemiological	O
+office	O
+.	O
+
+Methods	O
+We	O
+report	O
+a	O
+study	O
+regarding	O
+106	O
+cases	O
+of	O
+confirmed	O
+SARS	O
+-	O
+CoV-2	O
+infection	O
+cases	O
+in	O
+PCR	O
+from	O
+a	O
+nasopharyngeal	O
+swab	O
+(	O
+age	O
+range	O
+1	O
+-	O
+month	O
+-	O
+17	O
+-	O
+years	O
+)	O
+.	O
+
+In	O
+all	O
+cases	O
+,	O
+history	O
+was	O
+taken	O
+.	O
+
+In	O
+children	O
+who	O
+required	O
+hospital	O
+admission	O
+,	O
+physical	O
+examination	O
+and	O
+laboratory	O
+test	O
+were	O
+performed	O
+according	O
+to	O
+clinical	O
+indications	O
+.	O
+
+Results	O
+Twelve	O
+of	O
+the	O
+patients	O
+required	O
+admission	O
+to	O
+the	O
+hospital	O
+.	O
+
+The	O
+most	O
+common	O
+symptoms	O
+were	O
+anosmia	O
+and	O
+dysgeusia	O
+(	O
+75	O
+%	O
+)	O
+and	O
+headaches	O
+(	O
+49	O
+%	O
+)	O
+in	O
+outpatients	O
+and	O
+fever	O
+in	O
+hospitalised	O
+children	O
+(	O
+75	O
+%	O
+)	O
+.	O
+
+Three	O
+children	O
+from	O
+the	O
+hospitalised	O
+group	O
+developed	O
+a	O
+severe	O
+course	O
+with	O
+increased	O
+inflammatory	O
+indexes	O
+.	O
+
+The	O
+clinical	O
+picture	O
+was	O
+more	O
+severe	O
+in	O
+younger	O
+children	O
+from	O
+the	O
+hospitalised	O
+group	O
+.	O
+
+Treatment	O
+options	O
+were	O
+regarded	O
+individually	O
+in	O
+all	O
+cases	O
+.	O
+
+Conclusion	O
+Our	O
+study	O
+is	O
+the	O
+first	O
+tour	O
+knowledge	O
+regarding	O
+the	O
+clinical	O
+course	O
+of	O
+COVID-19	O
+in	O
+Polish	O
+children	O
+.	O
+
+In	O
+general	O
+,	O
+the	O
+clinical	O
+course	O
+of	O
+COVID-19	O
+was	O
+mild	O
+with	O
+anosmia	O
+and	O
+dysgeusia	O
+as	O
+the	O
+most	O
+common	O
+symptoms	O
+.	O
+
+However	O
+,	O
+in	O
+hospitalised	O
+children	O
+,	O
+a	O
+severe	O
+progression	O
+of	O
+the	O
+disease	O
+and	O
+less	O
+typical	O
+signs	O
+as	O
+aplastic	O
+anaemia	O
+may	O
+be	O
+developed	O
+.	O
+
+MYH9	O
+-related	O
+disease	O
+(	O
+MYH9	O
+-RD	O
+)	O
+is	O
+an	O
+autosomal	O
+-	O
+dominant	O
+thrombocytopenia	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+gene	O
+for	O
+non	O
+-	O
+muscle	O
+myosin	O
+heavy	O
+chain	O
+IIA	O
+(	O
+NMMHC	O
+-	O
+IIA	O
+)	O
+.	O
+
+Patients	O
+present	O
+congenital	O
+macrothrombocytopenia	O
+and	O
+inclusions	O
+of	O
+NMMHC	O
+-	O
+IIA	O
+in	O
+leukocytes	O
+,	O
+and	O
+have	O
+a	O
+variable	O
+risk	O
+of	O
+developing	O
+kidney	O
+damage	O
+,	O
+sensorineural	O
+deafness	O
+,	O
+presenile	O
+cataracts	O
+and/or	O
+liver	O
+enzymes	O
+abnormalities	O
+.	O
+
+The	O
+spectrum	O
+of	O
+mutations	O
+found	O
+in	O
+MYH9	O
+-RD	O
+patients	O
+is	O
+limited	O
+and	O
+the	O
+incidence	B-EPI
+and	O
+severity	O
+of	O
+the	O
+non	O
+-	O
+congenital	O
+features	O
+are	O
+predicted	O
+by	O
+the	O
+causative	O
+MYH9	O
+variant	O
+.	O
+
+In	O
+particular	O
+,	O
+different	O
+alterations	O
+of	O
+the	O
+C	O
+-	O
+terminal	O
+tail	O
+domain	O
+of	O
+NMMHC	O
+-	O
+IIA	O
+associate	O
+with	O
+remarkably	O
+different	O
+disease	O
+evolution	O
+.	O
+
+We	O
+report	O
+four	O
+novel	O
+MYH9	O
+mutations	O
+affecting	O
+the	O
+tail	O
+domain	O
+of	O
+NMMHC	O
+-	O
+IIA	O
+and	O
+responsible	O
+for	O
+MYH9	O
+-RD	O
+in	O
+four	O
+families	O
+.	O
+
+Two	O
+variants	O
+cause	O
+amino	O
+acid	O
+substitutions	O
+in	O
+the	O
+coiled	O
+-	O
+coil	O
+region	O
+of	O
+NMMHC	O
+-	O
+IIA	O
+,	O
+while	O
+the	O
+other	O
+two	O
+are	O
+a	O
+splicing	O
+variant	O
+and	O
+a	O
+single	O
+nucleotide	O
+deletion	O
+both	O
+resulting	O
+in	O
+frameshift	O
+alterations	O
+of	O
+the	O
+short	O
+non	O
+-	O
+helical	O
+tailpiece	O
+.	O
+
+Characterization	O
+of	O
+phenotypes	O
+of	O
+affected	O
+individuals	O
+shows	O
+that	O
+all	O
+of	O
+these	O
+novel	O
+variants	O
+are	O
+associated	O
+with	O
+a	O
+mild	O
+clinical	O
+evolution	O
+of	O
+the	O
+disease	O
+.	O
+
+Introduction	O
+Angelman	O
+syndrome	O
+(	O
+AS	O
+)	O
+is	O
+a	O
+neurodevelopmental	O
+disorder	O
+characterized	O
+by	O
+cognitive	O
+disability	O
+,	O
+speech	O
+impairment	O
+,	O
+hyperactivity	O
+and	O
+seizures	O
+.	O
+
+Movement	O
+disorders	O
+have	O
+been	O
+reported	O
+in	O
+almost	O
+all	O
+AS	O
+subjects	O
+and	O
+they	O
+are	O
+described	O
+as	O
+	O
+tremulous	O
+movements	O
+of	O
+limbs	O
+,	O
+unsteadiness	O
+,	O
+clumsiness	O
+or	O
+quick	O
+,	O
+jerky	O
+motions	O
+	O
+.	O
+
+The	O
+presence	O
+of	O
+dystonia	O
+has	O
+barely	O
+been	O
+mentioned	O
+in	O
+subjects	O
+with	O
+AS	O
+and	O
+has	O
+never	O
+been	O
+studied	O
+in	O
+detail	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+is	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+,	O
+clinical	O
+features	O
+and	O
+severity	O
+of	O
+dystonia	O
+in	O
+a	O
+series	O
+of	O
+adolescents	O
+and	O
+adults	O
+with	O
+AS	O
+.	O
+
+Methods	O
+Whole	O
+body	O
+video	O
+recordings	O
+of	O
+patients	O
+with	O
+genetically	O
+confirmed	O
+AS	O
+were	O
+evaluated	O
+.	O
+
+Dystonia	O
+was	O
+evaluated	O
+by	O
+mean	O
+of	O
+the	O
+movement	O
+subscale	O
+of	O
+Burke	O
+-	O
+Fahn	O
+-	O
+Marsden	O
+Dystonia	O
+Rating	O
+Scale	O
+(	O
+BFM	O
+)	O
+.	O
+
+Results	O
+Forty	O
+-	O
+four	O
+subjects	O
+with	O
+AS	O
+were	O
+evaluated	O
+.	O
+
+Fourteen	O
+recordings	O
+were	O
+excluded	O
+due	O
+to	O
+poor	O
+cooperation	O
+.	O
+
+We	O
+finally	O
+analyzed	O
+data	O
+of	O
+30	O
+subjects	O
+(	O
+15	O
+F	O
+)	O
+with	O
+a	O
+median	O
+age	O
+of	O
+28	O
+years	O
+(	O
+range	O
+15	O
+-	O
+51	O
+)	O
+.	O
+
+Dystonia	O
+was	O
+present	O
+in	O
+28/30	B-STAT
+(	O
+93.3	O
+%	O
+)	O
+subjects	O
+.	O
+
+Among	O
+these	O
+,	O
+dystonia	O
+involved	O
+the	O
+upper	O
+limbs	O
+in	O
+28/28	B-STAT
+(	O
+100	O
+%	O
+)	O
+,	O
+lower	O
+limbs	O
+in	O
+8/28	B-STAT
+(	O
+28.5	O
+%	O
+)	O
+,	O
+mouth	O
+in	O
+7/28	B-STAT
+(	O
+25	O
+%	O
+)	O
+,	O
+neck	O
+in	O
+3/28	B-STAT
+(	O
+10.7	O
+%	O
+)	O
+,	O
+trunk	O
+in	O
+1/28	B-STAT
+(	O
+3.6	O
+%	O
+)	O
+.	O
+
+Severity	O
+of	O
+dystonia	O
+ranged	O
+from	O
+slight	O
+to	O
+moderate	O
+.	O
+
+There	O
+was	O
+a	O
+linear	O
+correlation	O
+between	O
+severity	O
+of	O
+dystonia	O
+and	O
+increasing	O
+age	O
+.	O
+
+There	O
+was	O
+no	O
+difference	O
+in	O
+terms	O
+of	O
+severity	O
+of	O
+dystonia	O
+among	O
+genetic	O
+subgroups	O
+.	O
+
+Conclusions	O
+Dystonia	O
+is	O
+a	O
+common	O
+and	O
+previously	O
+underrecognized	O
+clinical	O
+feature	O
+of	O
+adults	O
+and	O
+adolescents	O
+with	O
+AS	O
+.	O
+
+Background	O
+and	O
+aims	O
+Hybanthus	O
+austrocaledonicus	O
+(	O
+Violaceae	O
+)	O
+is	O
+a	O
+nickel	O
+(	O
+Ni	O
+)	O
+hyperaccumulator	O
+endemic	O
+to	O
+New	B-LOC
+Caledonia	I-LOC
+.	O
+
+One	O
+of	O
+the	O
+specimens	O
+stored	O
+at	O
+the	O
+local	O
+herbarium	O
+had	O
+a	O
+strip	O
+of	O
+bark	O
+with	O
+a	O
+remarkably	O
+green	O
+phloem	O
+tissue	O
+attached	O
+to	O
+the	O
+sheet	O
+containing	O
+over	O
+4	O
+wt%	O
+Ni	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+collect	O
+field	O
+samples	O
+from	O
+the	O
+original	O
+H.	O
+austrocaledonicus	O
+locality	O
+to	O
+confirm	O
+the	O
+nature	O
+of	O
+the	O
+green	O
+'	O
+nickel	O
+-	O
+rich	O
+phloem	O
+'	O
+in	O
+this	O
+taxon	O
+and	O
+to	O
+systematically	O
+assess	O
+the	O
+occurrence	B-EPI
+of	O
+Ni	O
+hyperaccumulation	O
+in	O
+H.	O
+austrocaledonicus	O
+and	O
+Hybanthus	O
+caledonicus	O
+populations	O
+.	O
+
+Methods	O
+X	O
+-	O
+ray	O
+fluorescence	O
+spectroscopy	O
+scanning	O
+of	O
+all	O
+collections	O
+of	O
+the	O
+genus	O
+Hybanthus	O
+(	O
+236	O
+specimens	O
+)	O
+was	O
+undertaken	O
+at	O
+the	O
+Herbarium	O
+of	O
+New	O
+Caledonia	O
+to	O
+reveal	O
+incidences	B-EPI
+of	O
+Ni	O
+accumulation	O
+in	O
+populations	O
+of	O
+H.	O
+austrocaledonicus	O
+and	O
+H.	O
+caledonicus	O
+.	O
+
+In	O
+parallel	O
+,	O
+micro	O
+-	O
+analytical	O
+investigations	O
+were	O
+performed	O
+via	O
+synchrotron	O
+X	O
+-	O
+ray	O
+fluorescence	O
+microscopy	O
+(	O
+XFM	O
+)	O
+and	O
+scanning	O
+electron	O
+microscopy	O
+with	O
+X	O
+-	O
+ray	O
+microanalysis	O
+(	O
+SEM	O
+-	O
+EDS	O
+)	O
+.	O
+
+Key	O
+results	O
+The	O
+extensive	O
+scanning	O
+demonstrated	O
+that	O
+Ni	O
+hyperaccumulation	O
+is	O
+not	O
+a	O
+characteristic	O
+common	O
+to	O
+all	O
+populations	O
+in	O
+the	O
+endemic	O
+Hybanthus	O
+species	O
+.	O
+
+Synchrotron	O
+XFM	O
+revealed	O
+that	O
+Ni	O
+was	O
+exclusively	O
+concentrated	O
+in	O
+the	O
+epidermal	O
+cells	O
+of	O
+the	O
+leaf	O
+blade	O
+and	O
+petiole	O
+,	O
+conforming	O
+with	O
+the	O
+majority	O
+of	O
+(	O
+tropical	O
+)	O
+Ni	O
+hyperaccumulator	O
+plants	O
+studied	O
+to	O
+date	O
+.	O
+
+SEM	O
+-	O
+EDS	O
+of	O
+freeze	O
+-	O
+dried	O
+and	O
+frozen	O
+-	O
+hydrated	O
+samples	O
+revealed	O
+the	O
+presence	O
+of	O
+dense	O
+solid	O
+deposits	O
+in	O
+the	O
+phloem	O
+bundles	O
+that	O
+contained	O
+>	O
+8	O
+wt%	O
+nickel	O
+.	O
+
+Conclusions	O
+The	O
+occurrence	B-EPI
+of	O
+extremely	O
+Ni	O
+-	O
+rich	O
+green	O
+phloem	O
+tissues	O
+appears	O
+to	O
+be	O
+a	O
+characteristic	O
+feature	O
+of	O
+tropical	O
+Ni	O
+hyperaccumulator	O
+plants	O
+.	O
+
+Acute	O
+kidney	O
+injury	O
+(	O
+AKI	O
+)	O
+is	O
+a	O
+fatal	O
+complication	O
+of	O
+the	O
+new	O
+severe	O
+acute	O
+respiratory	O
+syndrome	O
+coronavirus	O
+(	O
+SARS	O
+-	O
+CoV-2	O
+)	O
+which	O
+causes	O
+COVID-19	O
+disease	O
+.	O
+
+Here	O
+,	O
+we	O
+performed	O
+a	O
+scoping	O
+review	O
+and	O
+meta	O
+-	O
+analysis	O
+including	O
+clinical	O
+studies	O
+on	O
+patients	O
+with	O
+SARS	O
+-	O
+CoV-2	O
+infection	O
+with	O
+data	O
+on	O
+AKI	O
+assessment	O
+and	O
+characteristics	O
+,	O
+and	O
+the	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+AKI	O
+was	O
+estimated	O
+using	O
+a	O
+random	O
+-	O
+effects	O
+model	O
+.	O
+
+We	O
+identified	O
+21	O
+articles	O
+which	O
+passed	O
+the	O
+search	O
+criteria	O
+.	O
+
+All	O
+were	O
+quantitative	O
+observational	O
+studies	O
+which	O
+used	O
+a	O
+cross	O
+-	O
+sectional	O
+,	O
+retrospective	O
+,	O
+case	O
+report	O
+,	O
+or	O
+cohort	O
+methodology	O
+.	O
+
+This	O
+showed	O
+that	O
+aging	O
+,	O
+diabetes	O
+,	O
+cardiovascular	O
+disease	O
+,	O
+previous	O
+chronic	O
+disease	O
+,	O
+and	O
+other	O
+comorbidities	O
+were	O
+risk	O
+factors	O
+of	O
+AKI	O
+.	O
+
+Although	O
+the	O
+prevalence	B-EPI
+of	O
+proteinuria	O
+,	O
+hematuria	O
+,	O
+and	O
+increased	O
+serum	O
+creatinine	O
+was	O
+reported	O
+for	O
+up	O
+to	O
+60	B-STAT
+%	O
+of	O
+the	O
+patients	O
+with	O
+COVID-19	O
+,	O
+the	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+AKI	O
+was	O
+estimated	O
+to	O
+be	O
+8	B-STAT
+%	I-STAT
+.	O
+
+We	O
+conclude	O
+that	O
+although	O
+approximately	O
+two	O
+-	O
+thirds	O
+of	O
+patients	O
+with	O
+COVID-19	O
+had	O
+symptoms	O
+of	O
+kidney	O
+damage	O
+,	O
+most	O
+of	O
+these	O
+did	O
+not	O
+meet	O
+the	O
+diagnostic	O
+criteria	O
+for	O
+AKI	O
+.	O
+
+Further	O
+studies	O
+should	O
+be	O
+performed	O
+to	O
+validate	O
+biomarkers	O
+for	O
+improved	O
+AKI	O
+diagnosis	O
+in	O
+COVID-19	O
+patients	O
+and	O
+new	O
+treatment	O
+options	O
+are	O
+required	O
+to	O
+reduce	O
+the	O
+rate	O
+of	O
+mortality	O
+.	O
+
+In	O
+this	O
+paper	O
+,	O
+the	O
+author	O
+enumerates	O
+cardiac	O
+defects	O
+with	O
+a	O
+functionally	O
+single	O
+ventricle	O
+,	O
+summarizes	O
+single	O
+ventricle	O
+physiology	O
+,	O
+presents	O
+a	O
+summary	O
+of	O
+management	O
+strategies	O
+to	O
+address	O
+the	O
+single	O
+ventricle	O
+defects	O
+,	O
+goes	O
+over	O
+the	O
+steps	O
+of	O
+staged	O
+total	O
+cavo	O
+-	O
+pulmonary	O
+connection	O
+,	O
+cites	O
+the	O
+prevalence	B-EPI
+of	O
+inter	O
+-	O
+stage	O
+mortality	O
+,	O
+names	O
+the	O
+causes	O
+of	O
+inter	O
+-	O
+stage	O
+mortality	O
+,	O
+discusses	O
+strategies	O
+to	O
+address	O
+the	O
+inter	O
+-	O
+stage	O
+mortality	O
+,	O
+reviews	O
+post	O
+-	O
+Fontan	O
+issues	O
+,	O
+and	O
+introduces	O
+alternative	O
+approaches	O
+to	O
+Fontan	O
+circulation	O
+.	O
+
+Introduction	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+(	O
+21	O
+-	O
+OHD	O
+)	O
+is	O
+the	O
+most	O
+common	O
+form	O
+of	O
+congenital	O
+adrenal	O
+hyperplasia	O
+(	O
+CAH	O
+)	O
+.	O
+
+In	O
+adulthood	O
+,	O
+most	O
+studies	O
+are	O
+reported	O
+in	O
+females	O
+.	O
+
+By	O
+contrast	O
+,	O
+data	O
+on	O
+adult	O
+males	O
+are	O
+scarce	O
+.	O
+
+Objective	O
+To	O
+describe	O
+a	O
+series	O
+of	O
+adult	O
+males	O
+with	O
+classic	O
+21	O
+-	O
+OHD	O
+and	O
+to	O
+assess	O
+the	O
+presence	O
+of	O
+adrenal	O
+masses	O
+and	O
+testicular	O
+adrenal	O
+rest	O
+tumors	O
+(	O
+TARTs	O
+)	O
+.	O
+
+Material	O
+and	O
+methods	O
+Eight	O
+males	O
+(	O
+21	O
+-	O
+42	O
+years	O
+)	O
+were	O
+included	O
+.	O
+
+We	O
+evaluated	O
+clinical	O
+presentation	O
+,	O
+17	O
+-	O
+Hydroxyprogesterone	O
+(	O
+17	O
+-	O
+OHP	O
+)	O
+,	O
+Testosterone	O
+(	O
+T	O
+)	O
+,	O
+Δ4Androstenedione	O
+(	O
+Δ4A	O
+)	O
+ACTH	O
+,	O
+LH	O
+,	O
+FSH	O
+and	O
+plasma	O
+renin	O
+activitiy	O
+(	O
+PRA	O
+)	O
+levels	O
+at	O
+consultation	O
+.	O
+
+Molecular	O
+studies	O
+of	O
+the	O
+CYP21A2	O
+gene	O
+,	O
+testicular	O
+ultrasound	O
+(	O
+US	B-LOC
+)	O
+,	O
+semen	O
+analysis	O
+and	O
+adrenal	O
+computed	O
+tomography	O
+(	O
+CT	O
+)	O
+scan	O
+were	O
+performed	O
+.	O
+
+Treatment	O
+and	O
+compliance	O
+were	O
+assessed	O
+.	O
+
+Results	O
+Basal	O
+17	O
+-	O
+OHP	O
+levels	O
+were	O
+>	O
+20ng	O
+/	O
+ml	O
+in	O
+all	O
+patients	O
+.	O
+
+At	O
+consultation	O
+,	O
+median	O
+17OH	O
+-	O
+P	O
+was	O
+11.5	O
+(	O
+2.3	O
+-	O
+81	O
+)	O
+ng	O
+/	O
+ml	O
+,	O
+FSH	O
+:	O
+3	O
+(	O
+0.3	O
+-	O
+4	O
+)	O
+mUI	O
+/	O
+ml	O
+,	O
+LH	O
+:	O
+1.1	O
+(	O
+0.1	O
+-	O
+6	O
+)	O
+mUI	O
+/	O
+ml	O
+,	O
+T	O
+:	O
+4.3	O
+(	O
+1.7	O
+-	O
+8)	O
+ng	O
+/	O
+ml	O
+,	O
+Δ4A	O
+:	O
+5.7	O
+(	O
+1.4	O
+-	O
+16	O
+)	O
+ng	O
+/	O
+ml	O
+,	O
+ACTH	O
+:	O
+86.4	O
+(	O
+76	O
+-	O
+334	O
+)	O
+pg	O
+/	O
+ml	O
+,	O
+PRA	O
+:	O
+9.5	O
+(	O
+1.3	O
+-	O
+23.6	O
+)	O
+ng	O
+/	O
+ml	O
+/	O
+h.	O
+
+Semen	O
+analysis	O
+was	O
+performed	O
+in	O
+5/8	B-STAT
+patients	O
+,	O
+showing	O
+azoospermia	O
+in	O
+two	O
+.	O
+
+Molecular	O
+genetic	O
+analysis	O
+was	O
+performed	O
+in	O
+4/8	B-STAT
+patients	O
+.	O
+
+TARTs	O
+were	O
+found	O
+in	O
+5/6	B-STAT
+,	O
+being	O
+bilateral	O
+in	O
+four	O
+.	O
+
+Adrenal	O
+masses	O
+were	O
+found	O
+in	O
+4/6	B-STAT
+.	O
+
+In	O
+the	O
+7	O
+patients	O
+diagnosed	O
+in	O
+childhood	O
+,	O
+their	O
+follow	O
+-	O
+up	O
+was	O
+referred	O
+to	O
+as	O
+irregular	O
+,	O
+both	O
+in	O
+their	O
+attendance	O
+at	O
+consultations	O
+and	O
+in	O
+compliance	O
+with	O
+the	O
+indicated	O
+treatment	O
+.	O
+
+Conclusions	O
+To	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+series	O
+on	O
+adult	O
+males	O
+with	O
+classic	O
+21	O
+-	O
+OHD	O
+which	O
+concomitantly	O
+assesses	O
+clinical	O
+presentation	O
+,	O
+molecular	O
+biology	O
+,	O
+adrenal	O
+and	O
+testicular	O
+imaging	O
+studies	O
+,	O
+semen	O
+analysis	O
+and	O
+compliance	O
+to	O
+treatment	O
+.	O
+
+A	O
+high	O
+prevalence	B-EPI
+of	O
+adrenal	O
+masses	O
+and	O
+TARTs	O
+was	O
+observed	O
+,	O
+possibly	O
+associated	O
+with	O
+poor	O
+treatment	O
+compliance	O
+leading	O
+to	O
+elevated	O
+ACTH	O
+and	O
+increased	O
+proliferation	O
+.	O
+
+Our	O
+findings	O
+on	O
+TARTs	O
+agree	O
+with	O
+reports	O
+in	O
+international	O
+publications	O
+of	O
+CAH	O
+in	O
+males	O
+,	O
+with	O
+adrenal	O
+imaging	O
+being	O
+added	O
+in	O
+our	O
+group	O
+.	O
+
+Although	O
+we	O
+are	O
+aware	O
+that	O
+further	O
+studies	O
+with	O
+a	O
+larger	O
+sample	O
+size	O
+and	O
+more	O
+data	O
+are	O
+needed	O
+,	O
+we	O
+consider	O
+that	O
+our	O
+findings	O
+contribute	O
+to	O
+the	O
+clinical	O
+management	O
+of	O
+classical	O
+21	O
+-	O
+OHD	O
+in	O
+the	O
+male	O
+population	O
+.	O
+
+Background	O
+Q	O
+fever	O
+osteoarticular	O
+infections	O
+are	O
+a	O
+rare	O
+complication	O
+of	O
+the	O
+chronic	O
+form	O
+of	O
+Q	O
+fever	O
+.	O
+
+We	O
+aimed	O
+to	O
+characterize	O
+chronic	O
+Q	O
+fever	O
+vertebral	O
+osteomyelitis	O
+through	O
+our	O
+experience	O
+and	O
+a	O
+review	O
+of	O
+the	O
+literature	O
+.	O
+
+Methods	O
+Four	O
+adult	O
+patients	O
+with	O
+Q	O
+fever	O
+vertebral	O
+osteomyelitis	O
+diagnosed	O
+in	O
+a	O
+tertiary	O
+hospital	O
+in	O
+northern	O
+Israel	B-LOC
+between	O
+2016	O
+to	O
+2020	O
+are	O
+described	O
+.	O
+
+In	O
+addition	O
+,	O
+a	O
+30	O
+years	O
+'	O
+literature	O
+review	O
+of	O
+Q	O
+fever	O
+vertebral	O
+osteomyelitis	O
+,	O
+characterizing	O
+predisposing	O
+factors	O
+,	O
+clinical	O
+presentation	O
+,	O
+course	O
+of	O
+disease	O
+,	O
+treatment	O
+and	O
+outcomes	O
+,	O
+was	O
+performed	O
+.	O
+
+Results	O
+Thirty	O
+-	O
+four	O
+adult	O
+patients	O
+with	O
+Q	O
+fever	O
+vertebral	O
+osteomyelitis	O
+were	O
+identified	O
+.	O
+
+The	O
+vast	O
+majority	O
+were	O
+male	O
+(	O
+30/34	B-STAT
+,	O
+88	O
+%	O
+)	O
+with	O
+a	O
+mean	O
+age	O
+of	O
+67.2	O
+±	O
+10	O
+years	O
+.	O
+
+Involvement	O
+of	O
+the	O
+adjacent	O
+aorta	O
+,	O
+likely	O
+the	O
+origin	O
+of	O
+the	O
+infection	O
+,	O
+was	O
+observed	O
+in	O
+23/34	B-STAT
+(	O
+68	O
+%	O
+)	O
+of	O
+the	O
+patients	O
+,	O
+usually	O
+among	O
+patients	O
+with	O
+aortic	O
+graft	O
+or	O
+aneurysm	O
+.	O
+
+Clinical	O
+presentation	O
+was	O
+insidious	O
+and	O
+fever	O
+was	O
+frequently	O
+absent	O
+.	O
+
+Delayed	O
+diagnosis	O
+for	O
+months	O
+to	O
+years	O
+after	O
+symptoms	O
+onset	O
+was	O
+frequently	O
+reported	O
+.	O
+
+Vascular	O
+infections	O
+were	O
+managed	O
+with	O
+or	O
+without	O
+extraction	O
+of	O
+the	O
+infected	O
+aneurysm	O
+/	O
+aorta	O
+and	O
+graft	O
+placement	O
+.	O
+
+The	O
+outcome	O
+was	O
+variable	O
+with	O
+limited	O
+follow	O
+-	O
+up	O
+data	O
+in	O
+most	O
+cases	O
+.	O
+
+Patients	O
+were	O
+usually	O
+treated	O
+with	O
+prolonged	O
+antimicrobial	O
+therapy	O
+,	O
+most	O
+commonly	O
+doxycycline	O
+and	O
+hydroxychloroquine	O
+combination	O
+therapy	O
+.	O
+
+Conclusion	O
+Q	O
+fever	O
+should	O
+be	O
+included	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+vertebral	O
+osteomyelitis	O
+in	O
+endemic	O
+settings	O
+,	O
+in	O
+particular	O
+when	O
+concomitant	O
+adjacent	O
+vascular	O
+infection	O
+exists	O
+.	O
+
+Since	O
+the	O
+discovery	O
+of	O
+the	O
+FMR1	O
+gene	O
+and	O
+the	O
+clinical	O
+and	O
+molecular	O
+characterization	O
+of	O
+Fragile	O
+X	O
+Syndrome	O
+in	O
+1991	O
+,	O
+more	O
+than	O
+141	O
+genes	O
+have	O
+been	O
+identified	O
+in	O
+the	O
+X	O
+-	O
+chromosome	O
+in	O
+these	O
+28	O
+years	O
+thanks	O
+to	O
+applying	O
+continuously	O
+evolving	O
+molecular	O
+techniques	O
+to	O
+X	O
+-	O
+linked	O
+intellectual	O
+disability	O
+(	O
+XLID	O
+)	O
+families	O
+.	O
+
+In	O
+the	O
+past	O
+decade	O
+,	O
+array	O
+comparative	O
+genomic	O
+hybridization	O
+and	O
+next	O
+generation	O
+sequencing	O
+technologies	O
+have	O
+accelerated	O
+gene	O
+discovery	O
+exponentially	O
+.	O
+
+Classically	O
+,	O
+XLID	O
+has	O
+been	O
+subdivided	O
+in	O
+syndromic	O
+intellectual	O
+disability	O
+(	O
+S	O
+-	O
+XLID)-where	O
+intellectual	O
+disability	O
+(	O
+ID	O
+)	O
+is	O
+always	O
+associated	O
+with	O
+other	O
+recognizable	O
+physical	O
+and/or	O
+neurological	O
+features	O
+-	O
+and	O
+non	O
+-	O
+specific	O
+or	O
+non	O
+-	O
+syndromic	O
+intellectual	O
+disability	O
+(	O
+NS	O
+-	O
+XLID	O
+)	O
+where	O
+the	O
+only	O
+common	O
+feature	O
+is	O
+ID	O
+.	O
+
+Nevertheless	O
+,	O
+new	O
+advances	O
+on	O
+the	O
+study	O
+of	O
+these	O
+entities	O
+have	O
+showed	O
+that	O
+this	O
+classification	O
+is	O
+not	O
+always	O
+clear	O
+-	O
+cut	O
+because	O
+distinct	O
+variants	O
+in	O
+several	O
+of	O
+these	O
+XLID	O
+genes	O
+can	O
+result	O
+in	O
+S	O
+-	O
+XLID	O
+as	O
+well	O
+as	O
+in	O
+NS	O
+-	O
+XLID	O
+.	O
+
+This	O
+review	O
+focuses	O
+on	O
+the	O
+current	O
+knowledge	O
+on	O
+the	O
+XLID	O
+genes	O
+involved	O
+in	O
+non	O
+-	O
+syndromic	O
+forms	O
+,	O
+with	O
+the	O
+emphasis	O
+on	O
+their	O
+pathogenic	O
+mechanism	O
+,	O
+thus	O
+allowing	O
+the	O
+possibility	O
+to	O
+elucidate	O
+why	O
+some	O
+of	O
+them	O
+can	O
+give	O
+both	O
+syndromic	O
+and	O
+non	O
+-	O
+syndromic	O
+phenotypes	O
+.	O
+
+Background	O
+:	O
+Endolymphatic	O
+hydrops	O
+(	O
+EH	O
+)	O
+is	O
+the	O
+histopathological	O
+hallmark	O
+of	O
+Ménière	O
+'s	O
+disease	O
+(	O
+MD	O
+)	O
+and	O
+has	O
+been	O
+found	O
+by	O
+in	O
+vivo	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+in	O
+patients	O
+with	O
+several	O
+inner	O
+ear	O
+syndromes	O
+without	O
+definite	O
+MD	B-LOC
+criteria	O
+.	O
+
+The	O
+incidence	B-EPI
+and	O
+relevance	O
+of	O
+this	O
+finding	O
+is	O
+under	O
+debate	O
+.	O
+
+Purpose	O
+:	O
+The	O
+purpose	O
+of	O
+the	O
+study	O
+is	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+and	O
+characteristics	O
+of	O
+EH	O
+and	O
+audiovestibular	O
+test	O
+results	O
+in	O
+groups	O
+of	O
+patients	O
+with	O
+fluctuating	O
+audiovestibular	O
+symptoms	O
+not	O
+fulfilling	O
+the	O
+actual	O
+criteria	O
+for	O
+definite	O
+MD	B-LOC
+and	O
+compare	O
+them	O
+with	O
+a	O
+similar	O
+group	O
+of	O
+patients	O
+with	O
+definite	O
+MD	B-LOC
+and	O
+a	O
+group	O
+of	O
+patients	O
+with	O
+recent	O
+idiopathic	O
+sudden	O
+neurosensory	O
+hearing	O
+loss	O
+(	O
+ISSNHL	O
+)	O
+.	O
+
+Material	O
+and	O
+Methods	O
+:	O
+170	O
+patients	O
+were	O
+included	O
+,	O
+83	O
+with	O
+definite	O
+MD	B-LOC
+,	O
+38	O
+with	O
+fluctuating	O
+sensorineural	O
+hearing	O
+loss	O
+,	O
+34	O
+with	O
+recurrent	O
+vertigo	O
+,	O
+and	O
+15	O
+with	O
+ISSNHL	O
+.	O
+
+The	O
+clinical	O
+variables	O
+,	O
+audiovestibular	O
+tests	O
+,	O
+and	O
+EH	O
+were	O
+evaluated	O
+and	O
+compared	O
+.	O
+
+Logistic	O
+proportional	O
+hazard	O
+models	O
+were	O
+used	O
+to	O
+obtain	O
+the	O
+odds	O
+ratio	O
+for	O
+hydrops	O
+development	O
+,	O
+including	O
+a	O
+multivariable	O
+adjusted	O
+model	O
+for	O
+potential	O
+confounders	O
+.	O
+
+Results	O
+:	O
+No	O
+statistical	O
+differences	O
+between	O
+groups	O
+were	O
+found	O
+regarding	O
+disease	O
+duration	O
+,	O
+episodes	O
+,	O
+Tumarkin	O
+spells	O
+,	O
+migraine	O
+,	O
+vascular	O
+risk	O
+factors	O
+,	O
+or	O
+vestibular	O
+tests	O
+;	O
+only	O
+hearing	O
+loss	O
+showed	O
+differences	O
+.	O
+
+Regarding	O
+EH	O
+,	O
+we	O
+found	O
+significant	O
+differences	O
+between	O
+groups	O
+,	O
+with	O
+odds	O
+ratio	O
+(	O
+OR	O
+)	O
+for	O
+EH	O
+presence	O
+in	O
+definite	O
+MD	B-LOC
+group	O
+vs.	O
+all	O
+other	O
+patients	O
+of	O
+11.43	O
+(	O
+4.5	O
+-	O
+29.02	O
+;	O
+p	O
+<	O
+0.001	O
+)	O
+.	O
+
+If	O
+the	O
+ISSNHL	O
+group	O
+was	O
+used	O
+as	O
+reference	O
+,	O
+OR	O
+was	O
+55.2	O
+(	O
+11.9	O
+-	O
+253.9	O
+;	O
+p	O
+<	O
+0.001	O
+)	O
+for	O
+the	O
+definite	O
+MD	B-LOC
+group	O
+,	O
+9.9	O
+(	O
+2.1	O
+-	O
+38.9	O
+;	O
+p	O
+=	O
+0.003	O
+)	O
+for	O
+the	O
+recurrent	O
+vertigo	O
+group	O
+,	O
+and	O
+5.1	O
+(	O
+1.2	O
+-	O
+21.7	O
+;	O
+p	O
+=	O
+0.03	O
+)	O
+for	O
+the	O
+group	O
+with	O
+fluctuating	O
+sensorineural	O
+hearing	O
+loss	O
+.	O
+
+Conclusion	O
+:	O
+The	O
+percentage	O
+of	O
+patients	O
+with	O
+EH	O
+varies	O
+between	O
+groups	O
+.	O
+
+It	O
+is	O
+minimal	O
+in	O
+the	O
+ISSNHL	O
+group	O
+and	O
+increases	O
+in	O
+groups	O
+with	O
+increasing	O
+fluctuating	O
+audiovestibular	O
+symptoms	O
+,	O
+with	O
+a	O
+rate	O
+of	O
+severe	O
+EH	O
+similar	O
+to	O
+the	O
+known	O
+rate	O
+of	O
+progression	O
+to	O
+definite	O
+MD	B-LOC
+in	O
+those	O
+groups	O
+,	O
+suggesting	O
+that	O
+presence	O
+of	O
+EH	O
+by	O
+MRI	O
+could	O
+be	O
+related	O
+to	O
+the	O
+risk	O
+of	O
+progression	O
+to	O
+definite	O
+MD	B-LOC
+.	O
+
+Thus	O
+,	O
+EH	O
+imaging	O
+in	O
+these	O
+patients	O
+is	O
+recommended	O
+.	O
+
+Congenital	O
+factor	O
+X	O
+(	O
+FX	O
+)	O
+deficiency	O
+is	O
+a	O
+rare	O
+bleeding	O
+disorder	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+one	O
+in	O
+one	O
+million	O
+.	O
+
+The	O
+proband	O
+,	O
+a	O
+2	O
+-	O
+year	O
+-	O
+old	O
+girl	O
+,	O
+exhibited	O
+easy	O
+bruising	O
+and	O
+a	O
+history	O
+of	O
+umbilical	O
+cord	O
+bleeding	O
+at	O
+birth	O
+.	O
+
+Prothrombin	O
+time	O
+(	O
+>	O
+40	O
+s	O
+)	O
+and	O
+activated	O
+partial	O
+thromboplastin	O
+time	O
+(	O
+65.0	O
+s	O
+)	O
+were	O
+prolonged	O
+.	O
+
+Marked	O
+declines	O
+in	O
+FX	O
+activity	O
+(	O
+<	O
+1	O
+%	O
+)	O
+and	O
+FX	O
+antigen	O
+levels	O
+(	O
+5	O
+%	O
+)	O
+were	O
+also	O
+observed	O
+.	O
+
+Genetic	O
+analysis	O
+of	O
+the	O
+proband	O
+identified	O
+two	O
+types	O
+of	O
+single	O
+-	O
+base	O
+substitutions	O
+,	O
+c.353G	O
+>	O
+A	O
+(	O
+p.	O
+Gly118Asp	O
+)	O
+and	O
+c.1303G	O
+>	O
+A	O
+(	O
+p.	O
+Gly435Ser	O
+)	O
+,	O
+indicating	O
+compound	O
+heterozygous	O
+congenital	O
+FX	O
+deficiency	O
+.	O
+
+Genetic	O
+analysis	O
+of	O
+family	O
+members	O
+revealed	O
+that	O
+her	O
+father	O
+and	O
+older	O
+sister	O
+(	O
+5	O
+-	O
+year	O
+-	O
+old	O
+)	O
+were	O
+also	O
+heterozygous	O
+for	O
+p.	O
+Gly118Asp	O
+,	O
+and	O
+that	O
+her	O
+mother	O
+was	O
+heterozygous	O
+for	O
+p.	O
+Gly435Ser	O
+.	O
+
+To	O
+improve	O
+the	O
+bleeding	O
+tendency	O
+,	O
+the	O
+proband	O
+received	O
+regular	O
+replacement	O
+of	O
+500	O
+units	O
+of	O
+PPSB	O
+-	O
+HT	O
+,	O
+a	O
+prothrombin	O
+complex	O
+concentrate	O
+(	O
+PCC	O
+)	O
+.	O
+
+Following	O
+continued	O
+regular	O
+replacement	O
+of	O
+500	O
+units	O
+of	O
+PPSB	O
+-	O
+HT	O
+once	O
+per	O
+week	O
+,	O
+the	O
+proband	O
+has	O
+exhibited	O
+no	O
+bleeding	O
+tendencies	O
+and	O
+no	O
+new	O
+bruises	O
+have	O
+been	O
+observed	O
+.	O
+
+There	O
+are	O
+no	O
+previous	O
+report	O
+of	O
+the	O
+use	O
+of	O
+PPSB	O
+-	O
+HT	O
+for	O
+regular	O
+FX	O
+replacement	O
+.	O
+
+Regular	O
+replacement	O
+therapy	O
+with	O
+PPSB	O
+-	O
+HT	O
+may	O
+be	O
+an	O
+effective	O
+method	O
+for	O
+preventative	O
+control	O
+of	O
+bleeding	O
+tendencies	O
+in	O
+FX	O
+deficiency	O
+.	O
+
+Coronavirus	O
+disease	O
+2019	O
+(	O
+COVID-19	O
+)	O
+is	O
+emerging	O
+as	O
+the	O
+greatest	O
+public	O
+health	O
+crisis	O
+in	O
+the	O
+early	O
+21	O
+st	O
+century	O
+.	O
+
+Its	O
+causative	O
+agent	O
+,	O
+Severe	O
+Acute	O
+Respiratory	O
+Syndrome	O
+coronavirus	O
+2	O
+(	O
+SARS	O
+-	O
+CoV-2	O
+)	O
+,	O
+is	O
+an	O
+enveloped	O
+single	O
+stranded	O
+positive	O
+-	O
+sense	O
+ribonucleic	O
+acid	O
+virus	O
+that	O
+enters	O
+cells	O
+via	O
+the	O
+angiotensin	O
+converting	O
+enzyme	O
+2	O
+receptor	O
+or	O
+several	O
+other	O
+receptors	O
+.	O
+
+While	O
+COVID-19	O
+primarily	O
+affects	O
+the	O
+respiratory	O
+system	O
+,	O
+other	O
+organs	O
+including	O
+the	O
+brain	O
+can	O
+be	O
+involved	O
+.	O
+
+In	O
+Western	O
+clinical	O
+studies	O
+,	O
+relatively	O
+mild	O
+neurological	O
+dysfunction	O
+such	O
+as	O
+anosmia	O
+and	O
+dysgeusia	O
+is	O
+frequent	O
+(	O
+~70	B-STAT
+-	O
+84	O
+%	O
+)	O
+while	O
+severe	O
+neurologic	O
+disorders	O
+such	O
+as	O
+stroke	O
+(	O
+~1	O
+-	O
+6	O
+%	O
+)	O
+and	O
+meningoencephalitis	O
+are	O
+less	O
+common	O
+.	O
+
+It	O
+is	O
+unclear	O
+how	O
+much	O
+SARS	O
+-	O
+CoV-2	O
+infection	O
+contributes	O
+to	O
+the	O
+incidence	B-EPI
+of	O
+stroke	O
+given	O
+co	O
+-	O
+morbidities	O
+in	O
+the	O
+affected	O
+patient	O
+population	O
+.	O
+
+Rarely	O
+,	O
+clinically	O
+-	O
+defined	O
+cases	O
+of	O
+acute	O
+disseminated	O
+encephalomyelitis	O
+,	O
+Guillain	O
+-	O
+Barré	O
+syndrome	O
+and	O
+acute	O
+necrotizing	O
+encephalopathy	O
+have	O
+been	O
+reported	O
+in	O
+COVID-19	O
+patients	O
+.	O
+
+Common	O
+neuropathological	O
+findings	O
+in	O
+the	O
+184	O
+patients	O
+reviewed	O
+include	O
+microglial	O
+activation	O
+(	O
+42.9	O
+%	O
+)	O
+with	O
+microglial	O
+nodules	O
+in	O
+a	O
+subset	O
+(	O
+33.3	O
+%	O
+)	O
+,	O
+lymphoid	O
+inflammation	O
+(	O
+37.5	O
+%	O
+)	O
+,	O
+acute	O
+hypoxic	O
+-	O
+ischemic	O
+changes	O
+(	O
+29.9	O
+%	O
+)	O
+,	O
+astrogliosis	O
+(	O
+27.7	O
+%	O
+)	O
+,	O
+acute	O
+/	O
+subacute	O
+brain	O
+infarcts	O
+(	O
+21.2	O
+%	O
+)	O
+,	O
+spontaneous	O
+hemorrhage	O
+(	O
+15.8	O
+%	O
+)	O
+,	O
+and	O
+microthrombi	O
+(	O
+15.2	O
+%	O
+)	O
+.	O
+
+In	O
+our	O
+institutional	O
+cases	O
+,	O
+we	O
+also	O
+note	O
+occasional	O
+anterior	O
+pituitary	O
+infarcts	O
+.	O
+
+COVID-19	O
+coagulopathy	O
+,	O
+sepsis	O
+,	O
+and	O
+acute	O
+respiratory	O
+distress	O
+likely	O
+contribute	O
+to	O
+a	O
+number	O
+of	O
+these	O
+findings	O
+.	O
+
+When	O
+present	O
+,	O
+central	O
+nervous	O
+system	O
+lymphoid	O
+inflammation	O
+is	O
+often	O
+minimal	O
+to	O
+mild	O
+,	O
+is	O
+detected	O
+best	O
+by	O
+immunohistochemistry	O
+and	O
+,	O
+in	O
+one	O
+study	O
+,	O
+indistinguishable	O
+from	O
+control	O
+sepsis	O
+cases	O
+.	O
+
+Some	O
+cases	O
+evince	O
+microglial	O
+nodules	O
+or	O
+neuronophagy	O
+,	O
+strongly	O
+supporting	O
+viral	O
+meningoencephalitis	O
+,	O
+with	O
+a	O
+proclivity	O
+for	O
+involvement	O
+of	O
+the	O
+medulla	O
+oblongata	O
+.	O
+
+The	O
+virus	O
+is	O
+detectable	O
+by	O
+reverse	O
+transcriptase	O
+polymerase	O
+chain	O
+reaction	O
+,	O
+immunohistochemistry	O
+,	O
+or	O
+electron	O
+microscopy	O
+in	O
+human	O
+cerebrum	O
+,	O
+cerebellum	O
+,	O
+cranial	O
+nerves	O
+,	O
+olfactory	O
+bulb	O
+,	O
+as	O
+well	O
+as	O
+in	O
+the	O
+olfactory	O
+epithelium	O
+;	O
+neurons	O
+and	O
+endothelium	O
+can	O
+also	O
+be	O
+infected	O
+.	O
+
+Review	O
+of	O
+the	O
+extant	O
+cases	O
+has	O
+limitations	O
+including	O
+selection	O
+bias	O
+and	O
+limited	O
+clinical	O
+information	O
+in	O
+some	O
+cases	O
+.	O
+
+Much	O
+remains	O
+to	O
+be	O
+learned	O
+about	O
+the	O
+effects	O
+of	O
+direct	O
+viral	O
+infection	O
+of	O
+brain	O
+cells	O
+and	O
+whether	O
+SARS	O
+-	O
+CoV-2	O
+persists	O
+long	O
+-	O
+term	O
+contributing	O
+to	O
+chronic	O
+symptomatology	O
+.	O
+
+Few	O
+studies	O
+have	O
+investigated	O
+transient	O
+global	O
+amnesia	O
+(	O
+TGA	O
+)	O
+in	O
+the	O
+context	O
+of	O
+a	O
+concussion	O
+and	O
+the	O
+concussion	O
+sequelae	O
+following	O
+TGA	O
+.	O
+
+Here	O
+we	O
+review	O
+the	O
+case	O
+of	O
+a	O
+43	O
+-	O
+year	O
+-	O
+old	O
+male	O
+with	O
+onset	O
+of	O
+transient	O
+global	O
+anterograde	O
+and	O
+retrograde	O
+amnesia	O
+22	O
+days	O
+after	O
+a	O
+sustained	O
+concussion	O
+.	O
+
+The	O
+patient	O
+'s	O
+head	O
+CT	O
+,	O
+MRI	O
+of	O
+brain	O
+,	O
+and	O
+EEG	O
+were	O
+reported	O
+normal	O
+,	O
+and	O
+the	O
+patient	O
+regained	O
+full	O
+cognitive	O
+function	O
+8	O
+h	O
+after	O
+the	O
+TGA	O
+episode	O
+,	O
+with	O
+no	O
+recollection	O
+of	O
+the	O
+conspiring	O
+events	O
+.	O
+
+Following	O
+the	O
+TGA	O
+episode	O
+,	O
+the	O
+patient	O
+experienced	O
+notable	O
+worsening	O
+of	O
+concussive	O
+symptoms	O
+,	O
+including	O
+headache	O
+,	O
+head	O
+pressure	O
+,	O
+anxiety	O
+,	O
+neck	O
+pain	O
+,	O
+feeling	O
+slowed	O
+down	O
+,	O
+fogginess	O
+,	O
+not	O
+feeling	O
+right	O
+,	O
+difficulty	O
+remembering	O
+,	O
+and	O
+fatigue	O
+.	O
+
+The	O
+patient	O
+remained	O
+symptomatic	O
+for	O
+32	O
+days	O
+after	O
+the	O
+TGA	O
+episode	O
+.	O
+
+We	O
+suggest	O
+that	O
+a	O
+lingering	O
+window	O
+of	O
+post	O
+-	O
+concussion	O
+cerebral	O
+vulnerability	O
+,	O
+which	O
+may	O
+extend	O
+beyond	O
+clinical	O
+recovery	O
+,	O
+could	O
+lead	O
+to	O
+increased	O
+susceptibility	O
+to	O
+acute	O
+cognitive	O
+deficits	O
+,	O
+such	O
+as	O
+TGA	O
+.	O
+
+Background	O
+and	O
+purpose	O
+Vascular	O
+Ehlers	O
+-	O
+Danlos	O
+syndrome	O
+is	O
+a	O
+rare	O
+inherited	O
+connective	O
+tissue	O
+disorder	O
+because	O
+of	O
+pathogenic	O
+variants	O
+in	O
+the	O
+COL3A1	O
+gene	O
+.	O
+
+Arterial	O
+complications	O
+can	O
+affect	O
+all	O
+anatomic	O
+areas	O
+and	O
+about	O
+25	O
+%	O
+involve	O
+supra	O
+-	O
+aortic	O
+trunks	O
+(	O
+SATs	O
+)	O
+but	O
+no	O
+systematic	O
+assessment	O
+of	O
+cervical	O
+artery	O
+lesions	O
+has	O
+been	O
+made	O
+.	O
+
+The	O
+primary	O
+objective	O
+was	O
+to	O
+determine	O
+an	O
+accurate	O
+prevalence	B-EPI
+of	O
+spontaneous	O
+SAT	O
+lesions	O
+in	O
+a	O
+large	O
+series	O
+of	O
+patients	O
+with	O
+vascular	O
+Ehlers	O
+-	O
+Danlos	O
+syndrome	O
+at	O
+diagnosis	O
+and	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+Secondary	O
+objectives	O
+were	O
+to	O
+study	O
+their	O
+neurological	O
+consequences	O
+(	O
+transient	O
+ischemic	O
+attack	O
+or	O
+stroke	O
+)	O
+and	O
+the	O
+possible	O
+relationships	O
+with	O
+sex	O
+,	O
+genotype	O
+,	O
+ascertainment	O
+status	O
+.	O
+
+Methods	O
+A	O
+retrospective	O
+review	O
+of	O
+a	O
+monocentric	O
+cohort	O
+of	O
+patients	O
+with	O
+molecularly	O
+proven	O
+vascular	O
+Ehlers	O
+-	O
+Danlos	O
+syndrome	O
+followed	O
+in	O
+a	O
+tertiary	O
+referral	O
+center	O
+from	O
+2000	O
+to	O
+2017	O
+.	O
+
+Results	O
+One	O
+hundred	O
+forty	O
+-	O
+four	O
+patients	O
+were	O
+analyzed	O
+,	O
+56.9	O
+%	O
+(	O
+n=82	O
+)	O
+had	O
+SAT	O
+lesions	O
+:	O
+64.6	O
+%	O
+females	O
+,	O
+74.4	O
+%	O
+index	O
+-	O
+case	O
+patients	O
+.	O
+
+Most	O
+lesions	O
+were	O
+identified	O
+in	O
+early	O
+arterial	O
+assessment	O
+(	O
+48	O
+%	O
+at	O
+first	O
+work	O
+-	O
+up	O
+,	O
+mean	O
+age	O
+of	O
+35.7±13.0	O
+years	O
+)	O
+.	O
+
+Cumulative	B-EPI
+incidence	I-EPI
+of	O
+a	O
+first	O
+identification	O
+of	O
+a	O
+SAT	O
+lesion	O
+was	O
+41.7	O
+%	O
+at	O
+40	O
+years	O
+old	O
+.	O
+
+On	O
+the	O
+complete	O
+period	O
+of	O
+survey	O
+,	O
+183	O
+SAT	O
+lesions	O
+(	O
+with	O
+132	O
+dissections	O
+and	O
+33	O
+aneurysms	O
+)	O
+were	O
+identified	O
+,	O
+mainly	O
+in	O
+internal	O
+carotid	O
+arteries	O
+(	O
+56.3	O
+%	O
+)	O
+and	O
+vertebral	O
+arteries	O
+(	O
+28.9	O
+%	O
+)	O
+,	O
+more	O
+rarely	O
+in	O
+patients	O
+with	O
+COL3A1	O
+null	O
+mutations	O
+(	O
+P	O
+=	O
+0.008	O
+)	O
+.	O
+
+Transient	O
+ischemic	O
+attack	O
+or	O
+stroke	O
+were	O
+reported	O
+in	O
+n=16	O
+(	O
+19.5	O
+%	O
+)	O
+of	O
+the	O
+82	O
+patients	O
+with	O
+SAT	O
+lesions	O
+without	O
+relation	O
+with	O
+age	O
+,	O
+sex	O
+,	O
+treatment	O
+,	O
+or	O
+hypertension	O
+.	O
+
+Conclusions	O
+Cervical	O
+artery	O
+lesions	O
+are	O
+frequent	O
+and	O
+mostly	O
+asymptomatic	O
+in	O
+patients	O
+with	O
+vascular	O
+Ehlers	O
+-	O
+Danlos	O
+syndrome	O
+.	O
+
+Local	O
+dissections	O
+and	O
+aneurysms	O
+are	O
+the	O
+most	O
+frequent	O
+type	O
+of	O
+lesions	O
+,	O
+but	O
+transient	O
+ischemic	O
+attack	O
+or	O
+stroke	O
+seem	O
+rare	O
+.	O
+
+Background	O
+Birth	O
+defect	O
+is	O
+widely	O
+used	O
+as	O
+a	O
+term	O
+for	O
+congenital	O
+anomalies	O
+.	O
+
+Children	O
+with	O
+cleft	O
+lip	O
+and	O
+palate	O
+may	O
+have	O
+serious	O
+speech	O
+,	O
+hearing	O
+,	O
+nutrition	O
+,	O
+and	O
+mental	O
+and	O
+social	O
+development	O
+disorders	O
+;	O
+therefore	O
+,	O
+this	O
+study	O
+was	O
+designed	O
+to	O
+determine	O
+the	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+cleft	O
+palate	O
+,	O
+lip	O
+,	O
+and	O
+cleft	O
+palate	O
+through	O
+systematic	O
+review	O
+and	O
+meta	O
+-	O
+analysis	O
+.	O
+
+Methods	O
+In	O
+this	O
+study	O
+,	O
+systematic	O
+review	O
+and	O
+meta	O
+-	O
+analysis	O
+of	O
+data	O
+from	O
+studies	O
+on	O
+the	O
+prevalence	B-EPI
+of	O
+cleft	O
+lip	O
+and	O
+palate	O
+in	O
+Scopus	O
+,	O
+Embase	O
+,	O
+Magiran	B-LOC
+,	O
+Web	O
+of	O
+Science	O
+(	O
+WoS	O
+)	O
+,	O
+PubMed	O
+and	O
+Science	O
+Direct	O
+databases	O
+were	O
+extracted	O
+between	O
+January	O
+2000	O
+and	O
+June	O
+2020	O
+.	O
+
+In	O
+order	O
+to	O
+perform	O
+the	O
+analysis	O
+of	O
+qualified	O
+studies	O
+,	O
+the	O
+model	O
+of	O
+random	O
+effects	O
+was	O
+used	O
+and	O
+the	O
+inconsistency	O
+of	O
+studies	O
+with	O
+I	O
+2	O
+index	O
+was	O
+investigated	O
+.	O
+
+Data	O
+analysis	O
+was	O
+performed	O
+with	O
+Comprehensive	O
+Meta	O
+-	O
+Analysis	O
+software	O
+(	O
+Version	O
+2	O
+)	O
+.	O
+
+Results	O
+According	O
+to	O
+the	O
+results	O
+of	O
+the	O
+present	O
+study	O
+on	O
+cleft	O
+palate	O
+,	O
+the	O
+total	O
+number	O
+of	O
+samples	O
+entered	O
+in	O
+the	O
+study	O
+in	O
+59	O
+studies	O
+were	O
+21,088,517	O
+individuals	O
+,	O
+the	O
+prevalence	B-EPI
+of	O
+cleft	O
+palate	O
+based	O
+on	O
+the	O
+meta	O
+-	O
+analysis	O
+of	O
+the	O
+reviewed	O
+studies	O
+in	O
+every	O
+1000	O
+live	O
+births	O
+was	O
+obtained	O
+0.33	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0.28	O
+-	O
+0.38	O
+)	O
+.	O
+
+In	O
+the	O
+case	O
+of	O
+cleft	O
+lip	O
+,	O
+the	O
+total	O
+number	O
+of	O
+samples	O
+entered	O
+in	O
+the	O
+57	O
+reviewed	O
+studies	O
+were	O
+17,907,569	O
+individuals	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+cleft	O
+lip	O
+obtained	O
+based	O
+on	O
+the	O
+meta	O
+-	O
+analysis	O
+of	O
+the	O
+reviewed	O
+studies	O
+was	O
+0.3	O
+in	O
+every	O
+1000	O
+live	O
+births	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0.26	O
+-	O
+0.34	O
+)	O
+,	O
+and	O
+in	O
+the	O
+case	O
+of	O
+cleft	O
+lip	O
+and	O
+palate	O
+,	O
+the	O
+total	O
+number	O
+of	O
+samples	O
+entered	O
+in	O
+the	O
+55	O
+reviewed	O
+studies	O
+was	O
+17,894,673	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+cleft	O
+lip	O
+and	O
+palate	O
+based	O
+on	O
+the	O
+meta	O
+-	O
+analysis	O
+of	O
+the	O
+studies	O
+reviewed	O
+in	O
+each	O
+1000	O
+live	O
+births	O
+was	O
+0.45	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0.38	O
+-	O
+0.52	O
+)	O
+.	O
+
+Conclusion	O
+Due	O
+to	O
+the	O
+high	O
+prevalence	B-EPI
+of	O
+oral	O
+clefts	O
+such	O
+as	O
+cleft	O
+palate	O
+,	O
+cleft	O
+lip	O
+,	O
+and	O
+cleft	O
+lip	O
+and	O
+palate	O
+;	O
+health	O
+system	O
+policymakers	O
+need	O
+to	O
+take	O
+precautionary	O
+measures	O
+to	O
+reduce	O
+the	O
+number	O
+of	O
+patients	O
+,	O
+as	O
+well	O
+as	O
+diagnostic	O
+and	O
+therapeutic	O
+measures	O
+to	O
+reduce	O
+the	O
+effects	O
+of	O
+this	O
+disorder	O
+in	O
+children	O
+.	O
+
+To	O
+evaluate	O
+the	O
+incidence	B-EPI
+and	O
+predictive	O
+risk	O
+factors	O
+of	O
+complications	O
+in	O
+patients	O
+who	O
+underwent	O
+thyroid	O
+surgery	O
+at	O
+our	O
+hospital	O
+with	O
+a	O
+residency	O
+training	O
+program	O
+.	O
+
+This	O
+retrospective	O
+cohort	O
+study	O
+analyzed	O
+the	O
+complications	O
+in	O
+all	O
+patients	O
+who	O
+underwent	O
+thyroid	O
+surgery	O
+between	O
+January	O
+2008	O
+and	O
+December	O
+2017	O
+.	O
+
+Demographic	O
+data	O
+,	O
+preoperative	O
+diagnosis	O
+based	O
+on	O
+fine	O
+needle	O
+aspiration	O
+cytology	O
+,	O
+surgical	O
+approach	O
+,	O
+permanent	O
+pathology	O
+,	O
+postoperative	O
+complications	O
+,	O
+and	O
+factors	O
+associated	O
+with	O
+complications	O
+were	O
+recorded	O
+.	O
+
+At	O
+our	O
+hospital	O
+,	O
+456	O
+patients	O
+underwent	O
+thyroidectomy	O
+.	O
+
+The	O
+most	O
+common	O
+surgical	O
+complications	O
+were	O
+asymptomatic	O
+biochemical	O
+hypocalcemia	O
+and	O
+symptomatic	O
+hypocalcemia	O
+in	O
+109	B-STAT
+(	O
+23.9	O
+%	O
+)	O
+and	O
+50	B-STAT
+(	O
+11	O
+%	O
+)	O
+patients	O
+,	O
+respectively	O
+.	O
+
+Other	O
+surgical	O
+complications	O
+included	O
+permanent	O
+hypocalcemia	O
+,	O
+transient	O
+vocal	O
+cord	O
+palsy	O
+,	O
+permanent	O
+vocal	O
+cord	O
+palsy	O
+,	O
+hematoma	O
+,	O
+seroma	O
+,	O
+chyle	O
+fistula	O
+,	O
+and	O
+Horner	O
+'s	O
+syndrome	O
+.	O
+
+Mean	O
+age	O
+>	O
+45	O
+years	O
+and	O
+more	O
+extensive	O
+surgery	O
+were	O
+significantly	O
+associated	O
+with	O
+overall	O
+complications	O
+(	O
+P	O
+=	O
+0.003	O
+;	O
+<	O
+0.001	O
+)	O
+.	O
+
+Mean	O
+age	O
+>	O
+50	O
+years	O
+and	O
+vitamin	O
+D	O
+level	O
+<	O
+25	O
+nmol	O
+/	O
+L	O
+(	O
+<	O
+10	O
+ng	O
+/	O
+mL	O
+)	O
+were	O
+significantly	O
+associated	O
+with	O
+hypocalcemia	O
+(	O
+P	O
+=	O
+0.008	O
+;	O
+<	O
+0.001	O
+)	O
+.	O
+
+Moreover	O
+,	O
+the	O
+extent	O
+of	O
+surgery	O
+and	O
+advanced	O
+thyroid	O
+carcinoma	O
+were	O
+significantly	O
+associated	O
+with	O
+vocal	O
+cord	O
+palsy	O
+(	O
+P	O
+<	O
+0.001	O
+;	O
+0.05	O
+)	O
+.	O
+
+Hypocalcemia	O
+and	O
+vocal	O
+cord	O
+palsy	O
+are	O
+the	O
+most	O
+significant	O
+complications	O
+.	O
+
+Thyroid	O
+surgery	O
+can	O
+be	O
+performed	O
+safely	O
+by	O
+senior	O
+residents	O
+in	O
+the	O
+residency	O
+training	O
+program	O
+under	O
+the	O
+direct	O
+supervision	O
+of	O
+an	O
+experienced	O
+surgeon	O
+.	O
+
+In	O
+contrast	O
+to	O
+acute	O
+peripheral	O
+nerve	O
+injury	O
+,	O
+the	O
+molecular	O
+response	O
+of	O
+Schwann	O
+cells	O
+in	O
+chronic	O
+neuropathies	O
+remains	O
+poorly	O
+understood	O
+.	O
+
+Onion	O
+bulb	O
+structures	O
+are	O
+a	O
+pathological	O
+hallmark	O
+of	O
+demyelinating	O
+neuropathies	O
+,	O
+but	O
+the	O
+nature	O
+of	O
+these	O
+formations	O
+is	O
+unknown	O
+.	O
+
+Here	O
+,	O
+we	O
+show	O
+that	O
+Schwann	O
+cells	O
+induce	O
+the	O
+expression	O
+of	O
+Neuregulin-1	O
+type	O
+I	O
+(	O
+NRG1	O
+-	O
+I	O
+)	O
+,	O
+a	O
+paracrine	O
+growth	O
+factor	O
+,	O
+in	O
+various	O
+chronic	O
+demyelinating	O
+diseases	O
+.	O
+
+Genetic	O
+disruption	O
+of	O
+Schwann	O
+cell	O
+-	O
+derived	O
+NRG1	O
+signalling	O
+in	O
+a	O
+mouse	O
+model	O
+of	O
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+Disease	O
+1A	O
+(	O
+CMT1A	O
+)	O
+,	O
+suppresses	O
+hypermyelination	O
+and	O
+the	O
+formation	O
+of	O
+onion	O
+bulbs	O
+.	O
+
+Transgenic	O
+overexpression	O
+of	O
+NRG1	O
+-	O
+I	O
+in	O
+Schwann	O
+cells	O
+on	O
+a	O
+wildtype	O
+background	O
+is	O
+sufficient	O
+to	O
+mediate	O
+an	O
+interaction	O
+between	O
+Schwann	O
+cells	O
+via	O
+an	O
+ErbB2	O
+receptor	O
+-	O
+MEK	O
+/	O
+ERK	O
+signaling	O
+axis	O
+,	O
+which	O
+causes	O
+onion	O
+bulb	O
+formations	O
+and	O
+results	O
+in	O
+a	O
+peripheral	O
+neuropathy	O
+reminiscent	O
+of	O
+CMT1A.	O
+
+We	O
+suggest	O
+that	O
+diseased	O
+Schwann	O
+cells	O
+mount	O
+a	O
+regeneration	O
+program	O
+that	O
+is	O
+beneficial	O
+in	O
+acute	O
+nerve	O
+injury	O
+,	O
+but	O
+that	O
+overstimulation	O
+of	O
+Schwann	O
+cells	O
+in	O
+chronic	O
+neuropathies	O
+is	O
+detrimental	O
+.	O
+
+Background	O
+/	O
+objectives	O
+This	O
+retrospective	O
+study	O
+evaluated	O
+the	O
+prevalence	B-EPI
+of	O
+dental	O
+anomalies	O
+of	O
+number	O
+in	O
+different	O
+subphenotypes	O
+of	O
+isolated	O
+cleft	O
+palate	O
+.	O
+
+Materials	O
+/	O
+methods	O
+The	O
+sample	O
+comprised	O
+26	O
+individuals	O
+with	O
+submucous	O
+cleft	O
+palate	O
+(	O
+group	O
+S	O
+)	O
+and	O
+68	O
+individuals	O
+with	O
+complete	O
+cleft	O
+palate	O
+(	O
+group	O
+C	O
+)	O
+aged	O
+between	O
+9	O
+and	O
+12	O
+years	O
+from	O
+a	O
+single	O
+centre	O
+.	O
+
+Panoramic	O
+radiographs	O
+were	O
+evaluated	O
+regarding	O
+the	O
+presence	O
+of	O
+dental	O
+anomalies	O
+of	O
+number	O
+in	O
+permanent	O
+teeth	O
+.	O
+
+Intergroup	O
+comparison	O
+was	O
+performed	O
+using	O
+chi	O
+-	O
+square	O
+tests	O
+(	O
+P	O
+<	O
+0.05	O
+)	O
+.	O
+
+Results	O
+Tooth	O
+agenesis	O
+was	O
+found	O
+in	O
+34.61	O
+and	O
+36.76	O
+per	O
+cent	O
+of	O
+group	O
+S	O
+and	O
+group	O
+C	O
+,	O
+respectively	O
+.	O
+
+The	O
+most	O
+commonly	O
+missing	O
+teeth	O
+were	O
+the	O
+maxillary	O
+second	O
+premolar	O
+,	O
+maxillary	O
+lateral	O
+incisor	O
+,	O
+and	O
+mandibular	O
+second	O
+premolar	O
+.	O
+
+Supernumerary	O
+teeth	O
+were	O
+found	O
+in	O
+none	O
+and	O
+1.47	O
+per	O
+cent	O
+of	O
+the	O
+individuals	O
+with	O
+submucous	O
+and	O
+complete	O
+cleft	O
+palate	O
+,	O
+respectively	O
+.	O
+
+No	O
+statistically	O
+significant	O
+difference	O
+was	O
+found	O
+between	O
+groups	O
+for	O
+the	O
+frequency	O
+of	O
+tooth	O
+agenesis	O
+and	O
+supernumerary	O
+teeth	O
+.	O
+
+Limitations	O
+Only	O
+dental	O
+anomalies	O
+of	O
+number	O
+were	O
+evaluated	O
+.	O
+
+Conclusions	O
+/	O
+implications	O
+Individuals	O
+with	O
+submucous	O
+and	O
+complete	O
+cleft	O
+palate	O
+showed	O
+similar	O
+prevalence	B-EPI
+for	O
+tooth	O
+agenesis	O
+and	O
+supernumerary	O
+teeth	O
+.	O
+
+Dental	O
+anomalies	O
+frequency	O
+seems	O
+not	O
+to	O
+be	O
+a	O
+discriminator	O
+for	O
+subphenotypes	O
+of	O
+cleft	O
+palate	O
+.	O
+
+Objective	O
+This	O
+study	O
+aimed	O
+to	O
+evaluate	O
+the	O
+epidemiological	O
+and	O
+clinicopathological	O
+spectrum	O
+of	O
+ocular	O
+malignancies	O
+among	O
+patients	O
+presenting	O
+to	O
+a	O
+teaching	O
+hospital	O
+in	O
+Northern	B-LOC
+India	I-LOC
+.	O
+
+Methods	O
+A	O
+total	O
+of	O
+246	O
+histopathologically	O
+diagnosed	O
+patients	O
+with	O
+ocular	O
+malignancies	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+Tumor	O
+type	O
+and	O
+size	O
+,	O
+primary	O
+origin	O
+and	O
+location	O
+of	O
+tumor	O
+,	O
+clinical	O
+staging	O
+,	O
+radiological	O
+findings	O
+,	O
+histopathological	O
+type	O
+,	O
+and	O
+treatment	O
+outcomes	O
+were	O
+assessed	O
+.	O
+
+Results	O
+Overall	O
+,	O
+males	O
+over	O
+55	O
+years	O
+of	O
+age	O
+were	O
+most	O
+commonly	O
+affected	O
+and	O
+the	O
+majority	O
+of	O
+cases	O
+were	O
+primary	O
+ocular	O
+or	O
+adnexal	O
+malignancies	O
+(	O
+n	O
+=	O
+226	B-STAT
+;	O
+91.87	O
+%	O
+)	O
+.	O
+
+The	O
+eyelids	O
+and	O
+periocular	O
+structures	O
+(	O
+n	O
+=	O
+92	B-STAT
+;	O
+37.40	O
+%	O
+)	O
+were	O
+the	O
+most	O
+commonly	O
+involved	O
+site	O
+,	O
+followed	O
+by	O
+the	O
+orbit	O
+(	O
+n	O
+=	O
+72	B-STAT
+;	O
+29.27	O
+%	O
+)	O
+,	O
+ocular	O
+surface	O
+(	O
+n	O
+=	O
+46	B-STAT
+;	O
+18.70	O
+%	O
+)	O
+and	O
+intraocular	O
+region	O
+(	O
+n	O
+=	O
+36	B-STAT
+;	O
+14.63	O
+%	O
+)	O
+.	O
+
+The	O
+majority	O
+of	O
+the	O
+patients	O
+(	O
+n	O
+=	O
+68	B-STAT
+;	O
+27.64	O
+%	O
+)	O
+were	O
+managed	O
+by	O
+primary	O
+surgical	O
+excision	O
+and	O
+reconstruction	O
+.	O
+
+However	O
+,	O
+46	O
+patients	O
+(	O
+18.70	O
+%	O
+)	O
+with	O
+advanced	O
+lesions	O
+underwent	O
+neoadjuvant	O
+chemotherapy	O
+followed	O
+by	O
+surgical	O
+excision	O
+and	O
+more	O
+extensive	O
+orbital	O
+lesions	O
+were	O
+treated	O
+by	O
+exenteration	O
+followed	O
+by	O
+adjuvant	O
+chemotherapy	O
+(	O
+n=48	O
+;	O
+19.51	O
+%	O
+)	O
+,	O
+while	O
+patients	O
+with	O
+metastatic	O
+tumor	O
+were	O
+given	O
+palliative	O
+chemotherapy	O
+/	O
+external	O
+beam	O
+radiation	O
+therapy	O
+(	O
+n=	O
+46	B-STAT
+;	O
+18.70	O
+%	O
+)	O
+.	O
+
+Overall	O
+,	O
+45.12	O
+%	O
+of	O
+patients	O
+were	O
+cured	O
+completely	O
+,	O
+15.45	O
+%	O
+showed	O
+a	O
+partial	O
+response	O
+to	O
+the	O
+treatment	O
+,	O
+13.04	O
+%	O
+had	O
+progressive	O
+disease	O
+and	O
+16.67	O
+%	O
+demonstrated	O
+disease	O
+recurrence	O
+.	O
+
+Conclusion	O
+A	O
+clinicopathological	O
+analysis	O
+of	O
+ocular	O
+malignancies	O
+at	O
+a	O
+teaching	O
+hospital	O
+in	O
+Northern	B-LOC
+India	I-LOC
+indicated	O
+the	O
+preponderance	O
+of	O
+primary	O
+ocular	O
+malignancies	O
+,	O
+with	O
+eyelid	O
+sebaceous	O
+gland	O
+carcinomas	O
+being	O
+the	O
+most	O
+common	O
+pathological	O
+diagnosis	O
+.	O
+
+Most	O
+of	O
+our	O
+patients	O
+had	O
+advanced	O
+and	O
+extensive	O
+disease	O
+among	O
+them	O
+majority	O
+belonged	O
+to	O
+the	O
+rural	O
+background	O
+and	O
+poor	O
+socio	O
+-	O
+economic	O
+status	O
+.	O
+
+Varicella	O
+is	O
+a	O
+highly	O
+contagious	O
+,	O
+infectious	O
+disease	O
+caused	O
+by	O
+the	O
+varicella	O
+-	O
+zoster	O
+virus	O
+.	O
+
+Those	O
+at	O
+higher	O
+risk	O
+of	O
+severe	O
+complications	O
+are	O
+immunocompromised	O
+individuals	O
+,	O
+adults	O
+,	O
+non	O
+-	O
+immune	O
+pregnant	O
+women	O
+,	O
+and	O
+newborns	O
+.	O
+
+According	O
+to	O
+the	O
+gestational	O
+time	O
+,	O
+when	O
+varicella	O
+-	O
+zoster	O
+virus	O
+infection	O
+is	O
+acquired	O
+during	O
+pregnancy	O
+,	O
+serious	O
+complications	O
+can	O
+potentially	O
+occur	O
+for	O
+both	O
+the	O
+woman	O
+and	O
+the	O
+fetus	O
+.	O
+
+The	O
+present	O
+study	O
+was	O
+conducted	O
+to	O
+assess	O
+the	O
+profile	O
+of	O
+varicella	O
+susceptibility	O
+in	O
+pregnant	O
+women	O
+in	O
+Apulia	B-LOC
+,	O
+a	O
+large	O
+region	O
+in	O
+Southern	B-LOC
+Italy	I-LOC
+,	O
+from	O
+2016	O
+to	O
+2019	O
+.	O
+
+The	O
+data	O
+showed	O
+that	O
+pregnant	O
+women	O
+between	O
+the	O
+age	O
+of	O
+15	O
+-	O
+24	O
+and	O
+40	O
+-	O
+49	O
+years	O
+,	O
+the	O
+youngest	O
+and	O
+the	O
+oldest	O
+,	O
+respectively	O
+,	O
+are	O
+the	O
+most	O
+protected	O
+against	O
+varicella	O
+-	O
+zoster	O
+virus	O
+infection	O
+,	O
+exceeding	O
+the	O
+prevalence	B-EPI
+rate	O
+of	O
+90	B-STAT
+%	I-STAT
+.	O
+
+Conversely	O
+,	O
+pregnant	O
+women	O
+between	O
+the	O
+age	O
+of	O
+25	O
+and	O
+34	O
+years	O
+seem	O
+to	O
+be	O
+the	O
+most	O
+vulnerable	O
+and	O
+the	O
+most	O
+at	O
+risk	O
+for	O
+acquiring	O
+varicella	O
+-	O
+zoster	O
+virus	O
+infection	O
+during	O
+pregnancy	O
+.	O
+
+Analysis	O
+of	O
+the	O
+immunity	O
+status	O
+against	O
+varicella	O
+should	O
+be	O
+introduced	O
+as	O
+a	O
+screening	O
+test	O
+before	O
+pregnancy	O
+,	O
+together	O
+with	O
+a	O
+strategic	O
+vaccination	O
+campaign	O
+targeting	O
+non	O
+-	O
+immune	O
+women	O
+of	O
+childbearing	O
+age	O
+,	O
+in	O
+order	O
+to	O
+reduce	O
+the	O
+risk	O
+of	O
+congenital	O
+and	O
+perinatal	O
+varicella	O
+.	O
+
+Objectives	O
+Determine	O
+the	O
+types	O
+,	O
+incidence	B-EPI
+,	O
+mortality	O
+rate	O
+,	O
+and	O
+clinical	O
+status	O
+of	O
+youth	O
+diabetes	O
+at	O
+Bach	O
+Christian	O
+Hospital	O
+(	O
+BCH	B-LOC
+)	O
+,	O
+Qalandarabad	B-LOC
+,	O
+Pakistan	B-LOC
+.	O
+
+Methods	O
+Analysis	O
+of	O
+incidence	B-EPI
+and	O
+mortality	O
+data	O
+of	O
+all	O
+patients	O
+(	O
+<	O
+25	O
+year	O
+(	O
+y	O
+)	O
+)	O
+diagnosed	O
+from	O
+January	O
+2014	O
+-	O
+June	O
+2019	O
+,	O
+and	O
+also	O
+analysis	O
+of	O
+clinical	O
+status	O
+of	O
+patients	O
+<	O
+25y	O
+seen	O
+in	O
+2018/2019	O
+.	O
+
+Results	O
+Ninety	O
+-	O
+three	O
+patients	O
+were	O
+seen	O
+over	O
+the	O
+study	O
+period	O
+.	O
+
+Eighty	O
+-	O
+eight	O
+were	O
+type	O
+1	O
+diabetes	O
+(	O
+T1D	O
+)	O
+,	O
+51.1	O
+%	O
+female	O
+.	O
+
+Age	O
+of	O
+diagnosis	O
+was	O
+0.8	O
+-	O
+24.5	O
+years	O
+(	O
+y	O
+)	O
+(	O
+mean	O
+=	O
+11.4	O
+y	O
+,	O
+SD	O
+=	O
+6.2y	O
+)	O
+.	O
+
+15.1	B-STAT
+%	I-STAT
+were	O
+0	O
+-	O
+4y	O
+,	O
+31.4	O
+%	O
+5	O
+-	O
+9	O
+y	O
+,	O
+24.4	O
+%	O
+10	O
+-	O
+14y	O
+,	O
+19.8	O
+%	O
+15	O
+-	O
+19y	O
+,	O
+and	O
+9.3	O
+%	O
+20	O
+-	O
+24y	O
+.	O
+
+Minimum	O
+incidence	B-EPI
+for	O
+the	O
+Mansehra	O
+tehsil	O
+administrative	O
+district	O
+was	O
+calculated	O
+as	O
+1.0	B-STAT
+per	I-STAT
+100,000	I-STAT
+population	I-STAT
+<	O
+15y	O
+/	O
+y	O
+,	O
+1.2	B-STAT
+per	I-STAT
+100,000	I-STAT
+<	O
+20y	O
+/	O
+y	O
+and	O
+1.1	B-STAT
+per	I-STAT
+100,000	I-STAT
+<	O
+25y	O
+/	O
+y	O
+;	O
+the	O
+degree	O
+of	O
+ascertainment	O
+could	O
+not	O
+be	O
+assessed	O
+.	O
+
+A	O
+further	O
+four	O
+patients	O
+were	O
+diagnosed	O
+with	O
+thiamine	O
+-	O
+responsive	O
+megaloblastic	O
+anaemia	O
+(	O
+TRMA	O
+)	O
+,	O
+all	O
+male	O
+,	O
+three	O
+from	O
+the	O
+same	O
+consanguineous	O
+family	O
+,	O
+and	O
+were	O
+treated	O
+with	O
+high	O
+-	O
+dose	O
+thiamine	O
+.	O
+
+One	O
+other	O
+patient	O
+was	O
+diagnosed	O
+with	O
+type	O
+2	O
+diabetes	O
+.	O
+
+Three	O
+T1D	O
+and	O
+one	O
+TRMA	O
+patient	O
+died	O
+during	O
+the	O
+study	O
+period	O
+.	O
+
+The	O
+standardised	O
+mortality	O
+rate	O
+for	O
+T1D	O
+was	O
+9.4	O
+,	O
+but	O
+vital	O
+status	O
+was	O
+unknown	O
+for	O
+13	O
+patients	O
+.	O
+
+The	O
+mean	O
+/	O
+median	O
+HbA1c	O
+of	O
+T1D	O
+patients	O
+seen	O
+in	O
+2018/2019	O
+was	O
+9.1%/9.2	O
+%	O
+(	O
+76/77	O
+mmol	O
+/	O
+mol	O
+)	O
+.	O
+
+Conclusions	O
+Minimum	O
+T1D	O
+incidence	B-EPI
+in	O
+Mansehra	O
+tehsil	O
+is	O
+double	O
+the	O
+previously	O
+reported	O
+value	O
+for	O
+Pakistan	B-LOC
+(	O
+from	O
+1990	O
+to	O
+1999	O
+)	O
+,	O
+although	O
+is	O
+still	O
+low	O
+compared	O
+to	O
+most	O
+other	O
+countries	O
+.	O
+
+Considering	O
+the	O
+limited	O
+resources	O
+available	O
+,	O
+patients	O
+attending	O
+BCH	B-LOC
+are	O
+achieving	O
+fair	O
+glycemic	O
+control	O
+.	O
+
+The	O
+TRMA	O
+cases	O
+show	O
+the	O
+importance	O
+of	O
+genetic	O
+testing	O
+in	O
+atypical	O
+cases	O
+.	O
+
+COVID-19	O
+(	O
+coronavirus	O
+disease	O
+2019	O
+)	O
+represents	O
+a	O
+prothrombotic	O
+disorder	O
+,	O
+and	O
+there	O
+have	O
+been	O
+several	O
+reports	O
+of	O
+platelet	O
+factor	O
+4	O
+/	O
+heparin	O
+antibodies	O
+being	O
+present	O
+in	O
+COVID-19	O
+-	O
+infected	O
+patients	O
+.	O
+
+This	O
+has	O
+thus	O
+been	O
+identified	O
+in	O
+some	O
+publications	O
+as	O
+representing	O
+a	O
+high	O
+incidence	B-EPI
+of	O
+heparin	O
+-	O
+induced	O
+thrombocytopenia	O
+(	O
+HIT	O
+)	O
+,	O
+whereas	O
+in	O
+others	O
+,	O
+findings	O
+have	O
+been	O
+tempered	O
+by	O
+general	O
+lack	O
+of	O
+functional	O
+reactivity	O
+using	O
+confirmation	O
+assays	O
+of	O
+serotonin	O
+release	O
+assay	O
+(	O
+SRA	O
+)	O
+or	O
+heparin	O
+-	O
+induced	O
+platelet	O
+aggregation	O
+(	O
+HIPA	O
+)	O
+.	O
+
+Moreover	O
+,	O
+in	O
+at	O
+least	O
+two	O
+publications	O
+,	O
+data	O
+are	O
+provided	O
+suggesting	O
+that	O
+antibodies	O
+can	O
+arise	O
+in	O
+heparin	O
+naïve	O
+patients	O
+or	O
+that	O
+platelet	O
+activation	O
+may	O
+not	O
+be	O
+heparin	O
+-	O
+dependent	O
+.	O
+
+From	O
+this	O
+literature	O
+,	O
+we	O
+would	O
+conclude	O
+that	O
+platelet	O
+factor	O
+4	O
+/	O
+heparin	O
+antibodies	O
+can	O
+be	O
+observed	O
+in	O
+COVID-19	O
+-	O
+infected	O
+patients	O
+,	O
+and	O
+they	O
+may	O
+occur	O
+at	O
+higher	O
+incidence	B-EPI
+than	O
+in	O
+historical	O
+non	O
+-	O
+COVID-19	O
+-	O
+infected	O
+cohorts	O
+.	O
+
+However	O
+,	O
+the	O
+situation	O
+is	O
+complex	O
+,	O
+since	O
+not	O
+all	O
+platelet	O
+factor	O
+4	O
+/	O
+heparin	O
+antibodies	O
+may	O
+lead	O
+to	O
+platelet	O
+activation	O
+,	O
+and	O
+not	O
+all	O
+identified	O
+antibodies	O
+are	O
+heparin	O
+-	O
+dependent	O
+,	O
+such	O
+that	O
+they	O
+do	O
+not	O
+necessarily	O
+reflect	O
+	O
+true	O
+	O
+HIT	O
+.	O
+
+Most	O
+recently	O
+,	O
+a	O
+	O
+HIT	O
+-	O
+like	O
+	O
+syndrome	O
+has	O
+reported	O
+in	O
+patients	O
+who	O
+have	O
+been	O
+vaccinated	O
+against	O
+COVID-19	O
+.	O
+
+Accordingly	O
+,	O
+much	O
+more	O
+is	O
+yet	O
+to	O
+be	O
+learnt	O
+about	O
+the	O
+insidious	O
+disease	O
+that	O
+COVID-19	O
+represents	O
+,	O
+including	O
+autoimmune	O
+outcomes	O
+in	O
+affected	O
+patients	O
+.	O
+
+After	O
+a	O
+female	O
+patient	O
+had	O
+presented	O
+with	O
+advanced	O
+renal	O
+failure	O
+,	O
+bilateral	O
+enormous	O
+increase	O
+in	O
+kidney	O
+size	O
+radiologically	O
+,	O
+urinary	O
+tract	O
+infection	O
+(	O
+E.	O
+coli	O
+)	O
+and	O
+septicemia	O
+,	O
+autopsy	O
+disclosed	O
+megalocytic	O
+interstitial	O
+nephritis	O
+(	O
+MIN	O
+)	O
+.	O
+
+Clinical	O
+and	O
+pathological	O
+differentiation	O
+from	O
+renal	O
+parenchymal	O
+malakoplakia	O
+(	O
+RPM	O
+)	O
+is	O
+discussed	O
+.	O
+
+A	O
+literature	O
+survey	O
+of	O
+15	O
+cases	O
+of	O
+MIN	O
+and	O
+35	O
+observations	O
+of	O
+RPM	O
+points	O
+to	O
+certain	O
+differences	O
+between	O
+the	O
+two	O
+entities	O
+,	O
+i.e.	O
+
+an	O
+increased	O
+incidence	B-EPI
+of	O
+bilateral	O
+pathology	O
+in	O
+MIN	O
+,	O
+mor	O
+frequent	O
+extrarenal	O
+localizations	O
+in	O
+RPM	O
+,	O
+absent	O
+Michaelis	O
+-	O
+Gutmann	O
+bodies	O
+and	O
+a	O
+predominantly	O
+cortical	O
+distribution	O
+in	O
+MIN	O
+.	O
+
+The	O
+similarities	O
+,	O
+however	O
+,	O
+suggest	O
+that	O
+the	O
+two	O
+conditions	O
+might	O
+represent	O
+different	O
+stages	O
+of	O
+one	O
+and	O
+the	O
+same	O
+disease	O
+process	O
+.	O
+
+OBJECTIVE	O
+:	O
+Intracranial	O
+aneurysms	O
+are	O
+not	O
+common	O
+in	O
+young	O
+age	O
+patients	O
+.	O
+
+We	O
+sought	O
+to	O
+find	O
+the	O
+characteristics	O
+of	O
+the	O
+intracranial	O
+aneurysms	O
+in	O
+patients	O
+under	O
+20	O
+years	O
+of	O
+age	O
+.	O
+
+METHODS	O
+:	O
+We	O
+reviewed	O
+23	O
+consecutive	O
+patients	O
+≤20	O
+years	O
+of	O
+age	O
+treated	O
+for	O
+their	O
+intracranial	O
+aneurysms	O
+during	O
+the	O
+period	O
+from	O
+1995	O
+to	O
+2017	O
+.	O
+
+From	O
+medical	O
+records	O
+and	O
+imaging	O
+studies	O
+,	O
+we	O
+gathered	O
+data	O
+on	O
+age	O
+,	O
+sex	O
+,	O
+presentation	O
+,	O
+associated	O
+medical	O
+condition	O
+,	O
+location	O
+and	O
+characteristics	O
+of	O
+aneurysms	O
+,	O
+treatment	O
+and	O
+clinical	O
+outcomes	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+patients	O
+'	O
+ages	O
+ranged	O
+from	O
+13	O
+months	O
+to	O
+20	O
+years	O
+(	O
+median	O
+,	O
+14	O
+years	O
+)	O
+.	O
+
+There	O
+were	O
+16	O
+males	O
+and	O
+seven	O
+females	O
+(	O
+male	O
+to	O
+female	O
+ratio	O
+,	O
+2.3	O
+:	O
+1	B-STAT
+)	I-STAT
+with	I-STAT
+31	I-STAT
+aneurysms	O
+.	O
+
+Clinical	O
+presentations	O
+included	O
+sudden	O
+severe	O
+headache	O
+in	O
+61	O
+%	O
+,	O
+followed	O
+by	O
+altered	O
+mentality	O
+in	O
+17	O
+%	O
+and	O
+seizure	O
+in	O
+17	B-STAT
+%	I-STAT
+.	O
+
+More	O
+than	O
+one	O
+-	O
+fourth	O
+patients	O
+had	O
+specific	O
+medical	O
+conditions	O
+related	O
+to	O
+the	O
+development	O
+of	O
+the	O
+cerebral	O
+aneurysms	O
+.	O
+
+The	O
+majority	O
+of	O
+aneurysms	O
+occurred	O
+in	O
+the	O
+anterior	O
+circulation	O
+(	O
+71	O
+%	O
+)	O
+,	O
+and	O
+were	O
+saccular	O
+(	O
+71	O
+%	O
+)	O
+.	O
+
+There	O
+were	O
+each	O
+three	O
+patients	O
+with	O
+false	O
+aneurysms	O
+(	O
+13	O
+%	O
+)	O
+and	O
+giant	O
+aneurysms	O
+(	O
+13	O
+%	O
+)	O
+,	O
+and	O
+only	O
+one	O
+patient	O
+with	O
+multiple	O
+aneurysms	O
+(	O
+4	O
+%	O
+)	O
+.	O
+
+We	O
+treated	O
+22	O
+patients	O
+:	O
+21	O
+aneurysms	O
+with	O
+the	O
+endovascular	O
+methods	O
+,	O
+three	O
+with	O
+open	O
+surgery	O
+,	O
+and	O
+one	O
+with	O
+combined	O
+treatment	O
+.	O
+
+Good	O
+functional	O
+outcome	O
+could	O
+be	O
+achieved	O
+in	O
+86	O
+%	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+this	O
+series	O
+,	O
+the	O
+young	O
+-	O
+age	O
+patients	O
+with	O
+intracranial	O
+aneurysms	O
+were	O
+characterized	O
+by	O
+male	O
+predominance	O
+,	O
+related	O
+specific	O
+medical	O
+conditions	O
+,	O
+low	O
+incidence	B-EPI
+of	O
+multiple	O
+aneurysms	O
+,	O
+high	O
+incidence	B-EPI
+of	O
+giant	O
+aneurysms	O
+and	O
+good	O
+functional	O
+outcome	O
+after	O
+treatment	O
+.	O
+
+The	O
+inherited	O
+platelet	O
+glycoprotein	O
+deficiencies	O
+,	O
+Glanzmann	O
+thrombasthenia	O
+(	O
+GT	O
+)	O
+and	O
+Bernard	O
+Soulier	O
+syndrome	O
+(	O
+BSS	O
+)	O
+are	O
+rare	O
+but	O
+important	O
+long	O
+-	O
+term	O
+bleeding	O
+disorders	O
+.	O
+
+Once	O
+diagnosed	O
+,	O
+affected	O
+patients	O
+should	O
+be	O
+referred	O
+to	O
+a	O
+specialist	O
+centre	O
+for	O
+bleeding	O
+disorders	O
+for	O
+general	O
+advice	O
+and	O
+ongoing	O
+management	O
+.	O
+
+Patients	O
+do	O
+not	O
+require	O
+prophylactic	O
+treatment	O
+and	O
+so	O
+the	O
+management	O
+of	O
+GT	O
+and	O
+BSS	O
+focuses	O
+around	O
+prophylactic	O
+treatment	O
+prior	O
+to	O
+high	O
+risk	O
+procedures	O
+and	O
+treatment	O
+in	O
+response	O
+to	O
+non	O
+-	O
+surgical	O
+bleeding	O
+events	O
+and	O
+,	O
+in	O
+women	O
+,	O
+the	O
+management	O
+of	O
+menorrhagia	O
+and	O
+pregnancy	O
+.	O
+
+There	O
+is	O
+no	O
+consistent	O
+approach	O
+to	O
+the	O
+treatment	O
+or	O
+prevention	O
+of	O
+bleeding	O
+complications	O
+.	O
+
+Management	O
+must	O
+be	O
+tailored	O
+for	O
+each	O
+individual	O
+and	O
+the	O
+approach	O
+may	O
+not	O
+be	O
+the	O
+same	O
+for	O
+different	O
+events	O
+,	O
+even	O
+for	O
+the	O
+same	O
+patient	O
+,	O
+depending	O
+on	O
+the	O
+type	O
+of	O
+accident	O
+or	O
+invasive	O
+procedure	O
+,	O
+the	O
+extent	O
+of	O
+bleeding	O
+and	O
+the	O
+presence	O
+or	O
+not	O
+of	O
+platelet	O
+refractoriness	O
+.	O
+
+Herpes	O
+simplex	O
+virus	O
+types	O
+1	O
+(	O
+HSV-1	O
+)	O
+and	O
+2	O
+(	O
+HSV-2	O
+)	O
+are	O
+highly	O
+prevalent	B-EPI
+viruses	O
+capable	O
+of	O
+establishing	O
+lifelong	O
+infection	O
+.	O
+
+Genital	O
+herpes	O
+in	O
+women	O
+of	O
+childbearing	O
+age	O
+represents	O
+a	O
+major	O
+risk	O
+for	O
+mother	O
+-	O
+to	O
+-	O
+child	O
+transmission	O
+(	O
+MTCT	O
+)	O
+of	O
+HSV	O
+infection	O
+,	O
+with	O
+primary	O
+and	O
+first	O
+-	O
+episode	O
+genital	O
+HSV	O
+infections	O
+posing	O
+the	O
+highest	O
+risk	O
+.	O
+
+The	O
+advent	O
+of	O
+antiviral	O
+therapy	O
+with	O
+parenteral	O
+acyclovir	O
+has	O
+led	O
+to	O
+significant	O
+improvement	O
+in	O
+neonatal	O
+HSV	O
+disease	O
+mortality	O
+.	O
+
+Further	O
+studies	O
+are	O
+needed	O
+to	O
+improve	O
+the	O
+clinician	O
+'s	O
+ability	O
+to	O
+identify	O
+infants	O
+at	O
+increased	O
+risk	O
+for	O
+HSV	O
+infection	O
+and	O
+prevent	O
+MTCT	O
+,	O
+and	O
+to	O
+develop	O
+novel	O
+antiviral	O
+agents	O
+with	O
+increased	O
+efficacy	O
+in	O
+infants	O
+with	O
+HSV	O
+infection	O
+.	O
+
+Background	O
+The	O
+data	O
+in	O
+the	O
+literature	O
+suggests	O
+that	O
+Methimazole	O
+(	O
+MMI)/Carbimazole	O
+(	O
+CMZ	O
+)	O
+embryopathy	O
+is	O
+rare	O
+.	O
+
+This	O
+study	O
+examined	O
+the	O
+incidence	B-EPI
+of	O
+CMZ	O
+embryopathy	O
+in	O
+the	B-LOC
+Hong	I-LOC
+Kong	I-LOC
+Chinese	O
+population	O
+and	O
+the	O
+factors	O
+associated	O
+with	O
+its	O
+development	O
+.	O
+
+Methods	O
+Of	O
+the	O
+145	O
+pregnant	O
+women	O
+with	O
+hyperthyroidism	O
+managed	O
+from	O
+2008	O
+to	O
+2010	O
+,	O
+29	B-STAT
+(	O
+20	O
+%	O
+)	O
+had	O
+taken	O
+CMZ	O
+during	O
+pregnancy	O
+.	O
+
+The	O
+presence	O
+and	O
+details	O
+of	O
+birth	O
+defects	O
+,	O
+the	O
+dosage	O
+of	O
+CMZ	O
+,	O
+and	O
+the	O
+period	O
+of	O
+exposure	O
+during	O
+pregnancy	O
+were	O
+examined	O
+in	O
+these	O
+29	O
+pregnancies	O
+.	O
+
+All	O
+cases	O
+of	O
+CMZ	O
+embryopathy	O
+in	O
+the	O
+English	O
+literature	O
+were	O
+reviewed	O
+in	O
+the	O
+same	O
+way	O
+.	O
+
+Results	O
+Of	O
+the	O
+27	O
+babies	O
+(	O
+93.1	O
+%	O
+)	O
+with	O
+known	O
+outcome	O
+,	O
+3	O
+had	O
+aplasia	O
+cutis	O
+and	O
+1	O
+had	O
+an	O
+omphalocele	O
+in	O
+addition	O
+,	O
+and	O
+1	O
+affected	O
+baby	O
+had	O
+a	O
+sibling	O
+with	O
+aplasia	O
+cutis	O
+and	O
+patent	O
+vitellointestinal	O
+duct	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+CMZ	O
+embryopathy	O
+in	O
+our	O
+study	O
+group	O
+is	O
+11.1	B-STAT
+%	I-STAT
+.	O
+
+Amongst	O
+the	O
+21	O
+cases	O
+of	O
+CMZ	O
+embryopathy	O
+in	O
+the	O
+literature	O
+,	O
+85	O
+%	O
+were	O
+exposed	O
+to	O
+a	O
+CMZ	O
+dosage	O
+of	O
+≥20	O
+mg	O
+/	O
+day	O
+,	O
+and	O
+the	O
+minimum	O
+duration	O
+of	O
+exposure	O
+being	O
+7	O
+weeks	O
+from	O
+last	O
+menstrual	O
+period	O
+.	O
+
+The	O
+most	O
+common	O
+abnormality	O
+is	O
+ectodermal	O
+anomaly	O
+(	O
+62	O
+%	O
+)	O
+,	O
+followed	O
+by	O
+oro	O
+-	O
+nasal	O
+anomaly	O
+(	O
+48	O
+%	O
+)	O
+,	O
+facial	O
+dysmorphism	O
+(	O
+38	O
+%	O
+)	O
+,	O
+gastrointestinal	O
+anomaly	O
+(	O
+33	O
+%	O
+)	O
+and	O
+abdominal	O
+wall	O
+defect	O
+(	O
+19	O
+%	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+relationship	O
+between	O
+the	O
+type	O
+of	O
+abnormality	O
+and	O
+the	O
+dosage	O
+or	O
+duration	O
+of	O
+exposure	O
+to	O
+CMZ	O
+.	O
+
+Conclusions	O
+The	O
+incidence	B-EPI
+of	O
+CMZ	O
+embryopathy	O
+in	O
+our	O
+study	O
+group	O
+is	O
+11.1	B-STAT
+%	I-STAT
+.	O
+
+Critical	O
+factors	O
+for	O
+its	O
+development	O
+are	O
+exposure	O
+to	O
+a	O
+CMZ	O
+dosage	O
+of	O
+≥20	O
+mg	O
+/	O
+day	O
+before	O
+7	O
+weeks	O
+of	O
+gestation	O
+.	O
+
+Genetic	O
+susceptibility	O
+may	O
+also	O
+play	O
+a	O
+role	O
+.	O
+
+Background	O
+Orbital	O
+hypertelorism	O
+(	O
+OHT	O
+)	O
+represents	O
+a	O
+congenital	O
+condition	O
+defined	O
+by	O
+lateralization	O
+of	O
+the	O
+bony	O
+orbit	O
+,	O
+unlike	O
+soft	O
+tissue	O
+telecanthus	O
+in	O
+which	O
+there	O
+is	O
+an	O
+increase	O
+in	O
+intercanthal	O
+distance	O
+without	O
+true	O
+bony	O
+lateralization	O
+.	O
+
+Existing	O
+literature	O
+remains	O
+very	O
+limited	O
+in	O
+its	O
+postoperative	O
+assessment	O
+of	O
+bony	O
+versus	O
+soft	O
+tissue	O
+relapse	O
+,	O
+which	O
+may	O
+both	O
+clinically	O
+present	O
+as	O
+telecanthus	O
+.	O
+
+We	O
+performed	O
+a	O
+critical	O
+appraisal	O
+of	O
+the	O
+literature	O
+to	O
+determine	O
+the	O
+postoperative	O
+incidence	B-EPI
+of	O
+bony	O
+versus	O
+soft	O
+tissue	O
+relapse	O
+following	O
+OHT	O
+repair	O
+.	O
+
+Methods	O
+The	O
+PubMed	O
+,	O
+MEDLINE	O
+,	O
+EMBASE	O
+,	O
+Scopus	O
+,	O
+Cochrane	O
+Central	O
+Register	O
+of	O
+Controlled	O
+Trials	O
+,	O
+and	O
+clinicaltrials.org	O
+were	O
+searched	O
+systematically	O
+for	O
+all	O
+English	O
+studies	O
+published	O
+in	O
+any	O
+time	O
+frame	O
+reporting	O
+relapse	O
+rates	O
+following	O
+primary	O
+OHT	O
+repair	O
+.	O
+
+The	O
+primary	O
+outcome	O
+was	O
+incidence	B-EPI
+of	O
+bony	O
+and	O
+soft	O
+tissue	O
+relapse	O
+defined	O
+as	O
+orbital	O
+lateralization	O
+and	O
+medial	O
+canthal	O
+drift	O
+,	O
+respectively	O
+.	O
+
+The	O
+secondary	O
+outcome	O
+measures	O
+include	O
+postoperative	O
+complications	O
+,	O
+predictors	O
+of	O
+postoperative	O
+complications	O
+,	O
+timing	O
+and	O
+type	O
+of	O
+surgery	O
+,	O
+and	O
+revision	O
+rates	O
+.	O
+
+Results	O
+Eleven	O
+articles	O
+were	O
+included	O
+.	O
+
+A	O
+total	O
+of	O
+84	B-STAT
+(	O
+35.3	O
+%	O
+)	O
+patients	O
+experienced	O
+bony	O
+relapse	O
+while	O
+43	B-STAT
+(	O
+27.2	O
+%	O
+)	O
+patients	O
+experienced	O
+soft	O
+tissue	O
+relapse	O
+.	O
+
+Age	O
+at	O
+time	O
+of	O
+intervention	O
+(	O
+p	O
+<	O
+0.92	O
+)	O
+,	O
+severity	O
+at	O
+presentation	O
+(	O
+p	O
+<	O
+0.90	O
+)	O
+,	O
+and	O
+surgical	O
+technique	O
+(	O
+p	O
+<	O
+0.09	O
+)	O
+were	O
+not	O
+found	O
+be	O
+significantly	O
+associated	O
+with	O
+relapse	O
+rate	O
+.	O
+
+Methods	O
+for	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+were	O
+not	O
+standardized	O
+,	O
+and	O
+there	O
+was	O
+no	O
+consistent	O
+measure	O
+to	O
+objectively	O
+assess	O
+telecanthus	O
+.	O
+
+Conclusions	O
+There	O
+is	O
+no	O
+general	O
+consensus	O
+on	O
+predictive	O
+factors	O
+of	O
+long	O
+-	O
+term	O
+relapse	O
+following	O
+OHT	O
+repair	O
+in	O
+the	O
+form	O
+of	O
+box	O
+osteotomy	O
+or	O
+facial	O
+bipartition	O
+.	O
+
+These	O
+findings	O
+call	O
+for	O
+cross	O
+-	O
+sectional	O
+outcome	O
+standardization	O
+to	O
+better	O
+understand	O
+long	O
+-	O
+term	O
+outcomes	O
+across	O
+institutional	O
+,	O
+provider	O
+,	O
+and	O
+patient	O
+differences	O
+.	O
+
+Background	O
+Human	O
+lipodystrophies	O
+are	O
+uncommon	O
+disorders	O
+,	O
+with	O
+important	O
+clinical	O
+consequences	O
+,	O
+which	O
+are	O
+often	O
+undiagnosed	O
+.	O
+
+The	O
+Barraquer	O
+-	O
+Simons	O
+syndrome	O
+is	O
+a	O
+form	O
+of	O
+partial	O
+symmetric	O
+lipodystrophy	O
+of	O
+unknown	O
+etiology	O
+,	O
+characterized	O
+by	O
+the	O
+loss	O
+of	O
+subcutaneous	O
+adipose	O
+tissue	O
+,	O
+limited	O
+to	O
+upper	O
+part	O
+of	O
+the	O
+body	O
+.	O
+
+Insulin	O
+resistance	O
+and	O
+metabolic	O
+complications	O
+are	O
+less	O
+common	O
+than	O
+with	O
+other	O
+lipodystrophy	O
+subtypes	O
+.	O
+
+Patients	O
+usually	O
+have	O
+decreased	O
+serum	O
+complement	O
+-	O
+component	O
+3	O
+levels	O
+,	O
+associated	O
+with	O
+complement	O
+activation	O
+by	O
+the	O
+alternative	O
+pathway	O
+,	O
+which	O
+may	O
+indicate	O
+the	O
+presence	O
+of	O
+renal	O
+involvement	O
+.	O
+
+Case	O
+presentation	O
+The	O
+authors	O
+report	O
+a	O
+case	O
+of	O
+a	O
+31	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+progressive	O
+loss	O
+of	O
+subcutaneous	O
+fat	O
+,	O
+limited	O
+to	O
+the	O
+face	O
+,	O
+neck	O
+and	O
+thorax	O
+.	O
+
+She	O
+presented	O
+no	O
+severe	O
+metabolic	O
+complications	O
+,	O
+neither	O
+signs	O
+of	O
+insulin	O
+resistance	O
+.	O
+
+Laboratory	O
+tests	O
+revealed	O
+mild	O
+dyslipidemia	O
+,	O
+and	O
+low	O
+serum	O
+levels	O
+of	O
+complement	O
+-	O
+component	O
+3	O
+.	O
+
+Clinical	O
+and	O
+biochemical	O
+characteristics	O
+were	O
+consistent	O
+with	O
+the	O
+diagnosis	O
+of	O
+Barraquer	O
+-	O
+Simons	O
+syndrome	O
+.	O
+
+Conclusion	O
+The	O
+present	O
+case	O
+illustrates	O
+the	O
+importance	O
+of	O
+recognizing	O
+the	O
+clinical	O
+features	O
+of	O
+this	O
+lipodystrophic	O
+syndrome	O
+,	O
+which	O
+may	O
+present	O
+potentially	O
+severe	O
+consequences	O
+and	O
+psychological	O
+distress	O
+.	O
+
+A	O
+brief	O
+overview	O
+is	O
+made	O
+,	O
+addressing	O
+the	O
+clinical	O
+signs	O
+of	O
+the	O
+disease	O
+,	O
+its	O
+course	O
+,	O
+and	O
+how	O
+to	O
+manage	O
+it	O
+.	O
+
+Significant	O
+part	O
+of	O
+Southeastern	B-LOC
+Europe	I-LOC
+(	O
+with	O
+a	O
+population	O
+of	O
+76	O
+million	O
+)	O
+has	O
+newborn	O
+screening	O
+(	O
+NBS	O
+)	O
+programs	O
+non	O
+-	O
+harmonized	O
+with	O
+developed	O
+European	O
+countries	O
+.	O
+
+Initial	O
+survey	O
+was	O
+conducted	O
+in	O
+2013/2014	O
+among	O
+11	O
+countries	O
+from	O
+the	O
+region	O
+(	O
+Albania	B-LOC
+,	O
+Bulgaria	B-LOC
+,	O
+Bosnia	B-LOC
+and	I-LOC
+Herzegovina	I-LOC
+(	O
+BIH	O
+)	O
+,	O
+Croatia	B-LOC
+,	O
+Kosovo	B-LOC
+,	O
+Macedonia	B-LOC
+,	O
+Moldova	B-LOC
+,	O
+Montenegro	B-LOC
+,	O
+Romania	B-LOC
+,	O
+Serbia	B-LOC
+,	O
+and	O
+Slovenia	B-LOC
+)	O
+to	O
+assess	O
+the	O
+main	O
+characteristics	O
+of	O
+their	O
+NBS	O
+programs	O
+and	O
+their	O
+future	O
+plans	O
+.	O
+
+Their	O
+cumulative	O
+population	O
+at	O
+that	O
+time	O
+was	O
+~52,5	O
+million	O
+.	O
+
+At	O
+that	O
+time	O
+,	O
+none	O
+of	O
+the	O
+countries	O
+had	O
+an	O
+expanded	O
+NBS	O
+program	O
+,	O
+while	O
+phenylketonuria	O
+screening	O
+was	O
+not	O
+introduced	O
+in	O
+four	O
+and	O
+congenital	O
+hypothyroidism	O
+in	O
+three	O
+of	O
+11	O
+countries	O
+.	O
+
+We	O
+repeated	O
+the	O
+survey	O
+in	O
+2020	O
+inviting	O
+the	O
+same	O
+11	O
+countries	O
+,	O
+adding	O
+Cyprus	O
+,	O
+Greece	B-LOC
+,	O
+Hungary	B-LOC
+,	O
+and	O
+Malta	B-LOC
+(	O
+due	O
+to	O
+their	O
+geographical	O
+position	O
+in	O
+the	O
+wider	O
+region	O
+)	O
+.	O
+
+The	O
+aims	O
+were	O
+to	O
+assess	O
+the	O
+current	O
+state	O
+,	O
+to	O
+evaluate	O
+the	O
+change	O
+in	O
+the	O
+period	O
+,	O
+and	O
+to	O
+identify	O
+the	O
+main	O
+obstacles	O
+impacting	O
+the	O
+implementation	O
+of	O
+expanded	O
+NBS	O
+and/or	O
+reaching	O
+a	O
+wider	O
+population	O
+.	O
+
+Responses	O
+were	O
+collected	O
+from	O
+12	O
+countries	O
+(	O
+BIH	O
+-	O
+Federation	O
+of	O
+BIH	O
+,	O
+BIH	O
+-	O
+Republic	O
+of	O
+Srpska	B-LOC
+,	O
+Bulgaria	B-LOC
+,	O
+Croatia	B-LOC
+,	O
+Greece	B-LOC
+,	O
+Hungary	B-LOC
+,	O
+Kosovo	B-LOC
+,	O
+North	B-LOC
+Macedonia	I-LOC
+,	O
+Malta	B-LOC
+,	O
+Montenegro	B-LOC
+,	O
+Romania	B-LOC
+,	O
+Serbia	B-LOC
+,	O
+Slovenia	B-LOC
+)	O
+with	O
+a	O
+population	O
+of	O
+68.5	O
+million	O
+.	O
+
+The	O
+results	O
+of	O
+the	O
+survey	O
+showed	O
+that	O
+the	O
+regional	O
+situation	O
+regarding	O
+NBS	O
+only	O
+modestly	O
+improved	O
+in	O
+this	O
+period	O
+.	O
+
+All	O
+of	O
+the	O
+surveyed	O
+countries	O
+except	O
+Kosovo	B-LOC
+screened	O
+for	O
+at	O
+least	O
+congenital	O
+hypothyroidism	O
+,	O
+while	O
+phenylketonuria	O
+was	O
+not	O
+screened	O
+in	O
+four	O
+of	O
+12	O
+countries	O
+.	O
+
+Croatia	B-LOC
+and	O
+Slovenia	B-LOC
+implemented	O
+an	O
+expanded	O
+NBS	O
+program	O
+using	O
+tandem	O
+mass	O
+spectrometry	O
+from	O
+the	O
+time	O
+of	O
+last	O
+survey	O
+.	O
+
+In	O
+conclusion	O
+,	O
+the	O
+current	O
+status	O
+of	O
+NBS	O
+programs	O
+in	O
+Southeastern	B-LOC
+Europe	I-LOC
+is	O
+very	O
+variable	O
+and	O
+is	O
+still	O
+underdeveloped	O
+(	O
+or	O
+even	O
+non	O
+-	O
+existent	O
+)	O
+in	O
+some	O
+of	O
+the	O
+countries	O
+.	O
+
+We	O
+suggest	O
+establishing	O
+an	O
+international	O
+task	O
+-	O
+force	O
+to	O
+assist	O
+with	O
+implementation	O
+and	O
+harmonization	O
+of	O
+basic	O
+NBS	O
+services	O
+where	O
+needed	O
+.	O
+
+Background	O
+:	O
+Chronic	O
+kidney	O
+disease	O
+(	O
+CKD	O
+)	O
+in	O
+childhood	O
+and	O
+adolescence	O
+occurs	B-EPI
+with	O
+a	O
+median	O
+incidence	B-EPI
+of	O
+9	B-STAT
+per	I-STAT
+million	I-STAT
+of	I-STAT
+the	O
+age	O
+-	O
+related	O
+population	O
+.	O
+
+Over	O
+70	O
+%	O
+of	O
+CKD	O
+cases	O
+under	O
+the	O
+age	O
+of	O
+25	O
+years	O
+can	O
+be	O
+attributed	O
+to	O
+a	O
+hereditary	O
+kidney	O
+disease	O
+.	O
+
+Among	O
+these	O
+are	O
+hereditary	O
+podocytopathies	O
+,	O
+ciliopathies	O
+and	O
+(	O
+monogenic	O
+)	O
+congenital	O
+anomalies	O
+of	O
+the	O
+kidney	O
+and	O
+urinary	O
+tract	O
+(	O
+CAKUT	O
+)	O
+.	O
+
+These	O
+disease	O
+entities	O
+can	O
+present	O
+with	O
+a	O
+vast	O
+variety	O
+of	O
+extrarenal	O
+manifestations	O
+.	O
+
+So	O
+far	O
+,	O
+skeletal	O
+anomalies	O
+(	O
+SA	O
+)	O
+have	O
+been	O
+infrequently	O
+described	O
+as	O
+extrarenal	O
+manifestation	O
+in	O
+these	O
+entities	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+retrospectively	O
+investigate	O
+a	O
+cohort	O
+of	O
+individuals	O
+with	O
+hereditary	O
+podocytopathies	O
+,	O
+ciliopathies	O
+or	O
+CAKUT	O
+,	O
+in	O
+which	O
+molecular	O
+genetic	O
+testing	O
+had	O
+been	O
+performed	O
+,	O
+for	O
+the	O
+extrarenal	O
+manifestation	O
+of	O
+SA	O
+.	O
+
+Material	O
+and	O
+Methods	O
+:	O
+A	O
+cohort	O
+of	O
+65	O
+unrelated	O
+individuals	O
+with	O
+a	O
+clinically	O
+presumed	O
+hereditary	O
+podocytopathy	O
+(	O
+focal	O
+segmental	O
+glomerulosclerosis	O
+,	O
+steroid	O
+resistant	O
+nephrotic	O
+syndrome	O
+)	O
+,	O
+ciliopathy	O
+(	O
+nephronophthisis	O
+,	O
+Bardet	O
+-	O
+Biedl	O
+syndrome	O
+,	O
+autosomal	O
+recessive	O
+/	O
+dominant	O
+polycystic	O
+kidney	O
+disease	O
+)	O
+,	O
+or	O
+CAKUT	O
+was	O
+screened	O
+for	O
+SA	O
+.	O
+
+Data	O
+was	O
+acquired	O
+using	O
+a	O
+standardized	O
+questionnaire	O
+and	O
+medical	O
+reports	O
+.	O
+
+57/65	B-STAT
+(	O
+88	O
+%	O
+)	O
+of	O
+the	O
+index	O
+cases	O
+were	O
+analyzed	O
+using	O
+exome	O
+sequencing	O
+(	O
+ES	O
+)	O
+.	O
+
+Results	O
+:	O
+8/65	B-STAT
+(	O
+12	O
+%	O
+)	O
+index	O
+individuals	O
+presented	O
+with	O
+a	O
+hereditary	O
+podocytopathy	O
+,	O
+ciliopathy	O
+,	O
+or	O
+CAKUT	O
+and	O
+an	O
+additional	O
+skeletal	O
+phenotype	O
+.	O
+
+In	O
+5/8	B-STAT
+families	O
+(	O
+63	O
+%	O
+)	O
+,	O
+pathogenic	O
+variants	O
+in	O
+known	O
+disease	O
+-	O
+associated	O
+genes	O
+(	O
+1x	O
+BBS1	O
+,	O
+1x	O
+MAFB	O
+,	O
+2x	O
+PBX1	O
+,	O
+1x	O
+SIX2	O
+)	O
+could	O
+be	O
+identified	O
+.	O
+
+Conclusions	O
+:	O
+This	O
+study	O
+highlights	O
+the	O
+genetic	O
+heterogeneity	O
+and	O
+clinical	O
+variability	O
+of	O
+hereditary	O
+nephropathies	O
+in	O
+respect	O
+of	O
+skeletal	O
+anomalies	O
+as	O
+extrarenal	O
+manifestation	O
+.	O
+
+Barth	O
+syndrome	O
+is	O
+a	O
+rare	O
+X	O
+-	O
+linked	O
+recessive	O
+disorder	O
+characterized	O
+by	O
+a	O
+broad	O
+spectrum	O
+of	O
+clinical	O
+features	O
+including	O
+cardiac	O
+and	O
+skeletal	O
+myopathy	O
+,	O
+neutropenia	O
+,	O
+exercise	O
+intolerance	O
+,	O
+and	O
+growth	O
+delay	O
+.	O
+
+Most	O
+affected	O
+patients	O
+are	O
+diagnosed	O
+during	O
+childhood	O
+,	O
+and	O
+mortality	O
+is	O
+highest	O
+in	O
+the	O
+first	O
+years	O
+of	O
+life	O
+.	O
+
+As	O
+a	O
+consequence	O
+,	O
+Barth	O
+syndrome	O
+is	O
+often	O
+considered	O
+a	O
+paediatric	O
+disease	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+a	O
+case	O
+where	O
+the	O
+diagnosis	O
+was	O
+established	O
+in	O
+a	O
+39	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+left	O
+ventricular	O
+non	O
+-	O
+compaction	O
+and	O
+neutropenia	O
+.	O
+
+The	O
+clinical	O
+course	O
+of	O
+the	O
+patient	O
+presented	O
+here	O
+was	O
+relatively	O
+benign	O
+.	O
+
+This	O
+suggests	O
+that	O
+the	O
+prevalence	B-EPI
+of	O
+Barth	O
+syndrome	O
+in	O
+adults	O
+may	O
+be	O
+underestimated	O
+.	O
+
+Barth	O
+syndrome	O
+should	O
+be	O
+considered	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+male	O
+patients	O
+with	O
+cardiomyopathy	O
+and	O
+neutropenia	O
+.	O
+
+The	O
+Arab	O
+population	O
+encompasses	O
+over	O
+420	O
+million	O
+people	O
+characterized	O
+by	O
+genetic	O
+admixture	O
+and	O
+a	O
+consequent	O
+rich	O
+genetic	O
+diversity	O
+.	O
+
+A	O
+number	O
+of	O
+genetic	O
+diseases	O
+have	O
+been	O
+reported	O
+for	O
+the	O
+first	O
+time	O
+from	O
+the	O
+population	O
+.	O
+
+Additionally	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+some	O
+genetic	O
+diseases	O
+including	O
+autosomal	O
+recessive	O
+disorders	O
+such	O
+as	O
+hemoglobinopathies	O
+and	O
+familial	O
+mediterranean	O
+fever	O
+have	O
+been	O
+found	O
+in	O
+the	O
+population	O
+and	O
+across	O
+the	O
+region	O
+.	O
+
+There	O
+is	O
+a	O
+paucity	O
+of	O
+databases	O
+cataloguing	O
+genetic	O
+variants	O
+of	O
+clinical	O
+relevance	O
+from	O
+the	O
+population	O
+.	O
+
+The	O
+availability	O
+of	O
+such	O
+a	O
+catalog	O
+could	O
+have	O
+implications	O
+in	O
+precise	O
+diagnosis	O
+,	O
+genetic	O
+epidemiology	O
+and	O
+prevention	O
+of	O
+disease	O
+.	O
+
+To	O
+fill	O
+in	O
+the	O
+gap	O
+,	O
+we	O
+have	O
+compiled	O
+DALIA	O
+,	O
+a	O
+comprehensive	O
+compendium	O
+of	O
+genetic	O
+variants	O
+reported	O
+in	O
+literature	O
+and	O
+implicated	O
+in	O
+genetic	O
+diseases	O
+reported	O
+from	O
+the	O
+Arab	O
+population	O
+.	O
+
+The	O
+database	O
+aims	O
+to	O
+act	O
+as	O
+an	O
+effective	O
+resource	O
+for	O
+population	O
+-	O
+scale	O
+and	O
+sub	O
+-	O
+population	O
+specific	O
+variant	O
+analyses	O
+,	O
+enabling	O
+a	O
+ready	O
+reference	O
+aiding	O
+clinical	O
+interpretation	O
+of	O
+genetic	O
+variants	O
+,	O
+genetic	O
+epidemiology	O
+,	O
+as	O
+well	O
+as	O
+facilitating	O
+rapid	O
+screening	O
+and	O
+a	O
+quick	O
+reference	O
+for	O
+evaluating	O
+evidence	O
+on	O
+genetic	O
+diseases	O
+.	O
+
+Purpose	O
+VACTERL	O
+association	O
+is	O
+a	O
+rare	O
+and	O
+complex	O
+condition	O
+of	O
+congenital	O
+malformations	O
+,	O
+often	O
+requiring	O
+repeated	O
+surgery	O
+and	O
+entailing	O
+various	O
+physical	O
+sequelae	O
+.	O
+
+Due	O
+to	O
+scarcity	O
+of	O
+knowledge	O
+,	O
+the	O
+study	O
+aim	O
+was	O
+to	O
+investigate	O
+self	O
+-	O
+reported	O
+health	O
+-	O
+related	O
+quality	O
+of	O
+life	O
+(	O
+HRQoL	O
+)	O
+,	O
+anxiety	O
+,	O
+depression	O
+and	O
+self	O
+-	O
+concept	O
+in	O
+children	O
+and	O
+adolescents	O
+with	O
+VACTERL	O
+association	O
+and	O
+self	O
+-	O
+reported	O
+anxiety	O
+and	O
+depression	O
+in	O
+their	O
+parents	O
+.	O
+
+Methods	O
+Patients	O
+aged	O
+8	O
+-	O
+17	O
+years	O
+with	O
+VACTERL	O
+association	O
+and	O
+their	O
+parents	O
+were	O
+recruited	O
+from	O
+three	O
+of	O
+four	O
+Swedish	O
+paediatric	O
+surgical	O
+centres	O
+during	O
+2015	O
+-	O
+2019	O
+.	O
+
+The	O
+well	O
+-	O
+established	O
+validated	O
+questionnaires	O
+DISABKIDS	O
+,	O
+Beck	O
+Youth	O
+Inventories	O
+,	O
+Beck	O
+Anxiety	O
+Inventory	O
+and	O
+Beck	O
+Depression	O
+Inventory	O
+were	O
+sent	O
+to	O
+the	O
+families	O
+.	O
+
+Data	O
+were	O
+analysed	O
+using	O
+descriptives	O
+,	O
+t	O
+tests	O
+and	O
+multivariable	O
+analysis	O
+.	O
+
+Results	O
+were	O
+compared	O
+with	O
+norm	O
+groups	O
+and	O
+reference	O
+samples	O
+.	O
+
+Results	O
+The	O
+questionnaires	O
+were	O
+returned	O
+by	O
+40	O
+patients	O
+,	O
+38	O
+mothers	O
+and	O
+33	O
+fathers	O
+.	O
+
+The	O
+mean	O
+HRQoL	O
+was	O
+M	O
+=	O
+80.4	O
+,	O
+comparable	O
+to	O
+children	O
+with	O
+asthma	O
+(	O
+M	O
+=	O
+80.2	O
+)	O
+and	O
+diabetes	O
+(	O
+M	O
+=	O
+79.5	O
+)	O
+.	O
+
+Self	O
+-	O
+reported	O
+psychological	O
+well	O
+-	O
+being	O
+was	O
+comparable	O
+to	O
+the	O
+norm	O
+group	O
+of	O
+Swedish	O
+school	O
+children	O
+,	O
+and	O
+was	O
+significantly	O
+higher	O
+than	O
+a	O
+clinical	O
+sample	O
+.	O
+
+Factors	O
+negatively	O
+influencing	O
+children	O
+'s	O
+HRQoL	O
+and	O
+psychological	O
+well	O
+-	O
+being	O
+were	O
+identified	O
+.	O
+
+The	O
+parents	O
+'	O
+self	O
+-	O
+reports	O
+of	O
+anxiety	O
+and	O
+depression	O
+were	O
+comparable	O
+to	O
+non	O
+-	O
+clinical	O
+samples	O
+.	O
+
+Conclusions	O
+Although	O
+children	O
+and	O
+adolescents	O
+with	O
+VACTERL	O
+association	O
+reported	O
+similar	O
+HRQoL	O
+to	O
+those	O
+of	O
+European	O
+children	O
+with	O
+chronic	O
+conditions	O
+,	O
+their	O
+psychological	O
+well	O
+-	O
+being	O
+was	O
+comparable	O
+to	O
+Swedish	O
+school	O
+children	O
+in	O
+general	O
+.	O
+
+Nevertheless	O
+,	O
+some	O
+individuals	O
+among	O
+both	O
+children	O
+and	O
+parents	O
+were	O
+in	O
+need	O
+of	O
+extra	O
+support	O
+.	O
+
+This	O
+attained	O
+knowledge	O
+is	O
+valuable	O
+when	O
+counselling	O
+parents	O
+regarding	O
+the	O
+prognosis	O
+for	O
+children	O
+with	O
+VACTERL	O
+association	O
+.	O
+
+The	O
+mermaid	O
+syndrome	O
+(	O
+sirenomelia	O
+)	O
+is	O
+an	O
+extremely	O
+rare	O
+anomaly	O
+,	O
+an	O
+incidence	B-EPI
+of	O
+1	O
+in	O
+100,000	O
+births	O
+,	O
+in	O
+which	O
+a	O
+newborn	O
+born	O
+with	O
+legs	O
+joined	O
+together	O
+featuring	O
+a	O
+mermaid	O
+-	O
+like	O
+appearance	O
+(	O
+head	O
+and	O
+trunk	O
+like	O
+humans	O
+and	O
+tail	O
+like	O
+fish	O
+)	O
+,	O
+and	O
+in	O
+most	O
+cases	O
+die	O
+shortly	O
+after	O
+birth	O
+.	O
+
+Gastrointestinal	O
+and	O
+urogenital	O
+anomalies	O
+and	O
+single	O
+umbilical	O
+artery	O
+are	O
+clinical	O
+outcome	O
+of	O
+this	O
+syndrome	O
+.	O
+
+There	O
+are	O
+two	O
+important	O
+hypotheses	O
+for	O
+pathogenesis	O
+of	O
+mermaid	O
+syndrome	O
+:	O
+vitelline	O
+artery	O
+steal	O
+hypothesis	O
+and	O
+defective	O
+blastogenesis	O
+hypothesis	O
+.	O
+
+The	O
+cause	O
+of	O
+the	O
+mermaid	O
+syndrome	O
+is	O
+unknown	O
+,	O
+but	O
+there	O
+are	O
+some	O
+possible	O
+factors	O
+such	O
+as	O
+age	O
+younger	O
+than	O
+20	O
+years	O
+and	O
+older	O
+than	O
+40	O
+years	O
+in	O
+mother	O
+and	O
+exposure	O
+of	O
+fetus	O
+to	O
+teratogenics	O
+.	O
+
+Here	O
+,	O
+we	O
+introduced	O
+19	O
+-	O
+year	O
+-	O
+old	O
+mother	O
+'s	O
+first	O
+neonate	O
+with	O
+mermaid	O
+syndrome	O
+.	O
+
+The	O
+mother	O
+had	O
+gestational	O
+diabetes	O
+mellitus	O
+and	O
+neonate	O
+was	O
+born	O
+with	O
+single	O
+lower	O
+limb	O
+,	O
+ambiguous	O
+genitalia	O
+,	O
+and	O
+thumb	O
+anomalies	O
+,	O
+and	O
+4	O
+days	O
+after	O
+birth	O
+,	O
+the	O
+neonate	O
+died	O
+due	O
+to	O
+multiple	O
+anomalies	O
+and	O
+imperforated	O
+anus	O
+.	O
+
+The	O
+use	O
+of	O
+proton	O
+pump	O
+inhibitors	O
+(	O
+PPIs	O
+)	O
+over	O
+the	O
+last	O
+30	O
+years	O
+has	O
+rapidly	O
+increased	O
+both	O
+in	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+and	O
+worldwide	B-LOC
+.	O
+
+PPIs	O
+are	O
+not	O
+only	O
+very	O
+widely	O
+used	O
+both	O
+for	O
+approved	O
+indications	O
+(	O
+peptic	O
+ulcer	O
+disease	O
+,	O
+gastroesophageal	O
+reflux	O
+disease	O
+(	O
+GERD	O
+)	O
+,	O
+Helicobacter	O
+pylori	O
+eradication	O
+regimens	O
+,	O
+stress	O
+ulcer	O
+prevention	O
+)	O
+,	O
+but	O
+are	O
+also	O
+one	O
+of	O
+the	O
+most	O
+frequently	O
+off	O
+-	O
+label	O
+used	O
+drugs	O
+(	O
+25	B-STAT
+-	O
+70	O
+%	O
+of	O
+total	O
+)	O
+.	O
+
+An	O
+increasing	O
+number	O
+of	O
+patients	O
+with	O
+moderate	O
+to	O
+advanced	O
+gastroesophageal	O
+reflux	O
+disease	O
+are	O
+remaining	O
+on	O
+PPI	O
+indefinitely	O
+.	O
+
+Whereas	O
+numerous	O
+studies	O
+show	O
+PPIs	O
+remain	O
+effective	O
+and	O
+safe	O
+,	O
+most	O
+of	O
+these	O
+studies	O
+are	O
+<	O
+5	O
+years	O
+of	O
+duration	O
+and	O
+little	O
+data	O
+exist	O
+for	O
+>	O
+10	O
+years	O
+of	O
+treatment	O
+.	O
+
+Recently	O
+,	O
+based	O
+primarily	O
+on	O
+observational	O
+/	O
+epidemiological	O
+studies	O
+,	O
+there	O
+have	O
+been	O
+an	O
+increasing	O
+number	O
+of	O
+reports	O
+raising	O
+issues	O
+about	O
+safety	O
+and	O
+side	O
+-	O
+effects	O
+with	O
+very	O
+long	O
+-	O
+term	O
+chronic	O
+treatment	O
+.	O
+
+Some	O
+of	O
+these	O
+safety	O
+issues	O
+are	O
+related	O
+to	O
+the	O
+possible	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+chronic	O
+hypergastrinemia	O
+,	O
+which	O
+occurs	B-EPI
+in	O
+all	O
+patients	O
+taking	O
+chronic	O
+PPIs	O
+,	O
+others	O
+are	O
+related	O
+to	O
+the	O
+hypo-/achlorhydria	O
+that	O
+frequently	O
+occurs	B-EPI
+with	O
+chronic	O
+PPI	O
+treatment	O
+,	O
+and	O
+in	O
+others	O
+the	O
+mechanisms	O
+are	O
+unclear	O
+.	O
+
+These	O
+issues	O
+have	O
+raised	O
+considerable	O
+controversy	O
+in	O
+large	O
+part	O
+because	O
+of	O
+lack	O
+of	O
+long	O
+-	O
+term	O
+PPI	O
+treatment	O
+data	O
+(	O
+>	O
+10	O
+-	O
+20	O
+years	O
+)	O
+.	O
+
+Zollinger	O
+-	O
+Ellison	O
+syndrome	O
+(	O
+ZES	O
+)	O
+is	O
+caused	O
+by	O
+ectopic	O
+secretion	O
+of	O
+gastrin	O
+from	O
+a	O
+neuroendocrine	O
+tumor	O
+resulting	O
+in	O
+severe	O
+acid	O
+hypersecretion	O
+requiring	O
+life	O
+-	O
+long	O
+antisecretory	O
+treatment	O
+with	O
+PPIs	O
+,	O
+which	O
+are	O
+the	O
+drugs	O
+of	O
+choice	O
+.	O
+
+Because	O
+in	O
+<	O
+30	O
+%	O
+of	O
+patients	O
+with	O
+ZES	O
+,	O
+a	O
+long	O
+-	O
+term	O
+cure	O
+is	O
+not	O
+possible	O
+,	O
+these	O
+patients	O
+have	O
+life	O
+-	O
+long	O
+hypergastrinemia	O
+and	O
+require	O
+life	O
+-	O
+long	O
+treatment	O
+with	O
+PPIs	O
+.	O
+
+Therefore	O
+,	O
+ZES	O
+patients	O
+have	O
+been	O
+proposed	O
+as	O
+a	O
+good	O
+model	O
+of	O
+the	O
+long	O
+-	O
+term	O
+effects	O
+of	O
+hypergastrinemia	O
+in	O
+man	O
+as	O
+well	O
+as	O
+the	O
+effects	O
+/	O
+side	O
+-	O
+effects	O
+of	O
+very	O
+long	O
+-	O
+term	O
+PPI	O
+treatment	O
+.	O
+
+In	O
+this	O
+article	O
+,	O
+the	O
+insights	O
+from	O
+studies	O
+on	O
+ZES	O
+into	O
+these	O
+controversial	O
+issues	O
+with	O
+pertinence	O
+to	O
+chronic	O
+PPI	O
+use	O
+in	O
+non	B-LOC
+-	I-LOC
+ZES	I-LOC
+patients	O
+is	O
+reviewed	O
+,	O
+primarily	O
+concentrating	O
+on	O
+data	O
+from	O
+the	O
+prospective	O
+long	O
+-	O
+term	O
+studies	O
+of	O
+ZES	O
+patients	O
+at	O
+NIH	O
+.	O
+
+Aarskog	O
+-	O
+Scott	O
+syndrome	O
+is	O
+a	O
+genetically	O
+and	O
+clinically	O
+heterogeneous	O
+rare	O
+condition	O
+caused	O
+by	O
+a	O
+pathogenic	O
+variant	O
+in	O
+the	O
+FGD1	O
+gene	O
+.	O
+
+A	O
+systematic	O
+review	O
+was	O
+carried	O
+out	O
+to	O
+analyse	O
+the	O
+prevalence	B-EPI
+of	O
+clinical	O
+manifestations	O
+found	O
+in	O
+patients	O
+,	O
+as	O
+well	O
+as	O
+to	O
+evaluate	O
+the	O
+genotype	O
+-	O
+phenotype	O
+correlation	O
+.	O
+
+The	O
+results	O
+obtained	O
+show	O
+that	O
+clinical	O
+findings	O
+of	O
+the	O
+craniofacial	O
+,	O
+orthopaedic	O
+,	O
+and	O
+genitourinary	O
+tract	O
+correspond	O
+to	O
+the	O
+highest	O
+scores	O
+of	O
+prevalence	B-EPI
+.	O
+
+The	O
+authors	O
+reclassified	O
+the	O
+primary	O
+,	O
+secondary	O
+,	O
+and	O
+additional	O
+criteria	O
+based	O
+on	O
+their	O
+prevalence	B-EPI
+.	O
+
+Furthermore	O
+,	O
+it	O
+was	O
+possible	O
+to	O
+observe	O
+,	O
+in	O
+accordance	O
+with	O
+previous	O
+reports	O
+,	O
+that	O
+the	O
+reported	O
+phenotypes	O
+do	O
+not	O
+present	O
+a	O
+direct	O
+relation	O
+to	O
+the	O
+underlying	O
+genotypes	O
+.	O
+
+This	O
+study	O
+aims	O
+to	O
+identify	O
+the	O
+baseline	O
+patient	O
+characteristics	O
+,	O
+clinical	O
+presentation	O
+,	O
+and	O
+response	O
+to	O
+treatment	O
+of	O
+11	O
+patients	O
+who	O
+were	O
+diagnosed	O
+with	O
+thrombotic	O
+thrombocytopenic	O
+purpura	O
+(	O
+TTP	O
+)	O
+between	O
+2014	O
+and	O
+2020	O
+at	O
+Brookdale	O
+University	O
+Hospital	O
+Medical	O
+Center	O
+,	O
+Brooklyn	B-LOC
+,	O
+NY	B-LOC
+.	O
+
+Laboratory	O
+and	O
+clinical	O
+parameters	O
+were	O
+recorded	O
+for	O
+29	O
+patients	O
+who	O
+received	O
+plasmapheresis	O
+in	O
+this	O
+time	O
+period	O
+.	O
+
+Of	O
+29	O
+patients	O
+,	O
+11	O
+had	O
+confirmed	O
+TTP	O
+and	O
+one	O
+was	O
+diagnosed	O
+with	O
+hereditary	O
+TTP	O
+.	O
+
+Young	O
+,	O
+black	O
+,	O
+and	O
+female	O
+patients	O
+made	O
+up	O
+the	O
+majority	O
+of	O
+our	O
+patient	O
+population	O
+.	O
+
+A	O
+high	O
+prevalence	B-EPI
+of	O
+obesity	O
+and	O
+drug	O
+abuse	O
+were	O
+seen	O
+among	O
+our	O
+patients	O
+.	O
+
+Five	O
+out	O
+of	O
+11	O
+were	O
+obese	O
+and	O
+four	O
+of	O
+them	O
+were	O
+morbidly	O
+obese	O
+;	O
+six	O
+out	O
+of	O
+11	O
+patients	O
+were	O
+positive	O
+for	O
+the	O
+drug	O
+screen	O
+including	O
+cannabinoids	O
+(	O
+3	O
+)	O
+,	O
+opiates	O
+(	O
+2	O
+)	O
+,	O
+benzodiazepines	O
+(	O
+1	O
+)	O
+,	O
+PCP	O
+(	O
+1	O
+)	O
+,	O
+and	O
+methadone	O
+(	O
+1	O
+)	O
+.	O
+
+Four	O
+patients	O
+with	O
+a	O
+positive	O
+drug	O
+screen	O
+had	O
+acute	O
+kidney	O
+injury	O
+(	O
+AKI	O
+)	O
+,	O
+and	O
+plasmapheresis	O
+helped	O
+them	O
+enhance	O
+their	O
+kidney	O
+function	O
+.	O
+
+We	O
+observed	O
+a	O
+high	O
+incidence	B-EPI
+of	O
+AKI	O
+and	O
+high	O
+TTP	O
+exacerbation	O
+rates	O
+in	O
+patients	O
+who	O
+were	O
+drug	O
+abusers	O
+and	O
+those	O
+who	O
+were	O
+morbidly	O
+obese	O
+.	O
+
+There	O
+is	O
+a	O
+paucity	O
+of	O
+data	O
+on	O
+the	O
+relationship	O
+of	O
+TTP	O
+with	O
+obesityor	O
+drug	O
+abuse	O
+and	O
+this	O
+needs	O
+further	O
+study	O
+.	O
+
+Background	O
+Gastric	O
+enterochromaffin	O
+-	O
+like	O
+cell	O
+(	O
+ECL	O
+)	O
+tumours	O
+can	O
+occur	O
+in	O
+patients	O
+with	O
+multiple	O
+endocrine	O
+neoplasia	O
+type	O
+1	O
+(	O
+MEN1	O
+)	O
+,	O
+especially	O
+in	O
+those	O
+affected	O
+by	O
+Zollinger	O
+Ellison	O
+syndrome	O
+(	O
+ZES	O
+)	O
+.	O
+
+Since	O
+the	O
+prevalence	B-EPI
+of	O
+ECL	O
+lesions	O
+is	O
+not	O
+well	O
+defined	O
+yet	O
+,	O
+the	O
+present	O
+study	O
+evaluated	O
+the	O
+presence	O
+and	O
+extent	O
+of	O
+ECL	O
+lesions	O
+in	O
+MEN1	O
+patients	O
+with	O
+and	O
+without	O
+ZES	O
+.	O
+
+Methods	O
+Multiple	O
+endocrine	O
+neoplasia	O
+type	O
+1	O
+patients	O
+being	O
+part	O
+of	O
+a	O
+regular	O
+screening	O
+program	O
+(	O
+2014	O
+-	O
+2018	O
+)	O
+underwent	O
+gastroduodenoscopies	O
+with	O
+biopsies	O
+of	O
+the	O
+stomach	O
+and	O
+determination	O
+of	O
+serum	O
+gastrin	O
+and	O
+chromogranin	O
+A	O
+levels	O
+.	O
+
+Haematoxylin-	O
+and	O
+immunostaining	O
+with	O
+chromogranin	O
+A	O
+,	O
+gastrin	O
+and	O
+VMAT	O
+I	O
+and	O
+II	O
+(	O
+vesicular	O
+monoamine	O
+transporter	O
+I	O
+and	O
+II	O
+)	O
+of	O
+the	O
+biopsies	O
+were	O
+performed	O
+.	O
+
+Results	O
+Thirty	O
+-	O
+eight	O
+MEN1	O
+patients	O
+,	O
+of	O
+whom	O
+16	B-STAT
+(	O
+42	O
+%	O
+)	O
+were	O
+diagnosed	O
+and	O
+treated	O
+earlier	O
+for	O
+ZES	O
+,	O
+were	O
+analysed	O
+.	O
+
+In	O
+ten	O
+of	O
+16	B-STAT
+(	O
+62.5	O
+%	O
+)	O
+ZES	O
+patients	O
+,	O
+a	O
+locally	O
+scattered	O
+,	O
+mixed	O
+image	O
+of	O
+diffuse	O
+,	O
+linear	O
+and	O
+micronodular	O
+mild	O
+hyperplasia	O
+was	O
+present	O
+.	O
+
+In	O
+addition	O
+,	O
+two	O
+of	O
+these	O
+patients	O
+(	O
+13	O
+%	O
+)	O
+showed	O
+small	O
+(	O
+max	O
+1.5	O
+mm	O
+in	O
+size	O
+)	O
+intramucosal	O
+ECL	O
+tumours	O
+.	O
+
+Neither	O
+ECL	O
+changes	O
+,	O
+nor	O
+tumours	O
+were	O
+found	O
+in	O
+MEN1	O
+patients	O
+without	O
+ZES	O
+(	O
+n	O
+=	O
+22	O
+)	O
+.	O
+
+In	O
+MEN1	O
+/	O
+ZES	O
+patients	O
+,	O
+the	O
+median	O
+serum	O
+gastrin	O
+level	O
+was	O
+significantly	O
+elevated	O
+compared	O
+to	O
+MEN1	O
+patients	O
+without	O
+ZES	O
+(	O
+206	O
+pg	O
+/	O
+ml	O
+vs.	O
+30.5	O
+pg	O
+/	O
+ml	O
+,	O
+p	O
+<	O
+.001	O
+)	O
+.	O
+
+A	O
+subgroup	O
+analysis	O
+of	O
+the	O
+serum	O
+gastrin	O
+and	O
+chromogranin	O
+A	O
+levels	O
+of	O
+MEN1	O
+/	O
+ZES	O
+patients	O
+with	O
+or	O
+without	O
+ECL	O
+hyperplasia	O
+did	O
+not	O
+show	O
+significant	O
+differences	O
+(	O
+gastrin	O
+level	O
+:	O
+p	O
+=	O
+.302	O
+,	O
+chromogranin	O
+A	O
+:	O
+p	O
+=	O
+.464	O
+)	O
+.	O
+
+Conclusion	O
+Enterochromaffin	O
+-	O
+like	O
+cell	O
+hyperplasia	O
+and	O
+gastric	O
+carcinoids	O
+occur	O
+only	O
+in	O
+MEN1	O
+patients	O
+with	O
+ZES	O
+,	O
+but	O
+less	O
+frequently	O
+than	O
+reported	O
+.	O
+
+The	O
+Dandy	O
+-	O
+Walker	O
+Malformation	O
+was	O
+first	O
+described	O
+in	O
+1914	O
+by	O
+Dandy	O
+and	O
+Blackfan	O
+and	O
+is	O
+characterized	O
+by	O
+hypoplasia	O
+of	O
+the	O
+vermis	O
+,	O
+pseudocystic	O
+fourth	O
+ventricle	O
+,	O
+upward	O
+displacement	O
+of	O
+the	O
+tentorium	O
+,	O
+torcular	O
+and	O
+lateral	O
+sinuses	O
+,	O
+and	O
+anteroposterior	O
+enlargement	O
+of	O
+the	O
+posterior	O
+fossa	O
+.	O
+
+This	O
+syndrome	O
+commonly	O
+manifests	O
+as	O
+hydrocephalus	O
+in	O
+children	O
+,	O
+though	O
+rare	O
+adult	O
+cases	O
+have	O
+been	O
+reported	O
+.	O
+
+The	O
+literature	O
+reveals	O
+adult	O
+symptomatology	O
+including	O
+brainstem	O
+infarction	O
+,	O
+psychosis	O
+,	O
+and	O
+neuromuscular	O
+disease	O
+.	O
+
+Stroke	O
+is	O
+an	O
+exceptionally	O
+rare	O
+presentation	O
+of	O
+this	O
+malformation	O
+,	O
+with	O
+only	O
+one	O
+ischemic	O
+event	O
+reported	O
+in	O
+the	O
+literature	O
+.	O
+
+This	O
+case	O
+offers	O
+a	O
+rare	O
+opportunity	O
+for	O
+diagnosis	O
+in	O
+an	O
+adult	O
+presenting	O
+with	O
+a	O
+hemorrhagic	O
+stroke	O
+of	O
+the	O
+basal	O
+ganglia	O
+in	O
+an	O
+otherwise	O
+asymptomatic	O
+young	O
+adult	O
+male	O
+.	O
+
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+of	O
+a	O
+hemorrhagic	O
+stroke	O
+in	O
+an	O
+adult	O
+patient	O
+with	O
+Dandy	O
+-	O
+Walker	O
+Malformation	O
+.	O
+
+Hypertrophic	O
+cardiomyopathy	O
+(	O
+HCM	O
+)	O
+is	O
+a	O
+myocardial	O
+disease	O
+characterized	O
+by	O
+left	O
+ventricular	O
+hypertrophy	O
+not	O
+solely	O
+explained	O
+by	O
+abnormal	O
+loading	O
+conditions	O
+.	O
+
+Despite	O
+its	O
+rare	O
+prevalence	B-EPI
+in	O
+pediatric	O
+age	O
+,	O
+HCM	O
+carries	O
+a	O
+relevant	O
+risk	O
+of	O
+mortality	O
+and	O
+morbidity	O
+in	O
+both	O
+infants	O
+and	O
+children	O
+.	O
+
+Pediatric	O
+HCM	O
+is	O
+a	O
+large	O
+heterogeneous	O
+group	O
+of	O
+disorders	O
+.	O
+
+Other	O
+than	O
+mutations	O
+in	O
+sarcomeric	O
+genes	O
+,	O
+which	O
+represent	O
+the	O
+most	O
+important	O
+cause	O
+of	O
+HCM	O
+in	O
+adults	O
+,	O
+childhood	O
+HCM	O
+includes	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+non	O
+-	O
+sarcomeric	O
+causes	O
+,	O
+including	O
+inherited	O
+errors	O
+of	O
+metabolism	O
+(	O
+i.e.	O
+,	O
+glycogen	O
+storage	O
+diseases	O
+,	O
+lysosomal	O
+storage	O
+diseases	O
+,	O
+and	O
+fatty	O
+acid	O
+oxidation	O
+disorders	O
+)	O
+,	O
+malformation	O
+syndromes	O
+,	O
+neuromuscular	O
+diseases	O
+,	O
+and	O
+mitochondrial	O
+disease	O
+,	O
+which	O
+globally	O
+represent	O
+up	O
+to	O
+35	B-STAT
+%	O
+of	O
+children	O
+with	O
+HCM	O
+.	O
+
+The	O
+age	O
+of	O
+presentation	O
+and	O
+the	O
+underlying	O
+etiology	O
+significantly	O
+impact	O
+the	O
+prognosis	O
+of	O
+children	O
+with	O
+HCM	O
+.	O
+
+Moreover	O
+,	O
+in	O
+recent	O
+years	O
+,	O
+different	O
+targeted	O
+approaches	O
+for	O
+non	O
+-	O
+sarcomeric	O
+etiologies	O
+of	O
+HCM	O
+have	O
+emerged	O
+.	O
+
+Therefore	O
+,	O
+the	O
+etiological	O
+diagnosis	O
+is	O
+a	O
+fundamental	O
+step	O
+in	O
+designing	O
+specific	O
+management	O
+and	O
+therapy	O
+in	O
+these	O
+subjects	O
+.	O
+
+The	O
+present	O
+review	O
+aims	O
+to	O
+provide	O
+an	O
+overview	O
+of	O
+the	O
+non	O
+-	O
+sarcomeric	O
+causes	O
+of	O
+HCM	O
+in	O
+children	O
+,	O
+focusing	O
+on	O
+the	O
+pathophysiology	O
+,	O
+clinical	O
+features	O
+,	O
+diagnosis	O
+,	O
+and	O
+treatment	O
+of	O
+these	O
+rare	O
+disorders	O
+.	O
+
+Background	O
+and	O
+Objectives	O
+:	O
+This	O
+is	O
+the	O
+first	O
+study	O
+assessing	O
+risk	O
+factors	O
+for	O
+cerebral	O
+palsy	O
+(	O
+CP	O
+)	O
+among	O
+children	O
+born	O
+in	O
+Moldova	B-LOC
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+identify	O
+and	O
+describe	O
+risk	O
+factors	O
+for	O
+cerebral	O
+palsy	O
+(	O
+CP	O
+)	O
+among	O
+children	O
+born	O
+in	O
+Moldova	B-LOC
+,	O
+which	O
+is	O
+one	O
+of	O
+the	O
+low	O
+-	O
+middle	O
+income	O
+countries	O
+in	O
+Europe	B-LOC
+.	O
+
+Materials	O
+and	O
+Methods	O
+:	O
+We	O
+identified	O
+351	O
+children	O
+with	O
+CP	O
+born	O
+during	O
+2009	O
+and	O
+2010	O
+in	O
+Moldova	B-LOC
+.	O
+
+Detailed	O
+information	O
+on	O
+417	O
+children	O
+without	O
+CP	O
+served	O
+as	O
+a	O
+reference	O
+group	O
+.	O
+
+Logistic	O
+regression	O
+analyses	O
+were	O
+applied	O
+to	O
+the	O
+calculate	O
+crude	O
+and	O
+adjusted	O
+odds	O
+ratios	O
+(	O
+OR	O
+)	O
+for	O
+CP	O
+with	O
+95	O
+%	O
+confidence	O
+intervals	O
+(	O
+CI	O
+)	O
+in	O
+addition	O
+to	O
+attributable	O
+fraction	O
+(	O
+AF	O
+)	O
+.	O
+
+Results	O
+:	O
+Among	O
+children	O
+with	O
+CP	O
+(	O
+40.5	O
+%	O
+girls	O
+)	O
+,	O
+26	O
+%	O
+had	O
+spastic	O
+unilateral	O
+,	O
+54	O
+%	O
+bilateral	O
+,	O
+13	O
+%	O
+dyskinetic	O
+,	O
+5	O
+%	O
+ataxic	O
+and	O
+2	O
+%	O
+unclassified	O
+CP	O
+.	O
+
+Significant	O
+risk	O
+factors	O
+for	O
+CP	O
+included	O
+maternal	O
+alcohol	O
+consumption	O
+during	O
+pregnancy	O
+(	O
+OR	O
+1.7	O
+,	O
+p	O
+=	O
+0.002	O
+)	O
+,	O
+maternal	O
+hypertension	O
+(	O
+OR	O
+2.0	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+children	O
+born	O
+to	O
+mothers	O
+from	O
+the	O
+rural	O
+areas	O
+(	O
+OR	O
+1.6	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+maternal	O
+age	O
+≥35	O
+years	O
+(	O
+OR	O
+0.6	O
+,	O
+p	O
+=	O
+0.018	O
+)	O
+,	O
+maternal	O
+epilepsy	O
+(	O
+OR	O
+4.3	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+breech	O
+delivery	O
+(	O
+OR	O
+3.1	O
+,	O
+p	O
+=	O
+0.001	O
+)	O
+,	O
+home	O
+births	O
+(	O
+OR	O
+6.3	O
+,	O
+p	O
+=	O
+0.001	O
+)	O
+,	O
+umbilical	O
+cord	O
+around	O
+neck	O
+(	O
+OR	O
+2.2	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+AVD	O
+(	O
+OR	O
+3.1	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+male	O
+gender	O
+(	O
+OR	O
+1.3	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+SGA	O
+(	O
+OR	O
+1.3	O
+,	O
+p	O
+=	O
+0.027	O
+)	O
+,	O
+multiple	O
+gestations	O
+(	O
+OR	O
+1.7	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+and	O
+hyperbilirubinemia	O
+(	O
+OR	O
+4.5	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+.	O
+
+Multivariable	O
+analyses	O
+showed	O
+that	O
+the	O
+AF	O
+of	O
+CP	O
+was	O
+64	O
+%	O
+for	O
+rural	O
+residence	O
+(	O
+OR	O
+2.8	O
+,	O
+p	O
+=	O
+0.002	O
+)	O
+,	O
+87	O
+%	O
+for	O
+home	O
+birth	O
+(	O
+7.6	O
+,	O
+p	O
+=	O
+0.005	O
+)	O
+,	O
+79	O
+%	O
+for	O
+pre	O
+-	O
+labor	O
+rupture	O
+of	O
+membrane	O
+(	O
+OR	O
+4.9	O
+,	O
+p	O
+=	O
+0.001	O
+)	O
+,	O
+66	O
+%	O
+for	O
+breech	O
+delivery	O
+(	O
+OR	O
+2.9	O
+,	O
+p	O
+=	O
+0.002	O
+)	O
+and	O
+81	O
+%	O
+for	O
+hyperbilirubinemia	O
+(	O
+OR	O
+5.4	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+.	O
+
+Conclusions	O
+:	O
+A	O
+combination	O
+of	O
+factors	O
+related	O
+to	O
+the	O
+mother	O
+,	O
+the	O
+delivery	O
+and	O
+the	O
+child	O
+were	O
+risk	O
+factors	O
+for	O
+CP	O
+in	O
+Moldova	B-LOC
+,	O
+many	O
+of	O
+them	O
+possibly	O
+avoidable	O
+.	O
+
+Improved	O
+pregnancy	O
+and	O
+maternity	O
+care	O
+would	O
+potentially	O
+reduce	O
+the	O
+risk	O
+of	O
+CP	O
+.	O
+
+A	O
+national	O
+CP	O
+registry	O
+in	O
+Moldova	B-LOC
+is	O
+suggested	O
+as	O
+an	O
+opportunity	O
+to	O
+follow	O
+up	O
+on	O
+these	O
+findings	O
+.	O
+
+Usher	O
+syndrome	O
+,	O
+the	O
+most	O
+prevalent	B-EPI
+cause	O
+of	O
+combined	O
+hereditary	O
+vision	O
+and	O
+hearing	O
+impairment	O
+,	O
+is	O
+clinically	O
+and	O
+genetically	O
+heterogeneous	O
+.	O
+
+Moreover	O
+,	O
+several	O
+conditions	O
+with	O
+phenotypes	O
+overlapping	O
+Usher	O
+syndrome	O
+have	O
+been	O
+described	O
+.	O
+
+This	O
+makes	O
+the	O
+molecular	O
+diagnosis	O
+of	O
+hereditary	O
+deaf	O
+-	O
+blindness	O
+challenging	O
+.	O
+
+Here	O
+,	O
+we	O
+performed	O
+exome	O
+sequencing	O
+and	O
+analysis	O
+on	O
+7	O
+Mexican	O
+and	O
+52	O
+Iranian	O
+probands	O
+with	O
+combined	O
+retinal	O
+degeneration	O
+and	O
+hearing	O
+impairment	O
+(	O
+without	O
+intellectual	O
+disability	O
+)	O
+.	O
+
+Clinical	O
+assessment	O
+involved	O
+ophthalmological	O
+examination	O
+and	O
+hearing	O
+loss	O
+questionnaire	O
+.	O
+
+Usher	O
+syndrome	O
+,	O
+most	O
+frequently	O
+due	O
+to	O
+biallelic	O
+variants	O
+in	O
+MYO7A	O
+(	O
+USH1B	O
+in	O
+16	O
+probands	O
+)	O
+,	O
+USH2A	O
+(	O
+17	O
+probands	O
+)	O
+,	O
+and	O
+ADGRV1	O
+(	O
+USH2C	O
+in	O
+7	O
+probands	O
+)	O
+,	O
+was	O
+diagnosed	O
+in	O
+44	O
+of	O
+59	B-STAT
+(	O
+75	O
+%	O
+)	O
+unrelated	O
+probands	O
+.	O
+
+Almost	O
+half	O
+of	O
+the	O
+identified	O
+variants	O
+were	O
+novel	O
+.	O
+
+Nine	O
+of	O
+59	B-STAT
+(	O
+15	O
+%	O
+)	O
+probands	O
+displayed	O
+other	O
+genetic	O
+entities	O
+with	O
+dual	O
+sensory	O
+impairment	O
+,	O
+including	O
+Alström	O
+syndrome	O
+(	O
+3	O
+patients	O
+)	O
+,	O
+cone	O
+-	O
+rod	O
+dystrophy	O
+and	O
+hearing	O
+loss	O
+1	B-STAT
+(	I-STAT
+2	I-STAT
+probands	O
+)	O
+,	O
+and	O
+Heimler	O
+syndrome	O
+(	O
+1	O
+patient	O
+)	O
+.	O
+
+Unexpected	O
+findings	O
+included	O
+one	O
+proband	O
+each	O
+with	O
+Scheie	O
+syndrome	O
+,	O
+coenzyme	O
+Q10	O
+deficiency	O
+,	O
+and	O
+pseudoxanthoma	O
+elasticum	O
+.	O
+
+In	O
+four	O
+probands	O
+,	O
+including	O
+three	O
+Usher	O
+cases	O
+,	O
+dual	O
+sensory	O
+impairment	O
+was	O
+either	O
+modified	O
+/	O
+aggravated	O
+or	O
+caused	O
+by	O
+variants	O
+in	O
+distinct	O
+genes	O
+associated	O
+with	O
+retinal	O
+degeneration	O
+and/or	O
+hearing	O
+loss	O
+.	O
+
+The	O
+overall	O
+diagnostic	O
+yield	O
+of	O
+whole	O
+exome	O
+analysis	O
+in	O
+our	O
+deaf	O
+-	O
+blind	O
+cohort	O
+was	O
+92	B-STAT
+%	I-STAT
+.	O
+
+Two	O
+(	O
+3	O
+%	O
+)	O
+probands	O
+were	O
+partially	O
+solved	O
+and	O
+only	O
+3	B-STAT
+(	O
+5	O
+%	O
+)	O
+remained	O
+without	O
+any	O
+molecular	O
+diagnosis	O
+.	O
+
+In	O
+many	O
+cases	O
+,	O
+the	O
+molecular	O
+diagnosis	O
+is	O
+important	O
+to	O
+guide	O
+genetic	O
+counseling	O
+,	O
+to	O
+support	O
+prognostic	O
+outcomes	O
+and	O
+decisions	O
+with	O
+currently	O
+available	O
+and	O
+evolving	O
+treatment	O
+modalities	O
+.	O
+
+Introduction	O
+We	O
+investigated	O
+the	O
+prevalence	B-EPI
+of	O
+human	O
+T	O
+-	O
+cell	O
+lymphotropic	O
+virus	O
+types	O
+1	B-STAT
+and	I-STAT
+2	I-STAT
+(	O
+HTLV-1/2	O
+)	O
+infection	O
+in	O
+patients	O
+with	O
+hematological	O
+diseases	O
+from	O
+the	O
+western	O
+Amazon	O
+region	O
+of	O
+Brazil	B-LOC
+.	O
+
+Methods	O
+Samples	O
+from	O
+306	O
+patients	O
+were	O
+submitted	O
+for	O
+the	O
+molecular	O
+diagnosis	O
+of	O
+HTLV-1/2	O
+infection	O
+by	O
+real	O
+time	O
+PCR	O
+(	O
+qPCR	O
+)	O
+,	O
+with	O
+amplification	O
+,	O
+sequencing	O
+,	O
+and	O
+phylogenetic	O
+analysis	O
+of	O
+the	O
+long	O
+terminal	O
+repeat	O
+(	O
+LTR	O
+)	O
+region	O
+.	O
+
+Results	O
+A	O
+29	O
+-	O
+year	O
+-	O
+old	O
+male	O
+carrier	O
+of	O
+sickle	O
+cell	O
+anemia	O
+with	O
+a	O
+history	O
+of	O
+multiple	O
+blood	O
+transfusions	O
+was	O
+diagnosed	O
+with	O
+the	O
+HTLV-2c	O
+subtype	O
+.	O
+
+Conclusions	O
+This	O
+study	O
+describes	O
+the	O
+first	O
+known	O
+occurrence	B-EPI
+of	O
+HTLV-2c	O
+in	O
+the	O
+urban	O
+area	O
+of	O
+Brazil	B-LOC
+'s	O
+western	O
+Amazon	O
+region	O
+.	O
+
+Background	O
+Vitiligo	O
+is	O
+a	O
+disfiguring	O
+skin	O
+disease	O
+with	O
+profound	O
+psychosocial	O
+impacts	O
+,	O
+such	O
+as	O
+anxiety	O
+,	O
+but	O
+the	O
+reported	O
+effect	O
+sizes	O
+of	O
+associations	O
+vary	O
+.	O
+
+We	O
+aimed	O
+to	O
+conduct	O
+a	O
+meta	O
+-	O
+analysis	O
+to	O
+quantify	O
+the	O
+strength	O
+of	O
+association	O
+between	O
+anxiety	O
+and	O
+vitiligo	O
+and	O
+to	O
+estimate	O
+the	O
+prevalence	B-EPI
+of	O
+anxiety	O
+among	O
+individuals	O
+with	O
+vitiligo	O
+.	O
+
+Methods	O
+A	O
+systematic	O
+literature	O
+search	O
+was	O
+performed	O
+in	O
+five	O
+online	O
+databases	O
+(	O
+MEDLINE	O
+,	O
+Embase	O
+,	O
+Web	O
+of	O
+Science	O
+,	O
+Cochrane	O
+Library	O
+,	O
+and	O
+PsycINFO	O
+)	O
+from	O
+inception	O
+until	O
+March	O
+20	O
+,	O
+2020	O
+.	O
+
+All	O
+of	O
+the	O
+eligible	O
+studies	O
+were	O
+comprehensively	O
+reviewed	O
+,	O
+and	O
+all	O
+of	O
+the	O
+available	O
+data	O
+were	O
+analyzed	O
+according	O
+to	O
+our	O
+predefined	O
+criteria	O
+.	O
+
+Results	O
+Twenty	B-STAT
+-	I-STAT
+one	I-STAT
+studies	I-STAT
+involving	I-STAT
+3259	I-STAT
+patients	O
+in	O
+11	O
+countries	O
+were	O
+included	O
+in	O
+this	O
+meta	O
+-	O
+analysis	O
+.	O
+
+Compared	O
+with	O
+the	O
+healthy	O
+control	O
+group	O
+,	O
+patients	O
+with	O
+vitiligo	O
+often	O
+had	O
+concomitant	O
+anxiety	O
+(	O
+OR	O
+=	O
+6.14	O
+[	O
+95	O
+%	O
+CI	O
+:	O
+3.35	O
+-	O
+11.24	O
+]	O
+,	O
+I	O
+2	B-STAT
+=	O
+30.1	O
+%	O
+)	O
+.	O
+
+The	O
+pooled	B-EPI
+prevalence	I-EPI
+of	O
+anxiety	O
+in	O
+female	O
+patients	O
+was	O
+significantly	O
+higher	O
+than	O
+that	O
+in	O
+males	O
+(	O
+OR	O
+=	O
+2.24	O
+[	O
+95	O
+%	O
+CI	O
+:	O
+1.31	O
+-	O
+3.84	O
+]	O
+,	O
+I	O
+2	B-STAT
+=	I-STAT
+0.0	I-STAT
+%	I-STAT
+)	O
+.	O
+
+Subgroup	O
+analysis	O
+showed	O
+that	O
+the	O
+pooled	B-EPI
+prevalence	I-EPI
+of	O
+clinical	O
+anxiety	O
+disorder	O
+and	O
+anxiety	O
+symptoms	O
+was	O
+12	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+7%-16	O
+%	O
+,	O
+I	O
+2	B-STAT
+=	O
+76.3	O
+%	O
+)	O
+and	O
+34	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+21%-46	O
+%	O
+,	O
+I	O
+2	B-STAT
+=	O
+94.7	O
+%	O
+)	O
+,	O
+respectively	O
+.	O
+
+No	O
+publication	O
+bias	O
+has	O
+been	O
+detected	O
+by	O
+Begg	O
+'s	O
+funnel	O
+plot	O
+and	O
+Egger	O
+'s	O
+test	O
+.	O
+
+Conclusion	O
+Patients	O
+with	O
+vitiligo	O
+have	O
+high	O
+anxiety	O
+comorbidity	O
+,	O
+with	O
+female	O
+predominance	O
+.	O
+
+Dermatologists	O
+and	O
+psychiatrists	O
+should	O
+be	O
+vigilant	O
+to	O
+the	O
+presence	O
+of	O
+anxiety	O
+,	O
+apply	O
+appropriate	O
+interventions	O
+to	O
+reduce	O
+the	O
+psychological	O
+impacts	O
+in	O
+a	O
+timely	O
+manner	O
+,	O
+and	O
+thus	O
+promote	O
+recovery	O
+in	O
+vitiligo	O
+patients	O
+.	O
+
+However	O
+,	O
+due	O
+to	O
+some	O
+objective	O
+limitations	O
+(	O
+poor	O
+information	O
+about	O
+the	O
+OR	O
+and	O
+diversity	O
+in	O
+assessment	O
+tools	O
+among	O
+included	O
+studies	O
+)	O
+,	O
+findings	O
+should	O
+be	O
+interpreted	O
+with	O
+caution	O
+.	O
+
+Congenital	O
+hepatic	O
+fibrosis	O
+(	O
+CHF	O
+)	O
+is	O
+a	O
+rare	O
+autosomal	O
+recessive	O
+disease	O
+derived	O
+from	O
+biliary	O
+dysgenesis	O
+secondary	O
+to	O
+ductal	O
+plate	O
+malformation	O
+;	O
+it	O
+often	O
+coexists	O
+with	O
+Caroli	O
+'s	O
+disease	O
+,	O
+von	O
+Meyenburg	O
+complexes	O
+,	O
+autosomal	O
+dominant	O
+polycystic	O
+kidney	O
+disease	O
+(	O
+ADPKD	O
+)	O
+,	O
+and	O
+autosomal	O
+recessive	O
+polycystic	O
+kidney	O
+disease	O
+(	O
+ARPKD	O
+)	O
+.	O
+
+Although	O
+CHF	O
+was	O
+first	O
+named	O
+and	O
+described	O
+in	O
+detail	O
+by	O
+Kerr	O
+et	O
+al	O
+.	O
+
+in	O
+1961	O
+.	O
+
+Its	O
+pathogenesis	O
+still	O
+remains	O
+unclear	O
+.	O
+
+The	O
+exact	O
+incidence	B-EPI
+and	O
+prevalence	B-EPI
+are	O
+not	O
+known	O
+,	O
+and	O
+only	O
+a	O
+few	O
+hundred	O
+patients	O
+with	O
+CHF	O
+have	O
+been	O
+reported	O
+in	O
+the	O
+literature	O
+to	O
+date	O
+.	O
+
+However	O
+,	O
+with	O
+the	O
+development	O
+of	O
+noninvasive	O
+diagnostic	O
+techniques	O
+such	O
+as	O
+ultrasound	O
+,	O
+computed	O
+tomography	O
+(	O
+CT	O
+)	O
+,	O
+and	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+,	O
+CHF	O
+may	O
+now	O
+be	O
+more	O
+frequently	O
+detected	O
+.	O
+
+Anatomopathological	O
+examination	O
+of	O
+liver	O
+biopsy	O
+is	O
+the	O
+gold	O
+standard	O
+in	O
+diagnosis	O
+of	O
+CHF	O
+.	O
+
+Patients	O
+with	O
+CHF	O
+exhibit	O
+variable	O
+clinical	O
+presentations	O
+,	O
+ranging	O
+from	O
+no	O
+symptoms	O
+to	O
+severe	O
+symptoms	O
+such	O
+as	O
+acute	O
+hepatic	O
+decompensation	O
+and	O
+even	O
+cirrhosis	O
+.	O
+
+The	O
+most	O
+common	O
+presentations	O
+in	O
+these	O
+patients	O
+are	O
+splenomegaly	O
+,	O
+esophageal	O
+varices	O
+,	O
+and	O
+gastrointestinal	O
+bleeding	O
+due	O
+to	O
+portal	O
+hypertension	O
+.	O
+
+In	O
+addition	O
+,	O
+in	O
+younger	O
+children	O
+,	O
+CHF	O
+often	O
+is	O
+accompanied	O
+by	O
+renal	O
+cysts	O
+or	O
+increased	O
+renal	O
+echogenicity	O
+.	O
+
+Great	O
+variability	O
+exists	O
+among	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+the	O
+disease	O
+from	O
+early	O
+childhood	O
+to	O
+the	O
+5	O
+th	O
+or	O
+6	O
+th	O
+decade	O
+of	O
+life	O
+,	O
+and	O
+in	O
+most	O
+patients	O
+the	O
+disorder	O
+is	O
+diagnosed	O
+during	O
+adolescence	O
+or	O
+young	O
+adulthood	O
+.	O
+
+Here	O
+,	O
+we	O
+present	O
+two	O
+cases	O
+of	O
+congenital	O
+hepatic	O
+fibrosis	O
+in	O
+2	O
+-	O
+years	O
+-	O
+old	O
+girl	O
+and	O
+12	O
+-	O
+year	O
+-	O
+old	O
+male	O
+who	O
+had	O
+been	O
+referred	O
+for	O
+evaluation	O
+of	O
+an	O
+abdominal	O
+distension	O
+with	O
+persistent	O
+hyper	O
+-	O
+transaminasemia	O
+and	O
+cholestasis	O
+,	O
+the	O
+diagnostic	O
+was	O
+made	O
+according	O
+to	O
+the	O
+results	O
+of	O
+medical	O
+imaging	O
+(	O
+CT	O
+or	O
+MRI	O
+)	O
+,	O
+a	O
+liver	O
+biopsy	O
+,	O
+and	O
+genetic	O
+testing	O
+.	O
+
+BACKGROUND	O
+:	O
+Balanced	O
+reciprocal	O
+chromosomal	O
+translocations	O
+(	O
+RCTs	O
+)	O
+are	O
+the	O
+ones	O
+of	O
+the	O
+most	O
+common	O
+structural	O
+aberrations	O
+in	O
+the	O
+population	O
+,	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+1:625	O
+.	O
+
+RCT	O
+carriers	O
+usually	O
+do	O
+not	O
+demonstrate	O
+changes	O
+in	O
+phenotype	O
+,	O
+except	O
+when	O
+the	O
+translocation	O
+results	O
+in	O
+gene	O
+interruption	O
+.	O
+
+However	O
+,	O
+these	O
+people	O
+are	O
+at	O
+risk	O
+of	O
+production	O
+of	O
+unbalanced	O
+gametes	O
+during	O
+meiosis	O
+,	O
+as	O
+a	O
+result	O
+of	O
+various	O
+forms	O
+of	O
+chromosome	O
+segregation	O
+.	O
+
+This	O
+may	O
+cause	O
+infertility	O
+,	O
+non	O
+-	O
+implantation	O
+of	O
+the	O
+embryo	O
+,	O
+shorter	O
+embryo	O
+or	O
+foetus	O
+survival	O
+,	O
+as	O
+well	O
+as	O
+congenital	O
+defects	O
+and	O
+developmental	O
+disorders	O
+in	O
+children	O
+after	O
+birth	O
+.	O
+
+The	O
+increasing	O
+popularity	O
+of	O
+cytogenetic	O
+molecular	O
+techniques	O
+,	O
+such	O
+as	O
+microarray	O
+-	O
+based	O
+CGH	O
+(	O
+aCGH	O
+)	O
+,	O
+contributed	O
+to	O
+the	O
+improved	O
+detection	O
+of	O
+chromosomal	O
+abnormalities	O
+in	O
+patients	O
+with	O
+intellectual	O
+disability	O
+,	O
+however	O
+,	O
+these	O
+modern	O
+techniques	O
+do	O
+not	O
+allow	O
+the	O
+identification	O
+of	O
+the	O
+balanced	O
+in	O
+potential	O
+carriers	O
+.	O
+
+Therefore	O
+,	O
+classical	O
+chromosome	O
+analysis	O
+with	O
+GTG	O
+technique	O
+still	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+identification	O
+of	O
+balanced	O
+rearrangements	O
+in	O
+every	O
+case	O
+of	O
+procreation	O
+failure	O
+.	O
+
+CASE	O
+PRESENTATION	O
+:	O
+In	O
+this	O
+article	O
+,	O
+a	O
+family	O
+with	O
+multiple	O
+occurrences	B-EPI
+of	O
+17p13.3	O
+duplication	O
+syndrome	O
+in	O
+the	O
+offspring	O
+and	O
+multiple	O
+miscarriages	O
+resulting	O
+from	O
+carrying	O
+of	O
+the	O
+balanced	O
+reciprocal	O
+translocation	O
+t(7;17)(p22;p13.2	O
+)	O
+by	O
+proband	O
+father	O
+is	O
+presented	O
+.	O
+
+The	O
+aCGH	O
+diagnostics	O
+allowed	O
+the	O
+identification	O
+of	O
+an	O
+unbalanced	O
+fragment	O
+responsible	O
+for	O
+the	O
+occurrence	B-EPI
+of	O
+clinical	O
+signs	O
+in	O
+the	O
+female	O
+patient	O
+,	O
+while	O
+karyotyping	O
+and	O
+FISH	O
+using	O
+specific	O
+probes	O
+allowed	O
+the	O
+localization	O
+of	O
+the	O
+additional	O
+material	O
+in	O
+the	O
+patient	O
+chromosomes	O
+,	O
+and	O
+identified	O
+the	O
+type	O
+of	O
+this	O
+translocation	O
+in	O
+the	O
+carriers	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Identification	O
+of	O
+a	O
+balanced	O
+structural	O
+aberration	O
+in	O
+one	O
+of	O
+the	O
+partners	O
+allows	O
+direct	O
+diagnostics	O
+for	O
+the	O
+exclusion	O
+or	O
+confirmation	O
+of	O
+genetic	O
+imbalance	O
+in	O
+the	O
+foetus	O
+via	O
+traditional	O
+invasive	O
+prenatal	O
+diagnostics	O
+.	O
+
+It	O
+is	O
+also	O
+possible	O
+to	O
+use	O
+an	O
+alternative	O
+method	O
+,	O
+Preimplantation	O
+Genetic	O
+Diagnosis	O
+(	O
+PGD	O
+)	O
+after	O
+in	O
+vitro	O
+fertilization	O
+,	O
+which	O
+prevents	O
+initiating	O
+pregnancy	O
+if	O
+genetic	O
+imbalance	O
+is	O
+detected	O
+in	O
+the	O
+embryo	O
+.	O
+
+Introduction	O
+New	O
+neurological	O
+symptoms	O
+in	O
+methylmalonic	O
+acidemia	O
+(	O
+MMA	O
+)	O
+patients	O
+after	O
+liver	O
+and/or	O
+kidney	O
+transplantation	O
+(	O
+LKT	O
+)	O
+are	O
+often	O
+described	O
+as	O
+metabolic	O
+stroke	O
+-	O
+like	O
+-	O
+events	O
+.	O
+
+Since	O
+calcineurin	O
+inhibitors	O
+(	O
+CNIs	O
+)	O
+are	O
+a	O
+well	O
+-	O
+known	O
+cause	O
+of	O
+new	O
+neurological	O
+symptoms	O
+in	O
+non	B-LOC
+-	I-LOC
+MMA	I-LOC
+transplanted	O
+patients	O
+,	O
+we	O
+investigated	O
+the	O
+incidence	B-EPI
+of	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+including	O
+posterior	O
+reversible	O
+encephalopathy	O
+syndrome	O
+(	O
+PRES	O
+)	O
+in	O
+post	O
+-	O
+transplanted	O
+MMA	O
+patients	O
+.	O
+
+Methods	O
+We	O
+report	O
+the	O
+two	O
+MMA	O
+patients	O
+treated	O
+with	O
+LKT	O
+in	O
+our	O
+center	O
+.	O
+
+Additionally	O
+,	O
+we	O
+performed	O
+a	O
+systematic	O
+review	O
+of	O
+case	O
+reports	O
+/	O
+series	O
+of	O
+post	O
+-	O
+transplanted	O
+MMA	O
+patients	O
+and	O
+determined	O
+if	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+/	O
+PRES	O
+was	O
+a	O
+likely	O
+cause	O
+of	O
+new	O
+neurological	O
+symptoms	O
+.	O
+
+Definite	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+was	O
+defined	O
+as	O
+new	O
+neurological	O
+symptoms	O
+during	O
+CNI	O
+treatment	O
+with	O
+symptom	O
+improvement	O
+after	O
+CNI	O
+dose	O
+reduction	O
+/	O
+discontinuation	O
+.	O
+
+PRES	O
+was	O
+defined	O
+as	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+with	O
+signs	O
+of	O
+vasogenic	O
+edema	O
+on	O
+brain	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI)-scan	O
+post	O
+-	O
+transplantation	O
+.	O
+
+Results	O
+Our	O
+two	O
+MMA	O
+patients	O
+both	O
+developed	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+,	O
+one	O
+had	O
+PRES	O
+.	O
+
+In	O
+literature	O
+,	O
+230	O
+transplanted	O
+MMA	O
+patients	O
+were	O
+identified	O
+.	O
+
+Neurological	O
+follow	O
+-	O
+up	O
+was	O
+reported	O
+in	O
+54	O
+of	O
+them	O
+,	O
+of	O
+which	O
+24	O
+were	O
+excluded	O
+from	O
+analysis	O
+since	O
+no	O
+anti	O
+-	O
+rejection	O
+medication	O
+was	O
+reported	O
+.	O
+
+Thirty	O
+patients	O
+,	O
+all	O
+using	O
+CNI	O
+,	O
+were	O
+included	O
+.	O
+
+Sixteen	O
+patients	O
+(	O
+53	O
+%	O
+)	O
+had	O
+no	O
+new	O
+neurological	O
+symptoms	O
+post	O
+-	O
+transplantation	O
+and	O
+five	O
+patients	O
+(	O
+17	O
+%	O
+)	O
+had	O
+definite	O
+CNI	O
+neurotoxicity	O
+of	O
+whom	O
+two	O
+had	O
+PRES	O
+.	O
+
+Including	O
+our	O
+cases	O
+this	O
+results	O
+in	O
+a	O
+pooled	B-EPI
+incidence	I-EPI
+of	O
+22	O
+%	O
+(	O
+7/32	O
+)	O
+definite	O
+CNI	O
+neurotoxicity	O
+and	O
+9	O
+%	O
+PRES	O
+(	O
+3/32	B-STAT
+)	O
+in	O
+post	O
+-	O
+transplanted	O
+MMA	O
+patients	O
+on	O
+CNI	O
+.	O
+
+Conclusion	O
+In	O
+MMA	O
+post	O
+-	O
+transplanted	O
+patients	O
+with	O
+new	O
+neurological	O
+symptoms	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+/	O
+PRES	O
+should	O
+be	O
+considered	O
+.	O
+
+Early	O
+recognition	O
+of	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+is	O
+essential	O
+to	O
+initiate	O
+dose	O
+reduction	O
+/	O
+discontinuation	O
+of	O
+CNI	O
+to	O
+minimize	O
+persistent	O
+neurologic	O
+damage	O
+and	O
+improve	O
+outcome	O
+.	O
+
+Concise	O
+one	O
+sentence	O
+take	O
+home	O
+message	O
+In	O
+all	O
+post	O
+-	O
+transplanted	O
+MMA	O
+patients	O
+with	O
+new	O
+neurological	O
+symptoms	O
+CNI	O
+-	O
+induced	O
+neurotoxicity	O
+/	O
+PRES	O
+should	O
+be	O
+considered	O
+,	O
+and	O
+directly	O
+reducing	O
+the	O
+dose	O
+/	O
+discontinuation	O
+of	O
+CNI	O
+is	O
+essential	O
+.	O
+
+Introduction	O
+Primitive	O
+neuroectodermal	O
+tumors	O
+(	O
+PNET	O
+)	O
+form	O
+a	O
+group	O
+of	O
+tumors	O
+defined	O
+by	O
+their	O
+appearance	O
+that	O
+are	O
+thought	O
+to	O
+develop	O
+from	O
+primitive	O
+(	O
+undifferentiated	O
+)	O
+nerve	O
+cells	O
+in	O
+the	O
+brain	O
+.	O
+
+They	O
+are	O
+rare	O
+tumors	O
+and	O
+their	O
+incidence	B-EPI
+is	O
+not	O
+well	O
+defined	O
+.	O
+
+Case	O
+presentation	O
+An	O
+18	O
+-	O
+month	O
+-	O
+old	O
+male	O
+presenting	O
+with	O
+typical	O
+Cushingoid	O
+appearance	O
+(	O
+moon	O
+face	O
+,	O
+central	O
+obesity	O
+,	O
+hirsutism	O
+and	O
+growth	O
+arrest	O
+)	O
+was	O
+admitted	O
+for	O
+evaluation	O
+of	O
+endocrine	O
+problems	O
+.	O
+
+Subsequent	O
+laboratory	O
+studies	O
+revealed	O
+markedly	O
+elevated	O
+adrenocorticotropic	O
+(	O
+ACTH	O
+)	O
+and	O
+cortisol	O
+levels	O
+,	O
+as	O
+well	O
+as	O
+a	O
+hypokalemic	O
+metabolic	O
+alkalosis	O
+,	O
+these	O
+data	O
+are	O
+consistent	O
+with	O
+the	O
+diagnosis	O
+of	O
+Cushing	O
+'s	O
+disease	O
+.	O
+
+He	O
+was	O
+treated	O
+with	O
+metyrapone	O
+to	O
+control	O
+hypercortisolemia	O
+.	O
+
+One	O
+month	O
+and	O
+a	O
+half	O
+later	O
+,	O
+a	O
+mass	O
+was	O
+detected	O
+in	O
+the	O
+abdomen	O
+by	O
+ultrasonography	O
+.	O
+
+An	O
+abdominal	O
+Computed	O
+tomography	O
+confirmed	O
+a	O
+large	O
+heterogeneous	O
+retroperitoneal	O
+mass	O
+with	O
+a	O
+significant	O
+amount	O
+of	O
+extension	O
+into	O
+surrounding	O
+structures	O
+which	O
+was	O
+removed	O
+by	O
+laparoscopic	O
+abdominal	O
+surgery	O
+.	O
+
+The	O
+patient	O
+'s	O
+symptoms	O
+completely	O
+resolved	O
+and	O
+the	O
+ACTH	O
+and	O
+cortisol	O
+levels	O
+were	O
+also	O
+greatly	O
+reduced	O
+.	O
+
+Histologically	O
+,	O
+the	O
+tumor	O
+tissue	O
+consistent	O
+with	O
+the	O
+diagnosis	O
+of	O
+the	O
+retroperitoneal	O
+primitive	O
+neuroectodermal	O
+tumor	O
+which	O
+was	O
+confirmed	O
+immunohistochemically	O
+.	O
+
+This	O
+case	O
+demonstrates	O
+the	O
+successful	O
+diagnosis	O
+and	O
+treatment	O
+of	O
+a	O
+rare	O
+neoplasm	O
+.	O
+
+Conclusion	O
+This	O
+is	O
+the	O
+first	O
+rare	O
+case	O
+with	O
+ectopic	O
+ACTH	O
+syndrome	O
+caused	O
+by	O
+the	O
+peripheral	O
+primitive	O
+neuroectodermal	O
+tumor	O
+.	O
+
+Non	O
+-	O
+obstructive	O
+azoospermia	O
+accounts	O
+for	O
+10	B-STAT
+-	O
+15	O
+%	O
+of	O
+male	O
+infertility	O
+,	O
+resulting	O
+in	O
+60	O
+%	O
+of	O
+all	O
+cases	O
+of	O
+azoospermia	O
+and	O
+affecting	O
+about	O
+1	O
+%	O
+of	O
+the	O
+male	O
+population	O
+.	O
+
+About	O
+30	O
+%	O
+of	O
+these	O
+cases	O
+are	O
+due	O
+to	O
+Y	O
+chromosome	O
+microdeletions	O
+,	O
+chromosome	O
+abnormalities	O
+,	O
+or	O
+hormonal	O
+disorders	O
+.	O
+
+Pathogenic	O
+variants	O
+in	O
+genes	O
+on	O
+the	O
+sex	O
+chromosomes	O
+have	O
+key	O
+roles	O
+in	O
+spermatogenic	O
+failure	O
+.	O
+
+The	O
+co	O
+-	O
+occurrence	B-EPI
+of	O
+azoospermia	O
+and	O
+congenital	O
+cataracts	O
+ranges	O
+between	O
+1	O
+in	O
+165,000	O
+and	O
+1	O
+in	O
+500,000	O
+.	O
+
+Our	O
+28	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+with	O
+normal	O
+intelligence	O
+and	O
+abnormally	O
+shaped	O
+teeth	O
+presented	O
+with	O
+both	O
+disorders	O
+.	O
+
+A	O
+microarray	O
+revealed	O
+a	O
+microdeletion	O
+at	O
+Xp23.13	O
+with	O
+a	O
+whole	O
+NHS	O
+gene	O
+deletion	O
+as	O
+well	O
+as	O
+a	O
+contiguous	O
+deletion	O
+of	O
+two	O
+other	O
+genes	O
+[	O
+SCML1	O
+and	O
+RAI2	O
+]	O
+.	O
+
+This	O
+observation	O
+represents	O
+the	O
+first	O
+report	O
+of	O
+non	O
+-	O
+obstructive	O
+azoospermia	O
+with	O
+congenital	O
+cataracts	O
+and	O
+a	O
+contiguous	O
+deletion	O
+of	O
+the	O
+SCML1	O
+gene	O
+,	O
+a	O
+transcript	O
+of	O
+which	O
+is	O
+exclusively	O
+expressed	O
+in	O
+the	O
+testis	O
+.	O
+
+SCML1	O
+is	O
+the	O
+putative	O
+culprit	O
+gene	O
+,	O
+which	O
+requires	O
+functional	O
+study	O
+or	O
+animal	O
+experiments	O
+.	O
+
+Our	O
+analysis	O
+of	O
+60	O
+known	O
+spermatogenesis	O
+failure	O
+-	O
+related	O
+genes	O
+by	O
+whole	O
+-	O
+exome	O
+sequencing	O
+revealed	O
+no	O
+other	O
+candidate	O
+.	O
+
+The	O
+Nance	O
+-	O
+Horan	O
+syndrome	O
+due	O
+to	O
+pathogenic	O
+variants	O
+in	O
+the	O
+NHS	O
+gene	O
+at	O
+Xp23.13	O
+including	O
+whole	O
+gene	O
+deletion	O
+does	O
+not	O
+have	O
+azoospermia	O
+as	O
+a	O
+feature	O
+.	O
+
+Our	O
+report	O
+adds	O
+to	O
+the	O
+completeness	O
+of	O
+genetic	O
+counseling	O
+for	O
+an	O
+individual	O
+with	O
+azoospermia	O
+and	O
+congenital	O
+cataracts	O
+.	O
+
+Hyperthyroidism	O
+in	O
+pregnancy	O
+is	O
+associated	O
+with	O
+a	O
+increased	O
+incidence	B-EPI
+of	O
+low	O
+birth	O
+weight	O
+,	O
+preterm	O
+birth	O
+and	O
+admission	O
+to	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+.	O
+
+However	O
+,	O
+available	O
+treatment	O
+options	O
+are	O
+limited	O
+.	O
+
+In	O
+this	O
+report	O
+,	O
+we	O
+present	O
+a	O
+case	O
+of	O
+fetal	O
+gastroschisis	O
+with	O
+a	O
+history	O
+of	O
+intrauterine	O
+exposure	O
+to	O
+methimazole	O
+.	O
+
+A	O
+37	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+was	O
+diagnosed	O
+with	O
+Grave	O
+'s	O
+disease	O
+3	O
+years	O
+before	O
+her	O
+pregnancy	O
+.	O
+
+She	O
+had	O
+a	O
+poor	O
+response	O
+to	O
+propylthiouracil	O
+and	O
+required	O
+high	O
+-	O
+dose	O
+methimazole	O
+before	O
+her	O
+pregnancy	O
+.	O
+
+During	O
+the	O
+first	O
+trimester	O
+,	O
+she	O
+received	O
+methimazole	O
+120	O
+mg	O
+/	O
+day	O
+.	O
+
+After	O
+her	O
+12th	O
+week	O
+of	O
+pregnancy	O
+,	O
+she	O
+received	O
+block	O
+-	O
+and	O
+-	O
+replace	O
+therapy	O
+(	O
+levothyroxine	O
+[	O
+LT4	O
+]	O
+50	O
+µg	O
+/	O
+day	O
+)	O
+because	O
+of	O
+the	O
+risk	O
+of	O
+hypothyroidism	O
+,	O
+and	O
+the	O
+dose	O
+of	O
+methimazole	O
+was	O
+downtitrated	O
+to	O
+60	O
+mg	O
+/	O
+day	O
+.	O
+
+Fetal	O
+ultrasonography	O
+showed	O
+fetal	O
+growth	O
+retardation	O
+and	O
+gastroschisis	O
+at	O
+gestational	O
+week	O
+33	O
+.	O
+
+The	O
+relationship	O
+between	O
+the	O
+very	O
+high	O
+doses	O
+of	O
+methimazole	O
+in	O
+the	O
+first	O
+trimester	O
+of	O
+pregnancy	O
+and	O
+the	O
+incidence	B-EPI
+of	O
+gastroschisis	O
+in	O
+this	O
+patient	O
+was	O
+not	O
+fully	O
+understood	O
+because	O
+evidence	O
+of	O
+a	O
+relationship	O
+between	O
+the	O
+use	O
+of	O
+antithyroid	O
+drugs	O
+in	O
+the	O
+first	O
+trimester	O
+and	O
+congenital	O
+abnormalities	O
+in	O
+the	O
+fetus	O
+is	O
+lacking	O
+.	O
+
+Furthermore	O
+block	O
+-	O
+and	O
+-	O
+replace	O
+therapy	O
+is	O
+not	O
+recommended	O
+in	O
+pregnancy	O
+because	O
+it	O
+requires	O
+a	O
+higher	O
+dose	O
+of	O
+methimazole	O
+.	O
+
+We	O
+recommend	O
+preconception	O
+counseling	O
+and	O
+early	O
+screening	O
+of	O
+thyroid	O
+function	O
+.	O
+
+The	O
+counseling	O
+should	O
+include	O
+the	O
+best	O
+timeline	O
+for	O
+pregnancy	O
+and	O
+a	O
+discussion	O
+of	O
+the	O
+risks	O
+and	O
+benefits	O
+of	O
+hyperthyroidism	O
+treatment	O
+options	O
+.	O
+
+Objective	O
+Health	O
+-	O
+related	O
+quality	O
+of	O
+life	O
+is	O
+impaired	O
+in	O
+idiopathic	O
+inflammatory	O
+myopathies	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+identify	O
+the	O
+main	O
+areas	O
+of	O
+the	O
+health	O
+-	O
+related	O
+quality	O
+of	O
+life	O
+environment	O
+domain	O
+that	O
+are	O
+affected	O
+in	O
+patients	O
+with	O
+myositis	O
+.	O
+
+Methods	O
+A	O
+qualitative	O
+study	O
+was	O
+performed	O
+using	O
+focus	O
+groups	O
+and	O
+applying	O
+the	O
+International	O
+Classification	O
+of	O
+Functioning	O
+,	O
+Disability	O
+,	O
+and	O
+Health	O
+.	O
+
+Participants	O
+were	O
+recruited	O
+from	O
+a	O
+cohort	O
+of	O
+323	O
+adult	O
+inflammatory	O
+myopathy	O
+patients	O
+consulting	O
+at	O
+a	O
+reference	O
+center	O
+for	O
+idiopathic	O
+inflammatory	O
+myopathy	O
+in	O
+Spain	B-LOC
+,	O
+selected	O
+by	O
+the	O
+maximum	O
+variation	O
+strategy	O
+,	O
+and	O
+placed	O
+in	O
+focus	O
+groups	O
+with	O
+5	B-STAT
+to	I-STAT
+7	I-STAT
+patients	I-STAT
+per	I-STAT
+group	I-STAT
+.	O
+
+The	O
+number	O
+of	O
+focus	O
+groups	O
+required	O
+was	O
+determined	O
+by	O
+data	O
+saturation	O
+.	O
+
+Results	O
+Twenty	O
+-	O
+five	O
+patients	O
+distributed	O
+in	O
+4	O
+focus	O
+groups	O
+were	O
+interviewed	O
+.	O
+
+The	O
+verbatim	O
+provided	O
+54	O
+categories	O
+directly	O
+related	O
+with	O
+environmental	O
+factors	O
+.	O
+
+Those	O
+associated	O
+with	O
+products	O
+or	O
+substances	O
+for	O
+personal	O
+consumption	O
+(	O
+e110	O
+)	O
+,	O
+health	O
+professionals	O
+(	O
+e355	O
+)	O
+,	O
+health	O
+services	O
+,	O
+systems	O
+and	O
+policies	O
+(	O
+e580	O
+)	O
+,	O
+products	O
+and	O
+technology	O
+for	O
+personal	O
+use	O
+in	O
+daily	O
+living	O
+(	O
+e115	O
+)	O
+,	O
+and	O
+immediate	O
+family	O
+(	O
+e310	O
+)	O
+were	O
+the	O
+ones	O
+most	O
+frequently	O
+reported	O
+.	O
+
+Conclusion	O
+The	O
+results	O
+of	O
+this	O
+study	O
+led	O
+to	O
+identification	O
+of	O
+several	O
+environmental	O
+factors	O
+that	O
+affect	O
+the	O
+health	O
+-	O
+related	O
+quality	O
+of	O
+life	O
+of	O
+patients	O
+with	O
+myositis	O
+.	O
+
+Remedial	O
+interventions	O
+should	O
+be	O
+designed	O
+to	O
+address	O
+some	O
+of	O
+these	O
+factors	O
+.	O
+
+Objective	O
+In	O
+observational	O
+data	O
+,	O
+lower	O
+levels	O
+of	O
+lipoprotein(a	O
+)	O
+have	O
+been	O
+associated	O
+with	O
+greater	O
+prevalence	B-EPI
+of	O
+type	O
+2	O
+diabetes	O
+.	O
+
+Whether	O
+pharmacologic	O
+lowering	O
+of	O
+lipoprotein(a	O
+)	O
+influences	O
+incident	O
+type	O
+2	O
+diabetes	O
+is	O
+unknown	O
+.	O
+
+We	O
+determined	O
+the	O
+relationship	O
+of	O
+lipoprotein(a	O
+)	O
+concentration	O
+with	O
+incident	O
+type	O
+2	O
+diabetes	O
+and	O
+effects	O
+of	O
+treatment	O
+with	O
+alirocumab	O
+,	O
+a	O
+PCSK9	O
+inhibitor	O
+.	O
+
+Research	O
+design	O
+and	O
+methods	O
+In	O
+the	O
+ODYSSEY	O
+OUTCOMES	O
+trial	O
+alirocumab	O
+was	O
+compared	O
+with	O
+placebo	O
+in	O
+patients	O
+with	O
+acute	O
+coronary	O
+syndrome	O
+.	O
+
+Incident	O
+diabetes	O
+was	O
+determined	O
+from	O
+laboratory	O
+,	O
+medication	O
+,	O
+and	O
+adverse	O
+event	O
+data	O
+.	O
+
+Results	O
+Among	O
+13,480	O
+patients	O
+without	O
+diabetes	O
+at	O
+baseline	O
+,	O
+1,324	O
+developed	O
+type	O
+2	O
+diabetes	O
+over	O
+a	O
+median	O
+2.7	O
+years	O
+.	O
+
+Median	O
+baseline	O
+lipoprotein(a	O
+)	O
+was	O
+21.9	O
+mg	O
+/	O
+dL.	O
+
+With	O
+placebo	O
+,	O
+10	O
+mg	O
+/	O
+dL	O
+lower	O
+baseline	O
+lipoprotein(a	O
+)	O
+was	O
+associated	O
+with	O
+hazard	O
+ratio	O
+1.04	O
+(	O
+95	O
+%	O
+CI	O
+1.02	O
+-	O
+1.06	O
+,	O
+P	O
+<	O
+0.001	O
+)	O
+for	O
+incident	O
+type	O
+2	O
+diabetes	O
+.	O
+
+Alirocumab	O
+reduced	O
+lipoprotein(a	O
+)	O
+by	O
+a	O
+median	O
+23.2	O
+%	O
+with	O
+greater	O
+absolute	O
+reductions	O
+from	O
+higher	O
+baseline	O
+levels	O
+and	O
+no	O
+overall	O
+effect	O
+on	O
+incident	O
+type	O
+2	O
+diabetes	O
+(	O
+hazard	O
+ratio	O
+0.95	O
+,	O
+95	O
+%	O
+CI	O
+0.85	O
+-	O
+1.05	O
+)	O
+.	O
+
+At	O
+low	O
+baseline	O
+lipoprotein(a	O
+)	O
+levels	O
+,	O
+alirocumab	O
+tended	O
+to	O
+reduce	O
+incident	O
+type	O
+2	O
+diabetes	O
+,	O
+while	O
+at	O
+high	O
+baseline	O
+lipoprotein(a	O
+)	O
+alirocumab	O
+tended	O
+to	O
+increase	O
+incident	O
+type	O
+2	O
+diabetes	O
+compared	O
+with	O
+placebo	O
+(	O
+treatment	O
+-	O
+baseline	O
+lipoprotein(a	O
+)	O
+interaction	O
+P	O
+=	O
+0.006	O
+)	O
+.	O
+
+In	O
+the	O
+alirocumab	O
+group	O
+,	O
+a	O
+10	O
+mg	O
+/	O
+dL	O
+decrease	O
+in	O
+lipoprotein(a	O
+)	O
+from	O
+baseline	O
+was	O
+associated	O
+with	O
+hazard	O
+ratio	O
+1.07	O
+(	O
+95	O
+%	O
+CI	O
+1.03	O
+-	O
+1.12	O
+;	O
+P	O
+=	O
+0.0002	O
+)	O
+for	O
+incident	O
+type	O
+2	O
+diabetes	O
+.	O
+
+Conclusions	O
+In	O
+patients	O
+with	O
+acute	O
+coronary	O
+syndrome	O
+,	O
+baseline	O
+lipoprotein(a	O
+)	O
+concentration	O
+associated	O
+inversely	O
+with	O
+incident	O
+type	O
+2	O
+diabetes	O
+.	O
+
+Alirocumab	O
+had	O
+neutral	O
+overall	O
+effect	O
+on	O
+incident	O
+type	O
+2	O
+diabetes	O
+.	O
+
+However	O
+,	O
+treatment	O
+-	O
+related	O
+reductions	O
+in	O
+lipoprotein(a	O
+)	O
+,	O
+more	O
+pronounced	O
+from	O
+high	O
+baseline	O
+levels	O
+,	O
+were	O
+associated	O
+with	O
+increased	O
+risk	O
+of	O
+incident	O
+type	O
+2	O
+diabetes	O
+.	O
+
+Whether	O
+these	O
+findings	O
+pertain	O
+to	O
+other	O
+therapies	O
+that	O
+reduce	O
+lipoprotein(a	O
+)	O
+is	O
+undetermined	O
+.	O
+
+Pneumocystis	O
+jirovecii	O
+pneumonia	O
+(	O
+PJP	O
+)	O
+is	O
+an	O
+opportunistic	O
+infectious	O
+disease	O
+well	O
+described	O
+in	O
+patients	O
+living	O
+with	O
+HIV	O
+(	O
+PLHIV	O
+)	O
+but	O
+that	O
+can	O
+occur	O
+in	O
+other	O
+immunosuppressed	O
+patients	O
+.	O
+
+Currently	O
+,	O
+its	O
+incidence	B-EPI
+decreases	O
+in	O
+PLHIV	O
+but	O
+increases	O
+in	O
+non	O
+-	O
+HIV	O
+immunosuppressed	O
+patients	O
+,	O
+particularly	O
+in	O
+case	O
+of	O
+hematological	O
+diseases	O
+.	O
+
+Thus	O
+,	O
+in	O
+elderly	O
+,	O
+the	O
+diagnosis	O
+of	O
+PJP	O
+should	O
+be	O
+evoked	O
+in	O
+case	O
+of	O
+subacute	O
+pneumonia	O
+rapidly	O
+evolving	O
+to	O
+an	O
+acute	O
+respiratory	O
+distress	O
+,	O
+with	O
+or	O
+without	O
+interstitial	O
+pneumonia	O
+at	O
+chest	O
+radiography	O
+,	O
+and	O
+a	O
+context	O
+of	O
+immunosuppression	O
+.	O
+
+Introduction	O
+Patients	O
+with	O
+Noonan	O
+and	O
+Williams	O
+-	O
+Beuren	O
+syndrome	O
+present	O
+similar	O
+facial	O
+phenotypes	O
+modulated	O
+by	O
+their	O
+ethnic	O
+background	O
+.	O
+
+Although	O
+distinctive	O
+facial	O
+features	O
+have	O
+been	O
+reported	O
+,	O
+studies	O
+show	O
+a	O
+variable	O
+incidence	B-EPI
+of	O
+those	O
+characteristics	O
+in	O
+populations	O
+with	O
+diverse	O
+ancestry	O
+.	O
+
+Hence	O
+,	O
+a	O
+differential	O
+diagnosis	O
+based	O
+on	O
+reported	O
+facial	O
+features	O
+can	O
+be	O
+challenging	O
+.	O
+
+Although	O
+accurate	O
+diagnoses	O
+are	O
+possible	O
+with	O
+genetic	O
+testing	O
+,	O
+they	O
+are	O
+not	O
+available	O
+in	O
+developing	O
+and	O
+remote	O
+regions	O
+.	O
+
+Methods	O
+We	O
+used	O
+a	O
+facial	O
+analysis	O
+technology	O
+to	O
+identify	O
+the	O
+most	O
+discriminative	O
+facial	O
+metrics	O
+between	O
+286	O
+patients	O
+with	O
+Noonan	O
+and	O
+161	O
+with	O
+Williams	O
+-	O
+Beuren	O
+syndrome	O
+with	O
+diverse	O
+ethnic	O
+background	O
+.	O
+
+We	O
+quantified	O
+the	O
+most	O
+discriminative	O
+metrics	O
+,	O
+and	O
+their	O
+ranges	O
+both	O
+globally	O
+and	O
+in	O
+different	O
+ethnic	O
+groups	O
+.	O
+
+We	O
+also	O
+created	O
+population	O
+-	O
+based	O
+appearance	O
+images	O
+that	O
+are	O
+useful	O
+not	O
+only	O
+as	O
+clinical	O
+references	O
+but	O
+also	O
+for	O
+training	O
+purposes	O
+.	O
+
+Finally	O
+,	O
+we	O
+trained	O
+both	O
+global	O
+and	O
+ethnic	O
+-	O
+specific	O
+machine	O
+learning	O
+models	O
+with	O
+previous	O
+metrics	O
+to	O
+distinguish	O
+between	O
+patients	O
+with	O
+Noonan	O
+and	O
+Williams	O
+-	O
+Beuren	O
+syndromes	O
+.	O
+
+Results	O
+We	O
+obtained	O
+a	O
+classification	O
+accuracy	O
+of	O
+85.68	O
+%	O
+in	O
+the	O
+global	O
+population	O
+evaluated	O
+using	O
+cross	O
+-	O
+validation	O
+,	O
+which	O
+improved	B-STAT
+to	O
+90.38	O
+%	O
+when	O
+we	O
+adapted	O
+the	O
+facial	O
+metrics	O
+to	O
+the	O
+ethnicity	O
+of	O
+the	O
+patients	O
+(	O
+p	O
+=	O
+0.024	O
+)	O
+.	O
+
+Conclusion	O
+Our	O
+facial	O
+analysis	O
+provided	O
+for	O
+the	O
+first	O
+time	O
+quantitative	O
+reference	O
+facial	O
+metrics	O
+for	O
+the	O
+differential	O
+diagnosis	O
+Noonan	O
+and	O
+Williams	O
+-	O
+Beuren	O
+syndromes	O
+in	O
+diverse	O
+populations	O
+.	O
+
+Testicular	O
+cancer	O
+is	O
+the	O
+most	O
+common	O
+malignant	O
+tumor	O
+in	O
+young	O
+men	O
+,	O
+and	O
+its	O
+incidence	B-EPI
+has	O
+increased	O
+in	O
+recent	O
+years	O
+.	O
+
+The	O
+tumor	O
+microenvironment	O
+(	O
+TME	O
+)	O
+plays	O
+a	O
+crucial	O
+role	O
+in	O
+the	O
+development	O
+and	O
+progression	O
+of	O
+tumors	O
+;	O
+however	O
+,	O
+the	O
+TME	O
+of	O
+testicular	O
+germ	O
+cell	O
+tumor	O
+(	O
+TGCT	O
+)	O
+is	O
+poorly	O
+understood	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+downloaded	O
+information	O
+for	O
+156	O
+TGCT	O
+cases	O
+from	O
+The	O
+Cancer	O
+Genome	O
+Atlas	O
+(	O
+TCGA	O
+)	O
+database	O
+,	O
+used	O
+the	O
+ESTIMATE	O
+method	O
+to	O
+determine	O
+immune	O
+and	O
+stromal	O
+scores	O
+,	O
+and	O
+used	O
+CIBERSORT	O
+to	O
+calculate	O
+the	O
+proportion	O
+of	O
+tumor	O
+-	O
+infiltrating	O
+immune	O
+cells	O
+(	O
+TICs	O
+)	O
+.	O
+
+The	O
+differentially	O
+expressed	O
+genes	O
+were	O
+subjected	O
+to	O
+a	O
+COX	O
+regression	O
+analysis	O
+and	O
+used	O
+for	O
+the	O
+construction	O
+of	O
+a	O
+protein	O
+-	O
+protein	O
+interaction	O
+(	O
+PPI	O
+)	O
+network	O
+.	O
+
+Toll	O
+-	O
+like	O
+receptor	O
+2	O
+(	O
+TLR2	O
+)	O
+was	O
+identified	O
+as	O
+a	O
+predictive	O
+marker	O
+by	O
+combining	O
+the	O
+results	O
+of	O
+the	O
+Cox	O
+regression	O
+analysis	O
+and	O
+PPI	O
+network	O
+.	O
+
+A	O
+survival	O
+analysis	O
+showed	O
+that	O
+TLR2	O
+was	O
+positively	O
+correlated	O
+with	O
+TGCT	O
+survival	O
+.	O
+
+A	O
+gene	O
+set	O
+enrichment	O
+analysis	O
+indicated	O
+that	O
+genes	O
+in	O
+the	O
+high	O
+TLR2	O
+expression	O
+group	O
+were	O
+enriched	O
+for	O
+cell	O
+adhesion	O
+molecules	O
+(	O
+CAMs	O
+)	O
+and	O
+the	O
+chemokine	O
+signaling	O
+pathway	O
+,	O
+and	O
+genes	O
+in	O
+the	O
+low	O
+TLR2	O
+expression	O
+group	O
+were	O
+mainly	O
+enriched	O
+in	O
+the	O
+spliceosome	O
+.	O
+
+Regarding	O
+proportions	O
+of	O
+TICs	O
+,	O
+naive	O
+B	O
+cells	O
+and	O
+follicular	O
+helper	O
+T	O
+cells	O
+were	O
+negatively	O
+correlated	O
+with	O
+the	O
+expression	O
+of	O
+TLR2	O
+.	O
+
+This	O
+suggests	O
+that	O
+as	O
+TLR2	O
+expression	O
+increases	O
+,	O
+the	O
+immunocompetence	O
+of	O
+the	O
+TME	O
+decreases	O
+.	O
+
+The	O
+expression	O
+of	O
+TLR2	O
+may	O
+affect	O
+the	O
+prognosis	O
+of	O
+TGCT	O
+,	O
+suggesting	O
+that	O
+this	O
+locus	O
+can	O
+be	O
+used	O
+as	O
+a	O
+prognostic	O
+factor	O
+for	O
+TGCT	O
+.	O
+
+The	O
+clinical	O
+presentation	O
+of	O
+optic	O
+neuritis	O
+is	O
+quite	O
+characteristic	O
+,	O
+and	O
+the	O
+epidemiology	O
+,	O
+differential	O
+diagnosis	O
+,	O
+and	O
+treatment	O
+protocol	O
+are	O
+well	O
+established	O
+.	O
+
+However	O
+,	O
+when	O
+the	O
+presentation	O
+of	O
+optic	O
+neuritis	O
+is	O
+atypical	O
+,	O
+bilateral	O
+,	O
+and	O
+intravenous	O
+steroid	O
+-	O
+resistant	O
+,	O
+the	O
+treatment	O
+guidelines	O
+are	O
+quite	O
+nebulous	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+bilateral	O
+severe	O
+double	O
+-	O
+seronegative	O
+optic	O
+neuritis	O
+with	O
+catastrophic	O
+vision	O
+loss	O
+and	O
+intravenous	O
+steroid	O
+resistance	O
+.	O
+
+After	O
+an	O
+exhaustive	O
+investigation	O
+,	O
+we	O
+empirically	O
+treated	O
+our	O
+patient	O
+with	O
+plasma	O
+exchange	O
+therapy	O
+and	O
+obtained	O
+a	O
+dramatic	O
+recovery	O
+of	O
+vision	O
+.	O
+
+When	O
+an	O
+immune	O
+etiology	O
+is	O
+suspected	O
+,	O
+this	O
+case	O
+is	O
+instructive	O
+vis	O
+-	O
+a	O
+-	O
+vis	O
+the	O
+utility	O
+of	O
+plasma	O
+exchange	O
+in	O
+refractory	O
+cases	O
+of	O
+optic	O
+neuritis	O
+despite	O
+seronegativity	O
+.	O
+
+Despite	O
+the	O
+known	O
+association	O
+of	O
+cardiac	O
+rupture	O
+with	O
+acute	O
+myocardial	O
+infarction	O
+(	O
+AMI	O
+)	O
+,	O
+it	O
+is	O
+still	O
+unclear	O
+whether	O
+the	O
+clinical	O
+characteristics	O
+are	O
+associated	O
+with	O
+the	O
+risk	O
+of	O
+in	O
+-	O
+hospital	O
+mortality	O
+in	O
+patients	O
+with	O
+AMI	O
+complicated	O
+by	O
+cardiac	O
+rupture	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+association	O
+between	O
+the	O
+time	O
+of	O
+cardiac	O
+rupture	O
+occurrence	B-EPI
+and	O
+the	O
+risk	O
+of	O
+in	O
+-	O
+hospital	O
+mortality	O
+after	O
+AMI	O
+.	O
+
+We	O
+conducted	O
+a	O
+retrospective	O
+analysis	O
+of	O
+multicenter	O
+registry	O
+data	O
+from	O
+eight	O
+medical	O
+universities	O
+in	O
+Eastern	B-LOC
+Japan	I-LOC
+.	O
+
+From	O
+10,278	O
+consecutive	O
+patients	O
+with	O
+AMI	O
+,	O
+we	O
+included	O
+183	O
+patients	O
+who	O
+had	O
+cardiac	O
+rupture	O
+after	O
+AMI	O
+,	O
+and	O
+examined	O
+the	O
+incidence	B-EPI
+of	O
+in	O
+-	O
+hospital	O
+deaths	O
+during	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+26	O
+days	O
+.	O
+
+Patients	O
+were	O
+stratified	O
+into	O
+three	O
+groups	O
+according	O
+to	O
+the	O
+AMI	O
+-	O
+to	O
+-	O
+cardiac	O
+rupture	O
+time	O
+,	O
+namely	O
+the	O
+>	O
+24	O
+-	O
+h	O
+group	O
+(	O
+n	O
+=	O
+111	O
+)	O
+,	O
+24	O
+-	O
+48	O
+-	O
+h	O
+group	O
+(	O
+n	O
+=	O
+20	O
+)	O
+,	O
+and	O
+<	O
+48	O
+-	O
+h	O
+group	O
+(	O
+n	O
+=	O
+52	O
+)	O
+.	O
+
+Cox	O
+proportional	O
+hazards	O
+regression	O
+analysis	O
+was	O
+used	O
+to	O
+estimate	O
+the	O
+hazard	O
+ratio	O
+(	O
+HR	O
+)	O
+and	O
+the	O
+confidence	O
+interval	O
+(	O
+CI	O
+)	O
+for	O
+in	O
+-	O
+hospital	O
+mortality	O
+.	O
+
+Around	O
+87	B-STAT
+(	O
+48	O
+%	O
+)	O
+patients	O
+experienced	O
+in	O
+-	O
+hospital	O
+death	O
+and	O
+126	B-STAT
+(	O
+67	O
+%	O
+)	O
+underwent	O
+a	O
+cardiac	O
+surgery	O
+.	O
+
+Multivariable	O
+Cox	O
+regression	O
+analysis	O
+revealed	O
+a	O
+non	O
+-	O
+linear	O
+association	O
+across	O
+the	O
+three	O
+groups	O
+for	O
+mortality	O
+(	O
+HR	O
+[	O
+CI	O
+]	O
+;	O
+<	O
+24	O
+h	O
+:	O
+1.0	O
+,	O
+reference	O
+;	O
+24	O
+-	O
+48	O
+h	O
+:	O
+0.73	O
+[	O
+0.27	O
+-	O
+1.86	O
+]	O
+;	O
+>	O
+48	O
+h	O
+:	O
+2.25	O
+[	O
+1.22	O
+-	O
+4.15	O
+]	O
+)	O
+after	O
+adjustments	O
+for	O
+age	O
+,	O
+sex	O
+,	O
+Killip	O
+classification	O
+,	O
+percutaneous	O
+coronary	O
+intervention	O
+,	O
+blood	O
+pressure	O
+,	O
+creatinine	O
+,	O
+peak	O
+creatine	O
+kinase	O
+myocardial	O
+band	O
+fraction	O
+,	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+,	O
+and	O
+type	O
+of	O
+rupture	O
+.	O
+
+Cardiac	O
+surgery	O
+was	O
+independently	O
+associated	O
+with	O
+a	O
+reduction	O
+in	O
+the	O
+HR	O
+of	O
+mortality	O
+(	O
+HR	O
+[	O
+CI	O
+]	O
+:	O
+0.27	O
+[	O
+0.12	O
+-	O
+0.61	O
+]	O
+)	O
+and	O
+attenuated	O
+the	O
+association	O
+between	O
+the	O
+three	O
+AMI	O
+-	O
+to	O
+-	O
+cardiac	O
+rupture	O
+time	O
+categories	O
+and	O
+mortality	O
+(	O
+statistically	O
+non	O
+-	O
+significant	O
+)	O
+in	O
+the	O
+Cox	O
+model	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+the	O
+AMI	O
+-	O
+to	O
+-	O
+cardiac	O
+rupture	O
+time	O
+contributes	O
+significantly	O
+to	O
+the	O
+risk	O
+of	O
+in	O
+-	O
+hospital	O
+mortality	O
+;	O
+however	O
+,	O
+rapid	O
+diagnosis	O
+and	O
+prompt	O
+surgical	O
+interventions	O
+are	O
+crucial	O
+for	O
+improving	O
+outcomes	O
+in	O
+patients	O
+with	O
+cardiac	O
+rupture	O
+after	O
+AMI	O
+.	O
+
+The	O
+inherited	O
+bone	O
+marrow	O
+failure	O
+syndromes	O
+(	O
+IBMFS	O
+)	O
+are	O
+a	O
+rare	O
+yet	O
+clinically	O
+important	O
+cause	O
+of	O
+neonatal	O
+hematological	O
+and	O
+non	O
+-	O
+hematological	O
+manifestations	O
+.	O
+
+Many	O
+of	O
+these	O
+syndromes	O
+,	O
+such	O
+as	O
+Fanconi	O
+anemia	O
+,	O
+dyskeratosis	O
+congenita	O
+and	O
+Diamond	O
+-	O
+Blackfan	O
+anemia	O
+,	O
+confer	O
+risks	O
+of	O
+multiple	O
+medical	O
+complications	O
+later	O
+in	O
+life	O
+,	O
+including	O
+an	O
+increased	O
+risk	O
+of	O
+cancer	O
+.	O
+
+Some	O
+IBMFS	O
+may	O
+present	O
+with	O
+cytopenias	O
+in	O
+the	O
+neonatal	O
+period	O
+whereas	O
+others	O
+may	O
+present	O
+only	O
+with	O
+congenital	O
+physical	O
+abnormalities	O
+and	O
+progress	O
+to	O
+pancytopenia	O
+later	O
+in	O
+life	O
+.	O
+
+A	O
+thorough	O
+family	O
+history	O
+and	O
+detailed	O
+physical	O
+examination	O
+are	O
+integral	O
+to	O
+the	O
+work	O
+-	O
+up	O
+of	O
+any	O
+neonate	O
+in	O
+whom	O
+there	O
+is	O
+a	O
+high	O
+index	O
+of	O
+suspicion	O
+for	O
+an	O
+IBMFS	O
+.	O
+
+Correct	O
+detection	O
+and	O
+diagnosis	O
+of	O
+these	O
+disorders	O
+is	O
+important	O
+for	O
+appropriate	O
+long	O
+-	O
+term	O
+medical	O
+surveillance	O
+and	O
+counseling	O
+not	O
+only	O
+for	O
+the	O
+patient	O
+but	O
+also	O
+for	O
+appropriate	O
+genetic	O
+counselling	O
+of	O
+their	O
+families	O
+regarding	O
+recurrence	O
+risks	O
+in	O
+future	O
+children	O
+and	O
+generations	O
+.	O
+
+Background	O
+May	O
+-	O
+Hegglin	O
+anomaly	O
+is	O
+an	O
+autosomal	O
+dominant	O
+inherited	O
+condition	O
+,	O
+characterized	O
+by	O
+thrombocytopenia	O
+,	O
+giant	O
+platelets	O
+and	O
+Dohle	O
+-	O
+like	O
+bodies	O
+.	O
+
+Incidence	B-EPI
+is	O
+unknown	O
+and	O
+affected	O
+individuals	O
+can	O
+show	O
+from	O
+mild	O
+to	O
+moderate	O
+-	O
+severe	O
+haemorrhagic	O
+symptoms	O
+.	O
+
+The	O
+cyst	O
+of	O
+cavum	O
+veli	O
+interpositi	O
+(	O
+a	O
+virtual	O
+space	O
+filled	O
+with	O
+fluid	O
+within	O
+the	O
+third	O
+ventricle	O
+)	O
+is	O
+rarely	O
+reported	O
+in	O
+the	O
+foetal	O
+period	O
+.	O
+
+Furthermore	O
+,	O
+it	O
+is	O
+unclear	O
+whether	O
+isolated	O
+cavum	O
+veli	O
+interpositi	O
+cysts	O
+are	O
+a	O
+normal	O
+variant	O
+or	O
+developmental	O
+malformations	O
+.	O
+
+The	O
+simultaneous	O
+presence	O
+of	O
+these	O
+two	O
+anomalies	O
+was	O
+never	O
+described	O
+.	O
+
+Case	O
+presentation	O
+We	O
+describe	O
+a	O
+very	O
+rare	O
+case	O
+of	O
+a	O
+twin	O
+monochorionic	O
+pregnancy	O
+in	O
+a	O
+woman	O
+with	O
+the	O
+May	O
+-	O
+Hegglin	O
+anomaly	O
+,	O
+whose	O
+foetuses	O
+carried	O
+cavum	O
+veli	O
+interpositi	O
+cysts	O
+.	O
+
+Since	O
+childhood	O
+,	O
+our	O
+patient	O
+had	O
+shown	O
+macro	O
+-	O
+thrombocytopenia	O
+,	O
+deafness	O
+and	O
+bleeding	O
+(	O
+epistaxis	O
+and	O
+menorrhagia	O
+)	O
+,	O
+but	O
+she	O
+was	O
+misdiagnosed	O
+until	O
+the	O
+age	O
+of	O
+30	O
+years	O
+when	O
+our	O
+Centre	O
+identified	O
+a	O
+de	O
+novo	O
+allelic	O
+variant	O
+in	O
+the	O
+gene	O
+MYH9	O
+coding	O
+for	O
+the	O
+non	O
+-	O
+muscle	O
+myosin	O
+heavy	O
+chain	O
+IIa	O
+.	O
+
+Our	O
+patient	O
+bled	O
+neither	O
+during	O
+the	O
+pregnancy	O
+,	O
+nor	O
+in	O
+the	O
+peripartum	O
+period	O
+.	O
+
+Children	O
+are	O
+now	O
+eight	O
+-	O
+months	O
+-	O
+old	O
+and	O
+have	O
+never	O
+bled	O
+,	O
+although	O
+both	O
+inherited	O
+the	O
+MYH9	O
+variant	O
+and	O
+have	O
+thrombocytopenia	O
+with	O
+giant	O
+platelets	O
+.	O
+
+Furthermore	O
+,	O
+none	O
+of	O
+them	O
+developed	O
+psychomotor	O
+disorders	O
+.	O
+
+Conclusions	O
+To	O
+the	O
+best	O
+of	O
+our	O
+knowledge	O
+,	O
+this	O
+is	O
+the	O
+sixth	O
+case	O
+of	O
+twin	O
+pregnancy	O
+in	O
+a	O
+woman	O
+carrying	O
+May	O
+-	O
+Hegglin	O
+anomaly	O
+and	O
+the	O
+first	O
+one	O
+with	O
+cavum	O
+veli	O
+interpositi	O
+cysts	O
+in	O
+the	O
+neonates	O
+.	O
+
+We	O
+speculate	O
+that	O
+MYH9	O
+could	O
+have	O
+,	O
+at	O
+least	O
+in	O
+part	O
+,	O
+played	O
+a	O
+role	O
+in	O
+the	O
+development	O
+of	O
+both	O
+conditions	O
+,	O
+as	O
+this	O
+gene	O
+has	O
+a	O
+pleiotropic	O
+effect	O
+.	O
+
+Smith	O
+-	O
+Magenis	O
+syndrome	O
+(	O
+SMS	O
+)	O
+,	O
+characterized	O
+by	O
+dysmorphic	O
+features	O
+,	O
+neurodevelopmental	O
+disorder	O
+,	O
+and	O
+sleep	O
+disturbance	O
+,	O
+is	O
+due	O
+to	O
+an	O
+interstitial	O
+deletion	O
+of	O
+chromosome	O
+17p11.2	O
+(	O
+90	O
+%	O
+)	O
+or	O
+to	O
+point	O
+mutations	O
+in	O
+the	O
+RAI1	O
+gene	O
+.	O
+
+In	O
+this	O
+retrospective	O
+cohort	O
+,	O
+we	O
+studied	O
+the	O
+clinical	O
+,	O
+cognitive	O
+,	O
+and	O
+behavioral	O
+profile	O
+of	O
+47	O
+European	O
+patients	O
+with	O
+SMS	O
+caused	O
+by	O
+a	O
+17p11.2	O
+deletion	O
+.	O
+
+We	O
+update	O
+the	O
+clinical	O
+and	O
+neurobehavioral	O
+profile	O
+of	O
+SMS	O
+.	O
+
+Intrauterine	O
+growth	O
+was	O
+normal	O
+in	O
+most	O
+patients	O
+.	O
+
+Prenatal	O
+anomalies	O
+were	O
+reported	O
+in	O
+15	B-STAT
+%	I-STAT
+.	O
+
+60	B-STAT
+%	I-STAT
+of	O
+our	O
+patients	O
+older	O
+than	O
+10	O
+years	O
+were	O
+overweight	O
+.	O
+
+Prevalence	B-EPI
+of	O
+heart	O
+defects	O
+(	O
+6.5	O
+%	O
+tetralogy	O
+of	O
+Fallot	B-LOC
+,	O
+6.5	O
+%	O
+pulmonary	O
+stenosis	O
+)	O
+,	O
+ophthalmological	O
+problems	O
+(	O
+89	O
+%	O
+)	O
+,	O
+scoliosis	O
+(	O
+43	O
+%	O
+)	O
+,	O
+or	O
+deafness	O
+(	O
+32	O
+%	O
+)	O
+were	O
+consistent	O
+with	O
+previous	O
+reports	O
+.	O
+
+Epilepsy	O
+was	O
+uncommon	O
+(	O
+2	O
+%	O
+)	O
+.	O
+
+We	O
+identified	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+obstipation	O
+(	O
+45	O
+%	O
+)	O
+.	O
+
+All	O
+patients	O
+had	O
+learning	O
+difficulties	O
+and	O
+developmental	O
+delay	O
+,	O
+but	O
+ID	O
+range	O
+was	O
+wide	O
+and	O
+10	O
+%	O
+of	O
+patients	O
+had	O
+IQ	O
+in	O
+the	O
+normal	O
+range	O
+.	O
+
+Behavioral	O
+problems	O
+included	O
+temper	O
+tantrums	O
+and	O
+other	O
+difficult	O
+behaviors	O
+(	O
+84	O
+%	O
+)	O
+and	O
+night	O
+-	O
+time	O
+awakenings	O
+(	O
+86	O
+%	O
+)	O
+.	O
+
+Optimal	O
+care	O
+of	O
+SMS	O
+children	O
+is	O
+multidisciplinary	O
+and	O
+requires	O
+important	O
+parental	O
+involvement	O
+.	O
+
+In	O
+our	O
+series	O
+,	O
+half	O
+of	O
+patients	O
+were	O
+able	O
+to	O
+follow	O
+adapted	O
+schooling	O
+,	O
+but	O
+70	O
+%	O
+of	O
+parents	O
+had	O
+to	O
+adapt	O
+their	O
+working	O
+time	O
+,	O
+illustrating	O
+the	O
+medical	O
+,	O
+social	O
+,	O
+educative	O
+,	O
+and	O
+familial	O
+impact	O
+of	O
+having	O
+a	O
+child	O
+with	O
+SMS	O
+.	O
+
+Context	O
+:	O
+There	O
+has	O
+been	O
+concern	O
+that	O
+GH	O
+treatment	O
+of	O
+children	O
+might	O
+increase	O
+meningioma	O
+risk	O
+.	O
+
+Results	O
+of	O
+published	O
+studies	O
+have	O
+been	O
+inconsistent	O
+and	O
+limited	O
+.	O
+
+Objective	O
+:	O
+To	O
+examine	O
+meningioma	O
+risks	O
+in	O
+relation	O
+to	O
+GH	O
+treatment	O
+.	O
+
+Design	O
+:	O
+Cohort	O
+study	O
+with	O
+follow	O
+-	O
+up	O
+via	O
+cancer	O
+registries	O
+and	O
+other	O
+registers	O
+.	O
+
+Setting	O
+:	O
+Population	O
+-	O
+based	O
+.	O
+
+Patients	O
+:	O
+A	O
+cohort	O
+of	O
+10,403	O
+patients	O
+treated	O
+in	O
+childhood	O
+with	O
+recombinant	O
+GH	O
+in	O
+five	O
+European	O
+countries	O
+since	O
+this	O
+treatment	O
+was	O
+first	O
+used	O
+in	O
+1984	O
+.	O
+
+Expected	O
+rates	O
+from	O
+national	O
+cancer	O
+registration	O
+statistics	O
+.	O
+
+Main	O
+Outcome	O
+Measures	O
+:	O
+Risk	O
+of	O
+meningioma	O
+incidence	B-EPI
+.	O
+
+Results	O
+:	O
+During	O
+follow	O
+-	O
+up	O
+,	O
+38	O
+meningiomas	O
+occurred	O
+.	O
+
+Meningioma	O
+risk	O
+was	O
+greatly	O
+raised	O
+in	O
+the	O
+cohort	O
+overall	O
+[	O
+standardized	O
+incidence	B-EPI
+ratio	O
+(	O
+SIR	O
+)	O
+=	O
+75.4	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+54.9	O
+to	O
+103.6	O
+]	O
+,	O
+as	O
+a	O
+consequence	O
+of	O
+high	O
+risk	O
+in	O
+subjects	O
+who	O
+had	O
+received	O
+radiotherapy	O
+for	O
+underlying	O
+malignancy	O
+(	O
+SIR	O
+=	O
+658.4	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+460.4	O
+to	O
+941.7	O
+)	O
+.	O
+
+Risk	O
+was	O
+not	O
+significantly	O
+raised	O
+in	O
+patients	O
+who	O
+did	O
+not	O
+receive	O
+radiotherapy	O
+.	O
+
+Risk	O
+in	O
+radiotherapy	O
+-	O
+treated	O
+patients	O
+was	O
+not	O
+significantly	O
+related	O
+to	O
+mean	O
+daily	O
+dose	O
+of	O
+GH	O
+,	O
+duration	O
+of	O
+GH	O
+treatment	O
+,	O
+or	O
+cumulative	O
+dose	O
+of	O
+GH	O
+.	O
+
+Conclusions	O
+:	O
+Our	O
+data	O
+add	O
+to	O
+evidence	O
+of	O
+very	O
+high	O
+risk	O
+of	O
+meningioma	O
+in	O
+patients	O
+treated	O
+in	O
+childhood	O
+with	O
+GH	O
+after	O
+cranial	O
+radiotherapy	O
+,	O
+but	O
+suggest	O
+that	O
+GH	O
+may	O
+not	O
+affect	O
+radiotherapy	O
+-	O
+related	O
+risk	O
+,	O
+and	O
+that	O
+there	O
+is	O
+no	O
+material	O
+raised	O
+risk	O
+of	O
+meningioma	O
+in	O
+GH	O
+-	O
+treated	O
+patients	O
+who	O
+did	O
+not	O
+receive	O
+radiotherapy	O
+.	O
+
+Aims	O
+Takotsubo	O
+syndrome	O
+(	O
+TTS	O
+)	O
+is	O
+a	O
+form	O
+of	O
+acute	O
+myocardial	O
+inflammation	O
+,	O
+often	O
+triggered	O
+by	O
+catecholamine	O
+release	O
+surges	O
+,	O
+which	O
+accounts	O
+for	O
+approximately	O
+10	O
+%	O
+of	O
+'	O
+myocardial	O
+infarctions	O
+'	O
+in	O
+female	O
+patients	O
+above	O
+the	O
+age	O
+of	O
+50	O
+.	O
+
+Its	O
+associated	O
+substantial	O
+risk	O
+of	O
+in	O
+-	O
+hospital	O
+mortality	O
+is	O
+mainly	O
+driven	O
+by	O
+the	O
+development	O
+of	O
+hypotension	O
+and	O
+shock	O
+.	O
+
+While	O
+hypotension	O
+is	O
+induced	O
+largely	O
+by	O
+factors	O
+other	O
+than	O
+low	O
+cardiac	O
+output	O
+,	O
+its	O
+precise	O
+cause	O
+is	O
+unknown	O
+,	O
+and	O
+clinical	O
+parameters	O
+associated	O
+with	O
+hypotension	O
+have	O
+not	O
+been	O
+identified	O
+previously	O
+.	O
+
+We	O
+therefore	O
+sought	O
+to	O
+identify	O
+the	O
+incidence	B-EPI
+and	O
+clinical	O
+/	O
+laboratory	O
+correlates	O
+of	O
+early	O
+hypotension	O
+in	O
+TTS	O
+.	O
+
+Methods	O
+and	O
+results	O
+We	O
+analysed	O
+the	O
+in	O
+-	O
+hospital	O
+data	O
+of	O
+patients	O
+recruited	O
+to	O
+the	B-LOC
+South	I-LOC
+Australian	I-LOC
+TTS	I-LOC
+Registry	I-LOC
+.	O
+
+Associations	O
+between	O
+the	O
+development	O
+of	O
+hypotension	O
+,	O
+patient	O
+demographics	O
+,	O
+severity	O
+of	O
+the	O
+acute	O
+TTS	O
+attack	O
+,	O
+and	O
+key	O
+biochemical	O
+markers	O
+were	O
+sought	O
+.	O
+
+One	O
+hundred	O
+thirteen	O
+out	O
+of	O
+319	O
+patients	O
+(	O
+35	O
+%	O
+)	O
+were	O
+hypotensive	O
+(	O
+median	O
+systolic	O
+blood	O
+pressure	O
+80	O
+mmHg	O
+)	O
+during	O
+their	O
+index	O
+hospitalization	O
+.	O
+
+Development	O
+of	O
+hypotension	O
+preceded	O
+all	O
+in	O
+-	O
+hospital	O
+deaths	O
+(	O
+n	O
+=	O
+8)	O
+.	O
+
+On	O
+univariate	O
+analyses	O
+,	O
+patients	O
+who	O
+developed	O
+hypotension	O
+had	O
+lower	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+(	O
+P	O
+=	O
+0.009	O
+)	O
+,	O
+and	O
+higher	O
+plasma	O
+N	O
+-	O
+terminal	O
+pro	O
+brain	O
+natriuretic	O
+peptide	O
+and	O
+troponin	O
+-	O
+T	O
+concentrations	O
+(	O
+P	O
+=	O
+0.046	O
+and	O
+0.008	O
+,	O
+respectively	O
+)	O
+,	O
+all	O
+markers	O
+of	O
+severity	O
+of	O
+the	O
+TTS	O
+attack	O
+;	O
+hypotension	O
+also	O
+occurred	O
+less	O
+commonly	O
+in	O
+male	O
+than	O
+in	O
+female	O
+patients	O
+(	O
+P	O
+=	O
+0.014	O
+)	O
+.	O
+
+On	O
+multivariate	O
+linear	O
+regression	O
+analysis	O
+,	O
+female	O
+sex	O
+and	O
+lower	O
+left	O
+ventricular	O
+ejection	O
+fraction	O
+were	O
+independent	O
+correlates	O
+of	O
+the	O
+development	O
+of	O
+hypotension	O
+(	O
+P	O
+=	O
+0.009	O
+and	O
+0.010	O
+,	O
+respectively	O
+)	O
+.	O
+
+Conclusions	O
+Early	O
+development	O
+of	O
+hypotension	O
+is	O
+very	O
+common	O
+in	O
+TTS	O
+,	O
+and	O
+its	O
+presence	O
+is	O
+associated	O
+with	O
+a	O
+substantial	O
+risk	O
+of	O
+in	O
+-	O
+hospital	O
+mortality	O
+.	O
+
+Hypotension	O
+is	O
+a	O
+marker	O
+of	O
+severe	O
+TTS	O
+attacks	O
+and	O
+occurs	B-EPI
+more	O
+commonly	O
+in	O
+female	O
+TTS	O
+patients	O
+.	O
+
+Background	O
+Using	O
+data	O
+from	O
+the	O
+GARFIELD	O
+-	O
+AF	O
+(	O
+Global	O
+Anticoagulant	O
+Registry	O
+in	O
+the	O
+FIELD	O
+-Atrial	O
+Fibrillation	O
+)	O
+,	O
+we	O
+evaluated	O
+the	O
+impact	O
+of	O
+chronic	O
+kidney	O
+disease	O
+(	O
+CKD	O
+)	O
+stage	O
+on	O
+clinical	O
+outcomes	O
+in	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+atrial	O
+fibrillation	O
+(	O
+AF	O
+)	O
+.	O
+
+Methods	O
+and	O
+Results	O
+GARFIELD	O
+-	O
+AF	O
+is	O
+a	O
+prospective	O
+registry	O
+of	O
+patients	O
+from	O
+35	O
+countries	O
+,	O
+including	O
+patients	O
+from	O
+Asia	B-LOC
+(	O
+China	B-LOC
+,	O
+India	B-LOC
+,	O
+Japan	B-LOC
+,	O
+Singapore	B-LOC
+,	O
+South	B-LOC
+Korea	I-LOC
+,	O
+and	O
+Thailand	B-LOC
+)	O
+.	O
+
+Consecutive	O
+patients	O
+enrolled	O
+(	O
+2013	O
+-	O
+2016	O
+)	O
+were	O
+classified	O
+with	O
+no	O
+,	O
+mild	O
+,	O
+or	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+,	O
+based	O
+on	O
+the	O
+National	O
+Kidney	O
+Foundation	O
+'s	O
+Kidney	O
+Disease	O
+Outcomes	O
+Quality	O
+Initiative	O
+guidelines	O
+.	O
+
+Data	O
+on	O
+CKD	O
+status	O
+and	O
+outcomes	O
+were	O
+available	O
+for	O
+33	O
+024	O
+of	O
+34	O
+854	O
+patients	O
+(	O
+including	O
+9491	O
+patients	O
+from	O
+Asia	B-LOC
+)	O
+;	O
+10.9	O
+%	O
+(	O
+n=3613	O
+)	O
+had	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+,	O
+16.9	O
+%	O
+(	O
+n=5595	O
+)	O
+mild	O
+CKD	O
+,	O
+and	O
+72.1	O
+%	O
+(	O
+n=23	O
+816	O
+)	O
+no	O
+CKD	O
+.	O
+
+The	O
+use	O
+of	O
+oral	O
+anticoagulants	O
+was	O
+influenced	O
+by	O
+stroke	O
+risk	O
+(	O
+ie	O
+,	O
+post	O
+hoc	O
+assessment	O
+of	O
+CHA	O
+2	O
+DS	O
+2	O
+-	O
+VAS	O
+c	O
+score	O
+)	O
+,	O
+but	O
+not	O
+by	O
+CKD	O
+stage	O
+.	O
+
+The	O
+quality	O
+of	O
+anticoagulant	O
+control	O
+with	O
+vitamin	O
+K	O
+antagonists	O
+did	O
+not	O
+differ	O
+with	O
+CKD	O
+stage	O
+.	O
+
+After	O
+adjusting	O
+for	O
+baseline	O
+characteristics	O
+and	O
+antithrombotic	O
+use	O
+,	O
+both	O
+mild	O
+and	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+were	O
+independent	O
+risk	O
+factors	O
+for	O
+all	O
+-	O
+cause	O
+mortality	O
+.	O
+
+Moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+was	O
+independently	O
+associated	O
+with	O
+a	O
+higher	O
+risk	O
+of	O
+stroke	O
+/	O
+systemic	O
+embolism	O
+,	O
+major	O
+bleeding	O
+,	O
+new	O
+-	O
+onset	O
+acute	O
+coronary	O
+syndrome	O
+,	O
+and	O
+new	O
+or	O
+worsening	O
+heart	O
+failure	O
+.	O
+
+The	O
+impact	O
+of	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+on	O
+mortality	O
+was	O
+significantly	O
+greater	O
+in	O
+patients	O
+from	O
+Asia	B-LOC
+than	O
+the	O
+rest	O
+of	O
+the	O
+world	O
+(	O
+P=0.001	O
+)	O
+.	O
+
+Conclusions	O
+In	O
+GARFIELD	O
+-	O
+AF	O
+,	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+was	O
+independently	O
+associated	O
+with	O
+stroke	O
+/	O
+systemic	O
+embolism	O
+,	O
+major	O
+bleeding	O
+,	O
+and	O
+mortality	O
+.	O
+
+The	O
+effect	O
+of	O
+moderate	O
+-	O
+to	O
+-	O
+severe	O
+CKD	O
+on	O
+mortality	O
+was	O
+even	O
+greater	O
+in	O
+patients	O
+from	O
+Asia	B-LOC
+than	O
+the	O
+rest	O
+of	O
+the	O
+world	O
+.	O
+
+Clinical	O
+Trial	O
+Registration	O
+URL	O
+:	O
+http://www.clinicaltrials.gov	O
+.	O
+
+Unique	O
+identifier	O
+:	O
+NCT	O
+01090362	O
+.	O
+
+The	O
+high	O
+incidence	B-EPI
+of	O
+surgically	O
+induced	O
+heart	O
+block	O
+in	O
+patients	O
+with	O
+levotransposition	O
+of	O
+the	O
+great	O
+arteries	O
+is	O
+now	O
+better	O
+understood	O
+because	O
+of	O
+recent	O
+anatomic	O
+demonstration	O
+of	O
+an	O
+unusual	O
+anterior	O
+location	O
+of	O
+the	O
+atrioventricular	O
+specialized	O
+conducting	O
+tissue	O
+.	O
+
+The	O
+two	O
+cases	O
+reported	O
+herein	O
+proved	O
+electrophysiologic	O
+confirmation	O
+of	O
+this	O
+previously	O
+described	O
+anatomy	O
+.	O
+
+The	O
+specialized	O
+conducting	O
+bundle	O
+was	O
+easily	O
+and	O
+consistently	O
+identified	O
+and	O
+then	O
+avoided	O
+in	O
+successful	O
+surgical	O
+correction	O
+in	O
+one	O
+patient	O
+with	O
+common	O
+ventricle	O
+,	O
+type	O
+A-3	O
+,	O
+and	O
+in	O
+another	O
+with	O
+corrected	O
+transposition	O
+,	O
+large	O
+ventricular	O
+septal	O
+defect	O
+,	O
+and	O
+valvular	O
+pulmonary	O
+stenosis	O
+.	O
+
+Electrophysiologic	O
+identification	O
+of	O
+the	O
+atrioventricular	O
+conduction	O
+tissue	O
+at	O
+the	O
+time	O
+of	O
+operation	O
+may	O
+decrease	O
+the	O
+incidence	O
+of	O
+heart	O
+block	O
+and	O
+offers	O
+additional	O
+optimism	O
+for	O
+successful	O
+correction	O
+of	O
+levotransposition	O
+complexes	O
+.	O
+
+Objective	O
+Intellectual	O
+Disability	O
+(	O
+ID	O
+)	O
+represents	O
+a	O
+neuropsychiatric	O
+disorder	O
+,	O
+which	O
+its	O
+etiopathogenesis	O
+remains	O
+insufficiently	O
+understood	O
+.	O
+
+Mutations	O
+in	O
+the	O
+Aristaless	O
+Related	O
+Homeobox	O
+gene	O
+(	O
+ARX	O
+)	O
+have	O
+been	O
+identified	O
+to	O
+cause	O
+syndromic	O
+and	O
+nonsyndromic	O
+(	O
+NS	O
+-	O
+ID	O
+)	O
+.	O
+
+The	O
+most	O
+recurrent	O
+mutation	O
+of	O
+this	O
+gene	O
+is	O
+a	O
+duplication	O
+of	O
+24pb	O
+,	O
+c.428	O
+-	O
+451dup	O
+.	O
+
+Epidemiological	O
+and	O
+genetic	O
+studies	O
+about	O
+ID	O
+in	O
+the	O
+Moroccan	O
+population	O
+remain	O
+very	O
+scarce	O
+,	O
+and	O
+none	O
+study	O
+is	O
+carried	O
+out	O
+on	O
+the	O
+ARX	O
+gene	O
+.	O
+
+This	O
+work	O
+aimed	O
+to	O
+study	O
+c.428	O
+-	O
+451dup	O
+(	O
+24	O
+bp	O
+)	O
+mutation	O
+in	O
+the	O
+exon	O
+2	O
+of	O
+the	O
+ARX	O
+gene	O
+in	O
+118	O
+males	O
+'	O
+Moroccan	O
+patients	O
+with	O
+milder	O
+NS	O
+-	O
+ID	O
+to	O
+evaluate	O
+if	O
+the	O
+gene	O
+screening	O
+is	O
+a	O
+good	O
+tool	O
+for	O
+identifying	O
+NS	O
+-	O
+ID	O
+.	O
+
+Results	O
+Our	O
+mutational	O
+analysis	O
+did	O
+not	O
+show	O
+any	O
+dup(24pb	O
+)	O
+in	O
+our	O
+patients	O
+.	O
+
+This	O
+is	O
+because	O
+based	O
+on	O
+findings	O
+from	O
+previous	O
+studies	O
+that	O
+found	O
+ARX	O
+mutations	O
+in	O
+70	O
+%	O
+of	O
+families	O
+with	O
+NS	O
+-	O
+ID	O
+,	O
+and	O
+in	O
+most	O
+cases	O
+,	O
+1.5	B-STAT
+-	O
+6.1	O
+%	O
+of	O
+individuals	O
+with	O
+NS	O
+-	O
+ID	O
+have	O
+this	O
+duplication	O
+.	O
+
+Since	O
+1/118	B-STAT
+=	O
+0.0084	O
+(	O
+0.84	B-STAT
+%	I-STAT
+)	O
+is	O
+not	O
+much	O
+different	O
+from	O
+1.5	O
+%	O
+,	O
+then	O
+it	O
+is	O
+reasonable	O
+that	O
+this	O
+could	O
+a	O
+sample	O
+size	O
+artifact	O
+.	O
+
+A	O
+complete	O
+screening	O
+of	O
+the	O
+entire	O
+ARX	O
+gene	O
+,	O
+including	O
+the	O
+five	O
+exons	O
+,	O
+should	O
+be	O
+fulfilled	O
+.	O
+
+Further	O
+investigations	O
+are	O
+required	O
+to	O
+confirm	O
+these	O
+results	O
+.	O
+
+Snakebites	O
+in	O
+Europe	B-LOC
+are	O
+mostly	O
+due	O
+to	O
+bites	O
+from	O
+Viperidae	O
+species	O
+of	O
+the	O
+genus	O
+Vipera	O
+.	O
+
+This	O
+represents	O
+a	O
+neglected	O
+public	O
+health	O
+hazard	O
+with	O
+poorly	O
+defined	O
+incidence	B-EPI
+,	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+In	O
+Europe	B-LOC
+,	O
+fourteen	O
+species	O
+of	O
+	O
+true	O
+vipers	O
+	O
+(	O
+subfamily	O
+Viperinae	O
+)	O
+are	O
+present	O
+,	O
+eleven	O
+of	O
+which	O
+belong	O
+to	O
+the	O
+genus	O
+Vipera	O
+.	O
+
+Amongst	O
+these	O
+,	O
+the	O
+main	O
+medically	O
+relevant	O
+species	O
+due	O
+to	O
+their	O
+greater	O
+diffusion	O
+across	O
+Europe	B-LOC
+and	O
+the	O
+highest	O
+number	O
+of	O
+registered	O
+snakebites	O
+are	O
+six	O
+,	O
+namely	O
+:	O
+Vipera	O
+ammodytes	O
+,	O
+V.	O
+aspis	O
+,	O
+V.	O
+berus	O
+,	O
+V.	O
+latastei	O
+,	O
+V.	O
+seoanei	O
+and	O
+V.	O
+ursinii	O
+.	O
+
+Generally	O
+speaking	O
+,	O
+viper	O
+venom	O
+composition	O
+is	O
+characterised	O
+by	O
+many	O
+different	O
+toxin	O
+families	O
+,	O
+like	O
+phospholipases	O
+A2	O
+,	O
+snake	O
+venom	O
+serine	O
+proteases	O
+,	O
+snake	O
+venom	O
+metalloproteases	O
+,	O
+cysteine	O
+-	O
+rich	O
+secretory	O
+proteins	O
+,	O
+C	O
+-	O
+type	O
+lectins	O
+,	O
+disintegrins	O
+,	O
+haemorrhagic	O
+factors	O
+and	O
+coagulation	O
+inhibitors	O
+.	O
+
+A	O
+suspected	O
+snakebite	O
+is	O
+often	O
+associated	O
+with	O
+severe	O
+pain	O
+,	O
+erythema	O
+,	O
+oedema	O
+and	O
+,	O
+subsequently	O
+,	O
+the	O
+onset	O
+of	O
+an	O
+ecchymotic	O
+area	O
+around	O
+one	O
+or	O
+two	O
+visible	O
+fang	O
+marks	O
+.	O
+
+In	O
+the	O
+field	O
+,	O
+the	O
+affected	O
+limb	O
+should	O
+be	O
+immobilised	O
+and	O
+mildly	O
+compressed	O
+with	O
+a	O
+bandage	O
+,	O
+which	O
+can	O
+then	O
+be	O
+removed	O
+once	O
+the	O
+patient	O
+is	O
+being	O
+treated	O
+in	O
+hospital	O
+.	O
+
+The	O
+clinician	O
+should	O
+advise	O
+the	O
+patient	O
+to	O
+remain	O
+calm	O
+to	O
+reduce	O
+blood	O
+circulation	O
+and	O
+,	O
+therefore	O
+,	O
+decrease	O
+the	O
+spread	O
+of	O
+the	O
+toxins	O
+.	O
+
+In	O
+the	O
+case	O
+of	O
+pain	O
+,	O
+an	O
+analgesic	O
+therapy	O
+can	O
+be	O
+administered	O
+,	O
+the	O
+affected	O
+area	O
+can	O
+be	O
+treated	O
+with	O
+hydrogen	O
+peroxide	O
+or	O
+clean	O
+water	O
+.	O
+
+However	O
+,	O
+anti	O
+-	O
+inflammatory	O
+drugs	O
+and	O
+disinfection	O
+with	O
+alcohol	O
+or	O
+alcoholic	O
+substances	O
+should	O
+be	O
+avoided	O
+.	O
+
+For	O
+each	O
+patient	O
+,	O
+clinical	O
+chemistry	O
+and	O
+ECG	O
+are	O
+always	O
+a	O
+pre	O
+-	O
+requisite	O
+as	O
+well	O
+as	O
+the	O
+evaluation	O
+of	O
+the	O
+tetanus	O
+immunisation	O
+status	O
+and	O
+for	O
+which	O
+immunisation	O
+may	O
+be	O
+provided	O
+if	O
+needed	O
+.	O
+
+The	O
+treatment	O
+of	O
+any	O
+clinical	O
+complication	O
+,	O
+due	O
+to	O
+the	O
+envenomation	O
+,	O
+does	O
+not	O
+differ	O
+from	O
+treatments	O
+of	O
+emergency	O
+nature	O
+.	O
+
+Antivenom	O
+is	O
+recommended	O
+when	O
+signs	O
+of	O
+systemic	O
+envenomation	O
+exist	O
+or	O
+in	O
+case	O
+of	O
+advanced	O
+local	O
+or	O
+systemic	O
+progressive	O
+symptoms	O
+.	O
+
+Recommendations	O
+for	O
+future	O
+work	O
+concludes	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+review	O
+is	O
+to	O
+support	O
+clinicians	O
+for	O
+the	O
+clinical	O
+management	O
+of	O
+viper	O
+envenomation	O
+,	O
+through	O
+taxonomic	O
+keys	O
+for	O
+main	O
+species	O
+identification	O
+,	O
+description	O
+of	O
+venom	O
+composition	O
+and	O
+mode	O
+of	O
+action	O
+of	O
+known	O
+toxins	O
+and	O
+provide	O
+a	O
+standardised	O
+clinical	O
+protocol	O
+and	O
+antivenom	O
+administration	O
+.	O
+
+Objective	O
+To	O
+determine	O
+the	O
+incidence	B-EPI
+,	O
+time	O
+trends	O
+,	O
+risk	O
+factors	O
+,	O
+and	O
+severity	O
+of	O
+herpes	O
+zoster	O
+in	O
+a	O
+population	O
+-	O
+based	O
+cohort	O
+of	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+rheumatoid	O
+arthritis	O
+(	O
+RA	O
+)	O
+compared	O
+to	O
+a	O
+group	O
+of	O
+individuals	O
+without	O
+RA	O
+from	O
+the	O
+same	O
+population	O
+.	O
+
+Methods	O
+All	O
+residents	O
+of	O
+Olmsted	B-LOC
+County	I-LOC
+,	O
+Minnesota	B-LOC
+fulfilling	O
+for	O
+the	O
+first	O
+time	O
+the	O
+1987	O
+American	O
+College	O
+of	O
+Rheumatology	O
+criteria	O
+for	O
+RA	O
+between	O
+January	O
+1	O
+,	O
+1980	O
+and	O
+December	O
+31	O
+,	O
+2007	O
+and	O
+a	O
+cohort	O
+of	O
+similar	O
+residents	O
+without	O
+RA	O
+were	O
+assembled	O
+and	O
+followed	O
+by	O
+retrospective	O
+chart	O
+review	O
+until	O
+death	O
+,	O
+migration	O
+,	O
+or	O
+December	O
+31	O
+,	O
+2008	O
+.	O
+
+Results	O
+There	O
+was	O
+no	O
+difference	O
+in	O
+the	O
+presence	O
+of	O
+herpes	O
+zoster	O
+prior	O
+to	O
+the	O
+RA	O
+incidence	B-EPI
+/	O
+index	O
+date	O
+between	O
+the	O
+cohorts	O
+(	O
+P	O
+=	O
+0.85	O
+)	O
+.	O
+
+During	O
+followup	O
+,	O
+84	O
+patients	O
+with	O
+RA	O
+(	O
+rate	O
+12.1	B-STAT
+cases	I-STAT
+per	I-STAT
+1,000	I-STAT
+person	I-STAT
+-	O
+years	O
+)	O
+and	O
+44	O
+subjects	O
+without	O
+RA	O
+(	O
+rate	O
+5.4	B-STAT
+cases	I-STAT
+per	I-STAT
+1,000	I-STAT
+person	I-STAT
+-	O
+years	O
+)	O
+developed	O
+herpes	O
+zoster	O
+.	O
+
+Patients	O
+with	O
+RA	O
+were	O
+more	O
+likely	O
+to	O
+develop	O
+herpes	O
+zoster	O
+than	O
+those	O
+without	O
+RA	O
+(	O
+hazard	O
+ratio	O
+[	O
+HR	O
+]	O
+2.4	O
+[	O
+95	O
+%	O
+confidence	O
+interval	O
+(	O
+95	O
+%	O
+CI	O
+)	O
+1.7	O
+-	O
+3.5	O
+]	O
+)	O
+.	O
+
+Herpes	O
+zoster	O
+occurred	O
+more	O
+frequently	O
+in	O
+patients	O
+diagnosed	O
+with	O
+RA	O
+more	O
+recently	O
+(	O
+HR	O
+1.06	O
+per	O
+year	O
+[	O
+95	O
+%	O
+CI	O
+1.02	O
+-	O
+1.10	O
+]	O
+)	O
+.	O
+
+Erosive	O
+disease	O
+,	O
+previous	O
+joint	O
+surgery	O
+,	O
+and	O
+use	O
+of	O
+hydroxychloroquine	O
+and	O
+corticosteroids	O
+were	O
+significantly	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+herpes	O
+zoster	O
+in	O
+RA	O
+.	O
+
+There	O
+was	O
+no	O
+apparent	O
+association	O
+of	O
+herpes	O
+zoster	O
+with	O
+the	O
+use	O
+of	O
+methotrexate	O
+or	O
+biologic	O
+agents	O
+.	O
+
+Complications	O
+of	O
+herpes	O
+zoster	O
+occurred	O
+at	O
+a	O
+similar	O
+rate	O
+in	O
+both	O
+cohorts	O
+.	O
+
+Conclusion	O
+The	O
+incidence	B-EPI
+of	O
+herpes	O
+zoster	O
+is	O
+increased	O
+in	O
+RA	O
+and	O
+has	O
+risen	O
+in	O
+recent	O
+years	O
+.	O
+
+There	O
+also	O
+has	O
+been	O
+an	O
+increasing	O
+incidence	B-EPI
+of	O
+herpes	O
+zoster	O
+in	O
+more	O
+recent	O
+years	O
+in	O
+the	O
+general	O
+population	O
+.	O
+
+RA	O
+disease	O
+severity	O
+is	O
+associated	O
+with	O
+the	O
+development	O
+of	O
+herpes	O
+zoster	O
+.	O
+
+Background	O
+Little	O
+information	O
+is	O
+available	O
+about	O
+the	O
+incidence	B-EPI
+of	O
+stiff	O
+-	O
+man	O
+syndrome	O
+(	O
+SMS	O
+)	O
+(	O
+the	O
+classic	O
+form	O
+or	O
+its	O
+variants	O
+)	O
+or	O
+about	O
+long	O
+-	O
+term	O
+treatment	O
+responses	O
+and	O
+outcomes	O
+.	O
+
+Objective	O
+To	O
+comprehensively	O
+describe	O
+the	O
+characteristics	O
+of	O
+a	O
+cohort	O
+of	O
+patients	O
+with	O
+SMS	O
+.	O
+
+Design	O
+Observational	O
+study	O
+.	O
+
+Setting	O
+Mayo	O
+Clinic	O
+,	O
+Rochester	B-LOC
+,	O
+Minnesota	B-LOC
+.	O
+
+Patients	O
+Ninety	O
+-	O
+nine	O
+patients	O
+with	O
+classic	O
+SMS	O
+vs	O
+variants	O
+of	O
+the	O
+disorder	O
+,	O
+both	O
+glutamic	O
+acid	O
+decarboxylase	O
+65	O
+kD	O
+isoform	O
+(	O
+GAD65	O
+)	O
+antibody	O
+seropositive	O
+and	O
+seronegative	O
+.	O
+
+Main	O
+outcome	O
+measures	O
+Neurological	O
+,	O
+autoimmune	O
+,	O
+serological	O
+,	O
+and	O
+oncological	O
+findings	O
+;	O
+treatments	O
+;	O
+and	O
+outcomes	O
+between	O
+January	O
+1984	O
+and	O
+December	O
+2008	O
+.	O
+
+Results	O
+The	O
+median	O
+follow	O
+-	O
+up	O
+duration	O
+was	O
+5	O
+years	O
+(	O
+range	O
+,	O
+0	O
+-	O
+23	O
+years	O
+)	O
+.	O
+
+Seventy	O
+-	O
+nine	O
+patients	O
+(	O
+59	O
+having	O
+classic	O
+SMS	O
+,	O
+19	O
+having	O
+partial	O
+SMS	O
+,	O
+and	O
+1	O
+having	O
+progressive	O
+encephalomyelitis	O
+with	O
+rigidity	O
+and	O
+myoclonus	O
+[	O
+PERM	O
+]	O
+)	O
+were	O
+GAD65	O
+antibody	O
+seropositive	O
+.	O
+
+Sixty	B-STAT
+-	O
+seven	O
+percent	O
+(	O
+53	O
+of	O
+79	O
+)	O
+of	O
+them	O
+had	O
+at	O
+least	O
+1	O
+coexisting	O
+autoimmune	O
+disease	O
+,	O
+and	O
+4	O
+%	O
+(	O
+3	O
+of	O
+79	O
+)	O
+had	O
+cancer	O
+.	O
+
+GAD65	O
+antibody	O
+values	O
+at	O
+initial	O
+evaluation	O
+were	O
+significantly	O
+higher	O
+among	O
+patients	O
+with	O
+classic	O
+SMS	O
+(	O
+median	O
+value	O
+,	O
+623	O
+nmol	O
+/	O
+L	O
+)	O
+than	O
+among	O
+patients	O
+with	O
+partial	O
+SMS	O
+(	O
+median	O
+value	O
+,	O
+163	O
+nmol	O
+/	O
+L	O
+)	O
+(	O
+P	O
+<	O
+.001	O
+)	O
+.	O
+
+The	O
+initial	O
+GAD65	O
+antibody	O
+value	O
+was	O
+positively	O
+correlated	O
+with	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+Rankin	O
+score	O
+(	O
+P	O
+=	O
+.03	O
+)	O
+.	O
+
+Among	O
+20	O
+patients	O
+who	O
+were	O
+GAD65	O
+antibody	O
+seronegative	O
+(	O
+6	O
+with	O
+classic	O
+SMS	O
+,	O
+12	O
+with	O
+partial	O
+SMS	O
+,	O
+and	O
+2	O
+with	O
+PERM	O
+)	O
+,	O
+15	O
+%	O
+(	O
+3	O
+of	O
+20	O
+)	O
+had	O
+at	O
+least	O
+1	O
+coexisting	O
+autoimmune	O
+disease	O
+,	O
+and	O
+25	O
+%	O
+(	O
+5	O
+of	O
+20	O
+)	O
+had	O
+cancer	O
+(	O
+3	O
+with	O
+amphiphysin	O
+autoimmunity	O
+and	O
+breast	O
+carcinoma	O
+and	O
+2	O
+with	O
+Hodgkin	O
+lymphoma	O
+)	O
+.	O
+
+Excluding	O
+patients	O
+with	O
+PERM	O
+,	O
+all	O
+patients	O
+but	O
+1	O
+had	O
+sustained	O
+improvements	O
+with	O
+at	O
+least	O
+1	O
+γ	O
+-	O
+aminobutyric	O
+acid	O
+agent	O
+,	O
+usually	O
+diazepam	O
+;	O
+the	O
+median	O
+dosage	O
+for	O
+patients	O
+with	O
+classic	O
+SMS	O
+was	O
+40.0	O
+mg	O
+/	O
+d.	O
+
+Additional	O
+improvements	O
+occurred	O
+among	O
+14	O
+of	O
+34	O
+patients	O
+(	O
+41	O
+%	O
+)	O
+who	O
+received	O
+immunotherapy	O
+(	O
+intravenous	O
+immune	O
+globulin	O
+,	O
+azathioprine	O
+,	O
+prednisone	O
+,	O
+mycophenolate	O
+mofetil	O
+,	O
+or	O
+cyclophosphamide	O
+)	O
+.	O
+
+Sixteen	O
+of	O
+25	O
+patients	O
+(	O
+64	O
+%	O
+)	O
+with	O
+extended	O
+follow	O
+-	O
+up	O
+duration	O
+remained	O
+ambulatory	O
+.	O
+
+Conclusions	O
+Recognition	O
+of	O
+classic	O
+SMS	O
+vs	O
+variants	O
+is	O
+important	O
+because	O
+appropriate	O
+therapy	O
+improves	O
+symptoms	O
+in	O
+most	O
+patients	O
+.	O
+
+Classification	O
+by	O
+anatomical	O
+extent	O
+and	O
+by	O
+GAD65	O
+antibody	O
+serostatus	O
+gives	O
+important	O
+diagnostic	O
+and	O
+prognostic	O
+information	O
+.	O
+
+Cutaneous	O
+squamous	O
+cell	O
+carcinoma	O
+(	O
+cSCC	O
+)	O
+is	O
+the	O
+second	O
+most	O
+prevalent	B-EPI
+skin	O
+cancer	O
+globally	O
+.	O
+
+Because	O
+most	O
+cSCC	O
+cases	O
+are	O
+manageable	O
+by	O
+local	O
+excision	O
+/	O
+radiotherapy	O
+and	O
+hardly	O
+become	O
+life	O
+-	O
+threatening	O
+,	O
+they	O
+are	O
+often	O
+excluded	O
+from	O
+cancer	O
+registries	O
+in	O
+most	O
+countries	O
+.	O
+
+Compared	O
+with	O
+cutaneous	O
+melanoma	O
+that	O
+originates	O
+from	O
+the	O
+melanin	O
+-	O
+producing	O
+,	O
+neural	O
+crest	O
+-	O
+derived	O
+epidermal	O
+resident	O
+,	O
+keratinocyte	O
+(	O
+KC)-derived	O
+cancers	O
+are	O
+influenced	O
+by	O
+the	O
+immune	O
+system	O
+with	O
+regards	O
+to	O
+their	O
+pathogenetic	O
+behaviour	O
+.	O
+
+Congenital	O
+or	O
+acquired	O
+immunosurveillance	O
+impairments	O
+compromise	O
+tumoricidal	O
+activity	O
+and	O
+raises	O
+cSCC	O
+incidence	B-EPI
+rates	O
+.	O
+
+Intriguingly	O
+,	O
+expanded	O
+applications	O
+of	O
+programmed	O
+death-1	O
+(	O
+PD-1	O
+)	O
+blockade	O
+therapies	O
+have	O
+revealed	O
+cSCC	O
+to	O
+be	O
+one	O
+of	O
+the	O
+most	O
+amenable	O
+targets	O
+,	O
+particularly	O
+when	O
+compared	O
+with	O
+the	O
+mucosal	O
+counterparts	O
+arisen	O
+in	O
+the	O
+esophagus	O
+or	O
+the	O
+cervix	O
+.	O
+
+The	O
+clinical	O
+observation	O
+reminds	O
+us	O
+that	O
+cutaneous	O
+tissue	O
+has	O
+a	O
+peculiarly	O
+high	O
+immunogenicity	O
+that	O
+can	O
+evoke	O
+tumoricidal	O
+recall	O
+responses	O
+topically	O
+.	O
+
+Here	O
+we	O
+attempt	O
+to	O
+redefine	O
+cSCC	O
+biology	O
+and	O
+review	O
+current	O
+knowledge	O
+about	O
+cSCC	O
+from	O
+multiple	O
+viewpoints	O
+that	O
+involve	O
+epidemiology	O
+,	O
+clinicopathology	O
+,	O
+molecular	O
+genetics	O
+,	O
+molecular	O
+immunology	O
+,	O
+and	O
+developmental	O
+biology	O
+.	O
+
+This	O
+synthesis	O
+not	O
+only	O
+underscores	O
+the	O
+primal	O
+importance	O
+of	O
+the	O
+immune	O
+system	O
+,	O
+rather	O
+than	O
+just	O
+a	O
+mere	O
+accumulation	O
+of	O
+ultraviolet	O
+-	O
+induced	O
+mutations	O
+but	O
+also	O
+reinforces	O
+the	O
+following	O
+hypothesis	O
+:	O
+PD-1	O
+blockade	O
+effectively	O
+restores	O
+the	O
+immunity	O
+specially	O
+allowed	O
+to	O
+exist	O
+within	O
+the	O
+fully	O
+cornified	O
+squamous	O
+epithelium	O
+,	O
+that	O
+is	O
+,	O
+the	O
+epidermis	O
+.	O
+
+Aim	O
+To	O
+investigate	O
+the	O
+point	O
+prevalence	B-EPI
+of	O
+hereditary	O
+neuromuscular	O
+disorders	O
+on	O
+January	O
+1	O
+,	O
+2020	O
+in	O
+Northern	B-LOC
+Norway	I-LOC
+.	O
+
+Methods	O
+From	O
+January	O
+1	O
+,	O
+1999	O
+,	O
+until	O
+January	O
+1	O
+,	O
+2020	O
+,	O
+we	O
+screened	O
+medical	O
+and	O
+genetic	O
+hospital	O
+records	O
+in	O
+Northern	B-LOC
+Norway	I-LOC
+for	O
+hereditary	O
+neuromuscular	O
+disorders	O
+.	O
+
+Results	O
+We	O
+identified	O
+542	O
+patients	O
+with	O
+a	O
+hereditary	O
+neuromuscular	O
+disorder	O
+living	O
+in	O
+Northern	B-LOC
+Norway	I-LOC
+,	O
+giving	O
+a	O
+point	O
+prevalence	B-EPI
+of	O
+111.9/100,000	B-STAT
+on	O
+January	O
+1	O
+,	O
+2020	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+children	O
+(	O
+<	O
+18	O
+years	O
+old	O
+)	O
+and	O
+adults	O
+(	O
+≥18	O
+years	O
+old	O
+)	O
+were	O
+57.8/100,000	B-STAT
+and	O
+125.1/100,000	B-STAT
+,	O
+respectively	O
+.	O
+
+Inherited	O
+neuropathies	O
+had	O
+a	O
+prevalence	B-EPI
+of	O
+38.8/100,000	B-STAT
+.	O
+
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+and	O
+hereditary	O
+neuropathy	O
+with	O
+liability	O
+to	O
+pressure	O
+palsies	O
+had	O
+a	O
+prevalence	B-EPI
+of	O
+29.9/100,000	B-STAT
+and	O
+8.3/100,000	B-STAT
+,	O
+respectively	O
+.	O
+
+We	O
+calculated	O
+a	O
+prevalence	B-EPI
+of	O
+3.7/100,000	B-STAT
+for	O
+spinal	O
+muscular	O
+atrophies	O
+and	O
+2.4/100,000	B-STAT
+for	O
+Kennedy	O
+disease	O
+.	O
+
+Inherited	O
+myopathies	O
+were	O
+found	O
+in	O
+67.7/100,000	B-STAT
+.	O
+
+Among	O
+these	O
+,	O
+we	O
+registered	O
+13.4/100,000	B-STAT
+myotonic	O
+dystrophy	O
+type	O
+1	B-STAT
+,	I-STAT
+6.8/100,000	I-STAT
+myotonic	O
+dystrophy	O
+type	O
+2	B-STAT
+,	I-STAT
+7.3/100,000	I-STAT
+Duchenne	O
+muscular	O
+dystrophy	O
+,	O
+1.6/100,000	B-STAT
+Becker	O
+muscular	O
+dystrophy	O
+,	O
+3.7/100,000	B-STAT
+facioscapulohumeral	O
+muscular	O
+dystrophy	O
+,	O
+12.8/100,000	B-STAT
+limb	O
+-	O
+girdle	O
+muscular	O
+dystrophy	O
+,	O
+2.5/100,000	B-STAT
+hypokalemic	O
+periodic	O
+paralysis	O
+and	O
+11.4/100,000	B-STAT
+myotonia	O
+congenita	O
+.	O
+
+Conclusion	O
+Our	O
+total	O
+prevalence	B-EPI
+was	O
+higher	O
+than	O
+previously	O
+hypothesized	O
+in	O
+European	O
+population	O
+-	O
+based	O
+studies	O
+.	O
+
+The	O
+prevalence	B-EPI
+was	O
+especially	O
+high	O
+for	O
+myotonia	O
+congenita	O
+and	O
+limb	O
+-	O
+girdle	O
+muscular	O
+dystrophy	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+polyneuropathy	O
+was	O
+higher	O
+than	O
+in	O
+most	O
+European	O
+studies	O
+,	O
+but	O
+lower	O
+than	O
+previously	O
+reported	O
+in	O
+epidemiological	O
+studies	O
+in	O
+other	O
+regions	O
+of	O
+Norway	B-LOC
+.	O
+
+About	O
+30	O
+%	O
+of	O
+patients	O
+with	O
+MEN1	O
+develop	O
+a	O
+Zollinger	O
+-	O
+Ellison	O
+syndrome	O
+.	O
+
+Meanwhile	O
+it	O
+is	O
+well	O
+established	O
+that	O
+the	O
+causative	O
+gastrinomas	O
+are	O
+almost	O
+exclusively	O
+localized	O
+in	O
+the	O
+duodenum	O
+and	O
+not	O
+in	O
+the	O
+pancreas	O
+,	O
+MEN1	O
+gastrinomas	O
+occur	O
+multicentric	O
+and	O
+are	O
+associated	O
+with	O
+hyperplastic	O
+gastrin	O
+cell	O
+lesions	O
+and	O
+tiny	O
+gastrin	O
+-	O
+producing	O
+micro	O
+tumors	O
+in	O
+contrast	O
+to	O
+sporadic	O
+duodenal	O
+gastrinomas	O
+.	O
+
+Regardless	O
+of	O
+the	O
+high	O
+prevalence	B-EPI
+of	O
+early	O
+lymphatic	O
+metastases	O
+,	O
+the	O
+survival	O
+is	O
+generally	O
+good	O
+with	O
+an	O
+aggressive	O
+course	O
+of	O
+disease	O
+in	O
+only	O
+about	O
+20	B-STAT
+%	O
+of	O
+patients	O
+.	O
+
+Symptoms	O
+can	O
+be	O
+controlled	O
+medically	O
+.	O
+
+The	O
+indication	O
+,	O
+timing	O
+,	O
+type	O
+,	O
+and	O
+extent	O
+of	O
+surgery	O
+are	O
+highly	O
+controversial	O
+and	O
+are	O
+discussed	O
+in	O
+detail	O
+in	O
+this	O
+article	O
+by	O
+a	O
+thorough	O
+and	O
+critical	O
+review	O
+of	O
+literature	O
+.	O
+
+More	O
+radical	O
+procedures	O
+,	O
+like	O
+partial	O
+pancreaticoduodenectomy	O
+,	O
+are	O
+weighed	O
+against	O
+less	O
+aggressive	O
+local	O
+excision	O
+of	O
+gastrinomas	O
+and	O
+the	O
+pros	O
+and	O
+cons	O
+of	O
+both	O
+approaches	O
+are	O
+discussed	O
+in	O
+terms	O
+of	O
+long	O
+-	O
+term	O
+morbidity	O
+,	O
+biochemical	O
+cure	O
+,	O
+and	O
+survival	O
+.	O
+
+The	O
+review	O
+lists	O
+the	O
+genetic	O
+diseases	O
+reported	O
+in	O
+Lebanese	O
+individuals	O
+,	O
+surveys	O
+genetic	O
+programs	O
+and	O
+services	O
+,	O
+and	O
+highlights	O
+the	O
+absence	O
+of	O
+basic	O
+genetic	O
+health	O
+services	O
+at	O
+the	O
+individual	O
+and	O
+community	O
+level	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+individual	O
+diseases	O
+is	O
+not	O
+determined	O
+,	O
+yet	O
+the	O
+variety	O
+of	O
+genetic	O
+diseases	O
+reported	O
+is	O
+tremendous	O
+,	O
+most	O
+of	O
+which	O
+follow	O
+autosomal	O
+recessive	O
+inheritance	O
+reflecting	O
+the	O
+social	O
+norms	O
+in	O
+the	O
+population	O
+,	O
+including	O
+high	O
+rates	O
+of	O
+consanguinity	O
+,	O
+which	O
+favor	O
+the	O
+increase	O
+in	O
+incidence	B-EPI
+of	O
+these	O
+diseases	O
+.	O
+
+Genetic	O
+services	O
+including	O
+all	O
+activities	O
+for	O
+the	O
+diagnosis	O
+,	O
+care	O
+,	O
+and	O
+prevention	O
+of	O
+genetic	O
+diseases	O
+at	O
+community	O
+level	O
+are	O
+extremely	O
+inadequate	O
+.	O
+
+Services	O
+are	O
+limited	O
+to	O
+some	O
+clinical	O
+and	O
+laboratory	O
+diagnostic	O
+services	O
+with	O
+no	O
+genetic	O
+counseling	O
+.	O
+
+These	O
+services	O
+are	O
+localized	O
+within	O
+the	O
+capital	O
+thus	O
+preventing	O
+their	O
+accessibility	O
+to	O
+high	O
+-	O
+risk	O
+communities	O
+.	O
+
+Screening	O
+programs	O
+,	O
+which	O
+are	O
+at	O
+the	O
+core	O
+of	O
+public	O
+health	O
+prevention	O
+services	O
+,	O
+are	O
+minimal	O
+and	O
+not	O
+nationally	O
+mandated	O
+.	O
+
+The	O
+absence	O
+of	O
+adequate	O
+genetic	O
+services	O
+is	O
+attributed	O
+to	O
+many	O
+factors	O
+undermining	O
+the	O
+importance	O
+of	O
+genetic	O
+diseases	O
+and	O
+their	O
+burden	O
+on	O
+society	O
+,	O
+the	O
+most	O
+important	O
+of	O
+which	O
+is	O
+genetic	O
+illiteracy	O
+at	O
+all	O
+levels	O
+of	O
+the	O
+population	O
+,	O
+including	O
+high	O
+-	O
+risk	O
+families	O
+,	O
+the	O
+general	O
+public	O
+,	O
+and	O
+most	O
+importantly	O
+health	O
+care	O
+providers	O
+and	O
+public	O
+health	O
+officials	O
+.	O
+
+Thus	O
+,	O
+a	O
+country	O
+like	O
+Lebanon	B-LOC
+,	O
+where	O
+genetic	O
+diseases	O
+are	O
+expected	O
+to	O
+be	O
+highly	O
+prevalent	B-EPI
+,	O
+is	O
+in	O
+utmost	O
+need	O
+for	O
+community	O
+genetics	O
+services	O
+.	O
+
+Strategies	O
+need	O
+to	O
+be	O
+developed	O
+to	O
+familiarize	O
+public	O
+health	O
+officials	O
+and	O
+medical	O
+professionals	O
+with	O
+medical	O
+genetics	O
+leading	O
+to	O
+a	O
+public	O
+health	O
+infrastructure	O
+that	O
+delivers	O
+community	O
+genetics	O
+services	O
+for	O
+the	O
+prevention	O
+and	O
+care	O
+of	O
+genetic	O
+disorders	O
+at	O
+community	O
+level	O
+.	O
+
+Background	O
+Congenital	O
+malformations	O
+involving	O
+the	O
+Müllerian	O
+ducts	O
+are	O
+observed	O
+in	O
+around	O
+5	O
+%	O
+of	O
+infertile	O
+women	O
+.	O
+
+Complete	O
+aplasia	O
+of	O
+the	O
+uterus	O
+,	O
+cervix	O
+,	O
+and	O
+upper	O
+vagina	O
+,	O
+also	O
+termed	O
+Müllerian	O
+aplasia	O
+or	O
+Mayer	O
+-	O
+Rokitansky	O
+-	O
+Kuster	O
+-	O
+Hauser	O
+(	O
+MRKH	O
+)	O
+syndrome	O
+,	O
+occurs	B-EPI
+with	O
+an	O
+incidence	B-EPI
+of	O
+around	O
+1	B-STAT
+in	I-STAT
+4500	I-STAT
+female	I-STAT
+births	I-STAT
+,	O
+and	O
+occurs	B-EPI
+in	O
+both	O
+isolated	O
+and	O
+syndromic	O
+forms	O
+.	O
+
+Previous	O
+reports	O
+have	O
+suggested	O
+that	O
+a	O
+proportion	O
+of	O
+cases	O
+,	O
+especially	O
+syndromic	O
+cases	O
+,	O
+are	O
+caused	O
+by	O
+variation	O
+in	O
+copy	O
+number	O
+at	O
+different	O
+genomic	O
+loci	O
+.	O
+
+Methods	O
+In	O
+order	O
+to	O
+obtain	O
+an	O
+overview	O
+of	O
+the	O
+contribution	O
+of	O
+copy	O
+number	O
+variation	O
+to	O
+both	O
+isolated	O
+and	O
+syndromic	O
+forms	O
+of	O
+Müllerian	O
+aplasia	O
+,	O
+copy	O
+number	O
+assays	O
+were	O
+performed	O
+in	O
+a	O
+series	O
+of	O
+63	O
+cases	O
+,	O
+of	O
+which	O
+25	O
+were	O
+syndromic	O
+and	O
+38	O
+isolated	O
+.	O
+
+Results	O
+A	O
+high	O
+incidence	B-EPI
+(	O
+9/63	B-STAT
+,	O
+14	O
+%	O
+)	O
+of	O
+recurrent	O
+copy	O
+number	O
+variants	O
+in	O
+this	O
+cohort	O
+is	O
+reported	O
+here	O
+.	O
+
+These	O
+comprised	O
+four	O
+cases	O
+of	O
+microdeletion	O
+at	O
+16p11.2	O
+,	O
+an	O
+autism	O
+susceptibility	O
+locus	O
+not	O
+previously	O
+associated	O
+with	O
+Müllerian	O
+aplasia	O
+,	O
+four	O
+cases	O
+of	O
+microdeletion	O
+at	O
+17q12	O
+,	O
+and	O
+one	O
+case	O
+of	O
+a	O
+distal	O
+22q11.2	O
+microdeletion	O
+.	O
+
+Microdeletions	O
+at	O
+16p11.2	O
+and	O
+17q12	O
+were	O
+found	O
+in	O
+4/38	B-STAT
+(	O
+10.5	O
+%	O
+)	O
+cases	O
+with	O
+isolated	O
+Müllerian	O
+aplasia	O
+,	O
+and	O
+at	O
+16p11.2	O
+,	O
+17q12	O
+and	O
+22q11.2	O
+(	O
+distal	O
+)	O
+in	O
+5/25	B-STAT
+cases	O
+(	O
+20	O
+%	O
+)	O
+with	O
+syndromic	O
+Müllerian	O
+aplasia	O
+.	O
+
+Conclusion	O
+The	O
+finding	O
+of	O
+microdeletion	O
+at	O
+16p11.2	O
+in	O
+2/38	B-STAT
+(	O
+5	O
+%	O
+)	O
+of	O
+isolated	O
+and	O
+2/25	B-STAT
+(	O
+8	O
+%	O
+)	O
+of	O
+syndromic	O
+cases	O
+suggests	O
+a	O
+significant	O
+contribution	O
+of	O
+this	O
+copy	O
+number	O
+variant	O
+alone	O
+to	O
+the	O
+pathogenesis	O
+of	O
+Müllerian	O
+aplasia	O
+.	O
+
+Overall	O
+,	O
+the	O
+high	O
+incidence	B-EPI
+of	O
+recurrent	O
+copy	O
+number	O
+variants	O
+in	O
+all	O
+forms	O
+of	O
+Müllerian	O
+aplasia	O
+has	O
+implications	O
+for	O
+the	O
+understanding	O
+of	O
+the	O
+aetiopathogenesis	O
+of	O
+the	O
+condition	O
+,	O
+and	O
+for	O
+genetic	O
+counselling	O
+in	O
+families	O
+affected	O
+by	O
+it	O
+.	O
+
+The	O
+parkinsonian	O
+syndromes	O
+comprise	O
+a	O
+highly	O
+heterogeneous	O
+group	O
+of	O
+disorders	O
+.	O
+
+Although	O
+15	O
+loci	O
+are	O
+linked	O
+to	O
+predominantly	O
+familial	O
+Parkinson	O
+'s	O
+disease	O
+(	O
+PD	O
+)	O
+,	O
+additional	O
+PD	O
+loci	O
+are	O
+likely	O
+to	O
+exist	O
+.	O
+
+We	O
+recently	O
+identified	O
+a	O
+multigenerational	O
+family	O
+of	O
+Danish	O
+and	O
+German	O
+descent	O
+in	O
+which	O
+five	O
+males	O
+in	O
+three	O
+generations	O
+presented	O
+with	O
+a	O
+unique	O
+syndrome	O
+characterized	O
+by	O
+parkinsonian	O
+features	O
+and	O
+variably	O
+penetrant	O
+spasticity	O
+for	O
+which	O
+X	O
+-	O
+linked	O
+disease	O
+transmission	O
+was	O
+strongly	O
+suggested	O
+(	O
+XPDS	O
+)	O
+.	O
+
+Autopsy	O
+in	O
+one	O
+individual	O
+failed	O
+to	O
+reveal	O
+synucleinopathy	O
+;	O
+however	O
+,	O
+there	O
+was	O
+a	O
+significant	O
+four	O
+-	O
+repeat	O
+tauopathy	O
+in	O
+the	O
+striatum	O
+.	O
+
+Our	O
+objective	O
+was	O
+to	O
+identify	O
+the	O
+locus	O
+responsible	O
+for	O
+this	O
+unique	O
+parkinsonian	O
+disorder	O
+.	O
+
+Members	O
+of	O
+the	O
+XPDS	O
+family	O
+were	O
+genotyped	O
+for	O
+markers	O
+spanning	O
+the	O
+X	O
+chromosome	O
+.	O
+
+Two	O
+-	O
+point	O
+and	O
+multipoint	O
+linkage	O
+analyses	O
+were	O
+performed	O
+and	O
+the	O
+candidate	O
+region	O
+refined	O
+by	O
+analyzing	O
+additional	O
+markers	O
+.	O
+
+A	O
+multipoint	O
+LOD(max	O
+)	O
+score	O
+of	O
+2.068	O
+was	O
+obtained	O
+between	O
+markers	O
+DXS991	O
+and	O
+DXS993	O
+.	O
+
+Haplotype	O
+examination	O
+revealed	O
+an	O
+approximately	O
+20	O
+cM	O
+region	O
+bounded	O
+by	O
+markers	O
+DXS8042	O
+and	O
+DXS1216	O
+that	O
+segregated	O
+with	O
+disease	O
+in	O
+all	O
+affected	O
+males	O
+and	O
+obligate	O
+carrier	O
+females	O
+and	O
+was	O
+not	O
+carried	O
+by	O
+unaffected	O
+at	O
+-	O
+risk	O
+males	O
+.	O
+
+To	O
+reduce	O
+the	O
+possibility	O
+of	O
+a	O
+false	O
+-	O
+positive	O
+linkage	O
+result	O
+,	O
+multiple	O
+loci	O
+and	O
+genes	O
+associated	O
+with	O
+other	O
+parkinsonian	O
+or	O
+spasticity	O
+syndromes	O
+were	O
+excluded	O
+.	O
+
+In	O
+conclusion	O
+,	O
+we	O
+have	O
+identified	O
+a	O
+unique	O
+X	O
+-	O
+linked	O
+parkinsonian	O
+syndrome	O
+with	O
+variable	O
+spasticity	O
+and	O
+four	O
+-	O
+repeat	O
+tau	O
+pathology	O
+,	O
+and	O
+defined	O
+a	O
+novel	O
+candidate	O
+gene	O
+locus	O
+spanning	O
+approximately	O
+28	O
+Mb	O
+from	O
+Xp11.2	O
+-	O
+Xq13.3	O
+.	O
+
+Background	O
+Most	O
+epidemiological	O
+data	O
+on	O
+vitiligo	O
+refer	O
+to	O
+selected	O
+environments	O
+or	O
+focus	O
+on	O
+the	O
+prevalence	B-EPI
+of	O
+comorbidity	O
+unrelated	O
+to	O
+the	O
+population	O
+.	O
+
+Objective	O
+Aim	O
+of	O
+the	O
+study	O
+was	O
+to	O
+gain	O
+robust	O
+representative	O
+prevalence	B-EPI
+data	O
+on	O
+vitiligo	O
+and	O
+on	O
+associated	O
+dermatologic	O
+comorbidity	O
+in	O
+the	O
+German	O
+adult	O
+population	O
+.	O
+
+Methods	O
+A	O
+dual	O
+population	O
+-	O
+based	O
+approach	O
+was	O
+applied	O
+with	O
+1	O
+)	O
+primary	O
+data	O
+obtained	O
+between	O
+2004	O
+and	O
+2014	O
+from	O
+dermatological	O
+exams	O
+in	O
+the	O
+general	O
+working	O
+population	O
+;	O
+2	O
+)	O
+claims	O
+data	O
+from	O
+a	O
+large	O
+German	O
+statutory	O
+health	O
+insurance	O
+,	O
+reference	O
+year	O
+2010	O
+.	O
+
+Results	O
+In	O
+the	O
+working	O
+cohort	O
+(	O
+N	O
+=	O
+121,783	O
+;	O
+57	O
+%	O
+male	O
+;	O
+mean	O
+age	O
+43	O
+years	O
+)	O
+,	O
+the	O
+prevalence	B-EPI
+of	O
+vitiligo	O
+was	O
+0.77	B-STAT
+%	I-STAT
+(	O
+0.84	B-STAT
+%	I-STAT
+in	O
+men	O
+;	O
+0.67	B-STAT
+%	I-STAT
+in	O
+women	O
+)	O
+.	O
+
+In	O
+the	O
+claims	O
+data	O
+(	O
+N	O
+=	O
+1,619,678	O
+;	O
+38	O
+%	O
+male	O
+;	O
+mean	O
+age	O
+46	O
+years	O
+)	O
+,	O
+prevalence	B-EPI
+was	O
+0.17	B-STAT
+%	I-STAT
+(	O
+0.14	B-STAT
+%	I-STAT
+in	O
+men	O
+;	O
+0.18	B-STAT
+%	I-STAT
+in	O
+women	O
+)	O
+.	O
+
+In	O
+the	O
+working	O
+cohort	O
+,	O
+vitiligo	O
+was	O
+significantly	O
+more	O
+common	O
+in	O
+people	O
+with	O
+fair	O
+skin	O
+type	O
+,	O
+ephelides	O
+and	O
+port	O
+-	O
+wine	O
+stains	O
+and	O
+less	O
+common	O
+in	O
+people	O
+with	O
+acne	O
+and	O
+solar	O
+lentigines	O
+.	O
+
+In	O
+the	O
+claims	O
+data	O
+,	O
+vitiligo	O
+was	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+skin	O
+conditions	O
+,	O
+eg	O
+,	O
+atopic	O
+dermatitis	O
+,	O
+psoriasis	O
+and	O
+alopecia	O
+areata	O
+.	O
+
+Conclusion	O
+The	O
+resulting	O
+discrepancy	O
+of	O
+claims	O
+vs	O
+primary	O
+data	O
+between	O
+0.17	B-STAT
+%	I-STAT
+and	O
+0.77	B-STAT
+%	I-STAT
+indicates	O
+the	O
+most	O
+probable	O
+spectrum	O
+of	O
+vitiligo	O
+prevalence	B-EPI
+in	O
+Germany	B-LOC
+.	O
+
+It	O
+is	O
+more	O
+frequently	O
+observed	O
+in	O
+clinical	O
+exams	O
+than	O
+recorded	O
+in	O
+claims	O
+data	O
+,	O
+indicating	O
+a	O
+marked	O
+proportion	O
+of	O
+people	O
+seeking	O
+no	O
+medical	O
+help	O
+.	O
+
+Such	O
+nonattendance	O
+may	O
+result	O
+from	O
+the	O
+fact	O
+that	O
+many	O
+treatment	O
+options	O
+do	O
+not	O
+provide	O
+satisfying	O
+benefits	O
+to	O
+the	O
+patients	O
+.	O
+
+Background	O
+Unilateral	O
+lung	O
+agenesis	O
+is	O
+an	O
+uncommon	O
+congenital	O
+abnormality	O
+,	O
+with	O
+a	O
+lack	O
+of	O
+reported	O
+accurate	O
+incidence	B-EPI
+estimates	O
+.	O
+
+Prognosis	O
+is	O
+also	O
+uncertain	O
+,	O
+with	O
+older	O
+literature	O
+reporting	O
+poor	O
+outcomes	O
+.	O
+
+Methods	O
+The	O
+North	O
+of	O
+England	O
+register	O
+of	O
+congenital	O
+anomalies	O
+(	O
+Northern	O
+Congenital	O
+Abnormality	O
+Survey	O
+)	O
+records	O
+cases	O
+of	O
+congenital	O
+anomalies	O
+to	O
+mothers	O
+'	O
+resident	O
+in	O
+the	O
+region	O
+.	O
+
+We	O
+used	O
+the	O
+register	O
+to	O
+identify	O
+all	O
+patients	O
+with	O
+congenital	O
+lung	O
+agenesis	O
+born	O
+between	O
+2004	O
+and	O
+2013	O
+to	O
+calculate	O
+an	O
+accurate	O
+incidence	B-EPI
+estimate	O
+and	O
+report	O
+clinical	O
+outcomes	O
+with	O
+contemporary	O
+management	O
+.	O
+
+Results	O
+Four	O
+patients	O
+with	O
+congenital	O
+lung	O
+agenesis	O
+were	O
+born	O
+during	O
+the	O
+study	O
+period	O
+,	O
+giving	O
+an	O
+estimated	B-EPI
+incidence	I-EPI
+in	O
+the	B-LOC
+North	I-LOC
+of	I-LOC
+England	I-LOC
+of	O
+1.22	B-STAT
+per	I-STAT
+100,000	I-STAT
+live	I-STAT
+births	I-STAT
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+0.33	O
+-	O
+3.11	O
+)	O
+.	O
+
+Two	O
+patients	O
+had	O
+associated	O
+congenital	O
+heart	O
+disease	O
+requiring	O
+corrective	O
+surgery	O
+,	O
+and	O
+one	O
+had	O
+musculoskeletal	O
+anomalies	O
+.	O
+
+All	O
+four	O
+patients	O
+are	O
+alive	O
+and	O
+well	O
+without	O
+a	O
+regular	O
+oxygen	O
+requirement	O
+.	O
+
+Conclusion	O
+Contrary	O
+to	O
+previous	O
+reports	O
+,	O
+the	O
+medium	O
+term	O
+outcomes	O
+in	O
+our	O
+patients	O
+have	O
+been	O
+good	O
+,	O
+even	O
+when	O
+lung	O
+agenesis	O
+is	O
+associated	O
+with	O
+other	O
+congenital	O
+anomalies	O
+.	O
+
+Long	O
+-	O
+term	O
+prognosis	O
+with	O
+modern	O
+management	O
+remains	O
+unknown	O
+,	O
+and	O
+the	O
+potential	O
+for	O
+the	O
+development	O
+of	O
+pulmonary	O
+hypertension	O
+remains	O
+a	O
+concern	O
+.	O
+
+Birth	O
+Defects	O
+Research	O
+109:857	B-STAT
+-	O
+859	O
+,	O
+2017	O
+.	O
+
+©	O
+2017	O
+Wiley	O
+Periodicals	O
+,	O
+Inc.	O
+
+The	O
+disease	O
+and	O
+the	O
+case	O
+reported	O
+here	O
+are	O
+relevant	O
+especially	O
+because	O
+of	O
+their	O
+varied	O
+clinical	O
+presentation	O
+,	O
+possibility	O
+of	O
+being	O
+associated	O
+with	O
+other	O
+disorders	O
+affecting	O
+several	O
+organs	O
+and	O
+possible	O
+differential	O
+diagnoses	O
+.	O
+
+Congenital	O
+Hepatic	O
+Fibrosis	O
+is	O
+an	O
+autosomal	O
+recessive	O
+disease	O
+due	O
+to	O
+mutation	O
+in	O
+the	O
+PKHD1	O
+gene	O
+,	O
+which	O
+encodes	O
+the	O
+fibrocystin	O
+/	O
+polyductine	O
+protein	O
+.	O
+
+It	O
+is	O
+a	O
+cholangiopathy	O
+,	O
+characterized	O
+by	O
+varying	O
+degrees	O
+of	O
+periportal	O
+fibrosis	O
+and	O
+irregular	O
+proliferation	O
+of	O
+bile	O
+ducts	O
+.	O
+
+Affected	O
+patients	O
+are	O
+typically	O
+diagnosed	O
+in	O
+childhood	O
+,	O
+but	O
+in	O
+some	O
+cases	O
+the	O
+disease	O
+may	O
+remain	O
+asymptomatic	O
+for	O
+many	O
+years	O
+.	O
+
+The	O
+exact	O
+prevalence	B-EPI
+and	O
+incidence	B-EPI
+of	O
+the	O
+disease	O
+are	O
+not	O
+known	O
+,	O
+but	O
+it	O
+is	O
+consider	O
+a	O
+rare	O
+disease	O
+,	O
+with	O
+a	O
+few	O
+hundred	O
+cases	O
+described	O
+worldwide	B-LOC
+.	O
+
+It	O
+can	O
+affect	O
+all	O
+ethnic	O
+groups	O
+and	O
+occur	O
+associated	O
+with	O
+various	O
+hereditary	O
+and	O
+non	O
+-	O
+hereditary	O
+disorders	O
+.	O
+
+The	O
+clinical	O
+presentation	O
+is	O
+quite	O
+variable	O
+,	O
+with	O
+melena	O
+and	O
+hematemesis	O
+being	O
+initial	O
+symptoms	O
+in	O
+30%-70	O
+%	O
+of	O
+the	O
+cases	O
+.	O
+
+More	O
+rarely	O
+,	O
+they	O
+may	O
+present	O
+episodes	O
+of	O
+cholangitis	O
+.	O
+
+The	O
+disease	O
+has	O
+been	O
+classified	O
+into	O
+four	O
+types	O
+:	O
+portal	O
+hypertension	O
+,	O
+cholestasis	O
+/	O
+cholangitis	O
+,	O
+mixed	O
+and	O
+latent	O
+.	O
+
+Diagnosis	O
+begins	O
+with	O
+imaging	O
+tests	O
+,	O
+but	O
+the	O
+definition	O
+is	O
+made	O
+by	O
+the	O
+histopathological	O
+sample	O
+.	O
+
+So	O
+far	O
+,	O
+there	O
+is	O
+no	O
+specific	O
+therapy	O
+that	O
+can	O
+stop	O
+or	O
+reverse	O
+the	O
+pathological	O
+process	O
+.	O
+
+Currently	O
+,	O
+the	O
+therapeutic	O
+strategy	O
+is	O
+to	O
+treat	O
+the	O
+complications	O
+of	O
+the	O
+disease	O
+.	O
+
+Impetigo	O
+is	O
+a	O
+common	O
+superficial	O
+bacterial	O
+infection	O
+of	O
+the	O
+skin	O
+,	O
+with	O
+a	O
+global	O
+disease	O
+burden	O
+of	O
+greater	O
+than	O
+140	O
+million	O
+.	O
+
+Children	O
+are	O
+more	O
+affected	O
+than	O
+adults	O
+and	O
+incidence	B-EPI
+decreases	O
+with	O
+age	O
+.	O
+
+Principal	O
+pathogens	O
+implicated	O
+include	O
+Staphylococcus	O
+aureus	O
+and	O
+Streptococcus	O
+pyogenes	O
+.	O
+
+There	O
+are	O
+two	O
+common	O
+variants	O
+of	O
+impetigo	O
+:	O
+nonbullous	O
+(	O
+70	O
+%	O
+)	O
+and	O
+bullous	O
+(	O
+30	O
+%	O
+)	O
+.	O
+
+Nonbullous	O
+impetigo	O
+is	O
+caused	O
+by	O
+S.	O
+aureus	O
+and	O
+S.	O
+pyogenes	O
+whereas	O
+bullous	O
+impetigo	O
+is	O
+caused	O
+by	O
+S.	O
+aureus	O
+.	O
+
+The	O
+classic	O
+appearance	O
+of	O
+distinctive	O
+honey	O
+-	O
+colored	O
+,	O
+crusted	O
+legions	O
+aids	O
+in	O
+diagnosis	O
+,	O
+which	O
+is	O
+most	O
+often	O
+based	O
+on	O
+clinical	O
+presentation	O
+.	O
+
+The	O
+disease	O
+is	O
+generally	O
+mild	O
+and	O
+felt	O
+to	O
+be	O
+self	O
+-	O
+limited	O
+;	O
+however	O
+,	O
+antimicrobial	O
+treatment	O
+is	O
+often	O
+initiated	O
+to	O
+reduce	O
+spread	O
+and	O
+shorten	O
+clinical	O
+course	O
+.	O
+
+Treatment	O
+for	O
+limited	O
+impetigo	O
+is	O
+topical	O
+whereas	O
+oral	O
+therapy	O
+is	O
+recommended	O
+for	O
+extensive	O
+cases	O
+.	O
+
+Rising	O
+rates	O
+of	O
+bacterial	O
+resistance	O
+to	O
+standard	O
+treatment	O
+regimens	O
+should	O
+inform	O
+treatment	O
+decisions	O
+.	O
+
+Complications	O
+,	O
+while	O
+rare	O
+,	O
+can	O
+occur	O
+.	O
+
+Congenital	O
+hearing	O
+loss	O
+is	O
+the	O
+most	O
+common	O
+birth	O
+defect	O
+,	O
+estimated	O
+to	O
+affect	O
+2	O
+-	O
+3	O
+in	O
+every	O
+1000	O
+births	O
+.	O
+
+Currently	O
+there	O
+is	O
+no	O
+cure	O
+for	O
+hearing	O
+loss	O
+.	O
+
+Treatment	O
+options	O
+are	O
+limited	O
+to	O
+hearing	O
+aids	O
+for	O
+mild	O
+and	O
+moderate	O
+cases	O
+,	O
+and	O
+cochlear	O
+implants	O
+for	O
+severe	O
+and	O
+profound	O
+hearing	O
+loss	O
+.	O
+
+Here	O
+we	O
+provide	O
+a	O
+literature	O
+overview	O
+of	O
+the	O
+environmental	O
+and	O
+genetic	O
+causes	O
+of	O
+congenital	O
+hearing	O
+loss	O
+,	O
+common	O
+animal	O
+models	O
+and	O
+methods	O
+used	O
+for	O
+hearing	O
+research	O
+,	O
+as	O
+well	O
+as	O
+recent	O
+advances	O
+towards	O
+developing	O
+therapies	O
+to	O
+treat	O
+congenital	O
+deafness	O
+.	O
+
+©	O
+2021	O
+The	O
+Authors	O
+.	O
+
+Background	O
+Infection	O
+with	O
+Entamoeba	O
+histolytica	O
+and	O
+associated	O
+complications	O
+are	O
+relatively	O
+rare	O
+in	O
+developed	O
+countries	O
+.	O
+
+The	O
+overall	O
+low	O
+prevalence	B-EPI
+in	O
+the	O
+Western	O
+world	O
+as	O
+well	O
+as	O
+the	O
+possibly	O
+prolonged	O
+latency	O
+period	O
+between	O
+infection	O
+with	O
+the	O
+causing	O
+pathogen	O
+and	O
+onset	O
+of	O
+clinical	O
+symptoms	O
+may	O
+delay	O
+diagnosis	O
+of	O
+and	O
+adequate	O
+treatment	O
+for	O
+amoebiasis	O
+.	O
+
+Amoebic	O
+liver	O
+abscess	O
+(	O
+ALA	O
+)	O
+is	O
+the	O
+most	O
+common	O
+extraintestinal	O
+manifestation	O
+of	O
+invasive	O
+amoebiasis	O
+.	O
+
+Pregnancy	O
+has	O
+been	O
+described	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+development	O
+of	O
+invasive	O
+amoebiasis	O
+and	O
+management	O
+of	O
+these	O
+patients	O
+is	O
+especially	O
+complex	O
+.	O
+
+Case	O
+presentation	O
+A	O
+30	O
+-	O
+year	O
+-	O
+old	O
+Caucasian	O
+woman	O
+in	O
+early	O
+pregnancy	O
+presented	O
+to	O
+our	O
+emergency	O
+department	O
+with	O
+abdominal	O
+pain	O
+alongside	O
+elevated	O
+inflammatory	O
+markers	O
+and	O
+liver	O
+function	O
+tests	O
+.	O
+
+Travel	O
+history	O
+revealed	O
+multiple	O
+journeys	O
+to	O
+tropic	O
+and	O
+subtropic	O
+regions	O
+during	O
+the	O
+past	O
+decade	O
+and	O
+a	O
+prolonged	O
+episode	O
+of	O
+intermittently	O
+bloody	O
+diarrhea	O
+during	O
+a	O
+five	O
+month	O
+stay	O
+in	O
+Indonesia	B-LOC
+seven	O
+years	O
+prior	O
+to	O
+admission	O
+.	O
+
+Sonographic	O
+and	O
+magnetic	O
+resonance	O
+imaging	O
+revealed	O
+a	O
+5	O
+×	O
+4	O
+cm	O
+hepatic	O
+abscess	O
+.	O
+
+After	O
+ultrasound	O
+-	O
+guided	O
+transcutaneous	O
+liver	O
+drainage	O
+,	O
+both	O
+abscess	O
+fluids	O
+and	O
+blood	O
+cultures	O
+showed	O
+neither	O
+bacterial	O
+growth	O
+nor	O
+microscopic	O
+signs	O
+of	O
+parasitic	O
+disease	O
+.	O
+
+Serological	O
+testing	O
+confirmed	O
+an	O
+infection	O
+with	O
+Entamoeba	O
+histolytica	O
+,	O
+which	O
+was	O
+treated	O
+with	O
+metronidazole	O
+,	O
+followed	O
+by	O
+eradication	O
+therapy	O
+with	O
+paromomycin	O
+.	O
+
+Subsequent	O
+clinical	O
+,	O
+laboratory	O
+and	O
+imaging	O
+follow	O
+-	O
+up	O
+exams	O
+showed	O
+regression	O
+of	O
+the	O
+ALA	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+pregnancy	O
+completed	O
+without	O
+complications	O
+and	O
+a	O
+healthy	O
+baby	O
+boy	O
+was	O
+born	O
+7	O
+months	O
+after	O
+termination	O
+of	O
+treatment	O
+.	O
+
+Conclusions	O
+This	O
+case	O
+of	O
+invasive	O
+amoebiasis	O
+in	O
+early	O
+pregnancy	O
+outside	O
+of	O
+endemic	O
+regions	O
+and	O
+several	O
+years	O
+after	O
+exposure	O
+demonstrates	O
+the	O
+importance	O
+of	O
+broad	O
+differential	O
+diagnostics	O
+in	O
+the	O
+context	O
+of	O
+liver	O
+abscesses	O
+.	O
+
+The	O
+complex	O
+interdisciplinary	O
+decisions	O
+regarding	O
+the	O
+choice	O
+of	O
+imaging	O
+techniques	O
+as	O
+well	O
+as	O
+interventional	O
+and	O
+antibiotic	O
+therapy	O
+in	O
+the	O
+context	O
+of	O
+pregnancy	O
+are	O
+discussed	O
+.	O
+
+Furthermore	O
+,	O
+we	O
+present	O
+possible	O
+explanations	O
+for	O
+pregnancy	O
+as	O
+a	O
+risk	O
+factor	O
+for	O
+an	O
+invasive	O
+course	O
+of	O
+amoebiasis	O
+.	O
+
+Objective	O
+Myotonia	O
+Congenita	O
+(	O
+MC	O
+)	O
+is	O
+a	O
+hereditary	O
+neuromuscular	O
+disorder	O
+caused	O
+by	O
+a	O
+mutation	O
+in	O
+chloride	O
+voltage	O
+-	O
+gated	O
+channel	O
+1	O
+(	O
+CLCN1	O
+)	O
+gene	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+MC	O
+is	O
+estimated	O
+as	O
+1	O
+in	O
+100.000	O
+.	O
+
+The	O
+absence	O
+of	O
+left	O
+main	O
+coronary	O
+artery	O
+(	O
+LMCA	O
+)	O
+is	O
+a	O
+rare	O
+coronary	O
+anomaly	O
+.	O
+
+Here	O
+we	O
+present	O
+a	O
+family	O
+with	O
+four	O
+members	O
+who	O
+have	O
+MC	O
+variation	O
+carrier	O
+and	O
+cardiovascular	O
+risk	O
+.	O
+
+Method	O
+The	O
+demographic	O
+features	O
+,	O
+laboratory	O
+findings	O
+,	O
+anthropometric	O
+measurements	O
+and	O
+cardiological	O
+examination	O
+of	O
+the	O
+cases	O
+were	O
+recorded	O
+.	O
+
+In	O
+addition	O
+,	O
+CLCN1	O
+gene	O
+was	O
+sequenced	O
+by	O
+NGS	O
+(	O
+Next	O
+Generation	O
+Sequencing	O
+Method	O
+)	O
+and	O
+possible	O
+causes	O
+of	O
+inherited	O
+thrombophilia	O
+risk	O
+including	O
+MTHFR	O
+(	O
+A1298C	O
+)	O
+,	O
+Factor	O
+V	O
+Leiden	O
+(	O
+G1691A	O
+)	O
+,	O
+Factor	O
+II	O
+(	O
+G20210A	O
+)	O
+,	O
+MTHFR	O
+(	O
+C677	O
+T	O
+)	O
+,	O
+Factor	O
+V	O
+Cambridge	O
+(	O
+G1091C	O
+)	O
+,	O
+plasminogen	O
+activator	O
+inhibitor	O
+1	O
+(	O
+PAI-1	O
+)	O
+4G/5	B-STAT
+G	O
+,	O
+APOE	O
+,	O
+APOB	O
+,	O
+ITGB	O
+,	O
+ACE	O
+(	O
+ins	O
+/	O
+del	O
+)	O
+,	O
+FVHR2	O
+and	O
+FGB	O
+gene	O
+alterations	O
+were	O
+evaluated	O
+.	O
+
+Results	O
+Case	O
+1	O
+had	O
+homozygous	O
+c.1886T	O
+>	O
+C	O
+(	O
+p.	O
+Leu629Pro	O
+)	O
+alteration	O
+in	O
+CLCN1	O
+gene	O
+and	O
+also	O
+coronary	O
+artery	O
+disease	O
+,	O
+myocardial	O
+infarction	O
+(	O
+MI	O
+)	O
+history	O
+,	O
+hyperlipidemia	O
+,	O
+primary	O
+hypertension	O
+,	O
+vertigo	O
+,	O
+lomber	O
+disc	O
+herniation	O
+and	O
+hearing	O
+loss	O
+.	O
+
+LMCA	O
+was	O
+not	O
+detected	O
+in	O
+coronary	O
+angiography	O
+in	O
+Case	O
+1	O
+.	O
+
+Cases	O
+2	O
+,	O
+3	O
+and	O
+4	O
+had	O
+heterozygous	O
+c.1886T	O
+>	O
+C	O
+(	O
+p.	O
+Leu629Pro	O
+)	O
+alteration	O
+with	O
+normal	O
+electrocardiographic	O
+and	O
+echocardiographic	O
+findings	O
+.	O
+
+Additionally	O
+,	O
+all	O
+of	O
+family	O
+members	O
+had	O
+genetic	O
+risk	O
+factors	O
+for	O
+the	O
+related	O
+gene	O
+,	O
+which	O
+lead	O
+to	O
+an	O
+increased	O
+risk	O
+of	O
+cardiovascular	O
+disease	O
+.	O
+
+Conclusion	O
+Since	O
+alteration	O
+of	O
+chloride	O
+channels	O
+in	O
+cardiomyocytes	O
+leads	O
+to	O
+variable	O
+myocardial	O
+involvement	O
+,	O
+cases	O
+with	O
+MC	O
+should	O
+be	O
+regularly	O
+followed	O
+for	O
+cardiovascular	O
+risk	O
+.	O
+
+Moreover	O
+,	O
+the	O
+cases	O
+with	O
+MC	O
+and	O
+with	O
+genetic	O
+profile	O
+associated	O
+with	O
+high	O
+cardiovascular	O
+risk	O
+should	O
+also	O
+be	O
+regularly	O
+followed	O
+up	O
+by	O
+cardiologists	O
+.	O
+
+Bubonic	O
+plague	O
+has	O
+caused	O
+three	O
+deadly	O
+pandemics	O
+in	O
+human	O
+history	O
+:	O
+from	O
+the	O
+mid	O
+-	O
+sixth	O
+to	O
+mid	O
+-	O
+eighth	O
+century	O
+,	O
+from	O
+the	O
+mid	O
+-	O
+fourteenth	O
+to	O
+the	O
+mid	O
+-	O
+eighteenth	O
+century	O
+and	O
+from	O
+the	O
+end	O
+of	O
+the	O
+nineteenth	O
+until	O
+the	O
+mid	O
+-	O
+twentieth	O
+century	O
+.	O
+
+Between	O
+the	O
+second	O
+and	O
+the	O
+third	O
+pandemics	O
+,	O
+plague	O
+was	O
+causing	O
+sporadic	O
+outbreaks	O
+in	O
+only	O
+a	O
+few	O
+countries	O
+in	O
+the	B-LOC
+Middle	I-LOC
+East	I-LOC
+,	O
+including	O
+Egypt	B-LOC
+.	O
+
+Little	O
+is	O
+known	O
+about	O
+this	O
+historical	O
+phase	O
+of	O
+plague	O
+,	O
+even	O
+though	O
+it	O
+represents	O
+the	O
+temporal	O
+,	O
+geographical	O
+and	O
+phylogenetic	O
+transition	O
+between	O
+the	O
+second	O
+and	O
+third	O
+pandemics	O
+.	O
+
+Here	O
+we	O
+analysed	O
+in	O
+detail	O
+an	O
+outbreak	O
+of	O
+plague	O
+that	O
+took	O
+place	O
+in	O
+Cairo	B-LOC
+in	O
+1801	O
+,	O
+and	O
+for	O
+which	O
+epidemiological	O
+data	O
+are	O
+uniquely	O
+available	O
+thanks	O
+to	O
+the	O
+presence	O
+of	O
+medical	O
+officers	O
+accompanying	O
+the	O
+Napoleonic	O
+expedition	O
+into	O
+Egypt	B-LOC
+at	O
+that	O
+time	O
+.	O
+
+We	O
+propose	O
+a	O
+new	O
+stochastic	O
+model	O
+describing	O
+how	O
+bubonic	O
+plague	O
+outbreaks	O
+unfold	O
+in	O
+both	O
+rat	O
+and	O
+human	O
+populations	O
+,	O
+and	O
+perform	O
+Bayesian	O
+inference	O
+under	O
+this	O
+model	O
+using	O
+a	O
+particle	O
+Markov	O
+chain	O
+Monte	O
+Carlo	O
+.	O
+
+Rat	O
+carcasses	O
+were	O
+estimated	O
+to	O
+be	O
+infectious	O
+for	O
+approximately	O
+4	O
+days	O
+after	O
+death	O
+,	O
+which	O
+is	O
+in	O
+good	O
+agreement	O
+with	O
+local	O
+observations	O
+on	O
+the	O
+survival	O
+of	O
+infectious	O
+rat	O
+fleas	O
+.	O
+
+The	O
+estimated	O
+transmission	O
+rate	O
+between	O
+rats	O
+implies	O
+a	O
+basic	O
+reproduction	O
+number	O
+R	O
+0	O
+of	O
+approximately	O
+3	O
+,	O
+causing	O
+the	O
+collapse	O
+of	O
+the	O
+rat	O
+population	O
+in	O
+approximately	O
+100	O
+days	O
+.	O
+
+Simultaneously	O
+,	O
+the	O
+force	O
+of	O
+infection	O
+exerted	O
+by	O
+each	O
+infected	O
+rat	O
+carcass	O
+onto	O
+the	O
+human	O
+population	O
+increases	O
+progressively	O
+by	O
+more	O
+than	O
+an	O
+order	O
+of	O
+magnitude	O
+.	O
+
+We	O
+also	O
+considered	O
+human	O
+-	O
+to	O
+-	O
+human	O
+transmission	O
+via	O
+pneumonic	O
+plague	O
+or	O
+human	O
+specific	O
+vectors	O
+,	O
+but	O
+found	O
+this	O
+route	O
+to	O
+account	O
+for	O
+only	O
+a	O
+small	O
+fraction	O
+of	O
+cases	O
+and	O
+to	O
+be	O
+significantly	O
+below	O
+the	O
+threshold	O
+required	O
+to	O
+sustain	O
+an	O
+outbreak	O
+.	O
+
+The	O
+Quebec	O
+Neonatal	O
+Urine	O
+Screening	O
+Program	O
+was	O
+initiated	O
+in	O
+1971	O
+with	O
+overall	O
+screening	O
+inception	O
+of	O
+newborns	O
+in	O
+1973	O
+.	O
+
+Forty	O
+-	O
+seven	O
+years	O
+later	O
+,	O
+over	O
+3.5	O
+million	O
+babies	O
+have	O
+been	O
+screened	O
+for	O
+up	O
+to	O
+25	O
+inborn	O
+errors	O
+of	O
+metabolism	O
+divided	O
+into	O
+two	O
+groups	O
+:	O
+(	O
+1	O
+)	O
+urea	O
+cycle	O
+disorders	O
+and	O
+organic	O
+acidurias	O
+;	O
+and	O
+(	O
+2	O
+)	O
+disorders	O
+of	O
+amino	O
+acid	O
+metabolism	O
+and	O
+transport	O
+.	O
+
+The	O
+main	O
+goal	O
+of	O
+this	O
+preventive	O
+genetic	O
+medicine	O
+program	O
+is	O
+the	O
+detection	O
+of	O
+treatable	O
+diseases	O
+before	O
+the	O
+onset	O
+of	O
+clinical	O
+symptoms	O
+.	O
+
+Urine	O
+specimens	O
+from	O
+21	O
+-	O
+day	O
+-	O
+old	O
+babies	O
+are	O
+collected	O
+and	O
+dried	O
+on	O
+filter	O
+paper	O
+by	O
+parents	O
+at	O
+home	O
+.	O
+
+The	O
+participation	O
+is	O
+voluntary	O
+with	O
+a	O
+high	O
+compliance	O
+rate	O
+over	O
+the	O
+years	O
+(	O
+~90	O
+%	O
+)	O
+.	O
+
+Specimens	O
+are	O
+analyzed	O
+by	O
+thin	O
+layer	O
+chromatography	O
+(	O
+TLC	O
+)	O
+.	O
+
+The	O
+main	O
+objective	O
+of	O
+this	O
+evaluative	O
+research	O
+project	O
+was	O
+to	O
+assess	O
+the	O
+feasibility	O
+of	O
+a	O
+technological	O
+upgrade	O
+towards	O
+mass	O
+spectrometry	O
+.	O
+
+A	O
+2.85	O
+-	O
+min	O
+flow	O
+injection	O
+method	O
+was	O
+devised	O
+,	O
+normal	O
+values	O
+established	O
+,	O
+and	O
+abnormal	O
+profiles	O
+confirmed	O
+using	O
+second	O
+-	O
+tier	O
+tests	O
+.	O
+
+The	O
+validated	O
+assays	O
+are	O
+sensitive	O
+,	O
+specific	O
+,	O
+and	O
+suitable	O
+for	O
+populational	O
+screening	O
+,	O
+as	O
+well	O
+as	O
+for	O
+high	O
+-	O
+risk	O
+screening	O
+laboratories	O
+.	O
+
+Triple	O
+H	O
+syndrome	O
+,	O
+which	O
+would	O
+not	O
+be	O
+detected	O
+in	O
+newborns	O
+by	O
+blood	O
+screening	O
+at	O
+two	O
+days	O
+of	O
+age	O
+was	O
+found	O
+to	O
+be	O
+positive	O
+in	O
+the	O
+urine	O
+of	O
+an	O
+affected	O
+patient	O
+.	O
+
+Objective	O
+The	O
+diagnosis	O
+of	O
+childhood	O
+-	O
+onset	O
+cerebellar	O
+ataxia	O
+(	O
+CA	O
+)	O
+is	O
+often	O
+challenging	O
+due	O
+to	O
+variations	O
+in	O
+symptoms	O
+and	O
+etiologies	O
+.	O
+
+Despite	O
+the	O
+known	O
+regional	O
+differences	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+etiologies	O
+underlying	O
+CA	O
+,	O
+the	O
+frequency	O
+and	O
+characteristics	O
+of	O
+CA	O
+in	O
+Japan	B-LOC
+remain	O
+unclear	O
+.	O
+
+We	O
+conducted	O
+a	O
+questionnaire	O
+-	O
+based	O
+survey	O
+to	O
+identify	O
+the	O
+clinical	O
+characteristics	O
+of	O
+childhood	O
+-	O
+onset	O
+CA	O
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+Materials	O
+and	O
+methods	O
+Questionnaires	O
+were	O
+sent	O
+to	O
+1,103	O
+board	O
+-	O
+certified	O
+pediatric	O
+neurologists	O
+in	O
+Japan	B-LOC
+from	O
+2016	O
+to	O
+2017	O
+.	O
+
+The	O
+primary	O
+survey	O
+requested	O
+the	O
+number	O
+of	O
+patients	O
+with	O
+CA	O
+under	O
+care	O
+,	O
+and	O
+the	O
+follow	O
+-	O
+up	O
+secondary	O
+questionnaire	O
+requested	O
+additional	O
+clinical	O
+characteristics	O
+of	O
+the	O
+patients	O
+.	O
+
+Results	O
+The	O
+primary	O
+survey	O
+obtained	O
+578	O
+responses	O
+(	O
+response	O
+rate	O
+,	O
+52.4	O
+%	O
+)	O
+on	O
+385	O
+patients	O
+with	O
+CA	O
+,	O
+including	O
+171	O
+diagnosed	O
+and	O
+214	O
+undiagnosed	O
+cases	O
+(	O
+diagnostic	O
+rate	O
+,	O
+44.4	O
+%	O
+)	O
+.	O
+
+The	O
+most	O
+frequent	O
+etiology	O
+was	O
+dentatorubropallidoluysian	O
+atrophy	O
+(	O
+DRPLA	O
+)	O
+,	O
+followed	O
+by	O
+mitochondrial	O
+disorders	O
+and	O
+encephalitis	O
+.	O
+
+The	O
+secondary	O
+survey	O
+obtained	O
+the	O
+clinical	O
+characteristics	O
+of	O
+252	O
+cases	O
+(	O
+119	O
+diagnosed	O
+and	O
+133	O
+undiagnosed	O
+cases	O
+)	O
+.	O
+
+Multiple	O
+logistic	O
+regression	O
+analysis	O
+revealed	O
+that	O
+a	O
+younger	O
+age	O
+at	O
+onset	O
+,	O
+hearing	O
+issues	O
+,	O
+and	O
+short	O
+stature	O
+were	O
+associated	O
+with	O
+a	O
+higher	O
+risk	O
+of	O
+remaining	O
+undiagnosed	O
+with	O
+CA	O
+in	O
+Japan	B-LOC
+.	O
+
+Conclusions	O
+The	O
+diagnostic	O
+rate	O
+of	O
+childhood	O
+-	O
+onset	O
+CA	O
+in	O
+the	O
+current	O
+study	O
+was	O
+comparable	O
+to	O
+those	O
+reported	O
+in	O
+other	O
+countries	O
+.	O
+
+The	O
+high	O
+prevalence	B-EPI
+of	O
+autosomal	O
+dominant	O
+ataxia	O
+,	O
+especially	O
+DRPLA	O
+,	O
+was	O
+a	O
+signature	O
+of	O
+CA	O
+in	O
+Japan	B-LOC
+.	O
+
+These	O
+data	O
+offer	O
+insights	O
+into	O
+the	O
+characteristics	O
+of	O
+childhood	O
+-	O
+onset	O
+CA	O
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+Early	O
+detection	O
+of	O
+disabling	O
+diseases	O
+,	O
+prior	O
+to	O
+clinical	O
+manifestations	O
+,	O
+is	O
+the	O
+primary	O
+goal	O
+of	O
+newborn	O
+screening	O
+(	O
+NS	O
+)	O
+.	O
+
+Indeed	O
+,	O
+the	O
+required	O
+number	O
+of	O
+core	O
+and	O
+secondary	O
+conditions	O
+selected	O
+for	O
+screening	O
+panels	O
+is	O
+increasing	O
+in	O
+many	O
+countries	O
+.	O
+
+Furthermore	O
+,	O
+newborn	O
+screening	O
+can	O
+lead	O
+to	O
+diagnosis	O
+of	O
+maternal	O
+diseases	O
+such	O
+as	O
+vitamin	O
+B12	O
+deficiency	O
+or	O
+3	O
+-	O
+MethylcrotonylCoA	O
+-	O
+carboxylase	O
+deficiency	O
+(	O
+3MCC	O
+)	O
+.	O
+
+NS	O
+became	O
+mandatory	O
+in	O
+Sicily	B-LOC
+in	O
+December	O
+2017	O
+.	O
+
+Here	O
+we	O
+report	O
+NS	O
+data	O
+collected	O
+between	O
+December	O
+2017	O
+and	O
+April	O
+2020	O
+.	O
+
+Our	O
+results	O
+show	O
+that	O
+tandem	O
+mass	O
+spectrometry	O
+is	O
+a	O
+powerful	O
+tool	O
+for	O
+discovery	O
+of	O
+underestimated	O
+disease	O
+in	O
+newborns	O
+and	O
+their	O
+family	O
+members	O
+.	O
+
+Our	O
+panel	O
+included	O
+short	O
+chain	O
+acyl	O
+-	O
+CoA	O
+dehydrogenase	O
+deficiency	O
+(	O
+SCADD	O
+)	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+that	O
+results	O
+of	O
+our	O
+investigation	O
+led	O
+to	O
+reassessment	O
+of	O
+SCADD	O
+prevalence	B-EPI
+in	O
+our	O
+population	O
+.	O
+
+The	O
+infant	O
+and	O
+adult	O
+patients	O
+diagnosed	O
+in	O
+our	O
+study	O
+had	O
+previously	O
+not	O
+shown	O
+overt	O
+symptoms	O
+.	O
+
+Allogeneic	O
+islet	O
+transplantation	O
+is	O
+a	O
+standard	O
+of	O
+care	O
+treatment	O
+for	O
+patients	O
+with	O
+labile	O
+type	O
+1	O
+diabetes	O
+in	O
+many	O
+countries	O
+around	O
+the	O
+world	O
+,	O
+including	O
+Japan	B-LOC
+,	O
+the	B-LOC
+United	I-LOC
+Kingdom	I-LOC
+,	O
+Australia	B-LOC
+,	O
+much	O
+of	O
+continental	O
+Europe	B-LOC
+,	O
+and	O
+parts	O
+of	O
+Canada	B-LOC
+.	O
+
+The	B-LOC
+United	I-LOC
+States	I-LOC
+is	O
+now	O
+endorsing	O
+islet	O
+cell	O
+treatment	O
+for	O
+type	O
+1	O
+diabetes	O
+,	O
+but	O
+the	O
+FDA	O
+has	O
+chosen	O
+to	O
+consider	O
+islets	O
+as	O
+a	O
+biologic	O
+that	O
+requires	O
+licensure	O
+,	O
+making	O
+the	O
+universal	O
+implementation	O
+of	O
+the	O
+procedure	O
+in	O
+the	O
+clinic	O
+very	O
+challenging	O
+and	O
+opening	O
+the	O
+manufacture	O
+of	O
+islet	O
+grafts	O
+to	O
+private	O
+companies	O
+.	O
+
+The	O
+commercialization	O
+of	O
+human	O
+tissues	O
+raises	O
+significant	O
+legal	O
+and	O
+ethical	O
+issues	O
+and	O
+ironically	O
+leads	O
+to	O
+a	O
+situation	O
+where	O
+treatments	O
+developed	O
+as	O
+a	O
+result	O
+of	O
+the	O
+scientific	O
+and	O
+economic	O
+efforts	O
+of	O
+academia	O
+over	O
+several	O
+decades	O
+become	O
+exploited	O
+exclusively	O
+by	O
+for	O
+-	O
+profit	O
+entities	O
+.	O
+
+Background	O
+Many	O
+public	O
+health	O
+surveillance	O
+programs	O
+utilize	O
+hospital	O
+discharge	O
+data	O
+in	O
+their	O
+estimation	O
+of	O
+disease	O
+prevalence	B-EPI
+.	O
+
+These	O
+databases	O
+commonly	O
+use	O
+the	O
+International	O
+Classification	O
+of	O
+Diseases	O
+(	O
+ICD	O
+)	O
+coding	O
+scheme	O
+,	O
+which	O
+transitioned	O
+from	O
+the	O
+ICD-9	O
+clinical	O
+modification	O
+(	O
+ICD-9	O
+-	O
+CM	O
+)	O
+to	O
+ICD-10	O
+-	O
+CM	O
+on	O
+October	O
+1	O
+,	O
+2015	O
+.	O
+
+This	O
+study	O
+examined	O
+this	O
+transition	O
+'s	O
+impact	O
+on	O
+the	O
+prevalence	B-EPI
+of	O
+major	O
+birth	O
+defects	O
+among	O
+infant	O
+hospitalizations	O
+.	O
+
+Methods	O
+Using	O
+data	O
+from	O
+the	O
+Agency	O
+for	O
+Health	O
+Care	O
+Research	O
+and	O
+Quality	O
+-	O
+sponsored	O
+National	O
+Inpatient	O
+Sample	O
+,	O
+hospitalizations	O
+during	O
+the	O
+first	O
+year	O
+of	O
+life	O
+with	O
+a	O
+discharge	O
+date	O
+between	O
+January	O
+1	O
+,	O
+2012	O
+and	O
+December	O
+31	O
+,	O
+2016	O
+were	O
+used	O
+to	O
+estimate	O
+the	O
+monthly	O
+national	O
+hospital	O
+prevalence	B-EPI
+of	O
+46	O
+birth	O
+defects	O
+for	O
+the	O
+ICD-9	O
+-	O
+CM	O
+and	O
+ICD-10	O
+-	O
+CM	O
+timeframes	O
+separately	O
+.	O
+
+Survey	O
+-	O
+weighted	O
+Poisson	O
+regression	O
+was	O
+used	O
+to	O
+estimate	O
+95	O
+%	O
+confidence	O
+intervals	O
+for	O
+each	O
+hospital	O
+prevalence	B-EPI
+.	O
+
+Interrupted	O
+time	O
+series	O
+framework	O
+and	O
+corresponding	O
+segmented	O
+regression	O
+was	O
+used	O
+to	O
+estimate	O
+the	O
+immediate	O
+change	O
+in	O
+monthly	O
+hospital	O
+prevalence	B-EPI
+following	O
+the	O
+ICD-9	O
+-	O
+CM	O
+to	O
+ICD-10	O
+-	O
+CM	O
+transition	O
+.	O
+
+Results	O
+Between	O
+2012	O
+and	O
+2016	O
+,	O
+over	O
+21	O
+million	O
+inpatient	O
+hospitalizations	O
+occurred	O
+during	O
+the	O
+first	O
+year	O
+of	O
+life	O
+.	O
+
+Among	O
+the	O
+46	O
+defects	O
+studied	O
+,	O
+statistically	O
+significant	O
+decreases	O
+in	O
+the	O
+immediate	O
+hospital	O
+prevalence	B-EPI
+of	O
+five	O
+defects	O
+and	O
+significant	O
+increases	O
+in	O
+the	O
+immediate	O
+hospital	O
+prevalence	B-EPI
+of	O
+eight	O
+defects	O
+were	O
+observed	O
+after	O
+the	O
+ICD-10	O
+-	O
+CM	O
+transition	O
+.	O
+
+Conclusions	O
+Changes	O
+in	O
+prevalence	B-EPI
+were	O
+expected	O
+based	O
+on	O
+changes	O
+to	O
+ICD-10	O
+-	O
+CM	O
+.	O
+
+Observed	O
+changes	O
+for	O
+some	O
+conditions	O
+may	O
+result	O
+from	O
+variation	O
+in	O
+monthly	O
+hospital	O
+prevalence	B-EPI
+or	O
+initial	O
+unfamiliarity	O
+of	O
+coders	O
+with	O
+ICD-10	O
+-	O
+CM	O
+.	O
+
+These	O
+findings	O
+may	O
+help	O
+birth	O
+defects	O
+surveillance	O
+programs	O
+evaluate	O
+and	O
+interpret	O
+changes	O
+in	O
+their	O
+data	O
+related	O
+to	O
+the	O
+ICD-10	O
+-	O
+CM	O
+transition	O
+.	O
+
+Juvenile	O
+Idiopathic	O
+Arthritis	O
+is	O
+one	O
+of	O
+the	O
+most	O
+prevalent	B-EPI
+chronic	O
+diseases	O
+in	O
+children	O
+,	O
+with	O
+an	O
+annual	B-EPI
+incidence	I-EPI
+of	O
+2	B-STAT
+-	I-STAT
+20	I-STAT
+cases	I-STAT
+per	I-STAT
+100,000	I-STAT
+and	I-STAT
+a	O
+prevalence	B-EPI
+of	O
+16	B-STAT
+-	I-STAT
+150	I-STAT
+per	I-STAT
+100,000	I-STAT
+.	O
+
+It	O
+is	O
+associated	O
+with	O
+several	O
+complications	O
+that	O
+can	O
+cause	O
+short	O
+-	O
+term	O
+or	O
+long	O
+-	O
+term	O
+disability	O
+and	O
+reduce	O
+the	O
+quality	O
+of	O
+life	O
+.	O
+
+Among	O
+these	O
+,	O
+growth	O
+and	O
+pubertal	O
+disorders	O
+play	O
+an	O
+important	O
+role	O
+.	O
+
+Chronic	O
+inflammatory	O
+conditions	O
+are	O
+often	O
+associated	O
+with	O
+growth	O
+failure	O
+ranging	O
+from	O
+slight	O
+decrease	O
+in	O
+height	O
+velocity	O
+to	O
+severe	O
+forms	O
+of	O
+short	O
+stature	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+short	O
+stature	O
+in	O
+JIA	O
+varies	O
+from	O
+10.4	O
+%	O
+in	O
+children	O
+with	O
+polyarticular	O
+disease	B-STAT
+to	O
+41	O
+%	O
+of	O
+patients	O
+with	O
+the	O
+systemic	O
+form	O
+,	O
+while	O
+oligoarthritis	O
+is	O
+mostly	O
+associated	O
+with	O
+localized	O
+excessive	O
+bone	O
+growth	O
+of	O
+the	O
+affected	O
+limb	O
+,	O
+leading	O
+to	O
+limb	O
+dissymmetry	O
+.	O
+
+The	O
+pathogenesis	O
+of	O
+growth	O
+disorders	O
+is	O
+multifactorial	O
+and	O
+includes	O
+the	O
+role	O
+of	O
+chronic	O
+inflammation	O
+,	O
+long	O
+-	O
+term	O
+use	O
+of	O
+corticosteroids	O
+,	O
+undernutrition	O
+,	O
+altered	O
+body	O
+composition	O
+,	O
+delay	O
+of	O
+pubertal	O
+onset	O
+or	O
+slow	O
+pubertal	O
+progression	O
+.	O
+
+These	O
+factors	O
+can	O
+exert	O
+a	O
+systemic	O
+effect	O
+on	O
+the	O
+GH	O
+/	O
+IGF-1	O
+axis	O
+and	O
+on	O
+the	O
+GnRH	O
+-	O
+gonadotropin	O
+-	O
+gonadic	O
+axis	O
+,	O
+or	O
+a	O
+local	O
+influence	O
+on	O
+the	O
+growth	O
+plate	O
+homeostasis	O
+and	O
+function	O
+.	O
+
+Although	O
+new	O
+therapeutic	O
+options	O
+are	O
+available	O
+to	O
+control	O
+inflammation	O
+,	O
+there	O
+are	O
+still	O
+10	B-STAT
+-	O
+20	O
+%	O
+of	O
+patients	O
+with	O
+severe	O
+forms	O
+of	O
+the	O
+disease	O
+who	O
+show	O
+continuous	O
+growth	O
+impairment	O
+,	O
+ending	O
+in	O
+a	O
+short	O
+final	O
+stature	O
+.	O
+
+Moreover	O
+,	O
+delayed	O
+puberty	O
+is	O
+associated	O
+with	O
+a	O
+reduction	O
+in	O
+the	O
+peak	O
+bone	O
+mass	O
+with	O
+the	O
+possibility	O
+of	O
+concomitant	O
+or	O
+future	O
+bone	O
+fragility	O
+.	O
+
+Monitoring	O
+of	O
+puberty	O
+and	O
+bone	O
+health	O
+is	O
+essential	O
+for	O
+a	O
+complete	O
+health	O
+assessment	O
+of	O
+adolescents	O
+with	O
+JIA	O
+.	O
+
+In	O
+these	O
+patients	O
+,	O
+an	O
+assessment	O
+of	O
+the	O
+pubertal	O
+stage	O
+every	O
+6	O
+months	O
+from	O
+the	O
+age	O
+of	O
+9	O
+years	O
+is	O
+recommended	O
+.	O
+
+Also	O
+,	O
+linear	O
+growth	O
+should	O
+be	O
+always	O
+evaluated	O
+considering	O
+the	O
+patient	O
+'s	O
+bone	O
+age	O
+.	O
+
+The	O
+impact	O
+of	O
+rhGH	O
+therapy	O
+in	O
+children	O
+with	O
+JIA	O
+is	O
+still	O
+unclear	O
+,	O
+but	O
+it	O
+has	O
+been	O
+shown	O
+that	O
+if	O
+rhGH	O
+is	O
+added	O
+at	O
+high	O
+dose	O
+in	O
+a	O
+low	O
+-	O
+inflammatory	O
+condition	O
+,	O
+post	O
+steroids	O
+and	O
+on	O
+biologic	O
+therapy	O
+,	O
+it	O
+is	O
+able	O
+to	O
+favor	O
+a	O
+prepubertal	O
+growth	O
+acceleration	O
+,	O
+comparable	O
+with	O
+the	O
+catch	O
+-	O
+up	O
+growth	O
+response	O
+in	O
+GH	O
+-	O
+deficient	O
+patients	O
+.	O
+
+Here	O
+we	O
+provide	O
+a	O
+comprehensive	O
+review	O
+of	O
+the	O
+pathogenesis	O
+of	O
+puberty	O
+and	O
+growth	O
+disorders	O
+in	O
+children	O
+with	O
+JIA	O
+,	O
+which	O
+can	O
+help	O
+the	O
+pediatrician	O
+to	O
+properly	O
+and	O
+timely	O
+assess	O
+the	O
+presence	O
+of	O
+growth	O
+and	O
+pubertal	O
+disorders	O
+in	O
+JIA	O
+patients	O
+.	O
+
+Neonatal	O
+herpes	O
+simplex	O
+virus	O
+(	O
+HSV	O
+)	O
+infection	O
+is	O
+rare	O
+,	O
+with	O
+an	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+3.58	B-STAT
+per	I-STAT
+100	I-STAT
+000	I-STAT
+live	I-STAT
+births	I-STAT
+in	O
+the	O
+UK	B-LOC
+and	O
+should	O
+be	O
+suspected	O
+in	O
+any	O
+newborn	O
+with	O
+fever	O
+and	O
+bacterial	O
+culture	O
+-	O
+negative	O
+sepsis	O
+.	O
+
+We	O
+describe	O
+a	O
+case	O
+of	O
+a	O
+previously	O
+well	O
+full	O
+-	O
+term	O
+male	O
+neonate	O
+who	O
+presented	O
+with	O
+persistent	O
+fever	O
+and	O
+elevated	O
+ferritin	O
+level	O
+that	O
+was	O
+carried	O
+out	O
+during	O
+the	O
+era	O
+of	O
+the	O
+COVID-19	O
+pandemic	O
+as	O
+part	O
+of	O
+SARS	O
+-	O
+CoV-2	O
+panel	O
+investigations	O
+.	O
+
+Despite	O
+the	O
+initial	O
+negative	O
+HSV	O
+serology	O
+,	O
+HSV-1	O
+PCR	O
+from	O
+a	O
+scalp	O
+lesion	O
+returned	O
+positive	O
+.	O
+
+He	O
+made	O
+a	O
+full	O
+recovery	O
+after	O
+acyclovir	O
+therapy	O
+.	O
+
+This	O
+case	O
+highlights	O
+the	O
+importance	O
+of	O
+maintaining	O
+a	O
+high	O
+clinical	O
+index	O
+of	O
+suspicion	O
+of	O
+HSV	O
+infection	O
+in	O
+any	O
+febrile	O
+neonate	O
+even	O
+with	O
+absence	O
+of	O
+maternal	O
+history	O
+and	O
+negative	O
+serology	O
+,	O
+particularly	O
+if	O
+associated	O
+with	O
+hyperferritinaemia	O
+.	O
+
+We	O
+also	O
+address	O
+the	O
+challenge	O
+of	O
+interpreting	O
+inflammatory	O
+biomarkers	O
+'	O
+results	O
+for	O
+SARS	O
+-	O
+CoV-2	O
+infection	O
+in	O
+neonates	O
+.	O
+
+Herpes	O
+zoster	O
+oticus	O
+also	O
+known	O
+as	O
+Ramsay	O
+Hunt	O
+syndrome	O
+is	O
+a	O
+rare	O
+complication	O
+of	O
+herpes	O
+zoster	O
+in	O
+which	O
+reactivation	O
+of	O
+latent	O
+varicella	O
+zoster	O
+virus	O
+infection	O
+in	O
+the	O
+geniculate	O
+ganglion	O
+causes	O
+otalgia	O
+,	O
+auricular	O
+vesicles	O
+,	O
+and	O
+peripheral	O
+facial	O
+paralysis	O
+.	O
+
+Ramsay	O
+Hunt	O
+syndrome	O
+is	O
+rare	O
+in	O
+children	O
+and	O
+affects	O
+both	O
+sexes	O
+equally	O
+.	O
+
+Incidence	B-EPI
+and	O
+clinical	O
+severity	O
+increases	O
+when	O
+host	O
+immunity	O
+is	O
+compromised	O
+.	O
+
+Because	O
+these	O
+symptoms	O
+do	O
+not	O
+always	O
+present	O
+at	O
+the	O
+onset	O
+,	O
+this	O
+syndrome	O
+can	O
+be	O
+misdiagnosed	O
+.	O
+
+Although	O
+secondary	O
+to	O
+Bell	O
+'s	O
+palsy	O
+in	O
+terms	O
+of	O
+the	O
+cause	O
+of	O
+acute	O
+atraumatic	O
+peripheral	O
+facial	O
+paralysis	O
+,	O
+Ramsay	O
+Hunt	O
+syndrome	O
+,	O
+with	O
+incidence	B-EPI
+ranged	O
+from	O
+0.3	B-STAT
+to	O
+18	O
+%	O
+,	O
+has	O
+a	O
+worse	O
+prognosis	O
+.	O
+
+Herpes	O
+zoster	O
+oticus	O
+accounts	O
+for	O
+about	O
+12	O
+%	O
+cases	O
+of	O
+facial	O
+palsy	O
+,	O
+which	O
+is	O
+usually	O
+unilateral	O
+and	O
+complete	O
+and	O
+full	O
+recovery	O
+occurs	B-EPI
+in	O
+only	O
+about	O
+20	B-STAT
+%	O
+of	O
+untreated	O
+patients	O
+.	O
+
+The	O
+most	O
+advisable	O
+method	O
+to	O
+treat	O
+Ramsay	O
+Hunt	O
+syndrome	O
+is	O
+the	O
+combination	O
+therapy	O
+with	O
+acyclovir	O
+and	O
+prednisone	O
+but	O
+still	O
+not	O
+promising	O
+,	O
+and	O
+several	O
+prerequisites	O
+are	O
+required	O
+for	O
+better	O
+results	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+32	O
+-	O
+year	O
+-	O
+old	O
+man	O
+suffering	O
+from	O
+Ramsay	O
+Hunt	O
+syndrome	O
+with	O
+grade	O
+V	O
+facial	O
+palsy	O
+treated	O
+effectively	O
+with	O
+rehabilitation	O
+program	O
+,	O
+after	O
+the	O
+termination	O
+of	O
+the	O
+combination	O
+therapy	O
+of	O
+acyclovir	O
+and	O
+prednisone	O
+.	O
+
+The	O
+May	O
+-	O
+Hegglin	O
+anomaly	O
+is	O
+characterized	O
+by	O
+inherited	O
+thrombocytopenia	O
+,	O
+giant	O
+platelets	O
+,	O
+and	O
+leukocyte	O
+cytoplasmic	O
+inclusion	O
+bodies	O
+.	O
+
+The	O
+Fechtner	O
+,	O
+Sebastian	O
+,	O
+and	O
+Epstein	O
+syndromes	O
+are	O
+associated	O
+with	O
+mutations	O
+of	O
+the	O
+MYH9	O
+-	O
+coding	O
+nonmuscle	O
+myosin	O
+heavy	O
+chain	O
+ⅡA	O
+,	O
+similar	O
+to	O
+the	O
+May	O
+-	O
+Hegglin	O
+anomaly	O
+,	O
+and	O
+are	O
+together	O
+classified	O
+as	O
+MYH9	O
+disorders	O
+.	O
+
+MYH9	O
+disorders	O
+may	O
+include	O
+symptoms	O
+of	O
+Alport	O
+syndrome	O
+,	O
+including	O
+nephritis	O
+and	O
+auditory	O
+and	O
+ocular	O
+disorders	O
+.	O
+
+A	O
+6	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+was	O
+diagnosed	O
+with	O
+an	O
+MYH9	O
+disorder	O
+after	O
+incidental	O
+discovery	O
+of	O
+hematuria	O
+and	O
+proteinuria	O
+.	O
+
+Focal	O
+segmental	O
+glomerulosclerosis	O
+was	O
+detected	O
+on	O
+renal	O
+biopsy	O
+.	O
+
+However	O
+,	O
+despite	O
+no	O
+prior	O
+bleeding	O
+diatheses	O
+,	O
+he	O
+developed	O
+a	O
+large	O
+post	O
+-	O
+biopsy	O
+hematoma	O
+despite	O
+a	O
+preprocedural	O
+platelet	O
+transfusion	O
+calculated	O
+to	O
+increase	O
+the	O
+platelet	O
+count	O
+from	O
+54,000	O
+/	O
+μL	O
+to	O
+>	O
+150,000	O
+/	O
+μL.	O
+
+Idiopathic	O
+thrombocytopenic	O
+purpura	O
+is	O
+a	O
+major	O
+cause	O
+of	O
+pediatric	O
+thrombocytopenia	O
+following	O
+acute	O
+infection	O
+or	O
+vaccination	O
+,	O
+and	O
+patients	O
+with	O
+MYH9	O
+disorders	O
+may	O
+be	O
+misdiagnosed	O
+with	O
+idiopathic	O
+thrombocytopenic	O
+purpura	O
+and	O
+inappropriately	O
+treated	O
+with	O
+corticosteroids	O
+.	O
+
+Careful	O
+differential	O
+diagnosis	O
+is	O
+important	O
+in	O
+thrombocytopenic	O
+patients	O
+with	O
+hematuria	O
+and	O
+proteinuria	O
+for	O
+the	O
+early	O
+detection	O
+of	O
+thrombocytopenia	O
+.	O
+
+Patients	O
+with	O
+MYH9	O
+disorders	O
+require	O
+close	O
+follow	O
+-	O
+up	O
+and	O
+treatment	O
+with	O
+angiotensin	O
+Ⅱ	O
+receptor	O
+blockers	O
+to	O
+prevent	O
+the	O
+onset	O
+of	O
+progressive	O
+nephritis	O
+,	O
+which	O
+may	O
+necessitate	O
+hemodialysis	O
+or	O
+renal	O
+transplantation	O
+.	O
+
+The	O
+need	O
+for	O
+renal	O
+biopsy	O
+in	O
+patients	O
+with	O
+MYH9	O
+disorders	O
+should	O
+be	O
+carefully	O
+considered	O
+because	O
+there	O
+could	O
+be	O
+adverse	O
+outcomes	O
+even	O
+after	O
+platelet	O
+transfusion	O
+.	O
+
+Ehlers	O
+-	O
+Danlos	O
+Syndrome	O
+(	O
+EDS	O
+)	O
+is	O
+a	O
+family	O
+of	O
+multisystemic	O
+hereditary	O
+connective	O
+tissue	O
+disorders	O
+now	O
+comprised	O
+of	O
+13	O
+recognized	O
+subtypes	O
+,	O
+classical	O
+,	O
+classical	O
+-	O
+like	O
+,	O
+cardiac	O
+-	O
+valvular	O
+,	O
+vascular	O
+,	O
+hypermobile	O
+,	O
+arthrochlasia	O
+,	O
+dermosparaxis	O
+,	O
+kyphoscoliotic	O
+,	O
+brittle	O
+cornea	O
+syndrome	O
+,	O
+spondylodysplastic	O
+,	O
+musculocontractural	O
+,	O
+myopathic	O
+,	O
+and	O
+periodontal	O
+,	O
+as	O
+designated	O
+by	O
+the	O
+most	O
+recent	O
+2017	O
+International	O
+classification	O
+system	O
+.	O
+
+Clinical	O
+presentation	O
+of	O
+this	O
+disease	O
+can	O
+range	O
+from	O
+mild	O
+manifestations	O
+including	O
+skin	O
+hyperextensibility	O
+and	O
+joint	O
+hypermobility	O
+,	O
+to	O
+more	O
+severe	O
+complications	O
+such	O
+as	O
+vascular	O
+and	O
+organ	O
+rupture	O
+.	O
+
+While	O
+there	O
+may	O
+be	O
+accompanying	O
+inflammation	O
+in	O
+some	O
+of	O
+the	O
+subtypes	O
+of	O
+EDS	O
+,	O
+the	O
+pathogenic	O
+mechanisms	O
+have	O
+not	O
+been	O
+clearly	O
+defined	O
+.	O
+
+Thorough	O
+evaluation	O
+incorporates	O
+clinical	O
+examination	O
+,	O
+family	O
+history	O
+,	O
+laboratory	O
+testing	O
+,	O
+and	O
+imaging	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+studies	O
+have	O
+identified	O
+multiple	O
+gene	O
+variants	O
+involved	O
+in	O
+the	O
+pathogenesis	O
+of	O
+specific	O
+EDS	O
+subtypes	O
+as	O
+well	O
+as	O
+elaborate	O
+clinical	O
+diagnostic	O
+criteria	O
+and	O
+classification	O
+models	O
+used	O
+to	O
+differentiate	O
+overlapping	O
+conditions	O
+.	O
+
+The	O
+differential	O
+diagnosis	O
+of	O
+EDS	O
+includes	O
+hypermobility	O
+spectrum	O
+disorders	O
+,	O
+Marfan	O
+syndrome	O
+,	O
+Loey	O
+-	O
+Dietz	O
+syndrome	O
+,	O
+Cutis	O
+laxa	O
+syndromes	O
+,	O
+autosomal	O
+dominant	O
+polycystic	O
+kidney	O
+disease	O
+,	O
+osteogenesis	O
+Imperfecta	O
+Type	O
+1	O
+,	O
+fibromyalgia	O
+,	O
+depression	O
+,	O
+and	O
+chronic	O
+fatigue	O
+syndrome	O
+.	O
+
+Surgical	O
+treatment	O
+is	O
+reserved	O
+for	O
+complications	O
+,	O
+or	O
+emergencies	O
+involving	O
+vascular	O
+or	O
+orthopedic	O
+injury	O
+because	O
+of	O
+the	O
+risk	O
+of	O
+poor	O
+wound	O
+healing	O
+.	O
+
+Management	O
+techniques	O
+each	O
+have	O
+their	O
+own	O
+consequences	O
+and	O
+benefits	O
+,	O
+which	O
+will	O
+also	O
+be	O
+discussed	O
+in	O
+this	O
+review	O
+article	O
+.	O
+
+Patients	O
+affected	O
+by	O
+this	O
+spectrum	O
+of	O
+disorders	O
+are	O
+impacted	O
+both	O
+phenotypically	O
+and	O
+psychosocially	O
+,	O
+diminishing	O
+their	O
+quality	O
+of	O
+life	O
+.	O
+
+Objective	O
+To	O
+study	O
+the	O
+genetic	O
+cause	O
+of	O
+Mayer	O
+-	O
+Rokitansky	O
+-	O
+Kuster	O
+-	O
+Hauser	O
+syndrome	O
+(	O
+MRKH	O
+)	O
+.	O
+
+Although	O
+a	O
+few	O
+candidate	O
+genes	O
+and	O
+genomic	O
+domains	O
+for	O
+have	O
+been	O
+reported	O
+for	O
+MRKH	O
+,	O
+the	O
+genetic	O
+underpinnings	O
+remain	O
+largely	O
+unknown	O
+.	O
+
+Some	O
+of	O
+the	O
+top	O
+candidate	O
+genes	O
+are	O
+WNT4	O
+,	O
+HNF1B	B-LOC
+,	O
+and	O
+LHX1	O
+.	O
+
+The	O
+goals	O
+of	O
+this	O
+study	O
+were	O
+to	O
+:	O
+1	O
+)	O
+determine	O
+the	O
+prevalence	B-EPI
+of	O
+WNT4	O
+,	O
+HNF1B	B-LOC
+,	O
+and	O
+LHX1	O
+point	O
+mutations	O
+,	O
+as	O
+well	O
+as	O
+new	O
+copy	O
+number	O
+variants	O
+(	O
+CNVs	O
+)	O
+in	O
+people	O
+with	O
+MRKH	O
+;	O
+and	O
+2	O
+)	O
+identify	O
+and	O
+characterize	O
+MRKH	O
+cohorts	O
+.	O
+
+Design	O
+Laboratory-	O
+and	O
+community	O
+-	O
+based	O
+study	O
+.	O
+
+Setting	O
+Academic	O
+medical	O
+centers	O
+.	O
+
+Patient(s	O
+)	O
+A	O
+total	O
+of	O
+147	O
+MRKH	O
+probands	O
+and	O
+available	O
+family	O
+members	O
+.	O
+
+Interventions(s	O
+)	O
+DNA	O
+sequencing	O
+of	O
+WNT4	O
+,	O
+HNF1B	B-LOC
+,	O
+and	O
+LHX1	O
+in	O
+100	O
+MRKH	O
+patients	O
+,	O
+chromosomal	O
+microarray	O
+analysis	O
+in	O
+31	O
+North	O
+American	O
+MRKH	O
+patients	O
+,	O
+and	O
+characterization	O
+and	O
+sample	O
+collection	O
+of	O
+147	O
+North	O
+American	O
+and	O
+Turkish	O
+MRKH	O
+probands	O
+and	O
+their	O
+families	O
+.	O
+
+Main	O
+outcome	O
+measure(s	O
+)	O
+DNA	O
+sequence	O
+variants	O
+and	O
+CNVs	O
+;	O
+pedigree	O
+structural	O
+analysis	O
+.	O
+
+Result(s	O
+)	O
+We	O
+report	O
+finding	O
+CNVs	O
+in	O
+6/31	B-STAT
+people	O
+(	O
+∼19	O
+%	O
+)	O
+with	O
+MRKH	O
+,	O
+but	O
+no	O
+point	O
+mutations	O
+or	O
+small	O
+indels	O
+in	O
+WNT4	O
+,	O
+HNF1B	B-LOC
+,	O
+or	O
+LHX1	O
+in	O
+100	O
+MRKH	O
+patients	O
+.	O
+
+Our	O
+MRKH	O
+families	O
+included	O
+43	O
+quads	O
+,	O
+26	O
+trios	O
+,	O
+and	O
+30	O
+duos	O
+.	O
+
+Of	O
+our	O
+MRKH	O
+probands	O
+,	O
+87/147	B-STAT
+(	O
+59	O
+%	O
+)	O
+had	O
+MRKH	O
+type	O
+1	B-STAT
+and	I-STAT
+60/147	I-STAT
+(	O
+41	O
+%	O
+)	O
+had	O
+type	O
+2	O
+with	O
+additional	O
+anomalies	O
+.	O
+
+Conclusion(s	O
+)	O
+Although	O
+the	O
+prevalence	B-EPI
+of	O
+WNT4	O
+,	O
+HNF1B	B-LOC
+,	O
+and	O
+LHX1	O
+point	O
+mutations	O
+is	O
+low	O
+in	O
+people	O
+with	O
+MRKH	O
+,	O
+the	O
+prevalence	B-EPI
+of	O
+CNVs	O
+was	O
+∼19	O
+%	O
+.	O
+
+Further	O
+analysis	O
+of	O
+our	O
+large	O
+familial	O
+cohort	O
+of	O
+patients	O
+will	O
+facilitate	O
+gene	O
+discovery	O
+to	O
+better	O
+understand	O
+the	O
+complex	O
+etiology	O
+of	O
+MRKH	O
+.	O
+
+A	O
+novel	O
+coronavirus	O
+SARS	O
+-	O
+CoV-2	O
+causing	O
+Coronavirus	O
+disease	O
+2019	O
+(	O
+COVID-19	O
+)	O
+has	O
+entered	O
+the	O
+human	O
+population	O
+and	O
+has	O
+spread	O
+rapidly	O
+around	O
+the	O
+world	O
+in	O
+the	O
+first	O
+half	O
+of	O
+2020	O
+causing	O
+a	O
+global	O
+pandemic	O
+.	O
+
+The	O
+virus	O
+uses	O
+its	O
+spike	O
+glycoprotein	O
+receptor	O
+-	O
+binding	O
+domain	O
+to	O
+interact	O
+with	O
+host	O
+cell	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+2	O
+(	O
+ACE2	O
+)	O
+sites	O
+to	O
+initiate	O
+a	O
+cascade	O
+of	O
+events	O
+that	O
+culminate	O
+in	O
+severe	O
+acute	O
+respiratory	O
+syndrome	O
+in	O
+some	O
+individuals	O
+.	O
+
+In	O
+efforts	O
+to	O
+curtail	O
+viral	O
+spread	O
+,	O
+authorities	O
+initiated	O
+far	O
+-	O
+reaching	O
+lockdowns	O
+that	O
+have	O
+disrupted	O
+global	O
+economies	O
+.	O
+
+The	O
+scientific	O
+and	O
+medical	O
+communities	O
+are	O
+mounting	O
+serious	O
+efforts	O
+to	O
+limit	O
+this	O
+pandemic	O
+and	O
+subsequent	O
+waves	O
+of	O
+viral	O
+spread	O
+by	O
+developing	O
+preventative	O
+vaccines	O
+and	O
+repurposing	O
+existing	O
+drugs	O
+as	O
+potential	O
+therapies	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+focus	O
+on	O
+the	O
+latest	O
+developments	O
+in	O
+COVID-19	O
+vaccine	O
+development	O
+,	O
+including	O
+results	O
+of	O
+the	O
+first	O
+Phase	O
+I	O
+clinical	O
+trials	O
+and	O
+describe	O
+a	O
+number	O
+of	O
+the	O
+early	O
+candidates	O
+that	O
+are	O
+emerging	O
+in	O
+the	O
+field	O
+.	O
+
+We	O
+seek	O
+to	O
+provide	O
+a	O
+balanced	O
+coverage	O
+of	O
+the	O
+seven	O
+main	O
+platforms	O
+used	O
+in	O
+vaccine	O
+development	O
+that	O
+will	O
+lead	O
+to	O
+a	O
+desired	O
+target	O
+product	O
+profile	O
+for	O
+the	O
+	O
+ideal	O
+	O
+vaccine	O
+.	O
+
+Using	O
+tales	O
+of	O
+past	O
+vaccine	O
+discovery	O
+efforts	O
+that	O
+have	O
+taken	O
+many	O
+years	O
+or	O
+that	O
+have	O
+failed	O
+,	O
+we	O
+temper	O
+over	O
+exuberant	O
+enthusiasm	O
+with	O
+cautious	O
+optimism	O
+that	O
+the	O
+global	O
+medical	O
+community	O
+will	O
+reach	O
+the	O
+elusive	O
+target	O
+to	O
+treat	O
+COVID-19	O
+and	O
+end	O
+the	O
+pandemic	O
+.	O
+
+Background	O
+Many	O
+epidemiological	O
+studies	O
+have	O
+indicated	O
+that	O
+inbreeding	O
+has	O
+little	O
+or	O
+no	O
+effect	O
+on	O
+the	O
+incidence	B-EPI
+of	O
+cancer	O
+.	O
+
+Due	O
+to	O
+the	O
+high	O
+prevalence	B-EPI
+of	O
+consanguinity	O
+in	O
+Qatar	B-LOC
+(	O
+54	O
+%	O
+)	O
+,	O
+its	O
+influence	O
+may	O
+nevertheless	O
+be	O
+of	O
+special	O
+importance	O
+.	O
+
+Aim	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+examine	O
+whether	O
+parental	O
+consanguinity	O
+affects	O
+the	O
+risk	O
+of	O
+cancer	O
+in	O
+a	O
+local	O
+Arab	O
+highly	O
+inbred	O
+population	O
+.	O
+
+Design	O
+Matched	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+Setting	O
+The	O
+study	O
+was	O
+carried	O
+out	O
+in	O
+Al	O
+-	O
+Amal	O
+cancer	O
+hospital	O
+and	O
+primary	O
+health	O
+care	O
+centers	O
+in	O
+Qatar	B-LOC
+over	O
+a	O
+period	O
+from	O
+August	O
+2008	O
+to	O
+February	O
+2009	O
+.	O
+
+Subjects	O
+and	O
+methods	O
+The	O
+study	O
+included	O
+370	O
+Qataris	O
+and	O
+other	O
+Arab	O
+expatriates	O
+with	O
+various	O
+types	O
+of	O
+cancers	O
+and	O
+635	O
+controls	O
+matched	O
+by	O
+age	O
+and	O
+ethnicity	O
+.	O
+
+A	O
+questionnaire	O
+that	O
+included	O
+socio	O
+-	O
+demographic	O
+information	O
+,	O
+type	O
+of	O
+consanguinity	O
+,	O
+medical	O
+history	O
+,	O
+and	O
+tumor	O
+grade	O
+was	O
+designed	O
+to	O
+collect	O
+the	O
+information	O
+of	O
+cases	O
+and	O
+controls	O
+.	O
+
+Results	O
+The	O
+study	O
+revealed	O
+that	O
+the	O
+rate	O
+of	O
+parental	O
+consanguinity	O
+was	O
+similar	O
+in	O
+both	O
+cases	O
+(	O
+29.5	O
+%	O
+)	O
+and	O
+controls	O
+(	O
+29.9	O
+%	O
+)	O
+with	O
+a	O
+higher	O
+inbreeding	O
+coefficient	O
+in	O
+controls	O
+(	O
+0.017-/+0.03	B-STAT
+)	O
+,	O
+compared	O
+to	O
+cancer	O
+patients	O
+(	O
+0.0155-/+0.03	B-STAT
+)	O
+.	O
+
+Other	O
+Arab	O
+expatriates	O
+had	O
+a	O
+higher	O
+incidence	B-EPI
+of	O
+cancer	O
+(	O
+61.1	O
+%	O
+)	O
+than	O
+Qataris	O
+(	O
+38.9	O
+%	O
+)	O
+.	O
+
+The	O
+inbreeding	O
+coefficient	O
+was	O
+higher	O
+in	O
+male	O
+cancer	O
+patients	O
+(	O
+0.0189-/+0.03	B-STAT
+)	O
+,	O
+but	O
+lower	O
+in	O
+female	O
+cancer	O
+patients	O
+(	O
+0.014-/+0.03	B-STAT
+)	O
+as	O
+compared	O
+to	O
+controls	O
+.	O
+
+Controls	O
+were	O
+more	O
+inbred	O
+in	O
+the	O
+overall	O
+studied	O
+subjects	O
+(	O
+23.6	O
+%	O
+)	O
+and	O
+women	O
+(	O
+23.8	O
+%	O
+)	O
+than	O
+cases	O
+.	O
+
+The	O
+coefficient	O
+of	O
+inbreeding	O
+was	O
+lower	O
+in	O
+patients	O
+with	O
+breast	O
+(	O
+0.014	O
+)	O
+,	O
+skin	O
+(	O
+0.012	O
+)	O
+,	O
+thyroid	O
+(	O
+0.008	O
+)	O
+and	O
+female	O
+genital	O
+(	O
+0.014	O
+)	O
+cancers	O
+,	O
+whereas	O
+it	O
+was	O
+higher	O
+in	O
+cases	O
+for	O
+leukemia	O
+and	O
+lymphoma	O
+(	O
+0.018	O
+)	O
+,	O
+colorectal	O
+(	O
+0.025	O
+)	O
+and	O
+prostate	O
+(	O
+0.017	O
+)	O
+,	O
+with	O
+no	O
+significant	O
+difference	O
+between	O
+cases	O
+and	O
+controls	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+observed	O
+between	O
+cases	O
+and	O
+controls	O
+in	O
+the	O
+parental	O
+consanguinity	O
+,	O
+mean	O
+coefficient	O
+of	O
+inbreeding	O
+and	O
+proportion	O
+of	O
+more	O
+inbred	O
+subjects	O
+.	O
+
+Conclusions	O
+The	O
+study	O
+findings	O
+revealed	O
+that	O
+although	O
+the	O
+consanguinity	O
+rate	O
+is	O
+high	O
+in	O
+our	O
+Arab	O
+population	O
+,	O
+it	O
+has	O
+no	O
+effect	O
+on	O
+the	O
+incidence	B-EPI
+of	O
+cancers	O
+overall	O
+.	O
+
+However	O
+,	O
+there	O
+was	O
+an	O
+increased	O
+risk	O
+found	O
+for	O
+leukemia	O
+and	O
+lymphoma	O
+,	O
+colorectal	O
+and	O
+prostate	O
+cancer	O
+groups	O
+,	O
+but	O
+a	O
+reduced	O
+risk	O
+in	O
+breast	O
+,	O
+skin	O
+,	O
+thyroid	O
+and	O
+female	O
+genital	O
+cancer	O
+groups	O
+.	O
+
+Anaphylaxis	O
+is	O
+a	O
+severe	O
+allergic	O
+reaction	O
+,	O
+rapid	O
+in	O
+onset	O
+,	O
+and	O
+can	O
+lead	O
+to	O
+fatal	O
+consequences	O
+if	O
+not	O
+promptly	O
+treated	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+anaphylaxis	O
+has	O
+risen	O
+at	O
+an	O
+alarming	O
+rate	O
+in	O
+past	O
+decades	O
+and	O
+continues	O
+to	O
+rise	O
+.	O
+
+Therefore	O
+,	O
+there	O
+is	O
+a	O
+general	O
+interest	O
+in	O
+understanding	O
+the	O
+molecular	O
+mechanism	O
+that	O
+leads	O
+to	O
+an	O
+exacerbated	O
+response	O
+.	O
+
+The	O
+main	O
+effector	O
+cells	O
+are	O
+mast	O
+cells	O
+,	O
+commonly	O
+triggered	O
+by	O
+stimuli	O
+that	O
+involve	O
+the	O
+IgE	O
+-	O
+dependent	O
+or	O
+IgE	O
+-	O
+independent	O
+pathway	O
+.	O
+
+These	O
+signaling	O
+pathways	O
+converge	O
+in	O
+the	O
+release	O
+of	O
+proinflammatory	O
+mediators	O
+,	O
+such	O
+as	O
+histamine	O
+,	O
+tryptases	O
+,	O
+prostaglandins	O
+,	O
+etc	O
+.	O
+,	O
+in	O
+minutes	O
+.	O
+
+The	O
+action	O
+and	O
+cell	O
+targets	O
+of	O
+these	O
+proinflammatory	O
+mediators	O
+are	O
+linked	O
+to	O
+the	O
+pathophysiologic	O
+consequences	O
+observed	O
+in	O
+this	O
+severe	O
+allergic	O
+reaction	O
+.	O
+
+While	O
+many	O
+molecules	O
+are	O
+involved	O
+in	O
+cellular	O
+regulation	O
+,	O
+the	O
+expression	O
+and	O
+regulation	O
+of	O
+transcription	O
+factors	O
+involved	O
+in	O
+the	O
+synthesis	O
+of	O
+proinflammatory	O
+mediators	O
+and	O
+secretory	O
+granule	O
+homeostasis	O
+are	O
+of	O
+special	O
+interest	O
+,	O
+due	O
+to	O
+their	O
+ability	O
+to	O
+control	O
+gene	O
+expression	O
+and	O
+change	O
+phenotype	O
+,	O
+and	O
+they	O
+may	O
+be	O
+key	O
+in	O
+the	O
+severity	O
+of	O
+the	O
+entire	O
+reaction	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+will	O
+describe	O
+our	O
+current	O
+understanding	O
+of	O
+the	O
+pathophysiology	O
+of	O
+human	O
+anaphylaxis	O
+,	O
+focusing	O
+on	O
+the	O
+transcription	O
+factors	O
+'	O
+contributions	O
+to	O
+this	O
+systemic	O
+hypersensitivity	O
+reaction	O
+.	O
+
+Host	O
+mutation	O
+in	O
+transcription	O
+factor	O
+expression	O
+,	O
+or	O
+deregulation	O
+of	O
+their	O
+activity	O
+in	O
+an	O
+anaphylaxis	O
+context	O
+,	O
+will	O
+be	O
+updated	O
+.	O
+
+So	O
+far	O
+,	O
+the	O
+risk	O
+of	O
+anaphylaxis	O
+is	O
+unpredictable	O
+thus	O
+,	O
+increasing	O
+our	O
+knowledge	O
+of	O
+the	O
+molecular	O
+mechanism	O
+that	O
+leads	O
+and	O
+regulates	O
+mast	O
+cell	O
+activity	O
+will	O
+enable	O
+us	O
+to	O
+improve	O
+our	O
+understanding	O
+of	O
+how	O
+anaphylaxis	O
+can	O
+be	O
+prevented	O
+or	O
+treated	O
+.	O
+
+Background	O
+Childhood	O
+alopecia	O
+areata	O
+(	O
+AA	O
+)	O
+is	O
+a	O
+common	O
+cause	O
+of	O
+dermatologic	O
+consultation	O
+;	O
+however	O
+,	O
+data	O
+is	O
+scarce	O
+in	O
+the	O
+present	O
+set	O
+-	O
+up	O
+.	O
+
+Objectives	O
+To	O
+evaluate	O
+the	O
+clinico	O
+-	O
+epidemiological	O
+profile	O
+of	O
+childhood	O
+AA	O
+along	O
+with	O
+dermoscopic	O
+correlation	O
+.	O
+
+Methods	O
+We	O
+conducted	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+including	O
+50	O
+new	O
+cases	O
+of	O
+childhood	O
+AA	O
+for	O
+1	O
+year	O
+.	O
+
+Dermoscopy	O
+was	O
+performed	O
+in	O
+each	O
+child	O
+and	O
+findings	O
+recorded	O
+.	O
+
+Results	O
+Childhood	O
+AA	O
+was	O
+more	O
+common	O
+in	O
+girls	O
+(	O
+M	O
+:	O
+F	O
+1:1.4	O
+)	O
+,	O
+mean	O
+age	O
+being	O
+11.1	O
+±	O
+3.7	O
+years	O
+.	O
+
+Scalp	O
+was	O
+commonest	O
+site	O
+of	O
+involvement	O
+in	O
+86	O
+%	O
+cases	O
+,	O
+while	O
+32	B-STAT
+(	O
+64	O
+%	O
+)	O
+children	O
+had	O
+mild	O
+disease	O
+(	O
+<	O
+25	O
+%	O
+involvement	O
+)	O
+.	O
+
+Localized	O
+circumscribed	O
+patch	O
+was	O
+the	O
+commonest	O
+presentation	O
+in	O
+37	B-STAT
+(	O
+74	O
+%	O
+)	O
+children	O
+,	O
+while	O
+sisaipho	O
+was	O
+the	O
+least	O
+(	O
+2	O
+%	O
+)	O
+.	O
+
+A	O
+positive	O
+family	O
+history	O
+of	O
+AA	O
+was	O
+noted	O
+in	O
+5	B-STAT
+(	O
+10	O
+%	O
+)	O
+children	O
+.	O
+
+Twenty	O
+-	O
+four	O
+children	O
+(	O
+48	O
+%	O
+)	O
+provided	O
+a	O
+history	O
+of	O
+atopic	O
+disorders	O
+,	O
+while	O
+30	O
+%	O
+had	O
+a	O
+positive	O
+family	O
+history	O
+of	O
+atopy	O
+.	O
+
+Stress	O
+was	O
+the	O
+commonest	O
+precipitating	O
+factor	O
+in	O
+13	B-STAT
+(	O
+26	O
+%	O
+)	O
+subjects	O
+.	O
+
+Nail	O
+involvement	O
+was	O
+observed	O
+in	O
+19	B-STAT
+(	O
+38	O
+%	O
+)	O
+children	O
+(	O
+pitting	O
+>	O
+thinning	O
+)	O
+,	O
+while	O
+systemic	O
+associations	O
+like	O
+vitiligo	O
+and	O
+thyroid	O
+dysfunction	O
+were	O
+present	O
+in	O
+26	O
+%	O
+and	O
+24	O
+%	O
+cases	O
+,	O
+respectively	O
+.	O
+
+Dermoscopy	O
+revealed	O
+yellow	O
+-	O
+dots	O
+to	O
+be	O
+the	O
+commonest	O
+finding	O
+in	O
+44	B-STAT
+(	O
+88	O
+%	O
+)	O
+cases	O
+,	O
+followed	O
+by	O
+short	O
+vellus	O
+hair	O
+and	O
+black	O
+dots	O
+in	O
+76	O
+%	O
+and	O
+28	O
+%	O
+children	O
+,	O
+respectively	O
+,	O
+while	O
+exclamation	O
+-	O
+mark	O
+hair	O
+was	O
+rare	O
+.	O
+
+Conclusion	O
+Female	O
+gender	O
+,	O
+younger	O
+age	O
+,	O
+nail	O
+involvement	O
+,	O
+and	O
+presence	O
+of	O
+concomitant	O
+atopy	O
+,	O
+vitiligo	O
+,	O
+and	O
+thyroid	O
+dysfunction	O
+were	O
+associated	O
+with	O
+severe	O
+disease	O
+,	O
+but	O
+not	O
+statistically	O
+significant	O
+(	O
+p	O
+>	O
+0.05	O
+)	O
+.	O
+
+Regression	O
+model	O
+failed	O
+to	O
+detect	O
+any	O
+risk	O
+factors	O
+for	O
+severe	O
+AA	O
+.	O
+
+Dermoscopy	O
+is	O
+an	O
+important	O
+non	O
+-	O
+invasive	O
+tool	O
+for	O
+evaluating	O
+childhood	O
+AA	O
+.	O
+
+Friedreich	O
+ataxia	O
+(	O
+FA	O
+)	O
+represents	O
+the	O
+most	O
+frequent	O
+type	O
+of	O
+inherited	O
+ataxia	O
+.	O
+
+Most	O
+patients	O
+carry	O
+homozygous	O
+GAA	O
+expansions	O
+in	O
+the	O
+first	O
+intron	O
+of	O
+the	O
+frataxin	O
+gene	O
+on	O
+chromosome	O
+9	O
+.	O
+
+Due	O
+to	O
+epigenetic	O
+alterations	O
+,	O
+frataxin	O
+expression	O
+is	O
+significantly	O
+reduced	O
+.	O
+
+Frataxin	O
+is	O
+a	O
+mitochondrial	O
+protein	O
+.	O
+
+Its	O
+deficiency	O
+leads	O
+to	O
+mitochondrial	O
+iron	O
+overload	O
+,	O
+defective	O
+energy	O
+supply	O
+and	O
+generation	O
+of	O
+reactive	O
+oxygen	O
+species	O
+.	O
+
+This	O
+review	O
+gives	O
+an	O
+overview	O
+over	O
+clinical	O
+and	O
+genetic	O
+aspects	O
+of	O
+FA	O
+and	O
+discusses	O
+current	O
+concepts	O
+of	O
+frataxin	O
+biogenesis	O
+and	O
+function	O
+as	O
+well	O
+as	O
+new	O
+therapeutic	O
+strategies	O
+.	O
+
+Diastrophic	O
+dysplasia	O
+(	O
+DTD	O
+)	O
+is	O
+a	O
+rare	O
+osteochondrodysplasia	O
+characterized	O
+by	O
+short	O
+-	O
+limbed	O
+short	O
+stature	O
+and	O
+joint	O
+dysplasia	O
+.	O
+
+DTD	O
+is	O
+caused	O
+by	O
+mutations	O
+in	O
+SLC26A2	O
+and	O
+is	O
+particularly	O
+common	O
+in	O
+the	O
+Finnish	O
+population	O
+.	O
+
+However	O
+,	O
+the	O
+disease	O
+incidence	B-EPI
+in	O
+Finland	B-LOC
+and	O
+clinical	O
+features	O
+in	O
+affected	O
+individuals	O
+have	O
+not	O
+been	O
+recently	O
+explored	O
+.	O
+
+This	O
+registry	O
+-	O
+based	O
+study	O
+aimed	O
+to	O
+investigate	O
+the	O
+current	O
+incidence	B-EPI
+of	O
+DTD	O
+in	O
+Finland	B-LOC
+,	O
+characterize	O
+the	O
+national	O
+cohort	O
+of	O
+pediatric	O
+subjects	O
+with	O
+DTD	O
+and	O
+review	O
+the	O
+disease	O
+-	O
+related	O
+literature	O
+.	O
+
+Subjects	O
+with	O
+SLC26A2	O
+-related	O
+skeletal	O
+dysplasia	O
+,	O
+born	O
+between	O
+2000	O
+and	O
+2020	O
+,	O
+were	O
+identified	O
+from	O
+the	O
+Skeletal	O
+dysplasia	O
+registry	O
+and	O
+from	O
+hospital	O
+patient	O
+registry	O
+and	O
+their	O
+clinical	O
+and	O
+molecular	O
+data	O
+were	O
+reviewed	O
+.	O
+
+Fourteen	O
+subjects	O
+were	O
+identified	O
+.	O
+
+Twelve	O
+of	O
+them	O
+were	O
+phenotypically	O
+classified	O
+as	O
+DTD	O
+and	O
+two	O
+,	O
+as	O
+recessive	O
+multiple	O
+epiphyseal	O
+dysplasia	O
+(	O
+rMED	O
+)	O
+.	O
+
+From	O
+the	O
+subjects	O
+with	O
+available	O
+genetic	O
+data	O
+,	O
+75	O
+%	O
+(	O
+9/12	O
+)	O
+were	O
+homozygous	O
+for	O
+the	O
+Finnish	O
+founder	O
+mutation	O
+c.-26	O
++	O
+2T	O
+>	O
+C.	O
+
+Two	O
+subjects	O
+with	O
+rMED	O
+phenotype	O
+were	O
+compound	O
+heterozygous	O
+for	O
+p.	O
+Arg279Trp	O
+and	O
+p.	O
+Thr512Lys	O
+variants	O
+.	O
+
+The	O
+variable	O
+phenotypes	O
+in	O
+our	O
+cohort	O
+highlight	O
+the	O
+wide	O
+spectrum	O
+of	O
+clinical	O
+features	O
+,	O
+ranging	O
+from	O
+a	O
+very	O
+severe	O
+form	O
+of	O
+DTD	O
+to	O
+milder	O
+forms	O
+of	O
+DTD	O
+and	O
+rMED	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+DTD	O
+in	O
+Finland	B-LOC
+has	O
+significantly	O
+decreased	O
+over	O
+the	O
+past	O
+decades	O
+,	O
+most	O
+likely	O
+due	O
+to	O
+increased	O
+prenatal	O
+diagnostics	O
+.	O
+
+The	O
+relationship	O
+between	O
+autoinflammatory	O
+and	O
+autoimmune	O
+conditions	O
+has	O
+been	O
+demonstrated	O
+in	O
+recent	O
+decades	O
+.	O
+
+Several	O
+autoimmune	O
+conditions	O
+exhibit	O
+an	O
+autoinflammatory	O
+component	O
+,	O
+which	O
+can	O
+manifest	O
+in	O
+various	O
+ways	O
+.	O
+
+Neutrophilic	O
+dermatosis	O
+in	O
+the	O
+context	O
+of	O
+lupus	O
+erythematosus	O
+(	O
+LE	O
+)	O
+is	O
+one	O
+example	O
+.	O
+
+Otherwise	O
+,	O
+neutrophils	O
+are	O
+rare	O
+in	O
+LE	O
+,	O
+except	O
+for	O
+the	O
+bullous	O
+variant	O
+and	O
+nonbullous	O
+neutrophilic	O
+LE	O
+.	O
+
+In	O
+this	O
+paper	O
+,	O
+we	O
+describe	O
+a	O
+case	O
+of	O
+scarring	O
+alopecia	O
+due	O
+to	O
+LE	O
+that	O
+stopped	O
+responding	O
+to	O
+a	O
+treatment	O
+that	O
+had	O
+been	O
+effective	O
+for	O
+years	O
+.	O
+
+The	O
+biopsy	O
+specimen	O
+demonstrated	O
+the	O
+presence	O
+of	O
+neutrophils	O
+in	O
+the	O
+inflammatory	O
+infiltrate	O
+.	O
+
+A	O
+treatment	O
+with	O
+dapsone	O
+was	O
+prescribed	O
+and	O
+yielded	O
+rapid	O
+improvement	O
+.	O
+
+This	O
+first	O
+case	O
+of	O
+scarring	O
+alopecia	O
+in	O
+the	O
+context	O
+of	O
+nonbullous	O
+neutrophilic	O
+LE	O
+emphasizes	O
+the	O
+importance	O
+of	O
+the	O
+infiltrate	O
+in	O
+determining	O
+the	O
+optimal	O
+therapeutic	O
+choice	O
+.	O
+
+Aims	O
+Medullary	O
+carcinoma	O
+is	O
+an	O
+uncommon	O
+colorectal	O
+tumour	O
+which	O
+appears	O
+poorly	O
+differentiated	O
+histologically	O
+.	O
+
+Consequently	O
+,	O
+it	O
+may	O
+be	O
+confused	O
+with	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+not	O
+otherwise	O
+specified	O
+(	O
+NOS	O
+)	O
+.	O
+
+The	O
+principal	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+review	O
+a	O
+large	O
+series	O
+of	O
+poorly	O
+differentiated	O
+colorectal	O
+cancers	O
+resected	O
+at	O
+a	O
+large	O
+National	O
+Health	O
+Service	O
+(	O
+NHS	O
+)	O
+Teaching	O
+Hospital	O
+to	O
+determine	O
+how	O
+often	O
+medullary	O
+carcinomas	O
+were	O
+misclassified	O
+.	O
+
+Secondary	O
+aims	O
+were	O
+to	O
+investigate	O
+how	O
+often	O
+neuroendocrine	O
+differentiation	O
+or	O
+metastatic	O
+tumours	O
+were	O
+considered	O
+in	O
+the	O
+differential	O
+diagnosis	O
+,	O
+and	O
+compare	O
+clinico	O
+-	O
+pathological	O
+features	O
+between	O
+medullary	O
+and	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+NOS	O
+.	O
+
+Methods	O
+and	O
+results	O
+Histology	O
+slides	O
+from	O
+302	O
+colorectal	O
+cancer	O
+resections	O
+originally	O
+reported	O
+as	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+were	O
+reviewed	O
+and	O
+cases	O
+fulfilling	O
+World	O
+Health	O
+Organisation	O
+(	O
+WHO	O
+)	O
+criteria	O
+for	O
+medullary	O
+carcinoma	O
+identified	O
+.	O
+
+The	O
+original	O
+pathology	O
+report	O
+was	O
+examined	O
+for	O
+any	O
+mention	O
+of	O
+medullary	O
+phenotype	O
+,	O
+consideration	O
+of	O
+neuroendocrine	O
+differentiation	O
+or	O
+consideration	O
+of	O
+metastasis	O
+from	O
+another	O
+site	O
+.	O
+
+Clinico	O
+-	O
+pathological	O
+features	O
+were	O
+compared	O
+to	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+NOS	O
+.	O
+
+Only	O
+one	O
+-	O
+third	O
+of	O
+medullary	O
+carcinomas	O
+were	O
+correctly	O
+identified	O
+between	O
+1997	O
+and	O
+2018	O
+.	O
+
+The	O
+other	O
+two	O
+-	O
+thirds	O
+were	O
+reported	O
+as	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+NOS	O
+.	O
+
+The	O
+possibility	O
+of	O
+an	O
+extracolonic	O
+origin	O
+or	O
+neuroendocrine	O
+carcinoma	O
+was	O
+considered	O
+in	O
+21	B-STAT
+and	O
+27	O
+%	O
+of	O
+reports	O
+.	O
+
+Most	O
+medullary	O
+carcinomas	O
+exhibited	O
+mismatch	O
+repair	O
+deficiency	O
+,	O
+were	O
+located	O
+in	O
+ascending	O
+colon	O
+and	O
+caecum	O
+and	O
+had	O
+a	O
+lower	O
+rate	O
+of	O
+vascular	O
+channel	O
+invasion	O
+and	O
+lymph	O
+node	O
+metastasis	O
+compared	O
+to	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+.	O
+
+Conclusions	O
+Medullary	O
+carcinoma	O
+of	O
+the	O
+colon	O
+is	O
+often	O
+mistaken	O
+for	O
+poorly	O
+differentiated	O
+adenocarcinoma	O
+NOS	O
+and	O
+occasionally	O
+for	O
+neuroendocrine	O
+or	O
+metastatic	O
+carcinoma	O
+.	O
+
+Greater	O
+familiarity	O
+with	O
+morphological	O
+criteria	O
+and	O
+use	O
+of	O
+mismatch	O
+repair	O
+protein	O
+staining	O
+should	O
+improve	O
+diagnosis	O
+.	O
+
+Sweden	B-LOC
+has	O
+one	O
+neonatal	O
+screening	O
+laboratory	O
+,	O
+receiving	O
+115	O
+to	O
+120	O
+thousand	B-STAT
+samples	I-STAT
+per	I-STAT
+year	I-STAT
+.	O
+
+Among	O
+the	O
+one	O
+million	O
+babies	O
+screened	O
+by	O
+tandem	O
+mass	O
+spectrometry	O
+from	O
+November	O
+2010	O
+until	O
+July	O
+2019	O
+,	O
+a	O
+total	O
+of	O
+665	O
+babies	O
+were	O
+recalled	O
+and	O
+311	O
+verified	O
+as	O
+having	O
+one	O
+of	O
+the	O
+diseases	O
+screened	O
+for	O
+with	O
+this	O
+methodology	O
+,	O
+giving	O
+a	O
+positive	O
+predictive	O
+value	O
+(	O
+PPV	O
+)	O
+of	O
+47	O
+%	O
+and	O
+an	O
+incidence	B-EPI
+of	O
+1:3200	O
+.	O
+
+The	O
+PPV	O
+was	O
+high	O
+(	O
+41	O
+%	O
+)	O
+already	O
+in	O
+the	O
+first	O
+year	O
+after	O
+start	O
+of	O
+screening	O
+,	O
+thanks	O
+to	O
+the	O
+availability	O
+of	O
+the	O
+collaborative	O
+project	O
+Region	O
+4	O
+Stork	O
+database	O
+.	O
+
+The	O
+PPV	O
+is	O
+presently	O
+58	B-STAT
+%	I-STAT
+.	O
+
+This	O
+improvement	O
+was	O
+achieved	O
+by	O
+the	O
+implementation	O
+of	O
+second	O
+-	O
+tier	O
+analyses	O
+in	O
+the	O
+screening	O
+for	O
+methylmalonic	O
+aciduria	O
+,	O
+propionic	O
+aciduria	O
+,	O
+isovaleric	O
+aciduria	O
+,	O
+and	O
+homocystinuria	O
+,	O
+and	O
+the	O
+employment	O
+of	O
+various	O
+post	O
+analytical	O
+tools	O
+of	O
+the	O
+Region	O
+4	O
+Stork	O
+,	O
+and	O
+its	O
+successor	O
+the	O
+collaborative	O
+laboratory	O
+integrated	O
+reports	O
+.	O
+
+Aims	O
+To	O
+review	O
+and	O
+present	O
+the	O
+current	O
+knowledge	O
+of	O
+incidence	B-EPI
+,	O
+signs	O
+and	O
+symptoms	O
+,	O
+diagnosis	O
+and	O
+treatment	O
+of	O
+the	O
+occipital	O
+encephalocele	O
+.	O
+
+Background	O
+Encephalocele	O
+(	O
+E	O
+)	O
+is	O
+a	O
+defect	O
+of	O
+the	O
+neural	O
+tube	O
+that	O
+refers	O
+to	O
+congenital	O
+malformations	O
+featured	O
+by	O
+skull	O
+defect	O
+and	O
+dura	O
+with	O
+extracranial	O
+spread	O
+of	O
+intracranial	O
+structures	O
+.	O
+
+Occipital	O
+encephalocele	O
+(	O
+OE	O
+)	O
+are	O
+the	O
+most	O
+common	O
+form	O
+of	O
+this	O
+congenital	O
+disorder	O
+and	O
+are	O
+manifested	O
+as	O
+a	O
+swelling	O
+of	O
+different	O
+sizes	O
+over	O
+the	O
+occipital	O
+bone	O
+in	O
+the	O
+midline	O
+.	O
+
+Proper	O
+diagnosis	O
+and	O
+treatment	O
+is	O
+highly	O
+important	O
+in	O
+the	O
+management	O
+of	O
+this	O
+congenital	O
+malformation	O
+of	O
+brain	O
+.	O
+
+Objective	O
+To	O
+review	O
+and	O
+present	O
+the	O
+current	O
+knowledge	O
+of	O
+incidence	B-EPI
+,	O
+signs	O
+and	O
+symptoms	O
+,	O
+diagnosis	O
+and	O
+treatment	O
+of	O
+the	O
+occipital	O
+encephalocele	O
+.	O
+
+Methods	O
+We	O
+conducted	O
+a	O
+search	O
+of	O
+case	O
+reports	O
+or	O
+case	O
+-	O
+series	O
+of	O
+patients	O
+by	O
+the	O
+use	O
+of	O
+electronic	O
+databases	O
+:	O
+Pub	O
+Med	O
+,	O
+Medline	O
+,	O
+Index	O
+Medicus	O
+,	O
+Scorpus	B-LOC
+.	O
+
+The	O
+key	O
+words	O
+were	O
+:	O
+encephalocele	O
+,	O
+occipital	O
+encephalocele	O
+,	O
+neural	O
+tube	O
+defect	O
+,	O
+congenital	O
+malformation	O
+.	O
+
+The	O
+search	O
+was	O
+updated	O
+to	O
+December	O
+31	O
+,	O
+2018	O
+.	O
+
+Papers	O
+published	O
+in	O
+English	O
+were	O
+the	O
+only	O
+source	O
+of	O
+information	O
+.	O
+
+Results	O
+Occipital	O
+encephalocelle	O
+are	O
+more	O
+frequent	O
+in	O
+females	O
+than	O
+in	O
+males	O
+.	O
+
+The	O
+incidence	B-EPI
+is	O
+between	O
+1	B-STAT
+in	I-STAT
+3000	I-STAT
+to	O
+1	O
+in	O
+10,000	O
+live	O
+births	O
+;	O
+approximately	O
+90	O
+%	O
+of	O
+them	O
+involve	O
+the	O
+midline	O
+.	O
+
+Magnetic	O
+resonance	O
+imaging	O
+is	O
+the	O
+method	O
+of	O
+choice	O
+in	O
+diagnosis	O
+and	O
+surgery	O
+is	O
+the	O
+best	O
+option	O
+for	O
+the	O
+treatment	O
+of	O
+OE	O
+.	O
+
+Overall	O
+morbidity	O
+and	O
+mortality	O
+is	O
+still	O
+high	O
+in	O
+spite	O
+of	O
+advenced	O
+surgical	O
+management	O
+,	O
+but	O
+have	O
+been	O
+significantly	O
+improved	O
+in	O
+recent	O
+years	O
+thanks	O
+to	O
+sophisticated	O
+highresolution	O
+imaging	O
+,	O
+adequate	O
+and	O
+proper	O
+surgical	O
+treatment	O
+and	O
+decent	O
+post	O
+-	O
+operative	O
+care	O
+.	O
+
+Conclusion	O
+Occipital	O
+encephalocele	O
+is	O
+the	O
+most	O
+common	O
+form	O
+of	O
+encephalocele	O
+.	O
+
+The	O
+diagnosis	O
+is	O
+mostly	O
+based	O
+by	O
+the	O
+use	O
+of	O
+neuroimaging	O
+techniques	O
+.	O
+
+Operation	O
+is	O
+the	O
+best	O
+option	O
+for	O
+treatment	O
+.	O
+
+Overall	O
+morbidity	O
+and	O
+mortality	O
+is	O
+still	O
+high	O
+,	O
+but	O
+have	O
+been	O
+significantly	O
+improved	O
+in	O
+recent	O
+years	O
+thanks	O
+to	O
+sophisticated	O
+high	O
+-	O
+resolution	O
+imaging	O
+,	O
+adequate	O
+and	O
+proper	O
+surgical	O
+treatment	O
+and	O
+decent	O
+post	O
+-	O
+operative	O
+care	O
+.	O
+
+This	O
+article	O
+reports	O
+the	O
+intent	O
+to	O
+receive	O
+a	O
+SARS	O
+-	O
+COV-2	O
+vaccine	O
+,	O
+its	O
+predictors	O
+and	O
+willingness	O
+to	O
+pay	O
+in	O
+Bangladesh	B-LOC
+.	O
+
+We	O
+carried	O
+out	O
+an	O
+online	O
+cross	O
+-	O
+sectional	O
+survey	O
+of	O
+697	O
+adults	O
+from	O
+the	O
+general	O
+population	O
+of	O
+Bangladesh	B-LOC
+in	O
+January	O
+2021	O
+.	O
+
+A	O
+structured	O
+questionnaire	O
+was	O
+used	O
+to	O
+assess	O
+vaccination	O
+intent	O
+.	O
+
+The	O
+questionnaire	O
+included	O
+sociodemographic	O
+variables	O
+and	O
+health	O
+belief	O
+model	O
+constructs	O
+which	O
+may	O
+predict	O
+vaccination	O
+intent	O
+.	O
+
+Among	O
+the	O
+participants	O
+,	O
+26	O
+%	O
+demonstrated	O
+a	O
+definite	O
+intent	O
+,	O
+43	O
+%	O
+probable	O
+intent	O
+,	O
+24	O
+%	O
+probable	O
+negative	O
+,	O
+and	O
+7	O
+%	O
+a	O
+definite	O
+negative	O
+intention	O
+.	O
+
+Multivariable	O
+logistic	O
+regression	O
+analyses	O
+suggest	O
+an	O
+association	O
+between	O
+definite	O
+intent	O
+and	O
+previous	O
+COVID-19	O
+infection	O
+(	O
+OR	O
+:	O
+2.86	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.71	O
+-	O
+4.78	O
+)	O
+,	O
+perceiving	O
+COVID-19	O
+as	O
+serious	O
+(	O
+OR	O
+:	O
+1.93	O
+;	O
+1.04	O
+-	O
+3.59	O
+)	O
+,	O
+the	O
+belief	O
+that	O
+vaccination	O
+would	O
+make	O
+them	O
+feel	O
+less	O
+worried	O
+about	O
+catching	O
+COVID-19	O
+(	O
+OR	O
+:	O
+4.42	O
+;	O
+2.25	O
+-	O
+8.68	O
+)	O
+,	O
+and	O
+concerns	O
+about	O
+vaccine	O
+affordability	O
+(	O
+OR	O
+:	O
+1.51	O
+;	O
+1.01	O
+-	O
+2.25	O
+)	O
+.	O
+
+Individuals	O
+afraid	O
+of	O
+the	O
+side	O
+effects	O
+(	O
+OR	O
+:	O
+0.34	O
+;	O
+0.21	O
+-	O
+0.53	O
+)	O
+and	O
+those	O
+who	O
+would	O
+take	O
+the	O
+vaccine	O
+if	O
+the	O
+vaccine	O
+were	O
+taken	O
+by	O
+many	O
+others	O
+(	O
+OR	O
+:	O
+0.44	O
+;	O
+0.29	O
+-	O
+0.67	O
+)	O
+are	O
+less	O
+likely	O
+to	O
+have	O
+a	O
+definite	O
+intent	O
+.	O
+
+A	O
+definite	O
+negative	O
+intent	O
+is	O
+associated	O
+with	O
+the	O
+concern	O
+that	O
+the	O
+vaccine	O
+may	O
+not	O
+be	O
+halal	O
+(	O
+OR	O
+:	O
+2.03	O
+;	O
+1.04	O
+-	O
+3.96	O
+)	O
+.	O
+
+Furthermore	O
+,	O
+68.4	O
+%	O
+are	O
+willing	O
+to	O
+pay	O
+for	O
+the	O
+vaccine	O
+.	O
+
+The	O
+median	O
+amount	O
+that	O
+they	O
+are	O
+willing	O
+to	O
+pay	O
+is	O
+USD	O
+7.08	O
+.	O
+
+The	O
+study	O
+findings	O
+reveal	O
+that	O
+the	O
+definite	O
+intent	O
+to	O
+receive	O
+the	O
+SARS	O
+-	O
+CoV-2	O
+vaccination	O
+among	O
+the	O
+general	O
+population	O
+varies	O
+depending	O
+on	O
+their	O
+COVID-19	O
+-	O
+related	O
+health	O
+beliefs	O
+and	O
+no	O
+significant	O
+association	O
+was	O
+found	O
+with	O
+sociodemographic	O
+variables	O
+.	O
+
+Overlapping	O
+syndromes	O
+such	O
+as	O
+Noonan	O
+,	O
+Cardio	O
+-	O
+Facio	O
+-	O
+Cutaneous	O
+,	O
+Noonan	O
+syndrome	O
+(	O
+NS	O
+)	O
+with	O
+multiple	O
+lentigines	O
+and	O
+Costello	O
+syndromes	O
+are	O
+genetically	O
+heterogeneous	O
+conditions	O
+sharing	O
+a	O
+dysregulation	O
+of	O
+the	O
+RAS	O
+/	O
+mitogen	O
+-	O
+activated	O
+protein	O
+kinase	O
+(	O
+MAPK	O
+)	O
+pathway	O
+and	O
+are	O
+known	O
+collectively	O
+as	O
+the	O
+RASopathies	O
+.	O
+
+PTPN11	O
+was	O
+the	O
+first	O
+disease	O
+-	O
+causing	O
+gene	O
+identified	O
+in	O
+NS	O
+and	O
+remains	O
+the	O
+more	O
+prevalent	B-EPI
+.	O
+
+We	O
+report	O
+seven	O
+patients	O
+from	O
+three	O
+families	O
+presenting	O
+heterozygous	O
+missense	O
+variants	O
+in	O
+PTPN11	O
+probably	O
+responsible	O
+for	O
+a	O
+disease	O
+phenotype	O
+distinct	O
+from	O
+the	O
+classical	O
+Noonan	O
+syndrome	O
+.	O
+
+The	O
+clinical	O
+presentation	O
+and	O
+common	O
+features	O
+of	O
+these	O
+seven	O
+cases	O
+overlap	O
+with	O
+the	O
+SHORT	O
+syndrome	O
+.	O
+
+The	O
+latter	O
+is	O
+the	O
+consequence	O
+of	O
+PI3K	B-LOC
+/	O
+AKT	O
+signaling	O
+deregulation	O
+with	O
+the	O
+predominant	O
+disease	O
+-	O
+causing	O
+gene	O
+being	O
+PIK3R1	O
+.	O
+
+Our	O
+data	O
+suggest	O
+that	O
+the	O
+phenotypic	O
+spectrum	O
+associated	O
+with	O
+pathogenic	O
+variants	O
+of	O
+PTPN11	O
+could	O
+be	O
+wider	O
+than	O
+previously	O
+described	O
+,	O
+and	O
+this	O
+could	O
+be	O
+due	O
+to	O
+the	O
+dual	O
+activity	O
+of	O
+SHP2	O
+(	O
+ie	O
+,	O
+PTPN11	O
+gene	O
+product	O
+)	O
+on	O
+the	O
+RAS	O
+/	O
+MAPK	O
+and	O
+PI3K	B-LOC
+/	O
+AKT	O
+signaling	O
+.	O
+
+Background	O
+Consanguineous	O
+marriages	O
+are	O
+common	O
+in	O
+the	B-LOC
+Middle	I-LOC
+East	I-LOC
+including	O
+the	O
+Gulf	B-LOC
+countries	O
+.	O
+
+The	O
+rate	O
+of	O
+consanguinity	O
+in	O
+Qatar	B-LOC
+is	O
+approximately	O
+54	O
+%	O
+,	O
+which	O
+are	O
+mainly	O
+first	O
+cousins	O
+'	O
+marriages	O
+.	O
+
+Previous	O
+studies	O
+showed	O
+that	O
+consanguinity	O
+increases	O
+the	O
+prevalence	B-EPI
+of	O
+birth	O
+defects	O
+and	O
+other	O
+genetic	O
+disorders	O
+.	O
+
+Thus	O
+,	O
+we	O
+studied	O
+the	O
+effects	O
+of	O
+consanguinity	O
+in	O
+a	O
+cohort	O
+of	O
+subjects	O
+with	O
+certain	O
+genetic	O
+disorders	O
+in	O
+Qatar	B-LOC
+.	O
+
+Methods	O
+This	O
+cross	O
+-	O
+sectional	O
+study	O
+was	O
+conducted	O
+at	O
+two	O
+centers	O
+in	O
+Qatar	B-LOC
+(	O
+Hamad	O
+Medical	O
+Corporation	O
+	O
+HMC	O
+	O
+and	O
+Shafallah	O
+	O
+SC	O
+	O
+)	O
+including	O
+599	O
+Qatari	O
+families	O
+with	O
+certain	O
+types	O
+of	O
+genetic	O
+and	O
+nongenetic	O
+anomalies	O
+.	O
+
+Results	O
+Consanguineous	O
+marriages	O
+were	O
+seen	O
+in	O
+397	O
+of	O
+599	B-STAT
+(	O
+66.2	O
+%	O
+)	O
+Qatari	O
+families	O
+and	O
+first	O
+cousin	O
+group	O
+counts	O
+for	O
+65	O
+%	O
+in	O
+Qatari	O
+population	O
+.	O
+
+In	O
+the	O
+total	O
+cohort	O
+and	O
+at	O
+HMC	O
+,	O
+all	O
+consanguineous	O
+marriages	O
+had	O
+a	O
+significantly	O
+higher	O
+risk	O
+of	O
+Autosomal	O
+Recessive	O
+disorders	O
+than	O
+nonconsanguineous	O
+marriages	O
+(	O
+total	O
+cohort	O
+:	O
+odds	O
+ratio	O
+(	O
+OR	O
+)	O
+=	O
+1.72	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.10	O
+,	O
+2.71	O
+;	O
+p	O
+=	O
+.02	O
+;	O
+HMC	O
+:	O
+OR	O
+=	O
+2.98	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.37	O
+,	O
+6.09	O
+;	O
+p	O
+=	O
+.005	O
+)	O
+.	O
+
+On	O
+the	O
+other	O
+hand	O
+,	O
+at	O
+HMC	O
+,	O
+nonconsanguinity	O
+was	O
+significantly	O
+related	O
+to	O
+chromosomal	O
+abnormality	O
+(	O
+OR	O
+=	O
+6.36	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.13	O
+,	O
+35.85	O
+;	O
+p	O
+=	O
+.036	O
+)	O
+.	O
+
+Conclusion	O
+Our	O
+data	O
+suggest	O
+a	O
+significant	O
+role	O
+of	O
+parental	O
+consanguinity	O
+in	O
+increasing	O
+the	O
+prevalence	B-EPI
+of	O
+genetic	O
+disorders	O
+;	O
+mainly	O
+Autosomal	O
+Recessive	O
+disorders	O
+.	O
+
+Chromosomal	O
+abnormality	O
+disorders	O
+were	O
+significantly	O
+higher	O
+among	O
+nonconsanguineous	O
+marriages	O
+.	O
+
+These	O
+results	O
+help	O
+better	O
+inform	O
+policy	O
+makers	O
+on	O
+social	O
+,	O
+educational	O
+,	O
+and	O
+public	O
+health	O
+initiatives	O
+that	O
+might	O
+mitigate	O
+the	O
+impact	O
+of	O
+genetic	O
+disease	O
+in	O
+the	O
+Qatari	O
+society	O
+.	O
+
+Loss	O
+-	O
+of	O
+-	O
+function	O
+(	O
+LoF	O
+)	O
+mutations	O
+in	O
+KCNQ1	B-LOC
+,	O
+encoding	O
+the	O
+voltage	O
+-	O
+gated	O
+K	O
++	O
+channel	O
+K	O
+v	O
+7.1	O
+,	O
+lead	O
+to	O
+long	O
+QT	O
+syndrome	O
+1	O
+(	O
+LQT1	O
+)	O
+.	O
+
+LQT1	O
+patients	O
+also	O
+present	O
+with	O
+post	O
+-	O
+prandial	O
+hyperinsulinemia	O
+and	O
+hypoglycaemia	O
+.	O
+
+In	O
+contrast	O
+,	O
+KCNQ1	O
+polymorphisms	O
+are	O
+associated	O
+with	O
+diabetes	O
+,	O
+and	O
+LQTS	O
+patients	O
+have	O
+a	O
+higher	O
+prevalence	B-EPI
+of	O
+diabetes	O
+.	O
+
+We	O
+developed	O
+a	O
+mouse	O
+model	O
+with	O
+a	O
+LoF	O
+Kcnq1	O
+mutation	O
+using	O
+CRISPR	O
+-	O
+Cas9	O
+and	O
+hypothesized	O
+that	O
+this	O
+mouse	O
+model	O
+would	O
+display	O
+QT	O
+prolongation	O
+,	O
+increased	O
+glucose	O
+-	O
+stimulated	O
+insulin	O
+secretion	O
+and	O
+allow	O
+for	O
+interrogation	O
+of	O
+K	O
+v	O
+7.1	O
+function	O
+in	O
+islets	O
+.	O
+
+Mice	O
+were	O
+characterized	O
+by	O
+electrocardiography	O
+and	O
+oral	O
+glucose	O
+tolerance	O
+tests	O
+.	O
+
+Ex	O
+vivo	O
+,	O
+islet	O
+glucose	O
+-	O
+induced	O
+insulin	O
+release	O
+was	O
+measured	O
+,	O
+and	O
+beta	O
+-	O
+cell	O
+area	O
+quantified	O
+by	O
+immunohistochemistry	O
+.	O
+
+Homozygous	O
+mice	O
+had	O
+QT	O
+prolongation	O
+.	O
+
+Ex	O
+vivo	O
+,	O
+glucose	O
+-	O
+stimulated	O
+insulin	O
+release	O
+was	O
+increased	O
+in	O
+islets	O
+from	O
+homozygous	O
+mice	O
+at	O
+12	O
+-	O
+14	O
+weeks	O
+,	O
+while	O
+beta	O
+-	O
+cell	O
+area	O
+was	O
+reduced	O
+.	O
+
+Non	O
+-	O
+fasting	O
+blood	O
+glucose	O
+levels	O
+were	O
+decreased	O
+at	O
+this	O
+age	O
+.	O
+
+In	O
+follow	O
+-	O
+up	O
+studies	O
+8	O
+-	O
+10	O
+weeks	O
+later	O
+,	O
+beta	O
+-	O
+cell	O
+area	O
+was	O
+similar	O
+in	O
+all	O
+groups	O
+,	O
+while	O
+glucose	O
+-	O
+stimulated	O
+insulin	O
+secretion	O
+was	O
+now	O
+reduced	O
+in	O
+islets	O
+from	O
+hetero-	O
+and	O
+homozygous	O
+mice	O
+.	O
+
+Non	O
+-	O
+fasting	O
+blood	O
+glucose	O
+levels	O
+had	O
+normalized	O
+.	O
+
+These	O
+data	O
+suggest	O
+that	O
+K	O
+v	O
+7.1	O
+dysfunction	O
+is	O
+involved	O
+in	O
+a	O
+transition	O
+from	O
+hyper-	O
+to	O
+hyposecretion	O
+of	O
+insulin	O
+,	O
+potentially	O
+explaining	O
+the	O
+association	O
+with	O
+both	O
+hypoglycemia	O
+and	O
+hyperglycemia	O
+in	O
+LQT1	O
+patients	O
+.	O
+
+Girls	O
+with	O
+Fragile	O
+-	O
+X	O
+-	O
+Syndrome	O
+(	O
+FXS	O
+)	O
+present	O
+high	O
+levels	O
+of	O
+social	O
+anxiety	O
+,	O
+social	O
+avoidance	O
+,	O
+extreme	O
+shyness	O
+,	O
+tendency	O
+to	O
+social	O
+isolation	O
+,	O
+poor	O
+eye	O
+contact	O
+,	O
+learning	O
+difficulties	O
+,	O
+and	O
+depression	O
+.	O
+
+The	O
+aims	O
+of	O
+the	O
+present	O
+study	O
+,	O
+which	O
+is	O
+based	O
+on	O
+a	O
+group	O
+of	O
+young	O
+females	O
+with	O
+FXS	O
+are	O
+:	O
+1	O
+)	O
+to	O
+analyze	O
+the	O
+possible	O
+associations	O
+between	O
+emotion	O
+recognition	O
+,	O
+theory	O
+of	O
+mind	O
+,	O
+and	O
+social	O
+anxiety	O
+,	O
+and	O
+adaptive	O
+behavior	O
+,	O
+and	O
+emotional	O
+state	O
+;	O
+2	O
+)	O
+to	O
+study	O
+the	O
+relationship	O
+between	O
+intelligence	O
+quotient	O
+(	O
+IQ	O
+)	O
+and	O
+adaptive	O
+behavior	O
+;	O
+and	O
+3	O
+)	O
+to	O
+assess	O
+whether	O
+social	O
+anxiety	O
+is	O
+more	O
+prevalent	B-EPI
+in	O
+girls	O
+with	O
+FXS	O
+.	O
+
+The	O
+study	O
+has	O
+40	O
+female	O
+participants	O
+aged	O
+between	O
+7	O
+and	O
+16	O
+years	O
+(	O
+26	O
+positive	O
+full	O
+mutation	O
+FXS	O
+and	O
+14	O
+as	O
+a	O
+control	O
+group	O
+)	O
+.	O
+
+A	O
+neuropsychological	O
+assessment	O
+was	O
+conducted	O
+using	O
+the	O
+following	O
+tests	O
+:	O
+WISC	O
+-	O
+V	O
+,	O
+NEPSY	O
+-	O
+II	O
+,	O
+SENA	O
+,	O
+ADHD	O
+Rating	O
+Scale	O
+,	O
+BAS	O
+,	O
+and	O
+ABAS	O
+-	O
+II	O
+.	O
+
+In	O
+comparison	O
+with	O
+the	O
+control	O
+group	O
+,	O
+the	O
+group	O
+with	O
+FXS	O
+presented	O
+a	O
+greater	O
+association	O
+between	O
+IQ	O
+and	O
+self	O
+-	O
+direction	O
+ability	O
+,	O
+and	O
+between	O
+emotion	O
+recognition	O
+and	O
+leadership	O
+.	O
+
+The	O
+FXS	O
+group	O
+presented	O
+higher	O
+levels	O
+of	O
+social	O
+anxiety	O
+and	O
+shyness	O
+.	O
+
+In	O
+the	O
+group	O
+of	O
+girls	O
+with	O
+FXS	O
+,	O
+IQ	O
+may	O
+have	O
+prognostic	O
+value	O
+for	O
+both	O
+self	O
+-	O
+direction	O
+ability	O
+and	O
+social	O
+adaptation	O
+level	O
+.	O
+
+Purpose	O
+We	O
+observed	O
+four	O
+individuals	O
+in	O
+two	O
+unrelated	O
+but	O
+consanguineous	O
+families	O
+from	O
+Portugal	B-LOC
+and	O
+Brazil	B-LOC
+affected	O
+by	O
+early	O
+-	O
+onset	O
+retinal	O
+degeneration	O
+,	O
+sensorineural	O
+hearing	O
+loss	O
+,	O
+microcephaly	O
+,	O
+intellectual	O
+disability	O
+,	O
+and	O
+skeletal	O
+dysplasia	O
+with	O
+scoliosis	O
+and	O
+short	O
+stature	O
+.	O
+
+The	O
+phenotype	O
+precisely	O
+matched	O
+that	O
+of	O
+an	O
+individual	O
+of	O
+Azorean	O
+descent	O
+published	O
+in	O
+1986	O
+by	O
+Liberfarb	B-LOC
+and	O
+coworkers	O
+.	O
+
+Methods	O
+Patients	O
+underwent	O
+specialized	O
+clinical	O
+examinations	O
+(	O
+including	O
+ophthalmological	O
+,	O
+audiological	O
+,	O
+orthopedic	O
+,	O
+radiological	O
+,	O
+and	O
+developmental	O
+assessment	O
+)	O
+.	O
+
+Exome	O
+and	O
+targeted	O
+sequencing	O
+was	O
+performed	O
+on	O
+selected	O
+individuals	O
+.	O
+
+Minigene	O
+constructs	O
+were	O
+assessed	O
+by	O
+quantitative	O
+polymerase	O
+chain	O
+reaction	O
+(	O
+qPCR	O
+)	O
+and	O
+Sanger	O
+sequencing	O
+.	O
+
+Results	O
+Affected	O
+individuals	O
+shared	O
+a	O
+3.36	O
+-	O
+Mb	O
+region	O
+of	O
+autozygosity	O
+on	O
+chromosome	O
+22q12.2	O
+,	O
+including	O
+a	O
+10	O
+-	O
+bp	O
+deletion	O
+(	O
+NM_014338.3	O
+:	O
+c.904	O
+-	O
+12_904	O
+-	O
+3delCTATCACCAC	O
+)	O
+,	O
+immediately	O
+upstream	O
+of	O
+the	O
+last	O
+exon	O
+of	O
+the	O
+PISD	O
+(	O
+phosphatidylserine	O
+decarboxylase	O
+)	O
+gene	O
+.	O
+
+Sequencing	O
+of	O
+PISD	O
+from	O
+paraffin	O
+-	O
+embedded	O
+tissue	O
+from	O
+the	O
+1986	O
+case	O
+revealed	O
+the	O
+identical	O
+homozygous	O
+variant	O
+.	O
+
+In	O
+HEK293	B-LOC
+T	O
+cells	O
+,	O
+this	O
+variant	O
+led	O
+to	O
+aberrant	O
+splicing	O
+of	O
+PISD	O
+transcripts	O
+.	O
+
+Conclusion	O
+We	O
+have	O
+identified	O
+the	O
+genetic	O
+etiology	O
+of	O
+the	O
+Liberfarb	B-LOC
+syndrome	O
+,	O
+affecting	O
+brain	O
+,	O
+eye	O
+,	O
+ear	O
+,	O
+bone	O
+,	O
+and	O
+connective	O
+tissue	O
+.	O
+
+Our	O
+work	O
+documents	O
+the	O
+migration	O
+of	O
+a	O
+rare	O
+Portuguese	O
+founder	O
+variant	O
+to	O
+two	O
+continents	O
+and	O
+highlights	O
+the	O
+link	O
+between	O
+phospholipid	O
+metabolism	O
+and	O
+bone	O
+formation	O
+,	O
+sensory	O
+defects	O
+,	O
+and	O
+cerebral	O
+development	O
+,	O
+while	O
+raising	O
+the	O
+possibility	O
+of	O
+therapeutic	O
+phospholipid	O
+replacement	O
+.	O
+
+Hemimelia	O
+is	O
+a	O
+rare	O
+anomaly	O
+affecting	O
+the	O
+distal	O
+long	O
+bones	O
+of	O
+extremities	O
+,	O
+with	O
+an	O
+occurrence	B-EPI
+of	O
+1	B-STAT
+-	I-STAT
+20	I-STAT
+cases	I-STAT
+per	I-STAT
+million	I-STAT
+of	I-STAT
+live	I-STAT
+births	I-STAT
+depending	O
+on	O
+the	O
+affected	O
+bone	O
+.	O
+
+Hemimelia	B-LOC
+can	O
+be	O
+an	O
+isolated	O
+defect	O
+or	O
+be	O
+part	O
+of	O
+complex	O
+syndromes	O
+that	O
+affect	O
+extra	O
+skeletal	O
+structures	O
+.	O
+
+Prenatal	O
+detection	O
+by	O
+routine	O
+ultrasound	O
+imaging	O
+is	O
+difficult	O
+and	O
+yields	O
+low	O
+detection	O
+rates	O
+.	O
+
+The	O
+prenatal	O
+diagnosis	O
+of	O
+hemimelia	O
+should	O
+prompt	O
+a	O
+complete	O
+and	O
+detailed	O
+study	O
+of	O
+the	O
+fetal	O
+anatomy	O
+,	O
+since	O
+it	O
+can	O
+be	O
+associated	O
+with	O
+defects	O
+in	O
+other	O
+structures	O
+and	O
+systems	O
+,	O
+as	O
+the	O
+reported	O
+in	O
+this	O
+case	O
+.	O
+
+The	O
+prognosis	O
+depends	O
+upon	O
+the	O
+associated	O
+anomalies	O
+.	O
+
+Objective	O
+To	O
+evaluate	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+radiofrequency	O
+ablation	O
+(	O
+RFA	O
+)	O
+for	O
+metastatic	O
+lymph	O
+nodes	O
+(	O
+LNs	O
+)	O
+in	O
+children	O
+and	O
+adolescents	O
+with	O
+papillary	O
+Thyroid	O
+Carcinoma	O
+(	O
+PTC	O
+)	O
+.	O
+
+Materials	O
+and	O
+methods	O
+From	O
+December	O
+2014	O
+to	O
+March	O
+2018	O
+,	O
+10	O
+metastatic	O
+LNs(mean	B-LOC
+volume	O
+0.30	O
+±	O
+0.38	O
+ml	O
+,	O
+range	O
+0.06	O
+-	O
+1.23ml	O
+)	O
+in	O
+5	O
+children	O
+and	O
+adolescents	O
+(	O
+3	O
+females	O
+,	O
+2	O
+males	O
+;	O
+mean	O
+age	O
+15.60	O
+±	O
+2.97	O
+years	O
+,	O
+range	O
+12	O
+-	O
+19	O
+years	O
+)	O
+with	O
+PTC	O
+treated	O
+by	O
+RFA	O
+were	O
+evaluated	O
+in	O
+this	O
+study	O
+.	O
+
+The	O
+mean	O
+number	O
+of	O
+surgical	O
+procedures	O
+performed	O
+before	O
+RFA	O
+was	O
+1.2	O
+(	O
+range	O
+1	B-STAT
+-	I-STAT
+2	I-STAT
+)	O
+and	O
+the	O
+mean	O
+number	O
+of	O
+treated	O
+metastatic	O
+LNs	O
+per	O
+patient	O
+was	O
+2	O
+(	O
+rang	O
+1	B-STAT
+-	I-STAT
+3	I-STAT
+)	O
+.	O
+
+RFA	O
+was	O
+performed	O
+with	O
+an	O
+18	O
+-	O
+gauge	O
+bipolar	O
+RF	O
+applicator	O
+under	O
+local	O
+anesthesia	O
+.	O
+
+Follow	O
+-	O
+up	O
+consisted	O
+of	O
+US	B-LOC
+and	O
+serum	O
+thyroglobulin	O
+(	O
+Tg	O
+)	O
+level	O
+at	O
+1	B-STAT
+,	I-STAT
+3	I-STAT
+,	O
+6	O
+,	O
+12	O
+months	O
+and	O
+every	O
+12	O
+months	O
+thereafter	O
+.	O
+
+Results	O
+All	O
+the	O
+patients	O
+were	O
+well	O
+tolerant	O
+to	O
+RFA	O
+procedure	O
+and	O
+no	O
+procedure	O
+-	O
+related	O
+complications	O
+occurred	O
+.	O
+
+During	O
+a	O
+mean	O
+follow	O
+-	O
+up	O
+time	O
+of	O
+52.00	O
+±	O
+21.44	O
+months	O
+,	O
+the	O
+initial	O
+volume	O
+of	O
+LNs	O
+was	O
+0.30	O
+±	O
+0.38	O
+ml	O
+,	O
+which	O
+significantly	O
+decreased	O
+to	O
+0.01	O
+±	O
+0.03	O
+ml	O
+(	O
+P	O
+=	O
+0.005	O
+)	O
+with	O
+a	O
+mean	O
+VRR	O
+of	O
+99.28	O
+±	O
+2.27	O
+%	O
+.	O
+
+A	O
+total	O
+of	O
+9	O
+metastatic	O
+LNs	O
+(	O
+90.00	O
+%	O
+)	O
+completely	O
+disappeared	O
+.	O
+
+After	O
+RFA	O
+,	O
+2	O
+patients	O
+developed	O
+newly	O
+metastases	O
+.	O
+
+One	O
+patient	O
+had	O
+additional	O
+RFA	O
+.	O
+
+The	O
+other	O
+one	O
+with	O
+multiple	O
+LN	O
+metastases	O
+underwent	O
+total	O
+thyroidectomy	O
+with	O
+central	O
+neck	O
+dissection	O
+.	O
+
+Conclusion	O
+As	O
+a	O
+less	O
+invasive	O
+and	O
+effective	O
+technique	O
+,	O
+RFA	O
+may	O
+provide	O
+another	O
+alternative	O
+to	O
+the	O
+existing	O
+therapeutic	O
+modalities	O
+for	O
+cervical	O
+metastatic	O
+LNs	O
+in	O
+children	O
+and	O
+adolescents	O
+with	O
+PTC	O
+.	O
+
+Background	O
+The	O
+prevalence	B-EPI
+of	O
+Multiple	O
+Sclerosis	O
+(	O
+MS	O
+)	O
+has	O
+been	O
+increasing	O
+worldwide	B-LOC
+and	O
+the	O
+highest	O
+prevalence	B-EPI
+ratio	O
+among	O
+Asian	O
+countries	O
+was	O
+reported	O
+in	O
+Iran	B-LOC
+.	O
+
+This	O
+study	O
+aims	O
+to	O
+estimate	O
+the	O
+increase	O
+in	O
+MS	O
+occurrence	B-EPI
+during	O
+more	O
+than	O
+three	O
+decades	O
+in	O
+Tehran	B-LOC
+and	O
+forecast	O
+the	O
+future	O
+condition	O
+of	O
+the	O
+disease	O
+using	O
+time	O
+series	O
+approaches	O
+for	O
+the	O
+next	O
+ten	O
+years	O
+.	O
+
+Methods	O
+The	O
+cross	O
+-	O
+sectional	O
+study	O
+was	O
+conducted	O
+from	O
+1999	O
+to	O
+2019	O
+based	O
+on	O
+records	O
+of	O
+MS	O
+cases	O
+from	O
+Iranian	O
+MS	O
+Society	O
+(	O
+IMSS	O
+)	O
+registry	O
+system	O
+.	O
+
+The	O
+prevalence	B-EPI
+was	O
+estimated	O
+using	O
+population	O
+data	O
+presented	O
+by	O
+the	O
+Statistical	O
+Centre	O
+of	O
+Iran	O
+.	O
+
+Through	O
+Bayesian	O
+Structural	O
+Time	O
+Series	O
+(	O
+BSTS	O
+)	O
+model	O
+,	O
+we	O
+want	O
+to	O
+predict	O
+the	O
+prevalence	B-EPI
+of	O
+familial	O
+and	O
+sporadic	O
+MS	O
+in	O
+the	O
+next	O
+ten	O
+years	O
+.	O
+
+.	O
+
+Results	O
+Among	O
+22,421	O
+cases	O
+with	O
+MS	O
+,	O
+16,831	O
+(	O
+75.1	O
+%	O
+)	O
+were	O
+female	O
+and	O
+5589	O
+(	O
+24.9	O
+%	O
+)	O
+were	O
+male	O
+.	O
+
+Female	O
+to	O
+male	O
+ratio	O
+was	O
+3.0:1	O
+and	O
+the	O
+number	O
+of	O
+familial	O
+MS	O
+cases	O
+were	O
+2982	O
+(	O
+13.3	O
+%	O
+)	O
+of	O
+subjects	O
+.	O
+
+Female	O
+gender	O
+was	O
+less	O
+responsible	O
+for	O
+higher	O
+rate	O
+of	O
+MS	O
+in	O
+familial	O
+definition	O
+(	O
+beta	O
+=	O
+0.020	O
+)	O
+in	O
+comparison	O
+to	O
+sporadic	O
+cases	O
+(	O
+beta	O
+=	O
+0.034	O
+)	O
+.	O
+
+Forecasting	O
+by	O
+BSTS	O
+revealed	O
+an	O
+increase	O
+in	O
+MS	O
+prevalence	B-EPI
+for	O
+the	O
+next	O
+ten	O
+years	O
+so	O
+that	O
+the	O
+prevalence	B-EPI
+rate	O
+for	O
+total	O
+,	O
+familial	O
+and	O
+sporadic	O
+MS	B-LOC
+respectively	O
+begins	O
+with	O
+189.50	O
+(	O
+183.94	O
+-	O
+195.14	O
+)	O
+,	O
+25.69	O
+(	O
+24.97	O
+-	O
+26.45	O
+)	O
+and	O
+163.74(159.06	O
+-	O
+168.57	O
+)	O
+in	O
+2020	O
+and	O
+ends	O
+with	O
+220.84	O
+(	O
+171.48	O
+-	O
+266.92	O
+)	O
+,	O
+30.79	O
+(	O
+24.16	O
+-	O
+37.15	O
+)	O
+,	O
+and	O
+189.33(146.97	O
+-	O
+230.19	O
+)	O
+in	O
+2029	O
+.	O
+
+Conclusions	O
+According	O
+to	O
+the	O
+findings	O
+,	O
+MS	O
+prevalence	B-EPI
+increased	O
+during	O
+three	O
+decades	O
+and	O
+it	O
+will	O
+increase	O
+over	O
+the	O
+next	O
+ten	O
+years	O
+.	O
+
+Tehran	B-LOC
+province	O
+is	O
+one	O
+of	O
+the	O
+regions	O
+with	O
+highest	O
+MS	O
+prevalence	B-EPI
+in	O
+Asia	B-LOC
+.	O
+
+The	O
+results	O
+of	O
+present	O
+study	O
+indicated	O
+that	O
+females	O
+are	O
+at	O
+higher	O
+risk	O
+for	O
+MS	O
+than	O
+males	O
+in	O
+both	O
+sporadic	O
+and	O
+familial	O
+MS	O
+.	O
+
+Background	O
+and	O
+aim	O
+This	O
+study	O
+aimed	O
+to	O
+describe	O
+the	O
+clinical	O
+,	O
+genetic	O
+,	O
+and	O
+epidemiological	O
+features	O
+of	O
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+disease	O
+(	O
+CMT	O
+)	O
+in	O
+Brazilian	O
+patients	O
+from	O
+a	O
+tertiary	O
+center	O
+,	O
+and	O
+to	O
+compare	O
+our	O
+data	O
+with	O
+previously	O
+published	O
+findings	O
+.	O
+
+Methods	O
+This	O
+retrospective	O
+observational	O
+study	O
+conducted	O
+between	O
+February	O
+2015	O
+and	O
+July	O
+2020	O
+evaluated	O
+503	O
+patients	O
+(	O
+94	O
+families	O
+and	O
+192	O
+unrelated	O
+individuals	O
+)	O
+,	O
+diagnosed	O
+with	O
+CMT	O
+.	O
+
+Clinical	O
+and	O
+neurophysiological	O
+data	O
+were	O
+obtained	O
+from	O
+electronic	O
+medical	O
+records	O
+and	O
+blood	O
+samples	O
+were	O
+used	O
+for	O
+genetic	O
+analyses	O
+.	O
+
+Multiplex	O
+ligation	O
+-	O
+dependent	O
+probe	O
+amplification	O
+was	O
+used	O
+to	O
+assess	O
+duplications	O
+/	O
+deletions	O
+in	O
+PMP22	O
+.	O
+
+Sanger	O
+sequencing	O
+of	O
+GJB1	O
+was	O
+performed	O
+in	O
+cases	O
+of	O
+suspected	O
+demyelinating	O
+CMT	O
+.	O
+
+Targeted	O
+gene	O
+panel	O
+sequencing	O
+was	O
+used	O
+for	O
+the	O
+remaining	O
+negative	O
+demyelinating	O
+cases	O
+and	O
+all	O
+axonal	O
+CMT	O
+cases	O
+.	O
+
+Results	O
+The	O
+first	O
+decade	O
+of	O
+life	O
+was	O
+the	O
+most	O
+common	O
+period	O
+of	O
+disease	O
+onset	O
+.	O
+
+In	O
+all	O
+,	O
+353	O
+patients	O
+had	O
+demyelinating	O
+CMT	O
+,	O
+39	O
+had	O
+intermediate	O
+CMT	O
+,	O
+and	O
+111	O
+had	O
+axonal	O
+CMT	O
+.	O
+
+Pathogenic	O
+or	O
+likely	O
+pathogenic	O
+variants	O
+were	O
+identified	O
+in	O
+197	O
+index	O
+cases	O
+.	O
+
+The	O
+most	O
+common	O
+causative	O
+genes	O
+among	O
+probands	O
+were	O
+PMP22	O
+(	O
+duplication	O
+)	O
+(	O
+n=116	O
+,	O
+58.88	O
+%	O
+)	O
+,	O
+GJB1	O
+(	O
+n=23	O
+,	O
+11.67	O
+%	O
+)	O
+,	O
+MFN2	O
+(	O
+n=12	O
+,	O
+6.09	O
+%	O
+)	O
+,	O
+GDAP1	O
+(	O
+n=7	O
+,	O
+3.55	O
+%	O
+)	O
+,	O
+MPZ	O
+(	O
+n=6	O
+,	O
+3.05	O
+%	O
+)	O
+,	O
+PMP22	O
+(	O
+point	O
+mutation	O
+)	O
+(	O
+n=6	O
+,	O
+3.05	O
+%	O
+)	O
+,	O
+NEFL	O
+(	O
+n=3	O
+,	O
+1.52	O
+%	O
+)	O
+,	O
+SBF2	O
+(	O
+n=3	O
+,	O
+1.52	O
+%	O
+)	O
+,	O
+and	O
+SH3TC2	O
+(	O
+n=3	O
+,	O
+1.52	O
+%	O
+)	O
+.	O
+
+Other	O
+identified	O
+variants	O
+were	O
+≤1	O
+%	O
+of	O
+index	O
+cases	O
+.	O
+
+Interpretation	O
+This	O
+study	O
+provides	O
+further	O
+data	O
+on	O
+the	O
+frequency	O
+of	O
+CMT	O
+subtypes	O
+in	O
+a	O
+Brazilian	O
+clinical	O
+-	O
+based	O
+population	O
+and	O
+highlights	O
+the	O
+importance	O
+of	O
+rarer	O
+and	O
+previously	O
+undiagnosed	O
+variants	O
+in	O
+clinical	O
+practice	O
+.	O
+
+This	O
+article	O
+is	O
+protected	O
+by	O
+copyright	O
+.	O
+
+All	O
+rights	O
+reserved	O
+.	O
+
+Aim	O
+To	O
+assess	O
+a	O
+total	O
+population	O
+of	O
+school	O
+-	O
+age	O
+children	O
+with	O
+cerebral	O
+palsy	O
+(	O
+CP	O
+)	O
+for	O
+autism	O
+and	O
+attention	O
+-	O
+deficit	O
+/	O
+hyperactivity	O
+disorder	O
+(	O
+ADHD	O
+)	O
+with	O
+a	O
+view	O
+to	O
+determining	O
+their	O
+prevalence	B-EPI
+and	O
+to	O
+relate	O
+findings	O
+to	O
+motor	O
+function	O
+,	O
+intellectual	O
+disability	O
+,	O
+and	O
+other	O
+associated	O
+impairments	O
+.	O
+
+Method	O
+Of	O
+264	O
+children	O
+,	O
+born	O
+between	O
+1999	O
+and	O
+2006	O
+,	O
+from	O
+the	O
+CP	O
+register	O
+of	O
+western	O
+Sweden	B-LOC
+,	O
+200	O
+children	O
+(	O
+109	O
+males	O
+,	O
+91	O
+females	O
+,	O
+median	O
+age	O
+at	O
+assessment	O
+14y	O
+,	O
+range	O
+7	O
+-	O
+18y	O
+)	O
+completed	O
+comprehensive	O
+screening	O
+and	O
+further	O
+neuropsychiatric	O
+clinical	O
+assessments	O
+.	O
+
+Results	O
+Ninety	O
+children	O
+(	O
+45	O
+%	O
+)	O
+were	O
+diagnosed	O
+with	O
+autism	O
+,	O
+ADHD	O
+,	O
+or	O
+both	O
+,	O
+59	B-STAT
+(	O
+30	O
+%	O
+)	O
+were	O
+diagnosed	O
+with	O
+autism	O
+,	O
+and	O
+60	B-STAT
+(	O
+30	O
+%	O
+)	O
+were	O
+diagnosed	O
+with	O
+ADHD	O
+.	O
+
+Intellectual	O
+disability	O
+was	O
+present	O
+in	O
+51	B-STAT
+%	I-STAT
+.	O
+
+Two	O
+-	O
+thirds	O
+had	O
+autism	O
+,	O
+ADHD	O
+,	O
+and/or	O
+intellectual	O
+disability	O
+.	O
+
+In	O
+regression	O
+models	O
+,	O
+autism	O
+was	O
+mainly	O
+predicted	O
+by	O
+intellectual	O
+disability	O
+(	O
+odds	O
+ratio	O
+[	O
+OR]=4.1	O
+)	O
+and	O
+ADHD	O
+(	O
+OR=3.2	O
+)	O
+,	O
+and	O
+ADHD	O
+was	O
+predicted	O
+by	O
+intellectual	O
+disability	O
+(	O
+OR=2.3	O
+)	O
+and	O
+autism	O
+(	O
+OR=3.0	O
+)	O
+.	O
+
+Autism	O
+was	O
+more	O
+common	O
+in	O
+children	O
+born	O
+preterm	O
+(	O
+OR=2.0	O
+)	O
+.	O
+
+Gross	O
+motor	O
+function	O
+was	O
+not	O
+associated	O
+with	O
+autism	O
+.	O
+
+ADHD	O
+prevalence	B-EPI
+was	O
+low	O
+in	O
+children	O
+with	O
+severe	O
+motor	O
+impairment	O
+,	O
+possibly	O
+due	O
+to	O
+diagnostic	O
+limitations	O
+.	O
+
+Interpretation	O
+Autism	O
+and	O
+ADHD	O
+were	O
+common	O
+in	O
+this	O
+population	O
+of	O
+children	O
+with	O
+CP	O
+and	O
+were	O
+mainlyindependent	O
+of	O
+motor	O
+severity	O
+and	O
+CP	O
+type	O
+.	O
+
+The	O
+strongest	O
+predictor	O
+of	O
+autism	O
+/	O
+ADHD	O
+was	O
+intellectual	O
+disability	O
+.	O
+
+Assessment	O
+for	O
+autism	O
+and	O
+ADHD	O
+is	O
+warranted	O
+as	O
+part	O
+of	O
+the	O
+evaluation	O
+in	O
+CP	O
+.	O
+
+What	O
+this	O
+paper	O
+adds	O
+Forty	B-STAT
+-	O
+five	O
+percent	O
+of	O
+the	O
+children	O
+with	O
+cerebral	O
+palsy	O
+also	O
+had	O
+autism	O
+,	O
+attention	O
+-	O
+deficit	O
+/	O
+hyperactivity	O
+disorder	O
+(	O
+ADHD	O
+)	O
+,	O
+or	O
+both	O
+.	O
+
+Autism	O
+and	O
+ADHD	O
+were	O
+predicted	O
+mainly	O
+by	O
+intellectual	O
+disability	O
+.	O
+
+Established	O
+diagnostic	O
+instruments	O
+worked	O
+well	O
+for	O
+all	O
+but	O
+the	O
+most	O
+disabled	O
+group	O
+of	O
+children	O
+.	O
+
+Background	O
+The	O
+VACTERL	O
+association	O
+(	O
+VACTERL	O
+)	O
+is	O
+the	O
+nonrandom	O
+occurrence	B-EPI
+of	O
+at	O
+least	O
+three	O
+of	O
+these	O
+congenital	O
+anomalies	O
+:	O
+vertebral	O
+,	O
+anal	O
+,	O
+cardiac	O
+,	O
+tracheoesophageal	O
+,	O
+renal	O
+,	O
+and	O
+limb	O
+anomalies	O
+.	O
+
+Despite	O
+suggestions	O
+for	O
+involvement	O
+of	O
+several	O
+genes	O
+and	O
+nongenetic	O
+risk	O
+factors	O
+from	O
+small	O
+studies	O
+,	O
+the	O
+etiology	O
+of	O
+VACTERL	O
+remains	O
+largely	O
+unknown	O
+.	O
+
+Objective	O
+To	O
+identify	O
+maternal	O
+risk	O
+factors	O
+for	O
+VACTERL	O
+in	O
+offspring	O
+in	O
+a	O
+large	O
+European	O
+study	O
+.	O
+
+Methods	O
+A	O
+case	O
+-	O
+control	O
+study	O
+was	O
+performed	O
+using	O
+data	O
+from	O
+28	O
+EUROCAT	O
+registries	O
+over	O
+the	O
+period	O
+1997	O
+-	O
+2015	O
+with	O
+case	O
+and	O
+control	O
+ascertainment	O
+through	O
+hospital	O
+records	O
+,	O
+birth	O
+and	O
+death	O
+certificates	O
+,	O
+questionnaires	O
+,	O
+and/or	O
+postmortem	O
+examinations	O
+.	O
+
+Cases	O
+were	O
+diagnosed	O
+with	O
+VACTERL	O
+,	O
+while	O
+controls	O
+had	O
+a	O
+genetic	O
+syndrome	O
+and/or	O
+chromosomal	O
+abnormality	O
+.	O
+
+Data	O
+collected	O
+included	O
+type	O
+of	O
+birth	O
+defect	O
+and	O
+maternal	O
+characteristics	O
+,	O
+such	O
+as	O
+age	O
+,	O
+use	O
+of	O
+assisted	O
+reproductive	O
+techniques	O
+(	O
+ART	O
+)	O
+,	O
+and	O
+chronic	O
+illnesses	O
+.	O
+
+Multivariable	O
+logistic	O
+regression	O
+analyses	O
+were	O
+performed	O
+to	O
+estimate	O
+confounder	O
+adjusted	O
+odds	O
+ratios	O
+(	O
+aOR	O
+)	O
+with	O
+95	O
+%	O
+confidence	O
+intervals	O
+(	O
+95	O
+%	O
+CI	O
+)	O
+.	O
+
+Results	O
+The	O
+study	O
+population	O
+consisted	O
+of	O
+329	O
+VACTERL	O
+cases	O
+and	O
+49,724	O
+controls	O
+with	O
+recognized	O
+syndromes	O
+or	O
+chromosomal	O
+abnormality	O
+.	O
+
+For	O
+couples	O
+who	O
+conceived	O
+through	O
+ART	O
+,	O
+we	O
+found	O
+an	O
+increased	O
+risk	O
+of	O
+VACTERL	O
+(	O
+aOR	O
+2.3	B-STAT
+[	O
+95	O
+%	O
+CI	O
+1.3	O
+,	O
+3.9	O
+]	O
+)	O
+in	O
+offspring	O
+.	O
+
+Pregestational	O
+diabetes	O
+(	O
+aOR	O
+3.1	O
+[	O
+95	O
+%	O
+CI	O
+1.1	O
+,	O
+8.6	O
+]	O
+)	O
+and	O
+chronic	O
+lower	O
+obstructive	O
+pulmonary	O
+diseases	O
+(	O
+aOR	O
+3.9	O
+[	O
+95	O
+%	O
+CI	O
+2.2	O
+,	O
+6.7	O
+]	O
+)	O
+also	O
+increased	O
+the	O
+risk	O
+of	O
+having	O
+a	O
+child	O
+with	O
+VACTERL	O
+.	O
+
+Twin	O
+pregnancies	O
+were	O
+not	O
+associated	O
+with	O
+VACTERL	O
+(	O
+aOR	O
+0.6	O
+[	O
+95	O
+%	O
+CI	O
+0.3	O
+,	O
+1.4	O
+]	O
+)	O
+.	O
+
+Conclusion	O
+We	O
+identified	O
+several	O
+maternal	O
+risk	O
+factors	O
+for	O
+VACTERL	O
+in	O
+offspring	O
+befitting	O
+a	O
+multifactorial	O
+etiology	O
+.	O
+
+Limb	O
+deficiency	O
+disorders	O
+are	O
+rare	O
+,	O
+etiologically	O
+heterogeneous	O
+skeletal	O
+dysplasias	O
+that	O
+occur	O
+as	O
+an	O
+isolated	O
+anomaly	O
+or	O
+as	O
+a	O
+part	O
+of	O
+a	O
+syndrome	O
+.	O
+
+The	O
+term	O
+limb	O
+deficiency	O
+incorporates	O
+both	O
+absence	O
+and	O
+size	O
+reduction	O
+of	O
+any	O
+of	O
+the	O
+120	O
+human	O
+limb	O
+bones	O
+,	O
+with	O
+around	O
+205	O
+identified	O
+abnormalities	O
+.	O
+
+Congenital	O
+absence	O
+of	O
+tibia	O
+is	O
+a	O
+rare	O
+and	O
+severe	O
+lower	O
+limb	O
+malformation	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+approximately	B-STAT
+1:1,000,000	I-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+Absence	O
+of	O
+tibia	O
+with	O
+ectrodactyly	O
+(	O
+lobster	O
+claw	O
+deformity	O
+)	O
+or	O
+tibial	O
+hemimelia	O
+with	O
+split	O
+hand	O
+/	O
+foot	O
+malformation	O
+(	O
+TH	O
+-	O
+SHFM	O
+)	O
+or	O
+Gollop	O
+-	O
+Wolfgang	O
+complex	O
+is	O
+a	O
+rarer	O
+malformation	O
+with	O
+highly	O
+variable	O
+manifestations	O
+.	O
+
+Background	O
+Craniosynostosis	O
+,	O
+defined	O
+as	O
+premature	O
+fusion	O
+of	O
+one	O
+or	O
+more	O
+cranial	O
+sutures	O
+,	O
+affects	O
+approximately	O
+1	B-STAT
+in	I-STAT
+every	I-STAT
+2000	I-STAT
+-	O
+2500	O
+live	O
+births	O
+.	O
+
+Sagittal	O
+craniosynostosis	O
+(	O
+CS	O
+)	O
+,	O
+the	O
+most	O
+prevalent	B-EPI
+form	O
+of	O
+isolated	O
+craniosynostosis	O
+,	O
+is	O
+caused	O
+by	O
+interplay	O
+between	O
+genetic	O
+and	O
+perinatal	O
+environmental	O
+insults	O
+.	O
+
+However	O
+,	O
+the	O
+underlying	O
+details	O
+remain	O
+largely	O
+unknown	O
+.	O
+
+Methods	O
+The	O
+proband	O
+(	O
+a	O
+female	O
+monochorionic	O
+twin	O
+diagnosed	O
+with	O
+CS	O
+)	O
+,	O
+her	O
+healthy	O
+co	O
+-	O
+twin	O
+sister	O
+and	O
+parents	O
+were	O
+enrolled	O
+.	O
+
+Obstetric	O
+history	O
+was	O
+extracted	O
+from	O
+medical	O
+records	O
+.	O
+
+Genetic	O
+screening	O
+was	O
+performed	O
+by	O
+whole	O
+exome	O
+sequencing	O
+(	O
+WES	O
+)	O
+and	O
+confirmed	O
+by	O
+Sanger	O
+sequencing	O
+.	O
+
+Functional	O
+annotation	O
+,	O
+conservation	O
+and	O
+structural	O
+analysis	O
+were	O
+predicted	O
+in	O
+public	O
+database	O
+.	O
+
+Phenotype	O
+data	O
+of	O
+Axin2	O
+knockout	O
+mice	O
+was	O
+downloaded	O
+from	O
+The	O
+International	O
+Mouse	O
+Phenotyping	O
+Consortium	O
+(	O
+IMPC	O
+,	O
+http://www.mousephenotype.org	O
+)	O
+.	O
+
+Results	O
+Obstetric	O
+medical	O
+records	O
+showed	O
+that	O
+,	O
+except	O
+for	O
+the	O
+shared	O
+perinatal	O
+risk	O
+factors	O
+by	O
+the	O
+twins	O
+,	O
+the	O
+proband	O
+suffered	O
+additional	O
+persistent	O
+breech	O
+presentation	O
+and	O
+intrauterine	O
+growth	O
+restriction	O
+.	O
+
+We	O
+identified	O
+a	O
+heterozygous	O
+mutation	O
+of	O
+Axin2	O
+(	O
+c.1181	O
+G	O
+>	O
+A	O
+,	O
+p.	O
+R394H	O
+,	O
+rs200899695	O
+)	O
+in	O
+monochorionic	O
+twins	O
+and	O
+their	O
+father	O
+,	O
+but	O
+not	O
+in	O
+the	O
+mother	O
+.	O
+
+This	O
+mutation	O
+is	O
+not	O
+reported	O
+in	O
+Asian	O
+population	O
+and	O
+results	O
+in	O
+replacement	O
+of	O
+Arg	O
+at	O
+residue	O
+394	O
+by	O
+His	O
+(	O
+p.	O
+R394H	O
+)	O
+.	O
+
+Arg	O
+394	O
+is	O
+located	O
+at	O
+the	O
+GSK3β	O
+binding	O
+domain	O
+of	O
+Axin2	O
+protein	O
+,	O
+which	O
+is	O
+highly	O
+conserved	O
+across	O
+species	O
+.	O
+
+The	O
+mutation	O
+was	O
+predicted	O
+to	O
+be	O
+potentially	O
+deleterious	O
+by	O
+in	O
+silico	O
+analysis	O
+.	O
+
+Incomplete	O
+penetrance	O
+of	O
+Axin2	O
+haploinsufficiency	O
+was	O
+found	O
+in	O
+female	O
+mice	O
+.	O
+
+Conclusions	O
+Axin2	O
+(	O
+c.1181	O
+G	O
+>	O
+A	O
+,	O
+p.	O
+R394H	O
+,	O
+rs200899695	O
+)	O
+mutation	O
+confers	O
+susceptibility	O
+and	O
+perinatal	O
+risk	O
+factors	O
+trigger	O
+the	O
+occurrence	B-EPI
+of	O
+sagittal	O
+craniosynostosis	O
+.	O
+
+Our	O
+findings	O
+provide	O
+a	O
+new	O
+evidence	O
+for	O
+the	O
+gene	O
+-	O
+environment	O
+interplay	O
+in	O
+understanding	O
+pathogenesis	O
+of	O
+craniosynostosis	O
+in	O
+Chinese	O
+population	O
+.	O
+
+Background	O
+The	O
+Global	O
+Anticoagulant	O
+Registry	O
+in	O
+the	O
+FIELD	O
+-	O
+Atrial	O
+Fibrillation	O
+(	O
+GARFIELD	O
+-	O
+AF	O
+)	O
+is	O
+an	O
+ongoing	O
+prospective	O
+noninterventional	O
+registry	O
+,	O
+which	O
+is	O
+providing	O
+important	O
+information	O
+on	O
+the	O
+baseline	O
+characteristics	O
+,	O
+treatment	O
+patterns	O
+,	O
+and	O
+1	O
+-	O
+year	O
+outcomes	O
+in	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+non	O
+-	O
+valvular	O
+atrial	O
+fibrillation	O
+(	O
+NVAF	O
+)	O
+.	O
+
+This	O
+report	O
+describes	O
+data	O
+from	O
+Indian	O
+patients	O
+recruited	O
+in	O
+this	O
+registry	O
+.	O
+
+Methods	O
+and	O
+results	O
+A	O
+total	O
+of	O
+52,014	O
+patients	O
+with	O
+newly	O
+diagnosed	O
+AF	O
+were	O
+enrolled	O
+globally	O
+;	O
+of	O
+these	O
+,	O
+1388	O
+patients	O
+were	O
+recruited	O
+from	O
+26	O
+sites	O
+within	O
+India	B-LOC
+(	O
+2012	O
+-	O
+2016	O
+)	O
+.	O
+
+In	O
+India	B-LOC
+,	O
+the	O
+mean	O
+age	O
+was	O
+65.8	O
+years	O
+at	O
+diagnosis	O
+of	O
+NVAF	O
+.	O
+
+Hypertension	O
+was	O
+the	O
+most	O
+prevalent	B-EPI
+risk	O
+factor	O
+for	O
+AF	O
+,	O
+present	O
+in	O
+68.5	O
+%	O
+of	O
+patients	O
+from	O
+India	B-LOC
+and	O
+in	O
+76.3	O
+%	O
+of	O
+patients	O
+globally	O
+(	O
+P	O
+<	O
+0.001	O
+)	O
+.	O
+
+Diabetes	O
+and	O
+coronary	O
+artery	O
+disease	O
+(	O
+CAD	O
+)	O
+were	O
+prevalent	B-EPI
+in	O
+36.2	O
+%	O
+and	O
+28.1	O
+%	O
+of	O
+patients	O
+as	O
+compared	O
+with	O
+global	B-LOC
+prevalence	B-EPI
+of	O
+22.2	O
+%	O
+and	O
+21.6	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0.001	O
+for	O
+both	O
+)	O
+.	O
+
+Antiplatelet	O
+therapy	O
+was	O
+the	O
+most	O
+common	O
+antithrombotic	O
+treatment	O
+in	O
+India	B-LOC
+.	O
+
+With	O
+increasing	O
+stroke	O
+risk	O
+,	O
+however	O
+,	O
+patients	O
+were	O
+more	O
+likely	O
+to	O
+receive	O
+oral	O
+anticoagulant	O
+therapy	O
+[	O
+mainly	O
+vitamin	O
+K	O
+antagonist	O
+(	O
+VKA	O
+)	O
+]	O
+,	O
+but	O
+average	O
+international	O
+normalized	O
+ratio	O
+(	O
+INR	O
+)	O
+was	O
+lower	O
+among	O
+Indian	O
+patients	O
+[	O
+median	O
+INR	O
+value	O
+1.6	O
+(	O
+interquartile	O
+range	O
+{	O
+IQR	O
+}	O
+:	O
+1.3	O
+-	O
+2.3	O
+)	O
+versus	O
+2.3	O
+(	O
+IQR	O
+1.8	O
+-	O
+2.8	O
+)	O
+(	O
+P	O
+<	O
+0.001	O
+)	O
+]	O
+.	O
+
+Compared	O
+with	O
+other	O
+countries	O
+,	O
+patients	O
+from	O
+India	B-LOC
+had	O
+markedly	O
+higher	O
+rates	O
+of	O
+all	O
+-	O
+cause	O
+mortality	O
+[	O
+7.68	B-STAT
+per	I-STAT
+100	I-STAT
+person	I-STAT
+-	O
+years	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+6.32	O
+-	O
+9.35	O
+)	O
+vs	O
+4.34	O
+(	O
+4.16	O
+-	O
+4.53	O
+)	O
+,	O
+P	O
+<	O
+0.0001	O
+]	O
+,	O
+while	O
+rates	O
+of	O
+stroke	O
+/	O
+systemic	O
+embolism	O
+and	O
+major	O
+bleeding	O
+were	O
+lower	O
+after	O
+1	B-STAT
+year	I-STAT
+of	I-STAT
+follow	O
+-	O
+up	O
+.	O
+
+Conclusion	O
+Compared	O
+to	O
+previously	O
+published	O
+registries	O
+from	O
+India	B-LOC
+,	O
+the	O
+GARFIELD	O
+-	O
+AF	O
+registry	O
+describes	O
+clinical	O
+profiles	O
+and	O
+outcomes	O
+in	O
+Indian	O
+patients	O
+with	O
+AF	O
+of	O
+a	O
+different	O
+etiology	O
+.	O
+
+The	O
+registry	O
+data	O
+show	O
+that	O
+compared	O
+to	O
+the	O
+rest	O
+of	O
+the	O
+world	O
+,	O
+Indian	O
+AF	O
+patients	O
+are	O
+younger	O
+in	O
+age	O
+and	O
+have	O
+more	O
+diabetes	O
+and	O
+CAD	O
+.	O
+
+Patients	O
+with	O
+a	O
+higher	O
+stroke	O
+risk	O
+are	O
+more	O
+likely	O
+to	O
+receive	O
+anticoagulation	O
+therapy	O
+with	O
+VKA	O
+but	O
+are	O
+underdosed	O
+compared	O
+with	O
+the	O
+global	O
+average	O
+in	O
+the	O
+GARFIELD	O
+-	O
+AF	O
+.	O
+
+CLINICAL	O
+TRIAL	O
+REGISTRATION	O
+-	O
+URL	O
+:	O
+http://www.clinicaltrials.gov	O
+.	O
+
+Unique	O
+identifier	O
+:	O
+NCT01090362	O
+.	O
+
+Takotsubo	O
+cardiomyopathy	O
+(	O
+TCM	O
+)	O
+,	O
+also	O
+known	O
+as	O
+broken	O
+heart	O
+syndrome	O
+or	O
+stress	O
+-	O
+induced	O
+cardiomyopathy	O
+,	O
+is	O
+a	O
+rare	O
+condition	O
+with	O
+an	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+0.02	B-STAT
+%	I-STAT
+of	O
+all	O
+hospitalizations	O
+in	O
+United	B-LOC
+States	I-LOC
+and	O
+2	O
+%	O
+of	O
+all	O
+acute	O
+coronary	O
+syndrome	O
+presentations	O
+.	O
+
+TCM	O
+predominately	O
+presents	O
+as	O
+a	O
+transient	O
+wall	O
+motion	O
+abnormality	O
+of	O
+the	O
+left	O
+ventricular	O
+apex	O
+due	O
+to	O
+emotional	O
+or	O
+physical	O
+stress	O
+.	O
+
+Cardiac	O
+rupture	O
+in	O
+the	O
+setting	O
+of	O
+TCM	O
+is	O
+an	O
+extremely	O
+rare	O
+phenomenon	O
+with	O
+limited	O
+published	O
+case	O
+reports	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+75	O
+-	O
+year	O
+-	O
+old	O
+female	O
+who	O
+had	O
+cardiac	O
+rupture	O
+secondary	O
+to	O
+TCM	O
+and	O
+performed	O
+a	O
+literature	O
+review	O
+using	O
+Ovid	O
+MEDLINE	O
+for	O
+published	O
+cases	O
+showing	O
+this	O
+association	O
+.	O
+
+After	O
+the	O
+literature	O
+review	O
+,	O
+we	O
+found	O
+20	O
+cases	O
+showing	O
+this	O
+association	O
+,	O
+which	O
+are	O
+listed	O
+in	O
+a	O
+tabular	O
+fashion	O
+.	O
+
+Although	O
+West	B-LOC
+Nile	I-LOC
+virus	O
+(	O
+WNV	O
+)	O
+is	O
+endemic	O
+to	O
+South	B-LOC
+Africa	I-LOC
+(	O
+RSA	O
+)	O
+,	O
+it	O
+has	O
+only	O
+become	O
+recognized	O
+as	O
+a	O
+significant	O
+cause	O
+of	O
+neurological	O
+disease	O
+in	O
+humans	O
+and	O
+horses	O
+locally	O
+in	O
+the	O
+past	O
+2	O
+decades	O
+,	O
+as	O
+it	O
+emerged	O
+globally	O
+.	O
+
+This	O
+article	O
+describes	O
+the	O
+epidemiological	O
+and	O
+clinical	O
+presentation	O
+of	O
+WNV	O
+in	O
+horses	O
+across	O
+RSA	O
+during	O
+2016	O
+-	O
+2017	O
+.	O
+
+In	O
+total	O
+,	O
+54	O
+WNV	O
+-	O
+positive	O
+cases	O
+were	O
+identified	O
+by	O
+passive	O
+surveillance	O
+in	O
+horses	O
+with	O
+febrile	O
+and/or	O
+neurological	O
+signs	O
+at	O
+the	O
+Centre	O
+for	O
+Viral	O
+Zoonoses	O
+,	O
+University	O
+of	O
+Pretoria	O
+.	O
+
+They	O
+were	O
+followed	O
+up	O
+and	O
+compared	O
+to	O
+120	O
+randomly	O
+selected	O
+WNV	O
+-	O
+negative	O
+controls	O
+with	O
+the	O
+same	O
+case	O
+definition	O
+and	O
+during	O
+the	O
+same	O
+time	O
+period	O
+.	O
+
+Of	O
+the	O
+WNV	O
+-	O
+positive	O
+cases	O
+,	O
+52	O
+%	O
+had	O
+fever	O
+,	O
+92	O
+%	O
+displayed	O
+neurological	O
+signs	O
+,	O
+and	O
+39	O
+%	O
+experienced	O
+mortality	O
+.	O
+
+Cases	O
+occurred	O
+mostly	O
+in	O
+WNV	O
+-	O
+unvaccinated	O
+horses	O
+<	O
+5	O
+years	O
+old	O
+,	O
+during	O
+late	O
+summer	O
+and	O
+autumn	O
+after	O
+heavy	O
+rain	O
+,	O
+in	O
+the	O
+temperate	O
+to	O
+warm	O
+eastern	O
+parts	O
+of	O
+RSA	O
+.	O
+
+WNV	O
+-	O
+positive	O
+cases	O
+that	O
+had	O
+only	O
+neurological	O
+signs	O
+without	O
+fever	O
+were	O
+more	O
+likely	O
+to	O
+die	O
+.	O
+
+In	O
+the	O
+multivariable	O
+analysis	O
+,	O
+the	O
+odds	O
+of	O
+WNV	O
+infection	O
+were	O
+associated	O
+with	O
+season	O
+(	O
+late	O
+summer	O
+)	O
+,	O
+higher	O
+altitude	O
+,	O
+more	O
+highly	O
+purebred	O
+animals	O
+,	O
+younger	O
+age	O
+,	O
+and	O
+failure	O
+to	O
+vaccinate	O
+against	O
+WNV	O
+.	O
+
+Vaccination	O
+is	O
+currently	O
+the	O
+most	O
+effective	O
+prophylactic	O
+measure	O
+to	O
+reduce	O
+WNV	O
+morbidity	O
+and	O
+mortality	O
+in	O
+horses	O
+.	O
+
+Objective	O
+To	O
+determine	O
+the	O
+prevalence	B-EPI
+,	O
+profile	O
+and	O
+predictors	O
+of	O
+infections	O
+in	O
+an	O
+Indian	O
+cohort	O
+of	O
+IIM	O
+.	O
+
+Methods	O
+We	O
+reviewed	O
+the	O
+records	O
+of	O
+a	O
+retrospective	O
+cohort	O
+of	O
+IIM	O
+enrolled	O
+from	O
+consecutive	O
+patients	O
+following	O
+up	O
+in	O
+the	O
+clinic	O
+as	O
+the	O
+observation	O
+cohort	O
+(	O
+OC	O
+)	O
+.	O
+
+A	O
+newly	O
+diagnosed	O
+inception	O
+cohort	O
+of	O
+IIM	O
+were	O
+followed	O
+prospectively	O
+as	O
+the	O
+validation	O
+cohort	O
+(	O
+VC	O
+)	O
+to	O
+confirm	O
+observations	O
+and	O
+compare	O
+with	O
+the	O
+OC	O
+.	O
+
+Results	O
+Among	O
+68	O
+patients	O
+in	O
+the	O
+OC	O
+(	O
+age	O
+33.4	O
+years	O
+,	O
+F	O
+:	O
+M	O
+4.2:1	O
+)	O
+,	O
+37(54.4	O
+%	O
+)	O
+experienced	O
+54	O
+infections	O
+,	O
+of	O
+which	O
+21(38.8	O
+%	O
+)	O
+were	O
+major	O
+and	O
+recurrent	O
+infections	O
+in	O
+11	O
+patients(16.17	O
+%	O
+)	O
+over	O
+3.08	O
+years	O
+.	O
+
+Tuberculosis	O
+was	O
+the	O
+most	O
+common	O
+infection(12	O
+,	O
+22.2	O
+%	O
+)	O
+,	O
+with	O
+predominance	O
+of	O
+extra	O
+-	O
+pulmonary	O
+forms	O
+.	O
+
+Serum	O
+protein(OR	O
+0.44	O
+)	O
+,	O
+platelets(0.44	O
+)	O
+at	O
+disease	O
+onset	O
+and	O
+daily	O
+steroid	O
+dose(1.04	O
+)	O
+predicted	O
+major	O
+infections	O
+on	O
+multivariate	O
+analysis	O
+.	O
+
+A	O
+higher	O
+daily	O
+dose	O
+of	O
+steroids	O
+at	O
+first	O
+infection	O
+correlated	O
+with	O
+number	O
+of	O
+recurrent	O
+infections	O
+.	O
+
+Infection	O
+free	O
+one	O
+-	O
+year	O
+survival	O
+was	O
+73.8%.Of	O
+70	O
+patients	O
+in	O
+VC	O
+(	O
+35.7	O
+years	O
+,	O
+F	O
+:	O
+M	O
+3.7:1	O
+)	O
+,	O
+three	O
+had	O
+myositis	O
+attributed	O
+to	O
+an	O
+infection	O
+.	O
+
+Similar	O
+proportion	O
+of	O
+total(22	O
+,	O
+33.3	O
+%	O
+)	O
+,	O
+major(10	O
+,	O
+45.4	O
+%	O
+)	O
+and	O
+recurrent(4,18	O
+%	O
+)	O
+infections	O
+were	O
+recorded	O
+.	O
+
+Most	O
+common	O
+infection	O
+was	O
+community	O
+acquired	O
+pneumonia	O
+,	O
+followed	O
+by	O
+Tuberculosis	O
+with	O
+serum	O
+albumin(OR	O
+0.25	O
+)	O
+at	O
+disease	O
+onset	O
+being	O
+the	O
+only	O
+predictor	O
+.	O
+
+One	O
+-	O
+year	O
+infection	O
+free	O
+survival	O
+was	O
+64.7	B-STAT
+%	I-STAT
+.	O
+
+Those	O
+who	O
+had	O
+a	O
+major	O
+infection	O
+had	O
+increased	O
+mortality	O
+at	O
+1	O
+year	O
+with	O
+survival	O
+of	O
+60	O
+%	O
+compared	O
+with	O
+89.09	O
+%	O
+in	O
+those	O
+without	O
+.	O
+In	O
+both	O
+cohorts	O
+,	O
+a	O
+daily	O
+prednisone	O
+dose	O
+>	O
+6.25	O
+mg	O
+predisposed	O
+to	O
+major	O
+infections	O
+.	O
+
+Conclusion	O
+Major	O
+and	O
+recurrent	O
+infections	O
+are	O
+common	O
+in	O
+Indian	O
+IIM	O
+patients	O
+and	O
+confer	O
+higher	O
+risk	O
+for	O
+future	O
+infections	O
+and	O
+lower	O
+survival	O
+.	O
+
+Respiratory	O
+and	O
+atypical	O
+bacterial	O
+infections	O
+such	O
+as	O
+Tuberculosis	O
+occur	O
+throughout	O
+the	O
+disease	O
+course	O
+.	O
+
+Over	O
+the	O
+last	O
+50	O
+years	O
+,	O
+significant	O
+muskrat	O
+(	O
+Ondatra	O
+zibethicus	O
+)	O
+harvest	O
+declines	O
+have	O
+been	O
+observed	O
+throughout	O
+North	B-LOC
+America	I-LOC
+.	O
+
+Several	O
+theories	O
+for	O
+the	O
+decline	O
+have	O
+been	O
+proposed	O
+,	O
+including	O
+increased	O
+parasite	O
+infections	O
+and	O
+disease	O
+within	O
+muskrat	O
+populations	O
+.	O
+
+No	O
+existing	O
+wholistic	O
+review	O
+of	O
+muskrat	O
+exposure	O
+to	O
+pathogens	O
+,	O
+contaminants	O
+,	O
+and	O
+diseases	O
+exists	O
+.	O
+
+To	O
+address	O
+this	O
+knowledge	O
+gap	O
+,	O
+we	O
+conducted	O
+a	O
+thorough	O
+review	O
+of	O
+existing	O
+literature	O
+on	O
+muskrat	O
+pathogens	O
+,	O
+contaminants	O
+,	O
+and	O
+diseases	O
+across	O
+their	O
+natural	O
+range	O
+.	O
+
+This	O
+review	O
+is	O
+comprised	O
+of	O
+131	O
+articles	O
+from	O
+1915	O
+to	O
+2019	O
+and	O
+from	O
+27	O
+U.S.	B-LOC
+states	O
+and	O
+9	O
+Canadian	O
+provinces	O
+.	O
+
+A	O
+wide	O
+diversity	O
+of	O
+contaminants	O
+,	O
+toxins	O
+,	O
+and	O
+pathogens	O
+were	O
+reported	O
+in	O
+muskrats	O
+,	O
+with	O
+the	O
+most	O
+common	O
+diseases	O
+being	O
+cysticercosis	O
+,	O
+tularemia	O
+,	O
+Tyzzer	O
+'s	O
+disease	O
+,	O
+and	O
+biotoxin	O
+poisoning	O
+from	O
+cyanobacteria	O
+.	O
+
+This	O
+review	O
+provides	O
+a	O
+summary	O
+of	O
+muskrat	O
+pathogens	O
+,	O
+contaminants	O
+,	O
+and	O
+diseases	O
+over	O
+a	O
+century	O
+that	O
+has	O
+observed	O
+significant	O
+population	O
+declines	O
+throughout	O
+the	O
+species	O
+'	O
+range	O
+in	O
+North	B-LOC
+America	I-LOC
+.	O
+
+Such	O
+data	O
+provide	O
+a	O
+baseline	O
+for	O
+understanding	O
+the	O
+potential	O
+role	O
+of	O
+disease	O
+in	O
+these	O
+declines	O
+.	O
+
+In	O
+addition	O
+,	O
+these	O
+data	O
+highlight	O
+critical	O
+knowledge	O
+gaps	O
+that	O
+warrant	O
+future	O
+research	O
+efforts	O
+.	O
+
+Pulmonary	O
+agenesis	O
+is	O
+a	O
+rarely	O
+encountered	O
+congenital	O
+anomaly	O
+,	O
+and	O
+its	O
+average	B-EPI
+prevalence	I-EPI
+is	O
+about	O
+1	O
+in	O
+100,000	O
+births	O
+.	O
+
+Anomalies	O
+of	O
+the	O
+cardiovascular	O
+,	O
+musculoskeletal	O
+,	O
+gastrointestinal	O
+,	O
+or	O
+genitourinary	O
+systems	O
+may	O
+accompany	O
+in	O
+nearly	O
+half	O
+of	O
+the	O
+cases	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+pulmonary	O
+agenesis	O
+is	O
+usually	O
+made	O
+during	O
+childhood	O
+,	O
+but	O
+the	O
+diagnosis	O
+may	O
+be	O
+delayed	O
+until	O
+adulthood	O
+in	O
+case	O
+of	O
+an	O
+absence	O
+of	O
+comorbid	O
+anomalies	O
+.	O
+
+Herein	O
+,	O
+we	O
+present	O
+a	O
+case	O
+of	O
+pulmonary	O
+agenesis	O
+that	O
+was	O
+diagnosed	O
+during	O
+adulthood	O
+.	O
+
+CT	O
+-	O
+based	O
+quantitative	O
+analysis	O
+of	O
+any	O
+ossification	O
+center	O
+in	O
+the	O
+cranium	O
+has	O
+not	O
+previously	O
+been	O
+carried	O
+out	O
+due	O
+to	O
+the	O
+limited	O
+availability	O
+of	O
+human	O
+fetal	O
+material	O
+.	O
+
+Detailed	O
+morphometric	O
+data	O
+on	O
+the	O
+development	O
+of	O
+ossification	O
+centers	O
+in	O
+the	O
+human	O
+fetus	O
+may	O
+be	O
+useful	O
+in	O
+the	O
+early	O
+detection	O
+of	O
+congenital	O
+defects	O
+.	O
+
+Ossification	O
+disorders	O
+in	O
+the	O
+cranium	O
+are	O
+associated	O
+with	O
+either	O
+a	O
+delayed	O
+development	O
+of	O
+ossification	O
+centers	O
+or	O
+their	O
+mineralization	O
+.	O
+
+These	O
+aberrations	O
+may	O
+result	O
+in	O
+the	O
+formation	O
+of	O
+accessory	O
+skull	O
+bones	O
+that	O
+differ	O
+in	O
+shape	O
+and	O
+size	O
+,	O
+and	O
+the	O
+incidence	B-EPI
+of	O
+which	O
+may	O
+be	O
+misdiagnosed	O
+as	O
+,	O
+e.g.	O
+,	O
+skull	O
+fractures	O
+.	O
+
+The	O
+study	O
+material	O
+comprised	O
+37	O
+human	O
+fetuses	O
+of	O
+both	O
+sexes	O
+(	O
+16	O
+♂	O
+,	O
+21	B-STAT
+♀	I-STAT
+)	O
+aged	O
+18	O
+-	O
+30	O
+weeks	O
+.	O
+
+Using	O
+CT	O
+,	O
+digital	O
+image	O
+analysis	O
+software	O
+,	O
+3D	O
+reconstruction	O
+and	O
+statistical	O
+methods	O
+,	O
+the	O
+linear	O
+,	O
+planar	O
+and	O
+spatial	O
+dimensions	O
+of	O
+the	O
+occipital	O
+squama	O
+ossification	O
+center	O
+were	O
+measured	O
+.	O
+
+The	O
+morphometric	O
+characteristics	O
+of	O
+the	O
+fused	O
+ossification	O
+center	O
+of	O
+the	O
+occipital	O
+squama	O
+show	O
+no	O
+right	O
+-	O
+left	O
+differences	O
+.	O
+
+In	O
+relation	O
+to	O
+gestational	O
+age	O
+,	O
+the	O
+ossification	O
+center	O
+of	O
+the	O
+occipital	O
+squama	O
+grows	O
+linearly	O
+in	O
+its	O
+right	O
+and	O
+left	O
+vertical	O
+diameters	O
+,	O
+logarithmically	O
+in	O
+its	O
+transverse	O
+diameters	O
+of	O
+both	O
+the	O
+interparietal	O
+and	O
+supraoccipital	O
+parts	O
+and	O
+projection	O
+surface	O
+area	O
+,	O
+and	O
+according	O
+to	O
+a	O
+quadratic	O
+function	O
+in	O
+its	O
+volume	O
+.	O
+
+The	O
+obtained	O
+numerical	O
+findings	O
+of	O
+the	O
+occipital	O
+squama	O
+ossification	O
+center	O
+may	O
+be	O
+considered	O
+age	O
+-	O
+specific	O
+references	O
+of	O
+relevance	O
+in	O
+both	O
+the	O
+estimation	O
+of	O
+gestational	O
+age	O
+and	O
+the	O
+diagnostic	O
+process	O
+of	O
+congenital	O
+defects	O
+.	O
+
+The	O
+congenital	O
+long	O
+QT	O
+syndrome	O
+(	O
+LQTS	O
+)	O
+is	O
+an	O
+inherited	O
+cardiac	O
+disorder	O
+characterized	O
+by	O
+increased	O
+QT	O
+intervals	O
+and	O
+a	O
+tendency	O
+to	O
+experience	O
+ventricular	O
+tachycardia	O
+,	O
+which	O
+can	O
+cause	O
+fainting	O
+,	O
+heart	O
+failure	O
+,	O
+or	O
+sudden	O
+death	O
+.	O
+
+A	O
+4	O
+-	O
+year	O
+-	O
+old	O
+female	O
+patient	O
+undergoing	O
+velopharyngeal	O
+correction	O
+surgery	O
+under	O
+general	O
+anesthesia	O
+suddenly	O
+developed	O
+Torsades	O
+de	O
+pointes	O
+.	O
+
+Although	O
+the	O
+patient	O
+spontaneously	O
+resolved	O
+to	O
+sinus	O
+rhythm	O
+without	O
+treatment	O
+,	O
+subsequent	O
+QT	O
+prolongation	O
+persisted	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+a	O
+case	O
+of	O
+concealed	O
+LQTS	O
+with	O
+a	O
+literature	O
+review	O
+.	O
+
+Context	O
+:	O
+Gestational	O
+trophoblastic	O
+disease	O
+(	O
+GTD	O
+)	O
+is	O
+a	O
+rare	O
+complication	O
+of	O
+pregnancy	O
+,	O
+ranging	O
+from	O
+molar	O
+pregnancy	O
+to	O
+choriocarcinoma	O
+.	O
+
+Twin	O
+pregnancies	O
+with	O
+GTD	O
+and	O
+coexisting	O
+normal	O
+fetus	O
+are	O
+extremely	O
+rare	O
+with	O
+an	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+1	B-STAT
+case	I-STAT
+per	I-STAT
+22,000	I-STAT
+-	I-STAT
+100,000	I-STAT
+pregnancies	O
+.	O
+
+Molecular	O
+mimicry	O
+between	O
+human	O
+chorionic	O
+gonadotrophin	O
+(	O
+hCG	O
+)	O
+and	O
+thyroid	O
+-	O
+stimulating	O
+hormone	O
+(	O
+TSH	O
+)	O
+leads	O
+to	O
+gestational	O
+trophoblastic	O
+hyperthyroidism	O
+(	O
+GTH	O
+)	O
+which	O
+is	O
+further	O
+associated	O
+with	O
+increased	O
+maternal	O
+and	O
+fetal	O
+complications	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+reported	O
+case	O
+in	O
+literature	O
+describing	O
+the	O
+delivery	O
+of	O
+a	O
+baby	O
+with	O
+biochemical	O
+euthyroid	O
+status	O
+following	O
+a	O
+twin	O
+pregnancy	O
+with	O
+hydatidiform	O
+mole	O
+(	O
+HM	O
+)	O
+associated	O
+with	O
+gestational	O
+trophoblastic	O
+hyperthyroidism	O
+(	O
+GTH	O
+)	O
+.	O
+
+Case	O
+Description	O
+:	O
+A	O
+24	O
+-	O
+year	O
+-	O
+old	O
+G4	O
+P3	O
+Caucasian	O
+female	O
+with	O
+twin	O
+gestation	O
+was	O
+admitted	O
+to	O
+hospital	O
+for	O
+gestation	O
+trophoblastic	O
+hyperthyroidism	O
+.	O
+
+She	O
+was	O
+later	O
+diagnosed	O
+to	O
+have	O
+twin	O
+pregnancy	O
+with	O
+complete	O
+mole	O
+and	O
+coexisting	O
+normal	O
+fetus	O
+complicated	O
+by	O
+gestational	O
+trophoblastic	O
+hyperthyroidism	O
+(	O
+GTH	O
+)	O
+.	O
+
+Despite	O
+the	O
+risk	O
+associated	O
+with	O
+the	O
+continuation	O
+of	O
+molar	O
+pregnancy	O
+,	O
+per	O
+patient	O
+request	O
+,	O
+pregnancy	O
+was	O
+continued	O
+till	O
+viability	O
+of	O
+the	O
+fetus	O
+.	O
+
+The	O
+patient	O
+underwent	O
+cesarean	O
+section	O
+due	O
+to	O
+worsening	O
+preeclampsia	O
+and	O
+delivered	O
+a	O
+euthyroid	O
+baby	O
+at	O
+the	O
+24th	O
+week	O
+of	O
+gestation	O
+.	O
+
+Conclusions	O
+:	O
+Twin	O
+pregnancy	O
+with	O
+gestational	O
+trophoblastic	O
+disease	O
+and	O
+coexisting	O
+normal	O
+fetus	O
+is	O
+associated	O
+with	O
+high	O
+risk	O
+of	O
+hyperthyroidism	O
+,	O
+and	O
+careful	O
+monitoring	O
+of	O
+the	O
+thyroid	O
+function	O
+test	O
+along	O
+with	O
+dose	O
+titration	O
+of	O
+thionamides	O
+is	O
+of	O
+utmost	O
+importance	O
+throughout	O
+the	O
+gestation	O
+.	O
+
+If	O
+normal	O
+thyroid	O
+hormone	O
+levels	O
+are	O
+maintained	O
+during	O
+the	O
+pregnancy	O
+,	O
+euthyroidism	O
+could	O
+be	O
+successfully	O
+achieved	O
+in	O
+the	O
+baby	O
+.	O
+
+Background	O
+Nonalcoholic	O
+steatohepatitis	O
+(	O
+NASH	O
+)	O
+is	O
+a	O
+subtype	O
+of	O
+non	O
+-	O
+alcoholic	O
+fatty	O
+liver	O
+disease	O
+(	O
+NAFLD	O
+)	O
+with	O
+a	O
+potentially	O
+progressive	O
+course	O
+to	O
+liver	O
+fibrosis	O
+,	O
+cirrhosis	O
+with	O
+its	O
+complications	O
+,	O
+or	O
+even	O
+hepatocellular	O
+carcinoma	O
+.	O
+
+NAFLD	O
+is	O
+a	O
+rapidly	O
+growing	O
+chronic	O
+liver	O
+disease	O
+,	O
+with	O
+a	O
+global	B-LOC
+prevalence	B-EPI
+of	O
+about	O
+25	O
+%	O
+,	O
+with	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+last	O
+2	O
+decades	O
+,	O
+changing	O
+the	O
+landscape	O
+of	O
+hepatology	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+undertake	O
+a	O
+bibliometric	O
+global	O
+analysis	O
+of	O
+research	O
+literature	O
+focusing	O
+on	O
+NASH	O
+.	O
+
+Methods	O
+We	O
+searched	O
+the	O
+Scopus	O
+database	O
+to	O
+identify	O
+all	O
+articles	O
+pertaining	O
+to	O
+	O
+non	O
+-	O
+alcoholic	O
+steatohepatitis	O
+	O
+or	O
+	O
+NASH	O
+	O
+-	O
+the	O
+2	O
+keywords	O
+used	O
+to	O
+search	O
+in	O
+the	O
+title	O
+or	O
+abstract	O
+within	O
+the	O
+time	O
+period	O
+1980	O
+to	O
+2018	O
+.	O
+
+The	O
+collected	O
+data	O
+included	O
+document	O
+type	O
+,	O
+author	O
+,	O
+journal	O
+,	O
+publication	O
+year	O
+,	O
+citation	O
+reports	O
+,	O
+country	O
+,	O
+and	O
+were	O
+analyzed	O
+using	O
+Microsoft	O
+Excel	O
+and	O
+Microsoft	O
+Word	O
+.	O
+
+Results	O
+A	O
+total	O
+number	O
+of	O
+6632	O
+articles	O
+published	O
+in	O
+1355	O
+journals	O
+were	O
+retrieved	O
+.	O
+
+English	O
+was	O
+the	O
+predominant	O
+language	O
+of	O
+publication	O
+,	O
+USA	B-LOC
+being	O
+the	O
+most	O
+productive	O
+with	O
+1937	O
+articles	O
+published	O
+(	O
+29.2	O
+%	O
+of	O
+the	O
+total	O
+number	O
+of	O
+publications	O
+)	O
+,	O
+followed	O
+by	O
+Japan	B-LOC
+with	O
+909	O
+,	O
+representing	O
+13.7	O
+%	O
+of	O
+publications	O
+.	O
+
+Hepatology	O
+,	O
+Journal	O
+of	O
+Hepatology	O
+and	O
+World	O
+Journal	O
+of	O
+Gastroenterology	O
+were	O
+the	O
+most	O
+active	O
+journals	O
+.	O
+
+Research	O
+articles	O
+were	O
+the	O
+most	O
+common	O
+type	O
+of	O
+publications	O
+(	O
+4524	B-STAT
+;	O
+68.22	O
+%	O
+)	O
+,	O
+followed	O
+by	O
+review	O
+articles	O
+(	O
+1359	O
+;	O
+20.49	O
+%	O
+)	O
+.	O
+
+The	O
+total	O
+number	O
+of	O
+citations	O
+received	O
+by	O
+all	O
+publications	O
+was	O
+274,041	O
+,	O
+with	O
+an	O
+average	O
+of	O
+41.32	B-STAT
+per	I-STAT
+article	I-STAT
+(	I-STAT
+range	O
+:	O
+0	O
+-	O
+4384	O
+)	O
+.	O
+
+The	O
+average	O
+number	O
+of	O
+authors	O
+per	O
+article	O
+has	O
+increased	O
+in	O
+the	O
+last	O
+2	O
+decades	O
+,	O
+whereas	O
+the	O
+trend	O
+of	O
+single-	O
+(	O
+or	O
+few	O
+)	O
+authored	O
+publications	O
+has	O
+decreased	O
+.	O
+
+Conclusion	O
+This	O
+study	O
+indicates	O
+that	O
+NASH	O
+is	O
+a	O
+significant	O
+topic	O
+in	O
+the	O
+hepatology	O
+research	O
+,	O
+as	O
+proved	O
+by	O
+the	O
+huge	O
+number	O
+of	O
+publications	O
+,	O
+recording	O
+an	O
+exponential	O
+growth	O
+in	O
+the	O
+last	O
+2	O
+decades	O
+.	O
+
+The	O
+USA	B-LOC
+stands	O
+out	O
+as	O
+by	O
+far	O
+the	O
+most	O
+productive	O
+country	O
+.	O
+
+Aim	O
+Heart	O
+failure	O
+is	O
+increasing	O
+in	O
+Japan	B-LOC
+,	O
+in	O
+particular	O
+that	O
+with	O
+preserved	O
+ejection	O
+fraction	O
+(	O
+HFpEF	O
+)	O
+prevalent	B-EPI
+in	O
+older	O
+-	O
+aged	O
+patients	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+investigate	O
+the	O
+pathophysiology	O
+during	O
+the	O
+early	O
+stage	O
+of	O
+left	O
+ventricular	O
+(	O
+LV	O
+)	O
+diastolic	O
+dysfunction	O
+by	O
+the	O
+quantitative	O
+proteome	O
+analysis	O
+of	O
+human	O
+myocardium	O
+.	O
+
+Methods	O
+Among	O
+331	O
+post	O
+-	O
+mortem	O
+autopsy	O
+patients	O
+,	O
+we	O
+selected	O
+23	O
+patients	O
+(	O
+aged	O
+79	O
+±	O
+9.6	O
+years	O
+)	O
+with	O
+echocardiographic	O
+data	O
+and	O
+without	O
+major	O
+comorbidities	O
+,	O
+except	O
+hypertension	O
+.	O
+
+Cryopreserved	O
+autopsy	O
+tissue	O
+of	O
+the	O
+LV	O
+myocardium	O
+was	O
+subjected	O
+to	O
+proteome	O
+analysis	O
+.	O
+
+LV	O
+diastolic	O
+function	O
+was	O
+evaluated	O
+by	O
+echocardiographic	O
+data	O
+.	O
+
+Thirteen	O
+patients	O
+were	O
+classified	O
+into	O
+the	O
+impaired	O
+diastolic	O
+function	O
+(	O
+IDF	O
+)	O
+group	O
+,	O
+and	O
+10	O
+the	O
+normal	O
+cardiac	O
+function	O
+group	O
+.	O
+
+We	O
+performed	O
+comparative	O
+proteome	O
+analysis	O
+between	O
+the	O
+IDF	O
+and	O
+normal	O
+groups	O
+by	O
+isobaric	O
+tags	O
+for	O
+relative	O
+and	O
+absolute	O
+quantitation	O
+(	O
+iTRAQ	O
+)	O
+using	O
+nano	O
+-	O
+liquid	O
+chromatography	O
+-	O
+tandem	O
+mass	O
+spectrometry	O
+.	O
+
+Results	O
+The	O
+iTRAQ	O
+-	O
+based	O
+proteome	O
+analysis	O
+revealed	O
+57	O
+differentially	O
+expressed	O
+proteins	O
+in	O
+the	O
+IDF	O
+group	O
+.	O
+
+Molecular	O
+network	O
+analysis	O
+of	O
+differentially	O
+expressed	O
+proteins	O
+indicated	O
+that	O
+endoplasmic	O
+reticulum	O
+(	O
+ER	O
+)	O
+stress	O
+was	O
+a	O
+potentially	O
+important	O
+event	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+expressions	O
+of	O
+proteins	O
+associated	O
+with	O
+the	O
+ER	O
+stress	O
+response	O
+,	O
+such	O
+as	O
+glucose	O
+-	O
+regulated	O
+protein	O
+78	O
+kDa	O
+,	O
+inositol	O
+-	O
+requiring	O
+kinase	O
+1α	O
+and	O
+spliced	O
+X	O
+-	O
+box	O
+binding	O
+protein	O
+1	B-STAT
+,	I-STAT
+were	O
+significantly	O
+decreased	O
+in	O
+the	O
+IDF	O
+group	O
+.	O
+
+Conclusions	O
+This	O
+study	O
+suggested	O
+that	O
+reduced	O
+ER	O
+stress	O
+responses	O
+were	O
+involved	O
+during	O
+the	O
+early	O
+stage	O
+of	O
+LV	O
+diastolic	O
+dysfunction	O
+.	O
+
+Geriatr	O
+Gerontol	O
+Int	O
+••	O
+;	O
+••	O
+:	O
+••-••	O
+Geriatr	O
+Gerontol	O
+Int	O
+2021	O
+;	O
+••	O
+:	O
+••-••.	O
+
+Although	O
+benzothiazole	O
+and	O
+its	O
+derivatives	O
+(	O
+BTHs	O
+)	O
+are	O
+considered	O
+emerging	O
+contaminants	O
+in	O
+diverse	O
+environments	O
+and	O
+organisms	O
+,	O
+little	O
+information	O
+is	O
+available	O
+about	O
+their	O
+contamination	O
+profiles	O
+and	O
+health	O
+impact	O
+in	O
+ambient	O
+particles	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+an	O
+optimized	O
+method	O
+of	O
+ultrasound	O
+-	O
+assisted	O
+extraction	O
+coupled	O
+with	O
+the	O
+selected	O
+reaction	O
+monitoring	O
+(	O
+SRM	O
+)	O
+mode	O
+of	O
+GC	O
+-	O
+EI	O
+-	O
+MS	O
+/	O
+MS	O
+was	O
+applied	O
+to	O
+characterize	O
+and	O
+analyze	O
+PM	O
+2.5	O
+-bound	O
+BTHs	O
+from	O
+three	O
+cities	O
+of	O
+China	B-LOC
+(	O
+Guangzhou	B-LOC
+,	O
+Shanghai	B-LOC
+,	O
+and	O
+Taiyuan	B-LOC
+)	O
+during	O
+the	O
+winter	O
+of	O
+2018	O
+.	O
+
+The	O
+total	O
+BTH	O
+concentration	O
+(	O
+ΣBTHs	O
+)	O
+in	O
+PM	O
+2.5	O
+samples	O
+from	O
+the	O
+three	O
+cities	O
+decreased	O
+in	O
+the	O
+order	O
+of	O
+Guangzhou	B-LOC
+>	O
+Shanghai	O
+>	O
+Taiyuan	O
+,	O
+independently	O
+of	O
+the	O
+PM	O
+2.5	O
+concentration	O
+.	O
+
+Despite	O
+the	O
+large	O
+variation	O
+in	O
+concentration	O
+of	O
+ΣBTHs	O
+in	O
+PM	O
+2.5	O
+,	O
+2	O
+-	O
+hydroxybenzothiazole	O
+(	O
+OTH	O
+)	O
+was	O
+always	O
+the	O
+predominant	O
+compound	O
+among	O
+the	O
+PM	O
+2.5	O
+-bound	O
+BTHs	O
+and	O
+accounted	O
+for	O
+50	B-STAT
+-	O
+80	O
+%	O
+of	O
+total	O
+BTHs	O
+in	O
+the	O
+three	O
+regions	O
+.	O
+
+Results	O
+from	O
+human	O
+exposure	O
+assessment	O
+and	O
+toxicity	O
+screening	O
+indicated	O
+that	O
+the	O
+outdoor	O
+exposure	O
+risk	O
+of	O
+PM	O
+2.5	O
+-bound	O
+BTHs	O
+in	O
+toddlers	O
+was	O
+much	O
+higher	O
+than	O
+in	O
+adults	O
+,	O
+especially	O
+for	O
+OTH	O
+.	O
+
+The	O
+developmental	O
+and	O
+reproduction	O
+toxicity	O
+of	O
+OTH	O
+was	O
+further	O
+explored	O
+in	O
+vivo	O
+and	O
+in	O
+vitro	O
+.	O
+
+Exposure	O
+of	O
+mouse	O
+embryonic	O
+stem	O
+cells	O
+(	O
+mESCs	O
+)	O
+to	O
+OTH	O
+for	O
+48	O
+h	O
+significantly	O
+increased	O
+the	O
+intracellular	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+and	O
+induced	O
+DNA	O
+damage	O
+and	O
+apoptosis	O
+via	O
+the	O
+functionally	O
+activating	O
+p53	O
+expression	O
+.	O
+
+In	O
+addition	O
+,	O
+the	O
+growth	O
+and	O
+development	O
+of	O
+zebrafish	O
+embryos	O
+were	O
+found	O
+to	O
+be	O
+severely	O
+affected	O
+after	O
+OTH	O
+treatment	O
+.	O
+
+An	O
+overall	O
+metabolomics	O
+study	O
+was	O
+conducted	O
+on	O
+the	O
+exposed	O
+zebrafish	O
+larvae	O
+.	O
+
+The	O
+results	O
+indicated	O
+that	O
+exposure	O
+to	O
+OTH	O
+inhibited	O
+the	O
+phenylalanine	O
+hydroxylation	O
+reaction	O
+,	O
+which	O
+further	O
+increased	O
+the	O
+accumulation	O
+of	O
+toxic	O
+phenylpyruvate	O
+and	O
+acetylphenylalanine	O
+in	O
+zebrafish	O
+.	O
+
+These	O
+findings	O
+provide	O
+important	O
+insights	O
+into	O
+the	O
+contamination	O
+profiles	O
+of	O
+PM	O
+2.5	O
+-bound	O
+BTHs	O
+and	O
+emphasize	O
+the	O
+health	O
+risk	O
+of	O
+OTH	O
+.	O
+
+Barth	O
+syndrome	O
+(	O
+BTHS	O
+)	O
+is	O
+a	O
+rare	O
+,	O
+X	O
+-	O
+linked	O
+recessive	O
+,	O
+infantile	O
+-	O
+onset	O
+debilitating	O
+disorder	O
+characterized	O
+by	O
+early	O
+-	O
+onset	O
+cardiomyopathy	O
+,	O
+skeletal	O
+muscle	O
+myopathy	O
+,	O
+growth	O
+delay	O
+,	O
+and	O
+neutropenia	O
+,	O
+with	O
+a	O
+worldwide	B-LOC
+incidence	B-EPI
+of	O
+1/300,000	B-STAT
+-	O
+400,000	O
+live	O
+births	O
+.	O
+
+The	O
+high	O
+mortality	O
+rate	O
+throughout	O
+infancy	O
+in	O
+BTHS	O
+patients	O
+is	O
+related	O
+primarily	O
+to	O
+progressive	O
+cardiomyopathy	O
+and	O
+a	O
+weakened	O
+immune	O
+system	O
+.	O
+
+BTHS	O
+is	O
+caused	O
+by	O
+defects	O
+in	O
+the	O
+TAZ	O
+gene	O
+that	O
+encodes	O
+tafazzin	O
+,	O
+a	O
+transacylase	O
+responsible	O
+for	O
+the	O
+remodeling	O
+and	O
+maturation	O
+of	O
+the	O
+mitochondrial	O
+phospholipid	O
+cardiolipin	O
+(	O
+CL	O
+)	O
+,	O
+which	O
+is	O
+critical	O
+to	O
+normal	O
+mitochondrial	O
+structure	O
+and	O
+function	O
+(	O
+i.e.	O
+,	O
+ATP	O
+generation	O
+)	O
+.	O
+
+A	O
+deficiency	O
+in	O
+tafazzin	O
+results	O
+in	O
+up	O
+to	O
+a	O
+95	O
+%	O
+reduction	O
+in	O
+levels	O
+of	O
+structurally	O
+mature	O
+CL	O
+.	O
+
+Because	O
+the	O
+heart	O
+is	O
+the	O
+most	O
+metabolically	O
+active	O
+organ	O
+in	O
+the	O
+body	O
+,	O
+with	O
+the	O
+highest	O
+mitochondrial	O
+content	O
+of	O
+any	O
+tissue	O
+,	O
+mitochondrial	O
+dysfunction	O
+plays	O
+a	O
+key	O
+role	O
+in	O
+the	O
+development	O
+of	O
+heart	O
+failure	O
+in	O
+patients	O
+with	O
+BTHS	O
+.	O
+
+Changes	O
+in	O
+mitochondrial	O
+oxidative	O
+phosphorylation	O
+reduce	O
+the	O
+ability	O
+of	O
+mitochondria	O
+to	O
+meet	O
+the	O
+ATP	O
+demands	O
+of	O
+the	O
+human	O
+heart	O
+as	O
+well	O
+as	O
+skeletal	O
+muscle	O
+,	O
+namely	O
+ATP	O
+synthesis	O
+does	O
+not	O
+match	O
+the	O
+rate	O
+of	O
+ATP	O
+consumption	O
+.	O
+
+The	O
+presence	O
+of	O
+several	O
+cardiomyopathic	O
+phenotypes	O
+have	O
+been	O
+described	O
+in	O
+BTHS	O
+,	O
+including	O
+dilated	O
+cardiomyopathy	O
+,	O
+left	O
+ventricular	O
+noncompaction	O
+,	O
+either	O
+alone	O
+or	O
+in	O
+conjunction	O
+with	O
+other	O
+cardiomyopathic	O
+phenotypes	O
+,	O
+endocardial	O
+fibroelastosis	O
+,	O
+hypertrophic	O
+cardiomyopathy	O
+,	O
+and	O
+an	O
+apical	O
+form	O
+of	O
+hypertrophic	O
+cardiomyopathy	O
+,	O
+among	O
+others	O
+,	O
+all	O
+of	O
+which	O
+can	O
+be	O
+directly	O
+attributed	O
+to	O
+the	O
+lack	O
+of	O
+CL	O
+synthesis	O
+,	O
+remodeling	O
+,	O
+and	O
+maturation	O
+with	O
+subsequent	O
+mitochondrial	O
+dysfunction	O
+.	O
+
+Several	O
+mechanisms	O
+by	O
+which	O
+these	O
+cardiomyopathic	O
+phenotypes	O
+exist	O
+have	O
+been	O
+proposed	O
+,	O
+thereby	O
+identifying	O
+potential	O
+targets	O
+for	O
+treatment	O
+.	O
+
+Dysfunction	O
+of	O
+the	O
+sarcoplasmic	O
+reticulum	O
+Ca	O
+2	O
++	O
+-ATPase	O
+pump	O
+and	O
+inflammation	O
+potentially	O
+triggered	O
+by	O
+circulating	O
+mitochondrial	O
+components	O
+have	O
+been	O
+identified	O
+.	O
+
+Currently	O
+,	O
+treatment	O
+modalities	O
+are	O
+aimed	O
+at	O
+addressing	O
+symptomatology	O
+of	O
+HF	O
+in	O
+BTHS	O
+,	O
+but	O
+do	O
+not	O
+address	O
+the	O
+underlying	O
+pathology	O
+.	O
+
+One	O
+novel	O
+therapeutic	O
+approach	O
+includes	O
+elamipretide	O
+,	O
+which	O
+crosses	O
+the	O
+mitochondrial	O
+outer	O
+membrane	O
+to	O
+localize	O
+to	O
+the	O
+inner	O
+membrane	O
+where	O
+it	O
+associates	O
+with	O
+cardiolipin	O
+to	O
+enhance	O
+ATP	O
+synthesis	O
+in	O
+several	O
+organs	O
+,	O
+including	O
+the	O
+heart	O
+.	O
+
+Encouraging	O
+clinical	O
+results	O
+of	O
+the	O
+use	O
+of	O
+elamipretide	O
+in	O
+treating	O
+patients	O
+with	O
+BTHS	O
+support	O
+the	O
+potential	O
+use	O
+of	O
+this	O
+drug	O
+for	O
+management	O
+of	O
+this	O
+rare	O
+disease	O
+.	O
+
+In	O
+1978	O
+,	O
+Sohar	O
+et	O
+al	O
+.	O
+
+described	O
+a	O
+strikingly	O
+peculiar	O
+syndrome	O
+in	O
+two	O
+Israeli	O
+sisters	O
+.	O
+
+These	O
+young	O
+women	O
+responded	O
+to	O
+environmental	O
+temperatures	O
+of	O
+18	O
+degrees	O
+C-7	O
+degrees	O
+C	O
+with	O
+profuse	O
+sweating	O
+on	O
+large	O
+segments	O
+on	O
+their	O
+back	O
+and	O
+chest	O
+.	O
+
+Both	O
+had	O
+additional	O
+abnormalities	O
+,	O
+including	O
+a	O
+high	O
+-	O
+arched	O
+palate	O
+,	O
+nasal	O
+voice	O
+,	O
+depressed	O
+nasal	O
+bridge	O
+,	O
+inability	O
+to	O
+fully	O
+extend	O
+their	O
+elbows	O
+,	O
+and	O
+kyphoscoliosis	O
+.	O
+
+We	O
+have	O
+observed	O
+this	O
+disorder	O
+in	O
+two	O
+Norwegian	O
+brothers	O
+.	O
+
+Genome	O
+-	O
+wide	O
+screening	O
+in	O
+the	O
+two	O
+families	O
+,	O
+followed	O
+by	O
+saturation	O
+marker	O
+studies	O
+and	O
+linkage	O
+analysis	O
+,	O
+identified	O
+a	O
+1.4	O
+-	O
+Mb	O
+homozygous	O
+candidate	O
+region	O
+on	O
+chromosome	O
+19p12	O
+.	O
+
+The	O
+maximum	O
+multipoint	O
+LOD	O
+score	O
+was	O
+4.22	O
+.	O
+
+In	O
+both	O
+families	O
+,	O
+DNA	O
+sequencing	O
+of	O
+25	O
+genes	O
+within	O
+the	O
+candidate	O
+region	O
+identified	O
+potentially	O
+deleterious	O
+CRLF1	O
+sequence	O
+variants	O
+that	O
+were	O
+not	O
+found	O
+in	O
+unaffected	O
+control	O
+individuals	O
+.	O
+
+Our	O
+findings	O
+confirm	O
+that	O
+the	O
+cold	O
+-	O
+induced	O
+sweating	O
+syndrome	O
+is	O
+an	O
+autosomal	O
+recessive	O
+disorder	O
+that	O
+is	O
+probably	O
+caused	O
+by	O
+impaired	O
+function	O
+of	O
+the	O
+CRLF1	O
+gene	O
+,	O
+and	O
+they	O
+suggest	O
+important	O
+developmental	O
+functions	O
+for	O
+human	O
+CRLF1	O
+.	O
+
+Clinical	O
+/	O
+methodological	O
+issue	O
+Brain	O
+tumors	O
+are	O
+the	O
+most	O
+common	O
+solid	O
+tumors	O
+in	O
+childhood	O
+and	O
+the	O
+most	O
+frequent	O
+cancer	O
+after	O
+leukemia	O
+.	O
+
+The	O
+incidence	B-EPI
+is	O
+continuously	O
+increasing	O
+.	O
+
+The	O
+WHO	O
+classification	O
+of	O
+brain	O
+tumors	O
+,	O
+valid	O
+since	O
+2016	O
+,	O
+is	O
+now	O
+based	O
+on	O
+the	O
+combination	O
+of	O
+histological	O
+and	O
+molecular	O
+genetic	O
+diagnostics	O
+.	O
+
+Standard	O
+radiological	O
+methods	O
+Diagnostics	O
+are	O
+mainly	O
+performed	O
+with	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+;	O
+only	O
+in	O
+emergencies	O
+with	O
+computed	O
+tomography	O
+(	O
+CT	O
+)	O
+.	O
+
+Methodological	O
+innovations	O
+Diffusion	O
+and	O
+susceptibility	O
+weighted	O
+and	O
+dynamic	O
+contrast	O
+-	O
+enhanced	O
+imaging	O
+and	O
+spectroscopy	O
+are	O
+used	O
+.	O
+
+Performance	O
+Improved	O
+diagnosis	O
+regarding	O
+dignity	O
+,	O
+size	O
+determination	O
+,	O
+adjacency	O
+assessment	O
+,	O
+and	O
+morphological	O
+description	O
+of	O
+tumor	O
+composition	O
+.	O
+
+Achievements	O
+Modern	O
+MRI	O
+with	O
+functional	O
+techniques	O
+is	O
+now	O
+the	O
+gold	O
+standard	O
+for	O
+differential	O
+diagnosis	O
+and	O
+staging	O
+of	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+tumors	O
+in	O
+pediatrics	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+diabetes	O
+continues	O
+to	O
+rise	O
+worldwide	B-LOC
+.	O
+
+In	O
+addition	O
+to	O
+rising	O
+rates	O
+of	O
+diabetic	O
+kidney	O
+disease	O
+,	O
+we	O
+are	O
+also	O
+seeing	O
+a	O
+parallel	O
+rise	O
+in	O
+nondiabetic	O
+kidney	O
+disease	O
+among	O
+patients	O
+with	O
+diabetes	O
+.	O
+
+These	O
+nondiabetic	O
+lesions	O
+include	O
+focal	O
+segmental	O
+glomerulosclerosis	O
+,	O
+IgA	O
+nephropathy	O
+,	O
+membranous	O
+nephropathy	O
+,	O
+and	O
+other	O
+glomerular	O
+diseases	O
+.	O
+
+The	O
+management	O
+of	O
+diabetic	O
+kidney	O
+disease	O
+is	O
+rapidly	O
+evolving	O
+to	O
+include	O
+,	O
+beyond	O
+glycemic	O
+control	O
+and	O
+renin	O
+angiotensin	O
+inhibition	O
+,	O
+the	O
+use	O
+of	O
+sodium	O
+-	O
+glucose	O
+cotransporter	O
+2	O
+(	O
+SGLT2	O
+)	O
+inhibitors	O
+and	O
+mineralocorticoid	O
+receptor	O
+antagonists	O
+.	O
+
+These	O
+and	O
+other	O
+new	O
+treatment	O
+strategies	O
+should	O
+be	O
+applicable	O
+to	O
+managing	O
+glomerular	O
+disease	O
+in	O
+diabetic	O
+patients	O
+to	O
+reduce	O
+toxicities	O
+associated	O
+with	O
+immunosuppression	O
+and	O
+,	O
+in	O
+particular	O
+,	O
+corticosteroids	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+glomerular	O
+disease	O
+in	O
+diabetic	O
+patients	O
+is	O
+underappreciated	O
+.	O
+
+Diagnosis	O
+and	O
+appropriately	O
+treating	O
+these	O
+diseases	O
+remain	O
+an	O
+important	O
+avenue	O
+to	O
+modify	O
+kidney	O
+outcomes	O
+in	O
+diabetic	O
+patients	O
+.	O
+
+Rationale	O
+A	O
+growing	O
+body	O
+of	O
+literature	O
+has	O
+identified	O
+a	O
+robust	O
+relationship	O
+between	O
+the	O
+experience	O
+of	O
+racial	O
+discrimination	O
+and	O
+negative	O
+self	O
+-	O
+reported	O
+physical	O
+and	O
+mental	O
+health	O
+outcomes	O
+.	O
+
+Objective	O
+The	O
+current	O
+study	O
+seeks	O
+to	O
+identify	O
+which	O
+factors	O
+-at	O
+the	O
+community	O
+level-	O
+predict	O
+racial	O
+disparities	O
+in	O
+actual	O
+disease	O
+manifestation	O
+.	O
+
+This	O
+study	O
+focuses	O
+on	O
+the	O
+extent	O
+to	O
+which	O
+regional	O
+demographics	O
+and	O
+racial	O
+attitudes	O
+,	O
+both	O
+implicit	O
+and	O
+explicit	O
+,	O
+are	O
+associated	O
+with	O
+prevalence	B-EPI
+rates	O
+of	O
+several	O
+diseases	O
+for	O
+Black	O
+and	O
+White	O
+patients	O
+in	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+.	O
+
+Methods	O
+Implicit	O
+and	O
+explicit	O
+racial	O
+attitudes	O
+obtained	O
+from	O
+Project	O
+Implicit	O
+(	O
+Xu	O
+et	O
+al	O
+.	O
+,	O
+2017	O
+)	O
+were	O
+aggregated	O
+at	O
+the	O
+county	O
+level	O
+to	O
+predict	O
+variation	O
+in	O
+the	O
+prevalence	B-EPI
+rates	O
+of	O
+several	O
+chronic	O
+illnesses	O
+among	O
+Medicare	O
+recipients	O
+.	O
+
+Results	O
+When	O
+controlling	O
+for	O
+economic	O
+indicators	O
+,	O
+Black	O
+and	O
+White	O
+patients	O
+who	O
+live	O
+in	O
+areas	O
+with	O
+high	O
+implicit	O
+and	O
+explicit	O
+racial	O
+bias	O
+tend	O
+to	O
+exhibit	O
+a	O
+higher	O
+incidence	B-EPI
+of	O
+chronic	O
+health	O
+problems	O
+,	O
+including	O
+cancer	O
+,	O
+stroke	O
+,	O
+asthma	O
+,	O
+diabetes	O
+,	O
+and	O
+heart	O
+failure	O
+.	O
+
+These	O
+relationships	O
+tended	O
+to	O
+be	O
+stronger	O
+for	O
+Black	O
+patients	O
+.	O
+
+Additionally	O
+,	O
+patients	O
+in	O
+racially	O
+diverse	O
+and	O
+racially	O
+segregated	O
+regions	O
+also	O
+tended	O
+to	O
+exhibit	O
+a	O
+higher	O
+incidence	B-EPI
+of	O
+chronic	O
+health	O
+problems	O
+.	O
+
+Conclusion	O
+Findings	O
+from	O
+the	O
+study	O
+highlight	O
+the	O
+reliable	O
+relationship	O
+between	O
+both	O
+racial	O
+biases	O
+and	O
+regional	O
+demographics	O
+and	O
+the	O
+incidence	B-EPI
+rates	O
+of	O
+several	O
+chronic	O
+diseases	O
+,	O
+particularly	O
+in	O
+Black	O
+patients	O
+.	O
+
+The	O
+deficiency	O
+of	O
+21	O
+-	O
+hydroxylase	O
+due	O
+to	O
+CYP21A2	O
+pathogenic	O
+variants	O
+is	O
+a	O
+rather	O
+frequent	O
+disease	O
+with	O
+serious	O
+consequences	O
+,	O
+going	O
+from	O
+a	O
+real	O
+mortality	O
+risk	O
+to	O
+infertility	O
+and	O
+to	O
+milder	O
+symptoms	O
+,	O
+nevertheless	O
+important	O
+for	O
+affecting	O
+the	O
+patients	O
+'	O
+self	O
+-	O
+esteem	O
+.	O
+
+In	O
+the	O
+most	O
+severe	O
+cases	O
+life	O
+-	O
+threatening	O
+adrenal	O
+salt	O
+wasting	O
+crises	O
+may	O
+occur	O
+.	O
+
+Significant	O
+morbidity	O
+including	O
+the	O
+possibility	O
+of	O
+mistaken	O
+gender	O
+determination	O
+,	O
+precocious	O
+puberty	O
+,	O
+infertility	O
+and	O
+growth	O
+arrest	O
+with	O
+consequent	O
+short	O
+stature	O
+may	O
+also	O
+affect	O
+these	O
+patients	O
+.	O
+
+In	O
+the	O
+less	O
+severe	O
+cases	O
+milder	O
+symptoms	O
+like	O
+hirsutism	O
+will	O
+likely	O
+affect	O
+the	O
+image	O
+of	O
+the	O
+self	O
+with	O
+strong	O
+psychological	O
+consequences	O
+.	O
+
+Its	O
+diagnosis	O
+is	O
+confirmed	O
+by	O
+17OH	O
+-	O
+progesterone	O
+dosages	O
+exceeding	O
+the	O
+cut	O
+-	O
+off	O
+value	O
+of	O
+10/15	B-STAT
+ng	O
+/	O
+ml	O
+but	O
+genotyping	O
+is	O
+progressively	O
+assuming	O
+an	O
+essential	O
+role	O
+in	O
+the	O
+study	O
+of	O
+these	O
+patients	O
+particularly	O
+in	O
+confirming	O
+difficult	O
+cases	O
+,	O
+determining	O
+some	O
+aspects	O
+of	O
+the	O
+prognosis	O
+and	O
+allowing	O
+a	O
+correct	O
+genetic	O
+counseling	O
+.	O
+
+Genotyping	O
+is	O
+a	O
+difficult	O
+process	O
+due	O
+to	O
+the	O
+occurrence	B-EPI
+of	O
+both	O
+a	O
+gene	O
+and	O
+a	O
+highly	O
+homologous	O
+pseudo	O
+gene	O
+.	O
+
+However	O
+,	O
+new	O
+tools	O
+are	O
+opening	O
+new	O
+possibilities	O
+to	O
+this	O
+analysis	O
+and	O
+improving	O
+the	O
+chances	O
+of	O
+a	O
+correct	O
+diagnosis	O
+and	O
+better	O
+understanding	O
+of	O
+the	O
+underlying	O
+mechanisms	O
+of	O
+the	O
+disease	O
+.	O
+
+Beyond	O
+the	O
+10	O
+classic	O
+pathogenic	O
+variants	O
+usually	O
+searched	O
+for	O
+in	O
+most	O
+laboratories	O
+,	O
+a	O
+correct	O
+analysis	O
+of	O
+21OH	O
+-	O
+deficiency	O
+cases	O
+implies	O
+completely	O
+sequencing	O
+of	O
+the	O
+entire	O
+gene	O
+and	O
+the	O
+determination	O
+of	O
+gene	O
+duplications	O
+.	O
+
+These	O
+are	O
+now	O
+recognized	O
+to	O
+occur	O
+frequently	O
+and	O
+can	O
+be	O
+responsible	O
+for	O
+some	O
+false	O
+positive	O
+cases	O
+.	O
+
+And	O
+finally	O
+,	O
+because	O
+gene	O
+conversions	O
+can	O
+include	O
+several	O
+pathogenic	O
+variants	O
+one	O
+can	O
+not	O
+be	O
+certain	O
+of	O
+identifying	O
+that	O
+both	O
+alleles	O
+are	O
+affected	O
+without	O
+studying	O
+parental	O
+DNA	O
+samples	O
+.	O
+
+A	O
+complete	O
+genotype	O
+characterization	O
+should	O
+be	O
+considered	O
+essential	O
+in	O
+the	O
+preparation	O
+for	O
+pregnancy	O
+,	O
+even	O
+in	O
+the	O
+case	O
+of	O
+parents	O
+with	O
+milder	O
+forms	O
+of	O
+the	O
+disease	O
+,	O
+or	O
+even	O
+just	O
+carriers	O
+,	O
+since	O
+it	O
+has	O
+been	O
+reported	O
+that	O
+giving	O
+birth	O
+to	O
+progeny	O
+with	O
+the	O
+severe	O
+classic	O
+forms	O
+occurs	B-EPI
+with	O
+a	O
+much	O
+higher	O
+frequency	O
+than	O
+expected	O
+.	O
+
+Background	O
+The	O
+degenerative	O
+cerebellar	O
+ataxias	O
+comprise	O
+a	O
+large	O
+and	O
+heterogeneous	O
+group	O
+of	O
+neurological	O
+diseases	O
+whose	O
+hallmark	O
+clinical	O
+feature	O
+is	O
+ataxia	O
+,	O
+and	O
+which	O
+are	O
+accompanied	O
+,	O
+to	O
+variable	O
+degrees	O
+,	O
+by	O
+other	O
+features	O
+that	O
+are	O
+attributable	O
+to	O
+cerebellar	O
+dysfunction	O
+.	O
+
+Essential	O
+tremor	O
+(	O
+ET	O
+)	O
+is	O
+an	O
+exceptionally	O
+common	O
+neurological	O
+disease	O
+whose	O
+primary	O
+motor	O
+feature	O
+is	O
+action	O
+tremor	O
+,	O
+although	O
+patients	O
+often	O
+manifest	O
+intention	O
+tremor	O
+,	O
+mild	O
+gait	O
+ataxia	O
+and	O
+several	O
+other	O
+features	O
+of	O
+cerebellar	O
+dysfunction	O
+.	O
+
+Main	O
+body	O
+In	O
+this	O
+paper	O
+,	O
+we	O
+review	O
+the	O
+abundant	O
+evidence	O
+derived	O
+from	O
+clinical	O
+,	O
+neuroimaging	O
+and	O
+postmortem	O
+studies	O
+,	O
+linking	O
+ET	O
+to	O
+cerebellar	O
+dysfunction	O
+.	O
+
+Furthermore	O
+,	O
+we	O
+review	O
+the	O
+combination	O
+of	O
+clinical	O
+,	O
+natural	O
+history	O
+and	O
+postmortem	O
+features	O
+suggesting	O
+that	O
+ET	O
+is	O
+neurodegenerative	O
+.	O
+
+We	O
+then	O
+compare	O
+the	O
+prevalence	B-EPI
+of	O
+ET	O
+(	O
+400	B-STAT
+-	I-STAT
+900	I-STAT
+cases	I-STAT
+per	I-STAT
+100,000	I-STAT
+)	I-STAT
+to	O
+that	O
+of	O
+the	O
+other	O
+cerebellar	O
+degenerations	O
+(	O
+ranging	O
+from	O
+<	O
+0.5	B-STAT
+-	I-STAT
+9	I-STAT
+cases	I-STAT
+per	I-STAT
+100,000	I-STAT
+,	I-STAT
+and	O
+in	O
+composite	O
+likely	O
+to	O
+be	O
+on	O
+the	O
+order	O
+of	O
+20	B-STAT
+cases	I-STAT
+per	I-STAT
+100,000	I-STAT
+)	I-STAT
+and	O
+conclude	O
+that	O
+ET	O
+is	O
+20	O
+to	O
+45	O
+times	O
+more	O
+prevalent	B-EPI
+than	O
+all	O
+other	O
+forms	O
+of	O
+cerebellar	O
+degeneration	O
+combined	O
+.	O
+
+Conclusion	O
+Given	O
+the	O
+data	O
+we	O
+present	O
+,	O
+it	O
+is	O
+logical	O
+to	O
+conclude	O
+that	O
+ET	O
+is	O
+,	O
+by	O
+far	O
+,	O
+the	O
+most	O
+common	O
+form	O
+of	O
+cerebellar	O
+degeneration	O
+.	O
+
+Background	O
+Cardiac	O
+rupture	O
+(	O
+CR	O
+)	O
+is	O
+a	O
+fatal	O
+complication	O
+of	O
+ST	B-LOC
+-	O
+elevation	O
+myocardial	O
+infarction	O
+(	O
+STEMI	O
+)	O
+with	O
+its	O
+incidence	B-EPI
+markedly	O
+declined	O
+in	O
+the	O
+recent	O
+decades	O
+.	O
+
+However	O
+,	O
+clinical	O
+features	O
+of	O
+CR	O
+patients	O
+now	O
+and	O
+the	O
+effect	O
+of	O
+reperfusion	O
+therapy	O
+to	O
+CR	O
+remain	O
+unclear	O
+.	O
+
+We	O
+investigated	O
+the	O
+clinical	O
+features	O
+of	O
+CR	O
+in	O
+STEMI	O
+patients	O
+and	O
+the	O
+effect	O
+of	O
+reperfusion	O
+therapy	O
+to	O
+CR	O
+in	O
+mice	O
+.	O
+
+Methods	O
+Two	O
+studies	O
+were	O
+conducted	O
+.	O
+
+In	O
+clinical	O
+study	O
+,	O
+data	O
+of	O
+1456	O
+STEMI	O
+patients	O
+admitted	O
+to	O
+the	O
+First	O
+Hospital	O
+,	O
+Xi'an	O
+Jiaotong	O
+University	O
+during	O
+2015.12	O
+.	O
+
+~	O
+2018.12	O
+.	O
+were	O
+analyzed	O
+.	O
+
+In	O
+experimental	O
+study	O
+,	O
+83	O
+male	O
+C57BL/6	O
+mice	O
+were	O
+operated	O
+to	O
+induce	O
+MI	O
+.	O
+
+Of	O
+them	O
+,	O
+39	O
+mice	O
+were	O
+permanent	O
+MI	O
+(	O
+group-1	O
+)	O
+,	O
+and	O
+remaining	O
+mice	O
+received	O
+reperfusion	O
+after	O
+1	O
+h	O
+ischemia	O
+(	O
+21	O
+mice	O
+,	O
+group-2	O
+)	O
+or	O
+4	O
+h	O
+ischemia	O
+(	O
+23	O
+mice	O
+,	O
+group-3	O
+)	O
+.	O
+
+All	O
+operated	O
+mice	O
+were	O
+monitored	O
+up	O
+to	O
+day-10	O
+.	O
+
+Animals	O
+were	O
+inspected	O
+three	O
+times	O
+daily	O
+for	O
+the	O
+incidence	B-EPI
+of	O
+death	O
+and	O
+autopsy	O
+was	O
+done	O
+for	O
+all	O
+mice	O
+found	O
+died	O
+to	O
+determine	O
+the	O
+cause	O
+of	O
+death	O
+.	O
+
+Results	O
+CR	O
+was	O
+diagnosed	O
+in	O
+40	O
+patients	O
+:	O
+free	O
+-	O
+wall	O
+rupture	O
+in	O
+17	O
+,	O
+ventricular	O
+septal	O
+rupture	O
+in	O
+20	O
+,	O
+and	O
+combined	O
+locations	O
+in	O
+3	O
+cases	O
+.	O
+
+CR	O
+presented	O
+in	O
+19	O
+patients	O
+at	O
+admission	O
+and	O
+diagnosed	O
+in	O
+another	O
+21	O
+patients	O
+during	O
+1	O
+~	O
+14	O
+days	O
+post	O
+-	O
+STEMI	O
+,	O
+giving	O
+an	O
+in	O
+-	O
+hospital	O
+incidence	B-EPI
+of	O
+1.4	B-STAT
+%	I-STAT
+.	O
+
+The	O
+mortality	O
+of	O
+CR	O
+patients	O
+was	O
+high	O
+during	O
+hospitalization	O
+accounting	O
+for	O
+39	O
+%	O
+of	O
+total	O
+in	O
+-	O
+hospital	O
+death	O
+.	O
+
+By	O
+multivariate	O
+logistic	O
+regression	O
+analysis	O
+,	O
+older	O
+age	O
+,	O
+peak	O
+CK	O
+-	O
+MB	O
+and	O
+peak	O
+hs	O
+-	O
+CRP	O
+were	O
+independent	O
+predictors	O
+of	O
+CR	O
+post	O
+-	O
+STEMI	O
+.	O
+
+In	O
+mice	O
+with	O
+non	O
+-	O
+reperfused	O
+MI	O
+,	O
+17	O
+animals	O
+(	O
+43.6	O
+%	O
+)	O
+died	O
+of	O
+CR	O
+that	O
+occurred	O
+during	O
+3	O
+-	O
+6	O
+days	O
+post	O
+-	O
+MI	O
+.	O
+
+In	O
+MI	O
+mice	O
+received	O
+early	O
+or	O
+delayed	O
+reperfusion	O
+,	O
+all	O
+mice	O
+survived	O
+to	O
+the	O
+end	O
+of	O
+experiment	O
+except	O
+one	O
+mouse	O
+died	O
+of	O
+acute	O
+heart	O
+failure	O
+.	O
+
+Conclusion	O
+CR	O
+remains	O
+as	O
+a	O
+major	O
+cause	O
+of	O
+in	O
+-	O
+hospital	O
+death	O
+in	O
+STEMI	O
+patients	O
+.	O
+
+CR	O
+patients	O
+are	O
+characterized	O
+of	O
+being	O
+elderly	O
+,	O
+having	O
+larger	O
+infarct	O
+and	O
+more	O
+server	O
+inflammation	O
+.	O
+
+Experimentally	O
+,	O
+reperfusion	O
+post	O
+-	O
+MI	O
+prevented	O
+CR	O
+.	O
+
+Purpose	O
+We	O
+evaluated	O
+the	O
+various	O
+accompanied	O
+malformations	O
+in	O
+patients	O
+with	O
+anal	O
+atresia	O
+or	O
+tracheoesophageal	O
+fistula	O
+(	O
+TEF	O
+)	O
+.	O
+
+Furthermore	O
+,	O
+we	O
+determined	O
+the	O
+prevalence	B-EPI
+of	O
+VACTERL	O
+association	O
+and	O
+compared	O
+the	O
+clinical	O
+findings	O
+with	O
+those	O
+of	O
+patients	O
+without	O
+VACTERL	O
+association	O
+.	O
+
+Methods	O
+We	O
+enrolled	O
+the	O
+patients	O
+with	O
+anal	O
+atresia	O
+or	O
+TEF	O
+with	O
+/	O
+without	O
+esophageal	O
+atresia	O
+.	O
+
+We	O
+collected	O
+the	O
+patient	O
+data	O
+pertaining	O
+to	O
+accompanied	O
+vertebral	O
+,	O
+cardiovascular	O
+,	O
+renal	O
+or	O
+limb	O
+anomalies	O
+,	O
+single	O
+umbilical	O
+artery	O
+,	O
+maternal	O
+diabetes	O
+mellitus	O
+or	O
+drug	O
+history	O
+,	O
+and	O
+gene	O
+research	O
+.	O
+
+Results	O
+A	O
+total	O
+155	O
+patients	O
+(	O
+65	O
+boys	O
+and	O
+90	O
+girls	O
+)	O
+were	O
+enrolled	O
+with	O
+147	O
+cases	O
+of	O
+anal	O
+atresia	O
+,	O
+3	O
+cases	O
+of	O
+TEF	O
+,	O
+and	O
+5	O
+cases	O
+of	O
+anal	O
+atresia	O
+with	O
+TEF	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+accompanied	O
+anomalies	O
+was	O
+67.1	O
+%	O
+in	O
+cardiovascular	O
+,	O
+27.1	O
+%	O
+in	O
+renal	O
+,	O
+9.7	O
+%	O
+in	O
+vertebral	O
+,	O
+2.6	O
+%	O
+in	O
+limb	O
+anomalies	O
+,	O
+and	O
+3.9	O
+%	O
+in	O
+single	O
+umbilical	O
+artery	O
+.	O
+
+Thirty	O
+-	O
+six	O
+(	O
+23.2	O
+%	O
+)	O
+patients	O
+were	O
+diagnosed	O
+with	O
+VACTERL	O
+association	O
+.	O
+
+The	O
+patients	O
+with	O
+VACTERL	O
+association	O
+had	O
+a	O
+significantly	O
+higher	O
+number	O
+of	O
+male	O
+patients	O
+(	O
+58.3	O
+vs.	O
+37.0	O
+%	O
+,	O
+p	O
+=	O
+.033	O
+)	O
+and	O
+single	O
+umbilical	O
+artery	O
+(	O
+11.1	O
+vs.	O
+1.7	O
+%	O
+,	O
+p	O
+=	O
+.026	O
+)	O
+,	O
+and	O
+had	O
+a	O
+significantly	O
+lower	O
+birth	O
+weight	O
+(	O
+2.8	O
+vs.	O
+3.1	O
+kg	O
+,	O
+p	O
+=	O
+.033	O
+)	O
+than	O
+the	O
+patients	O
+without	O
+VACTERL	O
+association	O
+.	O
+
+Genetic	O
+studies	O
+were	O
+performed	O
+in	O
+111	O
+patients	O
+,	O
+and	O
+8	B-STAT
+(	O
+7.2	O
+%	O
+)	O
+had	O
+chromosomal	O
+abnormalities-3	O
+in	O
+VACTERL	O
+and	O
+5	O
+in	O
+no	O
+VACTERL	O
+group	O
+.	O
+
+Conclusion	O
+We	O
+recommend	O
+a	O
+careful	O
+evaluation	O
+for	O
+VACTERL	O
+association	O
+in	O
+patients	O
+with	O
+anal	O
+atresia	O
+or	O
+TEF	O
+.	O
+
+It	O
+is	O
+particularly	O
+important	O
+to	O
+screen	O
+for	O
+a	O
+single	O
+umbilical	O
+artery	O
+for	O
+features	O
+of	O
+VACTERL	O
+association	O
+as	O
+well	O
+as	O
+for	O
+other	O
+congenital	O
+anomalies	O
+.	O
+
+Nonalcoholic	O
+fatty	O
+liver	O
+disease	O
+(	O
+NAFLD	O
+)	O
+is	O
+the	O
+most	O
+prevalent	B-EPI
+liver	O
+disease	O
+worldwide	B-LOC
+,	O
+with	O
+potential	O
+causes	O
+stemming	O
+from	O
+obesity	O
+,	O
+metabolic	O
+syndrome	O
+,	O
+genetic	O
+disorders	O
+,	O
+and	O
+drug	O
+toxicity	O
+.	O
+
+We	O
+report	O
+a	O
+42	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+with	O
+lipodystrophy	O
+and	O
+NAFLD	O
+due	O
+to	O
+a	O
+pathogenic	O
+variant	O
+in	O
+the	O
+LMNA	O
+(	O
+D300N	O
+)	O
+gene	O
+.	O
+
+This	O
+case	O
+report	O
+attempts	O
+to	O
+encourage	O
+clinicians	O
+to	O
+consider	O
+genetic	O
+diseases	O
+,	O
+specifically	O
+lipodystrophies	O
+,	O
+when	O
+working	O
+up	O
+uncommon	O
+causes	O
+of	O
+NAFLD	O
+.	O
+
+Aim	O
+Psychogenic	O
+nonepileptic	O
+seizures	O
+(	O
+PNES	O
+)	O
+or	O
+functional	O
+seizures	O
+are	O
+universal	O
+phenomena	O
+.	O
+
+However	O
+,	O
+data	O
+on	O
+their	O
+epidemiology	O
+is	O
+limited	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+current	O
+study	O
+was	O
+to	O
+review	O
+the	O
+literature	O
+on	O
+the	O
+epidemiology	O
+of	O
+PNES	O
+and	O
+to	O
+provide	O
+analytical	O
+estimates	O
+of	O
+its	O
+incidence	B-EPI
+and	O
+prevalence	B-EPI
+based	O
+on	O
+the	O
+direct	O
+data	O
+that	O
+are	O
+available	O
+from	O
+previous	O
+studies	O
+on	O
+PNES	O
+.	O
+
+Methods	O
+The	O
+methods	O
+of	O
+this	O
+work	O
+had	O
+two	O
+parts	O
+:	O
+(	O
+1	O
+)	O
+MEDLINE	O
+,	O
+PsycINFO	O
+,	O
+and	O
+Scopus	O
+from	O
+inception	O
+to	O
+19	O
+October	O
+2019	O
+were	O
+systematically	O
+searched	O
+.	O
+
+(	O
+2	O
+)	O
+The	O
+analytical	O
+study	O
+of	O
+the	O
+incidence	B-EPI
+and	O
+prevalence	B-EPI
+of	O
+PNES	O
+was	O
+performed	O
+,	O
+based	O
+on	O
+the	O
+following	O
+data	O
+from	O
+previous	O
+studies	O
+:	O
+incidence	B-EPI
+of	O
+PNES	O
+,	O
+duration	O
+of	O
+PNES	O
+before	O
+making	O
+a	O
+diagnosis	O
+,	O
+outcome	O
+and	O
+mortality	O
+of	O
+PNES	O
+.	O
+
+Results	O
+The	O
+search	O
+strategy	O
+yielded	O
+five	O
+articles	O
+;	O
+three	O
+were	O
+on	O
+the	O
+incidence	B-EPI
+and	O
+two	O
+on	O
+the	O
+prevalence	B-EPI
+.	O
+
+In	O
+the	O
+analytical	O
+part	O
+of	O
+the	O
+study	O
+,	O
+the	O
+incidence	B-EPI
+of	O
+PNES	O
+was	O
+calculated	O
+to	O
+be	O
+3.1	O
+(	O
+95	O
+%	O
+Confidence	O
+Interval	O
+:	O
+1.1	B-STAT
+-	I-STAT
+5.1	I-STAT
+)	I-STAT
+per	I-STAT
+100,000	B-STAT
+population	I-STAT
+per	I-STAT
+year	I-STAT
+.	O
+
+The	O
+calculated	O
+prevalence	B-EPI
+rate	O
+of	O
+PNES	O
+in	O
+2019	O
+was	O
+108.5	O
+(	O
+95	O
+%	O
+Confidence	O
+Interval	O
+:	O
+39.2	B-STAT
+-	I-STAT
+177.8	I-STAT
+)	I-STAT
+per	I-STAT
+100,000	I-STAT
+population	I-STAT
+,	O
+in	O
+the	O
+USA	B-LOC
+.	O
+
+Conclusion	O
+While	O
+,	O
+the	O
+generalizability	O
+of	O
+these	O
+calculated	O
+incidence	B-EPI
+and	O
+prevalence	B-EPI
+rates	O
+to	O
+other	O
+places	O
+in	O
+the	O
+world	O
+is	O
+limited	O
+,	O
+they	O
+give	O
+us	O
+a	O
+reasonable	O
+hint	O
+that	O
+PNES	O
+is	O
+a	O
+common	O
+condition	O
+and	O
+the	O
+prevalence	B-EPI
+is	O
+much	O
+more	O
+than	O
+that	O
+it	O
+was	O
+thought	O
+before	O
+.	O
+Supplemental	O
+data	O
+for	O
+this	O
+article	O
+is	O
+available	O
+online	O
+at	O
+https://doi.org/10.1080/00207454.2021.1942870	B-LOC
+.	O
+
+Background	O
+Studies	O
+have	O
+shown	O
+that	O
+the	O
+human	O
+T	O
+-	O
+lymphotropic	O
+virus	O
+2	O
+(	O
+HTLV-2	O
+)	O
+is	O
+endemic	O
+in	O
+several	O
+indigenous	O
+populations	O
+of	O
+the	O
+Brazilian	O
+Amazon	O
+and	O
+molecular	O
+analyses	O
+have	O
+shown	O
+the	O
+exclusive	O
+presence	O
+of	O
+HTLV-2	O
+subtype	O
+2c	O
+among	O
+the	O
+indigenous	O
+groups	O
+of	O
+this	O
+geographical	O
+region	O
+.	O
+
+Methods	O
+The	O
+present	O
+study	O
+characterizes	O
+the	O
+prevalence	B-EPI
+of	O
+HTLV-2	O
+infection	O
+in	O
+three	O
+new	O
+villages	O
+of	O
+the	O
+Xikrin	O
+tribe	O
+,	O
+in	O
+the	O
+Kayapo	O
+group	O
+,	O
+according	O
+to	O
+their	O
+distribution	O
+by	O
+sex	O
+and	O
+age	O
+.	O
+
+The	O
+study	O
+included	O
+263	O
+samples	O
+from	O
+individuals	O
+from	O
+the	O
+Kateté	O
+,	O
+Djujeko	O
+and	O
+Oodjã	O
+villages	O
+.	O
+
+Plasma	O
+samples	O
+were	O
+tested	O
+for	O
+the	O
+presence	O
+of	O
+anti	O
+-	O
+HTLV-1/2	O
+antibodies	O
+using	O
+enzyme	O
+-	O
+linked	O
+immunosorbent	O
+assays	O
+(	O
+ELISA	O
+)	O
+.	O
+
+Seropositive	O
+samples	O
+were	O
+confirmed	O
+using	O
+real	O
+-	O
+time	O
+PCR	O
+,	O
+nested	O
+PCR	O
+and	O
+sequencing	O
+.	O
+
+Results	O
+The	O
+serological	O
+and	O
+molecular	O
+results	O
+confirmed	O
+the	O
+sole	O
+presence	O
+of	O
+HTLV-2	O
+in	O
+77	B-STAT
+(	O
+29	O
+%	O
+)	O
+samples	O
+,	O
+with	O
+a	O
+prevalence	B-EPI
+of	O
+38	O
+%	O
+among	O
+women	O
+and	O
+18	O
+%	O
+among	O
+men	O
+.	O
+
+In	O
+these	O
+communities	O
+,	O
+it	O
+was	O
+found	O
+that	O
+the	O
+prevalence	B-EPI
+of	O
+HTLV-2	O
+infection	O
+increased	O
+with	O
+age	O
+.	O
+
+Nucleotide	O
+sequences	O
+(	O
+642	O
+bp	O
+,	O
+5'LTR	O
+)	O
+from	O
+eight	O
+samples	O
+were	O
+subjected	O
+to	O
+phylogenetic	O
+analysis	O
+by	O
+the	O
+neighbor	O
+-	O
+joining	O
+method	O
+to	O
+determine	O
+the	O
+viral	O
+subtype	O
+,	O
+which	O
+confirmed	O
+the	O
+presence	O
+of	O
+HTLV-2c	O
+.	O
+
+Conclusions	O
+The	O
+results	O
+of	O
+the	O
+present	O
+study	O
+establish	O
+the	O
+presence	O
+of	O
+HTLV-2	O
+infection	O
+in	O
+three	O
+new	O
+villages	O
+of	O
+the	O
+Xikrin	O
+tribe	O
+and	O
+confirm	O
+the	O
+high	O
+endemicity	O
+of	O
+the	O
+infection	O
+in	O
+the	O
+Kayapo	O
+indigenous	O
+group	O
+of	O
+the	O
+Brazilian	O
+Amazon	O
+.	O
+
+Objective	O
+To	O
+assess	O
+the	O
+prevalence	B-EPI
+and	O
+patterns	O
+of	O
+hypodontia	O
+in	O
+nonsyndromic	O
+Pierre	O
+Robin	O
+sequence	O
+(	O
+PRS	O
+)	O
+and	O
+compare	O
+it	O
+with	O
+hypodontia	O
+in	O
+nonsyndromic	O
+isolated	O
+cleft	O
+palates	O
+and	O
+isolated	O
+cleft	O
+lips	O
+.	O
+
+Design	O
+Retrospective	O
+cohort	O
+study	O
+.	O
+
+Setting	O
+Alder	O
+Hey	O
+Children	O
+'s	O
+Hospital	O
+,	O
+United	B-LOC
+Kingdom	I-LOC
+.	O
+
+Patients	O
+Patients	O
+with	O
+nonsyndromic	O
+PRS	O
+(	O
+group	O
+1	O
+)	O
+,	O
+isolated	O
+cleft	O
+palate	O
+(	O
+group	O
+2	O
+)	O
+,	O
+and	O
+isolated	O
+cleft	O
+lip	O
+(	O
+group	O
+3	O
+)	O
+.	O
+
+Main	O
+outcome	O
+measures	O
+Hypodontia	O
+in	O
+the	O
+permanent	O
+dentition	O
+assessed	O
+from	O
+orthopantomographs	O
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+154	O
+patients	O
+were	O
+included	O
+.	O
+
+Group	O
+1	O
+had	O
+the	O
+highest	O
+incidence	B-EPI
+of	O
+hypodontia	O
+with	O
+47	O
+%	O
+having	O
+at	O
+least	O
+one	O
+tooth	O
+congenitally	O
+absent	O
+.	O
+
+Groups	O
+2	O
+and	O
+3	O
+had	O
+reduced	O
+rates	O
+of	O
+hypodontia	O
+with	O
+27	O
+%	O
+and	O
+19	O
+%	O
+of	O
+the	O
+groups	O
+missing	O
+teeth	O
+,	O
+respectively	O
+;	O
+93	O
+%	O
+of	O
+cases	O
+of	O
+hypodontia	O
+in	O
+group	O
+1	O
+involved	O
+the	O
+absence	O
+of	O
+at	O
+least	O
+one	O
+second	O
+premolar	O
+.	O
+
+Of	O
+these	O
+patients	O
+,	O
+there	O
+was	O
+found	O
+to	O
+be	O
+bilateral	O
+agenesis	O
+of	O
+second	O
+premolars	O
+in	O
+50	O
+%	O
+of	O
+cases	O
+.	O
+
+Conclusions	O
+Patients	O
+with	O
+PRS	O
+and	O
+cleft	O
+palates	O
+are	O
+more	O
+likely	O
+to	O
+have	O
+hypodontia	O
+than	O
+those	O
+with	O
+isolated	O
+cleft	O
+palates	O
+or	O
+unilateral	O
+cleft	O
+lips	O
+.	O
+
+Patients	O
+with	O
+PRS	O
+have	O
+more	O
+severe	O
+hypodontia	O
+than	O
+those	O
+with	O
+isolated	O
+cleft	O
+palates	O
+or	O
+unilateral	O
+cleft	O
+lips	O
+.	O
+
+Bilateral	O
+agenesis	O
+of	O
+lower	O
+second	O
+premolars	O
+is	O
+a	O
+commonly	O
+seen	O
+pattern	O
+among	O
+patients	O
+with	O
+PRS	O
+.	O
+
+In	O
+this	O
+large	O
+UK	B-LOC
+study	O
+,	O
+a	O
+similar	O
+prevalence	B-EPI
+and	O
+pattern	O
+of	O
+hypodontia	O
+to	O
+other	O
+nonsyndromic	O
+PRS	O
+populations	O
+worldwide	B-LOC
+has	O
+been	O
+demonstrated	O
+.	O
+
+Objective	O
+To	O
+estimate	O
+pooled	B-EPI
+prevalence	I-EPI
+of	O
+cognitive	O
+impairment	O
+in	O
+neuromyelitis	O
+opticaspectrum	O
+disorders	O
+(	O
+NMOSD	O
+)	O
+cases	O
+.	O
+
+Methods	O
+We	O
+searched	O
+PubMed	O
+,	O
+Scopus	O
+,	O
+EMBASE	O
+,	O
+Web	O
+of	O
+Science	O
+,	O
+and	O
+google	O
+scholar	O
+.	O
+
+We	O
+also	O
+searched	O
+the	O
+gray	O
+literature	O
+including	O
+references	O
+of	O
+the	O
+included	O
+studies	O
+,	O
+and	O
+conference	O
+abstracts	O
+which	O
+were	O
+published	O
+up	O
+to	O
+20th	O
+October	O
+2020	O
+.	O
+
+The	O
+search	O
+strategy	O
+included	O
+the	O
+MeSH	O
+and	O
+text	O
+words	O
+as	O
+(	O
+(	O
+(	O
+Cognitive	O
+Dysfunctions	O
+)	O
+OR	O
+Cognitive	O
+Impairment	O
+)	O
+OR	O
+Cognitive	O
+Declines	O
+)	O
+OR	O
+Mild	O
+Cognitive	O
+Impairment	O
+)	O
+OR	O
+Mental	O
+Deterioration	O
+)	O
+AND	O
+(	O
+Neuromyelitis	O
+Optica	O
+spectrum	O
+disorder	O
+OR	O
+NMOSD	O
+OR	O
+Devic	O
+syndrome	O
+OR	O
+Neuromyelitis	O
+Optica	O
+spectrum	O
+disorders	O
+)	O
+.	O
+
+Results	O
+The	O
+literature	O
+search	O
+revealed	O
+1830	O
+articles	O
+,	O
+after	O
+deleting	O
+duplicates	O
+1434	O
+remained	O
+.	O
+
+For	O
+the	O
+meta	O
+-	O
+analysis	O
+,	O
+25	O
+studies	O
+were	O
+included	O
+.	O
+
+Totally	O
+,	O
+761	O
+NMOSD	O
+patients	O
+were	O
+evaluated	O
+and	O
+329	O
+patients	O
+had	O
+cognitive	O
+impairment	O
+.	O
+
+Mean	O
+age	O
+ranged	O
+from	O
+34	O
+-	O
+53	O
+years	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+cognitive	O
+impairment	O
+ranged	O
+from	O
+3	O
+%	O
+to	O
+75%.The	O
+pooled	B-EPI
+prevalence	I-EPI
+of	O
+cognitive	O
+impairment	O
+was	O
+44	O
+%	O
+,	O
+95%CI(35%-54	O
+%	O
+)	O
+,	O
+(	O
+I	O
+2	B-STAT
+=	O
+89.1	O
+%	O
+,	O
+P<0.001	O
+)	O
+which	O
+shows	O
+a	O
+high	O
+statistical	O
+heterogeneity	O
+.	O
+
+By	O
+excluding	O
+the	O
+abstract	O
+of	O
+Jung	O
+et	O
+al	O
+which	O
+was	O
+published	O
+in	O
+2009	O
+,	O
+we	O
+found	O
+that	O
+the	O
+pooled	B-EPI
+prevalence	I-EPI
+was	O
+34	O
+%	O
+(	O
+95	O
+%	O
+CI:31	O
+-	O
+37	O
+%	O
+)	O
+(	O
+I	O
+2	O
+=	O
+0	O
+)	O
+CONCLUSION	O
+:	O
+Cognitive	O
+impairment	O
+should	O
+be	O
+considered	O
+in	O
+NMOSD	O
+patients	O
+as	O
+its	O
+pooled	B-EPI
+prevalence	I-EPI
+is	O
+estimated	O
+as	O
+44	B-STAT
+%	I-STAT
+.	O
+
+Varicella	O
+-	O
+zoster	O
+virus	O
+(	O
+VZV	O
+)	O
+is	O
+a	O
+teratogen	O
+that	O
+can	O
+cross	O
+the	O
+placenta	O
+and	O
+cause	O
+the	O
+congenital	O
+varicella	O
+syndrome	O
+(	O
+CVS	O
+)	O
+,	O
+which	O
+is	O
+characterised	O
+by	O
+multi	O
+-	O
+system	O
+anomalies	O
+.	O
+
+There	O
+have	O
+been	O
+130	O
+reported	O
+cases	O
+of	O
+CVS	O
+from	O
+1947	O
+to	O
+2013	O
+.	O
+
+The	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+CVS	O
+was	O
+0.59	B-STAT
+%	I-STAT
+and	O
+0.84	B-STAT
+%	I-STAT
+for	O
+women	O
+infected	O
+with	O
+VZV	O
+during	O
+the	O
+entire	O
+pregnancy	O
+and	O
+for	O
+those	O
+infected	O
+the	O
+first	O
+20	O
+weeks	O
+of	O
+pregnancy	O
+,	O
+respectively	O
+.	O
+
+Nine	O
+cases	O
+were	O
+reported	O
+at	O
+21	O
+-	O
+27	O
+weeks	O
+of	O
+gestation	O
+and	O
+one	O
+case	O
+was	O
+identified	O
+at	O
+36	O
+weeks	O
+.	O
+
+Herpes	O
+zoster	O
+caused	O
+CVS	O
+in	O
+two	O
+cases	O
+.	O
+
+Regarding	O
+treatment	O
+,	O
+varicella	O
+zoster	O
+immunoglobulin	O
+treatment	O
+,	O
+irrespective	O
+of	O
+gestational	O
+age	O
+,	O
+should	O
+be	O
+considered	O
+in	O
+addition	O
+to	O
+antiviral	O
+drugs	O
+for	O
+women	O
+who	O
+have	O
+been	O
+exposed	O
+to	O
+or	O
+infected	O
+with	O
+virus	O
+.	O
+
+Transient	O
+global	O
+amnesia	O
+(	O
+TGA	O
+)	O
+is	O
+a	O
+benign	O
+memory	O
+disorder	O
+with	O
+etiologies	O
+that	O
+have	O
+been	O
+debated	O
+for	O
+a	O
+long	O
+time	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+stressful	O
+events	O
+before	O
+a	O
+TGA	O
+attack	O
+makes	O
+it	O
+hard	O
+to	O
+overlook	O
+these	O
+precipitating	O
+factors	O
+,	O
+given	O
+that	O
+stress	O
+has	O
+the	O
+potential	O
+to	O
+organically	O
+effect	O
+the	O
+brain	O
+.	O
+
+Cortical	O
+spreading	O
+depression	O
+(	O
+CSD	O
+)	O
+was	O
+proposed	O
+as	O
+a	O
+possible	O
+cause	O
+decades	O
+ago	O
+.	O
+
+Being	O
+a	O
+regional	O
+phenomenon	O
+,	O
+CSD	O
+seems	O
+to	O
+affect	O
+every	O
+aspect	O
+of	O
+the	O
+micro	O
+-	O
+mechanism	O
+in	O
+maintaining	O
+the	O
+homeostasis	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+(	O
+CNS	O
+)	O
+.	O
+
+Corresponding	O
+evidence	O
+regarding	O
+hemodynamic	O
+and	O
+morphological	O
+changes	O
+from	O
+TGA	O
+and	O
+CSD	O
+have	O
+been	O
+accumulated	O
+separately	O
+,	O
+but	O
+the	O
+resemblance	O
+between	O
+the	O
+two	O
+has	O
+not	O
+been	O
+systematically	O
+explored	O
+so	O
+far	O
+,	O
+which	O
+is	O
+surprising	O
+especially	O
+considering	O
+that	O
+CSD	O
+had	O
+been	O
+confirmed	O
+to	O
+cause	O
+secondary	O
+damage	O
+in	O
+the	O
+human	O
+brain	O
+.	O
+
+Thus	O
+,	O
+by	O
+deeply	O
+delving	O
+into	O
+the	O
+anatomic	O
+and	O
+electrophysiological	O
+properties	O
+of	O
+the	O
+CNS	O
+,	O
+the	O
+CSD	O
+-	O
+TGA	O
+model	O
+may	O
+render	O
+insights	O
+into	O
+the	O
+basic	O
+pathophysiology	O
+behind	O
+the	O
+façade	O
+of	O
+the	O
+enigmatic	O
+clinical	O
+presentation	O
+.	O
+
+Antiretroviral	O
+therapy	O
+(	O
+ART	O
+)	O
+has	O
+significantly	O
+improved	O
+life	O
+expectancy	O
+of	O
+infected	O
+subjects	O
+,	O
+generating	O
+a	O
+new	O
+epidemiological	O
+setting	O
+of	O
+people	O
+aging	O
+withHuman	O
+Immunodeficiency	O
+Virus	O
+(	O
+HIV	O
+)	O
+.	O
+
+People	O
+living	O
+with	O
+HIV	O
+(	O
+PLWH	O
+)	O
+,	O
+having	O
+longer	O
+life	O
+expectancy	O
+,	O
+now	O
+face	O
+several	O
+age	O
+-	O
+related	O
+conditions	O
+as	O
+well	O
+as	O
+side	O
+effects	O
+of	O
+long	O
+-	O
+term	O
+exposure	O
+of	O
+ART	O
+.	O
+
+Chronic	O
+kidney	O
+disease	O
+(	O
+CKD	O
+)	O
+is	O
+a	O
+common	O
+comorbidity	O
+in	O
+this	O
+population	O
+.	O
+
+CKD	O
+is	O
+a	O
+relentlessly	O
+progressive	O
+disease	O
+that	O
+may	O
+evolve	O
+toward	O
+end	O
+-	O
+stage	O
+renal	O
+disease	O
+(	O
+ESRD	O
+)	O
+and	O
+significantly	O
+affect	O
+quality	O
+of	O
+life	O
+and	O
+risk	O
+of	O
+death	O
+.	O
+
+Herein	O
+,	O
+we	O
+review	O
+current	O
+understanding	O
+of	O
+renal	O
+involvement	O
+in	O
+PLWH	O
+,	O
+mechanisms	O
+and	O
+risk	O
+factors	O
+for	O
+CKD	O
+as	O
+well	O
+as	O
+strategies	O
+for	O
+early	O
+recognition	O
+of	O
+renal	O
+dysfunction	O
+and	O
+best	O
+care	O
+of	O
+CKD	O
+.	O
+
+Epilepsy	O
+is	O
+common	O
+in	O
+early	O
+childhood	O
+.	O
+
+In	O
+this	O
+age	O
+group	O
+it	O
+is	O
+associated	O
+with	O
+high	O
+rates	O
+of	O
+therapy	O
+-	O
+resistance	O
+,	O
+and	O
+with	O
+cognitive	O
+,	O
+motor	O
+,	O
+and	O
+behavioural	O
+comorbidity	O
+.	O
+
+A	O
+large	O
+number	O
+of	O
+genes	O
+,	O
+with	O
+wide	O
+ranging	O
+functions	O
+,	O
+are	O
+implicated	O
+in	O
+its	O
+aetiology	O
+,	O
+especially	O
+in	O
+those	O
+with	O
+therapy	O
+-	O
+resistant	O
+seizures	O
+.	O
+
+Identifying	O
+the	O
+more	O
+common	O
+single	O
+-	O
+gene	O
+epilepsies	O
+will	O
+aid	O
+in	O
+targeting	O
+resources	O
+,	O
+the	O
+prioritization	O
+of	O
+diagnostic	O
+testing	O
+and	O
+development	O
+of	O
+precision	O
+therapy	O
+.	O
+
+Previous	O
+studies	O
+of	O
+genetic	O
+testing	O
+in	O
+epilepsy	O
+have	O
+not	O
+been	O
+prospective	O
+and	O
+population	O
+-	O
+based	O
+.	O
+
+Therefore	O
+,	O
+the	O
+population	O
+-	O
+incidence	B-EPI
+of	O
+common	O
+genetic	O
+epilepsies	O
+remains	O
+unknown	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+describe	O
+the	O
+incidence	B-EPI
+and	O
+phenotypic	O
+spectrum	O
+of	O
+the	O
+most	O
+common	O
+single	O
+-	O
+gene	O
+epilepsies	O
+in	O
+young	O
+children	O
+,	O
+and	O
+to	O
+calculate	O
+what	O
+proportion	O
+are	O
+amenable	O
+to	O
+precision	O
+therapy	O
+.	O
+
+This	O
+was	O
+a	O
+prospective	O
+national	O
+epidemiological	O
+cohort	O
+study	O
+.	O
+
+All	O
+children	O
+presenting	O
+with	O
+epilepsy	O
+before	O
+36	O
+months	O
+of	O
+age	O
+were	O
+eligible	O
+.	O
+
+Children	O
+presenting	O
+with	O
+recurrent	O
+prolonged	O
+(	O
+>	O
+10	O
+min	O
+)	O
+febrile	O
+seizures	O
+;	O
+febrile	O
+or	O
+afebrile	O
+status	O
+epilepticus	O
+(	O
+>	O
+30	O
+min	O
+)	O
+;	O
+or	O
+with	O
+clusters	O
+of	O
+two	O
+or	O
+more	O
+febrile	O
+or	O
+afebrile	O
+seizures	O
+within	O
+a	O
+24	O
+-	O
+h	O
+period	O
+were	O
+also	O
+eligible	O
+.	O
+
+Participants	O
+were	O
+recruited	O
+from	O
+all	O
+20	O
+regional	O
+paediatric	O
+departments	O
+and	O
+four	O
+tertiary	O
+children	O
+'s	O
+hospitals	O
+in	O
+Scotland	B-LOC
+over	O
+a	O
+3	O
+-	O
+year	O
+period	O
+.	O
+
+DNA	O
+samples	O
+were	O
+tested	O
+on	O
+a	O
+custom	O
+-	O
+designed	O
+104	O
+-	O
+gene	O
+epilepsy	O
+panel	O
+.	O
+
+Detailed	O
+clinical	O
+information	O
+was	O
+systematically	O
+gathered	O
+at	O
+initial	O
+presentation	O
+and	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+Clinical	O
+and	O
+genetic	O
+data	O
+were	O
+reviewed	O
+by	O
+a	O
+multidisciplinary	O
+team	O
+of	O
+clinicians	O
+and	O
+genetic	O
+scientists	O
+.	O
+
+The	O
+pathogenic	O
+significance	O
+of	O
+the	O
+genetic	O
+variants	O
+was	O
+assessed	O
+in	O
+accordance	O
+with	O
+the	O
+guidelines	O
+of	O
+UK	O
+Association	O
+of	O
+Clinical	O
+Genetic	O
+Science	O
+(	O
+ACGS	O
+)	O
+.	O
+
+Of	O
+the	O
+343	O
+patients	O
+who	O
+met	O
+inclusion	O
+criteria	O
+,	O
+333	O
+completed	O
+genetic	O
+testing	O
+,	O
+and	O
+80/333	B-STAT
+(	O
+24	O
+%	O
+)	O
+had	O
+a	O
+diagnostic	O
+genetic	O
+finding	O
+.	O
+
+The	O
+overall	O
+estimated	O
+annual	B-EPI
+incidence	I-EPI
+of	O
+single	O
+-	O
+gene	O
+epilepsies	O
+in	O
+this	O
+well	O
+-	O
+defined	O
+population	O
+was	O
+1	B-STAT
+per	I-STAT
+2120	I-STAT
+live	I-STAT
+births	I-STAT
+(	O
+47.2/100	B-STAT
+000	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+36.9	O
+-	O
+57.5	O
+)	O
+.	O
+
+PRRT2	O
+was	O
+the	O
+most	O
+common	O
+single	O
+-	O
+gene	O
+epilepsy	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+1	B-STAT
+per	I-STAT
+9970	I-STAT
+live	I-STAT
+births	I-STAT
+(	O
+10.0/100	B-STAT
+000	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+5.26	O
+-	O
+14.8	O
+)	O
+followed	O
+by	O
+SCN1A	O
+:	O
+1	B-STAT
+per	I-STAT
+12	I-STAT
+200	B-STAT
+(	I-STAT
+8.26/100	I-STAT
+000	I-STAT
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+3.93	O
+-	O
+12.6	O
+)	O
+;	O
+KCNQ2	O
+:	O
+1	B-STAT
+per	I-STAT
+17	I-STAT
+000	B-STAT
+(	I-STAT
+5.89/100	I-STAT
+000	I-STAT
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+2.24	O
+-	O
+9.56	O
+)	O
+and	O
+SLC2A1	O
+:	O
+1	B-STAT
+per	I-STAT
+24	I-STAT
+300	B-STAT
+(	I-STAT
+4.13/100	I-STAT
+000	I-STAT
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+1.07	O
+-	O
+7.19	O
+)	O
+.	O
+
+Presentation	O
+before	O
+the	O
+age	O
+of	O
+6	O
+months	O
+,	O
+and	O
+presentation	O
+with	O
+afebrile	O
+focal	O
+seizures	O
+were	O
+significantly	O
+associated	O
+with	O
+genetic	O
+diagnosis	O
+.	O
+
+Single	O
+-	O
+gene	O
+disorders	O
+accounted	O
+for	O
+a	O
+quarter	O
+of	O
+the	O
+seizure	O
+disorders	O
+in	O
+this	O
+cohort	O
+.	O
+
+Genetic	O
+testing	O
+is	O
+recommended	O
+to	O
+identify	O
+children	O
+who	O
+may	O
+benefit	O
+from	O
+precision	O
+treatment	O
+and	O
+should	O
+be	O
+mainstream	O
+practice	O
+in	O
+early	O
+childhood	O
+onset	O
+epilepsy	O
+.	O
+
+Methods	O
+:	O
+We	O
+analyzed	O
+high	O
+-	O
+resolution	O
+CT	O
+(	O
+HRCT	O
+)	O
+findings	O
+from	O
+six	O
+male	O
+patients	O
+(	O
+mean	O
+age	O
+,	O
+22.6	O
+years	O
+)	O
+with	O
+confirmed	O
+diagnoses	O
+of	O
+acute	O
+Q	O
+fever	O
+.	O
+
+Two	O
+chest	O
+radiologists	O
+analyzed	O
+the	O
+images	O
+and	O
+reached	O
+decisions	O
+by	O
+consensus	O
+.	O
+
+All	O
+patients	O
+presented	O
+fever	O
+,	O
+myalgia	O
+,	O
+prostation	O
+,	O
+headache	O
+,	O
+and	O
+dry	O
+cough	O
+.	O
+
+They	O
+also	O
+had	O
+common	O
+epidemiologic	O
+factors	O
+(	O
+recent	O
+travel	O
+for	O
+military	O
+service	O
+,	O
+where	O
+they	O
+had	O
+contact	O
+with	O
+sheep	O
+and	O
+capybara	O
+)	O
+.	O
+
+Diagnoses	O
+were	O
+confirmed	O
+by	O
+the	O
+detection	O
+of	O
+C.	O
+burnetii	O
+DNA	O
+in	O
+clinical	O
+samples	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+.	O
+
+Results	O
+:	O
+The	O
+predominant	O
+HRCT	O
+findings	O
+were	O
+areas	O
+of	O
+consolidation	O
+(	O
+100	O
+%	O
+)	O
+and	O
+nodules	O
+(	O
+66.6	O
+%	O
+)	O
+with	O
+halos	O
+of	O
+ground	O
+-	O
+glass	O
+opacity	O
+,	O
+predominantly	O
+with	O
+segmental	O
+and	O
+peripheral	O
+distributions	O
+.	O
+
+Lesions	O
+affected	O
+all	O
+lobes	O
+,	O
+and	O
+predominated	O
+in	O
+the	O
+left	O
+upper	O
+and	O
+lower	O
+lobes	O
+.	O
+
+Involvement	O
+of	O
+more	O
+than	O
+one	O
+lobe	O
+was	O
+observed	O
+in	O
+four	O
+patients	O
+.	O
+
+No	O
+pleural	O
+effusion	O
+or	O
+lymph	O
+node	O
+enlargement	O
+was	O
+found	O
+.	O
+
+Conclusion	O
+:	O
+The	O
+predominant	O
+HRCT	O
+findings	O
+in	O
+patients	O
+with	O
+acute	O
+Q	O
+fever	O
+pneumonia	O
+were	O
+bilateral	O
+,	O
+peripheral	O
+areas	O
+of	O
+consolidation	O
+and	O
+nodules	O
+with	O
+irregular	O
+contours	O
+and	O
+halos	O
+of	O
+ground	O
+-	O
+glass	O
+opacity	O
+.	O
+
+Advances	O
+in	O
+knowledge	O
+:	O
+Acute	O
+Q	O
+fever	O
+should	O
+be	O
+included	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+lesions	O
+with	O
+the	O
+halo	O
+sign	O
+on	O
+HRCT	O
+.	O
+
+Although	O
+AOA1	O
+(	O
+ataxia	O
+oculomotor	O
+apraxia1	O
+)	O
+is	O
+one	O
+of	O
+the	O
+most	O
+common	O
+causes	O
+of	O
+autosomal	O
+recessive	O
+cerebellar	O
+ataxias	O
+in	O
+Japanese	O
+population	O
+,	O
+it	O
+is	O
+reported	O
+from	O
+all	O
+over	O
+the	O
+world	O
+.	O
+
+The	O
+clinical	O
+manifestations	O
+are	O
+similar	O
+to	O
+ataxia	O
+telangiectasia	O
+in	O
+which	O
+non	O
+-	O
+neurological	O
+manifestations	O
+are	O
+absent	O
+and	O
+include	O
+almost	O
+10	O
+%	O
+of	O
+autosomal	O
+recessive	O
+cerebellar	O
+ataxias	O
+.	O
+
+Dysarthria	O
+and	O
+gait	O
+disorder	O
+are	O
+the	O
+most	O
+two	O
+common	O
+and	O
+typical	O
+manifestations	O
+.	O
+
+Oculomotor	O
+apraxia	O
+is	O
+usually	O
+seen	O
+a	O
+few	O
+years	O
+after	O
+the	O
+manifestations	O
+start	O
+.	O
+
+APTX	O
+gene	O
+on	O
+9p13.3	O
+chromosome	O
+is	O
+expressed	O
+in	O
+the	O
+cells	O
+of	O
+all	O
+human	O
+body	O
+tissues	O
+and	O
+different	O
+mutations	O
+had	O
+been	O
+discovered	O
+.	O
+
+Here	O
+we	O
+report	O
+two	O
+siblings	O
+(	O
+a	O
+girl	O
+and	O
+a	O
+boy	O
+)	O
+of	O
+consanguineous	O
+parents	O
+visited	O
+at	O
+Mofid	O
+Pediatrics	O
+Hospital	O
+in	O
+2015	O
+,	O
+with	O
+history	O
+of	O
+gait	O
+ataxia	O
+,	O
+titubation	O
+,	O
+tremor	O
+,	O
+and	O
+oculomotor	O
+apraxia	O
+around	O
+five	O
+yr	O
+old	O
+and	O
+after	O
+that	O
+.	O
+
+The	O
+brother	O
+showed	O
+symptoms	O
+of	O
+disease	O
+earlier	O
+and	O
+more	O
+severe	O
+than	O
+his	O
+sister	O
+did	O
+.	O
+
+After	O
+ruling	O
+out	O
+the	O
+common	O
+etiologies	O
+of	O
+progressive	O
+ataxia	O
+,	O
+we	O
+did	O
+genetic	O
+study	O
+for	O
+AOA1	O
+that	O
+showed	O
+a	O
+homozygous	O
+frameshift	O
+mutation	O
+as	O
+c.418_418	O
+del	O
+was	O
+found	O
+.	O
+
+This	O
+mutation	O
+was	O
+not	O
+reported	O
+before	O
+so	O
+this	O
+was	O
+a	O
+new	O
+mutation	O
+in	O
+APTX	O
+gene	O
+.	O
+
+In	O
+this	O
+study	O
+analysis	O
+of	O
+soil	O
+,	O
+water	O
+and	O
+plant	O
+residue	O
+samples	O
+is	O
+presented	O
+to	O
+evaluate	O
+the	O
+contamination	O
+levels	O
+and	O
+possible	O
+health	O
+risks	O
+.	O
+
+Hexachlorocyclohexane	O
+(	O
+HCH	O
+)	O
+is	O
+a	O
+persistent	O
+organic	O
+pollutant	O
+used	O
+as	O
+a	O
+pesticide	O
+in	O
+agricultural	O
+sector	O
+for	O
+pest	O
+control	O
+in	O
+order	O
+to	O
+obtain	O
+higher	O
+productivity	O
+.	O
+
+For	O
+analysis	O
+soil	O
+,	O
+water	O
+and	O
+crop	O
+residue	O
+samples	O
+were	O
+collected	O
+from	O
+different	O
+agricultural	O
+areas	O
+of	O
+the	O
+northern	O
+Punjab	B-LOC
+region	O
+of	O
+Pakistan	B-LOC
+.	O
+
+The	O
+investigation	O
+of	O
+the	O
+samples	O
+shows	O
+significant	O
+levels	O
+of	O
+HCH	O
+residues	O
+in	O
+all	O
+types	O
+of	O
+samples	O
+.	O
+
+Gas	O
+chromatography	O
+-	O
+mass	O
+spectrometry	O
+analysis	O
+was	O
+used	O
+to	O
+assess	O
+the	O
+higher	O
+residue	O
+levels	O
+of	O
+HCH	O
+in	O
+the	O
+samples	O
+.	O
+
+The	O
+concentration	O
+of	O
+HCH	O
+residues	O
+detected	O
+in	O
+samples	O
+ranged	O
+from	O
+2.43	O
+to	O
+8.88	O
+µg	O
+/	O
+g	O
+in	O
+soil	O
+,	O
+nd	O
+-5.87	O
+µg	O
+/	O
+l	O
+in	O
+water	O
+and	O
+nd	O
+-	O
+4.87	O
+µg	O
+/	O
+g	O
+in	O
+plants	O
+.	O
+
+The	O
+presence	O
+of	O
+HCH	O
+residues	O
+in	O
+soil	O
+,	O
+water	O
+and	O
+plant	O
+samples	O
+was	O
+beyond	O
+the	O
+recommended	O
+quality	O
+guidelines	O
+.	O
+
+Human	O
+health	O
+risk	O
+was	O
+evaluated	O
+for	O
+cancer	O
+and	O
+non	O
+-	O
+cancer	O
+risks	O
+through	O
+dietary	O
+and	O
+non	O
+-	O
+dietary	O
+exposure	O
+routes	O
+.	O
+
+The	O
+hazard	O
+index	O
+was	O
+HI	O
+>	B-STAT
+1	I-STAT
+in	I-STAT
+children	I-STAT
+and	O
+HI	O
+<	O
+1	O
+in	O
+adults	O
+,	O
+while	O
+the	O
+non	O
+-	O
+dietary	O
+incremental	O
+lifetime	O
+cancer	O
+risks	O
+(	O
+ILCR	O
+)	O
+were	O
+beyond	O
+the	O
+internationally	O
+acceptable	O
+limit	O
+of	O
+1	O
+×	O
+10	O
+-5	O
+.	O
+
+Hence	O
+,	O
+results	O
+of	O
+the	O
+present	O
+investigation	O
+concluded	O
+the	O
+presence	O
+of	O
+high	O
+levels	O
+of	O
+HCH	O
+residues	O
+in	O
+samples	O
+and	O
+pose	O
+high	O
+health	O
+risk	O
+to	O
+the	O
+inhabitants	O
+.	O
+
+These	O
+findings	O
+are	O
+alarming	O
+and	O
+apprise	O
+the	O
+concerned	O
+departments	O
+for	O
+the	O
+remediation	O
+of	O
+contamination	O
+and	O
+proper	O
+implementation	O
+of	O
+environmental	O
+laws	O
+in	O
+the	O
+area	O
+.	O
+
+The	O
+sexually	O
+transmitted	O
+enteric	O
+infections	O
+topic	O
+is	O
+one	O
+of	O
+the	O
+chapters	O
+of	O
+the	O
+Clinical	O
+Protocol	O
+and	O
+Therapeutic	O
+Guidelines	O
+for	O
+Comprehensive	O
+Care	O
+for	O
+People	O
+with	O
+Sexually	O
+Transmitted	O
+Infections	O
+,	O
+published	O
+by	O
+the	O
+Brazilian	O
+Ministry	O
+of	O
+Health	O
+in	O
+2020	O
+.	O
+
+The	O
+document	O
+was	O
+developed	O
+based	O
+on	O
+scientific	O
+evidence	O
+and	O
+validated	O
+in	O
+discussions	O
+with	O
+specialists	O
+.	O
+
+This	O
+article	O
+presents	O
+epidemiological	O
+and	O
+clinical	O
+aspects	O
+of	O
+these	O
+infections	O
+and	O
+guidance	O
+for	O
+service	O
+managers	O
+on	O
+their	O
+programmatic	O
+and	O
+operational	O
+management	O
+.	O
+
+The	O
+aim	O
+is	O
+to	O
+assist	O
+health	O
+professionals	O
+with	O
+screening	O
+,	O
+diagnosis	O
+,	O
+and	O
+treatment	O
+of	O
+people	O
+with	O
+sexually	O
+transmitted	O
+enteric	O
+infections	O
+and	O
+their	O
+sexual	O
+partners	O
+,	O
+in	O
+addition	O
+to	O
+supporting	O
+strategies	O
+for	O
+their	O
+surveillance	O
+,	O
+prevention	O
+,	O
+and	O
+control	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+anorectal	O
+sexually	O
+transmitted	O
+infections	O
+has	O
+increased	O
+over	O
+the	O
+last	O
+years	O
+,	O
+mainly	O
+due	O
+to	O
+the	O
+increase	O
+in	O
+the	O
+practice	O
+of	O
+unprotected	O
+receptive	O
+anal	O
+sexual	O
+intercourse	O
+.	O
+
+Bernard	O
+-	O
+Soulier	O
+syndrome	O
+is	O
+a	O
+rare	O
+autosomal	O
+recessive	O
+bleeding	O
+disorder	O
+and	O
+has	O
+a	O
+low	O
+incidence	B-EPI
+.	O
+
+Bernard	O
+-	O
+Soulier	O
+syndrome	O
+is	O
+caused	O
+by	O
+the	O
+deficiency	O
+of	O
+glycoprotein	O
+GPIb	O
+-	O
+V	O
+-	O
+IX	O
+complex	O
+,	O
+a	O
+receptor	O
+for	O
+von	O
+Willebrand	O
+factor	O
+and	O
+is	O
+characterized	O
+by	O
+thrombocytopenia	O
+,	O
+giant	O
+platelets	O
+and	O
+bleeding	O
+tendency	O
+.	O
+
+We	O
+are	O
+reporting	O
+three	O
+members	O
+of	O
+a	O
+same	O
+family	O
+with	O
+variable	O
+phenotypic	O
+clinical	O
+presentation	O
+.	O
+
+The	O
+index	O
+case	O
+is	O
+a	O
+20	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+who	O
+has	O
+a	O
+frequent	O
+presentation	O
+with	O
+epistaxis	O
+,	O
+and	O
+low	O
+platelet	O
+counts	O
+(	O
+25	O
+×	O
+109	O
+/	O
+l	O
+)	O
+.	O
+
+He	O
+had	O
+been	O
+hospitalized	O
+multiple	O
+times	O
+and	O
+received	O
+platelet	O
+transfusions	O
+.	O
+
+His	O
+brother	O
+and	O
+cousin	O
+reported	O
+bleeding	O
+symptoms	O
+with	O
+less	O
+frequent	O
+medical	O
+intervention	O
+.	O
+
+Genetic	O
+analysis	O
+by	O
+next	O
+-	O
+generation	O
+sequencing	O
+identified	O
+a	O
+homozygous	O
+GP1BB	O
+variant	O
+(	O
+c.423C	O
+>	O
+A	O
+:p	O
+.	O
+Cys141Ter	O
+)	O
+,	O
+which	O
+segregated	O
+amongst	O
+the	O
+family	O
+members	O
+.	O
+
+The	O
+results	O
+led	O
+us	O
+to	O
+an	O
+improved	O
+insight	O
+into	O
+the	O
+disease	O
+for	O
+this	O
+family	O
+with	O
+variable	O
+phenotypic	O
+expression	O
+,	O
+in	O
+addition	O
+to	O
+the	O
+identification	O
+of	O
+a	O
+variant	O
+for	O
+further	O
+structural	O
+and	O
+functional	O
+characterization	O
+.	O
+
+Background	O
+:	O
+Thyroid	O
+cancer	O
+is	O
+a	O
+common	O
+malignancy	O
+whose	O
+detection	O
+has	O
+increased	O
+significantly	O
+in	O
+past	O
+decades	O
+.	O
+
+Most	O
+of	O
+the	O
+increased	O
+incidence	B-EPI
+is	O
+due	O
+to	O
+detection	O
+of	O
+early	O
+well	O
+-	O
+differentiated	O
+thyroid	O
+cancer	O
+,	O
+but	O
+the	O
+incidence	B-EPI
+of	O
+more	O
+advanced	O
+thyroid	O
+cancers	O
+has	O
+increased	O
+as	O
+well	O
+.	O
+
+Recent	O
+methodological	O
+advancements	O
+have	O
+allowed	O
+for	O
+a	O
+deep	O
+understanding	O
+of	O
+the	O
+molecular	O
+underpinnings	O
+of	O
+the	O
+various	O
+types	O
+of	O
+thyroid	O
+cancer	O
+.	O
+
+Summary	O
+:	O
+Thyroid	O
+cancers	O
+harbor	O
+a	O
+high	O
+frequency	O
+of	O
+potential	O
+druggable	O
+molecular	O
+alterations	O
+,	O
+including	O
+the	O
+highest	O
+frequency	O
+of	O
+oncogenic	O
+driver	O
+kinase	O
+fusions	O
+seen	O
+across	O
+all	O
+solid	O
+tumors	O
+.	O
+
+Analyses	O
+of	O
+poorly	O
+differentiated	O
+and	O
+anaplastic	O
+thyroid	O
+carcinoma	O
+confirmed	O
+that	O
+these	O
+tumors	O
+develop	O
+from	O
+more	O
+well	O
+-	O
+differentiated	O
+follicular	O
+-	O
+derived	O
+thyroid	O
+cancers	O
+through	O
+acquired	O
+additional	O
+mutations	O
+.	O
+
+The	O
+recognition	O
+of	O
+driver	O
+genomic	O
+alterations	O
+in	O
+thyroid	O
+cancers	O
+not	O
+only	O
+predicts	O
+tumor	O
+phenotype	O
+but	O
+also	O
+now	O
+can	O
+inform	O
+treatment	O
+approaches	O
+.	O
+
+Conclusions	O
+:	O
+Major	O
+progress	O
+in	O
+understanding	O
+the	O
+oncogenic	O
+molecular	O
+underpinnings	O
+across	O
+the	O
+array	O
+of	O
+thyroid	O
+cancers	O
+has	O
+led	O
+to	O
+considerable	O
+gains	O
+in	O
+gene	O
+-	O
+specific	O
+systemic	O
+therapies	O
+for	O
+many	O
+cancers	O
+.	O
+
+This	O
+article	O
+focuses	O
+on	O
+the	O
+molecular	O
+characteristics	O
+of	O
+aggressive	O
+follicular	O
+-	O
+derived	O
+thyroid	O
+cancers	O
+and	O
+medullary	O
+thyroid	O
+cancer	O
+and	O
+highlights	O
+advancements	O
+in	O
+treating	O
+thyroid	O
+cancer	O
+in	O
+the	O
+era	O
+of	O
+targeted	O
+therapy	O
+.	O
+
+Objective	O
+Renal	O
+tubular	O
+acidosis	O
+(	O
+RTA	O
+)	O
+is	O
+a	O
+clinical	O
+manifestation	O
+that	O
+occurs	B-EPI
+with	O
+insufficiency	O
+in	O
+restoring	O
+bicarbonate	O
+or	O
+disruption	O
+in	O
+hydrogen	O
+ion	O
+elimination	O
+as	O
+a	O
+result	O
+of	O
+a	O
+disruption	O
+in	O
+tubulus	O
+functions	O
+,	O
+causing	O
+normal	O
+anion	O
+gap	O
+-	O
+opening	O
+metabolic	O
+acidosis	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+aimed	O
+to	O
+investigate	O
+the	O
+prevalence	B-EPI
+of	O
+RTA	O
+in	O
+the	O
+largest	O
+systemic	O
+lupus	O
+erythematosus	O
+(	O
+SLE	O
+)	O
+patient	O
+population	O
+to	O
+date	O
+.	O
+
+Materials	O
+and	O
+methods	O
+SLE	O
+patients	O
+,	O
+who	O
+were	O
+followed	O
+up	O
+in	O
+2	O
+different	O
+healthcare	O
+centers	O
+,	O
+were	O
+included	O
+.	O
+
+Patients	O
+with	O
+metabolic	O
+acidosis	O
+(	O
+pH	O
+<	O
+7.35	O
+and	O
+HCO3	O
+<	O
+22	O
+mEq	O
+/	O
+L	O
+)	O
+in	O
+venous	O
+blood	O
+gas	O
+analysis	O
+were	O
+determined	O
+.	O
+
+The	O
+serum	O
+and	O
+urine	O
+anion	O
+GAP	O
+of	O
+these	O
+patients	O
+were	O
+estimated	O
+,	O
+and	O
+the	O
+urine	O
+pH	O
+was	O
+assessed	O
+.	O
+
+RTA	O
+presence	O
+was	O
+evaluated	O
+as	O
+metabolic	O
+acidosis	O
+with	O
+a	O
+normal	O
+serum	O
+anion	O
+gap	O
+and	O
+a	O
+positive	O
+urine	O
+anion	O
+GAP	O
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+108	O
+patients	O
+were	O
+included	O
+in	O
+the	O
+present	O
+study	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+the	O
+patients	O
+was	O
+41.5	O
+±	O
+1.2	O
+and	O
+87	O
+%	O
+were	O
+female	O
+.	O
+
+The	O
+SLE	O
+diagnosis	O
+duration	O
+was	O
+75	O
+±	O
+5	O
+months	O
+.	O
+
+The	O
+mean	O
+creatinine	O
+value	O
+​​was	O
+0.6	O
+±	O
+0.1	O
+mg	O
+/	O
+dL	O
+and	O
+the	O
+mean	O
+eGFR	O
+was	O
+111	O
+±	O
+2	O
+mL	O
+/	O
+min	O
+.	O
+
+According	O
+to	O
+the	O
+blood	O
+gas	O
+analysis	O
+,	O
+18	O
+patients	O
+(	O
+16.7	O
+%	O
+of	O
+the	O
+total	O
+)	O
+had	O
+RTA	O
+.	O
+
+Sixteen	O
+of	O
+these	O
+patients	O
+had	O
+type	O
+1	B-STAT
+RTA	I-STAT
+and	I-STAT
+2	I-STAT
+had	O
+type	O
+2	O
+RTA	O
+;	O
+type	O
+4	O
+RTA	O
+was	O
+not	O
+determined	O
+in	O
+any	O
+of	O
+the	O
+patients	O
+.	O
+
+Conclusion	O
+RTA	O
+should	O
+be	O
+considered	O
+in	O
+SLE	O
+patients	O
+even	O
+if	O
+they	O
+have	O
+normal	O
+eGFR	O
+values	O
+.	O
+
+This	O
+is	O
+the	O
+largest	O
+study	O
+to	O
+examine	O
+the	O
+prevalence	B-EPI
+of	O
+RTA	O
+in	O
+SLE	O
+patients	O
+in	O
+the	O
+literature	O
+.	O
+
+Syndactyly	O
+and	O
+polydactyly	O
+-	O
+respectively	O
+characterized	O
+by	O
+fused	O
+and	O
+supernumerary	O
+digits	O
+-	O
+are	O
+among	O
+the	O
+most	O
+common	O
+congenital	O
+limb	O
+malformations	O
+,	O
+with	O
+syndactyly	O
+presenting	O
+at	O
+an	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+1	O
+in	O
+2,000	O
+-	O
+3,000	O
+live	O
+births	O
+and	O
+polydactyly	O
+at	O
+a	O
+frequency	O
+of	O
+1	B-STAT
+in	I-STAT
+approximately	I-STAT
+700	I-STAT
+-	O
+1,000	O
+live	O
+births	O
+.	O
+
+Despite	O
+their	O
+relatively	O
+regular	O
+manifestation	O
+in	O
+the	O
+clinic	O
+,	O
+the	O
+etiologies	O
+of	O
+syndactyly	O
+and	O
+polydactyly	O
+remain	O
+poorly	O
+understood	O
+because	O
+of	O
+their	O
+phenotypic	O
+and	O
+genetic	O
+diversity	O
+.	O
+
+Further	O
+,	O
+even	O
+though	O
+concrete	O
+knowledge	O
+of	O
+genotypic	O
+links	O
+has	O
+been	O
+established	O
+for	O
+some	O
+variants	O
+of	O
+syndactyly	O
+and	O
+polydactyly	O
+,	O
+there	O
+appears	O
+to	O
+be	O
+no	O
+single	O
+comprehensive	O
+published	O
+summary	O
+of	O
+all	O
+syndromic	O
+and	O
+nonsyndromic	O
+syndactyly	O
+and	O
+polydactyly	O
+presentations	O
+,	O
+and	O
+there	O
+is	O
+decidedly	O
+no	O
+resource	O
+that	O
+maps	O
+all	O
+syndromic	O
+and	O
+nonsyndromic	O
+syndactylies	O
+and	O
+polydactylies	O
+to	O
+their	O
+genetic	O
+bases	O
+.	O
+
+This	O
+gap	O
+in	O
+the	O
+literature	O
+problematizes	O
+comprehensive	O
+carrier	O
+screening	O
+and	O
+prenatal	O
+diagnosis	O
+and	O
+complicates	O
+novel	O
+diagnostic	O
+attempts	O
+.	O
+
+This	O
+review	O
+thus	O
+attempts	O
+to	O
+collect	O
+all	O
+that	O
+is	O
+known	O
+about	O
+the	O
+genetic	O
+bases	O
+of	O
+syndromic	O
+and	O
+nonsyndromic	O
+syndactylies	O
+and	O
+polydactylies	O
+,	O
+as	O
+well	O
+as	O
+to	O
+highlight	O
+the	O
+dactyly	O
+manifestations	O
+for	O
+which	O
+no	O
+genetic	O
+bases	O
+are	O
+as	O
+yet	O
+known	O
+.	O
+
+Then	O
+,	O
+having	O
+established	O
+a	O
+summation	O
+of	O
+existing	O
+and	O
+missing	O
+knowledge	O
+,	O
+this	O
+work	O
+briefly	O
+outlines	O
+the	O
+diagnostic	O
+techniques	O
+that	O
+a	O
+genetics	O
+-	O
+reinforced	O
+understanding	O
+of	O
+syndactyly	O
+and	O
+polydactyly	O
+could	O
+inform	O
+.	O
+
+Little	O
+information	O
+is	O
+available	O
+on	O
+the	O
+prevalences	B-EPI
+of	O
+birth	O
+defects	O
+in	O
+Korea	B-LOC
+.	O
+
+The	O
+aims	O
+of	O
+this	O
+study	O
+were	O
+to	O
+estimate	O
+recent	O
+prevalences	B-EPI
+of	O
+selected	O
+birth	O
+defects	O
+and	O
+to	O
+analyze	O
+the	O
+prevalence	B-EPI
+trends	O
+of	O
+these	O
+defects	O
+during	O
+the	O
+period	O
+from	O
+2008	O
+to	O
+2014	O
+.	O
+
+Prevalences	B-EPI
+were	O
+calculated	O
+for	O
+69	O
+major	O
+birth	O
+defects	O
+using	O
+health	O
+insurance	O
+claim	O
+data	O
+obtained	O
+from	O
+the	O
+Korea	O
+National	O
+Health	O
+Insurance	O
+Service	O
+(	O
+NHIS	O
+)	O
+.	O
+
+Prevalence	B-EPI
+rate	O
+ratios	O
+were	O
+calculated	O
+using	O
+Poisson	O
+regression	O
+to	O
+analyze	O
+trends	O
+over	O
+the	O
+7	O
+-	O
+year	O
+study	O
+period	O
+.	O
+
+The	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+a	O
+major	O
+birth	O
+defect	O
+was	O
+446.3	B-STAT
+per	I-STAT
+10,000	I-STAT
+births	I-STAT
+(	O
+95	O
+%	O
+CI	O
+:	O
+444.0⁻448.6	O
+)	O
+;	O
+470.9	B-STAT
+per	I-STAT
+10,000	I-STAT
+births	I-STAT
+(	O
+95	O
+%	O
+CI	O
+:	O
+467.6⁻474.2	O
+)	O
+for	O
+males	O
+and	O
+420.2	B-STAT
+per	I-STAT
+10,000	I-STAT
+births	I-STAT
+(	O
+95	O
+%	O
+CI	O
+:	O
+417⁻423.4	O
+)	O
+for	O
+females	O
+.	O
+
+The	O
+prevalence	B-EPI
+rates	O
+of	O
+the	O
+most	O
+common	O
+birth	O
+defects	O
+over	O
+the	O
+study	O
+period	O
+were	O
+;	O
+septal	O
+defect	O
+(	O
+138.2	B-STAT
+per	I-STAT
+10,000	I-STAT
+;	O
+95	O
+%	O
+CI	O
+:	O
+136.9⁻139.5	O
+)	O
+,	O
+congenital	O
+hip	O
+dislocation	O
+(	O
+652	B-STAT
+per	I-STAT
+10,000	I-STAT
+;	O
+95	O
+%	O
+CI	O
+:	O
+64.1⁻65.9	O
+)	O
+,	O
+and	O
+ventricular	O
+septal	O
+defect	O
+(	O
+62.62	B-STAT
+per	I-STAT
+10,000	I-STAT
+;	O
+95	O
+%	O
+CI	O
+:	O
+61.7⁻63.5	O
+)	O
+.	O
+
+During	O
+the	O
+study	O
+period	O
+,	O
+a	O
+significant	O
+increase	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+a	O
+major	O
+birth	O
+defect	O
+was	O
+observed	O
+with	O
+a	O
+prevalence	B-EPI
+rate	O
+ratio	O
+(	O
+PRR	O
+)	O
+of	O
+1.091	O
+.	O
+
+The	O
+strongest	O
+trend	O
+was	O
+observed	O
+for	O
+renal	O
+dysplasia	O
+,	O
+which	O
+had	O
+a	O
+PRR	O
+of	O
+1.275	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+1.211⁻1.343	O
+)	O
+,	O
+and	O
+upward	O
+trends	O
+were	O
+observed	O
+for	O
+urogenital	O
+anomalies	O
+,	O
+such	O
+as	O
+,	O
+renal	O
+agenesis	O
+(	O
+PRR	O
+1.102	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+1.067⁻1.138	O
+)	O
+,	O
+undescended	O
+testis	O
+(	O
+PRR	O
+1.082	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+1.072⁻1.093	O
+)	O
+and	O
+hypospadias	O
+(	O
+PRR	O
+1.067	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+1.044⁻1.090	O
+)	O
+.	O
+
+This	O
+study	O
+shows	O
+an	O
+overall	O
+increase	O
+in	O
+the	O
+prevalences	B-EPI
+of	O
+birth	O
+defects	O
+,	O
+including	O
+hypospadias	O
+and	O
+undescended	O
+testis	O
+,	O
+which	O
+are	O
+known	O
+to	O
+be	O
+associated	O
+with	O
+endocrine	O
+factors	O
+.	O
+
+In	O
+the	O
+future	O
+,	O
+standardized	O
+birth	O
+defect	O
+registries	O
+should	O
+be	O
+established	O
+to	O
+enable	O
+these	O
+trends	O
+to	O
+be	O
+monitored	O
+.	O
+
+Holoprosencephaly	O
+is	O
+a	O
+rare	O
+spectrum	O
+of	O
+congenital	O
+malformation	O
+associated	O
+with	O
+midline	O
+facial	O
+defects	O
+and	O
+absence	O
+of	O
+olfactory	O
+tract	O
+.	O
+
+Sequence	O
+occurs	B-EPI
+at	O
+4th	O
+to	O
+8th	O
+week	O
+of	O
+gestational	O
+age	O
+due	O
+to	O
+failure	O
+or	O
+incomplete	O
+diverticulation	O
+and	O
+cleavage	O
+of	O
+primitive	O
+prosencephalon	O
+.	O
+
+It	O
+is	O
+most	O
+common	O
+brain	O
+malformation	O
+with	O
+an	O
+incidence	B-EPI
+1:250	O
+in	O
+conceptuses	O
+and	O
+associated	O
+with	O
+a	O
+high	O
+rate	O
+of	O
+spontaneous	O
+abortion	O
+,	O
+and	O
+prevalence	B-EPI
+of	O
+1:16000	B-STAT
+in	O
+live	O
+borns	O
+.	O
+
+The	O
+etiopathogenesis	O
+of	O
+holoprosencephaly	O
+is	O
+heterogeneous	O
+and	O
+multifactorial	O
+,	O
+may	O
+be	O
+environmental	O
+,	O
+metabolic	O
+factors	O
+or	O
+teratogenic	O
+including	O
+insulin	O
+-	O
+dependent	O
+maternal	O
+diabetes	O
+,	O
+alcohol	O
+consumption	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+described	O
+a	O
+case	O
+of	O
+holoprosencephaly	O
+neonate	O
+with	O
+34	O
+weeks	O
+gestational	O
+age	O
+and	O
+antenatal	O
+ultrasonography	O
+diagnosed	O
+as	O
+congenital	O
+defects	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+,	O
+asymmetric	O
+growth	O
+of	O
+head	O
+.	O
+
+After	O
+birth	O
+the	O
+infant	O
+was	O
+presented	O
+with	O
+multiple	O
+congenital	O
+anomalies	O
+(	O
+cleft	O
+lip	O
+,	O
+cleft	O
+palate	O
+,	O
+microphthalmia	O
+,	O
+absent	O
+philtrum	O
+,	O
+absent	O
+nasal	O
+septum	O
+with	O
+single	O
+naris	O
+)	O
+similar	O
+to	O
+holoprosencephaly	O
+sequence	O
+.	O
+
+Objectives	O
+Neonatal	O
+herpes	O
+simplex	O
+virus	O
+(	O
+HSV	O
+)	O
+infections	O
+are	O
+associated	O
+with	O
+high	O
+mortality	O
+and	O
+long	O
+-	O
+term	O
+morbidity	O
+.	O
+
+However	O
+,	O
+incidence	B-EPI
+is	O
+low	O
+and	O
+acyclovir	O
+,	O
+the	O
+treatment	O
+of	O
+choice	O
+,	O
+carries	O
+risk	O
+of	O
+toxicity	O
+.	O
+
+We	O
+aimed	O
+to	O
+increase	O
+the	O
+percentage	O
+of	O
+patients	O
+0	O
+to	O
+60	O
+days	O
+of	O
+age	O
+who	O
+are	O
+tested	O
+and	O
+treated	O
+for	O
+HSV	O
+in	O
+accordance	O
+with	O
+local	O
+guideline	O
+recommendations	O
+from	O
+40	O
+%	O
+to	O
+80	O
+%	I-STAT
+.	O
+
+Methods	O
+This	O
+quality	O
+improvement	O
+project	O
+took	O
+place	O
+at	O
+1	O
+freestanding	O
+children	O
+'s	O
+hospital	O
+.	O
+
+Multiple	O
+plan	O
+-	O
+do	O
+-	O
+study	O
+-	O
+act	O
+cycles	O
+were	O
+focused	O
+on	O
+interventions	O
+aimed	O
+at	O
+key	O
+drivers	O
+including	O
+provider	O
+buy	O
+-	O
+in	O
+,	O
+guideline	O
+availability	O
+,	O
+and	O
+accurate	O
+identification	O
+of	O
+high	O
+-	O
+risk	O
+patients	O
+.	O
+
+A	O
+run	O
+chart	O
+was	O
+used	O
+to	O
+track	O
+the	O
+effect	O
+of	O
+interventions	O
+on	O
+the	O
+percentage	O
+managed	O
+per	O
+guideline	O
+recommendations	O
+over	O
+time	O
+by	O
+using	O
+established	O
+rules	O
+for	O
+determining	O
+special	O
+cause	O
+.	O
+
+Pre-	O
+and	O
+postimplementation	O
+acyclovir	O
+use	O
+was	O
+compared	O
+by	O
+using	O
+a	O
+χ	O
+2	O
+test	O
+.	O
+
+In	O
+HSV	O
+-	O
+positive	O
+cases	O
+,	O
+delayed	O
+acyclovir	O
+initiation	O
+,	O
+defined	O
+as	O
+>	O
+1	O
+day	O
+from	O
+presentation	O
+,	O
+was	O
+tracked	O
+as	O
+a	O
+balancing	O
+measure	O
+.	O
+
+Results	O
+The	O
+median	O
+percentage	O
+of	O
+patients	O
+managed	O
+according	O
+to	O
+guideline	O
+recommendations	O
+increased	O
+from	O
+40	O
+%	O
+to	O
+80	O
+%	O
+within	O
+8	O
+months	O
+.	O
+
+Acyclovir	O
+use	O
+decreased	O
+from	O
+26	O
+%	O
+to	O
+7.9	O
+%	O
+(	O
+P	O
+<	O
+.001	O
+)	O
+in	O
+non	O
+-	O
+high	O
+-	O
+risk	O
+patients	O
+but	O
+did	O
+not	O
+change	O
+significantly	O
+in	O
+high	O
+-	O
+risk	O
+patients	O
+(	O
+73%-83	O
+%	O
+;	O
+P	O
+=	O
+.15	O
+)	O
+.	O
+
+There	O
+were	O
+no	O
+cases	O
+of	O
+delayed	O
+acyclovir	O
+initiation	O
+in	O
+HSV	O
+-	O
+positive	O
+cases	O
+.	O
+
+Conclusions	O
+Point	O
+-	O
+of	O
+-	O
+care	O
+availability	O
+of	O
+an	O
+evidence	O
+-	O
+based	O
+guideline	O
+and	O
+interventions	O
+targeted	O
+at	O
+provider	O
+engagement	O
+improved	O
+adherence	O
+to	O
+a	O
+new	O
+guideline	O
+for	O
+neonatal	O
+HSV	O
+management	O
+and	O
+decreased	O
+acyclovir	O
+use	O
+in	O
+non	O
+-	O
+high	O
+-	O
+risk	O
+infants	O
+.	O
+
+Further	O
+study	O
+is	O
+necessary	O
+to	O
+confirm	O
+the	O
+safety	O
+of	O
+these	O
+recommendations	O
+in	O
+other	O
+settings	O
+.	O
+
+Deficiency	O
+of	O
+hypoxanthine	O
+-	O
+guanine	O
+phosphoribosyltransferase	O
+(	O
+HPRT	O
+)	O
+activity	O
+is	O
+an	O
+inborn	O
+error	O
+of	O
+purine	O
+metabolism	O
+associated	O
+with	O
+uric	O
+acid	O
+overproduction	O
+and	O
+a	O
+continuum	O
+spectrum	O
+of	O
+neurological	O
+manifestations	O
+depending	O
+on	O
+the	O
+degree	O
+of	O
+the	O
+enzymatic	O
+deficiency	O
+.	O
+
+The	O
+prevalence	B-EPI
+is	O
+estimated	O
+at	O
+1/380,000	B-STAT
+live	I-STAT
+births	I-STAT
+in	O
+Canada	B-LOC
+,	O
+and	O
+1/235,000	B-STAT
+live	I-STAT
+births	I-STAT
+in	O
+Spain	B-LOC
+.	O
+
+Uric	O
+acid	O
+overproduction	O
+is	O
+present	O
+inall	O
+HPRT	O
+-	O
+deficient	O
+patients	O
+and	O
+is	O
+associated	O
+with	O
+lithiasis	O
+and	O
+gout	O
+.	O
+
+Neurological	O
+manifestations	O
+include	O
+severe	O
+action	O
+dystonia	O
+,	O
+choreoathetosis	O
+,	O
+ballismus	O
+,	O
+cognitive	O
+and	O
+attention	O
+deficit	O
+,	O
+and	O
+self	O
+-	O
+injurious	O
+behaviour	O
+.	O
+
+The	O
+most	O
+severe	O
+forms	O
+are	O
+known	O
+as	O
+Lesch	O
+-	O
+Nyhan	O
+syndrome	O
+(	O
+patients	O
+are	O
+normal	O
+at	O
+birth	O
+and	O
+diagnosis	O
+can	O
+be	O
+accomplished	O
+when	O
+psychomotor	O
+delay	O
+becomes	O
+apparent	O
+)	O
+.	O
+
+Partial	O
+HPRT	O
+-	O
+deficient	O
+patients	O
+present	O
+these	O
+symptoms	O
+with	O
+a	O
+different	O
+intensity	O
+,	O
+and	O
+in	O
+the	O
+least	O
+severe	O
+forms	O
+symptoms	O
+may	O
+be	O
+unapparent	O
+.	O
+
+Megaloblastic	O
+anaemia	O
+is	O
+also	O
+associated	O
+with	O
+the	O
+disease	O
+.	O
+
+Inheritance	O
+of	O
+HPRT	O
+deficiency	O
+is	O
+X	O
+-	O
+linked	O
+recessive	O
+,	O
+thus	O
+males	O
+are	O
+generally	O
+affected	O
+and	O
+heterozygous	O
+female	O
+are	O
+carriers	O
+(	O
+usually	O
+asymptomatic	O
+)	O
+.	O
+
+Human	O
+HPRT	O
+is	O
+encoded	O
+by	O
+a	O
+single	O
+structural	O
+gene	O
+on	O
+the	O
+long	O
+arm	O
+of	O
+the	O
+X	O
+chromosome	O
+at	O
+Xq26	O
+.	O
+
+To	O
+date	O
+,	O
+more	O
+than	O
+300	O
+disease	O
+-	O
+associated	O
+mutations	O
+in	O
+the	O
+HPRT1	O
+gene	O
+have	O
+been	O
+identified	O
+.	O
+
+The	O
+diagnosis	O
+is	O
+based	O
+on	O
+clinical	O
+and	O
+biochemical	O
+findings	O
+(	O
+hyperuricemia	O
+and	O
+hyperuricosuria	O
+associated	O
+with	O
+psychomotor	O
+delay	O
+)	O
+,	O
+and	O
+enzymatic	O
+(	O
+HPRT	O
+activity	O
+determination	O
+in	O
+haemolysate	O
+,	O
+intact	O
+erythrocytes	O
+or	O
+fibroblasts	O
+)	O
+and	O
+molecular	O
+tests	O
+.	O
+
+Molecular	O
+diagnosis	O
+allows	O
+faster	O
+and	O
+more	O
+accurate	O
+carrier	O
+and	O
+prenatal	O
+diagnosis	O
+.	O
+
+Prenatal	O
+diagnosis	O
+can	O
+be	O
+performed	O
+with	O
+amniotic	O
+cells	O
+obtained	O
+by	O
+amniocentesis	O
+at	O
+about	O
+15	O
+-	O
+18	O
+weeks	O
+'	O
+gestation	O
+,	O
+or	O
+chorionic	O
+villus	O
+cells	O
+obtained	O
+at	O
+about	O
+10	O
+-	O
+12	O
+weeks	O
+'	O
+gestation	O
+.	O
+
+Uric	O
+acid	O
+overproduction	O
+can	O
+be	O
+managed	O
+by	O
+allopurinol	O
+treatment	O
+.	O
+
+Doses	O
+must	O
+be	O
+carefully	O
+adjusted	O
+to	O
+avoid	O
+xanthine	O
+lithiasis	O
+.	O
+
+The	O
+lack	O
+of	O
+precise	O
+understanding	O
+of	O
+the	O
+neurological	O
+dysfunction	O
+has	O
+precluded	O
+development	O
+of	O
+useful	O
+therapies	O
+.	O
+
+Spasticity	B-LOC
+,	O
+when	O
+present	O
+,	O
+and	O
+dystonia	O
+can	O
+be	O
+managed	O
+with	O
+benzodiazepines	O
+and	O
+gamma	O
+-	O
+aminobutyric	O
+acid	O
+inhibitors	O
+such	O
+as	O
+baclofen	O
+.	O
+
+Physical	O
+rehabilitation	O
+,	O
+including	O
+management	O
+of	O
+dysarthria	O
+and	O
+dysphagia	O
+,	O
+special	O
+devices	O
+to	O
+enable	O
+hand	O
+control	O
+,	O
+appropriate	O
+walking	O
+aids	O
+,	O
+and	O
+a	O
+programme	O
+of	O
+posture	O
+management	O
+to	O
+prevent	O
+deformities	O
+are	O
+recommended	O
+.	O
+
+Self	O
+-	O
+injurious	O
+behaviour	O
+must	O
+be	O
+managed	O
+by	O
+a	O
+combination	O
+of	O
+physical	O
+restraints	O
+,	O
+behavioural	O
+and	O
+pharmaceutical	O
+treatments	O
+.	O
+
+Background	O
+The	O
+state	O
+of	O
+newborn	O
+screening	O
+(	O
+NBS	O
+)	O
+programmes	O
+for	O
+organic	O
+acidurias	O
+in	O
+Europe	B-LOC
+was	O
+assessed	O
+by	O
+a	O
+web	O
+-	O
+based	O
+questionnaire	O
+in	O
+the	O
+EU	O
+programme	O
+of	O
+Community	O
+Action	O
+in	O
+Public	O
+Health	O
+2010/2011	O
+among	O
+the	O
+-	O
+at	O
+that	O
+time	O
+-	O
+27	O
+EU	O
+member	O
+states	O
+,	O
+candidate	O
+countries	O
+,	O
+potential	O
+candidates	O
+and	O
+three	O
+EFTA	O
+countries	O
+.	O
+
+Results	O
+Thirty	O
+-	O
+seven	O
+data	O
+sets	O
+from	O
+39	O
+target	O
+countries	O
+were	O
+analysed	O
+.	O
+
+Newborn	O
+screening	O
+for	O
+glutaric	O
+aciduria	O
+type	O
+I	O
+(	O
+GA	O
+-	O
+I	O
+)	O
+was	O
+performed	O
+in	O
+ten	O
+,	O
+for	O
+isovaleric	O
+aciduria	O
+(	O
+IVA	O
+)	O
+in	O
+nine	O
+and	O
+for	O
+methylmalonic	O
+aciduria	O
+including	O
+cblA	O
+,	O
+cblB	O
+,	O
+cblC	O
+and	O
+cblD	O
+(	O
+MMACBL	O
+)	O
+as	O
+well	O
+as	O
+for	O
+propionic	O
+aciduria	O
+(	O
+PA	O
+)	O
+in	O
+seven	O
+countries	O
+.	O
+
+Samples	O
+were	O
+obtained	O
+at	O
+a	O
+median	O
+age	O
+of	O
+2.5	O
+days	O
+and	O
+laboratory	O
+analysis	O
+began	O
+at	O
+median	O
+age	O
+of	O
+4.5	O
+days	O
+.	O
+
+Positive	O
+screening	O
+results	O
+were	O
+mostly	O
+confirmed	O
+in	O
+specialised	O
+centres	O
+by	O
+analysis	O
+of	O
+organic	O
+acids	O
+in	O
+urine	O
+.	O
+
+Confirmation	O
+of	O
+a	O
+positive	O
+screening	O
+result	O
+usually	O
+did	O
+not	O
+start	O
+before	O
+the	O
+second	O
+week	O
+of	O
+life	O
+(	O
+median	O
+ages	O
+:	O
+9.5	O
+days	O
+[	O
+IVA	O
+]	O
+,	O
+9	O
+days	O
+[	O
+GA	O
+-	O
+I	O
+]	O
+,	O
+8.5	O
+days	O
+[	O
+PA	O
+,	O
+MMACBL	O
+]	O
+)	O
+and	O
+was	O
+completed	O
+early	O
+in	O
+the	O
+third	O
+week	O
+of	O
+life	O
+(	O
+median	O
+ages	O
+:	O
+15	O
+days	O
+[	O
+IVA	O
+,	O
+PA	O
+,	O
+MMA	O
+]	O
+,	O
+14.5	O
+days	O
+[	O
+GA	O
+-	O
+I	O
+]	O
+)	O
+.	O
+
+Treatment	O
+was	O
+initiated	O
+in	O
+GA	O
+-	O
+I	O
+and	O
+IVA	O
+at	O
+a	O
+median	O
+age	O
+of	O
+14	O
+days	O
+and	O
+in	O
+MMACBL	B-LOC
+and	O
+PA	O
+at	O
+a	O
+median	O
+age	O
+of	O
+15	O
+days	O
+.	O
+
+Conclusion	O
+NBS	O
+for	O
+organic	O
+acidurias	O
+in	O
+Europe	B-LOC
+is	O
+variable	O
+and	O
+less	O
+often	O
+established	O
+than	O
+for	O
+amino	O
+acid	O
+disorders	O
+.	O
+
+While	O
+for	O
+GA	O
+-	O
+I	O
+its	O
+benefit	O
+has	O
+already	O
+been	O
+demonstrated	O
+,	O
+there	O
+is	O
+room	O
+for	O
+debate	O
+of	O
+NBS	O
+for	O
+IVA	O
+and	O
+especially	O
+PA	O
+and	O
+MMACBL	O
+.	O
+
+Background	O
+IgA	O
+nephropathy	O
+(	O
+IgAN	O
+)	O
+is	O
+the	O
+most	O
+common	O
+primary	O
+glomerulonephritis	O
+worldwide	B-LOC
+.	O
+
+Although	O
+most	O
+IgAN	O
+cases	O
+are	O
+sporadic	O
+,	O
+few	O
+show	O
+a	O
+familial	O
+aggregation	O
+.	O
+
+However	O
+,	O
+the	O
+prevalence	B-EPI
+and	O
+prognosis	O
+of	O
+IgAN	O
+individuals	O
+with	O
+positive	O
+familial	O
+history	O
+(	O
+FH	O
+)	O
+of	O
+renal	O
+disorders	O
+remains	O
+uncertain	O
+.	O
+
+To	O
+address	O
+these	O
+issues	O
+,	O
+we	O
+conducted	O
+a	O
+longitudinal	O
+observational	O
+study	O
+on	O
+a	O
+single	O
+-	O
+institution	O
+cohort	O
+of	O
+patients	O
+with	O
+biopsy	O
+-	O
+proven	O
+IgAN	O
+.	O
+
+Methods	O
+A	O
+total	O
+of	O
+467	O
+IgAN	O
+patients	O
+who	O
+underwent	O
+renal	O
+biopsy	O
+during	O
+1994	O
+to	O
+2019	O
+were	O
+ascertained	O
+to	O
+have	O
+positive-	O
+or	O
+negative	O
+-	O
+FH	O
+by	O
+history	O
+taking	O
+and	O
+were	O
+followed	O
+for	O
+an	O
+average	O
+of	O
+8.9	O
+years	O
+.	O
+
+We	O
+compared	O
+the	O
+clinical	O
+and	O
+pathological	O
+features	O
+of	O
+the	O
+two	O
+subgroups	O
+.	O
+
+The	O
+primary	O
+outcome	O
+,	O
+a	O
+composite	O
+of	O
+a	O
+hard	O
+endpoint	O
+(	O
+end	O
+-	O
+stage	O
+renal	O
+disease	O
+[	O
+ESRD	O
+]	O
+)	O
+and	O
+surrogate	O
+endpoint	O
+(	O
+a	O
+50	O
+%	O
+or	O
+more	O
+reduction	O
+in	O
+the	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+[	O
+eGFR	O
+]	O
+from	O
+baseline	O
+)	O
+,	O
+was	O
+evaluated	O
+.	O
+
+To	O
+estimate	O
+the	O
+risk	O
+for	O
+progression	O
+to	O
+ESRD	O
+,	O
+a	O
+Cox	O
+proportional	O
+hazards	O
+analysis	O
+was	O
+performed	O
+for	O
+a	O
+subset	O
+of	O
+patients	O
+who	O
+underwent	O
+follow	O
+-	O
+up	O
+for	O
+>	O
+2	O
+years	O
+and	O
+had	O
+an	O
+eGFR	O
+>	O
+30	O
+mL	O
+/	O
+min/1.73	O
+m	O
+2	O
+at	O
+baseline	O
+(	O
+n	O
+=	O
+389	O
+;	O
+observation	O
+,	O
+8.7	O
+years	O
+)	O
+.	O
+
+Results	O
+Positive	O
+-	O
+FH	O
+subtype	O
+accounted	O
+for	O
+11.6	O
+%	O
+(	O
+n	O
+=	O
+54	O
+)	O
+of	O
+all	O
+IgAN	O
+patients	O
+.	O
+
+At	O
+baseline	O
+,	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+between	O
+the	O
+positive-	O
+and	O
+negative	O
+-	O
+FH	O
+subgroups	O
+regarding	O
+age	O
+,	O
+sex	O
+,	O
+comorbid	O
+disease	O
+,	O
+MEST	O
+-	O
+C	O
+score	O
+,	O
+observation	O
+period	O
+,	O
+and	O
+therapeutic	O
+interventions	O
+.	O
+
+However	O
+,	O
+the	O
+eGFR	O
+value	O
+at	O
+baselines	O
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+positive	O
+-	O
+FH	O
+subgroup	O
+than	O
+in	O
+the	O
+negative	O
+-	O
+FH	O
+subgroup	O
+(	O
+P	O
+<	O
+0.01	O
+)	O
+.	O
+
+On	O
+multivariate	O
+analysis	O
+,	O
+positive	O
+-	O
+FH	O
+emerged	O
+an	O
+independent	O
+determinant	O
+of	O
+poorer	O
+renal	O
+outcomes	O
+(	O
+odds	O
+ratio	O
+,	O
+2.31	O
+;	O
+95	O
+%	O
+confidence	O
+interval	O
+,	O
+1.10	O
+-	O
+4.85	O
+;	O
+P	O
+=	O
+0.03	O
+)	O
+,	O
+after	O
+adjusting	O
+for	O
+confounding	O
+factors	O
+.	O
+
+eGFR	O
+at	O
+follow	O
+-	O
+up	O
+was	O
+significantly	O
+lower	O
+in	O
+the	O
+positive	O
+-	O
+FH	O
+subgroup	O
+than	O
+in	O
+the	O
+negative	O
+-	O
+FH	O
+subgroup	O
+after	O
+adjustment	O
+for	O
+age	O
+and	O
+observation	O
+period	O
+.	O
+
+Conclusions	O
+Positive	O
+-	O
+FH	O
+was	O
+found	O
+in	O
+11.6	O
+%	O
+of	O
+all	O
+IgAN	O
+patients	O
+,	O
+consistent	O
+with	O
+the	O
+incidence	B-EPI
+seen	O
+in	O
+previous	O
+literature	O
+.	O
+
+A	O
+significantly	O
+lower	O
+eGFR	O
+at	O
+baseline	O
+and	O
+last	O
+follow	O
+-	O
+up	O
+and	O
+unfavorable	O
+renal	O
+outcomes	O
+in	O
+the	O
+positive	O
+-	O
+FH	O
+subgroup	O
+suggest	O
+that	O
+certain	O
+genetic	O
+risk	O
+factors	O
+predisposing	O
+to	O
+renal	O
+failure	O
+may	O
+exist	O
+in	O
+a	O
+fraction	O
+of	O
+our	O
+IgAN	O
+cohort	O
+.	O
+
+(	O
+331	O
+words	O
+)	O
+.	O
+
+The	O
+human	O
+T	O
+-	O
+cell	O
+leukemia	O
+virus	O
+type	O
+1	O
+(	O
+HTLV-1	O
+)	O
+and	O
+type	O
+2	O
+(	O
+HTLV-2	O
+)	O
+are	O
+two	O
+pathogenic	O
+retroviruses	O
+.	O
+
+Although	O
+both	O
+viruses	O
+share	O
+a	O
+common	O
+genome	O
+organization	O
+and	O
+amino	O
+acid	O
+homology	O
+in	O
+common	O
+viral	O
+proteins	O
+,	O
+the	O
+incidence	B-EPI
+of	O
+disease	O
+with	O
+infection	O
+is	O
+distinct	O
+.	O
+
+Infection	O
+with	O
+HTLV-1	O
+may	O
+result	O
+in	O
+the	O
+development	O
+of	O
+adult	O
+T	O
+-	O
+cell	O
+leukemia	O
+/	O
+lymphoma	O
+(	O
+ATL	O
+)	O
+,	O
+an	O
+aggressive	O
+neoplastic	O
+disease	O
+,	O
+or	O
+a	O
+variety	O
+of	O
+immune	O
+-	O
+mediated	O
+/	O
+inflammatory	O
+disorders	O
+such	O
+as	O
+HTLV-1	O
+associated	O
+myelopathy	O
+/	O
+tropical	O
+spastic	O
+paraparesis	O
+(	O
+HAM	O
+/	O
+TSP	O
+)	O
+,	O
+whereas	O
+HTLV-2	O
+is	O
+less	O
+pathogenic	O
+.	O
+
+Our	O
+studies	O
+focused	O
+on	O
+the	O
+open	O
+reading	O
+frame	O
+II	O
+encoded	O
+p28	O
+protein	O
+of	O
+HTLV-2	O
+,	O
+which	O
+has	O
+been	O
+shown	O
+to	O
+negatively	O
+regulate	O
+viral	O
+expression	O
+by	O
+the	O
+nuclear	O
+retention	O
+of	O
+the	O
+tax	O
+/	O
+rex	O
+mRNA	O
+.	O
+
+A	O
+similar	O
+post	O
+-	O
+transcriptional	O
+regulatory	O
+function	O
+has	O
+been	O
+observed	O
+with	O
+HTLV-1	O
+ORF	O
+-	O
+II	O
+p30	O
+.	O
+
+However	O
+,	O
+p28	O
+contrasts	O
+p30	O
+in	O
+that	O
+there	O
+appears	O
+to	O
+be	O
+no	O
+significant	O
+transcriptional	O
+effects	O
+.	O
+In	O
+Chapter	O
+2	O
+,	O
+we	O
+examined	O
+the	O
+functional	O
+significance	O
+of	O
+p28	O
+in	O
+HTLV-2	O
+infection	O
+,	O
+proliferation	O
+,	O
+and	O
+immortalization	O
+of	O
+primary	O
+T	O
+-	O
+cells	O
+in	O
+culture	O
+,	O
+and	O
+viral	O
+infection	O
+and	O
+survival	O
+in	O
+a	O
+rabbit	O
+model	O
+of	O
+HTLV	O
+infection	O
+.	O
+
+We	O
+generated	O
+a	O
+novel	O
+HTLV-2	O
+p28	O
+termination	O
+clone	O
+(	O
+HTLV2Deltap28	O
+)	O
+in	O
+which	O
+a	O
+stop	O
+codon	O
+had	O
+been	O
+introduced	O
+into	O
+the	O
+p28	O
+sequence	O
+without	O
+altering	O
+the	O
+amino	O
+acid	O
+sequence	O
+of	O
+the	O
+overlapping	O
+regulatory	O
+proteins	O
+,	O
+Tax	O
+and	O
+Rex	O
+.	O
+
+In	O
+short	O
+-	O
+term	O
+proliferation	O
+and	O
+long	O
+-	O
+term	O
+immortalization	O
+coculture	O
+assays	O
+,	O
+HTLV2Deltap28	O
+infected	O
+and	O
+immortalized	O
+primary	O
+human	O
+T	O
+-	O
+cells	O
+,	O
+similar	O
+to	O
+wtHTLV-2	O
+.	O
+
+However	O
+,	O
+HTLV2Deltap28	O
+had	O
+a	O
+lower	O
+capacity	O
+to	O
+establish	O
+persistent	O
+infection	O
+in	O
+rabbits	O
+,	O
+indicating	O
+the	O
+in	O
+vivo	O
+importance	O
+of	O
+HTLV-2	O
+p28	O
+.	O
+
+These	O
+results	O
+are	O
+consistent	O
+with	O
+the	O
+hypothesis	O
+that	O
+p28	O
+repression	O
+of	O
+Tax	O
+and	O
+Rex	O
+-	O
+mediated	O
+viral	O
+gene	O
+expression	O
+allows	O
+infected	O
+cells	O
+to	O
+avoid	O
+immune	O
+recognition	O
+and	O
+elimination	O
+,	O
+or	O
+acts	O
+to	O
+enhance	O
+early	O
+viral	O
+spread	O
+by	O
+enhancing	O
+the	O
+survival	O
+of	O
+HTLV-2	O
+infected	O
+cells	O
+.	O
+In	O
+Chapter	O
+3	O
+,	O
+we	O
+generated	O
+and	O
+characterized	O
+various	O
+dual	O
+-	O
+promoter	O
+and	O
+single	O
+-	O
+promoter	O
+lentiviral	O
+expression	O
+vectors	O
+.	O
+
+Post	O
+-	O
+transduction	O
+,	O
+p28	O
+protein	O
+was	O
+readily	O
+detected	O
+with	O
+the	O
+dual	O
+-	O
+promoter	O
+vectors	O
+in	O
+293	O
+T	O
+cells	O
+but	O
+not	O
+in	O
+Jurkat	B-LOC
+T	O
+-	O
+cells	O
+.	O
+
+The	O
+differential	O
+p28	O
+protein	O
+expression	O
+was	O
+found	O
+to	O
+be	O
+due	O
+to	O
+cell	O
+-	O
+type	O
+specific	O
+translation	O
+mechanisms	O
+.	O
+
+To	O
+circumvent	O
+this	O
+problem	O
+we	O
+utilized	O
+a	O
+single	O
+-	O
+promoter	O
+lentiviral	O
+vector	O
+that	O
+expresses	O
+p28	O
+via	O
+the	O
+murine	O
+stem	O
+cell	O
+virus	O
+(	O
+MSCV)-promoter	O
+,	O
+which	O
+resulted	O
+in	O
+efficient	O
+p28	O
+protein	O
+expression	O
+in	O
+both	O
+T	O
+-	O
+cell	O
+lines	O
+and	O
+primary	O
+human	O
+CD8	O
++	O
+T	O
+-	O
+lymphocytes	O
+.	O
+
+In	O
+Chapter	O
+4	O
+,	O
+the	O
+capacity	O
+of	O
+p28	O
+to	O
+modify	O
+cellular	O
+gene	O
+expression	O
+was	O
+examined	O
+.	O
+
+In	O
+transient	O
+transfection	O
+studies	O
+,	O
+low	O
+doses	O
+of	O
+p28	O
+modulated	O
+CRE-	O
+and	O
+NFκB	O
+-	O
+driven	O
+reporter	O
+constructs	O
+in	O
+293	O
+T	O
+cells	O
+,	O
+suggesting	O
+the	O
+ability	O
+of	O
+p28	O
+in	O
+modulating	O
+cellular	O
+gene	O
+expression	O
+.	O
+
+Interestingly	O
+,	O
+transduction	O
+of	O
+Jurkat	O
+T	O
+-	O
+cells	O
+with	O
+the	O
+lentiviral	O
+p28	O
+expression	O
+vector	O
+had	O
+no	O
+significant	O
+effect	O
+on	O
+cellular	O
+proliferation	O
+.	O
+
+Additionally	O
+,	O
+initial	O
+analysis	O
+of	O
+global	O
+cellular	O
+gene	O
+expression	O
+by	O
+microarray	O
+analysis	O
+suggests	O
+that	O
+p28	O
+results	O
+in	O
+nominal	O
+alterations	O
+in	O
+cellular	O
+gene	O
+expression	O
+.	O
+
+Collectively	O
+,	O
+data	O
+presented	O
+in	O
+this	O
+thesis	O
+indicates	O
+that	O
+p28	O
+is	O
+critical	O
+for	O
+the	O
+establishment	O
+and	O
+survival	O
+of	O
+HTLV-2	O
+,	O
+compatible	O
+with	O
+the	O
+conclusion	O
+that	O
+the	O
+regulation	O
+of	O
+HTLV	O
+gene	O
+expression	O
+is	O
+a	O
+tightly	O
+controlled	O
+and	O
+complex	O
+process	O
+.	O
+
+Ultimately	O
+,	O
+while	O
+minimal	O
+,	O
+the	O
+impact	O
+of	O
+p28	O
+upon	O
+cellular	O
+genes	O
+likely	O
+contributes	O
+to	O
+HTLV-2	O
+establishment	O
+of	O
+infection	O
+in	O
+vivo	O
+.	O
+
+Marfan	O
+syndrome	O
+(	O
+MFS	O
+)	O
+is	O
+a	O
+heritable	O
+connective	O
+tissue	O
+disorder	O
+(	O
+HCTD	O
+)	O
+caused	O
+by	O
+pathogenic	O
+variants	O
+in	O
+FBN1	O
+that	O
+frequently	O
+occur	O
+de	O
+novo	O
+.	O
+
+Although	O
+individuals	O
+with	O
+somatogonadal	O
+mosaicisms	O
+have	O
+been	O
+reported	O
+with	O
+respect	O
+to	O
+MFS	O
+and	O
+other	O
+HCTD	O
+,	O
+the	O
+overall	O
+frequency	O
+of	O
+parental	O
+mosaicism	O
+in	O
+this	O
+pathology	O
+is	O
+unknown	O
+.	O
+
+In	O
+an	O
+attempt	O
+to	O
+estimate	O
+this	O
+frequency	O
+,	O
+we	O
+reviewed	O
+all	O
+the	O
+333	O
+patients	O
+with	O
+a	O
+disease	O
+-	O
+causing	O
+variant	O
+in	O
+FBN1	O
+.	O
+
+We	O
+then	O
+used	O
+direct	O
+sequencing	O
+,	O
+combined	O
+with	O
+High	O
+Resolution	O
+Melting	O
+Analysis	O
+,	O
+to	O
+detect	O
+mosaicism	O
+in	O
+their	O
+parents	O
+,	O
+complemented	O
+by	O
+NGS	O
+when	O
+a	O
+mosaicism	O
+was	O
+objectivized	O
+.	O
+
+We	O
+found	O
+that	O
+(	O
+1	O
+)	O
+the	O
+number	O
+of	O
+apparently	O
+de	O
+novo	O
+events	O
+is	O
+much	O
+higher	O
+than	O
+the	O
+classically	O
+admitted	O
+number	O
+(	O
+around	O
+50	O
+%	O
+of	O
+patients	O
+and	O
+not	O
+25	O
+%	O
+as	O
+expected	O
+for	O
+FBN1	O
+)	O
+and	O
+(	O
+2	B-STAT
+)	I-STAT
+around	O
+5	O
+%	O
+of	O
+the	O
+FBN1	O
+disease	O
+-	O
+causing	O
+variants	O
+were	O
+not	O
+actually	O
+de	O
+novo	O
+as	O
+anticipated	O
+,	O
+but	O
+inherited	O
+in	O
+a	O
+context	O
+of	O
+somatogonadal	O
+mosaicisms	O
+revealed	O
+in	O
+parents	O
+from	O
+three	O
+families	O
+.	O
+
+High	O
+Resolution	O
+Melting	O
+Analysis	O
+and	O
+NGS	O
+were	O
+more	O
+efficient	O
+at	O
+detecting	O
+and	O
+evaluating	O
+the	O
+level	O
+of	O
+mosaicism	O
+compared	O
+to	O
+direct	O
+Sanger	O
+sequencing	O
+.	O
+
+We	O
+also	O
+investigated	O
+individuals	O
+with	O
+a	O
+causal	O
+variant	O
+in	O
+another	O
+gene	O
+identified	O
+through	O
+our	O
+	O
+aortic	O
+diseases	O
+genes	O
+	O
+NGS	O
+panel	O
+and	O
+report	O
+,	O
+for	O
+the	O
+first	O
+time	O
+,	O
+on	O
+an	O
+individual	O
+with	O
+a	O
+somatogonadal	O
+mosaicism	O
+in	O
+COL5A1	O
+.	O
+
+Our	O
+study	O
+shows	O
+that	O
+parental	O
+mosaicism	O
+is	O
+not	O
+that	O
+rare	O
+in	O
+Marfan	O
+syndrome	O
+and	O
+should	O
+be	O
+investigated	O
+with	O
+appropriate	O
+methods	O
+given	O
+its	O
+implications	O
+in	O
+patient	O
+'s	O
+management	O
+.	O
+
+Background	O
+The	O
+high	O
+incidence	B-EPI
+of	O
+aortic	O
+disease	O
+in	O
+subjects	O
+with	O
+congenital	O
+aortic	O
+valve	O
+malformations	O
+suggests	O
+a	O
+causative	O
+relationship	O
+between	O
+these	O
+2	O
+conditions	O
+.	O
+
+The	O
+histological	O
+observation	O
+in	O
+aortic	O
+dilatation	O
+/	O
+aneurysm	O
+/	O
+dissection	O
+is	O
+Erdheim	O
+cystic	O
+medial	O
+necrosis	O
+(	O
+CMN	O
+)	O
+,	O
+a	O
+noninflammatory	O
+loss	O
+of	O
+smooth	O
+muscle	O
+cells	O
+(	O
+SMCs	O
+)	O
+,	O
+fragmentation	O
+of	O
+elastic	O
+fibers	O
+,	O
+and	O
+mucoid	O
+degeneration	O
+.	O
+
+Methods	O
+and	O
+results	O
+To	O
+examine	O
+whether	O
+apoptosis	O
+is	O
+1	O
+of	O
+the	O
+mechanisms	O
+underlying	O
+CMN	O
+and	O
+aortic	O
+medial	O
+layer	O
+SMC	O
+loss	O
+,	O
+ascending	O
+aortic	O
+wall	O
+specimens	O
+from	O
+32	O
+patients	O
+were	O
+collected	O
+at	O
+cardiothoracic	O
+surgery	O
+and	O
+examined	O
+by	O
+histochemical	O
+staining	O
+and	O
+terminal	O
+deoxynucleotidyl	O
+transferase	O
+-	O
+mediated	O
+deoxyuridine	O
+triphosphate	O
+nick	O
+end	O
+labeling	O
+.	O
+
+From	O
+echocardiography	O
+results	O
+,	O
+4	O
+groups	O
+of	O
+patients	O
+were	O
+identified	O
+:	O
+bicuspid	O
+valve	O
+carriers	O
+with	O
+(	O
+bi	O
+/	O
+dil	O
+)	O
+or	O
+without	O
+(	O
+bi/0	O
+)	O
+aortic	O
+dilatation	O
+and	O
+tricuspid	O
+valve	O
+carriers	O
+with	O
+(	O
+tri	O
+/	O
+dil	O
+)	O
+or	O
+without	O
+(	O
+tri/0	O
+)	O
+aortic	O
+dilatation	O
+.	O
+
+Massive	O
+focal	O
+apoptosis	O
+was	O
+observed	O
+in	O
+the	O
+medial	O
+layers	O
+of	O
+bi	O
+/	O
+dil	O
+(	O
+mean	O
+apoptotic	O
+index	O
+[	O
+mAI	O
+]	O
+,	O
+8.1+/-6.0	B-STAT
+)	O
+and	O
+tri	O
+/	O
+dil	O
+(	O
+mAI	O
+,	O
+8.1+/-8.3	B-STAT
+)	O
+compared	O
+with	O
+tri/0	O
+(	O
+mAI	O
+,	O
+0.9+/-1.2	B-STAT
+;	O
+P=0.0079	O
+and	O
+P=0.037	O
+)	O
+.	O
+
+In	O
+bi/0	B-LOC
+(	O
+mAI	O
+,	O
+9.1+/-5.7	B-STAT
+)	O
+compared	O
+with	O
+tri/0	O
+(	O
+mAI	O
+,	O
+0.9+/-1.2	B-STAT
+)	O
+,	O
+rates	O
+of	O
+medial	O
+SMC	O
+apoptosis	O
+were	O
+increased	O
+(	O
+P=0.0025	O
+)	O
+.	O
+
+Bi	O
+/	O
+dil	O
+(	O
+mean	O
+age	O
+,	O
+40	O
+.	O
+
+6+/-15.7	B-STAT
+years	O
+)	O
+were	O
+significantly	O
+younger	O
+than	O
+tri	O
+/	O
+dil	O
+(	O
+mean	O
+age	O
+,	O
+56.4+/-12.8	B-STAT
+years	O
+)	O
+undergoing	O
+the	O
+same	O
+operation	O
+(	O
+P=0.0123	O
+)	O
+.	O
+
+Conclusions	O
+Premature	O
+medial	O
+layer	O
+SMC	O
+apoptosis	O
+could	O
+be	O
+part	O
+of	O
+a	O
+genetic	O
+program	O
+underlying	O
+aortic	O
+disease	O
+in	O
+patients	O
+with	O
+aortic	O
+valve	O
+malformations	O
+.	O
+
+Inherited	O
+epidermolysis	O
+bullosa	O
+is	O
+a	O
+group	O
+of	O
+genetic	O
+diseases	O
+characterized	O
+by	O
+skin	O
+fragility	O
+and	O
+blistering	O
+on	O
+the	O
+skin	O
+and	O
+mucous	O
+membranes	O
+in	O
+response	O
+to	O
+minimal	O
+trauma	O
+.	O
+
+Epidermolysis	O
+bullosa	O
+is	O
+clinically	O
+and	O
+genetically	O
+very	O
+heterogeneous	O
+,	O
+being	O
+classified	O
+into	O
+four	O
+main	O
+types	O
+according	O
+to	O
+the	O
+layer	O
+of	O
+skin	O
+in	O
+which	O
+blistering	O
+occurs	B-EPI
+:	O
+epidermolysis	O
+bullosa	O
+simplex	O
+(	O
+intraepidermal	O
+)	O
+,	O
+junctional	O
+epidermolysis	O
+bullosa	O
+(	O
+within	O
+the	O
+lamina	O
+lucida	O
+of	O
+the	O
+basement	O
+membrane	O
+)	O
+,	O
+dystrophic	O
+epidermolysis	O
+bullosa	O
+(	O
+below	O
+the	O
+basement	O
+membrane	O
+)	O
+,	O
+and	O
+Kindler	O
+epidermolysis	O
+bullosa	O
+(	O
+mixed	O
+skin	O
+cleavage	O
+pattern	O
+)	O
+.	O
+
+Furthermore	O
+,	O
+epidermolysis	O
+bullosa	O
+is	O
+stratified	O
+into	O
+several	O
+subtypes	O
+,	O
+which	O
+consider	O
+the	O
+clinical	O
+characteristics	O
+,	O
+the	O
+distribution	O
+of	O
+the	O
+blisters	O
+,	O
+and	O
+the	O
+severity	O
+of	O
+cutaneous	O
+and	O
+extracutaneous	O
+signs	O
+.	O
+
+Pathogenic	O
+variants	O
+in	O
+at	O
+least	O
+16	O
+genes	O
+that	O
+encode	O
+proteins	O
+essential	O
+for	O
+the	O
+integrity	O
+and	O
+adhesion	O
+of	O
+skin	O
+layers	O
+have	O
+already	O
+been	O
+associated	O
+with	O
+different	O
+subtypes	O
+of	O
+epidermolysis	O
+bullosa	O
+.	O
+
+The	O
+marked	O
+heterogeneity	O
+of	O
+the	O
+disease	O
+,	O
+which	O
+includes	O
+phenotypes	O
+with	O
+a	O
+broad	O
+spectrum	O
+of	O
+severity	O
+and	O
+many	O
+causal	O
+genes	O
+,	O
+hinders	O
+its	O
+classification	O
+and	O
+diagnosis	O
+.	O
+
+For	O
+this	O
+reason	O
+,	O
+dermatologists	O
+and	O
+geneticists	O
+regularly	O
+review	O
+and	O
+update	O
+the	O
+classification	O
+criteria	O
+.	O
+
+This	O
+review	O
+aimed	O
+to	O
+update	O
+the	O
+state	O
+of	O
+the	O
+art	O
+on	O
+inherited	O
+epidermolysis	O
+bullosa	O
+,	O
+with	O
+a	O
+special	O
+focus	O
+on	O
+the	O
+associated	O
+clinical	O
+and	O
+genetic	O
+aspects	O
+,	O
+presenting	O
+data	O
+from	O
+the	O
+most	O
+recent	O
+reclassification	O
+consensus	O
+,	O
+published	O
+in	O
+2020	O
+.	O
+
+The	O
+aggressive	O
+lymphoma	O
+,	O
+extranodal	O
+natural	O
+killer	O
+/	O
+T	O
+-	O
+cell	O
+lymphoma	O
+-	O
+nasal	O
+type	O
+,	O
+is	O
+strongly	O
+associated	O
+with	O
+Epstein	O
+-	O
+Barr	O
+virus	O
+(	O
+EBV	O
+)	O
+and	O
+is	O
+most	O
+common	O
+in	O
+Asia	B-LOC
+and	O
+in	O
+South	B-LOC
+and	O
+Central	B-LOC
+America	I-LOC
+.	O
+
+By	O
+contrast	O
+,	O
+incidence	B-EPI
+is	O
+low	O
+in	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+and	O
+Europe	B-LOC
+,	O
+where	O
+extranodal	O
+natural	O
+killer	O
+/	O
+T	O
+-	O
+cell	O
+lymphoma	O
+represents	O
+only	O
+0.2%-0.4	B-STAT
+%	I-STAT
+of	O
+all	O
+newly	O
+diagnosed	O
+non	O
+-	O
+Hodgkin	O
+lymphomas	O
+.	O
+
+At	O
+diagnosis	O
+,	O
+it	O
+is	O
+important	O
+to	O
+test	O
+for	O
+EBV	O
+DNA	O
+in	O
+plasma	O
+by	O
+polymerase	O
+chain	O
+reaction	O
+and	O
+to	O
+carry	O
+out	O
+positron	O
+emission	O
+tomography	O
+/	O
+computer	O
+tomography	O
+and	O
+magnetic	O
+resonance	O
+imaging	O
+of	O
+the	O
+nasopharynx	O
+.	O
+
+In	O
+stage	O
+I	O
+/	O
+II	O
+disease	O
+,	O
+radiotherapy	O
+is	O
+the	O
+most	O
+important	O
+treatment	O
+modality	O
+,	O
+but	O
+in	O
+high	O
+-	O
+risk	O
+stage	O
+I	O
+/	O
+II	O
+disease	O
+(	O
+stage	O
+II	O
+,	O
+age	O
+>	O
+60	O
+y	O
+,	O
+elevated	O
+lactate	O
+dehydrogenase	O
+,	O
+Eastern	O
+Cooperative	O
+Oncology	O
+Group	O
+performance	O
+score	O
+≥2	O
+,	O
+primary	O
+tumor	O
+invasion	O
+)	O
+,	O
+it	O
+should	O
+be	O
+combined	O
+with	O
+chemotherapy	O
+.	O
+
+The	O
+most	O
+optimal	O
+responses	O
+are	O
+reached	O
+with	O
+nonmultidrug	O
+resistance	O
+-	O
+based	O
+therapy	O
+(	O
+eg	O
+,	O
+asparaginase-	O
+or	O
+platinum	O
+-	O
+based	O
+therapy	O
+)	O
+.	O
+
+Therapeutic	O
+approaches	O
+consist	O
+of	O
+either	O
+platinum	O
+-	O
+based	O
+concurrent	O
+chemoradiotherapy	O
+or	O
+sequential	O
+chemoradiotherapy	O
+.	O
+
+The	O
+minimum	O
+dose	O
+of	O
+radiotherapy	O
+should	O
+be	O
+50	O
+-	O
+56	O
+Gy	O
+.	O
+
+Treatment	O
+of	O
+stage	O
+III	O
+/	O
+IV	O
+disease	O
+consists	O
+of	O
+3	O
+cycles	O
+of	O
+chemotherapy	O
+followed	O
+by	O
+autologous	O
+hematopoietic	O
+cell	O
+transplantation	O
+.	O
+
+Allogeneic	O
+hematopoietic	O
+cell	O
+transplantation	O
+should	O
+only	O
+be	O
+considered	O
+in	O
+case	O
+of	O
+relapsed	O
+disease	O
+or	O
+after	O
+difficulty	O
+reaching	O
+complete	O
+remission	O
+.	O
+
+During	O
+treatment	O
+and	O
+follow	O
+-	O
+up	O
+,	O
+plasma	O
+EBV	O
+levels	O
+should	O
+be	O
+monitored	O
+as	O
+a	O
+marker	O
+of	O
+tumor	O
+load	O
+.	O
+
+Rifampicin	O
+,	O
+discovered	O
+more	O
+than	O
+50	O
+years	O
+ago	O
+,	O
+represents	O
+the	O
+last	O
+novel	O
+class	O
+of	O
+antibiotics	O
+introduced	O
+for	O
+the	O
+first	O
+-	O
+line	O
+treatment	O
+of	O
+tuberculosis	O
+.	O
+
+Drugs	O
+in	O
+this	O
+class	O
+form	O
+part	O
+of	O
+a	O
+6	O
+-	O
+month	O
+regimen	O
+that	O
+is	O
+ineffective	O
+against	O
+MDR	O
+and	O
+XDR	O
+TB	O
+,	O
+and	O
+incompatible	O
+with	O
+many	O
+antiretroviral	O
+drugs	O
+.	O
+
+Investments	O
+in	O
+R&D	O
+strategies	O
+have	O
+increased	O
+substantially	O
+in	O
+the	O
+last	O
+decades	O
+.	O
+
+However	O
+,	O
+the	O
+number	O
+of	O
+new	O
+drugs	O
+approved	O
+by	O
+drug	O
+regulatory	O
+agencies	O
+worldwide	B-LOC
+does	O
+not	O
+increase	O
+correspondingly	O
+.	O
+
+Ruthenium	O
+complexes	O
+(	O
+SCAR	O
+)	O
+have	O
+been	O
+tested	O
+in	O
+our	O
+laboratory	O
+and	O
+showed	O
+promising	O
+activity	O
+against	O
+Mycobacterium	O
+tuberculosis	O
+.	O
+
+These	O
+complexes	O
+showed	O
+up	O
+to	O
+150	O
+times	O
+higher	O
+activity	O
+against	O
+MTB	O
+than	O
+its	O
+organic	O
+molecule	O
+without	O
+the	O
+metal	O
+(	O
+free	O
+ligand	O
+)	O
+,	O
+with	O
+low	O
+cytotoxicity	O
+and	O
+high	O
+selectivity	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+promising	O
+results	O
+inspired	O
+us	O
+to	O
+seek	O
+a	O
+better	O
+understanding	O
+of	O
+the	O
+biological	O
+activity	O
+of	O
+these	O
+complexes	O
+.	O
+
+The	O
+in	O
+vitro	O
+biological	O
+results	O
+obtained	O
+with	O
+the	O
+SCAR	O
+compounds	O
+were	O
+extremely	O
+promising	O
+,	O
+comparable	O
+to	O
+or	O
+better	O
+than	O
+those	O
+for	O
+first	O
+-	O
+line	O
+drugs	O
+and	O
+drugs	O
+in	O
+development	O
+.	O
+
+Moreover	O
+,	O
+SCAR	O
+1	B-STAT
+and	I-STAT
+4	I-STAT
+,	O
+which	O
+presented	O
+low	O
+acute	O
+toxicity	O
+,	O
+were	O
+assessed	O
+by	O
+Ames	O
+test	O
+,	O
+and	O
+results	O
+demonstrated	O
+absence	O
+of	O
+mutagenicity	O
+.	O
+
+Objective	O
+:	O
+The	O
+purpose	O
+of	O
+this	O
+meta	O
+-	O
+analysis	O
+of	O
+longitudinal	O
+studies	O
+is	O
+to	O
+determine	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+artesunate	O
+combined	O
+with	O
+other	O
+forms	O
+of	O
+adjunctive	O
+therapies	O
+for	O
+severe	O
+malaria	O
+.	O
+
+Methods	O
+:	O
+Following	O
+the	O
+PRISMA	O
+guidelines	O
+,	O
+we	O
+searched	O
+multiple	O
+databases	O
+with	O
+the	O
+search	O
+terms	O
+	O
+artesunate	O
+	O
+and	O
+	O
+adjunctive	O
+therapy	O
+	O
+and	O
+	O
+severe	O
+malaria	O
+	O
+in	O
+July	O
+2020	O
+.	O
+
+If	O
+the	O
+search	O
+showed	O
+a	O
+randomized	O
+controlled	O
+trial	O
+,	O
+the	O
+study	O
+was	O
+included	O
+in	O
+this	O
+meta	O
+-	O
+analysis	O
+.	O
+
+The	O
+random	O
+-	O
+effects	O
+model	O
+was	O
+used	O
+to	O
+calculate	O
+the	O
+combined	O
+incidence	B-EPI
+rate	O
+and	O
+relative	O
+risk	O
+or	O
+risk	O
+difference	O
+.	O
+
+Results	O
+:	O
+This	O
+meta	O
+-	O
+analysis	O
+included	O
+nine	O
+longitudinal	O
+studies	O
+with	O
+724	O
+participants	O
+.	O
+
+We	O
+found	O
+that	O
+the	O
+mortality	O
+rates	O
+in	O
+the	O
+artesunate	O
+monotherapy	O
+group	O
+and	O
+the	O
+artesunate	O
++	O
+adjuvant	O
+therapy	O
+group	O
+are	O
+similar	O
+(	O
+RD	O
+=	O
+-0.02	O
+,	O
+95	O
+%	O
+confidence	O
+interval	O
+:	O
+-0.06	O
+-	O
+0.02	O
+)	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+adverse	O
+reactions	O
+in	O
+the	O
+artesunate	O
+monotherapy	O
+group	O
+and	O
+the	O
+artesunate	O
++	O
+adjuvant	O
+therapy	O
+group	O
+was	O
+also	O
+similar	O
+.	O
+
+Conclusion	O
+:	O
+No	O
+significant	O
+differences	O
+in	O
+safety	O
+and	O
+efficacy	O
+were	O
+observed	O
+between	O
+the	O
+artesunate	O
+monotherapy	O
+group	O
+and	O
+the	O
+artesunate	O
++	O
+adjuvant	O
+therapy	O
+group	O
+.	O
+
+Higher	O
+quality	O
+and	O
+rigorously	O
+designed	O
+randomized	O
+controlled	O
+studies	O
+are	O
+needed	O
+to	O
+validate	O
+our	O
+findings	O
+.	O
+
+Vitamin	O
+K	O
+-	O
+dependent	O
+factor	O
+X	O
+(	O
+FX	O
+)	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+thrombin	O
+formation	O
+,	O
+and	O
+a	O
+deficiency	O
+in	O
+FX	O
+can	O
+cause	O
+impaired	O
+coagulation	O
+,	O
+the	O
+severity	O
+of	O
+which	O
+is	O
+usually	O
+correlated	O
+with	O
+the	O
+degree	O
+of	O
+deficiency	O
+.	O
+
+Due	O
+to	O
+the	O
+critical	O
+role	O
+that	O
+FX	O
+plays	O
+in	O
+the	O
+coagulation	O
+cascade	O
+,	O
+FX	O
+deficiency	O
+is	O
+associated	O
+with	O
+a	O
+higher	O
+risk	O
+of	O
+bleeding	O
+than	O
+deficiencies	O
+in	O
+other	O
+coagulation	O
+factors	O
+.	O
+
+Patients	O
+with	O
+the	O
+hereditary	O
+autosomal	O
+-	O
+recessive	O
+homozygous	O
+form	O
+of	O
+FX	O
+deficiency	O
+,	O
+which	O
+occurs	B-EPI
+in	O
+approximately	B-STAT
+1:1,000,000	I-STAT
+individuals	I-STAT
+worldwide	B-LOC
+,	O
+are	O
+often	O
+diagnosed	O
+when	O
+they	O
+present	O
+with	O
+spontaneous	O
+life	O
+-	O
+threatening	O
+haemorrhage	O
+(	O
+most	O
+often	O
+intracranial	O
+haemorrhage	O
+)	O
+during	O
+the	O
+first	O
+month	O
+of	O
+life	O
+.	O
+
+In	O
+addition	O
+to	O
+central	O
+nervous	O
+system	O
+bleeds	O
+,	O
+other	O
+severe	O
+bleeding	O
+types	O
+experienced	O
+by	O
+such	O
+patients	O
+may	O
+include	O
+umbilical	O
+cord	O
+bleeding	O
+,	O
+gastrointestinal	O
+or	O
+pulmonary	O
+haemorrhage	O
+,	O
+intramuscular	O
+haematomas	O
+and/or	O
+haemarthrosis	O
+.	O
+
+Delayed	O
+treatment	O
+or	O
+inadequate	O
+replacement	O
+of	O
+FX	O
+may	O
+result	O
+in	O
+developmental	O
+delays	O
+,	O
+musculoskeletal	O
+disabilities	O
+or	O
+death	O
+.	O
+
+The	O
+high	O
+risk	O
+of	O
+recurrent	O
+severe	O
+bleeding	O
+necessitates	O
+prophylactic	O
+replacement	O
+therapy	O
+for	O
+many	O
+individuals	O
+with	O
+severe	O
+FX	O
+deficiency	O
+.	O
+
+Available	O
+products	O
+for	O
+replacement	O
+therapy	O
+include	O
+plasma	O
+-	O
+derived	O
+FX	O
+concentrate	O
+and	O
+prothrombin	O
+complex	O
+concentrates	O
+.	O
+
+Fresh	O
+-	O
+frozen	O
+plasma	O
+may	O
+be	O
+used	O
+when	O
+concentrates	O
+are	O
+not	O
+available	O
+but	O
+is	O
+a	O
+less	O
+efficient	O
+means	O
+of	O
+FX	O
+replacement	O
+.	O
+
+This	O
+article	O
+reviews	O
+the	O
+literature	O
+on	O
+severe	O
+bleeding	O
+in	O
+individuals	O
+with	O
+hereditary	O
+FX	O
+deficiency	O
+and	O
+discusses	O
+current	O
+treatment	O
+options	O
+.	O
+
+A	O
+series	O
+of	O
+simplex	O
+cases	O
+have	O
+been	O
+reported	O
+under	O
+various	O
+diagnoses	O
+sharing	O
+early	O
+aging	O
+,	O
+especially	O
+evident	O
+in	O
+congenitally	O
+decreased	O
+subcutaneous	O
+fat	O
+tissue	O
+and	O
+sparse	O
+hair	O
+,	O
+bone	O
+dysplasia	O
+of	O
+the	O
+skull	O
+and	O
+fingers	O
+,	O
+a	O
+distinctive	O
+facial	O
+gestalt	O
+,	O
+and	O
+prenatal	O
+and	O
+postnatal	O
+growth	O
+retardation	O
+.	O
+
+For	O
+historical	O
+reasons	O
+,	O
+we	O
+suggest	O
+naming	O
+the	O
+entity	O
+Fontaine	O
+syndrome	O
+.	O
+
+Exome	O
+sequencing	O
+of	O
+four	O
+unrelated	O
+affected	O
+individuals	O
+showed	O
+that	O
+all	O
+carried	O
+the	O
+de	O
+novo	O
+missense	O
+variant	O
+c.649C	O
+>	O
+T	O
+(	O
+p.	O
+Arg217Cys	O
+)	O
+or	O
+c.650G	O
+>	O
+A	O
+(	O
+p.	O
+Arg217His	O
+)	O
+in	O
+SLC25A24	O
+,	O
+a	O
+solute	O
+carrier	O
+25	O
+family	O
+member	O
+coding	O
+for	O
+calcium	O
+-	O
+binding	O
+mitochondrial	O
+carrier	O
+protein	O
+(	O
+SCaMC-1	O
+,	O
+also	O
+known	O
+as	O
+SLC25A24	O
+)	O
+.	O
+
+SLC25A24	O
+allows	O
+an	O
+electro	O
+-	O
+neutral	O
+and	O
+reversible	O
+exchange	O
+of	O
+ATP	O
+-	O
+Mg	O
+and	O
+phosphate	O
+between	O
+the	O
+cytosol	O
+and	O
+mitochondria	O
+,	O
+which	O
+is	O
+required	O
+for	O
+maintaining	O
+optimal	O
+adenine	O
+nucleotide	O
+levels	O
+in	O
+the	O
+mitochondrial	O
+matrix	O
+.	O
+
+Molecular	O
+dynamic	O
+simulation	O
+studies	O
+predict	O
+that	O
+p.	O
+Arg217Cys	O
+and	O
+p.	O
+Arg217His	O
+narrow	O
+the	O
+substrate	O
+cavity	O
+of	O
+the	O
+protein	O
+and	O
+disrupt	O
+transporter	O
+dynamics	O
+.	O
+
+SLC25A24	O
+-	O
+mutant	O
+fibroblasts	O
+and	O
+cells	O
+expressing	O
+p.	O
+Arg217Cys	O
+or	O
+p.	O
+Arg217His	O
+variants	O
+showed	O
+altered	O
+mitochondrial	O
+morphology	O
+,	O
+a	O
+decreased	O
+proliferation	O
+rate	O
+,	O
+increased	O
+mitochondrial	O
+membrane	O
+potential	O
+,	O
+and	O
+decreased	O
+ATP	O
+-	O
+linked	O
+mitochondrial	O
+oxygen	O
+consumption	O
+.	O
+
+The	O
+results	O
+suggest	O
+that	O
+the	O
+SLC25A24	O
+mutations	O
+lead	O
+to	O
+impaired	O
+mitochondrial	O
+ATP	O
+synthesis	O
+and	O
+cause	O
+hyperpolarization	O
+and	O
+increased	O
+proton	O
+leak	O
+in	O
+association	O
+with	O
+an	O
+impaired	O
+energy	O
+metabolism	O
+.	O
+
+Our	O
+findings	O
+identify	O
+SLC25A24	O
+mutations	O
+affecting	O
+codon	O
+217	O
+as	O
+the	O
+underlying	O
+genetic	O
+cause	O
+of	O
+human	O
+progeroid	O
+Fontaine	O
+syndrome	O
+.	O
+
+Usher	O
+syndrome	O
+type	O
+1	O
+(	O
+US1	O
+)	O
+is	O
+an	O
+autosomal	O
+recessive	O
+disease	O
+characterized	O
+by	O
+profound	O
+congenital	O
+hearing	O
+impairment	O
+with	O
+unintelligible	O
+speech	O
+,	O
+early	O
+retinitis	O
+pigmentosa	O
+,	O
+and	O
+constant	O
+vestibular	O
+dysfunction	O
+.	O
+
+Three	O
+localizations	O
+have	O
+been	O
+described	O
+in	O
+US1	O
+:	O
+USH1A	O
+,	O
+14q32	O
+;	O
+USH1B	O
+,	O
+11q13.5	O
+;	O
+and	O
+USH1C	O
+,	O
+11p15	O
+.	O
+
+Studying	O
+a	O
+series	O
+of	O
+33	O
+affected	O
+individuals	O
+belonging	O
+to	O
+20	O
+US1	O
+pedigrees	O
+of	O
+French	O
+ancestry	O
+,	O
+we	O
+found	O
+that	O
+none	O
+of	O
+the	O
+three	O
+localizations	O
+accounted	O
+for	O
+all	O
+US1	O
+families	O
+in	O
+our	O
+series	O
+(	O
+Zmax	O
+=	O
+1.48	O
+at	O
+theta	O
+=	O
+0.10	O
+;	O
+Zmax	O
+=	O
+1.45	O
+at	O
+theta	O
+=	O
+0.10	O
+;	O
+and	O
+Zmax	O
+=	O
+0.36	O
+at	O
+theta	O
+=	O
+0.20	O
+for	O
+probes	O
+MLJ14	O
+,	O
+Zd5	O
+,	O
+and	O
+Mfd58	O
+,	O
+respectively	O
+,	O
+at	O
+loci	O
+D14S13	O
+,	O
+D11S527	O
+,	O
+and	O
+D11S419	O
+,	O
+respectively	O
+)	O
+.	O
+
+However	O
+,	O
+when	O
+our	O
+sample	O
+was	O
+split	O
+into	O
+two	O
+groups	O
+according	O
+to	O
+the	O
+geographic	O
+origin	O
+of	O
+the	O
+probands	O
+'	O
+grandparents	O
+,	O
+we	O
+were	O
+able	O
+to	O
+confirm	O
+the	O
+presence	O
+of	O
+a	O
+gene	O
+for	O
+US1	O
+on	O
+chromosome	O
+14q32	O
+(	O
+USH1A	O
+)	O
+in	O
+9	O
+families	O
+originating	O
+from	O
+the	O
+Poitou	B-LOC
+region	O
+in	O
+Western	B-LOC
+France	I-LOC
+(	O
+Department	O
+of	O
+Deux	O
+-	O
+Sèvres	O
+;	O
+Zmax	O
+=	O
+4.46	O
+at	O
+theta	O
+=	O
+0	O
+for	O
+probe	O
+MLJ14	O
+at	O
+the	O
+D14S13	O
+locus	O
+,	O
+Morton	O
+likelihood	O
+ratio	O
+test	O
+,	O
+P	O
+<	O
+0.01	O
+)	O
+.	O
+
+Moreover	O
+,	O
+we	O
+refined	O
+the	O
+genetic	O
+mapping	O
+of	O
+USH1A	O
+by	O
+showing	O
+that	O
+the	O
+disease	O
+gene	O
+maps	O
+to	O
+the	O
+D14S13	O
+locus	O
+,	O
+within	O
+the	O
+genetic	O
+interval	O
+defined	O
+by	O
+loci	O
+D14S78	O
+and	O
+D14S250	O
+(	O
+location	O
+score	O
+in	O
+log	O
+base	O
+10	O
+=	O
+4.90	O
+)	O
+.	O
+
+Consistent	O
+with	O
+this	O
+,	O
+nonsignificant	O
+lod	O
+score	O
+values	O
+for	O
+linkage	O
+to	O
+either	O
+USH1B	O
+or	O
+USH1C	O
+were	O
+found	O
+in	O
+this	O
+group	O
+.	O
+
+(	O
+ABSTRACT	O
+TRUNCATED	O
+AT	O
+250	O
+WORDS	O
+)	O
+
+Little	O
+information	O
+is	O
+available	O
+on	O
+the	O
+prevalence	B-EPI
+,	O
+geographic	O
+distribution	O
+and	O
+mutation	O
+spectrum	O
+of	O
+genetic	O
+skeletal	O
+disorders	O
+(	O
+GSDs	O
+)	O
+in	O
+China	B-LOC
+.	O
+
+This	O
+study	O
+systematically	O
+reviewed	O
+GSDs	O
+as	O
+defined	O
+in	O
+	O
+Nosology	O
+and	O
+Classification	O
+of	O
+genetic	O
+skeletal	O
+disorders	O
+(	O
+2010	O
+version	O
+)	O
+	O
+using	O
+Chinese	O
+biomedical	O
+literature	O
+published	O
+over	O
+the	O
+past	O
+34	O
+years	O
+from	O
+1978	O
+to	O
+2012	O
+.	O
+
+In	O
+total	O
+,	O
+16,099	O
+GSDs	O
+have	O
+been	O
+reported	O
+.	O
+
+The	O
+most	O
+frequently	O
+reported	O
+disorders	O
+were	O
+Marfan	O
+syndrome	O
+,	O
+osteogenesis	O
+imperfecta	O
+,	O
+fibrous	O
+dysplasia	O
+,	O
+mucopolysaccharidosis	O
+,	O
+multiple	O
+cartilaginous	O
+exostoses	O
+,	O
+neurofibromatosis	O
+type	O
+1	O
+(	O
+NF1	O
+)	O
+,	O
+osteopetrosis	O
+,	O
+achondroplasia	O
+,	O
+enchondromatosis	O
+(	O
+Ollier	O
+)	O
+,	O
+and	O
+osteopoikilosis	O
+,	O
+accounting	O
+for	O
+76.5	O
+%	O
+(	O
+12,312	O
+cases	O
+)	O
+of	O
+the	O
+total	O
+cases	O
+.	O
+
+Five	O
+groups	O
+(	O
+group	O
+8	O
+,	O
+12	O
+,	O
+14	O
+,	O
+18	O
+,	O
+21	O
+)	O
+defined	O
+by	O
+	O
+Nosology	O
+and	O
+Classification	O
+of	O
+genetic	O
+skeletal	O
+disorders	O
+	O
+have	O
+not	O
+been	O
+reported	O
+in	O
+the	O
+Chinese	O
+biomedical	O
+literature	O
+.	O
+
+Gene	O
+mutation	O
+testing	O
+was	O
+performed	O
+in	O
+only	O
+a	O
+minor	O
+portion	O
+of	O
+the	O
+16,099	O
+cases	O
+of	O
+GSDs	O
+(	O
+187	O
+cases	O
+,	O
+1.16	O
+%	O
+)	O
+.	O
+
+In	O
+total	O
+,	O
+37	O
+genes	O
+for	O
+41	O
+different	O
+GSDs	O
+were	O
+reported	O
+in	O
+Chinese	O
+biomedical	O
+literature	O
+,	O
+including	O
+43	O
+novel	O
+mutations	O
+.	O
+
+This	O
+review	O
+revealed	O
+a	O
+significant	O
+imbalance	O
+in	O
+rare	O
+disease	O
+identification	O
+in	O
+terms	O
+of	O
+geographic	O
+regions	O
+and	O
+hospital	O
+levels	O
+,	O
+suggesting	O
+the	O
+need	O
+to	O
+create	O
+a	O
+national	O
+multi	O
+-	O
+level	O
+network	O
+to	O
+meet	O
+the	O
+specific	O
+challenge	O
+of	O
+care	O
+for	O
+rare	O
+diseases	O
+in	O
+China	B-LOC
+.	O
+
+Newborn	O
+screening	O
+(	O
+NBS	O
+)	O
+in	O
+Alberta	B-LOC
+is	O
+delivered	O
+by	O
+a	O
+number	O
+of	O
+government	O
+and	O
+health	O
+service	O
+entities	O
+who	O
+work	O
+together	O
+to	O
+provide	O
+newborn	O
+screening	O
+to	O
+infants	O
+born	O
+in	O
+Alberta	B-LOC
+,	O
+the	B-LOC
+Northwest	I-LOC
+Territories	I-LOC
+,	O
+and	O
+the	O
+Kitikmeot	B-LOC
+region	O
+of	O
+the	O
+Nunavut	O
+territory	O
+.	O
+
+The	O
+Alberta	B-LOC
+panel	O
+screens	O
+for	O
+21	O
+disorders	O
+(	O
+16	O
+metabolic	O
+,	O
+two	O
+endocrine	O
+,	O
+cystic	O
+fibrosis	O
+,	O
+severe	O
+combined	O
+immunodeficiency	O
+,	O
+and	O
+sickle	O
+cell	O
+disease	O
+)	O
+.	O
+
+NBS	O
+is	O
+a	O
+standard	O
+of	O
+care	O
+,	O
+but	O
+is	O
+not	O
+mandatory	O
+.	O
+
+NBS	O
+performance	O
+is	O
+monitored	O
+by	O
+the	O
+Alberta	O
+Newborn	O
+Metabolic	O
+Screening	O
+(	O
+NMS	O
+)	O
+Program	O
+and	O
+NMS	O
+Laboratory	O
+,	O
+who	O
+strive	O
+for	O
+continuous	O
+quality	O
+improvement	O
+.	O
+
+Performance	O
+analysis	O
+found	O
+that	O
+over	O
+99	O
+%	O
+of	O
+registered	O
+infants	O
+in	O
+Alberta	B-LOC
+received	O
+a	O
+newborn	O
+screen	O
+and	O
+over	O
+98	O
+%	O
+of	O
+these	O
+infants	O
+received	O
+a	O
+screen	O
+result	O
+within	O
+10	O
+days	O
+of	O
+age	O
+.	O
+
+To	O
+date	O
+,	O
+retinal	O
+implants	O
+are	O
+the	O
+only	O
+available	O
+treatment	O
+for	O
+blind	O
+individuals	O
+with	O
+retinal	O
+degenerations	O
+such	O
+as	O
+retinitis	O
+pigmentosa	O
+.	O
+
+Argus	O
+II	O
+is	O
+the	O
+only	O
+visual	O
+implant	O
+with	O
+FDA	O
+approval	O
+,	O
+with	O
+more	O
+than	O
+300	O
+users	O
+worldwide	B-LOC
+.	O
+
+Argus	O
+II	O
+stimulation	O
+is	O
+based	O
+on	O
+a	O
+grayscale	O
+image	O
+coming	O
+from	O
+a	O
+head	O
+-	O
+mounted	O
+visible	O
+-	O
+light	O
+camera	O
+.	O
+
+Normally	O
+,	O
+the	O
+11	O
+°	O
+×19	O
+°	O
+field	O
+of	O
+view	O
+of	O
+the	O
+Argus	O
+II	O
+user	O
+is	O
+full	O
+of	O
+objects	O
+that	O
+may	O
+elicit	O
+similar	O
+phosphenes	O
+.	O
+
+The	O
+prosthesis	O
+can	O
+not	O
+meaningfully	O
+convey	O
+so	O
+much	O
+visual	O
+information	O
+,	O
+and	O
+the	O
+percept	O
+is	O
+reduced	O
+to	O
+an	O
+ambiguous	O
+impression	O
+of	O
+light	O
+.	O
+
+This	O
+study	O
+is	O
+aimed	O
+at	O
+investigating	O
+the	O
+efficacy	O
+of	O
+simplifying	O
+the	O
+video	O
+input	O
+in	O
+real	O
+-	O
+time	O
+using	O
+a	O
+heat	O
+-	O
+sensitive	O
+camera	O
+.	O
+
+Data	O
+were	O
+acquired	O
+from	O
+four	O
+Argus	O
+II	O
+users	O
+in	O
+5	O
+stationary	O
+tasks	O
+with	O
+either	O
+hot	O
+objects	O
+or	O
+human	O
+targets	O
+as	O
+stimuli	O
+.	O
+
+All	O
+tasks	O
+were	O
+of	O
+m	O
+-	O
+alternative	O
+forced	O
+choice	O
+design	O
+where	O
+precisely	O
+one	O
+of	O
+the	O
+m≥2	O
+response	O
+alternatives	O
+was	O
+defined	O
+to	O
+be	O
+	O
+correct	O
+	O
+by	O
+the	O
+experimenter	O
+.	O
+
+To	O
+compare	O
+performance	O
+with	O
+heat	O
+-	O
+sensitive	O
+and	O
+normal	O
+cameras	O
+across	O
+all	O
+tasks	O
+,	O
+regardless	O
+of	O
+m	O
+,	O
+we	O
+used	O
+an	O
+extension	O
+of	O
+signal	O
+detection	O
+theory	O
+to	O
+latent	O
+variables	O
+,	O
+estimating	O
+person	O
+ability	O
+and	O
+item	O
+difficulty	O
+in	O
+d	O
+'	O
+units	O
+.	O
+
+Results	O
+demonstrate	O
+that	O
+subject	O
+performance	O
+was	O
+significantly	O
+better	O
+across	O
+all	O
+tasks	O
+with	O
+the	O
+thermal	O
+camera	O
+compared	O
+to	O
+the	O
+regular	O
+Argus	O
+II	O
+camera	O
+.	O
+
+The	O
+future	O
+addition	O
+of	O
+thermal	O
+imaging	O
+to	O
+devices	O
+with	O
+very	O
+poor	O
+spatial	O
+resolution	O
+may	O
+have	O
+significant	O
+real	O
+-	O
+life	O
+benefits	O
+for	O
+orientation	O
+,	O
+personal	O
+safety	O
+,	O
+and	O
+social	O
+interactions	O
+,	O
+thereby	O
+improving	O
+quality	O
+of	O
+life	O
+.	O
+
+West	B-LOC
+Nile	I-LOC
+virus	O
+(	O
+WNV	O
+)	O
+is	O
+a	O
+flavivirus	O
+which	O
+transmission	O
+cycle	O
+is	O
+maintained	O
+between	O
+mosquitoes	O
+and	O
+birds	O
+,	O
+although	O
+it	O
+occasionally	O
+causes	O
+sporadic	O
+outbreaks	O
+in	O
+horses	O
+and	O
+humans	O
+that	O
+can	O
+result	O
+in	O
+serious	O
+diseases	O
+and	O
+even	O
+death	O
+.	O
+
+Since	O
+its	O
+first	O
+isolation	O
+in	O
+Africa	B-LOC
+in	O
+1937	O
+,	O
+WNV	O
+had	O
+been	O
+considered	O
+a	O
+neglected	O
+pathogen	O
+until	O
+its	O
+recent	O
+spread	O
+throughout	O
+Europe	B-LOC
+and	O
+the	O
+colonization	O
+of	O
+America	B-LOC
+,	O
+regions	O
+where	O
+it	O
+continues	O
+to	O
+cause	O
+outbreaks	O
+with	O
+severe	O
+neurological	O
+consequences	O
+in	O
+humans	O
+and	O
+horses	O
+.	O
+
+Although	O
+our	O
+knowledge	O
+about	O
+the	O
+characteristics	O
+and	O
+consequences	O
+of	O
+the	O
+virus	O
+has	O
+increased	O
+enormously	O
+lately	O
+,	O
+many	O
+questions	O
+remain	O
+to	O
+be	O
+resolved	O
+.	O
+
+Here	O
+,	O
+we	O
+thoroughly	O
+update	O
+our	O
+knowledge	O
+of	O
+different	O
+aspects	O
+of	O
+the	O
+WNV	O
+life	O
+cycle	O
+:	O
+virology	O
+and	O
+molecular	O
+classification	O
+,	O
+host	O
+cell	O
+interactions	O
+,	O
+transmission	O
+dynamics	O
+,	O
+host	O
+range	O
+,	O
+epidemiology	O
+and	O
+surveillance	O
+,	O
+immune	O
+response	O
+,	O
+clinical	O
+presentations	O
+,	O
+pathogenesis	O
+,	O
+diagnosis	O
+,	O
+prophylaxis	O
+(	O
+antivirals	O
+and	O
+vaccines	O
+)	O
+,	O
+and	O
+prevention	O
+,	O
+and	O
+we	O
+highlight	O
+those	O
+aspects	O
+that	O
+are	O
+still	O
+unknown	O
+and	O
+that	O
+undoubtedly	O
+require	O
+further	O
+investigation	O
+.	O
+
+The	O
+global	O
+spread	O
+of	O
+COVID-19	O
+constitutes	O
+the	O
+most	O
+dangerous	O
+pandemic	O
+to	O
+emerge	O
+during	O
+the	O
+last	O
+one	O
+hundred	O
+years	O
+.	O
+
+About	O
+seventy	O
+-	O
+nine	O
+million	O
+infections	O
+and	O
+more	O
+than	O
+1.7	O
+million	O
+death	O
+have	O
+been	O
+reported	O
+to	O
+date	O
+,	O
+along	O
+with	O
+destruction	O
+of	O
+the	O
+global	O
+economy	O
+.	O
+
+With	O
+the	O
+uncertainty	O
+evolved	O
+by	O
+alarming	O
+level	O
+of	O
+genome	O
+mutations	O
+,	O
+coupled	O
+with	O
+likelihood	O
+of	O
+generating	O
+only	O
+a	O
+short	O
+lived	O
+immune	O
+response	O
+by	O
+the	O
+vaccine	O
+injections	O
+,	O
+the	O
+identification	O
+of	O
+antiviral	O
+drugs	O
+for	O
+direct	O
+therapy	O
+is	O
+the	O
+need	O
+of	O
+the	O
+hour	O
+.	O
+
+Strategies	O
+to	O
+inhibit	O
+virus	O
+infection	O
+and	O
+replication	O
+focus	O
+on	O
+targets	O
+such	O
+as	O
+the	O
+spike	O
+protein	O
+and	O
+non	O
+-	O
+structural	O
+proteins	O
+including	O
+the	O
+highly	O
+conserved	O
+RNA	O
+-	O
+dependent	O
+-	O
+RNA	O
+-	O
+polymerase	O
+,	O
+nucleotidyl	O
+-	O
+transferases	O
+,	O
+main	O
+protease	O
+and	O
+papain	O
+-	O
+like	O
+proteases	O
+.	O
+
+There	O
+is	O
+also	O
+an	O
+indirect	O
+option	O
+to	O
+target	O
+the	O
+host	O
+cell	O
+recognition	O
+systems	O
+such	O
+as	O
+angiotensin	O
+-	O
+converting	O
+enzyme	O
+2	O
+(	O
+ACE2	O
+)	O
+,	O
+transmembrane	O
+protease	O
+,	O
+serine	O
+2	O
+,	O
+host	O
+cell	O
+expressed	O
+CD147	O
+,	O
+and	O
+the	O
+host	O
+furin	O
+.	O
+
+A	O
+drug	O
+search	O
+strategy	O
+consensus	O
+in	O
+tandem	O
+with	O
+analysis	O
+of	O
+currently	O
+available	O
+information	O
+is	O
+extremely	O
+important	O
+for	O
+the	O
+rapid	O
+identification	O
+of	O
+anti	O
+-	O
+viral	O
+.	O
+
+An	O
+unprecedented	O
+display	O
+of	O
+cooperation	O
+among	O
+the	O
+scientific	O
+community	O
+regarding	O
+SARS	O
+-	O
+CoV-2	O
+research	O
+has	O
+resulted	O
+in	O
+the	O
+accumulation	O
+of	O
+an	O
+enormous	O
+amount	O
+of	O
+literature	O
+that	O
+requires	O
+curation	O
+.	O
+
+Drug	O
+repurposing	O
+and	O
+drug	O
+combinations	O
+have	O
+drawn	O
+tremendous	O
+attention	O
+for	O
+rapid	O
+therapeutic	O
+application	O
+,	O
+while	O
+high	O
+throughput	O
+screening	O
+and	O
+virtual	O
+searches	O
+support	O
+de	O
+novo	O
+drug	O
+identification	O
+.	O
+
+Here	O
+,	O
+we	O
+examine	O
+how	O
+certain	O
+approved	O
+drugs	O
+targeting	O
+different	O
+viruses	O
+can	O
+play	O
+a	O
+role	O
+in	O
+combating	O
+this	O
+new	O
+virus	O
+and	O
+analyze	O
+how	O
+they	O
+demonstrate	O
+efficacy	O
+under	O
+clinical	O
+assessment	O
+.	O
+
+Suggestions	O
+on	O
+repurposing	O
+and	O
+de	O
+novo	O
+strategies	O
+are	O
+proposed	O
+to	O
+facilitate	O
+the	O
+fight	O
+against	O
+the	O
+COVID-19	O
+pandemic	O
+.	O
+
+The	O
+oral	O
+-	O
+facial	O
+-	O
+digital	O
+syndrome	O
+type	O
+I	O
+(	O
+OFD	O
+I	O
+)	O
+is	O
+characterized	O
+by	O
+multiple	O
+congenital	O
+malformations	O
+of	O
+the	O
+face	O
+,	O
+oral	O
+cavity	O
+and	O
+digits	O
+.	O
+
+A	O
+polycystic	O
+kidney	O
+disease	O
+(	O
+PKD	O
+)	O
+is	O
+found	O
+in	O
+about	O
+one	O
+-	O
+third	O
+of	O
+patients	O
+but	O
+long	O
+-	O
+term	O
+outcome	O
+and	O
+complications	O
+are	O
+not	O
+well	O
+described	O
+in	O
+the	O
+international	O
+literature	O
+.	O
+
+Renal	O
+findings	O
+have	O
+been	O
+retrospectively	O
+collected	O
+in	O
+a	O
+cohort	O
+of	O
+34	O
+females	O
+all	O
+carrying	O
+a	O
+pathogenic	O
+mutation	O
+in	O
+the	O
+OFD1	O
+gene	O
+with	O
+ages	O
+ranging	O
+from	O
+1	B-STAT
+to	I-STAT
+65	I-STAT
+years	O
+.	O
+
+Twelve	O
+patients	O
+presented	O
+with	O
+PKD	B-STAT
+-	I-STAT
+11/16	I-STAT
+(	O
+69	O
+%	O
+)	O
+if	O
+only	O
+adults	O
+were	O
+considered	O
+-with	O
+a	O
+median	O
+age	O
+at	O
+diagnosis	O
+of	O
+29	O
+years	O
+[	O
+IQR	O
+(	O
+interquartile	O
+range	O
+)	O
+=	O
+(	O
+23.5	O
+-	O
+38	O
+)	O
+]	O
+.	O
+
+Among	O
+them	O
+,	O
+10	O
+also	O
+presented	O
+with	O
+renal	O
+impairment	O
+and	O
+6	O
+were	O
+grafted	O
+(	O
+median	O
+age	O
+=	O
+38	O
+years	O
+[	O
+IQR	O
+=	O
+(	O
+25	O
+-	O
+48	O
+)	O
+]	O
+.	O
+
+One	O
+grafted	O
+patient	O
+under	O
+immunosuppressive	O
+treatment	O
+died	O
+from	O
+a	O
+tumor	O
+originated	O
+from	O
+a	O
+native	O
+kidney	O
+.	O
+
+The	O
+probability	O
+to	O
+develop	O
+renal	O
+failure	O
+was	O
+estimated	O
+to	O
+be	O
+more	O
+than	O
+50	B-STAT
+%	O
+after	O
+the	O
+age	O
+of	O
+36	O
+years	O
+.	O
+
+Besides	O
+,	O
+neither	O
+genotype	O
+-	O
+phenotype	O
+correlation	O
+nor	O
+clinical	O
+predictive	O
+association	O
+with	O
+renal	O
+failure	O
+could	O
+be	O
+evidenced	O
+.	O
+
+These	O
+data	O
+reveal	O
+an	O
+unsuspected	O
+high	O
+incidence	B-EPI
+rate	O
+of	O
+the	O
+renal	O
+impairment	O
+outcome	O
+in	O
+OFD	O
+I	O
+syndrome	O
+.	O
+
+A	O
+systematic	O
+ultrasound	O
+(	O
+US	B-LOC
+)	O
+and	O
+renal	O
+function	O
+follow	O
+-	O
+up	O
+is	O
+therefore	O
+highly	O
+recommended	O
+for	O
+all	O
+OFD	O
+I	O
+patients	O
+.	O
+
+Introduction	O
+Limited	O
+data	O
+are	O
+available	O
+on	O
+the	O
+incidence	B-EPI
+of	O
+primary	O
+ophthalmic	O
+cancers	O
+worldwide	B-LOC
+.	O
+
+We	O
+describe	O
+the	O
+incidence	B-EPI
+and	O
+trends	O
+of	O
+primary	O
+ophthalmic	O
+cancers	O
+in	O
+Singapore	B-LOC
+.	O
+
+Methods	O
+Data	O
+on	O
+ophthalmic	O
+cancers	O
+diagnosed	O
+in	O
+Singapore	B-LOC
+from	O
+1996	O
+to	O
+2016	O
+were	O
+retrieved	O
+from	O
+the	O
+Singapore	O
+Cancer	O
+Registry	O
+for	O
+analysis	O
+.	O
+
+All	O
+were	O
+histologically	O
+proven	O
+primary	O
+ophthalmic	O
+cancers	O
+.	O
+
+Calculations	O
+of	O
+incidence	B-EPI
+and	O
+age	O
+-	O
+specific	O
+frequency	O
+of	O
+ophthalmic	O
+malignancy	O
+were	O
+made	O
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+297	O
+cases	O
+were	O
+included	O
+,	O
+with	O
+males	O
+constituting	O
+59.9	B-STAT
+%	I-STAT
+.	O
+
+The	O
+race	O
+distribution	O
+was	O
+78.5	O
+%	O
+Chinese	O
+,	O
+16.5	O
+%	O
+Malay	O
+,	O
+3.7	O
+%	O
+Indians	O
+and	O
+1.3	O
+%	O
+others	O
+.	O
+
+There	O
+was	O
+an	O
+overall	O
+increase	O
+in	O
+ophthalmic	O
+malignancies	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+onset	O
+was	O
+47.4	O
+years	O
+.	O
+
+The	O
+most	O
+common	O
+cancers	O
+were	O
+retinoblastoma	O
+(	O
+93.3	O
+%	O
+)	O
+in	O
+patients	O
+younger	O
+than	O
+15	O
+years	O
+,	O
+and	O
+lymphoma	O
+(	O
+71.3	O
+%	O
+)	O
+in	O
+patients	O
+aged	O
+15	O
+years	O
+and	O
+older	O
+.	O
+
+There	O
+has	O
+been	O
+an	O
+increase	O
+in	O
+lymphomas	O
+from	O
+16.7	O
+%	O
+in	O
+1968	O
+-	O
+1995	O
+to	O
+71.3	O
+%	O
+in	O
+1996	O
+-	O
+2016	O
+in	O
+those	O
+aged	O
+15	O
+years	O
+and	O
+older	O
+.	O
+
+The	O
+most	O
+common	O
+types	O
+of	O
+ophthalmic	O
+cancer	O
+according	O
+to	O
+location	O
+are	O
+lymphoma	O
+of	O
+the	O
+orbit	O
+,	O
+conjunctiva	O
+,	O
+cornea	O
+and	O
+lacrimal	O
+gland	O
+;	O
+retinoblastoma	O
+of	O
+the	O
+retina	O
+;	O
+and	O
+malignant	O
+melanoma	O
+of	O
+the	O
+choroid	O
+and	O
+ciliary	O
+body	O
+.	O
+
+Conclusion	O
+Our	O
+study	O
+reported	O
+the	O
+incidence	B-EPI
+and	O
+trends	O
+of	O
+ophthalmic	O
+cancer	O
+in	O
+the	O
+Singapore	B-LOC
+population	O
+and	O
+showed	O
+an	O
+overall	O
+increase	O
+in	O
+ophthalmic	O
+malignancies	O
+in	O
+Singapore	B-LOC
+from	O
+1996	O
+-	O
+2016	O
+.	O
+
+A	O
+substantial	O
+increase	O
+in	O
+lymphomas	O
+over	O
+the	O
+last	O
+2	O
+decades	O
+was	O
+noted	O
+.	O
+
+The	O
+data	O
+could	O
+aid	O
+clinicians	O
+,	O
+epidemiologists	O
+and	O
+policymakers	O
+in	O
+implementing	O
+strategies	O
+to	O
+address	O
+trends	O
+in	O
+ophthalmic	O
+cancers	O
+and	O
+spur	O
+aetiological	O
+research	O
+to	O
+improve	O
+quality	O
+of	O
+life	O
+in	O
+patients	O
+with	O
+such	O
+cancers	O
+.	O
+
+Purpose	O
+of	O
+review	O
+Cardiovascular	O
+toxicity	O
+is	O
+a	O
+leading	O
+cause	O
+of	O
+mortality	O
+among	O
+cancer	O
+survivors	O
+and	O
+has	O
+become	O
+increasingly	O
+prevalent	B-EPI
+due	O
+to	O
+improved	O
+cancer	O
+survival	O
+rates	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+synthesize	O
+evidence	O
+illustrating	O
+how	O
+common	O
+cancer	O
+therapeutic	O
+agents	O
+,	O
+such	O
+as	O
+anthracyclines	O
+,	O
+human	O
+epidermal	O
+growth	O
+factors	O
+receptors	O
+(	O
+HER2	O
+)	O
+monoclonal	O
+antibodies	O
+,	O
+and	O
+tyrosine	O
+kinase	O
+inhibitors	O
+(	O
+TKIs	O
+)	O
+,	O
+have	O
+been	O
+evaluated	O
+in	O
+cardiomyocytes	O
+(	O
+CMs	O
+)	O
+derived	O
+from	O
+human	O
+-	O
+induced	O
+pluripotent	O
+stem	O
+cells	O
+(	O
+hiPSCs	O
+)	O
+to	O
+understand	O
+the	O
+underlying	O
+mechanisms	O
+of	O
+cardiovascular	O
+toxicity	O
+.	O
+
+We	O
+place	O
+this	O
+in	O
+the	O
+context	O
+of	O
+precision	O
+cardio	O
+-	O
+oncology	O
+,	O
+an	O
+emerging	O
+concept	O
+for	O
+personalizing	O
+the	O
+prevention	O
+and	O
+management	O
+of	O
+cardiovascular	O
+toxicities	O
+from	O
+cancer	O
+therapies	O
+,	O
+accounting	O
+for	O
+each	O
+individual	O
+patient	O
+'s	O
+unique	O
+factors	O
+.	O
+
+We	O
+outline	O
+steps	O
+that	O
+will	O
+need	O
+to	O
+be	O
+addressed	O
+by	O
+multidisciplinary	O
+teams	O
+of	O
+cardiologists	O
+and	O
+oncologists	O
+in	O
+partnership	O
+with	O
+regulators	O
+to	O
+implement	O
+future	O
+applications	O
+of	O
+hiPSCs	O
+in	O
+precision	O
+cardio	O
+-	O
+oncology	O
+.	O
+
+Recent	O
+findings	O
+Current	O
+prevention	O
+of	O
+cardiovascular	O
+toxicity	O
+involves	O
+routine	O
+screenings	O
+and	O
+management	O
+of	O
+modifiable	O
+risk	O
+factors	O
+for	O
+cancer	O
+patients	O
+,	O
+as	O
+well	O
+as	O
+the	O
+initiation	O
+of	O
+cardioprotective	O
+medications	O
+.	O
+
+Despite	O
+recent	O
+advancements	O
+in	O
+precision	O
+cardio	O
+-	O
+oncology	O
+,	O
+knowledge	O
+gaps	O
+remain	O
+and	O
+limit	O
+our	O
+ability	O
+to	O
+appropriately	O
+predict	O
+with	O
+precision	O
+which	O
+patients	O
+will	O
+develop	O
+cardiovascular	O
+toxicity	O
+.	O
+
+Investigations	O
+using	O
+patient	O
+-	O
+specific	O
+CMs	O
+facilitate	O
+pharmacological	O
+discovery	O
+,	O
+mechanistic	O
+toxicity	O
+studies	O
+,	O
+and	O
+the	O
+identification	O
+of	O
+cardioprotective	O
+pathways	O
+.	O
+
+Studies	O
+with	O
+hiPSCs	O
+demonstrate	O
+that	O
+patients	O
+with	O
+comorbidities	O
+have	O
+more	O
+frequent	O
+adverse	O
+responses	O
+,	O
+compared	O
+to	O
+their	O
+counterparts	O
+without	O
+cardiac	O
+disease	O
+.	O
+
+Further	O
+studies	O
+utilizing	O
+hiPSC	O
+modeling	O
+should	O
+be	O
+considered	O
+,	O
+to	O
+evaluate	O
+the	O
+impact	O
+and	O
+mitigation	O
+of	O
+known	O
+cardiovascular	O
+risk	O
+factors	O
+,	O
+including	O
+blood	O
+pressure	O
+,	O
+body	O
+mass	O
+index	O
+(	O
+BMI	O
+)	O
+,	O
+smoking	O
+status	O
+,	O
+diabetes	O
+,	O
+and	O
+physical	O
+activity	O
+in	O
+their	O
+role	O
+in	O
+cardiovascular	O
+toxicity	O
+after	O
+cancer	O
+therapy	O
+.	O
+
+Future	O
+real	O
+-	O
+world	O
+applications	O
+will	O
+depend	O
+on	O
+understanding	O
+the	O
+current	O
+use	O
+of	O
+hiPSC	O
+modeling	O
+in	O
+order	O
+for	O
+oncologists	O
+and	O
+cardiologists	O
+together	O
+to	O
+inform	O
+their	O
+potential	O
+to	O
+improve	O
+our	O
+clinical	O
+collaborative	O
+practice	O
+in	O
+cardio	O
+-	O
+oncology	O
+.	O
+
+When	O
+applying	O
+such	O
+in	O
+vitro	O
+characterization	O
+,	O
+it	O
+is	O
+hypothesized	O
+that	O
+a	O
+safety	O
+score	O
+can	O
+be	O
+assigned	O
+to	O
+each	O
+individual	O
+to	O
+determine	O
+who	O
+has	O
+a	O
+greater	O
+probability	O
+of	O
+developing	O
+cardiovascular	O
+toxicity	O
+.	O
+
+Using	O
+hiPSCs	O
+to	O
+create	O
+personalized	O
+models	O
+and	O
+ultimately	O
+evaluate	O
+the	O
+cardiovascular	O
+toxicity	O
+of	O
+individuals	O
+'	O
+treatments	O
+may	O
+one	O
+day	O
+lead	O
+to	O
+more	O
+patient	O
+-	O
+specific	O
+treatment	O
+plans	O
+in	O
+precision	O
+cardio	O
+-	O
+oncology	O
+while	O
+reducing	O
+cardiovascular	O
+disease	O
+(	O
+CVD	O
+)	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+Background	O
+and	O
+objective	O
+Congenital	O
+adrenal	O
+hyperplasia	O
+involves	O
+a	O
+series	O
+of	O
+autosomal	O
+recessive	O
+disorders	O
+where	O
+adrenal	O
+steroidogenesis	O
+is	O
+affected	O
+.	O
+
+We	O
+present	O
+a	O
+detailed	O
+molecular	O
+investigation	O
+of	O
+13	O
+newborns	O
+affected	O
+from	O
+the	O
+severe	O
+form	O
+of	O
+congenital	O
+adrenal	O
+hyperplasia	O
+related	O
+to	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+.	O
+
+Methods	O
+All	O
+patients	O
+were	O
+diagnosed	O
+with	O
+classical	O
+congenital	O
+adrenal	O
+hyperplasia	O
+in	O
+the	O
+neonatal	O
+period	O
+due	O
+to	O
+adrenal	O
+crisis	O
+and/or	O
+ambiguous	O
+genitalia	O
+presentation	O
+.	O
+
+None	O
+of	O
+the	O
+infants	O
+was	O
+identified	O
+through	O
+a	O
+congenital	O
+adrenal	O
+hyperplasia	O
+newborn	O
+screening	O
+program	O
+.	O
+
+A	O
+molecular	O
+analysis	O
+of	O
+the	O
+CYP21A2	O
+gene	O
+and	O
+a	O
+familiar	O
+segregation	O
+analysis	O
+were	O
+performed	O
+.	O
+
+Results	O
+Adrenal	O
+crisis	O
+was	O
+the	O
+most	O
+severe	O
+manifestation	O
+in	O
+the	O
+male	O
+salt	O
+-	O
+wasting	O
+newborns	O
+while	O
+all	O
+female	O
+patients	O
+presented	O
+with	O
+atypical	O
+genitalia	O
+.	O
+
+Newborns	O
+were	O
+correctly	O
+genotyped	O
+and	O
+no	O
+genotype	O
+-	O
+phenotype	O
+divergences	O
+were	O
+found	O
+.	O
+
+Two	O
+novel	O
+severe	O
+genotypes	O
+,	O
+not	O
+previously	O
+reported	O
+,	O
+were	O
+identified	O
+.	O
+
+The	O
+novel	O
+CYP21A2	O
+frameshift	O
+mutations	O
+(	O
+c.793delG	O
+and	O
+c.297dupG	O
+)	O
+were	O
+added	O
+to	O
+the	O
+other	O
+45	O
+variants	O
+recently	O
+reported	O
+in	O
+the	O
+literature	O
+,	O
+leading	O
+to	O
+a	O
+total	O
+count	O
+of	O
+279	O
+pathogenic	O
+variants	O
+affecting	O
+the	O
+gene	O
+.	O
+
+Conclusions	O
+We	O
+have	O
+successfully	O
+genotyped	O
+13	O
+infants	O
+diagnosed	O
+with	O
+classical	O
+congenital	O
+adrenal	O
+hyperplasia	O
+after	O
+birth	O
+.	O
+
+Our	O
+molecular	O
+approach	O
+led	O
+to	O
+the	O
+identification	O
+of	O
+two	O
+novel	O
+frameshift	O
+CYP21A2	O
+pathogenic	O
+variants	O
+related	O
+to	O
+the	O
+salt	O
+-	O
+wasting	O
+form	O
+of	O
+congenital	O
+adrenal	O
+hyperplasia	O
+.	O
+
+Idiopathic	O
+nephrotic	O
+syndrome	O
+newly	O
+affects	O
+1	B-STAT
+-	I-STAT
+3	B-STAT
+per	I-STAT
+100,000	I-STAT
+children	I-STAT
+per	I-STAT
+year	I-STAT
+.	O
+
+Approximately	O
+85	O
+%	O
+of	O
+cases	O
+show	O
+complete	O
+remission	O
+of	O
+proteinuria	O
+following	O
+glucocorticoid	O
+treatment	O
+.	O
+
+Patients	O
+who	O
+do	O
+not	O
+achieve	O
+complete	O
+remission	O
+within	O
+4	O
+-	O
+6	O
+weeks	O
+of	O
+glucocorticoid	O
+treatment	O
+have	O
+steroid	O
+-	O
+resistant	O
+nephrotic	O
+syndrome	O
+(	O
+SRNS	O
+)	O
+.	O
+
+In	O
+10	B-STAT
+-	O
+30	O
+%	O
+of	O
+steroid	O
+-	O
+resistant	O
+patients	O
+,	O
+mutations	O
+in	O
+podocyte	O
+-	O
+associated	O
+genes	O
+can	O
+be	O
+detected	O
+,	O
+whereas	O
+an	O
+undefined	O
+circulating	O
+factor	O
+of	O
+immune	O
+origin	O
+is	O
+assumed	O
+in	O
+the	O
+remaining	O
+ones	O
+.	O
+
+Diagnosis	O
+and	O
+management	O
+of	O
+SRNS	O
+is	O
+a	O
+great	O
+challenge	O
+due	O
+to	O
+its	O
+heterogeneous	O
+etiology	O
+,	O
+frequent	O
+lack	O
+of	O
+remission	O
+by	O
+further	O
+immunosuppressive	O
+treatment	O
+,	O
+and	O
+severe	O
+complications	O
+including	O
+the	O
+development	O
+of	O
+end	O
+-	O
+stage	O
+kidney	O
+disease	O
+and	O
+recurrence	O
+after	O
+renal	O
+transplantation	O
+.	O
+
+A	O
+team	O
+of	O
+experts	O
+including	O
+pediatric	O
+nephrologists	O
+and	O
+renal	O
+geneticists	O
+from	O
+the	O
+International	O
+Pediatric	O
+Nephrology	O
+Association	O
+(	O
+IPNA	O
+)	O
+,	O
+a	O
+renal	O
+pathologist	O
+,	O
+and	O
+an	O
+adult	O
+nephrologist	O
+have	O
+now	O
+developed	O
+comprehensive	O
+clinical	O
+practice	O
+recommendations	O
+on	O
+the	O
+diagnosis	O
+and	O
+management	O
+of	O
+SRNS	O
+in	O
+children	O
+.	O
+
+The	O
+team	O
+performed	O
+a	O
+systematic	O
+literature	O
+review	O
+on	O
+9	O
+clinically	O
+relevant	O
+PICO	O
+(	O
+Patient	O
+or	O
+Population	O
+covered	O
+,	O
+Intervention	O
+,	O
+Comparator	O
+,	O
+Outcome	O
+)	O
+questions	O
+,	O
+formulated	O
+recommendations	O
+and	O
+formally	O
+graded	O
+them	O
+at	O
+a	O
+consensus	O
+meeting	O
+,	O
+with	O
+input	O
+from	O
+patient	O
+representatives	O
+and	O
+a	O
+dietician	O
+acting	O
+as	O
+external	O
+advisors	O
+and	O
+a	O
+voting	O
+panel	O
+of	O
+pediatric	O
+nephrologists	O
+.	O
+
+Research	O
+recommendations	O
+are	O
+also	O
+given	O
+.	O
+
+Primary	O
+hyperaldosteronism	O
+(	O
+PA	O
+)	O
+is	O
+a	O
+common	O
+disease	O
+with	O
+a	O
+prevalence	B-EPI
+of	O
+5	B-STAT
+-	O
+10	O
+%	O
+in	O
+unselected	O
+patients	O
+with	O
+hypertension	O
+.	O
+
+Medullary	O
+nephrocalcinosis	O
+is	O
+a	O
+radiological	O
+diagnosis	O
+and	O
+refers	O
+to	O
+diffuse	O
+calcification	O
+in	O
+the	O
+renal	O
+parenchyma	O
+.	O
+
+The	O
+three	O
+commonest	O
+causes	O
+of	O
+nephrocalcinosis	O
+are	O
+hyperparathyroidism	O
+,	O
+distal	O
+renal	O
+tubular	O
+acidosis	O
+,	O
+and	O
+medullary	O
+sponge	O
+kidney	O
+.	O
+
+PA	O
+is	O
+not	O
+a	O
+recognized	O
+cause	O
+of	O
+nephrocalcinosis	O
+.	O
+
+There	O
+are	O
+a	O
+few	O
+case	O
+reports	O
+linking	O
+PA	O
+with	O
+nephrocalcinosis	O
+published	O
+till	O
+date	O
+.	O
+
+In	O
+this	O
+case	O
+series	O
+,	O
+we	O
+report	O
+three	O
+cases	O
+where	O
+PA	O
+was	O
+possibly	O
+associated	O
+with	O
+medullary	O
+nephrocalcinosis	O
+.	O
+
+In	O
+all	O
+three	O
+cases	O
+,	O
+the	O
+common	O
+causes	O
+of	O
+nephrocalcinosis	O
+were	O
+excluded	O
+by	O
+careful	O
+clinical	O
+history	O
+,	O
+biochemical	O
+evaluation	O
+,	O
+and	O
+radiological	O
+findings	O
+.	O
+
+We	O
+conclude	O
+and	O
+emphasize	O
+that	O
+a	O
+diagnosis	O
+of	O
+PA	O
+as	O
+an	O
+etiology	O
+of	O
+medullary	O
+nephrocalcinosis	O
+should	O
+be	O
+sought	O
+after	O
+common	O
+causes	O
+have	O
+been	O
+excluded	O
+,	O
+at	O
+least	O
+in	O
+those	O
+with	O
+hypertension	O
+that	O
+is	O
+difficult	O
+to	O
+control	O
+.	O
+
+The	O
+definition	O
+of	O
+congenital	O
+anomalies	O
+of	O
+the	O
+kidney	O
+and	O
+urinary	O
+tract	O
+(	O
+CAKUT	O
+)	O
+is	O
+the	O
+disease	O
+of	O
+structural	O
+malformations	O
+in	O
+the	O
+kidney	O
+and/or	O
+urinary	O
+tract	O
+containing	O
+vesicoureteral	O
+reflux	O
+(	O
+VUR	O
+)	O
+.	O
+
+These	O
+anomalies	O
+can	O
+cause	O
+pediatric	O
+chronic	O
+kidney	O
+disease	O
+.	O
+
+However	O
+,	O
+the	O
+pathogenesis	O
+of	O
+CAKUT	O
+is	O
+not	O
+well	O
+understood	O
+,	O
+because	O
+identifying	O
+the	O
+genetic	O
+architecture	O
+of	O
+CAKUT	O
+is	O
+difficult	O
+due	O
+to	O
+the	O
+phenotypic	O
+heterogeneity	O
+and	O
+multifactorial	O
+genetic	O
+penetrance	O
+.	O
+
+We	O
+describe	O
+the	O
+current	O
+genetic	O
+basis	O
+and	O
+mechanisms	O
+of	O
+CAKUT	O
+including	O
+VUR	O
+via	O
+approaching	O
+the	O
+steps	O
+and	O
+signaling	O
+pathways	O
+of	O
+kidney	O
+developmental	O
+processes	O
+.	O
+
+We	O
+also	O
+focus	O
+on	O
+the	O
+newly	O
+developed	O
+strategies	O
+and	O
+challenges	O
+to	O
+fully	O
+address	O
+the	O
+role	O
+of	O
+the	O
+associated	O
+genes	O
+in	O
+the	O
+pathogenesis	O
+of	O
+the	O
+disease	O
+.	O
+
+White	O
+-	O
+tailed	O
+deer	O
+(	O
+WTD	O
+)	O
+are	O
+abundant	O
+mammals	O
+widely	O
+distributed	O
+across	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+.	O
+
+As	O
+a	O
+result	O
+,	O
+WTD	O
+are	O
+considered	O
+to	O
+be	O
+excellent	O
+sentinels	O
+for	O
+detecting	O
+arboviral	O
+activity	O
+in	O
+certain	O
+geographic	O
+areas	O
+.	O
+
+Evidence	O
+of	O
+West	B-LOC
+Nile	I-LOC
+virus	O
+(	O
+WNV	O
+)	O
+antibody	O
+in	O
+WTD	O
+has	O
+been	O
+reported	O
+previously	O
+in	O
+several	O
+states	O
+.	O
+
+However	O
+,	O
+WNV	O
+infection	O
+in	O
+WTD	O
+has	O
+not	O
+been	O
+reported	O
+from	O
+Texas	B-LOC
+,	O
+where	O
+the	O
+incidence	B-EPI
+of	O
+human	O
+West	B-LOC
+Nile	I-LOC
+(	O
+WN	O
+)	O
+cases	O
+is	O
+among	O
+the	O
+highest	O
+in	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+.	O
+
+Therefore	O
+,	O
+the	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+prevalence	B-EPI
+of	O
+WNV	O
+antibody	O
+in	O
+WTD	O
+in	O
+central	O
+Texas	B-LOC
+.	O
+
+Sera	B-LOC
+samples	O
+(	O
+n	O
+=	O
+644	O
+)	O
+were	O
+collected	O
+from	O
+deer	O
+during	O
+the	O
+fall	O
+and	O
+winter	O
+in	O
+western	O
+Travis	B-LOC
+County	I-LOC
+,	O
+Texas	B-LOC
+from	O
+2014	O
+to	O
+2018	O
+and	O
+tested	O
+for	O
+WNV	O
+immunoglobulin	O
+G	O
+(	O
+IgG	O
+)	O
+antibody	O
+by	O
+an	O
+indirect	O
+enzyme	O
+-	O
+linked	O
+immunosorbent	O
+assay	O
+(	O
+ELISA	O
+)	O
+.	O
+
+ELISA	O
+antibody	O
+-	O
+positive	O
+samples	O
+were	O
+further	O
+tested	O
+for	O
+WNV	O
+and	O
+St.	B-LOC
+Louis	I-LOC
+encephalitis	O
+virus	O
+(	O
+SLEV	O
+)	O
+antibodies	O
+by	O
+an	O
+80	O
+%	O
+plaque	O
+-	O
+reduction	O
+neutralization	O
+tests	O
+(	O
+PRNT	O
+80	O
+)	O
+.	O
+
+Overall	O
+,	O
+9	O
+%	O
+(	O
+n	O
+=	O
+58	O
+)	O
+and	O
+0.31	B-STAT
+%	I-STAT
+(	O
+n	O
+=	O
+2	O
+)	O
+of	O
+the	O
+deer	O
+samples	O
+had	O
+serological	O
+evidence	O
+of	O
+WNV	O
+and	O
+SLEV	O
+infections	O
+,	O
+respectively	O
+.	O
+
+WNV	O
+seroprevalence	O
+differed	O
+significantly	O
+by	O
+age	O
+(	O
+p	O
+<	O
+0.05	O
+)	O
+,	O
+but	O
+there	O
+was	O
+no	O
+significant	O
+difference	O
+between	O
+sex	O
+.	O
+
+Interestingly	O
+,	O
+3.1	O
+%	O
+(	O
+n	O
+=	O
+20	O
+)	O
+of	O
+the	O
+samples	O
+were	O
+positive	O
+for	O
+Flavivirus	O
+IgG	O
+antibody	O
+by	O
+ELISA	O
+,	O
+but	O
+negative	O
+for	O
+SLEV	O
+and	O
+WNV	O
+antibodies	O
+,	O
+suggesting	O
+that	O
+other	O
+Flaviviruses	O
+may	O
+be	O
+circulating	O
+among	O
+WTD	O
+in	O
+Texas	B-LOC
+.	O
+
+Finally	O
+,	O
+these	O
+results	O
+supported	O
+WNV	O
+infection	O
+among	O
+WTD	O
+and	O
+highlight	O
+their	O
+potential	O
+role	O
+as	O
+sentinels	O
+for	O
+the	O
+detection	O
+of	O
+WNV	O
+in	O
+Texas	B-LOC
+and	O
+warrant	O
+further	O
+studies	O
+to	O
+determine	O
+the	O
+role	O
+WTD	O
+play	O
+in	O
+the	O
+maintenance	O
+and	O
+transmission	O
+of	O
+WNV	O
+.	O
+
+Objectives	O
+To	O
+analyse	O
+the	O
+characteristics	O
+and	O
+predictors	O
+of	O
+death	O
+in	O
+hospitalized	O
+patients	O
+with	O
+coronavirus	O
+disease	O
+2019	O
+(	O
+COVID-19	O
+)	O
+in	O
+Spain	B-LOC
+.	O
+
+Methods	O
+A	O
+retrospective	O
+observational	O
+study	O
+was	O
+performed	O
+of	O
+the	O
+first	O
+consecutive	O
+patients	O
+hospitalized	O
+with	O
+COVID-19	O
+confirmed	O
+by	O
+real	O
+-	O
+time	O
+PCR	O
+assay	O
+in	O
+127	O
+Spanish	O
+centres	O
+until	O
+17	O
+March	O
+2020	O
+.	O
+
+The	O
+follow	O
+-	O
+up	O
+censoring	O
+date	O
+was	O
+17	O
+April	O
+2020	O
+.	O
+
+We	O
+collected	O
+demographic	O
+,	O
+clinical	O
+,	O
+laboratory	O
+,	O
+treatment	O
+and	O
+complications	O
+data	O
+.	O
+
+The	O
+primary	O
+endpoint	O
+was	O
+all	O
+-	O
+cause	O
+mortality	O
+.	O
+
+Univariable	O
+and	O
+multivariable	O
+Cox	O
+regression	O
+analyses	O
+were	O
+performed	O
+to	O
+identify	O
+factors	O
+associated	O
+with	O
+death	O
+.	O
+
+Results	O
+Of	O
+the	O
+4035	O
+patients	O
+,	O
+male	O
+subjects	O
+accounted	O
+for	O
+2433	O
+(	O
+61.0	O
+%	O
+)	O
+of	O
+3987	O
+,	O
+the	O
+median	O
+age	O
+was	O
+70	O
+years	O
+and	O
+2539	O
+(	O
+73.8	O
+%	O
+)	O
+of	O
+3439	O
+had	O
+one	O
+or	O
+more	O
+comorbidity	O
+.	O
+
+The	O
+most	O
+common	O
+symptoms	O
+were	O
+a	O
+history	O
+of	O
+fever	O
+,	O
+cough	O
+,	O
+malaise	O
+and	O
+dyspnoea	O
+.	O
+
+During	O
+hospitalization	O
+,	O
+1255	O
+(	O
+31.5	O
+%	O
+)	O
+of	O
+3979	O
+patients	O
+developed	O
+acute	O
+respiratory	O
+distress	O
+syndrome	O
+,	O
+736	B-STAT
+(	O
+18.5	O
+%	O
+)	O
+of	O
+3988	O
+were	O
+admitted	O
+to	O
+intensive	O
+care	O
+units	O
+and	O
+619	B-STAT
+(	O
+15.5	O
+%	O
+)	O
+of	O
+3992	O
+underwent	O
+mechanical	O
+ventilation	O
+.	O
+
+Virus-	O
+or	O
+host	O
+-	O
+targeted	O
+medications	O
+included	O
+lopinavir	O
+/	O
+ritonavir	O
+(	O
+2820/4005	O
+,	O
+70.4	O
+%	O
+)	O
+,	O
+hydroxychloroquine	O
+(	O
+2618/3995	O
+,	O
+65.5	O
+%	O
+)	O
+,	O
+interferon	O
+beta	O
+(	O
+1153/3950	O
+,	O
+29.2	O
+%	O
+)	O
+,	O
+corticosteroids	O
+(	O
+1109/3965	O
+,	O
+28.0	O
+%	O
+)	O
+and	O
+tocilizumab	O
+(	O
+373/3951	B-STAT
+,	O
+9.4	O
+%	O
+)	O
+.	O
+
+Overall	O
+,	O
+1131	O
+(	O
+28	O
+%	O
+)	O
+of	O
+4035	O
+patients	O
+died	O
+.	O
+
+Mortality	O
+increased	O
+with	O
+age	O
+(	O
+85.6	O
+%	O
+occurring	O
+in	O
+older	O
+than	O
+65	O
+years	O
+)	O
+.	O
+
+Seventeen	O
+factors	O
+were	O
+independently	O
+associated	O
+with	O
+an	O
+increased	O
+hazard	O
+of	O
+death	O
+,	O
+the	O
+strongest	O
+among	O
+them	O
+including	O
+advanced	O
+age	O
+,	O
+liver	O
+cirrhosis	O
+,	O
+low	O
+age	O
+-	O
+adjusted	O
+oxygen	O
+saturation	O
+,	O
+higher	O
+concentrations	O
+of	O
+C	O
+-	O
+reactive	O
+protein	O
+and	O
+lower	O
+estimated	O
+glomerular	O
+filtration	O
+rate	O
+.	O
+
+Conclusions	O
+Our	O
+findings	O
+provide	O
+comprehensive	O
+information	O
+about	O
+characteristics	O
+and	O
+complications	O
+of	O
+severe	O
+COVID-19	O
+,	O
+and	O
+may	O
+help	O
+clinicians	O
+identify	O
+patients	O
+at	O
+a	O
+higher	O
+risk	O
+of	O
+death	O
+.	O
+
+Organ	O
+damage	O
+in	O
+sickle	O
+cell	O
+disease	O
+(	O
+SCD	O
+)	O
+is	O
+a	O
+crucial	O
+determinant	O
+for	O
+disease	O
+severity	O
+and	O
+prognosis	O
+.	O
+
+In	O
+a	O
+previous	O
+study	O
+,	O
+we	O
+analyzed	O
+the	O
+prevalence	B-EPI
+of	O
+SCD	O
+-	O
+related	O
+organ	O
+damage	O
+and	O
+complications	O
+in	O
+adult	O
+sickle	O
+cell	O
+patients	O
+.	O
+
+We	O
+now	O
+describe	O
+a	O
+seven	O
+-	O
+year	O
+follow	O
+-	O
+up	O
+of	O
+this	O
+cohort	O
+.	O
+All	O
+patients	O
+from	O
+the	O
+primary	O
+analysis	O
+in	O
+2006	O
+(	O
+n	O
+=	O
+104	O
+)	O
+,	O
+were	O
+included	O
+for	O
+follow	O
+-	O
+up	O
+.	O
+
+Patients	O
+were	O
+screened	O
+for	O
+SCD	O
+-	O
+related	O
+organ	O
+damage	O
+and	O
+complications	O
+(	O
+microalbuminuria	O
+,	O
+renal	O
+failure	O
+,	O
+elevated	O
+tricuspid	O
+regurgitation	O
+flow	O
+velocity	O
+(	O
+TRV	O
+)	O
+(	O
+≥2.5	O
+m	O
+/	O
+seconds	O
+)	O
+,	O
+retinopathy	O
+,	O
+iron	O
+overload	O
+,	O
+cholelithiasis	O
+,	O
+avascular	O
+osteonecrosis	O
+,	O
+leg	O
+ulcers	O
+,	O
+acute	O
+chest	O
+syndrome	O
+(	O
+ACS	O
+)	O
+,	O
+stroke	O
+,	O
+priapism	O
+and	O
+admissions	O
+for	O
+vaso	O
+-	O
+occlusive	O
+crises	O
+(	O
+VOC	O
+)	O
+biannually	O
+.	O
+
+Upon	O
+7	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+,	O
+progression	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+avascular	O
+osteonecrosis	O
+(	O
+from	O
+12.5	O
+%	O
+to	O
+20.4	O
+%	O
+)	O
+,	O
+renal	O
+failure	O
+(	O
+from	O
+6.7	O
+%	O
+to	O
+23.4	O
+%	O
+)	O
+,	O
+retinopathy	O
+(	O
+from	O
+39.7	O
+%	O
+to	O
+53.8	O
+%	O
+)	O
+was	O
+observed	O
+in	O
+the	O
+whole	O
+group	O
+.	O
+
+In	O
+HbSS	B-LOC
+/	O
+HbSβ	O
+0	O
+-thal	O
+patients	O
+also	O
+progression	O
+in	O
+microalbuminuria	O
+(	O
+from	O
+34	O
+%	O
+to	O
+45	O
+%	O
+)	O
+and	O
+elevated	O
+TRV	O
+(	O
+from	O
+40	O
+%	O
+to	O
+48	O
+%	O
+)	O
+was	O
+observed	O
+while	O
+hardly	O
+any	O
+progression	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+cholelithiasis	O
+,	O
+priapism	O
+,	O
+stroke	O
+or	O
+chronic	O
+ulcers	O
+was	O
+seen	O
+.	O
+
+The	O
+proportion	O
+of	O
+patients	O
+with	O
+at	O
+least	O
+one	O
+episode	O
+of	O
+ACS	O
+increased	O
+in	O
+the	O
+group	O
+of	O
+HbSS	B-LOC
+/	O
+HbSβ	O
+0	O
+-thal	O
+patients	O
+from	O
+32	O
+%	O
+to	O
+49.1	O
+%	I-STAT
+.	O
+
+In	O
+conclusion	O
+,	O
+62	O
+%	O
+of	O
+the	O
+sickle	O
+cell	O
+patients	O
+in	O
+this	O
+prospective	O
+cohort	O
+study	O
+developed	O
+a	O
+new	O
+SCD	O
+-	O
+related	O
+complication	O
+in	O
+a	O
+comprehensive	O
+care	O
+setting	O
+within	O
+7	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+Although	O
+the	O
+hospital	O
+admission	O
+rate	O
+for	O
+VOC	O
+remained	O
+stable	O
+,	O
+multiple	O
+forms	O
+of	O
+organ	O
+damage	O
+increased	O
+substantially	O
+.	O
+
+These	O
+observations	O
+underline	O
+the	O
+need	O
+for	O
+continued	O
+screening	O
+for	O
+organ	O
+damage	O
+in	O
+all	O
+adult	O
+patients	O
+with	O
+SCD	O
+.	O
+
+BACKGROUND	O
+:	O
+Intellectual	O
+disability	O
+(	O
+ID	O
+)	O
+affects	O
+1	B-STAT
+-	O
+3	O
+%	O
+of	O
+the	O
+Western	O
+population	O
+and	O
+is	O
+heterogeneous	O
+in	O
+origin	O
+.	O
+
+Mutations	O
+in	O
+X	O
+-	O
+linked	O
+genes	O
+represent	O
+5	B-STAT
+-	O
+10	O
+%	O
+of	O
+ID	O
+in	O
+males	O
+.	O
+
+Fragile	O
+X	O
+syndrome	O
+,	O
+due	O
+to	O
+the	O
+silencing	O
+of	O
+the	O
+FMR1	O
+gene	O
+,	O
+is	O
+the	O
+most	O
+common	O
+form	O
+of	O
+ID	O
+,	O
+with	O
+a	O
+prevalence	B-EPI
+of	O
+around	B-STAT
+1:5000	I-STAT
+males	I-STAT
+.	I-STAT
+
+Females	O
+are	O
+usually	O
+non-	O
+or	O
+mildly	O
+affected	O
+carriers	O
+,	O
+and	O
+in	O
+a	O
+few	O
+rare	O
+cases	O
+,	O
+the	O
+only	O
+gender	O
+affected	O
+.	O
+
+Array	O
+comparative	O
+genome	O
+hybridization	O
+(	O
+aCGH	O
+)	O
+and	O
+next	O
+-	O
+generation	O
+sequencing	O
+(	O
+NGS	O
+)	O
+have	O
+dramatically	O
+changed	O
+the	O
+nature	O
+of	O
+human	O
+genome	O
+analysis	O
+leading	O
+to	O
+the	O
+identification	O
+of	O
+new	O
+X	O
+-	O
+linked	O
+intellectual	O
+disability	O
+syndromes	O
+and	O
+disease	O
+-	O
+causing	O
+genes	O
+.	O
+
+SOURCES	O
+OF	O
+DATA	O
+:	O
+Original	O
+papers	O
+,	O
+reviews	O
+,	O
+guidelines	O
+and	O
+experiences	O
+of	O
+the	O
+diagnostic	O
+laboratories	O
+.	O
+
+AREAS	O
+OF	O
+AGREEMENT	O
+:	O
+Family	O
+history	O
+and	O
+clinical	O
+examination	O
+still	O
+are	O
+essential	O
+to	O
+choose	O
+the	O
+appropriate	O
+diagnostic	O
+tests	O
+,	O
+including	O
+,	O
+a	O
+disease	O
+-	O
+specific	O
+genetic	O
+test	O
+,	O
+aCGH	O
+or	O
+FMR1	O
+molecular	O
+analysis	O
+.	O
+
+If	O
+negative	O
+,	O
+NGS	O
+approaches	O
+like	O
+well	O
+-	O
+defined	O
+gene	O
+panels	O
+,	O
+whole	O
+exome	O
+,	O
+or	O
+even	O
+whole	O
+genome	O
+sequencing	O
+,	O
+are	O
+increasingly	O
+being	O
+used	O
+,	O
+improving	O
+diagnostics	O
+and	O
+leading	O
+to	O
+the	O
+identification	O
+of	O
+novel	O
+disease	O
+mechanisms	O
+.	O
+
+AREAS	O
+OF	O
+CONTROVERSY	O
+:	O
+The	O
+main	O
+challenge	O
+in	O
+the	O
+era	O
+of	O
+NGS	O
+is	O
+filtering	O
+and	O
+interpretation	O
+of	O
+the	O
+data	O
+generated	O
+by	O
+the	O
+analysis	O
+of	O
+a	O
+single	O
+individual	O
+.	O
+
+In	O
+X	O
+-	O
+linked	O
+cases	O
+,	O
+assessing	O
+pathogenicity	O
+is	O
+particularly	O
+challenging	O
+,	O
+even	O
+more	O
+when	O
+the	O
+variant	O
+is	O
+found	O
+to	O
+be	O
+inherited	O
+from	O
+a	O
+healthy	O
+carrier	O
+mother	O
+or	O
+when	O
+a	O
+heterozygous	O
+X	O
+-	O
+linked	O
+mutation	O
+is	O
+found	O
+in	O
+an	O
+impaired	O
+female	O
+.	O
+
+GROWING	O
+POINTS	O
+:	O
+At	O
+present	O
+,	O
+variant	O
+interpretation	O
+remains	O
+a	O
+challenging	O
+task	O
+,	O
+especially	O
+in	O
+X	O
+-	O
+linked	O
+disorders	O
+.	O
+
+We	O
+review	O
+the	O
+main	O
+difficulties	O
+and	O
+propose	O
+a	O
+comprehensive	O
+overview	O
+that	O
+might	O
+aid	O
+in	O
+variant	O
+interpretation	O
+.	O
+
+Establishing	O
+a	O
+genetic	O
+diagnosis	O
+facilitates	O
+counseling	O
+and	O
+allows	O
+better	O
+delineation	O
+of	O
+clinical	O
+phenotypes	O
+.	O
+
+AREAS	O
+TIMELY	O
+FOR	O
+DEVELOPING	O
+RESEARCH	O
+:	O
+To	O
+improve	O
+variant	O
+interpretation	O
+,	O
+there	O
+is	O
+need	O
+to	O
+refine	O
+in	O
+silico	O
+predictions	O
+with	O
+specific	O
+criteria	O
+for	O
+each	O
+gene	O
+,	O
+and	O
+to	O
+develop	O
+cost	O
+-	O
+effective	O
+functional	O
+tools	O
+,	O
+which	O
+can	O
+be	O
+easily	O
+transferred	O
+to	O
+diagnostics	O
+.	O
+
+Our	O
+understanding	O
+about	O
+the	O
+epidemiological	O
+aspects	O
+,	O
+pathogenesis	O
+,	O
+molecular	O
+diagnosis	O
+,	O
+and	O
+targeted	O
+therapies	O
+of	O
+neuroendocrine	O
+neoplasms	O
+(	O
+NENs	O
+)	O
+have	O
+drastically	O
+advanced	O
+in	O
+the	O
+past	O
+decade	O
+.	O
+
+Gastroenteropancreatic	O
+(	O
+GEP	O
+)	O
+NENs	O
+originate	O
+from	O
+the	O
+enteroendocrine	O
+cells	O
+of	O
+the	O
+embryonic	O
+gut	O
+which	O
+share	O
+common	O
+endocrine	O
+and	O
+neural	O
+differentiation	O
+factors	O
+.	O
+
+Most	O
+NENs	O
+are	O
+well	O
+-	O
+differentiated	O
+,	O
+and	O
+slow	O
+growing	O
+.	O
+
+Specific	O
+neuroendocrine	O
+biomarkers	O
+that	O
+are	O
+used	O
+in	O
+the	O
+diagnosis	O
+of	O
+functional	O
+NENs	O
+include	O
+insulin	O
+,	O
+glucagon	O
+,	O
+vasoactive	O
+intestinal	O
+polypeptide	O
+,	O
+gastrin	O
+,	O
+somatostatin	O
+,	O
+adrenocorticotropin	O
+,	O
+growth	O
+hormone	O
+releasing	O
+hormone	O
+,	O
+parathyroid	O
+hormone	O
+-	O
+related	O
+peptide	O
+,	O
+serotonin	O
+,	O
+histamine	O
+,	O
+and	O
+5	O
+-	O
+hydroxy	O
+indole	O
+acetic	O
+acid	O
+(	O
+5	O
+-	O
+HIAA	O
+)	O
+.	O
+
+Biomarkers	O
+such	O
+as	O
+pancreatic	O
+polypeptide	O
+,	O
+human	O
+chorionic	O
+gonadotrophin	O
+subunits	O
+,	O
+neurotensin	O
+,	O
+ghrelin	O
+,	O
+and	O
+calcitonin	O
+are	O
+used	O
+in	O
+the	O
+diagnosis	O
+of	O
+non	O
+-	O
+functional	O
+NENs	O
+.	O
+
+5	O
+-	O
+HIAA	O
+levels	O
+correlate	O
+with	O
+tumour	O
+burden	O
+,	O
+prognosis	O
+and	O
+development	O
+of	O
+carcinoid	O
+heart	O
+disease	O
+and	O
+mesenteric	O
+fibrosis	O
+,	O
+however	O
+several	O
+diseases	O
+,	O
+medications	O
+and	O
+edible	O
+products	O
+can	O
+falsely	O
+elevate	O
+the	O
+5	O
+-	O
+HIAA	O
+levels	O
+.	O
+
+Organ	O
+-	O
+specific	O
+transcription	O
+factors	O
+are	O
+useful	O
+in	O
+the	O
+differential	O
+diagnosis	O
+of	O
+metastasis	O
+from	O
+an	O
+unknown	O
+primary	O
+of	O
+well	O
+-	O
+differentiated	O
+NENs	O
+.	O
+
+Emerging	O
+novel	O
+biomarkers	O
+include	O
+circulating	O
+tumour	O
+cells	O
+,	O
+circulating	O
+tumour	O
+DNA	O
+,	O
+circulating	O
+micro	O
+-	O
+RNAs	O
+,	O
+and	O
+neuroendocrine	O
+neoplasms	O
+test	O
+(	O
+NETest	O
+)	O
+(	O
+simultaneous	O
+measurement	O
+of	O
+51	O
+neuroendocrine	O
+-	O
+specific	O
+marker	O
+genes	O
+in	O
+the	O
+peripheral	O
+blood	O
+)	O
+.	O
+
+NETest	O
+has	O
+high	O
+sensitivity	O
+(	O
+85%-98	O
+%	O
+)	O
+and	O
+specificity	O
+(	O
+93%-97	O
+%	O
+)	O
+for	O
+the	O
+detection	O
+of	O
+gastrointestinal	O
+NENs	O
+,	O
+and	O
+is	O
+useful	O
+for	O
+monitoring	O
+treatment	O
+response	O
+,	O
+recurrence	O
+,	O
+and	O
+prognosis	O
+.	O
+
+In	O
+terms	O
+of	O
+management	O
+,	O
+surgery	O
+,	O
+radiofrequency	O
+ablation	O
+,	O
+symptom	O
+control	O
+with	O
+medications	O
+,	O
+chemotherapy	O
+and	O
+molecular	O
+targeted	O
+therapies	O
+are	O
+all	O
+considered	O
+as	O
+options	O
+.	O
+
+Surgery	O
+is	O
+the	O
+mainstay	O
+of	O
+treatment	O
+,	O
+but	O
+depends	O
+on	O
+factors	O
+including	O
+age	O
+of	O
+the	O
+individual	O
+,	O
+location	O
+,	O
+stage	O
+,	O
+grade	O
+,	O
+functional	O
+status	O
+,	O
+and	O
+the	O
+heredity	O
+of	O
+the	O
+tumour	O
+(	O
+sporadic	O
+vs	O
+inherited	O
+)	O
+.	O
+
+Medical	O
+management	O
+is	O
+helpful	O
+to	O
+alleviate	O
+the	O
+symptoms	O
+,	O
+manage	O
+inoperable	O
+lesions	O
+,	O
+suppress	O
+postoperative	O
+tumour	O
+growth	O
+,	O
+and	O
+manage	O
+recurrences	O
+.	O
+
+Several	O
+molecular	O
+-	O
+targeted	O
+therapies	O
+are	O
+considered	O
+second	O
+line	O
+to	O
+somatostatin	O
+analogues	O
+.	O
+
+This	O
+review	O
+is	O
+a	O
+clinical	O
+update	O
+on	O
+the	O
+pathophysiological	O
+aspects	O
+,	O
+diagnostic	O
+algorithm	O
+,	O
+and	O
+management	O
+of	O
+GEP	O
+NENs	O
+.	O
+
+Background	O
+Kawasaki	O
+disease	O
+(	O
+KD	O
+)	O
+incidence	B-EPI
+is	O
+increasing	O
+in	O
+Ontario	B-LOC
+.	O
+
+Cardiovascular	O
+sequelae	O
+following	O
+KD	O
+are	O
+well	O
+-	O
+described	O
+.	O
+
+However	O
+,	O
+there	O
+are	O
+limited	O
+data	O
+on	O
+non	O
+-	O
+cardiovascular	O
+outcomes	O
+.	O
+
+Objectives	O
+To	O
+determine	O
+the	O
+risk	O
+of	O
+hearing	O
+loss	O
+,	O
+anxiety	O
+,	O
+developmental	O
+disorders	O
+,	O
+intellectual	O
+disabilities	O
+and	O
+attention	O
+-	O
+deficit	O
+/	O
+hyperactivity	O
+disorder	O
+(	O
+ADHD	O
+)	O
+among	O
+KD	O
+survivors	O
+vs.	O
+non	O
+-	O
+exposed	O
+children	O
+.	O
+
+Methods	O
+We	O
+included	O
+all	O
+Ontario	O
+children	O
+(	O
+≤18	O
+yr	O
+)	O
+surviving	O
+hospitalization	O
+with	O
+a	O
+KD	O
+diagnosis	O
+between	O
+1995	O
+and	O
+2018	O
+,	O
+using	O
+population	O
+-	O
+based	O
+health	O
+administrative	O
+databases	O
+.	O
+
+We	O
+excluded	O
+children	O
+with	O
+prior	O
+KD	O
+diagnoses	O
+and	O
+non	O
+-	O
+residents	O
+.	O
+
+KD	O
+cases	O
+were	O
+matched	O
+with	O
+100	O
+non	O
+-	O
+exposed	O
+children	O
+by	O
+age	O
+,	O
+sex	O
+and	O
+year	O
+.	O
+
+Follow	O
+-	O
+up	O
+continued	O
+until	O
+death	O
+or	O
+March	O
+2019	O
+.	O
+
+We	O
+calculated	O
+the	O
+prevalence	B-EPI
+,	O
+incidence	B-EPI
+and	O
+adjusted	O
+hazard	O
+ratios	O
+(	O
+aHR	O
+[	O
+95%CI	O
+]	O
+)	O
+of	O
+outcomes	O
+between	O
+0	O
+-	O
+1	O
+yr	O
+,	O
+1	B-STAT
+-	I-STAT
+5	I-STAT
+yr	O
+,	O
+5	O
+-	O
+10	O
+yr	O
+and	O
+>	O
+10	O
+yr	O
+follow	O
+-	O
+up	O
+.	O
+
+Results	O
+Among	O
+4597	O
+KD	O
+survivors	O
+,	O
+364	B-STAT
+(	O
+7.9	O
+%	O
+)	O
+were	O
+diagnosed	O
+with	O
+hearing	O
+loss	O
+,	O
+1213	O
+(	O
+26.4	O
+%	O
+)	O
+anxiety	O
+disorders	O
+,	O
+398	B-STAT
+(	O
+8.7	O
+%	O
+)	O
+developmental	O
+disorders	O
+,	O
+51	B-STAT
+(	O
+1.1	O
+%	O
+)	O
+intellectual	O
+disability	O
+and	O
+21	B-STAT
+(	I-STAT
+0.5	I-STAT
+%	I-STAT
+)	O
+ADHD	O
+,	O
+during	O
+median	O
+11	O
+year	O
+follow	O
+-	O
+up	O
+.	O
+
+Compared	O
+to	O
+459,700	O
+non	O
+-	O
+exposed	O
+children	O
+,	O
+KD	O
+survivors	O
+were	O
+not	O
+at	O
+increased	O
+risk	O
+of	O
+hearing	O
+loss	O
+after	O
+adjustment	O
+for	O
+potential	O
+confounders	O
+.	O
+
+KD	O
+survivors	O
+were	O
+at	O
+increased	O
+risk	O
+of	O
+anxiety	O
+disorders	O
+between	O
+0	O
+-	O
+1	O
+yr	O
+(	O
+aHR	O
+1.75	O
+[	O
+1.46	O
+-	O
+2.10	O
+]	O
+)	O
+,	O
+1	B-STAT
+-	I-STAT
+5	I-STAT
+yr	O
+(	O
+aHR	O
+1.13	O
+[	O
+1.01	O
+-	O
+1.28	O
+]	O
+)	O
+,	O
+5	O
+-	O
+10	O
+yr	O
+(	O
+aHR	O
+1.14	O
+[	O
+1.03	O
+-	O
+1.28	O
+]	O
+)	O
+and	O
+>	O
+10	O
+yr	O
+(	O
+aHR	O
+1.11	O
+[	O
+1.02	O
+-	O
+1.22	O
+]	O
+)	O
+;	O
+developmental	O
+disorders	O
+between	O
+0	B-STAT
+-	I-STAT
+1	I-STAT
+yr	I-STAT
+(	O
+aHR	O
+1.49	O
+[	O
+1.28	O
+-	O
+1.74	O
+]	O
+)	O
+and	O
+1	O
+-	O
+5	O
+yr	O
+(	O
+aHR	O
+1.19	O
+[	O
+1.02	O
+-	O
+1.40	O
+]	O
+)	O
+;	O
+intellectual	O
+disabilities	O
+>	O
+10	O
+yr	O
+(	O
+aHR	O
+2.36	O
+[	O
+1.36	O
+-	O
+4.10	O
+]	O
+)	O
+;	O
+and	O
+ADHD	O
+>	O
+10	O
+yr	O
+(	O
+aHR	O
+2.01	O
+[	O
+1.14	O
+-	O
+3.57	O
+]	O
+)	O
+.	O
+
+Conclusions	O
+KD	O
+survivors	O
+are	O
+at	O
+increased	O
+risk	O
+of	O
+being	O
+diagnosed	O
+with	O
+anxiety	O
+disorders	O
+sooner	O
+,	O
+being	O
+diagnosed	O
+with	O
+developmental	O
+disorders	O
+between	O
+0	O
+and	O
+5	O
+yr	O
+and	O
+being	O
+diagnosed	O
+with	O
+intellectual	O
+disabilities	O
+or	O
+ADHD	O
+>	O
+10	O
+yr	O
+after	O
+KD	O
+diagnosis	O
+.	O
+
+This	O
+may	O
+justify	O
+enhanced	O
+developmental	O
+and	O
+audiological	O
+surveillance	O
+of	O
+KD	O
+survivors	O
+.	O
+
+Down	O
+syndrome	O
+(	O
+DS	O
+)	O
+is	O
+the	O
+most	O
+common	O
+chromosome	O
+abnormality	O
+with	O
+a	O
+unique	O
+cancer	O
+predisposition	O
+syndrome	O
+pattern	O
+:	O
+a	O
+higher	O
+risk	O
+to	O
+develop	O
+acute	O
+leukemia	O
+and	O
+a	O
+lower	O
+incidence	B-EPI
+of	O
+solid	O
+tumors	O
+.	O
+
+In	O
+particular	O
+,	O
+brain	O
+tumors	O
+are	O
+rarely	O
+reported	O
+in	O
+the	O
+DS	O
+population	O
+,	O
+and	O
+biological	O
+behavior	O
+and	O
+natural	O
+history	O
+are	O
+not	O
+well	O
+described	O
+and	O
+identified	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+a	O
+10	O
+-	O
+year	O
+-	O
+old	O
+child	O
+with	O
+DS	O
+who	O
+presented	O
+with	O
+a	O
+medulloblastoma	O
+(	O
+MB	O
+)	O
+.	O
+
+Histological	O
+examination	O
+revealed	O
+a	O
+classic	O
+MB	O
+with	O
+focal	O
+anaplasia	O
+and	O
+the	O
+molecular	O
+profile	O
+showed	O
+the	O
+presence	O
+of	O
+a	O
+CTNNB1	O
+variant	O
+associated	O
+with	O
+the	O
+wingless	O
+(	O
+WNT	O
+)	O
+molecular	O
+subgroup	O
+with	O
+a	O
+good	O
+prognosis	O
+in	O
+contrast	O
+to	O
+our	O
+case	O
+report	O
+that	O
+has	O
+shown	O
+an	O
+early	O
+metastatic	O
+relapse	O
+.	O
+
+The	O
+nearly	O
+seven	O
+-	O
+fold	O
+decreased	O
+risk	O
+of	O
+MB	O
+in	O
+children	O
+with	O
+DS	O
+suggests	O
+the	O
+presence	O
+of	O
+protective	O
+biological	O
+mechanisms	O
+.	O
+
+The	O
+cerebellum	O
+hypoplasia	O
+and	O
+the	O
+reduced	O
+volume	O
+of	O
+cerebellar	O
+granule	O
+neuron	O
+progenitor	O
+cells	O
+seem	O
+to	O
+be	O
+a	O
+possible	O
+favorable	O
+condition	O
+to	O
+prevent	O
+MB	O
+development	O
+via	O
+inhibition	O
+of	O
+neuroectodermal	O
+differentiation	O
+.	O
+
+Moreover	O
+,	O
+the	O
+NOTCH	O
+/	O
+WNT	O
+dysregulation	O
+in	O
+DS	O
+,	O
+which	O
+is	O
+probably	O
+associated	O
+with	O
+an	O
+increased	O
+risk	O
+of	O
+leukemia	O
+,	O
+suggests	O
+a	O
+pivotal	O
+role	O
+of	O
+this	O
+pathway	O
+alteration	O
+in	O
+the	O
+pathogenesis	O
+of	O
+MB	O
+;	O
+therefore	O
+,	O
+this	O
+condition	O
+should	O
+be	O
+further	O
+investigated	O
+in	O
+future	O
+studies	O
+by	O
+molecular	O
+characterizations	O
+.	O
+
+The	O
+end	O
+-	O
+of	O
+-	O
+outbreak	O
+declaration	O
+is	O
+an	O
+important	O
+step	O
+in	O
+controlling	O
+infectious	O
+disease	O
+outbreaks	O
+.	O
+
+Objective	O
+estimation	O
+of	O
+the	O
+confidence	O
+level	O
+that	O
+an	O
+outbreak	O
+is	O
+over	O
+is	O
+important	O
+to	O
+reduce	O
+the	O
+risk	O
+of	O
+postdeclaration	O
+flare	O
+-	O
+ups	O
+.	O
+
+We	O
+developed	O
+a	O
+simulation	O
+-	O
+based	O
+model	O
+with	O
+which	O
+to	O
+quantify	O
+that	O
+confidence	O
+and	O
+tested	O
+it	O
+on	O
+simulated	O
+Ebola	O
+virus	O
+disease	O
+data	O
+.	O
+
+We	O
+found	O
+that	O
+these	O
+confidence	O
+estimates	O
+were	O
+most	O
+sensitive	O
+to	O
+the	O
+instantaneous	O
+reproduction	O
+number	O
+,	O
+the	O
+reporting	O
+rate	O
+,	O
+and	O
+the	O
+time	O
+between	O
+the	O
+symptom	O
+onset	O
+and	O
+death	O
+or	O
+recovery	O
+of	O
+the	O
+last	O
+detected	O
+case	O
+.	O
+
+For	O
+Ebola	O
+virus	O
+disease	O
+,	O
+our	O
+results	O
+suggested	O
+that	O
+the	O
+current	O
+World	O
+Health	O
+Organization	O
+criterion	O
+of	O
+42	O
+days	O
+since	O
+the	O
+recovery	O
+or	O
+death	O
+of	O
+the	O
+last	O
+detected	O
+case	O
+is	O
+too	O
+short	O
+and	O
+too	O
+sensitive	O
+to	O
+underreporting	O
+.	O
+
+Therefore	O
+,	O
+we	O
+suggest	O
+a	O
+shift	O
+to	O
+a	O
+preliminary	O
+end	O
+-	O
+of	O
+-	O
+outbreak	O
+declaration	O
+after	O
+63	O
+days	O
+from	O
+the	O
+symptom	O
+onset	O
+day	O
+of	O
+the	O
+last	O
+detected	O
+case	O
+.	O
+
+This	O
+preliminary	O
+declaration	O
+should	O
+still	O
+be	O
+followed	O
+by	O
+90	O
+days	O
+of	O
+enhanced	O
+surveillance	O
+to	O
+capture	O
+potential	O
+flare	O
+-	O
+ups	O
+of	O
+cases	O
+,	O
+after	O
+which	O
+the	O
+official	O
+end	O
+of	O
+the	O
+outbreak	O
+can	O
+be	O
+declared	O
+.	O
+
+This	O
+sequence	O
+corresponds	B-STAT
+to	I-STAT
+more	I-STAT
+than	O
+95	O
+%	O
+confidence	O
+that	O
+an	O
+outbreak	O
+is	O
+over	O
+in	O
+most	O
+of	O
+the	O
+scenarios	O
+examined	O
+.	O
+
+Our	O
+framework	O
+is	O
+generic	O
+and	O
+therefore	O
+could	O
+be	O
+adapted	O
+to	O
+estimate	O
+end	O
+-	O
+of	O
+-	O
+outbreak	O
+confidence	O
+for	O
+other	O
+infectious	O
+diseases	O
+.	O
+
+Background	O
+Biatrial	O
+tachycardia	O
+(	O
+BiAT	O
+)	O
+is	O
+a	O
+rare	O
+form	O
+of	O
+macroreentry	O
+not	O
+previously	O
+characterized	O
+in	O
+adults	O
+with	O
+congenital	O
+heart	O
+disease	O
+(	O
+ACHD	O
+)	O
+OBJECTIVE	O
+:	O
+To	O
+determine	O
+the	O
+prevalence	B-EPI
+,	O
+mechanisms	O
+and	O
+outcomes	O
+of	O
+catheter	O
+ablation	O
+for	O
+BiAT	O
+in	O
+ACHD	O
+.	O
+
+Methods	O
+All	O
+ACHD	O
+undergoing	O
+catheter	O
+ablation	O
+for	O
+macroreentrant	O
+atrial	O
+tachycardia	O
+over	O
+a	O
+10	O
+-	O
+year	O
+period	O
+were	O
+evaluated	O
+for	O
+evidence	O
+of	O
+BiAT	O
+.	O
+
+Patient	O
+s	O
+were	O
+categorized	O
+as	O
+prior	O
+Senning	B-LOC
+,	O
+Fontan	O
+or	O
+other	O
+biventricular	O
+operation	O
+.	O
+
+A	O
+novel	O
+biatrial	O
+global	O
+activation	O
+histogram	O
+(	O
+GAH	O
+)	O
+analysis	O
+was	O
+used	O
+to	O
+demonstrate	O
+the	O
+presence	O
+of	O
+interatrial	O
+connections	O
+(	O
+IAC	O
+)	O
+.	O
+
+Results	O
+Among	O
+263	O
+ACHD	O
+,	O
+BiAT	O
+was	O
+identified	O
+at	O
+11	O
+procedures	O
+in	O
+10	O
+patients	O
+(	O
+4.2	O
+%	O
+;	O
+median	O
+age	O
+35	O
+y	O
+;	O
+30	O
+%	O
+male	O
+)	O
+.	O
+
+The	O
+congenital	O
+category	O
+was	O
+Fontan	O
+in	O
+6	O
+,	O
+Senning	B-LOC
+in	O
+3	O
+and	O
+biventricular	O
+in	O
+2	O
+.	O
+
+Diagnosis	O
+of	O
+BiAT	O
+was	O
+associated	O
+with	O
+ablation	O
+era	O
+and	O
+mapping	O
+technology	O
+(	O
+p<0.001	O
+)	O
+and	O
+could	O
+be	O
+confirmed	O
+with	O
+a	O
+novel	O
+GAH	O
+mapping	O
+approach	O
+for	O
+normally	O
+-	O
+septated	O
+atrial	O
+connections	O
+.	O
+
+Catheter	O
+ablation	O
+targeted	O
+an	O
+IAC	O
+in	O
+5	O
+cases	O
+(	O
+Bjork	O
+Fontan	O
+/	O
+biventricular	O
+operations	O
+)	O
+,	O
+a	O
+posterior	O
+isthmus	O
+in	O
+3	O
+(	O
+Senning	B-LOC
+operation	O
+)	O
+and	O
+the	O
+cavo	O
+-	O
+tricuspid	O
+isthmus	O
+(	O
+CTI	O
+)	O
+or	O
+equivalent	O
+in	O
+3	O
+(	O
+LT	O
+Fontan	O
+)	O
+.	O
+
+Recurrence	O
+was	O
+isolated	O
+to	O
+ablation	O
+to	O
+sites	O
+at	O
+the	O
+expected	O
+location	O
+of	O
+Bachmann	O
+'s	O
+bundle	O
+(	O
+BB	O
+)	O
+,	O
+and	O
+durable	O
+success	O
+could	O
+be	O
+achieved	O
+after	O
+repeat	O
+ablation	O
+.	O
+
+Conclusion	O
+BiAT	O
+occurs	B-EPI
+in	O
+approximately	O
+4	O
+%	O
+of	O
+ACHD	O
+but	O
+is	O
+likely	O
+significantly	O
+underrecognized	O
+.	O
+
+BiAT	O
+could	O
+be	O
+targeted	O
+at	O
+an	O
+IAC	O
+after	O
+biventricular	O
+heart	O
+/	O
+Bjork	O
+modified	O
+Fontan	O
+operations	O
+and	O
+at	O
+a	O
+conventional	O
+critical	O
+isthmus	O
+after	O
+Senning	B-LOC
+and	O
+LT	O
+Fontan	O
+operations	O
+.	O
+
+Objectives	O
+To	O
+determine	O
+the	O
+incidence	B-EPI
+of	O
+newborn	O
+screening	O
+(	O
+NBS	O
+)	O
+disorders	O
+and	O
+to	O
+study	O
+the	O
+key	O
+performance	O
+indicators	O
+of	O
+the	O
+program	O
+.	O
+
+Methods	O
+This	O
+retrospective	O
+single	O
+-	O
+center	O
+study	O
+enrolled	O
+all	O
+infants	O
+who	O
+underwent	O
+NBS	O
+from	O
+January	O
+2012	O
+to	O
+December	O
+2017	O
+at	O
+Prince	O
+Sultan	O
+Military	O
+Medical	O
+City	O
+,	O
+Riyadh	B-LOC
+,	O
+Saudi	B-LOC
+Arabia	I-LOC
+.	O
+
+We	O
+screened	O
+17	O
+NBS	O
+disorders	O
+.	O
+
+Blood	O
+samples	O
+were	O
+collected	O
+24	O
+hours	O
+after	O
+birth	O
+.	O
+
+If	O
+the	O
+initial	O
+result	O
+was	O
+positive	O
+,	O
+a	O
+second	O
+sample	O
+was	O
+collected	O
+.	O
+
+True	O
+positive	O
+cases	O
+were	O
+immediately	O
+referred	O
+for	O
+medical	O
+management	O
+.	O
+
+Data	O
+were	O
+extracted	O
+from	O
+laboratory	O
+computerized	O
+and	O
+non	O
+-	O
+computerized	O
+records	O
+using	O
+case	O
+report	O
+forms	O
+.	O
+
+Results	O
+During	O
+the	O
+study	O
+period	O
+,	O
+56632	O
+infants	O
+underwent	O
+NBS	O
+with	O
+a	O
+coverage	O
+rate	O
+of	O
+100	B-STAT
+%	I-STAT
+.	O
+
+Thirty	O
+-	O
+eight	O
+cases	O
+were	O
+confirmed	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+congenital	O
+hypothyroidism	O
+was	O
+1:3775	O
+.	O
+
+The	O
+positive	O
+predictive	O
+value	O
+for	O
+the	O
+detection	O
+of	O
+congenital	O
+hypothyroidism	O
+was	O
+11.8	B-STAT
+%	I-STAT
+.	O
+
+Propionic	O
+aciduria	O
+was	O
+the	O
+most	O
+common	O
+metabolic	O
+disorder	O
+,	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+1:14158	O
+.	O
+
+Very	O
+long	O
+-	O
+chain	O
+acyl	O
+CoA	O
+dehydrogenase	O
+deficiency	O
+and	O
+glutaric	O
+aciduria	O
+type	O
+1	O
+had	O
+an	O
+incidence	B-EPI
+of	O
+1:18877	B-STAT
+each	O
+.	O
+
+Phenylketonuria	O
+,	O
+biotinidase	O
+deficiency	O
+,	O
+maple	O
+syrup	O
+urine	O
+disease	O
+,	O
+and	O
+citrullinemia	O
+had	O
+an	O
+incidence	B-EPI
+of	O
+1:28316	B-STAT
+each	O
+.	O
+
+However	O
+,	O
+galactosemia	O
+and	O
+3	O
+-	O
+methyl	O
+crotonyl	O
+carboxylase	O
+deficiency	O
+had	O
+the	O
+lowest	O
+incidence	B-EPI
+of	O
+1:56632	O
+.	O
+
+Conclusion	O
+The	O
+NBS	O
+coverage	O
+rate	O
+at	O
+our	O
+facility	O
+was	O
+100	B-STAT
+%	I-STAT
+.	O
+
+Congenital	O
+hypothyroidism	O
+was	O
+the	O
+most	O
+frequently	O
+detected	O
+disorder	O
+with	O
+an	O
+incidence	B-EPI
+that	O
+matches	O
+worldwide	B-LOC
+figures	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+other	O
+inherited	O
+disorders	O
+was	O
+consistent	O
+with	O
+regional	O
+figures	O
+.	O
+
+There	O
+is	O
+an	O
+urgent	O
+public	O
+health	O
+need	O
+to	O
+better	O
+understand	O
+Severe	O
+Acute	O
+Respiratory	O
+Syndrome	O
+(	O
+SARS)-CoV-2	O
+/	O
+COVID-19	O
+,	O
+particularly	O
+how	O
+sequences	O
+of	O
+the	O
+viruses	O
+could	O
+lead	O
+to	O
+diverse	O
+incidence	B-EPI
+and	O
+mortality	O
+of	O
+COVID-19	O
+in	O
+different	O
+countries	O
+.	O
+
+However	O
+,	O
+because	O
+of	O
+its	O
+unknown	O
+ancestors	O
+and	O
+hosts	O
+,	O
+elucidating	O
+the	O
+genetic	O
+variations	O
+of	O
+the	O
+novel	O
+coronavirus	O
+,	O
+SARS	O
+-	O
+CoV-2	O
+,	O
+has	O
+been	O
+difficult	O
+.	O
+
+Without	O
+needing	O
+to	O
+know	O
+ancestors	O
+,	O
+we	O
+identified	O
+an	O
+uneven	O
+distribution	O
+of	O
+local	O
+genome	O
+similarities	O
+among	O
+the	O
+viruses	O
+categorized	O
+by	O
+geographic	O
+regions	O
+,	O
+and	O
+it	O
+was	O
+strongly	O
+correlated	O
+with	O
+incidence	B-EPI
+and	O
+mortality	O
+.	O
+
+To	O
+ensure	O
+unbiased	O
+and	O
+origin	O
+-	O
+independent	O
+analyses	O
+,	O
+we	O
+used	O
+a	O
+pairwise	O
+comparison	O
+of	O
+local	O
+genome	O
+sequences	O
+of	O
+virus	O
+genomes	O
+by	O
+Basic	O
+Local	O
+Alignment	O
+Search	O
+Tool	O
+(	O
+BLAST	O
+)	O
+.	O
+
+We	O
+found	O
+a	O
+strong	O
+statistical	O
+correlation	O
+between	O
+dominance	O
+of	O
+the	O
+SARS	O
+-	O
+CoV-2	O
+in	O
+distributions	O
+of	O
+uneven	O
+similarities	O
+and	O
+the	O
+incidence	B-EPI
+and	O
+mortality	O
+of	O
+illness	O
+.	O
+
+Genomic	O
+annotation	O
+of	O
+the	O
+BLAST	O
+hits	O
+also	O
+showed	O
+that	O
+viruses	O
+from	O
+geographic	O
+regions	O
+with	O
+severe	O
+infections	O
+tended	O
+to	O
+have	O
+more	O
+dynamic	O
+genomic	O
+regions	O
+in	O
+the	O
+SARS	O
+-	O
+CoV-2	O
+receptor	O
+-	O
+binding	O
+domain	O
+(	O
+RBD	O
+)	O
+and	O
+receptor	O
+-	O
+binding	O
+motif	O
+(	O
+RBM	O
+)	O
+of	O
+the	O
+spike	O
+protein	O
+(	O
+S	O
+protein	O
+)	O
+.	O
+
+Dynamic	O
+domains	O
+in	O
+the	O
+S	O
+protein	O
+were	O
+also	O
+confirmed	O
+by	O
+a	O
+canyon	O
+region	O
+of	O
+mismatches	O
+coincident	O
+with	O
+RBM	O
+and	O
+RBD	O
+,	O
+without	O
+hits	O
+of	O
+alignments	O
+of	O
+100	O
+%	O
+matching	O
+.	O
+
+Thus	O
+,	O
+our	O
+origin	O
+-	O
+independent	O
+analysis	O
+suggests	O
+that	O
+the	O
+dynamic	O
+and	O
+unstable	O
+SARS	O
+-	O
+CoV-2	O
+-	O
+RBD	O
+could	O
+be	O
+the	O
+main	O
+reason	O
+for	O
+diverse	O
+incidence	B-EPI
+and	O
+mortality	O
+of	O
+COVID-19	O
+infection	O
+.	O
+
+Our	O
+knowledge	O
+about	O
+inherited	O
+susceptibility	O
+to	O
+adrenocortical	O
+carcinoma	O
+(	O
+ACC	O
+)	O
+almost	O
+exclusively	O
+stems	O
+from	O
+experiences	O
+with	O
+familial	O
+cancer	O
+susceptibility	O
+syndromes	O
+,	O
+which	O
+are	O
+caused	O
+by	O
+single	O
+gene	O
+mutations	O
+(	O
+e.g.	O
+
+Li	O
+-	O
+Fraumeni	O
+syndrome	O
+(	O
+LFS	O
+)	O
+)	O
+.	O
+
+Population	O
+-	O
+based	O
+studies	O
+are	O
+largely	O
+unavailable	O
+.	O
+
+ACC	O
+diagnosed	O
+during	O
+childhood	O
+is	O
+known	O
+to	O
+be	O
+commonly	O
+part	O
+of	O
+hereditary	O
+cancer	O
+syndromes	O
+.	O
+
+Childhood	O
+ACC	O
+is	O
+part	O
+of	O
+the	O
+classical	O
+tumor	O
+spectrum	O
+of	O
+LFS	O
+and	O
+Beckwith	O
+-	O
+Wiedemann	O
+syndrome	O
+(	O
+BWS	O
+)	O
+.	O
+
+In	O
+adults	O
+ACC	O
+has	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+multiple	O
+endocrine	O
+neoplasia	O
+(	O
+MEN1	O
+)	O
+,	O
+familial	O
+adenomatous	O
+polyposis	O
+coli	O
+(	O
+FAP	O
+)	O
+and	O
+neurofibromatosis	O
+type	O
+1	O
+(	O
+NF1	O
+)	O
+.	O
+
+However	O
+,	O
+the	O
+evidence	O
+associating	O
+ACC	O
+with	O
+these	O
+syndromes	O
+is	O
+less	O
+well	O
+substantiated	O
+.	O
+
+Here	O
+,	O
+we	O
+will	O
+review	O
+the	O
+evidence	O
+for	O
+genetic	O
+predisposition	O
+in	O
+general	O
+and	O
+the	O
+association	O
+with	O
+known	O
+familial	O
+cancer	O
+susceptibility	O
+syndromes	O
+in	O
+particular	O
+.	O
+
+We	O
+will	O
+also	O
+review	O
+current	O
+recommendations	O
+regarding	O
+screening	O
+and	O
+surveillance	O
+of	O
+these	O
+patients	O
+as	O
+they	O
+apply	O
+to	O
+a	O
+specialized	O
+ACC	O
+or	O
+endocrine	O
+cancer	O
+clinic	O
+.	O
+
+Transient	O
+global	O
+amnesia	O
+(	O
+TGA	O
+)	O
+is	O
+an	O
+uncommon	O
+disease	O
+characterized	O
+by	O
+sudden	O
+onset	O
+anterograde	O
+amnesia	O
+that	O
+typically	O
+improves	O
+within	O
+24	O
+hours	O
+.	O
+
+A	O
+35	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+presented	O
+with	O
+complete	O
+disruption	O
+of	O
+memory	O
+that	O
+had	O
+started	O
+on	O
+the	O
+previous	O
+day	O
+.	O
+
+She	O
+had	O
+fever	O
+and	O
+heart	O
+murmur	O
+and	O
+was	O
+diagnosed	O
+as	O
+having	O
+infective	O
+endocarditis	O
+with	O
+Staphylococcus	O
+lugdunensis	O
+,	O
+a	O
+coagulase	O
+-	O
+negative	O
+staphylococcus	O
+.	O
+
+Septic	O
+embolizations	O
+were	O
+found	O
+in	O
+the	O
+spleen	O
+and	O
+kidney	O
+on	O
+CT	O
+scan	O
+.	O
+
+The	O
+patient	O
+underwent	O
+aortic	O
+valve	O
+replacement	O
+.	O
+
+MRI	O
+susceptibility	O
+-	O
+weighted	O
+imaging	O
+showed	O
+a	O
+dotted	O
+low	O
+intensity	O
+area	O
+in	O
+the	O
+right	O
+hippocampus	O
+.	O
+
+Recently	O
+,	O
+etiology	O
+of	O
+TGA	O
+is	O
+reported	O
+to	O
+be	O
+related	O
+to	O
+hippocampal	O
+disorder	O
+.	O
+
+We	O
+report	O
+a	O
+rare	O
+case	O
+of	O
+TGA	O
+with	O
+hippocampal	O
+infarction	O
+due	O
+to	O
+septic	O
+embolism	O
+from	O
+infective	O
+endocarditis	O
+.	O
+
+The	O
+10th	O
+International	O
+Meeting	O
+on	O
+Neuroacanthocytosis	O
+Syndromes	O
+was	O
+held	O
+online	O
+on	O
+March	O
+10th12th	O
+,	O
+2021	O
+.	O
+
+The	O
+COVID19	O
+pandemic	O
+situation	O
+made	O
+our	O
+planned	O
+meeting	O
+in	O
+Barcelona	B-LOC
+on	O
+March	O
+2020	O
+to	O
+be	O
+suspended	O
+by	O
+one	O
+year	O
+,	O
+and	O
+finally	O
+took	O
+place	O
+online	O
+.	O
+
+The	O
+meeting	O
+followed	O
+the	O
+previous	O
+nine	O
+international	O
+symposia	O
+,	O
+the	O
+last	O
+of	O
+which	O
+was	O
+held	O
+in	O
+Dresden	B-LOC
+,	O
+Germany	B-LOC
+in	O
+March	O
+,	O
+2018	O
+.	O
+
+The	O
+setting	O
+of	O
+the	O
+meeting	O
+encouraged	O
+interactions	O
+,	O
+exchange	O
+of	O
+ideas	O
+and	O
+networking	O
+opportunities	O
+among	O
+the	O
+high	O
+number	O
+of	O
+participants	O
+from	O
+around	O
+the	O
+globe	O
+,	O
+including	O
+scientists	O
+,	O
+neurologists	O
+and	O
+specially	O
+patients	O
+and	O
+caregivers	O
+.	O
+
+A	O
+total	O
+of	O
+27	O
+oral	O
+communications	O
+were	O
+distributed	O
+in	O
+8	O
+sessions	O
+with	O
+topics	O
+ranging	O
+from	O
+molecular	O
+and	O
+cellular	O
+functions	O
+of	O
+VPS13	O
+genes	O
+and	O
+proteins	O
+,	O
+their	O
+involvement	O
+in	O
+Neuroacanthocytosis	O
+Syndromes	O
+and	O
+finally	O
+clinical	O
+aspects	O
+and	O
+patients	O
+care	O
+.	O
+
+In	O
+addition	O
+,	O
+5	O
+posters	O
+were	O
+presented	O
+.	O
+
+Altogether	O
+,	O
+scientists	O
+and	O
+neurologists	O
+discussed	O
+recent	O
+advances	O
+and	O
+set	O
+the	O
+bases	O
+for	O
+next	O
+steps	O
+,	O
+action	O
+points	O
+,	O
+and	O
+future	O
+studies	O
+in	O
+close	O
+collaboration	O
+with	O
+the	O
+patients	O
+associations	O
+,	O
+which	O
+are	O
+always	O
+actively	O
+involved	O
+in	O
+the	O
+whole	O
+process	O
+.	O
+
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+(	O
+CMT	O
+)	O
+is	O
+the	O
+most	O
+prevalent	B-EPI
+category	O
+of	O
+inherited	O
+neuropathy	O
+.	O
+
+The	O
+most	O
+common	O
+inheritance	O
+pattern	O
+is	O
+autosomal	O
+dominant	O
+,	O
+though	O
+there	O
+also	O
+are	O
+X	O
+-	O
+linked	O
+and	O
+autosomal	O
+recessive	O
+subtypes	O
+.	O
+
+In	O
+addition	O
+to	O
+a	O
+variety	O
+of	O
+inheritance	O
+patterns	O
+,	O
+there	O
+are	O
+a	O
+myriad	O
+of	O
+genes	O
+associated	O
+with	O
+CMT	O
+,	O
+reflecting	O
+the	O
+heterogeneity	O
+of	O
+this	O
+disorder	O
+.	O
+
+Next	O
+generation	O
+sequencing	O
+(	O
+NGS	O
+)	O
+has	O
+expanded	O
+and	O
+simplified	O
+the	O
+diagnostic	O
+yield	O
+of	O
+genes	O
+/	O
+molecules	O
+underlying	O
+and/or	O
+associated	O
+with	O
+CMT	O
+,	O
+which	O
+is	O
+of	O
+paramount	O
+importance	O
+in	O
+providing	O
+a	O
+substrate	O
+for	O
+current	O
+and	O
+future	O
+targeted	O
+disease	O
+-	O
+modifying	O
+treatment	O
+options	O
+.	O
+
+Considerable	O
+research	O
+attention	O
+for	O
+disease	O
+-	O
+modifying	O
+therapy	O
+has	O
+been	O
+geared	O
+towards	O
+the	O
+most	O
+commonly	O
+encountered	O
+genetic	O
+mutations	O
+(	O
+PMP22	O
+,	O
+GJB1	O
+,	O
+MPZ	O
+,	O
+and	O
+MFN2	O
+)	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+highlight	O
+the	O
+clinical	O
+background	O
+,	O
+molecular	O
+understanding	O
+,	O
+and	O
+therapeutic	O
+investigations	O
+of	O
+these	O
+CMT	O
+subtypes	O
+,	O
+while	O
+also	O
+discussing	O
+therapeutic	O
+research	O
+pertinent	O
+to	O
+the	O
+remaining	O
+less	O
+common	O
+CMT	O
+subtypes	O
+.	O
+
+Purpose	O
+TP53germline	O
+(	O
+g	O
+)	O
+mutations	O
+,	O
+associated	O
+with	O
+the	O
+Li	O
+-	O
+Fraumeni	O
+syndrome	O
+(	O
+LFS	O
+)	O
+,	O
+have	O
+rarely	O
+been	O
+reported	O
+in	O
+the	O
+context	O
+of	O
+hereditary	O
+breast	O
+and	O
+ovarian	O
+cancer	O
+(	O
+HBOC	O
+)	O
+.	O
+
+The	O
+prevalence	B-EPI
+and	O
+cancer	O
+risks	O
+in	O
+this	O
+target	O
+group	O
+are	O
+unknown	O
+and	O
+counseling	O
+remains	O
+challenging	O
+.	O
+
+Notably	O
+an	O
+extensive	O
+high	O
+-	O
+risk	O
+surveillance	O
+program	O
+is	O
+implemented	O
+,	O
+which	O
+evokes	O
+substantial	O
+psychological	O
+discomfort	O
+.	O
+
+Emphasizing	O
+the	O
+lack	O
+of	O
+consensus	O
+about	O
+clinical	O
+implications	O
+,	O
+we	O
+aim	O
+to	O
+further	O
+characterize	O
+TP53	O
+g	O
+mutations	O
+in	O
+HBOC	O
+families	O
+.	O
+
+Methods	O
+Next	O
+-	O
+generation	O
+sequencing	O
+was	O
+conducted	O
+on	O
+1876	O
+breast	O
+cancer	O
+(	O
+BC	O
+)	O
+patients	O
+who	O
+fulfilled	O
+the	O
+inclusion	O
+criteria	O
+for	O
+HBOC	O
+.	O
+
+Results	O
+(	O
+Likely	O
+)	O
+pathogenic	O
+variants	O
+in	O
+TP53	O
+gene	O
+were	O
+present	O
+in	O
+0.6	B-STAT
+%	I-STAT
+of	O
+the	O
+BC	O
+cohort	O
+with	O
+higher	O
+occurrence	B-EPI
+in	O
+early	O
+onset	O
+BC	O
+<	O
+36	O
+years	O
+.	O
+
+(	O
+1.1	O
+%	O
+)	O
+and	O
+bilateral	O
+vs.	O
+unilateral	O
+BC	O
+(	O
+1.1	O
+%	O
+vs.	O
+0.3	O
+%	I-STAT
+)	O
+.	O
+
+Two	O
+out	O
+of	O
+eleven	O
+patients	O
+with	O
+a	O
+(	O
+likely	O
+)	O
+pathogenic	O
+TP53	O
+g	O
+variant	O
+(	O
+c.542	O
+G	O
+>	O
+A	O
+;	O
+c.375	O
+G	O
+>	O
+A	O
+)	O
+did	O
+not	O
+comply	O
+with	O
+classic	O
+LFS	O
+/	O
+Chompret	O
+criteria	O
+.	O
+
+Albeit	O
+located	O
+in	O
+the	O
+DNA	O
+-	O
+binding	O
+domain	O
+of	O
+the	O
+p53	O
+-	O
+protein	O
+and	O
+therefore	O
+revealing	O
+no	O
+difference	O
+to	O
+LFS	O
+-	O
+related	O
+variants	O
+,	O
+they	O
+only	O
+displayed	O
+a	O
+medium	O
+transactivity	O
+reduction	O
+constituting	O
+a	O
+retainment	O
+of	O
+wildtype	O
+-	O
+like	O
+anti	O
+-	O
+proliferative	O
+functionality	O
+.	O
+
+Conclusion	O
+Among	O
+our	O
+cohort	O
+of	O
+HBOC	O
+families	O
+,	O
+we	O
+were	O
+able	O
+to	O
+describe	O
+a	O
+clinical	O
+subgroup	O
+,	O
+which	O
+is	O
+distinct	O
+from	O
+the	O
+classic	O
+LFS	O
+-	O
+families	O
+.	O
+
+Strikingly	O
+,	O
+two	O
+families	O
+did	O
+not	O
+adhere	O
+to	O
+the	O
+LFS	O
+criteria	O
+,	O
+and	O
+functional	O
+analysis	O
+revealed	O
+a	O
+reduced	O
+impact	O
+on	O
+TP53	O
+activity	O
+,	O
+which	O
+may	O
+suit	O
+to	O
+the	O
+attenuated	O
+phenotype	O
+.	O
+
+This	O
+is	O
+an	O
+approach	O
+that	O
+could	O
+be	O
+useful	O
+in	O
+developing	O
+individualized	O
+screening	O
+efforts	O
+for	O
+TP53	O
+g	O
+mutation	O
+carrier	O
+in	O
+HBOC	O
+families	O
+.	O
+
+Due	O
+to	O
+the	O
+low	O
+incidence	B-EPI
+,	O
+national	O
+/	O
+international	O
+cooperation	O
+is	O
+necessary	O
+to	O
+further	O
+explore	O
+clinical	O
+implications	O
+.	O
+
+This	O
+might	O
+allow	O
+providing	O
+directions	O
+for	O
+clinical	O
+recommendations	O
+in	O
+the	O
+future	O
+.	O
+
+Neonatal	O
+herpes	O
+,	O
+seen	O
+roughly	O
+in	O
+1	B-STAT
+of	I-STAT
+3000	I-STAT
+live	I-STAT
+births	I-STAT
+in	O
+the	B-LOC
+United	I-LOC
+States	I-LOC
+,	O
+is	O
+the	O
+most	O
+serious	O
+manifestation	O
+of	O
+herpes	O
+simplex	O
+virus	O
+(	O
+HSV	O
+)	O
+infection	O
+in	O
+the	O
+perinatal	O
+period	O
+.	O
+
+Although	O
+acyclovir	O
+therapy	O
+decreases	O
+infant	O
+mortality	O
+associated	O
+with	O
+perinatal	O
+HSV	O
+transmission	O
+,	O
+development	O
+of	O
+permanent	O
+neurological	O
+disabilities	O
+is	O
+not	O
+uncommon	O
+.	O
+
+Mother	O
+-	O
+to	O
+-	O
+neonate	O
+HSV	O
+transmission	O
+is	O
+most	O
+efficient	O
+when	O
+maternal	O
+genital	O
+tract	O
+HSV	O
+infection	O
+is	O
+acquired	O
+proximate	O
+to	O
+the	O
+time	O
+of	O
+delivery	O
+,	O
+signifying	O
+that	O
+neonatal	O
+herpes	O
+prevention	O
+strategies	O
+need	O
+to	O
+focus	O
+on	O
+decreasing	O
+the	O
+incidence	B-EPI
+of	O
+maternal	O
+infection	O
+during	O
+pregnancy	O
+and	O
+more	O
+precisely	O
+identifying	O
+infants	O
+most	O
+likely	O
+to	O
+benefit	O
+from	O
+prophylactic	O
+antiviral	O
+therapy	O
+.	O
+
+Purpose	O
+Inflammatory	O
+bowel	O
+diseases	O
+(	O
+IBD	O
+)	O
+,	O
+including	O
+Crohn	O
+'s	O
+disease	O
+(	O
+CD	O
+)	O
+and	O
+ulcerative	O
+colitis	O
+(	O
+UC	O
+)	O
+,	O
+are	O
+chronic	O
+diseases	O
+.	O
+
+The	O
+aim	O
+was	O
+to	O
+validate	O
+diagnoses	O
+of	O
+IBD	O
+among	O
+patients	O
+aged	O
+50	O
++	O
+years	O
+in	O
+the	O
+Danish	O
+National	O
+Patient	O
+Registry	O
+(	O
+NPR	O
+)	O
+by	O
+comparison	O
+with	O
+patient	O
+medical	O
+records	O
+.	O
+
+Patients	O
+and	O
+methods	O
+Men	O
+and	O
+women	O
+in	O
+the	O
+Diet	O
+,	O
+Cancer	O
+and	O
+Health	O
+(	O
+DCH	O
+)	O
+cohort	O
+were	O
+linked	O
+to	O
+NPR	O
+,	O
+and	O
+cases	O
+with	O
+a	O
+diagnosis	O
+of	O
+IBD	O
+and	O
+their	O
+respective	O
+hospital	O
+records	O
+were	O
+identified	O
+.	O
+
+Validation	O
+was	O
+performed	O
+by	O
+comparing	O
+patient	O
+medical	O
+records	O
+with	O
+information	O
+on	O
+discharge	O
+diagnoses	O
+of	O
+IBD	O
+from	O
+the	O
+NPR	O
+.	O
+
+Results	O
+Of	O
+57,053	O
+individuals	O
+in	O
+the	O
+DCH	O
+-	O
+cohort	O
+,	O
+339	O
+were	O
+registered	O
+with	O
+an	O
+IBD	O
+diagnosis	O
+in	O
+NPR	O
+,	O
+with	O
+277	B-STAT
+(	O
+82	O
+%	O
+)	O
+records	O
+available	O
+for	O
+review	O
+.	O
+
+Among	O
+277	O
+patients	O
+,	O
+the	O
+positive	O
+predictive	O
+values	O
+(	O
+PPVs	O
+)	O
+of	O
+one	O
+CD	O
+or	O
+UC	O
+registration	O
+in	O
+NPR	O
+were	O
+78	O
+%	O
+for	O
+IBD	O
+overall	O
+,	O
+51	O
+%	O
+for	O
+CD	O
+and	O
+54	O
+%	O
+for	O
+UC	O
+.	O
+
+One	O
+hundred	O
+fifty	O
+-	O
+seven	O
+patients	O
+had	O
+at	O
+least	O
+two	O
+CD	O
+and/or	O
+UC	O
+registrations	O
+with	O
+PPVs	O
+of	O
+90	O
+%	O
+for	O
+IBD	O
+overall	O
+,	O
+65	O
+%	O
+for	O
+CD	O
+and	O
+73	O
+%	O
+for	O
+UC	O
+.	O
+
+One	O
+hundred	O
+and	O
+two	O
+patients	O
+had	O
+at	O
+least	O
+three	O
+registrations	O
+with	O
+PPVs	O
+of	O
+97	O
+%	O
+for	O
+IBD	O
+overall	O
+,	O
+75	O
+%	O
+for	O
+CD	O
+and	O
+88	O
+%	O
+for	O
+UC	O
+.	O
+
+96	B-STAT
+%	I-STAT
+were	O
+diagnosed	O
+at	O
+a	O
+specialized	O
+department	O
+.	O
+
+Other	O
+diagnoses	O
+coded	O
+as	O
+IBD	O
+mostly	O
+included	O
+microscopic	O
+colitis	O
+,	O
+irritable	O
+bowel	O
+syndrome	O
+and	O
+cancer	O
+.	O
+
+Conclusion	O
+Validity	O
+of	O
+IBD	O
+diagnoses	O
+in	O
+the	O
+registry	O
+of	O
+individuals	O
+aged	O
+50	O
++	O
+years	O
+increased	O
+with	O
+the	O
+number	O
+of	O
+registrations	O
+.	O
+
+It	O
+is	O
+recommended	O
+that	O
+these	O
+results	O
+are	O
+taken	O
+into	O
+consideration	O
+in	O
+future	O
+studies	O
+,	O
+especially	O
+in	O
+epidemiology	O
+research	O
+using	O
+NPR	O
+as	O
+a	O
+data	O
+source	O
+for	O
+patients	O
+diagnosed	O
+with	O
+IBD	O
+.	O
+
+Purpose	O
+To	O
+determine	O
+if	O
+there	O
+is	O
+an	O
+increased	O
+incidence	B-EPI
+rate	O
+of	O
+post	O
+-	O
+cataract	O
+surgery	O
+(	O
+pcs	O
+)	O
+anterior	O
+ischemic	O
+optic	O
+neuropathy	O
+(	O
+AION	O
+)	O
+compared	O
+to	O
+spontaneous	O
+AION	O
+(	O
+sAION	O
+)	O
+.	O
+
+Design	O
+Retrospective	O
+,	O
+population	O
+-	O
+based	O
+cohort	O
+.	O
+
+Methods	O
+Patients	O
+diagnosed	O
+with	O
+AION	O
+from	O
+January	O
+1	O
+,	O
+1990	O
+,	O
+through	O
+December	O
+31	O
+,	O
+2016	O
+,	O
+while	O
+residing	O
+in	O
+Olmsted	B-LOC
+County	I-LOC
+,	O
+Minnesota	B-LOC
+.	O
+
+Patients	O
+with	O
+cataract	O
+surgery	O
+preceding	O
+AION	O
+were	O
+included	O
+in	O
+the	O
+pcsAION	O
+cohort	O
+defined	O
+in	O
+2	O
+ways	O
+:	O
+AION	O
+within	O
+2	O
+months	O
+and	O
+AION	O
+within	O
+1	B-STAT
+year	I-STAT
+of	O
+cataract	O
+surgery	O
+.	O
+
+The	O
+incidence	B-EPI
+rates	O
+of	O
+pcsAION	B-LOC
+and	O
+sAION	O
+were	O
+compared	O
+using	O
+Poisson	O
+regression	O
+models	O
+.	O
+
+Results	O
+During	O
+the	O
+study	O
+period	O
+,	O
+102	O
+residents	O
+developed	O
+AION	O
+.	O
+
+The	O
+median	O
+age	O
+was	O
+65	O
+years	O
+(	O
+range	O
+,	O
+40	O
+-	O
+90	O
+years	O
+)	O
+,	O
+44	B-STAT
+(	O
+43.1	O
+%	O
+)	O
+were	O
+female	O
+.	O
+
+Twenty	O
+of	O
+102	B-STAT
+(	O
+19.6	O
+%	O
+)	O
+patients	O
+had	O
+previous	O
+cataract	O
+surgery	O
+,	O
+of	O
+which	O
+2	O
+and	O
+9	O
+developed	O
+AION	O
+within	O
+2	O
+months	O
+and	O
+1	B-STAT
+year	I-STAT
+of	O
+surgery	O
+,	O
+respectively	O
+.	O
+
+The	O
+annual	B-EPI
+incidence	I-EPI
+rate	O
+of	O
+pcsAION	O
+within	O
+2	O
+months	O
+of	O
+surgery	O
+(	O
+8.6	B-STAT
+per	I-STAT
+100,000	I-STAT
+)	I-STAT
+was	O
+not	O
+significantly	O
+greater	O
+than	O
+the	O
+annual	B-EPI
+incidence	I-EPI
+rate	O
+of	O
+sAION	O
+(	O
+6.9	B-STAT
+per	I-STAT
+100,000	I-STAT
+;	I-STAT
+P	O
+=	O
+.78	O
+)	O
+.	O
+
+However	O
+,	O
+the	O
+annual	B-EPI
+incidence	I-EPI
+rate	O
+of	O
+pcsAION	B-LOC
+within	O
+1	O
+year	O
+of	O
+surgery	O
+(	O
+38.9	B-STAT
+per	I-STAT
+100,000	I-STAT
+)	I-STAT
+was	O
+significantly	O
+higher	O
+than	O
+the	O
+incidence	B-EPI
+rate	O
+of	O
+sAION	O
+(	O
+6.5	B-STAT
+per	I-STAT
+100,000	I-STAT
+;	I-STAT
+P	O
+<	O
+.001	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+incidence	B-EPI
+of	O
+AION	O
+is	O
+increased	O
+in	O
+the	O
+first	O
+year	O
+after	O
+cataract	O
+surgery	O
+,	O
+but	O
+not	O
+in	O
+the	O
+early	O
+(	O
+i.e.	O
+,	O
+2	O
+months	O
+)	O
+postoperative	O
+period	O
+.	O
+
+Talaromyces	O
+marneffei	O
+causes	O
+life	O
+-	O
+threatening	O
+opportunistic	O
+infections	O
+,	O
+mainly	O
+in	O
+Southeast	B-LOC
+Asia	I-LOC
+and	O
+South	B-LOC
+China	I-LOC
+.	O
+
+T.	O
+marneffei	O
+mainly	O
+infects	O
+patients	O
+with	O
+human	O
+immunodeficiency	O
+virus	O
+(	O
+HIV	O
+)	O
+but	O
+also	O
+infects	O
+individuals	O
+without	O
+known	O
+immunosuppression	O
+.	O
+
+Here	O
+we	O
+investigated	O
+the	O
+involvement	O
+of	O
+anti	O
+-	O
+IFN	O
+-	O
+γ	O
+autoantibodies	O
+in	O
+severe	O
+T.	O
+marneffei	O
+infections	O
+in	O
+HIV	O
+-	O
+negative	O
+patients	O
+.	O
+
+We	O
+enrolled	O
+58	O
+HIV	O
+-	O
+negative	O
+adults	O
+with	O
+severe	O
+T.	O
+marneffei	O
+infections	O
+who	O
+were	O
+otherwise	O
+healthy	O
+.	O
+
+We	O
+found	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+neutralizing	O
+anti	O
+-	O
+IFN	O
+-	O
+γ	O
+autoantibodies	O
+(	O
+94.8	O
+%	O
+)	O
+in	O
+this	O
+cohort	O
+.	O
+
+The	O
+presence	O
+of	O
+anti	O
+-	O
+IFN	O
+-	O
+γ	O
+autoantibodies	O
+was	O
+strongly	O
+associated	O
+with	O
+HLA	O
+-	O
+DRB1	O
+*	O
+16:02	O
+and	O
+-DQB1	O
+*	O
+05:02	O
+alleles	O
+in	O
+these	O
+patients	O
+.	O
+
+We	O
+demonstrated	O
+that	O
+adult	O
+-	O
+onset	O
+acquired	O
+immunodeficiency	O
+due	O
+to	O
+autoantibodies	O
+against	O
+IFN	O
+-	O
+γ	O
+is	O
+the	O
+major	O
+cause	O
+of	O
+severe	O
+T.	O
+marneffei	O
+infections	O
+in	O
+HIV	O
+-	O
+negative	O
+patients	O
+in	O
+regions	O
+where	O
+this	O
+fungus	O
+is	O
+endemic	O
+.	O
+
+The	O
+high	O
+prevalence	B-EPI
+of	O
+anti	O
+-	O
+IFN	O
+-	O
+γ	O
+autoantibody	O
+-	O
+associated	O
+HLA	O
+class	O
+II	O
+DRB1	O
+*	O
+16:02	O
+and	O
+DQB1	O
+*	O
+05:02	O
+alleles	O
+may	O
+account	O
+for	O
+severe	O
+T.	O
+marneffei	O
+infections	O
+in	O
+Southeast	B-LOC
+Asia	I-LOC
+.	O
+
+Our	O
+findings	O
+clarify	O
+the	O
+pathogenesis	O
+of	O
+T.	O
+marneffei	O
+infection	O
+and	O
+pave	O
+the	O
+way	O
+for	O
+developing	O
+novel	O
+treatments	O
+.	O
+
+Congenital	O
+hypothyroidism	O
+(	O
+CH	O
+)	O
+is	O
+a	O
+highly	O
+prevalent	B-EPI
+but	O
+treatable	O
+neonatal	O
+endocrine	O
+disorder	O
+.	O
+
+Thyroid	O
+dyshormonogenesis	O
+is	O
+the	O
+main	O
+cause	O
+of	O
+congenital	O
+hypothyroidism	O
+in	O
+Chinese	O
+CH	O
+patients	O
+,	O
+and	O
+DUOX2	O
+is	O
+the	O
+most	O
+frequent	O
+mutated	O
+gene	O
+involved	O
+in	O
+H2O2	O
+production	O
+.	O
+
+In	O
+humans	O
+,	O
+the	O
+primary	O
+sources	O
+for	O
+H2O2	O
+production	O
+are	O
+DUOX1	O
+and	O
+DUOX2	O
+,	O
+while	O
+in	O
+zebrafish	O
+there	O
+is	O
+only	O
+a	O
+single	O
+orthologue	O
+for	O
+DUOX1	O
+and	O
+DUOX2	B-LOC
+.	O
+
+In	O
+this	O
+study	O
+,	O
+duox	O
+mutant	O
+zebrafish	O
+were	O
+generated	O
+through	O
+knockdown	O
+duox	O
+by	O
+morpholino	O
+or	O
+knockout	O
+duox	O
+by	O
+CRISPR	O
+Cas9	O
+.	O
+
+The	O
+associated	O
+phenotypes	O
+were	O
+investigated	O
+and	O
+rescued	O
+by	O
+thyroxine	O
+(	O
+T4	O
+)	O
+treatment	O
+.	O
+
+Mutant	O
+zebrafish	O
+displayed	O
+hypothyroid	O
+phenotypes	O
+including	O
+growth	O
+retardation	O
+,	O
+goiter	O
+and	O
+,	O
+infertility	O
+.	O
+
+Homozygous	O
+mutants	O
+in	O
+adults	O
+also	O
+displayed	O
+extrathyroidal	O
+abnormal	O
+phenotypes	O
+,	O
+including	O
+lacking	O
+barbels	O
+,	O
+pigmentation	O
+defects	O
+,	O
+erythema	O
+in	O
+the	O
+opercular	O
+region	O
+,	O
+ragged	O
+fins	O
+,	O
+and	O
+delayed	O
+scales	O
+.	O
+
+All	O
+these	O
+abnormal	O
+phenotypes	O
+can	O
+be	O
+rescued	O
+by	O
+10	O
+nM	O
+T4	O
+treatment	O
+.	O
+
+Strikingly	O
+,	O
+the	O
+fertility	O
+of	O
+zebrafish	O
+was	O
+dependent	O
+on	O
+thyroid	O
+hormone	O
+;	O
+T4	O
+treatment	O
+should	O
+be	O
+continued	O
+and	O
+can	O
+not	O
+be	O
+stopped	O
+over	O
+2	O
+weeks	O
+in	O
+hypothyroid	O
+zebrafish	O
+in	O
+order	O
+to	O
+achieve	O
+fertility	O
+.	O
+
+Thyroid	O
+hormones	O
+played	O
+a	O
+role	O
+in	O
+the	O
+developing	O
+and	O
+maturing	O
+of	O
+reproductive	O
+cells	O
+.	O
+
+Our	O
+work	O
+indicated	O
+that	O
+duox	O
+mutant	O
+zebrafish	O
+may	O
+provide	O
+a	O
+model	O
+for	O
+human	O
+congenital	O
+hypothyroidism	O
+.	O
+
+Context	O
+Aggrecan	O
+,	O
+encoded	O
+by	O
+the	O
+ACAN	O
+gene	O
+,	O
+is	O
+the	O
+main	O
+proteoglycan	O
+component	O
+in	O
+the	O
+extracellular	O
+cartilage	O
+matrix	O
+.	O
+
+Heterozygous	O
+mutations	O
+in	O
+ACAN	O
+have	O
+been	O
+reported	O
+to	O
+cause	O
+idiopathic	O
+short	O
+stature	O
+.	O
+
+However	O
+,	O
+the	O
+prevalence	B-EPI
+of	O
+ACAN	O
+pathogenic	O
+variants	O
+in	O
+Chinese	O
+short	O
+stature	O
+patients	O
+and	O
+clinical	O
+phenotypes	O
+remain	O
+to	O
+be	O
+evaluated	O
+.	O
+
+Objective	O
+We	O
+sought	O
+to	O
+determine	O
+the	O
+prevalence	B-EPI
+of	O
+ACAN	O
+pathogenic	O
+variants	O
+among	O
+Chinese	O
+short	O
+stature	O
+children	O
+and	O
+characterize	O
+the	O
+phenotypic	O
+spectrum	O
+and	O
+their	O
+responses	O
+to	O
+growth	O
+hormone	O
+therapies	O
+.	O
+
+Patients	O
+and	O
+methods	O
+Over	O
+1000	O
+unrelated	O
+short	O
+stature	O
+patients	O
+ascertained	O
+across	O
+China	B-LOC
+were	O
+genetically	O
+evaluated	O
+by	O
+next	O
+-	O
+generation	O
+sequencing	O
+-	O
+based	O
+test	O
+.	O
+
+Result	O
+We	O
+identified	O
+10	O
+novel	O
+likely	O
+pathogenic	O
+variants	O
+and	O
+2	O
+recurrent	O
+pathogenic	O
+variants	O
+in	O
+this	O
+cohort	O
+.	O
+
+None	O
+of	O
+ACAN	O
+mutation	O
+carriers	O
+exhibited	O
+significant	O
+dysmorphic	O
+features	O
+or	O
+skeletal	O
+abnormities	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+ACAN	O
+defect	O
+is	O
+estimated	O
+to	O
+be	O
+1.2	O
+%	O
+in	O
+the	O
+whole	O
+cohort	O
+;	O
+it	O
+increased	B-STAT
+to	O
+14.3	O
+%	O
+among	O
+those	O
+with	O
+advanced	O
+bone	O
+age	O
+and	O
+to	O
+35.7	B-STAT
+%	O
+among	O
+those	O
+with	O
+both	O
+advanced	O
+bone	O
+age	O
+and	O
+family	O
+history	O
+of	O
+short	O
+stature	O
+.	O
+
+Nonetheless	O
+,	O
+5	O
+of	O
+11	O
+ACAN	O
+mutation	O
+carries	O
+had	O
+no	O
+advanced	O
+bone	O
+age	O
+.	O
+
+Two	O
+individuals	O
+received	O
+growth	O
+hormone	O
+therapy	O
+with	O
+variable	O
+levels	O
+of	O
+height	O
+SD	O
+score	O
+improvement	O
+.	O
+
+Conclusion	O
+Our	O
+data	O
+suggest	O
+that	O
+ACAN	O
+mutation	O
+is	O
+1	O
+of	O
+the	O
+common	O
+causes	O
+of	O
+Chinese	O
+pediatric	O
+short	O
+stature	O
+.	O
+
+Although	O
+it	O
+has	O
+a	O
+higher	O
+detection	O
+rate	O
+among	O
+short	O
+stature	O
+patients	O
+with	O
+advanced	O
+bone	O
+age	O
+and	O
+family	O
+history	O
+,	O
+part	O
+of	O
+affected	O
+probands	O
+presented	O
+with	O
+delayed	O
+bone	O
+age	O
+in	O
+Chinese	O
+short	O
+stature	O
+population	O
+.	O
+
+The	O
+growth	O
+hormone	O
+treatment	O
+was	O
+moderately	O
+effective	O
+for	O
+both	O
+individuals	O
+.	O
+
+Purpose	O
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+review	O
+patients	O
+with	O
+xanthogranulomatous	O
+cholecystitis	O
+(	O
+XGC	O
+)	O
+.	O
+
+Methods	O
+A	O
+total	O
+of	O
+79	O
+patients	O
+diagnosed	O
+with	O
+XGC	O
+were	O
+included	O
+in	O
+the	O
+study	O
+.	O
+
+The	O
+criteria	O
+for	O
+XGC	O
+in	O
+the	O
+pathology	O
+specimens	O
+were	O
+the	O
+presence	O
+of	O
+histiocytes	O
+,	O
+cholesterol	O
+deposits	O
+,	O
+lipids	O
+,	O
+and	O
+focal	O
+or	O
+widespread	O
+wall	O
+enlargement	O
+.	O
+
+Results	O
+Patients	O
+were	O
+diagnosed	O
+with	O
+XGC	O
+,	O
+of	O
+which	O
+52	B-STAT
+(	O
+65.8	O
+%	O
+)	O
+were	O
+male	O
+and	O
+27	B-STAT
+(	O
+34.2	O
+%	O
+)	O
+were	O
+female	O
+,	O
+creating	O
+a	O
+male	O
+-	O
+to	O
+-	O
+female	O
+ratio	O
+of	O
+2:1	O
+.	O
+
+The	O
+mean	O
+age	O
+was	O
+65.8	O
+±	O
+14.3	O
+years	O
+(	O
+range	O
+,	O
+36	O
+-	O
+97	O
+years	O
+)	O
+.	O
+
+The	O
+most	O
+common	O
+presenting	O
+symptom	O
+was	O
+abdominal	O
+pain	O
+(	O
+63.3	O
+%	O
+)	O
+,	O
+and	O
+the	O
+least	O
+common	O
+presenting	O
+symptom	O
+was	O
+jaundice	O
+(	O
+8.9	O
+%	O
+)	O
+.	O
+
+Of	O
+the	O
+total	O
+,	O
+25	O
+patients	O
+were	O
+found	O
+to	O
+have	O
+pathological	O
+conditions	O
+with	O
+the	O
+potential	O
+to	O
+obstruct	O
+the	O
+bile	O
+duct	O
+or	O
+to	O
+slow	O
+bile	O
+flow	O
+.	O
+
+A	O
+frozen	O
+section	O
+examination	O
+was	O
+performed	O
+on	O
+20	O
+patients	O
+due	O
+to	O
+suspicion	O
+of	O
+a	O
+tumor	O
+by	O
+intraoperative	O
+macroscopic	O
+examination	O
+.	O
+
+However	O
+,	O
+no	O
+malignancy	O
+was	O
+detected	O
+in	O
+the	O
+cases	O
+who	O
+underwent	O
+a	O
+frozen	O
+section	O
+examination	O
+.	O
+
+An	O
+increase	O
+in	O
+wall	O
+thickness	O
+of	O
+the	O
+gallbladder	O
+was	O
+observed	O
+in	O
+81.6	O
+%	O
+(	O
+n	O
+=	O
+31	O
+)	O
+of	O
+the	O
+patients	O
+on	O
+computed	O
+tomography	O
+scans	O
+and	O
+in	O
+81.8	O
+%	O
+(	O
+n	O
+=	O
+18	O
+)	O
+of	O
+the	O
+patients	O
+on	O
+magnetic	O
+resonance	O
+imaging	O
+scans	O
+in	O
+which	O
+possible	O
+tumor	O
+lesions	O
+were	O
+reported	O
+,	O
+but	O
+no	O
+tumor	O
+was	O
+detected	O
+.	O
+
+Conclusion	O
+It	O
+is	O
+difficult	O
+to	O
+diagnose	O
+XGC	O
+either	O
+preoperatively	O
+or	O
+intraoperatively	O
+,	O
+and	O
+further	O
+imaging	O
+methods	O
+are	O
+needed	O
+in	O
+the	O
+preoperative	O
+period	O
+other	O
+than	O
+ultrasonography	O
+.	O
+
+However	O
+,	O
+a	O
+definitive	O
+diagnosis	O
+depends	O
+exclusively	O
+on	O
+pathologic	O
+examination	O
+.	O
+
+Adrenocortical	O
+carcinoma	O
+(	O
+ACC	O
+)	O
+is	O
+a	O
+rare	O
+endocrine	O
+malignancy	O
+arising	O
+from	O
+the	O
+adrenal	O
+cortex	O
+often	O
+with	O
+unexpected	O
+biological	O
+behavior	O
+.	O
+
+It	O
+can	O
+occur	O
+at	O
+any	O
+age	O
+,	O
+with	O
+two	O
+peaks	O
+of	O
+incidence	B-EPI
+:	O
+in	O
+the	O
+first	O
+and	O
+between	O
+fifth	O
+and	O
+seventh	O
+decades	O
+of	O
+life	O
+.	O
+
+Although	O
+ACC	O
+are	O
+mostly	O
+hormonally	O
+active	O
+,	O
+precursors	O
+and	O
+metabolites	O
+,	O
+rather	O
+than	O
+end	O
+products	O
+of	O
+steroidogenesis	O
+are	O
+produced	O
+by	O
+dedifferentiated	O
+and	O
+immature	O
+malignant	O
+cells	O
+.	O
+
+Distinguishing	O
+the	O
+etiology	O
+of	O
+adrenal	O
+mass	O
+,	O
+between	O
+benign	O
+adenomas	O
+,	O
+which	O
+are	O
+quite	O
+frequent	O
+in	O
+general	O
+population	O
+,	O
+and	O
+malignant	O
+carcinomas	O
+with	O
+dismal	O
+prognosis	O
+is	O
+often	O
+unfeasible	O
+.	O
+
+Even	O
+after	O
+pathohistological	O
+analysis	O
+,	O
+diagnosis	O
+of	O
+adrenocortical	O
+carcinomas	O
+is	O
+not	O
+always	O
+straightforward	O
+and	O
+represents	O
+a	O
+great	O
+challenge	O
+for	O
+experienced	O
+and	O
+multidisciplinary	O
+expert	O
+teams	O
+.	O
+
+No	O
+single	O
+imaging	O
+method	O
+,	O
+hormonal	O
+work	O
+-	O
+up	O
+or	O
+immunohistochemical	O
+labelling	O
+can	O
+definitively	O
+prove	O
+the	O
+diagnosis	O
+of	O
+ACC	O
+.	O
+
+Over	O
+several	O
+decades	O
+'	O
+great	O
+efforts	O
+have	O
+been	O
+made	O
+in	O
+finding	O
+novel	O
+reliable	O
+and	O
+available	O
+diagnostic	O
+and	O
+prognostic	O
+factors	O
+including	O
+steroid	O
+metabolome	O
+profiling	O
+or	O
+target	O
+gene	O
+identification	O
+.	O
+
+Despite	O
+these	O
+achievements	O
+,	O
+the	O
+5	O
+-	O
+year	O
+mortality	O
+rate	O
+still	O
+accounts	O
+for	O
+approximately	O
+75	O
+%	O
+to	O
+90	O
+%	O
+,	O
+ACC	O
+is	O
+frequently	O
+diagnosed	O
+in	O
+advanced	O
+stages	O
+and	O
+therapeutic	O
+options	O
+are	O
+unfortunately	O
+limited	O
+.	O
+
+Therefore	O
+,	O
+imperative	O
+is	O
+to	O
+identify	O
+new	O
+biological	O
+markers	O
+that	O
+can	O
+predict	O
+patient	O
+prognosis	O
+and	O
+provide	O
+new	O
+therapeutic	O
+options	O
+.	O
+
+Background	O
+Kindler	O
+poikiloderma	O
+is	O
+an	O
+inherited	O
+autosomal	O
+genodermatosis	O
+characterized	O
+by	O
+blistering	O
+of	O
+the	O
+epidermis	O
+and	O
+mucosae	O
+.	O
+
+Its	O
+prevalence	B-EPI
+is	O
+unknown	O
+.	O
+
+Case	O
+report	O
+We	O
+monitored	O
+two	O
+brothers	O
+suffering	O
+from	O
+this	O
+pathology	O
+.	O
+
+Oral	O
+manifestations	O
+mainly	O
+take	O
+the	O
+form	O
+of	O
+periodontal	O
+lesions	O
+.	O
+
+In	O
+our	O
+patients	O
+we	O
+noted	O
+gingivitis	O
+progressing	O
+to	O
+periodontitis	O
+as	O
+follow	O
+-	O
+up	O
+care	O
+was	O
+not	O
+effective	O
+.	O
+
+We	O
+also	O
+diagnosed	O
+enamel	O
+hypoplasia	O
+,	O
+described	O
+more	O
+rarely	O
+in	O
+this	O
+pathology	O
+.	O
+
+Conclusion	O
+Periodontitis	O
+in	O
+Kindler	O
+Syndrome	O
+responds	O
+to	O
+maintenance	O
+therapy	O
+,	O
+but	O
+the	O
+absence	O
+of	O
+surveillance	O
+is	O
+penalized	O
+by	O
+a	O
+deterioration	O
+in	O
+periodontal	O
+condition	O
+and	O
+complication	O
+of	O
+management	O
+.	O
+
+All	O
+restorative	O
+,	O
+endodontic	O
+,	O
+surgical	O
+,	O
+periodontal	O
+and	O
+orthodontic	O
+treatments	O
+should	O
+be	O
+performed	O
+with	O
+appropriate	O
+precautions	O
+.	O
+
+Background	O
+Several	O
+studies	O
+have	O
+shown	O
+a	O
+high	O
+rate	O
+of	O
+consanguinity	O
+and	O
+endogamy	O
+in	O
+North	O
+African	O
+populations	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+the	O
+frequency	O
+of	O
+autosomal	O
+recessive	O
+diseases	O
+is	O
+relatively	O
+high	O
+in	O
+the	O
+region	O
+with	O
+the	O
+co	O
+-	O
+occurrence	B-EPI
+of	O
+two	O
+or	O
+more	O
+diseases	O
+.	O
+
+Methods	O
+We	O
+report	O
+here	O
+on	O
+a	O
+consanguineous	O
+Libyan	O
+family	O
+whose	O
+child	O
+was	O
+initially	O
+diagnosed	O
+as	O
+presenting	O
+Fanconi	O
+anemia	O
+(	O
+FA	O
+)	O
+with	O
+uncommon	O
+skeletal	O
+deformities	O
+.	O
+
+The	O
+chromosome	O
+breakage	O
+test	O
+has	O
+been	O
+performed	O
+using	O
+mitomycin	O
+C	O
+(	O
+MMC	O
+)	O
+while	O
+molecular	O
+analysis	O
+was	O
+performed	O
+by	O
+a	O
+combined	O
+approach	O
+of	O
+linkage	O
+analysis	O
+and	O
+whole	O
+exome	O
+sequencing	O
+.	O
+
+Results	O
+Cytogenetic	O
+analyses	O
+showed	O
+that	O
+the	O
+karyotype	O
+of	O
+the	O
+female	O
+patient	O
+is	O
+46,XY	O
+suggesting	O
+the	O
+diagnosis	O
+of	O
+a	O
+disorder	O
+of	O
+sex	O
+development	O
+(	O
+DSD	O
+)	O
+.	O
+
+By	O
+looking	O
+at	O
+the	O
+genetic	O
+etiology	O
+of	O
+FA	O
+and	O
+DSD	O
+,	O
+we	O
+have	O
+identified	O
+p.[Arg798*];[Arg798	O
+*	O
+]	O
+mutation	O
+in	O
+FANCJ	O
+(	O
+OMIM	O
+#	O
+605882	O
+)	O
+gene	O
+responsible	O
+for	O
+FA	O
+and	O
+p.[Arg108*];[Arg1497Trp	O
+]	O
+in	O
+EFCAB6	O
+(	O
+Gene	O
+#	O
+64800	O
+)	O
+gene	O
+responsible	O
+for	O
+DSD	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+have	O
+incidentally	O
+discovered	O
+a	O
+novel	O
+mutation	O
+p.[Gly1372Arg];[Gly1372Arg	O
+]	O
+in	O
+the	O
+ERCC6	O
+(	O
+CSB	O
+)	O
+(	O
+OMIM	O
+#	O
+609413	O
+)	O
+gene	O
+responsible	O
+for	O
+COFS	O
+that	O
+might	O
+explain	O
+the	O
+atypical	O
+severe	O
+skeletal	O
+deformities	O
+.	O
+
+Conclusion	O
+The	O
+co	O
+-	O
+occurrence	B-EPI
+of	O
+clinical	O
+and	O
+overlapping	O
+genetic	O
+heterogeneous	O
+entities	O
+should	O
+be	O
+taken	O
+into	O
+consideration	O
+for	O
+better	O
+molecular	O
+and	O
+genetic	O
+counseling	O
+.	O
+
+Pyridoxine	O
+-	O
+dependent	O
+epilepsy	O
+(	O
+PDE	O
+)	O
+is	O
+a	O
+potentially	O
+treatable	O
+vitamin	O
+-	O
+responsive	O
+epileptic	O
+encephalopathy	O
+.	O
+
+The	O
+most	O
+prevalent	B-EPI
+form	O
+of	O
+PDE	O
+is	O
+due	O
+to	O
+an	O
+underlying	O
+genetic	O
+defect	O
+in	O
+ALDH7A1	O
+encoding	O
+Antiquitin	O
+(	O
+ATQ	O
+)	O
+,	O
+an	O
+enzyme	O
+with	O
+α	O
+-	O
+aminoadipic	O
+semialdehyde	O
+dehydrogenase	O
+(	O
+AASADH	O
+)	O
+activity	O
+which	O
+facilitates	O
+cerebral	O
+lysine	O
+degradation	O
+.	O
+
+Devastating	O
+outcomes	O
+including	O
+intellectual	O
+disability	O
+and	O
+significant	O
+developmental	O
+delays	O
+are	O
+still	O
+observed	O
+in	O
+75	O
+%	O
+to	O
+80	O
+%	O
+of	O
+pyridoxine	O
+responsive	O
+individuals	O
+with	O
+good	O
+seizure	O
+control	O
+,	O
+potentially	O
+attributable	O
+to	O
+the	O
+accumulation	O
+of	O
+toxic	O
+intermediates	O
+α	O
+-	O
+aminoadipic	O
+semialdehyde	O
+(	O
+AASA	O
+)	O
+and	O
+its	O
+cyclic	O
+form	O
+Δ	O
+1	O
+-piperideine-6	O
+-	O
+carboxylate	O
+(	O
+P6C	O
+)	O
+in	O
+plasma	O
+,	O
+urine	O
+and	O
+CSF	O
+.	O
+
+Thus	O
+,	O
+adjunct	O
+treatment	O
+strategies	O
+incorporating	O
+lysine	O
+restriction	O
+and	O
+arginine	O
+supplementation	O
+,	O
+separately	O
+or	O
+in	O
+combination	O
+with	O
+pyridoxine	O
+have	O
+been	O
+attempted	O
+to	O
+enhance	O
+seizure	O
+control	O
+and	O
+improve	O
+cognitive	O
+function	O
+.	O
+
+We	O
+describe	O
+a	O
+4	O
+year	O
+old	O
+girl	O
+with	O
+classical	O
+PDE	O
+who	O
+demonstrated	O
+significant	O
+improvements	O
+in	O
+clinical	O
+,	O
+neurological	O
+and	O
+developmental	O
+outcomes	O
+including	O
+absence	O
+of	O
+clinical	O
+seizures	O
+and	O
+cessation	O
+of	O
+antiepileptic	O
+medications	O
+since	O
+age	O
+3	O
+months	O
+,	O
+normalisation	O
+of	O
+EEG	O
+,	O
+significant	O
+improvement	O
+in	O
+the	O
+white	O
+matter	O
+signal	O
+throughout	O
+the	O
+cerebrum	O
+on	O
+neuroimaging	O
+and	O
+significant	O
+reduction	O
+in	O
+urine	O
+P6C	O
+and	O
+pipecolic	O
+acid	O
+levels	O
+post-	O
+combined	O
+therapy	O
+with	O
+lysine	O
+restricted	O
+diet	O
+in	O
+conjunction	O
+with	O
+pyridoxine	O
+and	O
+folinic	O
+acid	O
+.	O
+
+Lysine	O
+restriction	O
+was	O
+well	O
+tolerated	O
+with	O
+impressive	O
+compliance	O
+and	O
+plasma	O
+lysine	O
+levels	O
+remained	O
+within	O
+the	O
+lower	O
+reference	O
+ranges	O
+;	O
+mean	O
+level	O
+70	O
+μmol	O
+/	O
+L	O
+(	O
+ref	O
+range	O
+52	O
+-	O
+196	O
+μmol	O
+/	O
+L	O
+)	O
+.	O
+
+This	O
+case	O
+further	O
+emphasizes	O
+the	O
+benefit	O
+of	O
+early	O
+dietary	O
+intervention	O
+as	O
+an	O
+effective	O
+adjunct	O
+in	O
+the	O
+management	O
+of	O
+PDE	O
+.	O
+
+Neonatal	O
+herpes	O
+simplex	O
+virus	O
+infection	O
+(	O
+HSV	O
+)	O
+is	O
+rare	O
+in	O
+neonates	O
+,	O
+with	O
+an	O
+estimated	O
+global	B-LOC
+incidence	B-EPI
+of	O
+10	B-STAT
+per	I-STAT
+100,000	I-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+Neonatal	O
+HSV	O
+is	O
+challenging	O
+to	O
+diagnose	O
+due	O
+to	O
+often	O
+vague	O
+signs	O
+and	O
+symptoms	O
+.	O
+
+Untreated	O
+,	O
+the	O
+mortality	O
+of	O
+some	O
+HSV	O
+subtypes	O
+exceeds	O
+80	B-STAT
+%	I-STAT
+.	O
+
+Overtesting	O
+and	O
+overtreatment	O
+can	O
+result	O
+in	O
+prolonged	O
+hospitalizations	O
+and	O
+expose	O
+neonates	O
+to	O
+medication	O
+toxicity	O
+.	O
+
+In	O
+contrast	O
+,	O
+prompt	O
+evaluation	O
+and	O
+use	O
+of	O
+empiric	O
+antiviral	O
+therapy	O
+before	O
+the	O
+results	O
+of	O
+definitive	O
+testing	O
+can	O
+improve	O
+outcomes	O
+for	O
+infants	O
+with	O
+HSV	O
+.	O
+
+A	O
+wide	O
+degree	O
+of	O
+practice	O
+variation	O
+exists	O
+with	O
+respect	O
+to	O
+testing	O
+and	O
+treatment	O
+for	O
+neonatal	O
+HSV	O
+,	O
+and	O
+more	O
+research	O
+is	O
+required	O
+to	O
+safely	O
+risk	O
+-	O
+stratify	O
+this	O
+population	O
+.	O
+
+This	O
+review	O
+presents	O
+the	O
+epidemiology	O
+,	O
+risk	O
+factors	O
+,	O
+presenting	O
+features	O
+,	O
+and	O
+emergency	O
+department	O
+management	O
+of	O
+neonatal	O
+HSV	O
+infection	O
+.	O
+
+Since	O
+it	O
+was	O
+first	O
+documented	O
+in	O
+1948	O
+by	O
+Sir	O
+William	O
+Heneage	O
+Ogilvie	O
+,	O
+numerous	O
+cases	O
+of	O
+Ogilvie	O
+syndrome	O
+have	O
+been	O
+described	O
+in	O
+literature	O
+due	O
+to	O
+various	O
+medical	O
+and	O
+surgical	O
+causes	O
+.	O
+
+Nonetheless	O
+,	O
+only	O
+a	O
+handful	O
+of	O
+cases	O
+only	O
+have	O
+been	O
+documented	O
+due	O
+to	O
+underlying	O
+Acquired	O
+Immunodeficiency	O
+Syndrome	O
+(	O
+AIDS	O
+)	O
+.	O
+
+A	O
+41	O
+-	O
+year	O
+-	O
+old	O
+female	O
+was	O
+admitted	O
+with	O
+an	O
+acute	O
+abdomen	O
+secondary	O
+to	O
+partial	O
+mechanical	O
+intestinal	O
+obstruction	O
+or	O
+paralytic	O
+ileus	O
+based	O
+on	O
+signs	O
+and	O
+symptoms	O
+and	O
+Abdominal	O
+X	O
+-	O
+Ray	O
+(	O
+AXR	O
+)	O
+.	O
+
+She	O
+was	O
+known	O
+to	O
+be	O
+HIV	O
+/	O
+AIDS	O
+WHO	O
+clinical	O
+stage	O
+II	O
+on	O
+treatment	O
+.	O
+
+On	O
+diagnostic	O
+imaging	O
+studies	O
+she	O
+had	O
+distended	O
+large	O
+bowels	O
+without	O
+features	O
+of	O
+mechanical	O
+intestinal	O
+obstruction	O
+and	O
+the	O
+diagnosis	O
+of	O
+Ogilvie	O
+syndrome	O
+was	O
+suspected	O
+after	O
+other	O
+differentials	O
+were	O
+excluded	O
+.	O
+
+Early	O
+recognition	O
+and	O
+appropriate	O
+management	O
+are	O
+essential	O
+,	O
+because	O
+if	O
+left	O
+untreated	O
+the	O
+bowel	O
+distension	O
+may	O
+progress	O
+to	O
+caecal	O
+perforation	O
+and	O
+fatal	O
+peritonitis	O
+.	O
+
+Medical	O
+imaging	O
+with	O
+Computer	O
+Tomography	O
+(	O
+CT	O
+)	O
+scan	O
+and	O
+colonoscopy	O
+has	O
+helped	O
+in	O
+achieving	O
+an	O
+accurate	O
+diagnosis	O
+and	O
+avoiding	O
+unnecessary	O
+laparotomies	O
+.	O
+
+Although	O
+an	O
+uncommon	O
+disorder	O
+,	O
+for	O
+earlier	O
+and	O
+accurate	O
+diagnosis	O
+a	O
+high	O
+index	O
+of	O
+suspicion	O
+is	O
+required	O
+by	O
+clinicians	O
+and	O
+radiologists	O
+who	O
+are	O
+treating	O
+patients	O
+with	O
+underlying	O
+HIV	O
+/	O
+AIDS	O
+.	O
+
+Ogilvie	O
+'s	O
+syndrome	O
+is	O
+a	O
+rare	O
+condition	O
+and	O
+if	O
+missed	O
+can	O
+be	O
+fatal	O
+.	O
+
+In	O
+patients	O
+with	O
+HIV	O
+/	O
+AIDS	O
+,	O
+the	O
+symptoms	O
+may	O
+be	O
+directly	O
+due	O
+to	O
+HIV	O
+infection	O
+,	O
+secondary	O
+to	O
+opportunistic	O
+infections	O
+or	O
+possible	O
+neurotoxic	O
+effects	O
+of	O
+HIV	O
+treatment	O
+or	O
+lack	O
+of	O
+vitamin	O
+and	O
+minerals	O
+.	O
+
+It	O
+is	O
+important	O
+to	O
+exclude	O
+Ogilvie	O
+syndrome	O
+in	O
+patients	O
+from	O
+surgical	O
+causes	O
+of	O
+the	O
+acute	O
+abdomen	O
+to	O
+avoid	O
+unnecessary	O
+surgical	O
+procedures	O
+.	O
+
+Pathogenic	O
+variants	O
+in	O
+the	O
+fibroblast	O
+growth	O
+factor	O
+receptor	O
+3	O
+(	O
+FGFR3	O
+)	O
+gene	O
+are	O
+responsible	O
+for	O
+a	O
+broad	O
+spectrum	O
+of	O
+skeletal	O
+dysplasias	O
+,	O
+including	O
+achondroplasia	O
+(	O
+ACH	O
+)	O
+.	O
+
+The	O
+classic	O
+phenotype	O
+of	O
+ACH	O
+is	O
+caused	O
+by	O
+two	O
+highly	O
+prevalent	B-EPI
+mutations	O
+,	O
+c.1138	O
+G	O
+>	O
+A	O
+and	O
+c.1138	O
+G	O
+>	O
+C	O
+(	O
+p.	O
+Gly380Arg	O
+)	O
+.	O
+
+In	O
+the	O
+homozygous	O
+state	O
+,	O
+these	O
+variant	O
+results	O
+in	O
+a	O
+severe	O
+skeletal	O
+dysplasia	O
+,	O
+neurologic	O
+deficits	O
+,	O
+and	O
+early	O
+demise	O
+from	O
+respiratory	O
+insufficiency	O
+.	O
+
+Although	O
+homozygous	O
+biallelic	O
+mutations	O
+have	O
+been	O
+reported	O
+in	O
+patients	O
+with	O
+ACH	O
+in	O
+combination	O
+with	O
+hypochondroplasia	O
+or	O
+other	O
+dominant	O
+skeletal	O
+dysplasias	O
+,	O
+thus	O
+far	O
+,	O
+no	O
+cases	O
+of	O
+heterozygous	O
+biallelic	O
+pathogenic	O
+ACH	O
+-	O
+related	O
+variants	O
+in	O
+FGFR3	O
+have	O
+been	O
+reported	O
+.	O
+
+We	O
+describe	O
+a	O
+novel	O
+phenotype	O
+of	O
+an	O
+infant	O
+with	O
+two	O
+ACH	O
+-	O
+related	O
+mutations	O
+in	O
+FGFR3	O
+,	O
+p.	O
+Gly380Arg	O
+and	O
+p.	O
+Ser344Cys	O
+.	O
+
+Discordant	O
+features	O
+from	O
+classic	O
+ACH	O
+include	O
+atypical	O
+radiographic	O
+findings	O
+,	O
+severe	O
+obstructive	O
+sleep	O
+apnea	O
+,	O
+and	O
+focal	O
+,	O
+migrating	O
+seizures	O
+.	O
+
+We	O
+also	O
+report	O
+the	O
+long	O
+-	O
+term	O
+clinical	O
+course	O
+of	O
+her	O
+father	O
+,	O
+who	O
+harbors	O
+the	O
+p.	O
+Ser344Cys	O
+mutation	O
+that	O
+has	O
+only	O
+been	O
+reported	O
+once	O
+previously	O
+in	O
+a	O
+Japanese	O
+patient	O
+.	O
+
+The	O
+phenotype	O
+of	O
+heterozygous	O
+biallelic	O
+mutations	O
+in	O
+FGFR3	O
+associated	O
+with	O
+ACH	O
+is	O
+variable	O
+,	O
+underscoring	O
+the	O
+importance	O
+of	O
+recognition	O
+and	O
+accurate	O
+diagnosis	O
+to	O
+ensure	O
+appropriate	O
+management	O
+.	O
+
+The	O
+temperate	O
+United	B-LOC
+States	I-LOC
+has	O
+experienced	O
+increasing	O
+incidence	B-EPI
+of	O
+mosquito	O
+-	O
+borne	O
+diseases	O
+.	O
+
+Recent	O
+studies	O
+conducted	O
+in	O
+Baltimore	B-LOC
+,	O
+MD	B-LOC
+have	O
+demonstrated	O
+a	O
+negative	O
+relationship	O
+between	O
+abundances	O
+of	O
+Aedes	O
+albopictus	O
+(	O
+Skuse	O
+)	O
+and	O
+Culex	O
+mosquitoes	O
+and	O
+mean	O
+neighborhood	O
+income	O
+level	O
+,	O
+but	O
+have	O
+not	O
+looked	O
+at	O
+the	O
+presence	O
+of	O
+pathogens	O
+.	O
+
+Mosquitoes	O
+collected	O
+from	O
+five	O
+socioeconomically	O
+variable	O
+neighborhoods	O
+were	O
+tested	O
+for	O
+infection	O
+by	O
+West	B-LOC
+Nile	I-LOC
+,	O
+chikungunya	O
+,	O
+and	O
+Zika	O
+viruses	O
+in	O
+2015	O
+and	O
+2016	O
+,	O
+and	O
+again	O
+from	O
+four	O
+of	O
+the	O
+neighborhoods	O
+in	O
+2017	O
+.	O
+
+Minimum	O
+infection	O
+rates	O
+of	O
+pooled	O
+samples	O
+were	O
+compared	O
+among	O
+neighborhoods	O
+for	O
+each	O
+year	O
+,	O
+as	O
+well	O
+as	O
+among	O
+individual	O
+blocks	O
+in	O
+2017	O
+.	O
+
+West	B-LOC
+Nile	I-LOC
+virus	O
+was	O
+detected	O
+in	O
+both	O
+Ae	O
+.	O
+
+albopictus	O
+and	O
+Culex	O
+pools	O
+from	O
+all	O
+neighborhoods	O
+sampled	O
+in	O
+2015	O
+and	O
+2017	O
+.	O
+
+No	O
+infected	O
+pools	O
+were	O
+detected	O
+in	O
+any	O
+year	O
+for	O
+chikungunya	O
+or	O
+Zika	O
+viruses	O
+,	O
+and	O
+none	O
+of	O
+the	O
+target	O
+viruses	O
+were	O
+detected	O
+in	O
+2016	O
+.	O
+
+Infection	O
+rates	O
+were	O
+consistently	O
+higher	O
+for	O
+Culex	O
+than	O
+for	O
+Ae	O
+.	O
+
+albopictus	O
+.	O
+
+Minimum	O
+infection	O
+rate	O
+was	O
+negatively	O
+associated	O
+with	O
+mean	O
+neighborhood	O
+income	O
+for	O
+both	O
+species	O
+in	O
+2015	O
+.	O
+
+Although	O
+earlier	O
+work	O
+has	O
+shown	O
+a	O
+positive	O
+association	O
+between	O
+block	O
+-	O
+level	O
+abandonment	O
+and	O
+mosquito	O
+abundance	O
+,	O
+no	O
+association	O
+was	O
+detected	O
+in	O
+this	O
+study	O
+.	O
+
+Still	O
+,	O
+we	O
+demonstrate	O
+that	O
+viral	O
+infection	O
+in	O
+mosquito	O
+pools	O
+can	O
+differ	O
+substantially	O
+across	O
+adjacent	O
+urban	O
+neighborhoods	O
+that	O
+vary	O
+by	O
+income	O
+.	O
+
+Though	O
+trap	O
+security	O
+and	O
+accessibility	O
+often	O
+inform	O
+city	O
+sampling	O
+locations	O
+,	O
+detecting	O
+and	O
+managing	O
+arboviral	O
+risk	O
+requires	O
+surveillance	O
+across	O
+neighborhoods	O
+that	O
+vary	O
+in	O
+socioeconomics	O
+,	O
+including	O
+lower	O
+income	O
+areas	O
+that	O
+may	O
+be	O
+less	O
+accessible	O
+and	O
+secure	O
+but	O
+have	O
+higher	O
+infection	O
+rates	O
+.	O
+
+Li	O
+-	O
+Fraumeni	O
+syndrome	O
+(	O
+LFS	O
+)	O
+is	O
+an	O
+inherited	O
+cancer	O
+syndrome	O
+,	O
+characterized	O
+by	O
+an	O
+early	O
+onset	O
+of	O
+various	O
+types	O
+of	O
+cancers	O
+.	O
+
+LFS	O
+is	O
+associated	O
+with	O
+a	O
+germline	O
+mutation	O
+in	O
+the	O
+TP53	O
+gene	O
+.	O
+
+The	O
+risk	O
+of	O
+developing	O
+skin	O
+cancer	O
+in	O
+patients	O
+with	O
+LFS	O
+is	O
+unknown	O
+.	O
+
+To	O
+evaluate	O
+the	O
+cumulative	O
+risk	O
+of	O
+skin	O
+cancer	O
+in	O
+patients	O
+with	O
+LFS	O
+and	O
+to	O
+compare	O
+this	O
+risk	O
+to	O
+the	O
+general	O
+Dutch	O
+population	O
+.	O
+
+In	O
+this	O
+retrospective	O
+cohort	O
+study	O
+,	O
+all	O
+proven	O
+TP53	O
+mutation	O
+carriers	O
+in	O
+the	O
+Netherlands	O
+Cancer	O
+Institute	O
+were	O
+included	O
+from	O
+their	O
+first	O
+visit	O
+to	O
+the	O
+Institute	O
+until	O
+June	O
+2017	O
+.	O
+
+Medical	O
+charts	O
+and	O
+pathology	O
+reviews	O
+cross	O
+-	O
+referenced	O
+with	O
+PALGA	O
+,	O
+the	O
+nationwide	O
+network	O
+and	O
+registry	O
+of	O
+histo-	O
+and	O
+cytopathology	O
+were	O
+used	O
+to	O
+identify	O
+incident	O
+skin	O
+cancers	O
+.	O
+
+Cumulative	O
+risks	O
+were	O
+calculated	O
+by	O
+Kaplan	O
+-	O
+Meier	O
+analysis	O
+.	O
+
+Seventy	B-STAT
+-	I-STAT
+one	I-STAT
+patients	I-STAT
+(	O
+59	O
+%	O
+female	O
+)	O
+from	O
+33	O
+families	O
+were	O
+included	O
+.	O
+
+Ten	O
+patients	O
+(	O
+14	O
+%	O
+)	O
+developed	O
+a	O
+total	O
+of	O
+19	O
+skin	O
+cancers	O
+at	O
+a	O
+median	O
+age	O
+of	O
+41	O
+(	O
+25	O
+-	O
+65	O
+)	O
+years	O
+.	O
+
+The	O
+cumulative	O
+risk	O
+of	O
+skin	O
+cancer	O
+is	O
+10.4	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+4.4	O
+-	O
+23.5	O
+%	O
+)	O
+at	O
+age	O
+40	B-STAT
+,	O
+25.2	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+12.3	O
+-	O
+47.6	O
+%	O
+)	O
+at	O
+age	O
+60	O
+,	O
+and	O
+a	O
+at	O
+age	O
+70	O
+this	O
+risk	O
+is	O
+44.6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+22.9	O
+-	O
+73.9	O
+%	O
+)	O
+.	O
+
+The	O
+cumulative	O
+risks	O
+of	O
+melanoma	O
+and	O
+basal	O
+cell	O
+carcinoma	O
+at	O
+age	O
+70	O
+are	O
+increased	O
+compared	O
+to	O
+the	O
+general	O
+Dutch	O
+population	O
+,	O
+namely	O
+12.6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+3.6	O
+-	O
+38.4	O
+%	O
+)	O
+and	O
+34.6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+15.4	O
+-	O
+66.2	O
+%	O
+)	O
+,	O
+respectively	O
+.	O
+
+Patients	O
+with	O
+LFS	O
+have	O
+an	O
+increased	O
+risk	O
+of	O
+developing	O
+skin	O
+cancer	O
+.	O
+
+A	O
+dermatological	O
+consultation	O
+may	O
+be	O
+considered	O
+at	O
+least	O
+once	O
+in	O
+individuals	O
+with	O
+LFS	O
+to	O
+raise	O
+awareness	O
+for	O
+skin	O
+cancer	O
+and	O
+inform	O
+about	O
+risk	O
+factors	O
+.	O
+
+Background	O
+Intestinal	O
+malrotation	O
+is	O
+a	O
+potentially	O
+life	O
+-	O
+threatening	O
+congenital	O
+anomaly	O
+due	O
+to	O
+the	O
+risk	O
+of	O
+developing	O
+midgut	O
+volvulus	O
+.	O
+
+The	O
+reported	O
+incidence	B-EPI
+is	O
+0.2%-1	B-STAT
+%	I-STAT
+and	O
+both	O
+apparently	O
+hereditary	O
+and	O
+sporadic	O
+cases	O
+have	O
+been	O
+reported	O
+.	O
+
+Intestinal	O
+malrotation	O
+is	O
+associated	O
+with	O
+a	O
+few	O
+syndromes	O
+with	O
+known	O
+genotype	O
+but	O
+the	O
+genetic	O
+contribution	O
+in	O
+isolated	O
+intestinal	O
+malrotation	O
+has	O
+not	O
+yet	O
+been	O
+reported	O
+.	O
+
+Rare	O
+copy	O
+number	O
+variants	O
+(	O
+CNVs	O
+)	O
+have	O
+been	O
+implicated	O
+in	O
+many	O
+congenital	O
+anomalies	O
+,	O
+and	O
+hence	O
+we	O
+sought	O
+to	O
+investigate	O
+the	O
+potential	O
+contribution	O
+of	O
+rare	O
+CNVs	O
+in	O
+intestinal	O
+malrotation	O
+.	O
+
+Methods	O
+Analysis	O
+of	O
+array	O
+comparative	O
+genomic	O
+hybridization	O
+(	O
+aCGH	O
+)	O
+data	O
+from	O
+47	O
+patients	O
+with	O
+symptomatic	O
+intestinal	O
+malrotation	O
+was	O
+performed	O
+.	O
+
+Results	O
+We	O
+identified	O
+six	O
+rare	O
+CNVs	O
+in	O
+five	O
+patients	O
+.	O
+
+Five	O
+CNVs	O
+involved	O
+syndrome	O
+loci	O
+:	O
+7q11.23	O
+microduplication	O
+,	O
+16p13.11	O
+microduplication	O
+,	O
+18q	O
+terminal	O
+deletion	O
+,	O
+HDAC8	O
+(	O
+Cornelia	O
+de	O
+Lange	O
+syndrome	O
+type	O
+5	O
+and	O
+FOXF1	O
+)	O
+as	O
+well	O
+as	O
+one	O
+intragenic	O
+deletion	O
+in	O
+GALNT14	O
+,	O
+not	O
+previously	O
+implicated	O
+in	O
+human	O
+disease	O
+.	O
+
+Conclusion	O
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+identified	O
+rare	O
+CNVs	O
+contributing	O
+pathogenic	O
+or	O
+potentially	O
+pathogenic	O
+alleles	O
+in	O
+five	O
+patients	O
+with	O
+syndromic	O
+intestinal	O
+malrotation	O
+,	O
+suggesting	O
+that	O
+CNV	O
+screening	O
+is	O
+indicated	O
+in	O
+intestinal	O
+malrotation	O
+with	O
+associated	O
+malformations	O
+or	O
+neurological	O
+involvements	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+identified	O
+intestinal	O
+malrotation	O
+in	O
+two	O
+known	O
+syndromes	O
+(	O
+Cornelia	O
+de	O
+Lange	O
+type	O
+5	O
+and	O
+18q	O
+terminal	O
+deletion	O
+syndrome	O
+)	O
+that	O
+has	O
+not	O
+previously	O
+been	O
+associated	O
+with	O
+gastrointestinal	O
+malformations	O
+.	O
+
+Since	O
+the	O
+discovery	O
+of	O
+human	O
+leukocyte	O
+antigens	O
+(	O
+HLAs	O
+)	O
+,	O
+the	O
+function	O
+of	O
+major	O
+histocompatibility	O
+complex	O
+(	O
+MHC	O
+)	O
+gene	O
+families	O
+in	O
+a	O
+wide	O
+range	O
+of	O
+diseases	O
+have	O
+been	O
+the	O
+subject	O
+of	O
+research	O
+for	O
+decades	O
+.	O
+
+In	O
+particular	O
+,	O
+the	O
+associations	O
+of	O
+autoimmune	O
+disorders	O
+to	O
+allelic	O
+variants	O
+and	O
+candidate	O
+genes	O
+encoding	O
+the	O
+MHC	O
+are	O
+well	O
+documented	O
+.	O
+
+However	O
+,	O
+despite	O
+decades	O
+of	O
+research	O
+,	O
+the	O
+knowledge	O
+of	O
+MHC	O
+associations	O
+with	O
+human	O
+disease	O
+susceptibility	O
+have	O
+been	O
+predominantly	O
+studied	O
+in	O
+European	O
+origin	O
+,	O
+with	O
+limited	O
+understanding	O
+in	O
+different	O
+populations	O
+and	O
+ethnic	O
+groups	O
+.	O
+
+This	O
+is	O
+particularly	O
+evident	O
+in	O
+countries	O
+and	O
+ethnic	O
+populations	O
+of	O
+the	B-LOC
+Arabian	I-LOC
+Peninsula	I-LOC
+.	O
+
+Human	O
+MHC	O
+haplotypes	O
+,	O
+and	O
+its	O
+association	O
+with	O
+diseases	O
+,	O
+of	O
+the	O
+variable	O
+ethnic	O
+groups	O
+of	O
+this	O
+region	O
+are	O
+poorly	O
+studied	O
+.	O
+
+This	O
+review	O
+compiled	O
+published	O
+manuscripts	O
+that	O
+have	O
+reported	O
+a	O
+list	O
+of	O
+autoimmune	O
+diseases	O
+(	O
+insulin	O
+-	O
+dependent	O
+diabetes	O
+mellitus	O
+,	O
+systemic	O
+lupus	O
+erythematosus	O
+,	O
+myasthenia	O
+gravis	O
+,	O
+rheumatoid	O
+arthritis	O
+,	O
+psoriasis	O
+vulgaris	O
+,	O
+and	O
+multiple	O
+sclerosis	O
+)	O
+associated	O
+with	O
+MHC	O
+class	O
+I	O
+and	O
+class	O
+II	O
+in	O
+the	O
+populations	O
+of	O
+the	B-LOC
+Arabian	I-LOC
+Peninsula	I-LOC
+,	O
+specifically	O
+Bahrain	B-LOC
+,	O
+Kuwait	B-LOC
+,	O
+Oman	B-LOC
+,	O
+Qatar	B-LOC
+,	O
+Saudi	B-LOC
+Arabia	I-LOC
+,	O
+the	B-LOC
+United	I-LOC
+Arab	I-LOC
+Emirates	I-LOC
+,	O
+and	O
+Yemen	B-LOC
+.	O
+
+Data	O
+available	O
+was	O
+compared	O
+with	O
+other	O
+three	O
+ethnic	O
+groups	O
+,	O
+namely	O
+Caucasians	O
+,	O
+Asians	O
+,	O
+and	O
+Africans	O
+.	O
+
+The	O
+limited	O
+data	O
+available	O
+in	O
+the	O
+public	O
+domain	O
+on	O
+the	O
+association	O
+between	O
+MHC	O
+gene	O
+and	O
+autoimmune	O
+diseases	O
+highlight	O
+the	O
+challenges	O
+in	O
+the	O
+Middle	B-LOC
+Eastern	I-LOC
+region	O
+.	O
+
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+disease	O
+(	O
+CMT	O
+)	O
+is	O
+a	O
+common	O
+inherited	O
+peripheral	O
+neuropathy	O
+affecting	O
+up	O
+to	O
+1	B-STAT
+in	I-STAT
+1214	I-STAT
+of	O
+the	O
+general	O
+population	O
+with	O
+more	O
+than	O
+60	O
+nuclear	O
+genes	O
+implicated	O
+in	O
+its	O
+pathogenesis	O
+.	O
+
+Traditional	O
+molecular	O
+diagnostic	O
+pathways	O
+based	O
+on	O
+relative	O
+prevalence	B-EPI
+and	O
+clinical	O
+phenotyping	O
+are	O
+limited	O
+by	O
+long	O
+turnaround	O
+time	O
+,	O
+population	O
+-	O
+specific	O
+prevalence	B-EPI
+of	O
+causative	O
+variants	O
+and	O
+inability	O
+to	O
+assess	O
+multiple	O
+co	O
+-	O
+existing	O
+variants	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+a	O
+CMT	O
+gene	O
+panel	O
+comprising	O
+27	O
+genes	O
+was	O
+used	O
+to	O
+uncover	O
+the	O
+pathogenic	O
+mutations	O
+in	O
+two	O
+index	O
+patients	O
+.	O
+
+The	O
+first	O
+patient	O
+is	O
+a	O
+15	O
+-	O
+year	O
+-	O
+old	O
+boy	O
+,	O
+born	O
+of	O
+consanguineous	O
+parents	O
+,	O
+who	O
+has	O
+had	O
+frequent	O
+trips	O
+and	O
+falls	O
+since	O
+infancy	O
+,	O
+and	O
+was	O
+later	O
+found	O
+to	O
+have	O
+inverted	O
+champagne	O
+bottle	O
+appearance	O
+of	O
+bilateral	O
+legs	O
+and	O
+foot	O
+drop	O
+.	O
+
+His	O
+elder	O
+sister	O
+is	O
+similarly	O
+affected	O
+.	O
+
+The	O
+second	O
+patient	O
+is	O
+a	O
+37	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+referred	O
+for	O
+pre	O
+-	O
+pregnancy	O
+genetic	O
+diagnosis	O
+.	O
+
+During	O
+early	O
+adulthood	O
+,	O
+she	O
+developed	O
+progressive	O
+lower	O
+limb	O
+weakness	O
+,	O
+difficulties	O
+in	O
+tip	O
+-	O
+toe	O
+walking	O
+and	O
+thinning	O
+of	O
+calf	O
+muscles	O
+.	O
+
+Both	O
+patients	O
+are	O
+clinically	O
+compatible	O
+with	O
+CMT	O
+,	O
+have	O
+undergone	O
+multiple	O
+genetic	O
+testings	O
+and	O
+have	O
+not	O
+previously	O
+received	O
+a	O
+definitive	O
+genetic	O
+diagnosis	O
+.	O
+
+Patients	O
+1	B-STAT
+and	I-STAT
+2	I-STAT
+were	O
+found	O
+to	O
+have	O
+pathogenic	O
+homozygous	O
+HSPB1	O
+:	O
+NM_001540	O
+:	O
+c.250G	O
+>	O
+A	O
+(	O
+p.	O
+G84R	O
+)	O
+variant	O
+and	O
+heterozygous	O
+GDAP1	O
+:	O
+NM_018972	O
+:	O
+c.358C	O
+>	O
+T	O
+(	O
+p.	O
+R120W	O
+)	O
+variant	O
+,	O
+respectively	O
+.	O
+
+Advantages	O
+and	O
+limitations	O
+of	O
+the	O
+current	O
+approach	O
+are	O
+discussed	O
+.	O
+
+Mutations	O
+in	O
+the	O
+COL4A5	O
+gene	O
+,	O
+located	O
+at	O
+Xq22	O
+,	O
+cause	O
+Alport	O
+syndrome	O
+(	O
+AS	O
+)	O
+,	O
+a	O
+nephritis	O
+characterized	O
+by	O
+progressive	O
+deterioration	O
+of	O
+the	O
+glomerular	O
+basement	O
+membrane	O
+and	O
+usually	O
+associated	O
+with	O
+progressive	O
+hearing	O
+loss	O
+.	O
+
+We	O
+have	O
+identified	O
+a	O
+novel	O
+mutation	O
+,	O
+L1649R	O
+,	O
+present	O
+in	O
+9	O
+of	O
+121	O
+independently	O
+ascertained	O
+families	O
+.	O
+
+Affected	O
+males	O
+shared	O
+the	O
+same	O
+haplotype	O
+of	O
+eight	O
+polymorphic	O
+markers	O
+tightly	O
+linked	O
+to	O
+COL4A5	O
+,	O
+indicating	O
+common	O
+ancestry	O
+.	O
+
+Genealogical	O
+studies	O
+place	O
+the	O
+birth	O
+of	O
+this	O
+ancestor	O
+>	O
+200	O
+years	O
+ago	O
+.	O
+
+The	O
+L1649R	O
+mutation	O
+is	O
+a	O
+relatively	O
+common	O
+cause	O
+of	O
+Alport	B-LOC
+syndrome	O
+in	O
+the	O
+western	O
+United	B-LOC
+States	I-LOC
+,	O
+in	O
+part	O
+because	O
+of	O
+the	O
+rapid	O
+growth	O
+and	O
+migratory	O
+expansion	O
+of	O
+mid	O
+-	O
+nineteenth	O
+-	O
+century	O
+pioneer	O
+populations	O
+carrying	O
+the	O
+gene	O
+.	O
+
+L1649R	O
+affects	O
+a	O
+highly	O
+conserved	O
+residue	O
+in	O
+the	O
+NC1	O
+domain	O
+,	O
+which	O
+is	O
+involved	O
+in	O
+key	O
+inter-	O
+and	O
+intramolecular	O
+interactions	O
+,	O
+but	O
+results	O
+in	O
+a	O
+relatively	O
+mild	O
+disease	O
+phenotype	O
+.	O
+
+Renal	O
+failure	O
+in	O
+an	O
+L1649R	O
+male	O
+typically	O
+occurs	B-EPI
+in	O
+the	O
+4th	O
+or	O
+5th	O
+decade	O
+and	O
+precedes	O
+the	O
+onset	O
+of	O
+significant	O
+hearing	O
+loss	O
+by	O
+approximately	O
+10	O
+years	O
+.	O
+
+Background	O
+To	O
+evaluate	O
+clinical	O
+,	O
+genetic	O
+,	O
+and	O
+radiologic	O
+features	O
+of	O
+our	O
+patients	O
+with	O
+muscle	O
+-	O
+eye	O
+-	O
+brain	O
+disease	O
+.	O
+
+Methods	O
+The	O
+data	O
+of	O
+patients	O
+who	O
+were	O
+diagnosed	O
+with	O
+muscle	O
+-	O
+eye	O
+-	O
+brain	O
+disease	O
+from	O
+a	O
+cohort	O
+of	O
+patients	O
+with	O
+congenital	O
+muscular	O
+dystrophy	O
+in	O
+the	O
+Division	O
+of	O
+Pediatric	O
+Neurology	O
+of	O
+Dokuz	O
+Eylül	O
+University	O
+School	O
+of	O
+Medicine	O
+and	O
+Gaziantep	O
+Children	O
+'s	O
+Hospital	O
+between	O
+2005	O
+and	O
+2013	O
+were	O
+analyzed	O
+retrospectively	O
+.	O
+
+Results	O
+From	O
+a	O
+cohort	O
+of	O
+34	O
+patients	O
+with	O
+congenital	O
+muscular	O
+dystrophy	O
+,	O
+12	O
+patients	O
+from	O
+10	O
+families	O
+were	O
+diagnosed	O
+with	O
+muscle	O
+-	O
+eye	O
+-	O
+brain	O
+disease	O
+.	O
+
+The	O
+mean	O
+age	O
+of	O
+the	O
+patients	O
+was	O
+9	O
+±	O
+5.5	O
+years	O
+(	O
+2	O
+-	O
+19	O
+years	O
+)	O
+.	O
+
+Mean	O
+serum	O
+creatine	O
+kinase	O
+value	O
+was	O
+2485.80	O
+±	O
+1308.54	O
+IU	O
+/	O
+L	O
+(	O
+700	O
+-	O
+4267	O
+IU	O
+/	O
+L	O
+)	O
+.	O
+
+All	O
+patients	O
+presented	O
+with	O
+muscular	O
+hypotonia	O
+at	O
+birth	O
+followed	O
+by	O
+varying	O
+degrees	O
+of	O
+spasticity	O
+and	O
+exaggerated	O
+deep	O
+tendon	O
+reflexes	O
+in	O
+later	O
+stages	O
+of	O
+life	O
+.	O
+
+Three	O
+patients	O
+were	O
+able	O
+to	O
+walk	O
+.	O
+
+The	O
+most	O
+common	O
+ophthalmologic	O
+and	O
+radiologic	O
+abnormalities	O
+were	O
+cataracts	O
+,	O
+retinal	O
+detachment	O
+,	O
+periventricular	O
+white	O
+matter	O
+abnormalities	O
+,	O
+ventriculomegaly	O
+,	O
+pontocerebellar	O
+hypoplasia	O
+,	O
+and	O
+multiple	O
+cerebellar	O
+cysts	O
+.	O
+
+All	O
+of	O
+the	O
+patients	O
+had	O
+mutations	O
+in	O
+the	O
+POMGNT1	O
+gene	O
+.	O
+
+The	O
+most	O
+common	O
+mutation	O
+detected	O
+in	O
+66	O
+%	O
+of	O
+patients	O
+was	O
+c.1814	O
+G	O
+>	O
+A	O
+(	O
+p.	O
+R605H	O
+)	O
+.	O
+
+Two	O
+novel	O
+mutations	O
+were	O
+identified	O
+.	O
+
+Conclusions	O
+We	O
+suggest	O
+that	O
+muscle	O
+-	O
+eye	O
+-	O
+brain	O
+disease	O
+is	O
+a	O
+relatively	O
+common	O
+muscular	O
+dystrophy	O
+in	O
+Turkey	B-LOC
+.	O
+
+It	O
+should	O
+be	O
+suspected	O
+in	O
+patients	O
+with	O
+muscular	O
+hypotonia	O
+,	O
+increased	O
+creatine	O
+kinase	O
+,	O
+and	O
+structural	O
+eye	O
+and	O
+brain	O
+abnormalities	O
+.	O
+
+The	O
+c.1814	O
+G	O
+>	O
+A	O
+mutation	O
+in	O
+exon	O
+21	O
+of	O
+the	O
+POMGNT1	O
+gene	O
+is	O
+apparently	O
+a	O
+common	O
+mutation	O
+in	O
+the	O
+Turkish	O
+population	O
+.	O
+
+Individuals	O
+with	O
+this	O
+mutation	O
+show	O
+classical	O
+features	O
+of	O
+muscle	O
+-	O
+eye	O
+-	O
+brain	O
+disease	O
+,	O
+but	O
+others	O
+may	O
+exhibit	O
+a	O
+milder	O
+phenotype	O
+and	O
+retain	O
+the	O
+ability	O
+to	O
+walk	O
+independently	O
+.	O
+
+Congenital	O
+muscular	O
+dystrophy	O
+patients	O
+from	O
+Turkey	B-LOC
+carrying	O
+the	O
+clinical	O
+and	O
+radiologic	O
+features	O
+of	O
+muscle	O
+-	O
+eye	O
+-	O
+brain	O
+disease	O
+should	O
+be	O
+evaluated	O
+for	O
+mutations	O
+in	O
+POMGNT1	O
+gene	O
+.	O
+
+Since	O
+its	O
+first	O
+clinical	O
+description	O
+(	O
+on	O
+his	O
+son	O
+)	O
+by	O
+William	O
+James	O
+West	O
+(	O
+1793	O
+-	O
+1848	O
+)	O
+in	O
+1841	O
+,	O
+and	O
+the	O
+definition	O
+of	O
+the	O
+classical	O
+triad	O
+of	O
+(	O
+1	O
+)	O
+infantile	O
+spasms	O
+;	O
+(	O
+2	O
+)	O
+hypsarrhythmia	O
+,	O
+and	O
+(	O
+3	O
+)	O
+developmental	O
+arrest	O
+or	O
+regression	O
+as	O
+	O
+West	O
+syndrome	O
+	O
+,	O
+new	O
+and	O
+relevant	O
+advances	O
+have	O
+been	O
+recorded	O
+in	O
+this	O
+uncommon	O
+disorder	O
+.	O
+
+New	O
+approaches	O
+include	O
+terminology	O
+of	O
+clinical	O
+spasms	O
+(	O
+e.g.	O
+,	O
+infantile	O
+(	O
+IS	O
+)	O
+vs.	O
+epileptic	O
+spasms	O
+(	O
+ES	O
+)	O
+)	O
+,	O
+variety	O
+of	O
+clinical	O
+and	O
+electroencephalographic	O
+(	O
+EEG	O
+)	O
+features	O
+(	O
+e.g.	O
+,	O
+typical	O
+ictal	O
+phenomena	O
+without	O
+EEG	O
+abnormalities	O
+)	O
+,	O
+burden	O
+of	O
+developmental	O
+delay	O
+,	O
+spectrum	O
+of	O
+associated	O
+genetic	O
+abnormalities	O
+,	O
+pathogenesis	O
+,	O
+treatment	O
+options	O
+,	O
+and	O
+related	O
+outcome	O
+and	O
+prognosis	O
+.	O
+
+Aside	O
+the	O
+classical	O
+manifestations	O
+,	O
+IS	O
+or	O
+ES	O
+may	O
+present	O
+with	O
+atypical	O
+electroclinical	O
+phenotypes	O
+(	O
+e.g.	O
+,	O
+subtle	O
+spasms	O
+;	O
+modified	O
+hypsarrhythmia	O
+)	O
+and	O
+may	O
+have	O
+their	O
+onset	O
+outside	O
+infancy	O
+.	O
+
+An	O
+increasing	O
+number	O
+of	O
+genes	O
+,	O
+proteins	O
+,	O
+and	O
+signaling	O
+pathways	O
+play	O
+crucial	O
+roles	O
+in	O
+the	O
+pathogenesis	O
+.	O
+
+This	O
+condition	O
+is	O
+currently	O
+regarded	O
+as	O
+a	O
+spectrum	O
+of	O
+disorders	O
+:	O
+the	O
+so	O
+-	O
+called	O
+infantile	O
+spasm	O
+syndrome	O
+(	O
+ISs	O
+)	O
+,	O
+in	O
+association	O
+with	O
+other	O
+causal	O
+factors	O
+,	O
+including	O
+structural	O
+,	O
+infectious	O
+,	O
+metabolic	O
+,	O
+syndromic	O
+,	O
+and	O
+immunologic	O
+events	O
+,	O
+all	O
+acting	O
+on	O
+a	O
+genetic	O
+predisposing	O
+background	O
+.	O
+
+Hormonal	O
+therapy	O
+and	O
+ketogenic	O
+diet	O
+are	O
+widely	O
+used	O
+also	O
+in	O
+combination	O
+with	O
+(	O
+classical	O
+and	O
+recent	O
+)	O
+pharmacological	O
+drugs	O
+.	O
+
+Biologically	O
+targeted	O
+and	O
+gene	O
+therapies	O
+are	O
+increasingly	O
+studied	O
+.	O
+
+The	O
+present	O
+narrative	O
+review	O
+searched	O
+in	O
+seven	O
+electronic	O
+databases	O
+(	O
+primary	O
+MeSH	O
+terms	O
+/	O
+keywords	O
+included	O
+West	O
+syndrome	O
+,	O
+infantile	O
+spasms	O
+and	O
+infantile	O
+spasms	O
+syndrome	O
+and	O
+were	O
+coupled	O
+to	O
+25	O
+secondary	O
+clinical	O
+,	O
+EEG	O
+,	O
+therapeutic	O
+,	O
+outcomes	O
+,	O
+and	O
+associated	O
+conditions	O
+terms	O
+)	O
+including	O
+MEDLINE	O
+,	O
+Embase	O
+,	O
+Cochrane	O
+Central	O
+,	O
+Web	O
+of	O
+Sciences	O
+,	O
+Pubmed	O
+,	O
+Scopus	O
+,	O
+and	O
+OMIM	O
+to	O
+highlight	O
+the	O
+past	O
+knowledge	O
+and	O
+more	O
+recent	O
+advances	O
+.	O
+
+The	O
+urea	O
+cycle	O
+is	O
+a	O
+series	O
+of	O
+metabolic	O
+reactions	O
+that	O
+convert	O
+ammonia	O
+into	O
+urea	O
+in	O
+order	O
+to	O
+eliminate	O
+it	O
+from	O
+the	O
+body	O
+.	O
+
+Urea	O
+cycle	O
+disorders	O
+are	O
+characterized	O
+by	O
+hyperammonemia	O
+,	O
+which	O
+can	O
+cause	O
+irreversible	O
+damages	O
+in	O
+central	O
+nervous	O
+system	O
+.	O
+
+We	O
+report	O
+a	O
+series	O
+of	O
+three	O
+newborns	O
+presenting	O
+irritability	O
+,	O
+poor	O
+feeding	O
+and	O
+tachypnea	O
+.	O
+
+Their	O
+first	O
+gas	O
+analysis	O
+revealed	O
+respiratory	O
+alkalosis	O
+.	O
+
+Hyperammonemia	O
+was	O
+confirmed	O
+,	O
+and	O
+three	O
+different	O
+enzymatic	O
+blocks	O
+in	O
+the	O
+urea	O
+cycle	O
+were	O
+diagnosed	O
+.	O
+
+Immediate	O
+treatment	O
+consisted	O
+in	O
+the	O
+removal	O
+of	O
+ammonia	O
+by	O
+reduction	O
+of	O
+the	O
+catabolic	O
+state	O
+,	O
+dietary	O
+adjustments	O
+,	O
+use	O
+of	O
+nitrogen	O
+scavenging	O
+agents	O
+and	O
+ultimately	O
+hemodiafiltration	O
+.	O
+
+Hyperammonemia	O
+is	O
+a	O
+medical	O
+emergency	O
+whose	O
+treatment	O
+should	O
+not	O
+be	O
+delayed	O
+.	O
+
+This	O
+report	O
+aims	O
+to	O
+highlight	O
+the	O
+importance	O
+of	O
+suspecting	O
+urea	O
+cycle	O
+disorders	O
+in	O
+newborns	O
+with	O
+aspecific	O
+signs	O
+of	O
+hyperammonemia	O
+and	O
+respiratory	O
+alkalosis	O
+,	O
+and	O
+to	O
+sum	O
+up	O
+the	O
+broad	O
+lines	O
+of	O
+hyperammonemia	O
+management	O
+.	O
+
+Purpose	O
+The	O
+eye	O
+and	O
+its	O
+adnexal	O
+structures	O
+can	O
+give	O
+rise	O
+to	O
+first	O
+or	O
+consecutive	O
+primary	O
+malignancies	O
+or	O
+to	O
+encounter	O
+metastasis	O
+.	O
+
+Our	O
+aim	O
+was	O
+to	O
+define	O
+the	O
+characteristics	O
+of	O
+the	O
+second	O
+primary	O
+neoplasms	O
+affecting	O
+the	O
+eye	O
+and	O
+its	O
+adnexa	O
+and	O
+find	O
+the	O
+risk	O
+modifying	O
+factors	O
+for	O
+them	O
+after	O
+malignancies	O
+elsewhere	O
+in	O
+the	O
+body	O
+.	O
+
+Methods	O
+We	O
+have	O
+queried	O
+the	O
+Surveillance	O
+,	O
+Epidemiology	O
+and	O
+End	O
+-	O
+Results	O
+	O
+SEER-9	O
+program	O
+of	O
+the	O
+National	O
+Cancer	O
+Institute	O
+for	O
+the	O
+malignancies	O
+of	O
+the	O
+eye	O
+and	O
+its	O
+adnexa	O
+that	O
+occurred	O
+between	O
+1973	O
+and	O
+2015	O
+.	O
+
+The	O
+malignancies	O
+were	O
+ordered	O
+chronologically	O
+according	O
+to	O
+their	O
+incidence	B-EPI
+:	O
+first	O
+or	O
+second	O
+primary	O
+malignancies	O
+.	O
+
+The	O
+tumors	O
+were	O
+classified	O
+according	O
+to	O
+ICD	O
+-	O
+O-3	O
+classification	O
+.	O
+
+Standardized	O
+incidence	B-EPI
+ratios	O
+(	O
+SIR	O
+)	O
+and	O
+survival	O
+probabilities	O
+were	O
+calculated	O
+for	O
+subgroups	O
+.	O
+
+Results	O
+Among	O
+3,578,950	O
+cancer	O
+patients	O
+,	O
+1203	O
+experienced	O
+a	O
+second	O
+malignancies	O
+of	O
+the	O
+eye	O
+and	O
+its	O
+adnexa	O
+.	O
+
+The	O
+first	O
+malignancy	O
+was	O
+diagnosed	O
+between	O
+50	O
+and	O
+69	O
+years	O
+of	O
+age	O
+in	O
+58.94	O
+%	O
+of	O
+them	O
+.	O
+
+The	O
+eyelid	O
+showed	O
+280	O
+events	O
+,	O
+while	O
+50	O
+in	O
+lacrimal	O
+gland	O
+,	O
+181	O
+in	O
+the	O
+orbit	O
+,	O
+21	O
+in	O
+the	O
+overlapping	O
+lesions	O
+,	O
+15	O
+in	O
+optic	O
+nerve	O
+,	O
+148	O
+in	O
+the	O
+conjunctiva	O
+,	O
+9	O
+in	O
+the	O
+cornea	O
+,	O
+6	O
+in	O
+the	O
+Retina	O
+,	O
+379	O
+in	O
+the	O
+choroid	O
+,	O
+and	O
+93	O
+in	O
+the	O
+ciliary	O
+body	O
+.	O
+
+The	O
+SIR	O
+of	O
+a	O
+second	O
+malignancy	O
+after	O
+a	O
+prior	O
+non	O
+-	O
+Hodgkin	O
+lymphoma	O
+was	O
+2.42	O
+,	O
+and	O
+in	O
+case	O
+of	O
+previous	O
+skin	O
+carcinomas	O
+it	O
+was	O
+3.02	O
+,	O
+melanoma	O
+of	O
+skin	O
+,	O
+and	O
+2.13	O
+and	O
+1.58	O
+in	O
+oral	O
+cavity	O
+/	O
+pharynx	O
+malignancies	O
+.	O
+
+The	O
+second	O
+ocular	O
+and	O
+adnexal	O
+neoplasms	O
+increased	O
+steadily	O
+over	O
+the	O
+5	O
+-	O
+year	O
+periods	O
+on	O
+contrary	O
+to	O
+first	O
+primary	O
+neoplasms	O
+.	O
+
+The	O
+survival	O
+of	O
+patients	O
+affected	O
+with	O
+first	O
+ocular	O
+and	O
+adnexal	O
+neoplasms	O
+was	O
+significantly	O
+higher	O
+than	O
+those	O
+with	O
+second	O
+ocular	O
+and	O
+adnexal	O
+neoplasms	O
+.	O
+
+On	O
+the	O
+other	O
+side	O
+,	O
+second	O
+primary	O
+ocular	O
+and	O
+adnexal	O
+tumors	O
+showed	O
+a	O
+better	O
+survival	O
+than	O
+second	O
+primary	O
+malignancies	O
+elsewhere	O
+.	O
+
+Conclusions	O
+The	O
+epidemiological	O
+differences	O
+between	O
+first	O
+and	O
+second	O
+ocular	O
+and	O
+adnexal	O
+primaries	O
+suggest	O
+different	O
+underlying	O
+mechanisms	O
+.	O
+
+Careful	O
+ocular	O
+examination	O
+should	O
+be	O
+integrated	O
+in	O
+the	O
+long	O
+-	O
+term	O
+follow	O
+-	O
+up	O
+plan	O
+of	O
+cancer	O
+patients	O
+.	O
+
+Special	O
+attention	O
+should	O
+be	O
+given	O
+to	O
+patients	O
+with	O
+non	O
+-	O
+Hodgkin	O
+'s	O
+lymphoma	O
+and	O
+melanoma	O
+as	O
+first	O
+primary	O
+.	O
+
+Background	O
+Primary	O
+immune	O
+deficiencies	O
+(	O
+PIDs	O
+)	O
+are	O
+a	O
+heterogeneous	O
+group	O
+of	O
+disorders	O
+resulting	O
+from	O
+defects	O
+in	O
+immune	O
+system	O
+.	O
+
+They	O
+lead	O
+to	O
+increased	O
+susceptibility	O
+to	O
+infections	O
+and	O
+immune	O
+dysregulation	O
+.	O
+
+The	O
+resulting	O
+chronic	O
+inflammation	O
+can	O
+induce	O
+long	O
+-	O
+term	O
+complications	O
+,	O
+including	O
+AA	O
+amyloidosis	O
+(	O
+AAA	O
+)	O
+.	O
+
+Objectives	O
+To	O
+present	O
+the	O
+French	O
+cases	O
+of	O
+PID	O
+-	O
+related	O
+AAA	O
+and	O
+perform	O
+a	O
+systematic	O
+literature	O
+review	O
+to	O
+determine	O
+its	O
+main	O
+features	O
+and	O
+predisposing	O
+factors	O
+.	O
+
+Methods	O
+A	O
+systematic	O
+literature	O
+review	O
+was	O
+performed	O
+by	O
+searching	O
+MEDLINE	O
+up	O
+until	O
+2019	O
+.	O
+
+New	O
+French	O
+cases	O
+were	O
+identified	O
+with	O
+the	O
+help	O
+of	O
+the	O
+Reference	O
+Center	O
+for	O
+Auto	O
+-	O
+Inflammatory	O
+Diseases	O
+and	O
+AA	O
+Amyloidosis	O
+and	O
+the	O
+Reference	O
+Center	O
+for	O
+Hereditary	O
+Immune	O
+Deficiencies	O
+.	O
+
+Results	O
+Forty	O
+patients	O
+were	O
+identified	O
+including	O
+2	O
+new	O
+French	O
+cases	O
+.	O
+
+PIDs	O
+were	O
+varied	O
+:	O
+immunoglobulin	O
+deficits	O
+(	O
+n	O
+=	O
+30	O
+)	O
+,	O
+chronic	O
+granulomatous	O
+disease	O
+(	O
+n	O
+=	O
+3	O
+)	O
+,	O
+hyper	O
+-	O
+IgM	O
+syndrome	O
+(	O
+n	O
+=	O
+3	O
+)	O
+,	O
+hereditary	O
+complete	O
+C4	O
+deficiency	O
+(	O
+n	O
+=	O
+1	O
+)	O
+,	O
+leucocyte	O
+adhesion	O
+deficiency	O
+type	O
+1	O
+(	O
+n	O
+=	O
+1	O
+)	O
+,	O
+hyper	O
+-	O
+IgE	O
+syndrome	O
+(	O
+n	O
+=	O
+1	O
+)	O
+,	O
+and	O
+Chediak	O
+-	O
+Higashi	O
+syndrome	O
+(	O
+n	O
+=	O
+1	O
+)	O
+.	O
+
+The	O
+mean	O
+age	O
+at	O
+PID	O
+diagnosis	O
+was	O
+22.2	O
+±	O
+16.02	O
+years	O
+.	O
+
+Renal	O
+involvement	O
+was	O
+the	O
+most	O
+common	O
+manifestation	O
+of	O
+AAA	O
+(	O
+80	O
+%	O
+)	O
+.	O
+
+Infections	O
+were	O
+extremely	O
+heterogeneous	O
+;	O
+bacterial	O
+infection	O
+with	O
+pulmonary	O
+involvement	O
+was	O
+the	O
+most	O
+frequent	O
+.	O
+
+Bronchiectasis	O
+was	O
+particularly	O
+common	O
+(	O
+52.5	O
+%	O
+)	O
+.	O
+
+The	O
+delay	O
+between	O
+the	O
+first	O
+symptoms	O
+of	O
+PID	O
+and	O
+AAA	O
+diagnosis	O
+was	O
+16.18	O
+±	O
+7	O
+years	O
+.	O
+
+Thirteen	O
+concomitant	O
+diagnoses	O
+were	O
+made	O
+.	O
+
+Twenty	O
+patients	O
+died	O
+during	O
+follow	O
+-	O
+up	O
+.	O
+
+Conclusion	O
+AAA	O
+is	O
+a	O
+rare	O
+life	O
+-	O
+threatening	O
+complication	O
+of	O
+PID	O
+,	O
+especially	O
+in	O
+cases	O
+of	O
+long	O
+diagnostic	O
+and	O
+therapeutic	O
+delays	O
+.	O
+
+Bronchiectasis	O
+should	O
+be	O
+considered	O
+as	O
+a	O
+warning	O
+sign	O
+of	O
+chronic	O
+inflammation	O
+and	O
+increased	O
+risk	O
+of	O
+AAA	O
+.	O
+
+Objectives	O
+Generally	O
+,	O
+neuropathies	O
+of	O
+peripheral	O
+nerves	O
+are	O
+a	O
+frequent	O
+condition	O
+(	O
+prevalence	B-EPI
+2	B-STAT
+-	O
+3	O
+%	O
+)	O
+and	O
+most	O
+frequently	O
+due	O
+to	O
+alcoholism	O
+,	O
+diabetes	O
+,	O
+renal	O
+insufficiency	O
+,	O
+malignancy	O
+,	O
+toxins	O
+,	O
+or	O
+drugs	O
+.	O
+
+However	O
+,	O
+the	O
+vast	O
+majority	O
+of	O
+neuropathies	O
+has	O
+orphan	O
+status	O
+.	O
+
+This	O
+review	O
+focuses	O
+on	O
+the	O
+etiology	O
+,	O
+frequency	O
+,	O
+diagnosis	O
+,	O
+and	O
+treatment	O
+of	O
+orphan	O
+neuropathies	O
+.	O
+
+Methods	O
+Literature	O
+reviewResults	O
+:	O
+Rareness	O
+of	O
+diseases	O
+is	O
+not	O
+uniformly	O
+defined	O
+but	O
+in	O
+the	O
+US	B-LOC
+an	O
+orphan	O
+disease	O
+is	O
+diagnosed	O
+if	O
+the	O
+prevalence	B-EPI
+is	O
+<	B-STAT
+1:200000	I-STAT
+,	O
+in	O
+Europe	B-LOC
+if	O
+<	O
+5:10000	O
+.	O
+
+Most	O
+acquired	O
+and	O
+hereditary	O
+neuropathies	O
+are	O
+orphan	O
+diseases	O
+.	O
+
+Often	O
+the	O
+causative	O
+variant	O
+has	O
+been	O
+reported	O
+only	O
+in	O
+a	O
+single	O
+patient	O
+or	O
+family	O
+,	O
+particularly	O
+the	O
+ones	O
+that	O
+are	O
+newly	O
+detected	O
+(	O
+e.g.	O
+
+SEPT9	O
+,	O
+SORD	O
+)	O
+.	O
+
+Among	O
+the	O
+complex	O
+neuropathies	O
+(	O
+hereditary	O
+multisystem	O
+disorders	O
+with	O
+concomitant	O
+neuropathies	O
+)	O
+orphan	O
+forms	O
+have	O
+been	O
+reported	O
+among	O
+mitochondrial	O
+disorders	O
+(	O
+e.g.	O
+
+NARP	O
+,	O
+MNGIE	O
+,	O
+SANDO	O
+)	O
+,	O
+spinocerebellar	O
+ataxias	O
+(	O
+e.g.	O
+
+TMEM240	B-LOC
+)	O
+,	O
+hereditary	O
+spastic	O
+paraplegias	O
+(	O
+e.g	O
+UBAP1	O
+)	O
+,	O
+lysosomal	O
+storage	O
+disease	O
+(	O
+e.g.	O
+
+Schindler	O
+disease	O
+)	O
+,	O
+peroxisomal	O
+disorders	O
+,	O
+porphyrias	O
+,	O
+and	O
+other	O
+types	O
+(	O
+e.g.	O
+
+giant	O
+axonal	O
+neuropathy	O
+,	O
+Tangier	O
+disease	O
+)	O
+.	O
+
+Orphan	O
+acquired	O
+neuropathies	O
+include	O
+the	O
+metabolic	O
+neuropathies	O
+(	O
+e.g.	O
+
+vitamin	O
+-	O
+B1	O
+,	O
+folic	O
+acid	O
+)	O
+,	O
+toxic	O
+neuropathies	O
+(	O
+e.g.	O
+
+copper	O
+,	O
+lithium	O
+,	O
+lead	O
+,	O
+arsenic	O
+,	O
+thallium	O
+,	O
+mercury	O
+)	O
+,	O
+infectious	O
+neuropathies	O
+,	O
+immune	O
+-	O
+mediated	O
+(	O
+e.g.	O
+
+Bruns	O
+-	O
+Garland	O
+syndrome	O
+)	O
+,	O
+and	O
+neoplastic	O
+/	O
+paraneoplastic	O
+neuropathies	O
+.	O
+
+Conclusions	O
+Though	O
+orphan	O
+neuropathies	O
+are	O
+rare	O
+per	O
+definition	O
+they	O
+constitute	O
+the	O
+majority	O
+of	O
+neuropathies	O
+and	O
+should	O
+be	O
+considered	O
+as	O
+some	O
+of	O
+them	O
+are	O
+easy	O
+to	O
+identify	O
+and	O
+potentially	O
+treatable	O
+,	O
+as	O
+clarification	O
+of	O
+the	O
+underlying	O
+cause	O
+may	O
+contribute	O
+to	O
+the	O
+knowledge	O
+about	O
+etiology	O
+and	O
+pathophysiology	O
+of	O
+these	O
+conditions	O
+,	O
+and	O
+as	O
+the	O
+true	O
+prevalence	B-EPI
+may	O
+become	O
+obvious	O
+only	O
+if	O
+all	O
+ever	O
+diagnosed	O
+cases	O
+are	O
+reported	O
+.	O
+
+On	O
+3	O
+August	O
+1900	O
+,	O
+bubonic	O
+plague	O
+(	O
+Yersinia	O
+pestis	O
+)	O
+broke	O
+out	O
+in	O
+Glasgow	B-LOC
+for	O
+the	O
+first	O
+time	O
+during	O
+the	O
+Third	O
+Pandemic	O
+.	O
+
+The	O
+local	O
+sanitary	O
+authorities	O
+rigorously	O
+tracked	O
+the	O
+spread	O
+of	O
+the	O
+disease	O
+and	O
+they	O
+found	O
+that	O
+nearly	O
+all	O
+of	O
+the	O
+35	O
+cases	O
+could	O
+be	O
+linked	O
+by	O
+contact	O
+with	O
+a	O
+previous	O
+case	O
+.	O
+
+Despite	O
+trapping	O
+hundreds	O
+of	O
+rats	O
+in	O
+the	O
+area	O
+,	O
+there	O
+was	O
+no	O
+evidence	O
+of	O
+a	O
+rat	O
+epizootic	O
+and	O
+the	O
+investigators	O
+speculated	O
+that	O
+the	O
+outbreak	O
+could	O
+be	O
+due	O
+to	O
+human	O
+-	O
+to	O
+-	O
+human	O
+transmission	O
+of	O
+bubonic	O
+plague	O
+.	O
+
+Here	O
+we	O
+use	O
+a	O
+likelihood	O
+-	O
+based	O
+method	O
+to	O
+reconstruct	O
+transmission	O
+trees	O
+for	O
+the	O
+outbreak	O
+.	O
+
+From	O
+the	O
+description	O
+of	O
+the	O
+outbreak	O
+and	O
+the	O
+reconstructed	O
+trees	O
+,	O
+we	O
+infer	O
+several	O
+epidemiological	O
+parameters	O
+.	O
+
+We	O
+found	O
+that	O
+the	O
+estimated	O
+mean	O
+serial	O
+interval	O
+was	O
+7.4	O
+-	O
+9.2	O
+days	O
+and	O
+the	O
+mean	O
+effective	O
+reproduction	O
+number	O
+dropped	O
+below	O
+1	O
+after	O
+implementation	O
+of	O
+control	O
+measures	O
+.	O
+
+We	O
+also	O
+found	O
+a	O
+high	O
+rate	O
+of	O
+secondary	O
+transmissions	O
+within	O
+households	O
+and	O
+observations	O
+of	O
+transmissions	O
+from	O
+individuals	O
+who	O
+were	O
+not	O
+terminally	O
+septicaemic	O
+.	O
+
+Our	O
+results	O
+provide	O
+important	O
+insights	O
+into	O
+the	O
+epidemiology	O
+of	O
+a	O
+bubonic	O
+plague	O
+outbreak	O
+during	O
+the	O
+Third	O
+Pandemic	O
+in	O
+Europe	B-LOC
+.	O
+
+Aim	O
+To	O
+assess	O
+the	O
+prevalence	B-EPI
+of	O
+persistent	O
+lipid	O
+abnormalities	O
+in	O
+statin	O
+-	O
+treated	O
+patients	O
+with	O
+diabetes	O
+with	O
+and	O
+without	O
+the	O
+metabolic	O
+syndrome	O
+.	O
+
+Methods	O
+This	O
+was	O
+a	O
+cross	O
+-	O
+sectional	O
+study	O
+of	O
+22,063	O
+statin	O
+-	O
+treated	O
+outpatients	O
+consecutively	O
+recruited	O
+by	O
+clinicians	O
+in	O
+Canada	B-LOC
+and	O
+11	O
+European	O
+countries	O
+.	O
+
+Patient	O
+cardiovascular	O
+risk	O
+factors	O
+,	O
+risk	O
+level	O
+,	O
+lipid	O
+measurements	O
+and	O
+lipid	O
+-	O
+modifying	O
+medication	O
+regimens	O
+were	O
+recorded	O
+.	O
+
+Results	O
+Of	O
+the	O
+20,129	O
+subjects	O
+who	O
+had	O
+documented	O
+diabetes	O
+and/or	O
+metabolic	O
+syndrome	O
+status	O
+,	O
+41	O
+%	O
+had	O
+diabetes	O
+(	O
+of	O
+whom	O
+86.8	O
+%	O
+also	O
+had	O
+the	O
+metabolic	O
+syndrome	O
+)	O
+.	O
+
+Of	O
+those	O
+with	O
+diabetes	O
+,	O
+48.1	O
+%	O
+were	O
+not	O
+at	O
+total	O
+cholesterol	O
+target	O
+compared	O
+with	O
+58	O
+%	O
+of	O
+those	O
+without	O
+diabetes	O
+.	O
+
+Amongst	O
+those	O
+with	O
+diabetes	O
+,	O
+41.6	O
+and	O
+41.3	O
+%	O
+of	O
+those	O
+with	O
+and	O
+without	O
+the	O
+metabolic	O
+syndrome	O
+,	O
+respectively	O
+,	O
+were	O
+not	O
+at	O
+their	O
+LDL	O
+cholesterol	O
+goal	O
+relative	B-STAT
+to	O
+54.2	O
+%	O
+of	O
+those	O
+with	O
+metabolic	O
+syndrome	O
+and	O
+without	O
+diabetes	O
+,	O
+and	O
+52	O
+%	O
+of	O
+those	O
+with	O
+neither	O
+condition	O
+.	O
+
+Twenty	B-STAT
+per	I-STAT
+cent	I-STAT
+of	I-STAT
+people	O
+with	O
+diabetes	O
+but	O
+without	O
+the	O
+metabolic	O
+syndrome	O
+were	O
+not	O
+at	O
+the	O
+optimal	O
+HDL	O
+cholesterol	O
+level	O
+compared	O
+with	O
+9	O
+%	O
+of	O
+those	O
+with	O
+neither	O
+condition	O
+.	O
+
+Of	O
+people	O
+with	O
+diabetes	O
+and	O
+the	O
+metabolic	O
+syndrome	O
+,	O
+49.9	O
+%	O
+were	O
+not	O
+at	O
+optimal	O
+triglyceride	O
+level	O
+relative	B-STAT
+to	O
+13.5	O
+%	O
+of	O
+people	O
+with	O
+neither	O
+diabetes	O
+nor	O
+the	O
+metabolic	O
+syndrome	O
+.	O
+
+Simvastatin	O
+was	O
+the	O
+most	O
+commonly	O
+prescribed	O
+statin	O
+(	O
+>	O
+45	O
+%	O
+)	O
+and	O
+the	O
+most	O
+common	O
+statin	O
+potency	O
+was	O
+20	O
+-	O
+40	O
+mg	O
+/	O
+day	O
+(	O
+simvastatin	O
+equivalent	O
+)	O
+.	O
+
+Approximately	O
+14	O
+%	O
+of	O
+patients	O
+were	O
+taking	O
+ezetimibe	O
+alone	O
+or	O
+in	O
+combination	O
+with	O
+a	O
+statin	O
+.	O
+
+Conclusions	O
+Despite	O
+evidence	O
+supporting	O
+the	O
+benefits	O
+of	O
+lipid	O
+modification	O
+and	O
+international	O
+guideline	O
+recommendations	O
+,	O
+statin	O
+-	O
+treated	O
+patients	O
+with	O
+diabetes	O
+had	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+persistent	O
+lipid	O
+abnormalities	O
+.	O
+
+There	O
+is	O
+frequently	O
+room	O
+to	O
+optimize	O
+therapy	O
+through	O
+statin	O
+dose	O
+up	O
+-	O
+titration	O
+and/or	O
+addition	O
+of	O
+other	O
+lipid	O
+-	O
+modifying	O
+therapies	O
+.	O
+
+Osteogenesis	O
+imperfecta	O
+describes	O
+a	O
+group	O
+of	O
+genetic	O
+disorders	O
+that	O
+result	O
+from	O
+a	O
+defect	O
+in	O
+collagen	O
+type	O
+I	O
+and	O
+range	O
+in	O
+severity	O
+from	O
+a	O
+subtle	O
+increase	O
+in	O
+fracture	O
+frequency	O
+to	O
+death	O
+in	O
+the	O
+perinatal	O
+period	O
+.	O
+
+Osteogenesis	O
+imperfecta	O
+is	O
+mostly	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+COL1A1	O
+(	O
+17q21.33	O
+)	O
+and	O
+COL1A2	O
+(	O
+7q21.3	O
+)	O
+genes	O
+.	O
+
+There	O
+have	O
+only	O
+been	O
+a	O
+few	O
+case	O
+reports	O
+of	O
+implant	O
+-	O
+prosthetic	O
+treatment	O
+for	O
+patients	O
+with	O
+osteogenesis	O
+imperfecta	O
+.	O
+
+These	O
+reports	O
+indicated	O
+that	O
+implants	O
+and	O
+augmentation	O
+procedures	O
+can	O
+be	O
+implemented	O
+in	O
+such	O
+patients	O
+.	O
+
+However	O
+,	O
+for	O
+patients	O
+receiving	O
+additional	O
+antiresorptive	O
+therapy	O
+,	O
+cautious	O
+approaches	O
+should	O
+be	O
+chosen	O
+and	O
+the	O
+risk	O
+of	O
+drug	O
+-	O
+associated	O
+osteonecrosis	O
+should	O
+be	O
+considered	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+article	O
+is	O
+to	O
+report	O
+on	O
+the	O
+implant	O
+-	O
+prosthetic	O
+treatment	O
+of	O
+a	O
+patient	O
+with	O
+type	O
+I	O
+osteogenesis	O
+imperfecta	O
+.	O
+
+Microcephalic	O
+osteodysplastic	O
+primordial	O
+dwarfism	O
+type	O
+II	O
+(	O
+OMIM	O
+210720	O
+)	O
+is	O
+a	O
+rare	O
+autosomal	O
+recessive	O
+condition	O
+frequently	O
+associated	O
+with	O
+early	O
+-	O
+onset	O
+cerebrovascular	O
+disease	O
+.	O
+
+Presymptomatic	O
+detection	O
+and	O
+intervention	O
+could	O
+prevent	O
+the	O
+adverse	O
+consequences	O
+associated	O
+with	O
+this	O
+.	O
+
+We	O
+reviewed	O
+published	O
+cases	O
+of	O
+microcephalic	O
+osteodysplastic	O
+primordial	O
+dwarfism	O
+type	O
+II	O
+to	O
+ascertain	O
+prevalence	B-EPI
+and	O
+characteristics	O
+of	O
+cerebrovascular	O
+disease	O
+and	O
+use	O
+these	O
+data	O
+to	O
+propose	O
+an	O
+evidence	O
+-	O
+based	O
+approach	O
+to	O
+cerebrovascular	O
+screening	O
+.	O
+
+Of	O
+147	O
+cases	O
+identified	O
+,	O
+47	O
+had	O
+cerebrovascular	O
+disease	O
+(	O
+32	O
+%	O
+)	O
+,	O
+including	O
+occlusive	O
+arteriopathy	O
+(	O
+including	O
+moyamoya	O
+)	O
+and	O
+cerebral	O
+aneurysmal	O
+disease	O
+.	O
+
+Occlusive	O
+disease	O
+occurred	O
+in	O
+younger	O
+individuals	O
+,	O
+and	O
+progression	O
+can	O
+be	O
+both	O
+rapid	O
+and	O
+clinically	O
+silent	O
+.	O
+
+A	O
+reasonable	O
+screening	O
+approach	O
+would	O
+be	O
+magnetic	O
+resonance	O
+imaging	O
+and	O
+angiography	O
+of	O
+the	O
+cervical	O
+and	O
+intracranial	O
+circulation	O
+at	O
+diagnosis	O
+,	O
+repeated	O
+at	O
+yearly	O
+intervals	O
+until	O
+10	O
+years	O
+,	O
+and	O
+every	O
+2	O
+years	O
+thereafter	O
+,	O
+unless	O
+clinical	O
+concerns	O
+occur	O
+earlier	O
+.	O
+
+At	O
+present	O
+it	O
+would	O
+appear	O
+that	O
+this	O
+needs	O
+to	O
+be	O
+life	O
+-	O
+long	O
+.	O
+
+Families	O
+and	O
+professionals	O
+should	O
+be	O
+alerted	O
+to	O
+the	O
+potential	O
+significance	O
+of	O
+neurologic	O
+symptoms	O
+and	O
+measures	O
+should	O
+be	O
+taken	O
+to	O
+maintain	O
+good	O
+vascular	O
+health	O
+in	O
+affected	O
+individuals	O
+.	O
+
+Background	O
+Retroviruses	O
+of	O
+human	O
+T	O
+-	O
+lymphotropic	O
+viruses	O
+(	O
+HTLV-1	O
+and	O
+HTLV-2	O
+)	O
+have	O
+been	O
+demonstrated	O
+to	O
+be	O
+endemic	O
+in	O
+the	O
+north	O
+-	O
+eastern	O
+region	O
+of	O
+Iran	B-LOC
+.	O
+
+This	O
+study	O
+was	O
+aimed	O
+to	O
+determine	O
+the	O
+HTLV-1	O
+and	O
+HTLV-2	O
+prevalence	B-EPI
+among	O
+healthy	O
+individuals	O
+in	O
+Neyshabur	B-LOC
+City	I-LOC
+during	O
+2010	O
+-	O
+2014	O
+.	O
+
+Methods	O
+A	O
+total	O
+of	O
+8054	O
+blood	O
+samples	O
+were	O
+collected	O
+from	O
+healthy	O
+participants	O
+in	O
+Neyshabur	B-LOC
+,	O
+North	B-LOC
+-	I-LOC
+Eastern	I-LOC
+Iran	B-LOC
+.	O
+
+The	O
+blood	O
+samples	O
+were	O
+screened	O
+for	O
+the	O
+presence	O
+of	O
+specific	O
+antibodies	O
+against	O
+HTLV-1	O
+and	O
+HTLV-2	O
+by	O
+using	O
+ELISA	O
+according	O
+to	O
+the	O
+manufacturer	O
+'s	O
+instructions	O
+.	O
+
+Results	O
+The	O
+overall	O
+seropositivity	O
+rate	O
+for	O
+HTLV-1	O
+and	O
+HTLV-2	O
+was	O
+found	O
+to	O
+be	O
+6.55	O
+%	O
+(	O
+528	O
+out	O
+of	O
+8054	O
+)	O
+among	O
+participants	O
+.	O
+
+Conclusion	O
+Both	O
+HTLV-1	O
+and	O
+HTLV-2	O
+were	O
+demonstrated	O
+to	O
+be	O
+at	O
+a	O
+high	O
+rate	O
+in	O
+healthy	O
+individuals	O
+.	O
+
+However	O
+,	O
+a	O
+smaller	O
+number	O
+of	O
+asymptomatic	O
+carriers	O
+were	O
+found	O
+in	O
+this	O
+study	O
+,	O
+as	O
+compared	O
+to	O
+those	O
+identified	O
+in	O
+previous	O
+investigations	O
+in	O
+the	O
+city	O
+.	O
+
+The	O
+periampullary	O
+neuroendocrine	O
+tumour	O
+is	O
+an	O
+infrequently	O
+occurring	O
+tumour	O
+.	O
+
+Its	O
+prevalence	B-EPI
+among	O
+gastrointestinal	O
+neuroendocrine	O
+neoplasms	O
+is	O
+less	B-STAT
+than	I-STAT
+0.3	I-STAT
+%	I-STAT
+,	O
+and	O
+less	B-STAT
+than	O
+2	O
+%	O
+out	O
+of	O
+periampullary	O
+tumours	O
+.	O
+
+These	O
+neoplasms	O
+have	O
+relatively	O
+poor	O
+prognosis	O
+.	O
+
+Jaundice	O
+and	O
+pain	O
+in	O
+the	O
+abdomen	O
+are	O
+the	O
+early	O
+and	O
+most	O
+commonly	O
+occurring	O
+symptoms	O
+with	O
+weight	O
+loss	O
+being	O
+a	O
+late	O
+event	O
+.	O
+
+The	O
+carcinoid	O
+syndrome	O
+presents	O
+infrequently	O
+in	O
+periampullary	O
+neuroendocrine	O
+tumour	O
+and	O
+happens	O
+only	O
+if	O
+hepatic	O
+metastasis	O
+occurs	B-EPI
+.	O
+
+In	O
+this	O
+scenario	O
+,	O
+histopathology	O
+plays	O
+a	O
+paramount	O
+role	O
+in	O
+the	O
+diagnosis	O
+.	O
+
+Specific	O
+immunohistochemical	O
+staining	O
+is	O
+used	O
+for	O
+diagnosis	O
+while	O
+the	O
+treatment	O
+options	O
+are	O
+local	O
+excision	O
+,	O
+endoscopic	O
+excision	O
+and	O
+pancreaticoduodenectomy	O
+.	O
+
+Here	O
+is	O
+a	O
+case	O
+report	O
+of	O
+a	O
+42	O
+-	O
+year	O
+-	O
+old	O
+patient	O
+who	O
+presented	O
+with	O
+complaint	O
+of	O
+obstructive	O
+jaundice	O
+for	O
+one	O
+month	O
+.	O
+
+Periampullary	O
+carcinoid	O
+tumour	O
+was	O
+diagnosed	O
+on	O
+biopsy	O
+,	O
+and	O
+she	O
+underwent	O
+Pancreaticoduodenectomy	O
+as	O
+treatment	O
+.	O
+
+Literature	O
+shows	O
+that	O
+there	O
+is	O
+poor	O
+precision	O
+of	O
+preoperative	O
+and	O
+intraoperative	O
+lymph	O
+node	O
+metastatic	O
+involvement	O
+regardless	O
+of	O
+the	O
+size	O
+of	O
+the	O
+tumour	O
+.	O
+
+Hence	O
+,	O
+radical	O
+resection	O
+must	O
+be	O
+considered	O
+the	O
+standard	O
+approach	O
+.	O
+
+Mayer	O
+Rokitansky	O
+Kuster	O
+Hauser	O
+(	O
+MRKH	O
+)	O
+syndrome	O
+is	O
+a	O
+congenital	O
+disorder	O
+involving	O
+reproductive	O
+,	O
+genitourinary	O
+,	O
+bone	O
+,	O
+and	O
+cardiac	O
+malformation	O
+.	O
+
+The	O
+incidence	B-EPI
+is	O
+1	B-STAT
+in	I-STAT
+4000	I-STAT
+-	O
+5000	O
+females	O
+livebirths	O
+.	O
+
+The	O
+phenotype	O
+is	O
+female	O
+46	O
+XX	O
+karyotype	O
+,	O
+normal	O
+secondary	O
+sexual	O
+characteristics	O
+,	O
+and	O
+normal	O
+functional	O
+ovaries	O
+.	O
+
+The	O
+occurrence	B-EPI
+of	O
+leiomyoma	O
+in	O
+uterine	O
+remnant	O
+in	O
+MRKH	O
+syndrome	O
+is	O
+a	O
+very	O
+rare	O
+case	O
+,	O
+even	O
+though	O
+several	O
+cases	O
+have	O
+been	O
+reported	O
+.	O
+
+The	O
+diagnosis	O
+and	O
+management	O
+approach	O
+,	O
+in	O
+this	O
+case	O
+,	O
+is	O
+quite	O
+challenging	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+a	O
+38	O
+years	O
+old	O
+female	O
+who	O
+represents	O
+multiple	O
+leiomyomas	O
+on	O
+the	O
+rudimentary	O
+uterus	O
+,	O
+then	O
+we	O
+did	O
+laparoscopic	O
+removal	O
+of	O
+the	O
+fibroids	O
+and	O
+adjacent	O
+rudimentary	O
+uterus	O
+.	O
+
+Transient	O
+global	O
+amnesia	O
+(	O
+TGA	O
+)	O
+is	O
+a	O
+neurological	O
+syndrome	O
+with	O
+rather	O
+distinctive	O
+brain	O
+MRI	O
+features	O
+,	O
+namely	O
+hyperintense	O
+lesion	O
+in	O
+hippocampus	O
+on	O
+diffusion	O
+-	O
+weighted	O
+imaging	O
+(	O
+DWI	O
+)	O
+and	O
+fluid	O
+-	O
+attenuated	O
+inversion	O
+recovery	O
+(	O
+FLAIR	O
+)	O
+sequences	O
+.	O
+
+Post	O
+-	O
+traumatic	O
+amnesia	O
+is	O
+another	O
+amnestic	O
+syndrome	O
+which	O
+can	O
+also	O
+show	O
+hyperintense	O
+lesions	O
+in	O
+brain	O
+MRI	O
+due	O
+to	O
+cytotoxic	O
+oedema	O
+caused	O
+by	O
+traumatic	O
+brain	O
+injury	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+patient	O
+with	O
+post	O
+-	O
+traumatic	O
+amnesia	O
+with	O
+a	O
+brain	O
+MRI	O
+image	O
+mimic	O
+of	O
+TGA	O
+.	O
+
+Objectives	O
+West	B-LOC
+Nile	I-LOC
+virus	O
+(	O
+WNV	O
+)	O
+is	O
+a	O
+re	O
+-	O
+emerging	O
+mosquito	O
+-	O
+borne	O
+viral	O
+infection	O
+.	O
+
+This	O
+study	O
+investigated	O
+the	O
+pooled	B-EPI
+prevalence	I-EPI
+pattern	O
+and	O
+risk	O
+factors	O
+of	O
+WNV	O
+infection	O
+among	O
+humans	O
+and	O
+animals	O
+in	O
+Nigeria	B-LOC
+.	O
+
+Methods	O
+A	O
+systematic	O
+review	O
+was	O
+conducted	O
+of	O
+eligible	O
+studies	O
+published	O
+in	O
+PubMed	O
+,	O
+Scopus	O
+,	O
+Google	O
+Scholar	O
+,	O
+and	O
+Web	O
+of	O
+Science	O
+from	O
+January	O
+1	O
+,	O
+1950	O
+to	O
+August	O
+30	O
+,	O
+2020	O
+.	O
+
+Peer	O
+-	O
+reviewed	O
+cross	O
+-	O
+sectional	O
+studies	O
+describing	O
+WNV	O
+infections	O
+in	O
+humans	O
+and	O
+animals	O
+were	O
+systematically	O
+reviewed	O
+.	O
+
+Heterogeneity	O
+was	O
+assessed	O
+using	O
+the	O
+Cochrane	O
+Q	O
+statistic	O
+.	O
+
+Results	O
+Eighteen	O
+out	O
+of	O
+432	O
+available	O
+search	O
+output	O
+were	O
+eligible	O
+and	O
+included	O
+for	O
+this	O
+study	O
+.	O
+
+Of	O
+which	O
+13	O
+and	O
+5	O
+were	O
+WNV	O
+studies	O
+on	O
+humans	O
+and	O
+animals	O
+,	O
+respectively	O
+.	O
+
+Although	O
+61.5	O
+%	O
+of	O
+the	O
+human	O
+studies	O
+had	O
+a	O
+low	O
+risk	O
+of	O
+bias	O
+,	O
+they	O
+all	O
+had	O
+high	O
+heterogeneity	O
+.	O
+
+The	O
+South	B-LOC
+West	I-LOC
+geopolitical	O
+zone	O
+of	O
+Nigeria	B-LOC
+had	O
+the	O
+highest	O
+pooled	B-EPI
+prevalence	I-EPI
+of	O
+anti	O
+-	O
+WNV	O
+immunoglobulin	O
+M	O
+(	O
+IgM	O
+;	O
+7.8	O
+%	O
+in	O
+humans	O
+)	O
+.	O
+
+The	O
+pooled	O
+seroprevalence	O
+of	O
+anti	O
+-	O
+WNV	O
+IgM	O
+and	O
+immunoglobulin	O
+G	O
+(	O
+IgG	O
+)	O
+was	O
+7.1	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+5.9	O
+to	O
+8.3	O
+)	O
+and	O
+76.5	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+74.0	O
+to	O
+78.8	O
+)	O
+,	O
+respectively	O
+.	O
+
+The	O
+WNV	O
+RNA	O
+prevalence	B-EPI
+was	O
+1.9	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+1.4	O
+to	O
+2.9	O
+)	O
+,	O
+while	O
+14.3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+12.9	O
+to	O
+15.8	O
+)	O
+had	O
+WNV	O
+-	O
+neutralizing	O
+antibodies	O
+.	O
+
+In	O
+animals	O
+,	O
+the	O
+pooled	O
+seroprevalence	O
+of	O
+anti	O
+-	O
+WNV	O
+IgM	O
+and	O
+IgG	O
+was	O
+90.3	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+84.3	O
+to	O
+94.6	O
+)	O
+and	O
+3.5	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+1.9	O
+to	O
+5.8	O
+)	O
+,	O
+respectively	O
+,	O
+while	O
+20.0	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+12.9	O
+to	O
+21.4	O
+)	O
+had	O
+WNV	O
+-	O
+neutralizing	O
+antibodies	O
+.	O
+
+Age	O
+(	O
+odds	O
+ratio	O
+[	O
+OR	O
+]	O
+,	O
+3.73	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1.87	O
+to	O
+7.45	O
+;	O
+p<0.001	O
+)	O
+and	O
+level	O
+of	O
+education	O
+(	O
+no	O
+formal	O
+education	O
+:	O
+OR	O
+,	O
+4.31	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1.08	O
+to	O
+17.2	O
+;	O
+p<0.05	O
+;	O
+primary	O
+:	O
+OR	O
+,	O
+7.29	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+1.80	O
+to	O
+29.6	O
+;	O
+p<0.01	O
+)	O
+were	O
+significant	O
+risk	O
+factors	O
+for	O
+WNV	O
+IgM	O
+seropositivity	O
+in	O
+humans	O
+.	O
+
+Conclusions	O
+The	O
+findings	O
+of	O
+this	O
+study	O
+highlight	O
+the	O
+endemicity	O
+of	O
+WNV	O
+in	O
+animals	O
+and	O
+humans	O
+in	O
+Nigeria	B-LOC
+and	O
+underscore	O
+the	O
+need	O
+for	O
+the	O
+One	O
+Health	O
+prevention	O
+and	O
+control	O
+approach	O
+.	O
+
+Both	O
+axial	O
+spondyloarthritis	O
+(	O
+axSpA	O
+)	O
+and	O
+idiopathic	O
+inflammatory	O
+myopathy	O
+(	O
+IIM	O
+)	O
+are	O
+infrequent	O
+,	O
+and	O
+their	O
+coexistence	O
+is	O
+even	O
+rarer	O
+;	O
+there	O
+are	O
+a	O
+few	O
+reported	O
+cases	O
+in	O
+the	O
+literature	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+assess	O
+their	O
+association	O
+and	O
+clinical	O
+and	O
+laboratory	O
+features	O
+in	O
+our	O
+patients	O
+.	O
+
+The	O
+clinical	O
+data	O
+of	O
+patients	O
+with	O
+axSpA	O
+and	O
+IIM	O
+diagnosed	O
+in	O
+China	B-LOC
+-	O
+Japan	O
+Friendship	O
+Hospital	O
+from	O
+July	O
+2015	O
+to	O
+February	O
+2019	O
+were	O
+retrospectively	O
+analyzed	O
+.	O
+
+This	O
+study	O
+included	O
+7	O
+patients	O
+with	O
+axSpA	O
+who	O
+met	O
+the	O
+IIM	O
+criteria	O
+,	O
+including	O
+3	O
+males	O
+and	O
+4	O
+females	O
+.	O
+
+The	O
+age	O
+of	O
+onset	O
+was	O
+16	O
+to	O
+39	O
+years	O
+.	O
+
+Four	O
+patients	O
+were	O
+HLA	O
+-	O
+B27	O
+positive	O
+,	O
+and	O
+three	O
+were	O
+negative	O
+.	O
+
+All	O
+patients	O
+were	O
+first	O
+diagnosed	O
+as	O
+axSpA	O
+,	O
+and	O
+then	O
+IIM	O
+was	O
+detected	O
+after	O
+0.5	O
+-	O
+20	O
+years	O
+(	O
+mean	O
+±	O
+SD	O
+,	O
+9.9	O
+±	O
+5.0	O
+years	O
+)	O
+.	O
+
+After	O
+being	O
+diagnosed	O
+to	O
+have	O
+axSpA	O
+and	O
+IIM	O
+,	O
+those	O
+patients	O
+were	O
+given	O
+prednisone	O
+and	O
+immunosuppressant	O
+drugs	O
+,	O
+and	O
+their	O
+symptoms	O
+gradually	O
+improved	O
+.	O
+
+Our	O
+study	O
+provides	O
+further	O
+evidence	O
+of	O
+the	O
+coexistence	O
+of	O
+IIM	O
+with	O
+axSpA.	O
+
+In	O
+patients	O
+with	O
+axSpA	O
+who	O
+have	O
+skin	O
+rash	O
+,	O
+interstitial	O
+lung	O
+disease	O
+(	O
+ILD	O
+)	O
+,	O
+myalgia	O
+,	O
+or	O
+muscle	O
+weakness	O
+,	O
+we	O
+should	O
+suspect	O
+that	O
+they	O
+may	O
+have	O
+IIM	O
+.	O
+
+Summary	O
+Multiple	O
+endocrine	O
+neoplasia	O
+type	O
+1	O
+(	O
+MEN1	O
+)	O
+is	O
+a	O
+rare	O
+inherited	O
+endocrine	O
+disorder	O
+with	O
+a	O
+high	O
+rate	O
+of	O
+penetrance	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+MEN1	O
+is	O
+1/30,000	B-STAT
+in	O
+the	O
+general	O
+population	O
+;	O
+however	O
+,	O
+it	O
+is	O
+quite	O
+rare	O
+for	O
+a	O
+patient	O
+to	O
+present	O
+for	O
+medical	O
+attention	O
+with	O
+MEN1	O
+for	O
+the	O
+first	O
+time	O
+in	O
+pregnancy	O
+.	O
+
+Primary	O
+hyperparathyroidism	O
+(	O
+PHPT	O
+)	O
+is	O
+one	O
+of	O
+the	O
+most	O
+common	O
+features	O
+of	O
+MEN1	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+PHPT	O
+occurring	O
+in	O
+pregnancy	O
+is	O
+1	B-STAT
+%	I-STAT
+.	O
+
+Despite	O
+advances	O
+in	O
+the	O
+medical	O
+,	O
+surgical	O
+and	O
+obstetric	O
+care	O
+over	O
+the	O
+years	O
+,	O
+management	O
+of	O
+this	O
+condition	O
+during	O
+pregnancy	O
+may	O
+be	O
+challenging	O
+.	O
+
+It	O
+can	O
+be	O
+difficult	O
+to	O
+identify	O
+pregnant	O
+women	O
+with	O
+PHPT	O
+requiring	O
+intervention	O
+and	O
+to	O
+monitor	O
+safely	O
+.	O
+
+Hypercalcemia	O
+can	O
+result	O
+in	O
+significant	O
+maternal	O
+and	O
+fetal	O
+adverse	O
+outcomes	O
+including	O
+:	O
+miscarriage	O
+,	O
+intrauterine	O
+growth	O
+restriction	O
+,	O
+preterm	O
+delivery	O
+,	O
+neonatal	O
+hypocalcaemia	O
+,	O
+pre	O
+-	O
+eclampsia	O
+and	O
+maternal	O
+nephrolithiasis	O
+.	O
+
+Herein	O
+,	O
+we	O
+present	O
+a	O
+case	O
+study	O
+of	O
+a	O
+lady	O
+with	O
+a	O
+strong	O
+family	O
+history	O
+of	O
+MEN1	O
+,	O
+who	O
+was	O
+biochemically	O
+proven	O
+to	O
+have	O
+PHPT	O
+and	O
+evidence	O
+of	O
+Zollinger	O
+Ellison	O
+Syndrome	O
+(	O
+ZE	O
+)	O
+on	O
+endoscopy	O
+.	O
+
+This	O
+patient	O
+delayed	O
+her	O
+assisted	O
+pregnancy	O
+plans	O
+for	O
+in	O
+vitro	O
+fertilization	O
+(	O
+IVF	O
+)	O
+until	O
+completion	O
+of	O
+the	O
+MEN1	O
+workup	O
+;	O
+nevertheless	O
+,	O
+she	O
+spontaneously	O
+achieved	O
+an	O
+unplanned	O
+pregnancy	O
+.	O
+
+As	O
+a	O
+result	O
+,	O
+she	O
+required	O
+intervention	O
+with	O
+parathyroidectomy	O
+in	O
+the	O
+second	O
+trimester	O
+of	O
+her	O
+pregnancy	O
+as	O
+her	O
+calcium	O
+level	O
+continued	O
+to	O
+rise	O
+.	O
+
+This	O
+case	O
+study	O
+highlights	O
+the	O
+workup	O
+,	O
+follow	O
+up	O
+and	O
+management	O
+of	O
+MEN1	O
+presenting	O
+with	O
+PHPT	O
+and	O
+ZE	O
+in	O
+pregnancy	O
+.	O
+
+Learning	O
+points	O
+Women	O
+of	O
+childbearing	O
+age	O
+who	O
+are	O
+suspected	O
+to	O
+have	O
+a	O
+diagnosis	O
+of	O
+primary	O
+hyperparathyroidism	O
+ideally	O
+should	O
+have	O
+genetic	O
+testing	O
+and	O
+avoid	O
+pregnancy	O
+until	O
+definitive	O
+plans	O
+are	O
+in	O
+place	O
+.	O
+
+Zollinger	O
+Ellison	O
+syndrome	O
+in	O
+pregnancy	O
+means	O
+off	O
+-	O
+label	O
+use	O
+of	O
+high	O
+dose	O
+of	O
+proton	O
+pump	O
+inhibitors	O
+(	O
+PPI	O
+)	O
+.	O
+
+Use	O
+of	O
+PPI	O
+in	O
+pregnancy	O
+is	O
+considered	O
+to	O
+be	O
+safe	O
+based	O
+on	O
+retrospective	O
+studies	O
+.	O
+
+Omeprazole	O
+,	O
+however	O
+,	O
+is	O
+FDA	O
+class	O
+C	O
+drug	O
+because	O
+of	O
+lack	O
+of	O
+large	O
+prospective	O
+studies	O
+or	O
+large	O
+case	O
+series	O
+during	O
+pregnancy	O
+.	O
+
+Calcium	O
+supplements	O
+in	O
+the	O
+form	O
+of	O
+calcium	O
+carbonate	O
+must	O
+be	O
+converted	O
+to	O
+calcium	O
+chloride	O
+by	O
+gastric	O
+acid	O
+in	O
+order	O
+to	O
+be	O
+absorbed	O
+,	O
+however	O
+,	O
+patients	O
+rendered	O
+achlorhydric	O
+as	O
+a	O
+result	O
+of	O
+PPI	O
+use	O
+will	O
+have	O
+impaired	O
+absorption	O
+of	O
+calcium	O
+.	O
+
+Therefore	O
+,	O
+use	O
+of	O
+calcium	O
+citrate	O
+might	O
+be	O
+considered	O
+a	O
+better	O
+option	O
+in	O
+this	O
+case	O
+.	O
+
+Background	O
+Mitochondrial	O
+diseases	O
+,	O
+also	O
+known	O
+as	O
+oxidative	O
+phosphorylation	O
+(	O
+OXPHOS	O
+)	O
+disorders	O
+,	O
+with	O
+a	O
+prevalence	B-EPI
+rate	O
+of	O
+1:5000	B-STAT
+,	O
+are	O
+the	O
+most	O
+frequent	O
+inherited	O
+metabolic	O
+diseases	O
+.	O
+
+Leigh	O
+Syndrome	O
+French	O
+Canadian	O
+type	O
+(	O
+LSFC	O
+)	O
+,	O
+is	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+nuclear	O
+gene	O
+(	O
+2p16	O
+)	O
+leucine	O
+-	O
+rich	O
+pentatricopeptide	O
+repeat	O
+-	O
+containing	O
+(	O
+LRPPRC	O
+)	O
+.	O
+
+It	O
+is	O
+an	O
+autosomal	O
+recessive	O
+neurogenetic	O
+OXPHOS	O
+disorder	O
+,	O
+phenotypically	O
+distinct	O
+from	O
+other	O
+types	O
+of	O
+Leigh	O
+syndrome	O
+,	O
+with	O
+a	O
+carrier	O
+frequency	O
+up	O
+to	O
+1:23	B-STAT
+and	O
+an	O
+incidence	B-EPI
+of	O
+1:2063	B-STAT
+in	O
+the	O
+Saguenay	O
+-	O
+Lac	O
+-	O
+St	O
+Jean	O
+region	O
+of	O
+Quebec	B-LOC
+.	O
+
+Recently	O
+,	O
+LSFC	O
+has	O
+also	O
+been	O
+reported	O
+outside	O
+the	O
+French	O
+-	O
+Canadian	O
+population	O
+.	O
+
+Patient	O
+presentation	O
+We	O
+report	O
+a	O
+male	O
+Italian	O
+(	O
+Sicilian	O
+)	O
+child	O
+,	O
+born	O
+preterm	O
+at	O
+28	B-STAT
++	I-STAT
+6/7	I-STAT
+weeks	O
+gestation	O
+,	O
+carrying	O
+a	O
+novel	O
+LRPPRC	O
+compound	O
+heterozygous	O
+mutation	O
+,	O
+with	O
+facial	O
+dysmorphisms	O
+,	O
+neonatal	O
+hypotonia	O
+,	O
+non	O
+-	O
+epileptic	O
+paroxysmal	O
+motor	O
+phenomena	O
+,	O
+and	O
+absent	O
+sucking	O
+-	O
+swallowing	O
+-	O
+breathing	O
+coordination	O
+requiring	O
+,	O
+at	O
+4.5	O
+months	O
+,	O
+a	O
+percutaneous	O
+endoscopic	O
+gastrostomy	O
+tube	O
+placement	O
+.	O
+
+At	O
+5	O
+months	O
+brain	O
+Magnetic	O
+Resonance	O
+Imaging	O
+showed	O
+diffuse	O
+cortical	O
+atrophy	O
+,	O
+hypoplasia	O
+of	O
+corpus	O
+callosum	O
+,	O
+cerebellar	O
+vermis	O
+hypoplasia	O
+,	O
+and	O
+unfolded	O
+hippocampi	O
+.	O
+
+Both	O
+auditory	O
+and	O
+visual	O
+evoked	O
+potentials	O
+were	O
+pathological	O
+.	O
+
+In	O
+the	O
+following	O
+months	O
+Video	O
+EEG	O
+confirmed	O
+the	O
+persistence	O
+of	O
+sporadic	O
+non	O
+epileptic	O
+motor	O
+phenomena	O
+.	O
+
+No	O
+episode	O
+of	O
+metabolic	O
+decompensation	O
+,	O
+acidosis	O
+or	O
+ketosis	O
+,	O
+frequently	O
+observed	O
+in	O
+LSFC	B-LOC
+has	O
+been	O
+reported	O
+.	O
+
+Actually	O
+,	O
+aged	O
+14	O
+months	O
+corrected	O
+age	O
+for	O
+prematurity	O
+,	O
+the	O
+child	O
+shows	O
+a	O
+severe	O
+global	O
+developmental	O
+delay	O
+.	O
+
+Metabolic	O
+investigations	O
+and	O
+array	O
+Comparative	O
+Genomic	O
+Hybridization	O
+(	O
+aCGH	O
+)	O
+results	O
+were	O
+normal	O
+.	O
+
+Whole	O
+-	O
+exome	O
+sequencing	O
+(	O
+WES	O
+)	O
+found	O
+a	O
+compound	O
+heterozygous	O
+mutation	O
+in	O
+the	O
+LRPPRC	O
+gene	O
+,	O
+c.1921	O
+-	O
+7A	O
+>	O
+G	O
+and	O
+c.2056A	O
+>	O
+G	O
+(	O
+p.	O
+Ile686Val	O
+)	O
+,	O
+splicing	O
+-	O
+site	O
+and	O
+missense	O
+variants	O
+,	O
+inherited	O
+from	O
+the	O
+mother	O
+and	O
+the	O
+father	O
+,	O
+respectively	O
+.	O
+
+Conclusions	O
+We	O
+first	O
+characterized	O
+the	O
+clinical	O
+and	O
+molecular	O
+features	O
+of	O
+a	O
+novel	O
+LRPPRC	O
+variant	O
+in	O
+a	O
+male	O
+Sicilian	O
+child	O
+with	O
+early	O
+onset	O
+encephalopathy	O
+and	O
+psychomotor	O
+impairment	O
+.	O
+
+Our	O
+patient	O
+showed	O
+a	O
+phenotype	O
+characterized	O
+by	O
+a	O
+severe	O
+neurodevelopmental	O
+delay	O
+and	O
+absence	O
+of	O
+metabolic	O
+decompensation	O
+attributable	O
+to	O
+a	O
+probable	O
+residual	O
+enzymatic	O
+activity	O
+.	O
+
+LRPPRC	O
+is	O
+a	O
+rare	O
+cause	O
+of	O
+metabolic	O
+encephalopathy	O
+outside	O
+of	O
+Québec	B-LOC
+.	O
+
+Our	O
+patient	O
+adds	O
+to	O
+and	O
+broaden	O
+the	O
+spectrum	O
+of	O
+LSFC	O
+phenotypes	O
+.	O
+
+WES	O
+analysis	O
+is	O
+a	O
+pivotal	O
+genetic	O
+test	O
+and	O
+should	O
+be	O
+performed	O
+in	O
+infants	O
+and	O
+children	O
+with	O
+hypotonia	O
+and	O
+developmental	O
+delay	O
+in	O
+whom	O
+metabolic	O
+investigations	O
+and	O
+aCGH	O
+are	O
+normal	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+report	O
+of	O
+a	O
+32	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+diagnosed	O
+with	O
+opticomyelitis	O
+of	O
+Devic	O
+(	O
+OMD	O
+)	O
+and	O
+systemic	O
+lupus	O
+erythematosus	O
+(	O
+SLE	O
+)	O
+.	O
+
+The	O
+onset	O
+of	O
+neurological	O
+symptoms	O
+was	O
+with	O
+optic	O
+neuritis	O
+.	O
+
+Five	O
+months	O
+later	O
+the	O
+neurological	O
+deficit	O
+progressed	O
+within	O
+a	O
+few	O
+days	O
+to	O
+lower	O
+paraplegia	O
+and	O
+upper	O
+paraparesis	O
+,	O
+retention	O
+of	O
+urine	O
+and	O
+faeces	O
+,	O
+impaired	O
+somatic	O
+and	O
+deep	O
+sensation	O
+below	O
+the	O
+level	O
+of	O
+Th1	O
+dermatome	O
+.	O
+
+The	O
+results	O
+from	O
+laboratory	O
+investigations	O
+confirmed	O
+anaemic	O
+syndrome	O
+,	O
+increased	O
+urea	O
+and	O
+creatinine	O
+,	O
+hypoproteinemia	O
+and	O
+severe	O
+proteinuria	O
+.	O
+
+The	O
+results	O
+from	O
+CSF	O
+investigations	O
+demonstrated	O
+hyperproteinorachia	O
+with	O
+extremely	O
+high	O
+Ig	O
+fractions	O
+.	O
+
+Serum	O
+and	O
+CSF	O
+oligoclonal	O
+bands	O
+and	O
+positive	O
+serum	O
+Aquaporin	O
+IgG	O
+32	O
+times	O
+higher	O
+than	O
+the	O
+upper	O
+referent	O
+limit	O
+were	O
+found	O
+.	O
+
+The	O
+association	O
+with	O
+SLE	O
+was	O
+confirmed	O
+by	O
+the	O
+increased	O
+levels	O
+of	O
+total	O
+ANA	O
+and	O
+anti	O
+-	O
+ds	O
+-	O
+DNA	O
+ANA	O
+.	O
+
+MRT	O
+visualized	O
+the	O
+spinal	O
+cord	O
+as	O
+non	O
+-	O
+homogenously	O
+hypointense	O
+on	O
+T1	O
+and	O
+extremely	O
+hyperintense	O
+on	O
+FLAIR	O
+sequences	O
+through	O
+its	O
+whole	O
+length	O
+up	O
+to	O
+the	O
+bulbar	O
+-	O
+pontine	O
+region	O
+.	O
+
+The	O
+MRT	O
+findings	O
+and	O
+the	O
+serum	O
+Aquaporin	O
+IgG	O
+confirmed	O
+the	O
+diagnosis	O
+OMD	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+intravenous	O
+immunomodulating	O
+agents	O
+.	O
+
+We	O
+consider	O
+the	O
+presented	O
+case	O
+of	O
+special	O
+interest	O
+because	O
+of	O
+the	O
+comorbidity	O
+of	O
+an	O
+aggressive	O
+autoimmune	O
+systemic	O
+and	O
+an	O
+organ	O
+-	O
+specific	O
+disease	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+.	O
+
+Osteogenesis	O
+imperfecta	O
+(	O
+OI	O
+)	O
+is	O
+a	O
+heritable	O
+disorder	O
+that	O
+mainly	O
+affects	O
+the	O
+skeleton	O
+.	O
+
+The	O
+inheritance	O
+is	O
+mostly	O
+autosomal	O
+dominant	O
+and	O
+associated	O
+to	O
+mutations	O
+in	O
+one	O
+of	O
+the	O
+two	O
+genes	O
+,	O
+COL1A1	O
+and	O
+COL1A2	O
+,	O
+encoding	O
+for	O
+the	O
+type	O
+I	O
+collagen	O
+α	O
+chains	O
+.	O
+
+According	O
+to	O
+more	O
+than	O
+1500	O
+described	O
+mutation	O
+sites	O
+and	O
+to	O
+outcome	O
+spanning	O
+from	O
+very	O
+mild	O
+cases	O
+to	O
+perinatal	O
+-	O
+lethality	O
+,	O
+OI	O
+is	O
+characterized	O
+by	O
+a	O
+wide	O
+genotype	O
+/	O
+phenotype	O
+heterogeneity	O
+.	O
+
+In	O
+order	O
+to	O
+identify	O
+common	O
+affected	O
+molecular	O
+-	O
+pathways	O
+and	O
+disease	O
+biomarkers	O
+in	O
+OI	O
+probands	O
+with	O
+different	O
+mutations	O
+and	O
+lethal	O
+or	O
+surviving	O
+phenotypes	O
+,	O
+primary	O
+fibroblasts	O
+from	O
+dominant	O
+OI	O
+patients	O
+,	O
+carrying	O
+COL1A1	O
+or	O
+COL1A2	O
+defects	O
+,	O
+were	O
+investigated	O
+by	O
+applying	O
+a	O
+Tandem	O
+Mass	O
+Tag	O
+labeling	O
+-	O
+Liquid	O
+Chromatography	O
+-	O
+Tandem	O
+Mass	O
+Spectrometry	O
+(	O
+TMT	O
+LC	O
+-	O
+MS	O
+/	O
+MS	O
+)	O
+proteomics	O
+approach	O
+and	O
+bioinformatic	O
+tools	O
+for	O
+comparative	O
+protein	O
+-	O
+abundance	O
+profiling	O
+.	O
+
+While	O
+no	O
+difference	O
+in	O
+α1	O
+or	O
+α2	O
+abundance	O
+was	O
+detected	O
+among	O
+lethal	O
+(	O
+type	O
+II	O
+)	O
+and	O
+not	O
+-	O
+lethal	O
+(	O
+type	O
+III	O
+)	O
+OI	O
+patients	O
+,	O
+17	O
+proteins	O
+,	O
+with	O
+key	O
+effects	O
+on	O
+matrix	O
+structure	O
+and	O
+organization	O
+,	O
+cell	O
+signaling	O
+,	O
+and	O
+cell	O
+and	O
+tissue	O
+development	O
+and	O
+differentiation	O
+,	O
+were	O
+significantly	O
+different	O
+between	O
+type	O
+II	O
+and	O
+type	O
+III	O
+OI	O
+patients	O
+.	O
+
+Among	O
+them	O
+,	O
+some	O
+non	O
+-	O
+collagenous	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+proteins	O
+(	O
+e.g.	O
+,	O
+decorin	O
+and	O
+fibrillin-1	O
+)	O
+and	O
+proteins	O
+modulating	O
+cytoskeleton	O
+(	O
+e.g.	O
+,	O
+nestin	O
+and	O
+palladin	O
+)	O
+directly	O
+correlate	O
+to	O
+the	O
+severity	O
+of	O
+the	O
+disease	O
+.	O
+
+Their	O
+defective	O
+presence	O
+may	O
+define	O
+proband	O
+-	O
+failure	O
+in	O
+balancing	O
+aberrances	O
+related	O
+to	O
+mutant	O
+collagen	O
+.	O
+
+Objective	O
+To	O
+demonstrate	O
+that	O
+delayed	O
+cord	O
+clamping	O
+(	O
+DCC	O
+)	O
+is	O
+safe	O
+in	O
+mothers	O
+with	O
+confirmed	O
+SARS	O
+-	O
+CoV-2	O
+infection	O
+.	O
+
+Design	O
+,	O
+setting	O
+and	O
+participants	O
+Prospective	O
+observational	O
+study	O
+involving	O
+epidemiological	O
+information	O
+from	O
+403	O
+pregnant	O
+women	O
+with	O
+SARS	O
+-	O
+CoV-2	O
+between	O
+1	B-STAT
+March	O
+and	O
+31	O
+May	O
+2020	O
+.	O
+
+Data	O
+were	O
+collected	O
+from	O
+70	O
+centres	O
+that	O
+participate	O
+in	O
+the	O
+Spanish	O
+Registry	O
+of	O
+COVID-19	O
+.	O
+
+Methods	O
+Patients	O
+'	O
+information	O
+was	O
+collected	O
+from	O
+their	O
+medical	O
+chart	O
+.	O
+
+Main	O
+outcomes	O
+and	O
+measures	O
+The	O
+rate	O
+of	O
+perinatal	O
+transmission	O
+of	O
+SARS	O
+-	O
+CoV-2	O
+and	O
+development	O
+of	O
+the	O
+infection	O
+in	O
+neonates	O
+within	O
+14	O
+days	O
+postpartum	O
+.	O
+
+Results	O
+The	O
+early	O
+cord	O
+clamping	O
+(	O
+ECC	O
+)	O
+group	O
+consisted	O
+of	O
+231	O
+infants	O
+(	O
+57.3	O
+%	O
+)	O
+and	O
+the	O
+DCC	O
+group	O
+consisted	O
+of	O
+172	O
+infants	O
+(	O
+42.7	O
+%	O
+)	O
+.	O
+
+Five	O
+positive	O
+newborns	O
+(	O
+1.7	O
+%	O
+of	O
+total	O
+tests	O
+performed	O
+)	O
+were	O
+identified	O
+with	O
+the	O
+nasopharyngeal	O
+PCR	O
+tests	O
+performed	O
+in	O
+the	O
+first	O
+12	O
+hours	O
+postpartum	O
+,	O
+two	O
+from	O
+the	O
+ECC	O
+group	O
+(	O
+1.7	O
+%	O
+)	O
+and	O
+three	O
+from	O
+the	O
+DCC	O
+group	O
+(	O
+3.6	O
+%	O
+)	O
+.	O
+
+No	O
+significant	O
+differences	O
+between	O
+groups	O
+were	O
+found	O
+regarding	O
+neonatal	O
+tests	O
+for	O
+SARS	O
+-	O
+CoV-2	O
+.	O
+
+No	O
+confirmed	O
+cases	O
+of	O
+vertical	O
+transmission	O
+were	O
+detected	O
+.	O
+
+The	O
+percentage	O
+of	O
+mothers	O
+who	O
+made	O
+skin	O
+-	O
+to	O
+-	O
+skin	O
+contact	O
+within	O
+the	O
+first	O
+24	O
+hours	O
+after	O
+delivery	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+DCC	O
+group	O
+(	O
+84.3	O
+%	O
+versus	O
+45.9	O
+%	O
+)	O
+.	O
+
+Breastfeeding	O
+in	O
+the	O
+immediate	O
+postpartum	O
+period	O
+was	O
+also	O
+significantly	O
+higher	O
+in	O
+the	O
+DCC	O
+group	O
+(	O
+77.3	O
+%	O
+versus	O
+50.2	O
+%	O
+)	O
+.	O
+
+Conclusions	O
+The	O
+results	O
+of	O
+our	O
+study	O
+show	O
+no	O
+differences	O
+in	O
+perinatal	O
+outcomes	O
+when	O
+performing	O
+ECC	O
+or	O
+DCC	O
+,	O
+and	O
+skin	O
+-	O
+to	O
+-	O
+skin	O
+contact	O
+,	O
+or	O
+breastfeeding	O
+.	O
+
+Tweetable	O
+abstract	O
+This	O
+study	O
+demonstrates	O
+that	O
+delayed	O
+cord	O
+clamping	O
+is	O
+safe	O
+in	O
+mothers	O
+with	O
+confirmed	O
+SARS	O
+-	O
+CoV-2	O
+infection	O
+.	O
+
+Stroke	O
+is	O
+a	O
+leading	O
+cause	O
+of	O
+disability	O
+and	O
+mortality	O
+all	O
+over	O
+the	O
+world	O
+.	O
+
+Due	O
+to	O
+an	O
+aging	O
+population	O
+,	O
+the	O
+incidence	B-EPI
+of	O
+stroke	O
+is	O
+rising	O
+significantly	O
+,	O
+which	O
+has	O
+led	O
+to	O
+devastating	O
+consequences	O
+for	O
+patients	O
+.	O
+
+In	O
+addition	O
+to	O
+traditional	O
+risk	O
+factors	O
+such	O
+as	O
+age	O
+,	O
+hypertension	O
+,	O
+hyperlipidemia	O
+,	O
+diabetes	O
+and	O
+atrial	O
+fibrillation	O
+,	O
+sleep	O
+disorders	O
+,	O
+as	O
+independent	O
+modifiable	O
+risk	O
+factors	O
+for	O
+stroke	O
+,	O
+have	O
+been	O
+highlighted	O
+increasingly	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+provide	O
+an	O
+overview	O
+of	O
+common	O
+types	O
+of	O
+current	O
+sleep	O
+disturbances	O
+in	O
+cerebrovascular	O
+diseases	O
+,	O
+including	O
+insomnia	O
+,	O
+hypersomnia	O
+,	O
+breathing	O
+-	O
+related	O
+sleep	O
+disorders	O
+,	O
+and	O
+parasomnias	O
+.	O
+
+Moreover	O
+,	O
+evidence	O
+-	O
+based	O
+clinical	O
+therapeutic	O
+strategies	O
+and	O
+pitfalls	O
+of	O
+specific	O
+sleep	O
+disorders	O
+after	O
+stroke	O
+are	O
+discussed	O
+.	O
+
+We	O
+also	O
+review	O
+the	O
+neurobiological	O
+mechanisms	O
+of	O
+these	O
+treatments	O
+as	O
+well	O
+as	O
+their	O
+effects	O
+on	O
+stroke	O
+.	O
+
+Since	O
+depression	O
+after	O
+stroke	O
+is	O
+so	O
+prevalent	B-EPI
+and	O
+closely	O
+related	O
+to	O
+sleep	O
+disorders	O
+,	O
+treatments	O
+of	O
+post	O
+-	O
+stroke	O
+depression	O
+are	O
+also	O
+briefly	O
+mentioned	O
+in	O
+this	O
+review	O
+article	O
+.	O
+
+Metabolic	O
+liver	O
+diseases	O
+(	O
+MLD	O
+)	O
+are	O
+an	O
+important	O
+group	O
+of	O
+disorders	O
+presenting	O
+with	O
+neonatal	O
+cholestasis	O
+(	O
+NC	B-LOC
+)	O
+.	O
+
+The	O
+spectrum	O
+of	O
+liver	O
+involvement	O
+is	O
+wide	O
+and	O
+the	O
+presumptive	O
+diagnosis	O
+is	O
+traditionally	O
+based	O
+on	O
+clinical	O
+and	O
+laboratory	O
+findings	O
+.	O
+
+Recently	O
+,	O
+next	O
+-	O
+generation	O
+sequencing	O
+(	O
+NGS	O
+)	O
+panels	O
+have	O
+emerged	O
+as	O
+an	O
+appealing	O
+tool	O
+to	O
+diagnose	O
+neonatal	O
+/	O
+infantile	O
+cholestatic	O
+disorders	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+identify	O
+clinical	O
+phenotypes	O
+of	O
+liver	O
+injury	O
+and	O
+contribute	O
+to	O
+find	O
+a	O
+diagnostic	O
+methodology	O
+that	O
+integrates	O
+new	O
+molecular	O
+diagnostic	O
+tools	O
+.	O
+
+We	O
+retrospectively	O
+analyzed	O
+the	O
+clinical	O
+and	O
+biochemical	O
+features	O
+of	O
+16	O
+patients	O
+with	O
+MLD	O
+and	O
+NC	B-LOC
+.	O
+
+Patients	O
+were	O
+categorized	O
+into	O
+three	O
+groups	O
+:	O
+A	O
+-	O
+NC	O
+with	O
+liver	O
+failure	O
+(	O
+N	O
+=	O
+8)	O
+:	O
+tyrosinemia	O
+type	O
+I	O
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+classic	O
+galactosemia	O
+(	O
+n	O
+=	O
+5	O
+)	O
+,	O
+mitochondrial	O
+DNA	O
+depletion	O
+syndrome	O
+(	O
+n	O
+=	O
+1	O
+)	O
+;	O
+B	O
+-	O
+NC	O
+evolving	O
+with	O
+chronic	O
+liver	O
+disease	O
+(	O
+N	O
+=	O
+5	O
+):	O
+argininemia	O
+(	O
+n	O
+=	O
+2	O
+)	O
+;	O
+mitochondrial	O
+cytopathy	O
+(	O
+n	O
+=	O
+1	O
+)	O
+;	O
+congenital	O
+disorders	O
+of	O
+glycosylation	O
+type	O
+Ia	O
+(	O
+n	O
+=	O
+1	B-STAT
+)	I-STAT
+;	I-STAT
+Zellweger	O
+syndrome	O
+(	O
+n	O
+=	O
+1	O
+)	O
+;	O
+and	O
+C	O
+-	O
+transient	O
+NC	B-LOC
+(	O
+N	O
+=	O
+3	O
+):	O
+Niemann	O
+-	O
+Pick	O
+type	O
+C	O
+(	O
+n	O
+=	O
+2	O
+)	O
+,	O
+citrullinemia	O
+type	O
+II	O
+(	O
+n	O
+=	O
+1).Conclusion	O
+:	O
+MLD	O
+presenting	O
+with	O
+NC	B-LOC
+can	O
+be	O
+categorized	O
+into	O
+three	O
+main	O
+clinical	O
+phenotypes	O
+of	O
+liver	O
+injury	O
+.	O
+
+We	O
+highlight	O
+transient	O
+NC	B-LOC
+as	O
+a	O
+clue	O
+for	O
+MLD	O
+that	O
+must	O
+be	O
+pursued	O
+.	O
+
+New	O
+molecular	O
+diagnostic	O
+tools	O
+can	O
+play	O
+a	O
+key	O
+role	O
+,	O
+but	O
+application	O
+criteria	O
+must	O
+be	O
+established	O
+to	O
+make	O
+them	O
+cost	O
+-	O
+effective	O
+.	O
+
+What	O
+is	O
+Known	O
+:	O
+•	O
+Metabolic	O
+liver	O
+diseases	O
+are	O
+an	O
+important	O
+group	O
+of	O
+disorders	O
+presenting	O
+with	O
+neonatal	O
+cholestasis	O
+.	O
+
+•	O
+The	O
+diagnostic	O
+approach	O
+is	O
+challenging	O
+and	O
+traditionally	O
+based	O
+on	O
+clinical	O
+and	O
+laboratory	O
+findings	O
+.	O
+
+Next	O
+-	O
+generation	O
+sequencing	O
+is	O
+a	O
+recent	O
+and	O
+rapidly	O
+developing	O
+tool	O
+in	O
+pediatric	O
+hepatology	O
+.	O
+
+What	O
+is	O
+New	O
+:	O
+•	O
+We	O
+provide	O
+a	O
+liver	O
+-	O
+targeted	O
+characterization	O
+of	O
+metabolic	O
+liver	O
+diseases	O
+presenting	O
+with	O
+neonatal	O
+cholestasis	O
+,	O
+categorizing	O
+them	O
+into	O
+three	O
+clinical	O
+phenotypes	O
+that	O
+may	O
+narrow	O
+the	O
+diagnostic	O
+possibilities	O
+.	O
+
+•	O
+A	O
+clinical	O
+decision	O
+-	O
+making	O
+algorithm	O
+is	O
+proposed	O
+,	O
+in	O
+which	O
+the	O
+NGS	O
+technology	O
+is	O
+integrated	O
+.	O
+
+Many	O
+adrenocortical	O
+diseases	O
+are	O
+more	O
+prevalent	B-EPI
+in	O
+women	O
+than	O
+in	O
+men	O
+,	O
+but	O
+the	O
+reasons	O
+underlying	O
+this	O
+sex	O
+bias	O
+are	O
+still	O
+unknown	O
+.	O
+
+Recent	O
+studies	O
+involving	O
+gonadectomy	O
+and	O
+sex	O
+hormone	O
+replacement	O
+experiments	O
+in	O
+mice	O
+have	O
+shed	O
+some	O
+light	O
+onto	O
+the	O
+molecular	O
+basis	O
+of	O
+sexual	O
+dimorphism	O
+in	O
+the	O
+adrenal	O
+cortex	O
+.	O
+
+Indeed	O
+,	O
+it	O
+has	O
+been	O
+shown	O
+that	O
+gonadal	O
+hormones	O
+influence	O
+many	O
+aspects	O
+of	O
+adrenal	O
+physiology	O
+,	O
+ranging	O
+from	O
+stem	O
+cell	O
+-	O
+dependent	O
+tissue	O
+turnover	O
+to	O
+steroidogenesis	O
+and	O
+X	O
+-	O
+zone	O
+dynamics	O
+.	O
+
+This	O
+article	O
+reviews	O
+current	O
+knowledge	O
+on	O
+adrenal	O
+cortex	O
+sexual	O
+dimorphism	O
+and	O
+the	O
+potential	O
+mechanisms	O
+underlying	O
+sex	O
+hormone	O
+influence	O
+of	O
+adrenal	O
+homeostasis	O
+.	O
+
+Both	O
+topics	O
+are	O
+expected	O
+to	O
+contribute	O
+to	O
+personalized	O
+and	O
+novel	O
+therapeutic	O
+approaches	O
+in	O
+the	O
+future	O
+.	O
+
+Background	O
+The	O
+European	O
+Rare	O
+Kidney	O
+Disease	O
+Reference	O
+Network	O
+(	O
+ERKNet	O
+)	O
+recently	O
+established	O
+ERKReg	O
+,	O
+a	O
+Web	O
+-	O
+based	O
+registry	O
+for	O
+all	O
+patients	O
+with	O
+rare	O
+kidney	O
+diseases	O
+.	O
+
+The	O
+main	O
+objectives	O
+of	O
+this	O
+core	O
+registry	O
+are	O
+to	O
+generate	O
+epidemiological	O
+information	O
+,	O
+identify	O
+current	O
+patient	O
+cohort	O
+for	O
+clinical	O
+research	O
+,	O
+explore	O
+diagnostic	O
+and	O
+therapeutic	O
+management	O
+practices	O
+,	O
+and	O
+monitor	O
+treatment	O
+performance	O
+and	O
+patient	O
+'s	O
+outcomes	O
+.	O
+
+The	O
+registry	O
+has	O
+a	O
+modular	O
+design	O
+that	O
+allows	O
+to	O
+integrate	O
+comprehensive	O
+disease	O
+-	O
+specific	O
+registries	O
+as	O
+extensions	O
+to	O
+the	O
+core	O
+database	O
+.	O
+
+The	O
+diagnosis	O
+(	O
+Orphacode	O
+)	O
+and	O
+diagnostic	O
+information	O
+(	O
+clinical	O
+,	O
+imaging	O
+,	O
+histopathological	O
+,	O
+biochemical	O
+,	O
+immunological	O
+and	O
+genetic	O
+)	O
+are	O
+recorded	O
+.	O
+
+Anthropometric	O
+,	O
+kidney	O
+function	O
+,	O
+and	O
+disease	O
+-	O
+specific	O
+management	O
+and	O
+outcome	O
+items	O
+informing	O
+a	O
+set	O
+of	O
+61	O
+key	O
+performance	O
+indicators	O
+(	O
+KPIs	O
+)	O
+are	O
+obtained	O
+annually	O
+.	O
+
+Data	O
+quality	O
+is	O
+ensured	O
+by	O
+automated	O
+plausibility	O
+checks	O
+upon	O
+data	O
+entry	O
+and	O
+regular	O
+offline	O
+database	O
+checks	O
+prompting	O
+queries	O
+.	O
+
+Centre	O
+KPI	O
+statistics	O
+and	O
+benchmarking	O
+are	O
+calculated	O
+automatically	O
+.	O
+
+Results	O
+Within	O
+the	O
+first	O
+24	O
+months	O
+since	O
+its	O
+launch	O
+,	O
+7607	O
+patients	O
+were	O
+enrolled	O
+to	O
+the	O
+registry	O
+at	O
+45	O
+pediatric	O
+and	O
+12	O
+specialized	O
+adult	O
+nephrology	O
+units	O
+from	O
+21	O
+countries	O
+.	O
+
+A	O
+kidney	O
+disease	O
+diagnosis	O
+had	O
+been	O
+established	O
+in	O
+97.1	O
+%	O
+of	O
+these	O
+patients	O
+at	O
+time	O
+of	O
+enrolment	O
+.	O
+
+While	O
+199	O
+individual	O
+disease	O
+entities	O
+were	O
+reported	O
+by	O
+Orphacode	O
+,	O
+50	O
+%	O
+of	O
+the	O
+cohort	O
+could	O
+be	O
+classified	O
+with	O
+11	B-STAT
+,	O
+80	O
+%	O
+with	O
+43	O
+and	O
+95	O
+%	O
+with	O
+92	O
+codes	O
+.	O
+
+Two	O
+kidney	O
+diagnoses	O
+were	O
+assigned	O
+in	O
+6.5	O
+%	O
+of	O
+patients	O
+;	O
+5.9	O
+%	O
+suffered	O
+from	O
+syndromic	O
+disease	O
+.	O
+
+Whereas	O
+glomerulopathies	O
+(	O
+54.8	O
+%	O
+)	O
+and	O
+ciliopathies	O
+including	O
+autosomal	O
+dominant	O
+polycystic	O
+kidney	O
+disease	O
+(	O
+ADPKD	O
+)	O
+(	O
+31.5	O
+%	O
+)	O
+were	O
+the	O
+predominant	O
+disease	O
+groups	O
+among	O
+adults	O
+,	O
+the	O
+pediatric	O
+disease	O
+spectrum	O
+encompassed	O
+congenital	O
+anomalies	O
+of	O
+the	O
+kidney	O
+and	O
+urinary	O
+tract	O
+(	O
+CAKUT	O
+)	O
+(	O
+33.7	O
+%	O
+)	O
+,	O
+glomerulopathies	O
+(	O
+30.7	O
+%	O
+)	O
+,	O
+ciliopathies	O
+(	O
+14.0	O
+%	O
+)	O
+,	O
+tubulopathies	O
+(	O
+9.2	O
+%	O
+)	O
+,	O
+thrombotic	O
+microangiopathies	O
+(	O
+5.6	O
+%	O
+)	O
+,	O
+and	O
+metabolic	O
+nephropathies	O
+(	O
+4.1	O
+%	O
+)	O
+.	O
+
+Genetically	O
+confirmed	O
+diagnoses	O
+were	O
+reported	O
+in	O
+24	O
+%	O
+of	O
+all	O
+pediatric	O
+and	O
+12	O
+%	O
+adult	O
+patients	O
+,	O
+whereas	O
+glomerulopathies	O
+had	O
+been	O
+confirmed	O
+by	O
+kidney	O
+biopsy	O
+in	O
+80.4	O
+%	O
+adult	O
+versus	O
+38.5	O
+%	O
+pediatric	O
+glomerulopathy	O
+cases	O
+.	O
+
+Conclusions	O
+ERKReg	O
+is	O
+a	O
+rapidly	O
+growing	O
+source	O
+of	O
+epidemiological	O
+information	O
+and	O
+patient	O
+cohorts	O
+for	O
+clinical	O
+research	O
+,	O
+and	O
+an	O
+innovative	O
+tool	O
+to	O
+monitor	O
+management	O
+quality	O
+and	O
+patient	O
+outcomes	O
+.	O
+
+Pseudoachondroplasia	B-LOC
+(	O
+PSACH	O
+)	O
+is	O
+an	O
+autosomal	O
+dominant	O
+skeletal	O
+dysplasia	O
+with	O
+an	O
+estimated	B-EPI
+incidence	I-EPI
+of	O
+~1/60000	O
+that	O
+is	O
+characterized	O
+by	O
+disproportionate	O
+short	O
+stature	O
+,	O
+brachydactyly	O
+,	O
+joint	O
+laxity	O
+,	O
+and	O
+early	O
+-	O
+onset	O
+osteoarthritis	O
+.	O
+
+COMP	O
+encodes	O
+the	O
+cartilage	O
+oligomeric	O
+matrix	O
+protein	O
+,	O
+which	O
+is	O
+expressed	O
+predominantly	O
+in	O
+the	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+surrounding	O
+the	O
+cells	O
+that	O
+make	O
+up	O
+cartilage	O
+,	O
+ligaments	O
+,	O
+and	O
+tendons	O
+.	O
+
+Mutations	O
+in	O
+COMP	O
+are	O
+known	O
+to	O
+give	O
+rise	O
+to	O
+PSACH	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+identified	O
+a	O
+novel	O
+nucleotide	O
+mutation	O
+(	O
+NM_000095.2	O
+:	O
+c.1317C	O
+>	O
+G	O
+,	O
+p.	O
+D439E	O
+)	O
+in	O
+COMP	O
+responsible	O
+for	O
+PSACH	O
+in	O
+a	O
+Chinese	O
+family	O
+by	O
+employing	O
+whole	O
+-	O
+exome	O
+sequencing	O
+(	O
+WES	O
+)	O
+and	O
+built	O
+the	O
+structure	O
+model	O
+of	O
+the	O
+mutant	O
+protein	O
+to	O
+clarify	O
+its	O
+pathogenicity	O
+.	O
+
+The	O
+novel	O
+mutation	O
+cosegregated	O
+with	O
+the	O
+affected	O
+individuals	O
+.	O
+
+Our	O
+study	O
+expands	O
+the	O
+spectrum	O
+of	O
+COMP	O
+mutations	O
+and	O
+further	O
+provides	O
+additional	O
+genetic	O
+testing	O
+information	O
+for	O
+other	O
+PSACH	O
+patients	O
+.	O
+
+New	O
+born	O
+babies	O
+could	O
+suffer	O
+from	O
+multiple	O
+craniofacial	O
+abnormalities	O
+,	O
+such	O
+as	O
+Pierre	O
+Robin	O
+syndrome	O
+,	O
+which	O
+consists	O
+of	O
+micrognathia	O
+and	O
+relative	O
+macroglossia	O
+with	O
+or	O
+without	O
+cleft	O
+palate	O
+.	O
+
+Although	O
+Pierre	O
+Robin	O
+syndrome	O
+is	O
+well	O
+described	O
+in	O
+literature	O
+,	O
+only	O
+a	O
+few	O
+have	O
+mentioned	O
+its	O
+occurrence	B-EPI
+in	O
+identical	O
+twins	O
+.	O
+
+This	O
+paper	O
+presents	O
+a	O
+rare	O
+incident	O
+of	O
+full	O
+-	O
+term	O
+twin	O
+babies	O
+born	O
+with	O
+the	O
+sequence	O
+of	O
+Pierre	O
+Robin	O
+syndrome	O
+,	O
+which	O
+consists	O
+of	O
+micrognathia	O
+,	O
+cleft	O
+palate	O
+,	O
+and	O
+glossoptosis	O
+.	O
+
+Although	O
+it	O
+is	O
+a	O
+rare	O
+coincidence	O
+,	O
+Pierre	O
+Robin	O
+syndrome	O
+still	O
+can	O
+occur	O
+in	O
+identical	O
+twin	O
+babies	O
+.	O
+
+The	O
+treatment	O
+is	O
+a	O
+step	O
+-	O
+by	O
+-	O
+step	O
+approach	O
+,	O
+but	O
+all	O
+procedures	O
+are	O
+mainly	O
+directed	O
+to	O
+widening	O
+the	O
+pharyngeal	O
+space	O
+.	O
+
+Background	O
+Premarital	O
+sex	O
+practices	O
+and	O
+contraceptive	O
+prevalence	B-EPI
+rate	O
+(	O
+CPR	O
+)	O
+among	O
+unmarried	O
+women	O
+worldwide	B-LOC
+remain	O
+unclear	O
+,	O
+even	O
+though	O
+unmarried	O
+women	O
+tend	O
+to	O
+have	O
+multiple	O
+sex	O
+partners	O
+over	O
+time	O
+,	O
+which	O
+makes	O
+their	O
+sexual	O
+behaviors	O
+particularly	O
+important	O
+to	O
+the	O
+sexual	O
+and	O
+reproductive	O
+health	O
+of	O
+society	O
+more	O
+broadly	O
+.	O
+
+Methods	O
+We	O
+searched	O
+the	O
+MEDLINE	O
+,	O
+PubMed	O
+,	O
+and	O
+Google	O
+Scholar	O
+databases	O
+for	O
+relevant	O
+articles	O
+published	O
+between	O
+January	O
+1	O
+,	O
+1999	O
+and	O
+December	O
+31	O
+,	O
+2018	O
+.	O
+
+Data	O
+on	O
+prevalence	B-EPI
+of	O
+premarital	O
+sexual	O
+intercourse	O
+,	O
+use	O
+of	O
+highly	O
+prevalent	B-EPI
+contraceptive	O
+methods	O
+,	O
+as	O
+well	O
+as	O
+CPR	O
+overall	O
+and	O
+at	O
+first	O
+sexual	O
+intercourse	O
+were	O
+extracted	O
+and	O
+estimated	O
+using	O
+a	O
+DerSimonian-	O
+Laird	O
+random	O
+effects	O
+model	O
+.	O
+
+Results	O
+Of	O
+the	O
+3918	O
+articles	O
+identified	O
+,	O
+37	O
+covering	O
+19	O
+countries	O
+were	O
+included	O
+.	O
+
+The	O
+estimated	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+premarital	O
+sexual	O
+intercourse	O
+was	O
+41.9	O
+%	O
+(	O
+95%CI	O
+34.2	O
+-	O
+49.6	O
+%	O
+)	O
+.	O
+
+Pooled	O
+CPR	O
+was	O
+57.0	O
+%	O
+(	O
+95%CI	O
+44.3	O
+-	O
+69.8	O
+%	O
+)	O
+overall	O
+and	O
+57.6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+39.5-	O
+75.6	O
+%	O
+)	O
+at	O
+first	O
+intercourse	O
+.	O
+
+The	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+condom	O
+use	O
+was	O
+51.2	O
+%	O
+(	O
+95%CI	O
+42.7	O
+-	O
+59.7	O
+%	O
+)	O
+,	O
+followed	O
+by	O
+oral	O
+contraceptives	O
+(	O
+20.5	O
+%	O
+,	O
+95%CI	O
+13.7	O
+-	O
+27.3	O
+%	O
+)	O
+,	O
+withdrawal	O
+(	O
+12.7	O
+%	O
+,	O
+95%CI	O
+9.4	O
+-	O
+15.9	O
+%	O
+)	O
+,	O
+and	O
+rhythm	O
+(	O
+12.1	O
+%	O
+,	O
+95%CI	O
+6.7	O
+-	O
+17.4	O
+%	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+findings	O
+of	O
+this	O
+global	O
+study	O
+indicate	O
+worrying	O
+trends	O
+in	O
+unprotected	O
+intercourse	O
+and	O
+contraceptive	O
+practices	O
+,	O
+suggesting	O
+the	O
+need	O
+for	O
+greater	O
+attention	O
+and	O
+resources	O
+aimed	O
+at	O
+educating	O
+unmarried	O
+adolescent	O
+women	O
+about	O
+sexual	O
+and	O
+reproductive	O
+health	O
+.	O
+
+Systematic	O
+review	O
+registration	O
+number	O
+CRD42019132736	O
+.	O
+
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+disease	O
+(	O
+CMT	O
+)	O
+is	O
+a	O
+group	O
+of	O
+inherited	O
+neurological	O
+disorders	O
+of	O
+the	O
+peripheral	O
+nervous	O
+system	O
+.	O
+
+CMT	O
+is	O
+subdivided	O
+into	O
+two	O
+main	O
+types	O
+:	O
+a	O
+demyelinating	O
+form	O
+,	O
+known	O
+as	O
+CMT1	O
+,	O
+and	O
+an	O
+axonal	O
+form	O
+,	O
+known	O
+as	O
+CMT2	O
+.	O
+
+Nearly	O
+30	O
+genes	O
+have	O
+been	O
+identified	O
+as	O
+a	O
+cause	O
+of	O
+CMT2	O
+.	O
+
+One	O
+of	O
+these	O
+is	O
+the	O
+'	O
+dehydrogenase	O
+E1	O
+and	O
+transketolase	O
+domain	O
+containing	O
+1	O
+'	O
+(	O
+DHTKD1	O
+)	O
+gene	O
+.	O
+
+We	O
+previously	O
+demonstrated	O
+that	O
+a	O
+nonsense	O
+mutation	O
+[	O
+c.1455	O
+T	O
+>	O
+G	O
+(	O
+p.	O
+Y485	O
+*	O
+)	O
+]	O
+in	O
+exon	O
+8	O
+of	O
+DHTKD1	O
+is	O
+one	O
+of	O
+the	O
+disease	O
+-	O
+causing	O
+mutations	O
+in	O
+CMT2Q	O
+(	O
+MIM	O
+615025	O
+)	O
+.	O
+
+The	O
+aim	O
+of	O
+the	O
+current	O
+study	O
+was	O
+to	O
+investigate	O
+whether	O
+human	O
+disease	O
+-	O
+causing	O
+mutations	O
+in	O
+the	O
+Dhtkd1	O
+gene	O
+cause	O
+CMT2Q	O
+phenotypes	O
+in	O
+a	O
+mouse	O
+model	O
+in	O
+order	O
+to	O
+investigate	O
+the	O
+physiological	O
+function	O
+and	O
+pathogenic	O
+mechanisms	O
+associated	O
+with	O
+mutations	O
+in	O
+the	O
+Dhtkd1	O
+gene	O
+in	O
+vivo	O
+.	O
+
+Therefore	O
+,	O
+we	O
+generated	O
+a	O
+knock	O
+-	O
+in	O
+mouse	O
+model	O
+with	O
+the	O
+Dhtkd1	O
+Y486	O
+*	O
+point	O
+mutation	O
+.	O
+
+We	O
+observed	O
+that	O
+the	O
+Dhtkd1	O
+expression	O
+level	O
+in	O
+sciatic	O
+nerve	O
+of	O
+knock	O
+-	O
+in	O
+mice	O
+was	O
+significantly	O
+lower	O
+than	O
+in	O
+wild	O
+-	O
+type	O
+mice	O
+.	O
+
+Moreover	O
+,	O
+a	O
+histopathological	O
+phenotype	O
+was	O
+observed	O
+,	O
+reminiscent	O
+of	O
+a	O
+peripheral	O
+neuropathy	O
+,	O
+including	O
+reduced	O
+large	O
+axon	O
+diameter	O
+and	O
+abnormal	O
+myelination	O
+in	O
+peripheral	O
+nerves	O
+.	O
+
+The	O
+knock	O
+-	O
+in	O
+mice	O
+also	O
+displayed	O
+clear	O
+sensory	O
+defects	O
+,	O
+while	O
+no	O
+abnormalities	O
+in	O
+the	O
+motor	O
+performance	O
+were	O
+observed	O
+.	O
+
+In	O
+addition	O
+,	O
+accumulation	O
+of	O
+mitochondria	O
+and	O
+an	O
+elevated	O
+energy	O
+metabolic	O
+state	O
+was	O
+observed	O
+in	O
+the	O
+knock	O
+-	O
+in	O
+mice	O
+.	O
+
+Taken	O
+together	O
+,	O
+our	O
+study	O
+indicates	O
+that	O
+the	O
+Dhtkd1	O
+Y486	O
+*	O
+knock	O
+-	O
+in	O
+mice	O
+partially	O
+recapitulate	O
+the	O
+clinical	O
+phenotypes	O
+of	O
+CMT2Q	O
+patients	O
+and	O
+we	O
+hypothesize	O
+that	O
+there	O
+might	O
+be	O
+a	O
+compensatory	O
+effect	O
+from	O
+the	O
+elevated	O
+metabolic	O
+state	O
+in	O
+the	O
+knock	O
+-	O
+in	O
+mice	O
+that	O
+enables	O
+them	O
+to	O
+maintain	O
+their	O
+normal	O
+locomotor	O
+function	O
+.	O
+
+Although	O
+geographic	O
+information	O
+system	O
+-	O
+based	O
+studies	O
+are	O
+particularly	O
+increasing	O
+in	O
+other	O
+sectors	O
+,	O
+few	O
+have	O
+embraced	O
+their	O
+full	O
+potential	O
+in	O
+health	O
+services	O
+allocation	O
+in	O
+Malaysia	B-LOC
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+produce	O
+a	O
+visual	O
+map	O
+on	O
+the	O
+distribution	O
+of	O
+smoking	O
+cessation	O
+clinics	O
+(	O
+SCCs	O
+)	O
+in	O
+Malaysia	B-LOC
+and	O
+analyze	O
+its	O
+pattern	O
+against	O
+the	O
+national	O
+population	O
+of	O
+smokers	O
+.	O
+
+SCC	O
+addresses	O
+were	O
+obtained	O
+from	O
+the	O
+government	O
+website	O
+and	O
+mapped	O
+using	O
+geographic	O
+information	O
+system	O
+tools	O
+.	O
+
+A	O
+total	O
+of	O
+199	O
+and	O
+449	O
+private	O
+and	O
+public	O
+SCCs	O
+was	O
+mapped	O
+throughout	O
+the	O
+country	O
+,	O
+respectively	O
+.	O
+
+The	O
+lowest	O
+SCC	O
+to	O
+smoker	O
+population	O
+ratio	O
+was	O
+in	O
+the	O
+state	O
+of	O
+Negeri	O
+Sembilan	O
+with	O
+1:3000	O
+.	O
+
+The	O
+highest	O
+SCC	O
+to	O
+smoker	O
+population	O
+ratio	O
+was	O
+in	O
+Sabah	B-LOC
+with	O
+1	B-STAT
+SCC	I-STAT
+for	I-STAT
+15	I-STAT
+000	I-STAT
+smokers	O
+.	O
+
+Almost	O
+70	O
+%	O
+of	O
+SCCs	O
+were	O
+primary	O
+health	O
+clinics	O
+.	O
+
+Smoking	O
+cessation	O
+clinics	O
+were	O
+distributed	O
+throughout	O
+all	O
+the	O
+states	O
+in	O
+Malaysia	B-LOC
+except	O
+the	O
+state	O
+of	O
+Sabah	B-LOC
+.	O
+
+Background	O
+The	O
+incidence	B-EPI
+of	O
+hydrocephalus	O
+in	O
+the	O
+spinal	O
+muscular	O
+atrophy	O
+(	O
+SMA	O
+)	O
+population	O
+relative	O
+to	O
+the	O
+general	O
+population	O
+is	O
+currently	O
+unknown	O
+.	O
+
+Since	O
+the	O
+approval	O
+of	O
+nusinersen	O
+,	O
+an	O
+intrathecally	O
+administered	O
+drug	O
+for	O
+SMA	O
+,	O
+a	O
+small	O
+number	O
+of	O
+hydrocephalus	O
+cases	O
+among	O
+nusinersen	O
+users	O
+have	O
+been	O
+reported	O
+.	O
+
+Currently	O
+,	O
+the	O
+incidence	B-EPI
+of	O
+hydrocephalus	O
+in	O
+untreated	O
+SMA	O
+patients	O
+is	O
+not	O
+available	O
+,	O
+thereby	O
+making	O
+it	O
+difficult	O
+to	O
+determine	O
+if	O
+hydrocephalus	O
+is	O
+a	O
+side	O
+effect	O
+of	O
+nusinersen	O
+or	O
+part	O
+of	O
+SMA	O
+'s	O
+natural	O
+history	O
+.	O
+
+This	O
+retrospective	O
+,	O
+matched	O
+cohort	O
+study	O
+used	O
+electronic	O
+health	O
+records	O
+(	O
+EHRs	O
+)	O
+to	O
+estimate	O
+and	O
+compare	O
+the	O
+incidence	B-EPI
+of	O
+hydrocephalus	O
+in	O
+both	O
+SMA	O
+patients	O
+and	O
+matched	O
+non	O
+-	O
+SMA	O
+controls	O
+in	O
+the	O
+time	O
+period	O
+prior	O
+to	O
+the	O
+approval	O
+of	O
+nusinersen	O
+.	O
+
+Methods	O
+The	O
+U.S.	B-LOC
+Optum	O
+®	O
+de	O
+-	O
+identified	O
+EHR	O
+database	O
+contains	O
+records	O
+for	O
+approximately	O
+100	O
+million	O
+persons	O
+.	O
+
+The	O
+current	O
+study	O
+period	O
+spanned	O
+January	O
+1	O
+,	O
+2007	O
+-	O
+December	O
+22	O
+,	O
+2016	O
+.	O
+
+Patients	O
+with	O
+SMA	O
+were	O
+identified	O
+by	O
+one	O
+or	O
+more	O
+International	O
+Classification	O
+of	O
+Diseases	O
+(	O
+ICD)-9	O
+and/or	O
+ICD-10	O
+codes	O
+for	O
+SMA	O
+appearing	O
+as	O
+primary	O
+,	O
+admission	O
+,	O
+or	O
+discharge	O
+diagnoses	O
+,	O
+without	O
+a	O
+pregnancy	O
+diagnostic	O
+code	O
+in	O
+the	O
+1	O
+-	O
+year	O
+time	O
+before	O
+and	O
+after	O
+the	O
+first	O
+occurrence	B-EPI
+of	O
+SMA	O
+.	O
+
+The	O
+first	O
+occurrence	B-EPI
+of	O
+SMA	O
+defined	O
+the	O
+index	O
+date	O
+and	O
+non	O
+-	O
+SMA	O
+controls	O
+were	O
+matched	O
+to	O
+cases	O
+.	O
+
+Incident	O
+cases	O
+of	O
+hydrocephalus	O
+were	O
+identified	O
+with	O
+one	O
+or	O
+more	O
+ICD-9	B-LOC
+and/or	O
+ICD-10	O
+code	O
+for	O
+any	O
+type	O
+of	O
+hydrocephalus	O
+following	O
+the	O
+index	O
+date	O
+.	O
+
+Hydrocephalus	O
+incidence	B-EPI
+rates	O
+per	O
+person	O
+-	O
+months	O
+and	O
+the	O
+incidence	B-EPI
+rate	O
+ratio	O
+comparing	O
+SMA	O
+cases	O
+with	O
+non	O
+-	O
+SMA	O
+controls	O
+were	O
+calculated	O
+.	O
+
+Results	O
+There	O
+were	O
+5354	O
+SMA	O
+cases	O
+and	O
+an	O
+equal	O
+number	O
+of	O
+matched	O
+non	O
+-	O
+SMA	O
+controls	O
+.	O
+
+Incident	O
+hydrocephalus	O
+events	O
+were	O
+identified	O
+in	O
+42	O
+SMA	O
+cases	O
+and	O
+9	O
+non	O
+-	O
+SMA	O
+controls	O
+.	O
+
+Hydrocephalus	O
+incidence	B-STAT
+rates	I-STAT
+per	I-STAT
+100,000	I-STAT
+person	I-STAT
+-	O
+months	O
+were	O
+15.5	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+11.2	O
+-	O
+20.9	O
+)	O
+among	O
+SMA	O
+cases	O
+and	O
+3.3	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+1.5	O
+-	O
+6.3	O
+)	O
+among	O
+non	O
+-	O
+SMA	O
+controls	O
+.	O
+
+The	O
+incidence	B-EPI
+rate	O
+ratio	O
+was	O
+4.7	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+2.4	O
+-	O
+10.2	O
+)	O
+.	O
+
+Conclusions	O
+Based	O
+on	O
+this	O
+retrospective	O
+analysis	O
+utilizing	O
+US	B-LOC
+EHR	O
+data	O
+,	O
+SMA	O
+patients	O
+had	O
+an	O
+approximately	O
+fourfold	O
+increased	O
+risk	O
+of	O
+hydrocephalus	O
+compared	O
+with	O
+non	O
+-	O
+SMA	O
+controls	O
+in	O
+the	O
+era	O
+preceding	O
+nusinersen	O
+treatment	O
+.	O
+
+This	O
+study	O
+may	O
+assist	O
+in	O
+properly	O
+evaluating	O
+adverse	O
+events	O
+in	O
+nusinersen	O
+-	O
+treated	O
+SMA	O
+patients	O
+.	O
+
+Background	O
+Fulminant	O
+necrotising	O
+amoebic	O
+colitis	O
+(	O
+FulNAC	O
+)	O
+is	O
+an	O
+uncommon	O
+and	O
+grave	O
+complication	O
+of	O
+a	O
+very	O
+common	O
+infectious	O
+disease	O
+widely	O
+prevalent	B-EPI
+in	O
+tropical	O
+countries	O
+.	O
+
+In	O
+most	O
+of	O
+the	O
+cases	O
+reported	O
+,	O
+only	O
+a	O
+segment	O
+of	O
+large	O
+bowel	O
+was	O
+gangrenous	O
+.	O
+
+The	O
+involvement	O
+of	O
+the	O
+whole	O
+of	O
+the	O
+large	O
+bowel	O
+,	O
+as	O
+in	O
+our	O
+case	O
+,	O
+is	O
+very	O
+rare	O
+and	O
+has	O
+very	O
+high	O
+mortality	O
+ranging	O
+from	O
+55	O
+%	O
+to	O
+100	O
+%	I-STAT
+.	O
+
+Case	O
+Summary	O
+.	O
+
+A	O
+50	O
+-	O
+year	O
+-	O
+old	O
+gentleman	O
+presented	O
+with	O
+an	O
+acute	O
+abdomen	O
+with	O
+a	O
+history	O
+of	O
+crampy	O
+abdominal	O
+pain	O
+and	O
+passage	O
+of	O
+blood	O
+mixed	O
+with	O
+mucous	O
+and	O
+loose	O
+stools	O
+.	O
+
+After	O
+resuscitation	O
+and	O
+investigations	O
+,	O
+the	O
+patient	O
+was	O
+taken	O
+up	O
+for	O
+laparotomy	O
+and	O
+the	O
+findings	O
+showed	O
+that	O
+the	O
+caecum	O
+was	O
+sloughed	O
+off	O
+and	O
+the	O
+entire	O
+large	O
+bowel	O
+had	O
+multiple	O
+perforations	O
+.	O
+
+Subtotal	O
+colectomy	O
+with	O
+ileostomy	O
+was	O
+performed	O
+.	O
+
+Histopathological	O
+examination	O
+showed	O
+evidence	O
+of	O
+pancolitis	O
+with	O
+multiple	O
+colonies	O
+of	O
+amoebic	O
+trophozoites	O
+.	O
+
+Discussion	O
+.	O
+
+Entamoeba	O
+histolytica	O
+is	O
+a	O
+protozoon	O
+that	O
+affects	O
+the	O
+large	O
+intestine	O
+and	O
+liver	O
+in	O
+humans	O
+.	O
+
+There	O
+can	O
+be	O
+various	O
+presentations	O
+of	O
+amoebiasis	O
+:	O
+asymptomatic	O
+infection	O
+(	O
+90	O
+%	O
+)	O
+,	O
+symptomatic	O
+noninvasive	O
+infection	O
+(	O
+6	B-STAT
+-	O
+8	O
+%	O
+)	O
+,	O
+acute	O
+amoebic	O
+colitis	O
+(	O
+dysentery	O
+)	O
+,	O
+or	O
+fulminant	O
+colitis	O
+with	O
+perforation	O
+.	O
+
+FulNAC	O
+is	O
+an	O
+uncommon	O
+complication	O
+,	O
+difficult	O
+to	O
+diagnose	O
+and	O
+treat	O
+,	O
+and	O
+associated	O
+with	O
+a	O
+high	O
+mortality	O
+rate	O
+,	O
+ranging	O
+from	O
+55	O
+%	O
+to	O
+100	O
+%	I-STAT
+.	O
+
+Conclusion	O
+It	O
+is	O
+important	O
+to	O
+consider	O
+the	O
+possibility	O
+of	O
+fulminant	O
+necrotising	O
+amoebic	O
+colitis	O
+(	O
+FulNAC	O
+)	O
+as	O
+an	O
+uncommon	O
+and	O
+fatal	O
+complication	O
+of	O
+amoebiasis	O
+,	O
+especially	O
+in	O
+tropical	O
+countries	O
+,	O
+where	O
+amoebiasis	O
+is	O
+prevalent	B-EPI
+.	O
+
+Early	O
+diagnosis	O
+and	O
+antiamoebic	O
+treatment	O
+,	O
+along	O
+with	O
+urgent	O
+aggressive	O
+surgical	O
+resection	O
+of	O
+the	O
+involved	O
+segment	O
+and	O
+exteriorization	O
+of	O
+the	O
+proximal	O
+and	O
+distal	O
+bowel	O
+ends	O
+,	O
+are	O
+shown	O
+to	O
+reduce	O
+mortality	O
+.	O
+
+Tight	O
+junctions	O
+are	O
+cellular	O
+junctions	O
+that	O
+play	O
+a	O
+major	O
+role	O
+in	O
+the	O
+epithelial	O
+barrier	O
+function	O
+.	O
+
+In	O
+the	O
+inner	O
+ear	O
+,	O
+claudins	O
+,	O
+occludin	O
+,	O
+tricellulin	O
+,	O
+and	O
+angulins	O
+form	O
+the	O
+bicellular	O
+or	O
+tricellular	O
+binding	O
+of	O
+membrane	O
+proteins	O
+.	O
+
+In	O
+these	O
+,	O
+one	O
+type	O
+of	O
+claudin	O
+gene	O
+,	O
+CLDN14	O
+,	O
+was	O
+reported	O
+to	O
+be	O
+responsible	O
+for	O
+human	O
+hereditary	O
+hearing	O
+loss	O
+,	O
+DFNB29	O
+.	O
+
+Until	O
+now	O
+,	O
+nine	O
+pathogenic	O
+variants	O
+have	O
+been	O
+reported	O
+,	O
+and	O
+most	O
+phenotypic	O
+features	O
+remain	O
+unclear	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+genetic	O
+screening	O
+for	O
+68	O
+previously	O
+reported	O
+deafness	O
+causative	O
+genes	O
+was	O
+carried	O
+out	O
+to	O
+identify	O
+CLDN14	O
+variants	O
+in	O
+a	O
+large	O
+series	O
+of	O
+Japanese	O
+hearing	O
+loss	O
+patients	O
+,	O
+and	O
+to	O
+clarify	O
+the	O
+prevalence	B-EPI
+and	O
+clinical	O
+characteristics	O
+of	O
+DFNB29	O
+in	O
+the	O
+Japanese	O
+population	O
+.	O
+
+One	O
+patient	O
+had	O
+a	O
+homozygous	O
+novel	O
+variant	O
+(	O
+c.241C	O
+>	O
+T	O
+:	O
+p	O
+.	O
+Arg81Cys	O
+)	O
+(	O
+0.04	B-STAT
+%	I-STAT
+:	O
+1/2549	B-STAT
+)	O
+.	O
+
+The	O
+patient	O
+showed	O
+progressive	O
+bilateral	O
+hearing	O
+loss	O
+,	O
+with	O
+post	O
+-	O
+lingual	O
+onset	O
+.	O
+
+Pure	O
+-	O
+tone	O
+audiograms	O
+indicated	O
+a	O
+high	O
+-	O
+frequency	O
+hearing	O
+loss	O
+type	O
+,	O
+and	O
+the	O
+deterioration	O
+gradually	O
+spread	O
+to	O
+other	O
+frequencies	O
+.	O
+
+The	O
+patient	O
+showed	O
+normal	O
+vestibular	O
+function	O
+.	O
+
+Cochlear	O
+implantation	O
+improved	O
+the	O
+patient	O
+'s	O
+sound	O
+field	O
+threshold	O
+levels	O
+,	O
+but	O
+not	O
+speech	O
+discrimination	O
+scores	O
+.	O
+
+This	O
+report	O
+indicated	O
+that	O
+claudin-14	O
+is	O
+essential	O
+for	O
+maintaining	O
+the	O
+inner	O
+ear	O
+environment	O
+and	O
+suggested	O
+the	O
+possible	O
+phenotypic	O
+expansion	O
+of	O
+DFNB29	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+report	O
+of	O
+a	O
+patient	O
+with	O
+a	O
+tight	O
+junction	O
+variant	O
+receiving	O
+a	O
+cochlear	O
+implantation	O
+.	O
+
+Age	O
+-	O
+related	O
+bone	O
+disorders	O
+such	O
+as	O
+osteoporosis	O
+or	O
+osteoarthritis	O
+are	O
+a	O
+major	O
+public	O
+health	O
+problem	O
+due	O
+to	O
+the	O
+functional	O
+disability	O
+for	O
+millions	O
+of	O
+people	O
+worldwide	B-LOC
+.	O
+
+Furthermore	O
+,	O
+fractures	O
+are	O
+associated	O
+with	O
+a	O
+higher	O
+degree	O
+of	O
+morbidity	O
+and	O
+mortality	O
+in	O
+the	O
+long	O
+term	O
+,	O
+which	O
+generates	O
+greater	O
+financial	O
+and	O
+health	O
+costs	O
+.	O
+
+As	O
+the	O
+world	O
+population	O
+becomes	O
+older	O
+,	O
+the	O
+incidence	B-EPI
+of	O
+this	O
+type	O
+of	O
+disease	O
+increases	O
+and	O
+this	O
+effect	O
+seems	O
+notably	O
+greater	O
+in	O
+those	O
+countries	O
+that	O
+present	O
+a	O
+more	O
+westernized	O
+lifestyle	O
+.	O
+
+Thus	O
+,	O
+increased	O
+efforts	O
+are	O
+directed	O
+toward	O
+reducing	O
+risks	O
+that	O
+need	O
+to	O
+focus	O
+not	O
+only	O
+on	O
+the	O
+prevention	O
+of	O
+bone	O
+diseases	O
+,	O
+but	O
+also	O
+on	O
+the	O
+treatment	O
+of	O
+persons	O
+already	O
+afflicted	O
+.	O
+
+Evidence	O
+is	O
+accumulating	O
+that	O
+dietary	O
+lipids	O
+play	O
+an	O
+important	O
+role	O
+in	O
+bone	O
+health	O
+which	O
+results	O
+relevant	O
+to	O
+develop	O
+effective	O
+interventions	O
+for	O
+prevent	O
+bone	O
+diseases	O
+or	O
+alterations	O
+,	O
+especially	O
+in	O
+the	O
+elderly	O
+segment	O
+of	O
+the	O
+population	O
+.	O
+
+This	O
+review	O
+focuses	O
+on	O
+evidence	O
+about	O
+the	O
+effects	O
+of	O
+dietary	O
+lipids	O
+on	O
+bone	O
+health	O
+and	O
+describes	O
+possible	O
+mechanisms	O
+to	O
+explain	O
+how	O
+lipids	O
+act	O
+on	O
+bone	O
+metabolism	O
+during	O
+aging	O
+.	O
+
+Little	O
+work	O
+,	O
+however	O
+,	O
+has	O
+been	O
+accomplished	O
+in	O
+humans	O
+,	O
+so	O
+this	O
+is	O
+a	O
+challenge	O
+for	O
+future	O
+research	O
+.	O
+
+Sjögren	O
+'s	O
+syndrome	O
+(	O
+SS	O
+)	O
+is	O
+a	O
+common	O
+systemic	O
+autoimmune	O
+disease	O
+.	O
+
+SS	O
+usually	O
+occurs	B-EPI
+among	O
+middle	O
+-	O
+aged	O
+women	O
+with	O
+a	O
+peak	O
+incidence	B-EPI
+age	O
+of	O
+approximately	O
+50	O
+years	O
+old	O
+.	O
+
+Kidney	O
+involvement	O
+is	O
+relatively	O
+uncommon	O
+in	O
+SS	O
+,	O
+which	O
+is	O
+mostly	O
+characterized	O
+as	O
+interstitial	O
+nephritis	O
+and	O
+may	O
+result	O
+in	O
+renal	O
+tubular	O
+acidosis	O
+(	O
+RTA	O
+)	O
+.	O
+
+But	O
+premature	O
+onset	O
+of	O
+SS	O
+seems	O
+to	O
+be	O
+prone	O
+to	O
+RTA	O
+.	O
+
+Here	O
+we	O
+reported	O
+four	O
+cases	O
+of	O
+premature	O
+onset	O
+SS	O
+who	O
+developed	O
+into	O
+RTA	O
+at	O
+a	O
+relatively	O
+young	O
+age	O
+and	O
+three	O
+of	O
+whom	O
+suffered	O
+from	O
+severe	O
+osteomalacia	O
+.	O
+
+All	O
+of	O
+them	O
+shared	O
+a	O
+disease	O
+onset	O
+under	O
+age	O
+eighteen	O
+.	O
+
+Two	O
+of	O
+them	O
+presented	O
+hypokalemic	O
+periodic	O
+paralysis	O
+initially	O
+,	O
+one	O
+presented	O
+purpura	O
+and	O
+one	O
+endured	O
+xerophthalmia	O
+at	O
+first	O
+place	O
+.	O
+
+Three	O
+of	O
+them	O
+complicated	O
+with	O
+osteomalacia	O
+under	O
+age	O
+thirty	O
+.	O
+
+All	O
+the	O
+4	O
+cases	O
+did	O
+n't	O
+receive	O
+proper	O
+medical	O
+care	O
+in	O
+time	O
+due	O
+to	O
+a	O
+prolonged	O
+delay	O
+of	O
+diagnosis	O
+.	O
+
+We	O
+aim	O
+to	O
+raise	O
+the	O
+alarm	O
+over	O
+misdiagnosis	O
+/	O
+underdiagnosis	O
+of	O
+the	O
+disorder	O
+among	O
+young	O
+people	O
+.	O
+
+Autosomal	O
+recessive	O
+interleukin-1	O
+receptor	O
+-	O
+associated	O
+kinase	O
+(	O
+IRAK)-4	O
+and	O
+myeloid	O
+differentiation	O
+factor	O
+(	O
+MyD)88	O
+deficiencies	O
+impair	O
+Toll	O
+-	O
+like	O
+receptor	O
+(	O
+TLR)-	B-LOC
+and	O
+interleukin-1	O
+receptor	O
+-	O
+mediated	O
+immunity	O
+.	O
+
+We	O
+documented	O
+the	O
+clinical	O
+features	O
+and	O
+outcome	O
+of	O
+48	O
+patients	O
+with	O
+IRAK-4	O
+deficiency	O
+and	O
+12	O
+patients	O
+with	O
+MyD88	O
+deficiency	O
+,	O
+from	O
+37	O
+kindreds	O
+in	O
+15	O
+countries	O
+.	O
+The	O
+clinical	O
+features	O
+of	O
+IRAK-4	O
+and	O
+MyD88	O
+deficiency	O
+were	O
+indistinguishable	O
+.	O
+
+There	O
+were	O
+no	O
+severe	O
+viral	O
+,	O
+parasitic	O
+,	O
+and	O
+fungal	O
+diseases	O
+,	O
+and	O
+the	O
+range	O
+of	O
+bacterial	O
+infections	O
+was	O
+narrow	O
+.	O
+
+Noninvasive	O
+bacterial	O
+infections	O
+occurred	O
+in	O
+52	O
+patients	O
+,	O
+with	O
+a	O
+high	O
+incidence	B-EPI
+of	O
+infections	O
+of	O
+the	O
+upper	O
+respiratory	O
+tract	O
+and	O
+the	O
+skin	O
+,	O
+mostly	O
+caused	O
+by	O
+Pseudomonas	O
+aeruginosa	O
+and	O
+Staphylococcus	O
+aureus	O
+,	O
+respectively	O
+.	O
+
+The	O
+leading	O
+threat	O
+was	O
+invasive	O
+pneumococcal	O
+disease	O
+,	O
+documented	O
+in	O
+41	O
+patients	O
+(	O
+68	O
+%	O
+)	O
+and	O
+causing	O
+72	O
+documented	O
+invasive	O
+infections	O
+(	O
+52.2	O
+%	O
+)	O
+.	O
+
+P.	O
+aeruginosa	O
+and	O
+Staph	O
+.	O
+
+aureus	O
+documented	O
+invasive	O
+infections	O
+also	O
+occurred	O
+(	O
+16.7	O
+%	O
+and	O
+16	O
+%	O
+,	O
+respectively	O
+,	O
+in	O
+13	O
+and	O
+13	O
+patients	O
+,	O
+respectively	O
+)	O
+.	O
+
+Systemic	O
+signs	O
+of	O
+inflammation	O
+were	O
+usually	O
+weak	O
+or	O
+delayed	O
+.	O
+
+The	O
+first	O
+invasive	O
+infection	O
+occurred	O
+before	O
+the	O
+age	O
+of	O
+2	O
+years	O
+in	O
+53	B-STAT
+(	O
+88.3	O
+%	O
+)	O
+and	O
+in	O
+the	O
+neonatal	O
+period	O
+in	O
+19	B-STAT
+(	O
+32.7	O
+%	O
+)	O
+patients	O
+.	O
+
+Multiple	O
+or	O
+recurrent	O
+invasive	O
+infections	O
+were	O
+observed	O
+in	O
+most	O
+survivors	O
+(	O
+n	O
+=	O
+36/50	O
+,	O
+72%).Clinical	O
+outcome	O
+was	O
+poor	O
+,	O
+with	O
+24	O
+deaths	O
+,	O
+in	O
+10	O
+cases	O
+during	O
+the	O
+first	O
+invasive	O
+episode	O
+and	O
+in	O
+16	O
+cases	O
+of	O
+invasive	O
+pneumococcal	O
+disease	O
+.	O
+
+However	O
+,	O
+no	O
+death	O
+and	O
+invasive	O
+infectious	O
+disease	O
+were	O
+reported	O
+in	O
+patients	O
+after	O
+the	O
+age	O
+of	O
+8	O
+years	O
+and	O
+14	O
+years	O
+,	O
+respectively	O
+.	O
+
+Antibiotic	O
+prophylaxis	O
+(	O
+n	O
+=	O
+34	O
+)	O
+,	O
+antipneumococcal	O
+vaccination	O
+(	O
+n	O
+=	O
+31	O
+)	O
+,	O
+and/or	O
+IgG	O
+infusion	O
+(	O
+n	O
+=	O
+19	O
+)	O
+,	O
+when	O
+instituted	O
+,	O
+had	O
+a	O
+beneficial	O
+impact	O
+on	O
+patients	O
+until	O
+the	O
+teenage	O
+years	O
+,	O
+with	O
+no	O
+seemingly	O
+detectable	O
+impact	O
+thereafter	O
+.	O
+IRAK-4	O
+and	O
+MyD88	O
+deficiencies	O
+predispose	O
+patients	O
+to	O
+recurrent	O
+life	O
+-	O
+threatening	O
+bacterial	O
+diseases	O
+,	O
+such	O
+as	O
+invasive	O
+pneumococcal	O
+disease	O
+in	O
+particular	O
+,	O
+in	O
+infancy	O
+and	O
+early	O
+childhood	O
+,	O
+with	O
+weak	O
+signs	O
+of	O
+inflammation	O
+.	O
+
+Patients	O
+and	O
+families	O
+should	O
+be	O
+informed	O
+of	O
+the	O
+risk	O
+of	O
+developing	O
+life	O
+-	O
+threatening	O
+infections	O
+;	O
+empiric	O
+antibacterial	O
+treatment	O
+and	O
+immediate	O
+medical	O
+consultation	O
+are	O
+strongly	O
+recommended	O
+in	O
+cases	O
+of	O
+suspected	O
+infection	O
+or	O
+moderate	O
+fever	O
+.	O
+
+Prophylactic	O
+measures	O
+in	O
+childhood	O
+are	O
+beneficial	O
+,	O
+until	O
+spontaneous	O
+improvement	O
+occurs	B-EPI
+in	O
+adolescence	O
+.	O
+
+Methylmalonic	O
+acidemia	O
+/	O
+aciduria	O
+(	O
+MMA	O
+)	O
+is	O
+a	O
+genetically	O
+heterogeneous	O
+group	O
+of	O
+inherited	O
+metabolic	O
+disorders	O
+biochemically	O
+characterized	O
+by	O
+the	O
+accumulation	O
+of	O
+methylmalonic	O
+acid	O
+.	O
+
+Isolated	O
+MMA	O
+is	O
+primarily	O
+caused	O
+by	O
+the	O
+deficiency	O
+of	O
+methylmalonyl	O
+-	O
+CoA	O
+mutase	O
+(	O
+MMA	O
+mut	O
+;	O
+EC	O
+5.4.99.2	O
+)	O
+.	O
+
+A	O
+systematic	O
+literature	O
+review	O
+and	O
+a	O
+meta	O
+-	O
+analysis	O
+were	O
+undertaken	O
+to	O
+assess	O
+and	O
+compile	O
+published	O
+epidemiological	O
+data	O
+on	O
+MMA	O
+with	O
+a	O
+focus	O
+on	O
+the	O
+MMA	O
+mut	O
+subtype	O
+(	O
+OMIM	O
+#	O
+251000	O
+)	O
+.	O
+
+Of	O
+the	O
+1114	O
+identified	O
+records	O
+,	O
+227	O
+papers	O
+were	O
+assessed	O
+for	O
+eligibility	O
+in	O
+full	O
+text	O
+,	O
+48	O
+articles	O
+reported	O
+on	O
+disease	O
+epidemiology	O
+,	O
+and	O
+39	O
+articles	O
+were	O
+included	O
+into	O
+the	O
+quantitative	O
+synthesis	O
+.	O
+
+Implementation	O
+of	O
+newborn	O
+screening	O
+in	O
+various	O
+countries	O
+has	O
+allowed	O
+for	O
+the	O
+estimation	O
+of	O
+birth	O
+prevalence	B-EPI
+of	O
+MMA	O
+and	O
+its	O
+isolated	O
+form	O
+.	O
+
+Meta	O
+-	O
+analysis	O
+pooled	O
+point	O
+estimates	O
+of	O
+MMA	O
+(	O
+all	O
+types	O
+)	O
+detection	O
+rates	O
+were	O
+0.79	O
+,	O
+1.12	O
+,	O
+1.22	O
+and	O
+6.04	B-STAT
+per	I-STAT
+100,000	I-STAT
+newborns	I-STAT
+in	O
+Asia	B-LOC
+-	I-LOC
+Pacific	I-LOC
+,	O
+Europe	B-LOC
+,	O
+North	B-LOC
+America	I-LOC
+and	O
+the	B-LOC
+Middle	I-LOC
+East	I-LOC
+and	O
+North	B-LOC
+Africa	I-LOC
+(	O
+MENA	O
+)	O
+regions	O
+,	O
+respectively	O
+.	O
+
+The	O
+detection	O
+rate	O
+of	O
+isolated	O
+MMA	O
+was	O
+<	B-STAT
+1	I-STAT
+per	I-STAT
+100,000	I-STAT
+newborns	I-STAT
+in	O
+all	O
+regions	O
+with	O
+the	O
+exception	O
+of	O
+MENA	O
+where	O
+it	O
+approached	B-STAT
+6	I-STAT
+per	I-STAT
+100,000	I-STAT
+newborns	I-STAT
+.	O
+
+Few	O
+studies	O
+published	O
+data	O
+on	O
+the	O
+epidemiology	O
+of	O
+MMA	O
+mut	O
+,	O
+therefore	O
+no	O
+meta	O
+-	O
+analysis	O
+could	O
+have	O
+been	O
+performed	O
+on	O
+this	O
+subtype	O
+.	O
+
+Most	O
+of	O
+the	O
+identified	O
+papers	O
+reported	O
+birth	O
+prevalence	B-EPI
+estimates	O
+below	O
+1	B-STAT
+per	I-STAT
+100,000	I-STAT
+newborns	I-STAT
+for	O
+MMA	O
+mut	O
+.	O
+
+The	O
+systematic	O
+literature	O
+review	O
+clearly	O
+demonstrates	O
+that	O
+MMA	O
+and	O
+its	O
+subtypes	O
+are	O
+ultra	O
+-	O
+rare	O
+disorders	O
+.	O
+
+Background	O
+:	O
+Neuroendocrine	O
+tumors	O
+(	O
+NETs	O
+)	O
+are	O
+rare	O
+,	O
+but	O
+their	O
+worldwide	B-LOC
+incidence	B-EPI
+is	O
+gradually	O
+increasing	O
+.	O
+
+NETs	O
+are	O
+generally	O
+heterogeneous	O
+;	O
+however	O
+,	O
+in	O
+rare	O
+cases	O
+,	O
+they	O
+have	O
+been	O
+shown	O
+to	O
+change	O
+their	O
+phenotype	O
+(	O
+i.e.	O
+,	O
+nonfunctional	O
+to	O
+functional	O
+or	O
+one	O
+functional	O
+phenotype	O
+to	O
+the	O
+addition	O
+of	O
+another	O
+functional	O
+phenotype	O
+)	O
+.	O
+
+Here	O
+,	O
+we	O
+present	O
+two	O
+cases	O
+of	O
+liver	O
+metastatic	O
+NETs	O
+with	O
+phenotype	O
+transformation	O
+at	O
+the	O
+advanced	O
+stage	O
+that	O
+led	O
+to	O
+life	O
+-	O
+threatening	O
+events	O
+.	O
+
+Case	O
+presentation	O
+:	O
+A	O
+73	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+had	O
+a	O
+small	O
+intestinal	O
+nonfunctional	O
+NET	O
+with	O
+liver	O
+metastasis	O
+.	O
+
+After	O
+uncontrollable	O
+liver	O
+metastasis	O
+at	O
+the	O
+advanced	O
+stage	O
+,	O
+she	O
+developed	O
+duodenal	O
+perforation	O
+with	O
+hypergastremia	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+octreotide	O
+and	O
+proton	O
+pump	O
+inhibitors	O
+and	O
+underwent	O
+endoscopic	O
+closure	O
+for	O
+duodenal	O
+perforation	O
+,	O
+but	O
+her	O
+general	O
+condition	O
+gradually	O
+deteriorated	O
+,	O
+and	O
+she	O
+died	O
+2	O
+weeks	O
+after	O
+duodenal	O
+perforation	O
+.	O
+
+Another	O
+patient	O
+,	O
+a	O
+50	O
+-	O
+year	O
+-	O
+old	O
+man	O
+,	O
+had	O
+a	O
+functional	O
+NET	O
+(	O
+gastrinoma	O
+)	O
+with	O
+liver	O
+metastasis	O
+and	O
+duodenal	O
+ulcer	O
+.	O
+
+After	O
+uncontrollable	O
+liver	O
+metastasis	O
+at	O
+the	O
+advanced	O
+stage	O
+,	O
+he	O
+developed	O
+hypoglycemia	O
+.	O
+
+Although	O
+octoreotide	O
+and	O
+diazoxide	O
+were	O
+administrated	O
+for	O
+hyperalimentation	O
+,	O
+his	O
+hypoglycemia	O
+was	O
+uncontrollable	O
+,	O
+and	O
+he	O
+died	O
+after	O
+4	O
+months	O
+owing	O
+to	O
+general	O
+deterioration	O
+.	O
+
+Conclusion	O
+:	O
+The	O
+present	O
+cases	O
+show	O
+that	O
+advanced	O
+NETs	O
+with	O
+treatment	O
+-	O
+uncontrollable	O
+liver	O
+metastasis	O
+can	O
+transform	O
+their	O
+phenotype	O
+,	O
+specifically	O
+from	O
+a	O
+nonfunctional	O
+NET	O
+into	O
+a	O
+functional	O
+NET	O
+,	O
+and	O
+from	O
+one	O
+functional	O
+NET	O
+into	O
+the	O
+addition	O
+of	O
+another	O
+functional	O
+NET	O
+.	O
+
+These	O
+experiences	O
+suggest	O
+that	O
+the	O
+presence	O
+of	O
+treatment	O
+-	O
+resistant	O
+liver	O
+metastasis	O
+might	O
+be	O
+a	O
+hallmark	O
+of	O
+the	O
+potential	O
+to	O
+gain	O
+novel	O
+functions	O
+.	O
+
+Inherited	O
+forms	O
+of	O
+deafness	O
+account	O
+for	O
+a	O
+sizable	O
+portion	O
+of	O
+hearing	O
+loss	O
+among	O
+children	O
+and	O
+adult	O
+populations	O
+.	O
+
+Many	O
+patients	O
+with	O
+sensorineural	O
+deficits	O
+have	O
+pathological	O
+manifestations	O
+in	O
+the	O
+peripheral	O
+auditory	O
+system	O
+,	O
+the	O
+inner	O
+ear	O
+.	O
+
+Within	O
+the	O
+hearing	O
+organ	O
+,	O
+the	O
+cochlea	O
+,	O
+most	O
+of	O
+the	O
+genetic	O
+forms	O
+of	O
+hearing	O
+loss	O
+involve	O
+defects	O
+in	O
+sensory	O
+detection	O
+and	O
+to	O
+some	O
+extent	O
+,	O
+signaling	O
+to	O
+the	O
+brain	O
+via	O
+the	O
+auditory	O
+cranial	O
+nerve	O
+.	O
+
+This	O
+review	O
+focuses	O
+on	O
+peripheral	O
+forms	O
+of	O
+hereditary	O
+hearing	O
+loss	O
+and	O
+how	O
+these	O
+impairments	O
+can	O
+be	O
+studied	O
+in	O
+diverse	O
+animal	O
+models	O
+or	O
+patient	O
+-	O
+derived	O
+cells	O
+with	O
+the	O
+ultimate	O
+goal	O
+of	O
+using	O
+the	O
+knowledge	O
+gained	O
+to	O
+understand	O
+the	O
+underlying	O
+biology	O
+and	O
+treat	O
+hearing	O
+loss	O
+.	O
+
+The	O
+clinical	O
+presentation	O
+except	O
+age	O
+of	O
+onset	O
+is	O
+similar	O
+in	O
+different	O
+types	O
+of	O
+angioedema	O
+.	O
+
+A	O
+lymphoproliferative	O
+disorder	O
+like	O
+angioimmunoblastic	O
+T	O
+cell	O
+lymphoma	O
+(	O
+AITL	O
+)	O
+rarely	O
+presents	O
+with	O
+symptoms	O
+of	O
+angioedema	O
+.	O
+
+We	O
+present	O
+extremely	O
+rare	O
+case	O
+of	O
+elderly	O
+male	O
+with	O
+recurrent	O
+tongue	O
+swelling	O
+,	O
+pruritus	O
+with	O
+normal	O
+levels	O
+of	O
+complements	O
+and	O
+C1	O
+esterase	O
+inhibitor	O
+protein	O
+featuring	O
+as	O
+acquired	O
+angioedema	O
+,	O
+a	O
+rare	O
+manifestation	O
+of	O
+AITL	O
+.	O
+
+Initial	O
+response	O
+to	O
+corticosteroids	O
+may	O
+be	O
+misleading	O
+and	O
+occurs	B-EPI
+as	O
+a	O
+result	O
+of	O
+immunosuppression	O
+of	O
+AITL	O
+.	O
+
+High	O
+index	O
+of	O
+suspicion	O
+may	O
+prompt	O
+need	O
+for	O
+histopathological	O
+diagnosis	O
+of	O
+lymph	O
+node	O
+biopsy	O
+.	O
+
+Definitive	O
+chemotherapeutic	O
+treatment	O
+may	O
+achieve	O
+long	O
+term	O
+remission	O
+.	O
+
+Objective	O
+/	O
+background	O
+Knowledge	O
+of	O
+idiopathic	O
+hypersomnia	O
+symptomatology	O
+derives	O
+from	O
+clinical	O
+case	O
+series	O
+.	O
+
+Web	O
+-	O
+based	O
+registries	O
+provide	O
+complementary	O
+information	O
+by	O
+allowing	O
+larger	O
+sample	O
+sizes	O
+,	O
+with	O
+greater	O
+geographic	O
+and	O
+social	O
+diversity	O
+.	O
+
+Patients	O
+/	O
+methods	O
+Data	O
+were	O
+obtained	O
+from	O
+the	O
+Hypersomnia	O
+Foundation	O
+'s	O
+online	O
+registry	O
+.	O
+
+Common	O
+clinical	O
+features	O
+of	O
+idiopathic	O
+hypersomnia	O
+and	O
+other	O
+central	O
+disorders	O
+of	O
+hypersomnolence	O
+were	O
+queried	O
+,	O
+for	O
+the	O
+last	O
+thirty	O
+days	O
+and	O
+when	O
+symptoms	O
+were	O
+most	O
+severe	O
+.	O
+
+Symptoms	O
+were	O
+compared	O
+between	O
+idiopathic	O
+hypersomnia	O
+participants	O
+with	O
+and	O
+without	O
+long	O
+sleep	O
+durations	O
+and	O
+between	O
+participants	O
+with	O
+idiopathic	O
+hypersomnia	O
+and	O
+those	O
+with	O
+either	O
+form	O
+of	O
+narcolepsy	O
+.	O
+
+Frequency	O
+of	O
+medication	O
+use	O
+and	O
+residual	O
+symptoms	O
+on	O
+medication	O
+were	O
+evaluated	O
+.	O
+
+Results	O
+Five	O
+-	O
+hundred	O
+sixty	O
+-	O
+three	O
+registry	O
+respondents	O
+were	O
+included	O
+,	O
+with	O
+idiopathic	O
+hypersomnia	O
+(	O
+n	O
+=	O
+468	O
+)	O
+,	O
+narcolepsy	O
+type	O
+2	O
+(	O
+n	O
+=	O
+44	O
+)	O
+,	O
+and	O
+narcolepsy	O
+type	O
+1	O
+(	O
+n	O
+=	O
+51	O
+)	O
+.	O
+
+	O
+Brain	O
+fog	O
+,	O
+	O
+poor	O
+memory	O
+,	O
+and	O
+sleep	O
+drunkenness	O
+were	O
+all	O
+present	O
+in	O
+most	O
+idiopathic	O
+hypersomnia	O
+respondents	O
+,	O
+with	O
+brain	O
+fog	O
+and	O
+sleep	O
+drunkenness	O
+more	O
+commonly	O
+endorsed	O
+by	O
+those	O
+with	O
+long	O
+sleep	O
+durations	O
+.	O
+
+Eighty	B-STAT
+-	O
+two	O
+percent	O
+of	O
+participants	O
+with	O
+idiopathic	O
+hypersomnia	O
+were	O
+currently	O
+treated	O
+with	O
+medication	O
+,	O
+most	O
+commonly	O
+traditional	O
+psychostimulants	O
+such	O
+as	O
+amphetamine	O
+salts	O
+.	O
+
+Among	O
+treated	O
+patients	O
+,	O
+symptoms	O
+improved	O
+while	O
+on	O
+medication	O
+,	O
+but	O
+substantial	O
+residual	O
+hypersomnia	O
+symptoms	O
+remained	O
+.	O
+
+Participants	O
+with	O
+narcolepsy	O
+type	O
+1	O
+were	O
+more	O
+likely	O
+than	O
+those	O
+with	O
+idiopathic	O
+hypersomnia	O
+to	O
+endorse	O
+intentional	O
+and	O
+unintentional	O
+daytime	O
+naps	O
+and	O
+automatic	O
+behaviors	O
+.	O
+
+Conclusions	O
+Symptoms	O
+of	O
+idiopathic	O
+hypersomnia	O
+extend	O
+well	O
+beyond	O
+excessive	O
+daytime	O
+sleepiness	O
+,	O
+and	O
+these	O
+symptoms	O
+frequently	O
+persist	O
+despite	O
+treatment	O
+.	O
+
+These	O
+findings	O
+highlight	O
+the	O
+importance	O
+of	O
+online	O
+registries	O
+in	O
+identifying	O
+gaps	O
+in	O
+the	O
+use	O
+and	O
+effectiveness	O
+of	O
+current	O
+treatments	O
+.	O
+
+The	O
+Ehlers	O
+-	O
+Danlos	O
+syndromes	O
+(	O
+EDS	O
+)	O
+are	O
+a	O
+group	O
+of	O
+13	O
+disorders	O
+,	O
+clinically	O
+defined	O
+through	O
+features	O
+of	O
+joint	O
+hypermobility	O
+,	O
+skin	O
+hyperextensibility	O
+,	O
+and	O
+tissue	O
+fragility	O
+.	O
+
+Most	O
+subtypes	O
+are	O
+caused	O
+by	O
+mutations	O
+in	O
+genes	O
+affecting	O
+the	O
+structure	O
+or	O
+processing	O
+of	O
+the	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+protein	O
+collagen	O
+.	O
+
+The	O
+Hypermobility	O
+Spectrum	O
+Disorders	O
+(	O
+HSDs	O
+)	O
+are	O
+clinically	O
+indistinguishable	O
+disorders	O
+,	O
+but	O
+are	O
+considered	O
+to	O
+lack	O
+a	O
+genetic	O
+basis	O
+.	O
+
+The	O
+pathogenesis	O
+of	O
+all	O
+these	O
+disorders	O
+,	O
+however	O
+,	O
+remains	O
+poorly	O
+understood	O
+.	O
+
+Genotype	O
+-	O
+phenotype	O
+correlations	O
+are	O
+limited	O
+,	O
+and	O
+findings	O
+of	O
+aberrant	O
+collagen	O
+fibrils	O
+are	O
+inconsistent	O
+and	O
+associate	O
+poorly	O
+with	O
+the	O
+subtype	O
+and	O
+severity	O
+of	O
+the	O
+disorder	O
+.	O
+
+The	O
+defective	O
+ECM	O
+,	O
+however	O
+,	O
+also	O
+has	O
+consequences	O
+for	O
+cellular	O
+processes	O
+.	O
+
+EDS	O
+/	O
+HSD	O
+fibroblasts	O
+exhibit	O
+a	O
+dysfunctional	O
+phenotype	O
+including	O
+impairments	O
+in	O
+cell	O
+adhesion	O
+and	O
+cytoskeleton	O
+organization	O
+,	O
+though	O
+the	O
+pathological	O
+significance	O
+of	O
+this	O
+has	O
+remained	O
+unclear	O
+.	O
+
+Recent	O
+advances	O
+in	O
+our	O
+understanding	O
+of	O
+fibroblast	O
+mechanobiology	O
+suggest	O
+these	O
+changes	O
+may	O
+actually	O
+reflect	O
+features	O
+of	O
+a	O
+pathomechanism	O
+we	O
+herein	O
+define	O
+.	O
+
+This	O
+review	O
+departs	O
+from	O
+the	O
+traditional	O
+view	O
+of	O
+EDS	O
+/	O
+HSD	O
+,	O
+where	O
+pathogenesis	O
+is	O
+mediated	O
+by	O
+the	O
+structurally	O
+defective	O
+ECM	O
+.	O
+
+Instead	O
+,	O
+we	O
+propose	O
+EDS	O
+/	O
+HSD	O
+may	O
+be	O
+a	O
+disorder	O
+of	O
+membrane	O
+-	O
+bound	O
+collagen	O
+,	O
+and	O
+consider	O
+how	O
+aberrations	O
+in	O
+cell	O
+adhesion	O
+and	O
+cytoskeleton	O
+dynamics	O
+could	O
+drive	O
+the	O
+abnormal	O
+properties	O
+of	O
+the	O
+connective	O
+tissue	O
+,	O
+and	O
+be	O
+responsible	O
+for	O
+the	O
+pathogenesis	O
+of	O
+EDS	O
+/	O
+HSD	O
+.	O
+
+Recessive	O
+mutations	O
+in	O
+genes	O
+encoding	O
+mitochondrial	O
+DNA	O
+replication	O
+machinery	O
+lead	O
+to	O
+mitochondrial	O
+DNA	O
+depletion	O
+syndromes	O
+.	O
+
+This	O
+genetically	O
+and	O
+phenotypically	O
+heterogeneous	O
+group	O
+includes	O
+infantile	O
+onset	O
+spinocerebellar	O
+ataxia	O
+(	O
+OMIM	O
+#	O
+271245	O
+)	O
+a	O
+neurodegenerative	O
+disease	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+mtDNA	O
+helicase	O
+gene	O
+,	O
+c10orf2	O
+,	O
+with	O
+an	O
+increased	O
+frequency	O
+in	O
+the	O
+Finnish	O
+population	O
+due	O
+to	O
+a	O
+founder	O
+mutation	O
+.	O
+
+We	O
+describe	O
+a	O
+child	O
+of	O
+English	O
+descent	O
+who	O
+presented	O
+with	O
+a	O
+severe	O
+phenotype	O
+of	O
+IOSCA	O
+as	O
+a	O
+result	O
+of	O
+two	O
+-	O
+novel	O
+mutations	O
+in	O
+the	O
+c10orf2	O
+gene	O
+.	O
+
+This	O
+paper	O
+expands	O
+the	O
+phenotypic	O
+spectrum	O
+of	O
+IOSCA	O
+and	O
+adds	O
+further	O
+evidence	O
+for	O
+the	O
+presence	O
+of	O
+a	O
+genotype	O
+-	O
+phenotype	O
+correlation	O
+among	O
+patients	O
+with	O
+recessive	O
+mutations	O
+in	O
+this	O
+gene	O
+.	O
+
+The	O
+world	O
+of	O
+dermatology	O
+is	O
+pieced	O
+together	O
+by	O
+clinical	O
+conditions	O
+unique	O
+in	O
+their	O
+colors	O
+,	O
+morphology	O
+,	O
+and	O
+configuration	O
+.	O
+
+Dermatological	O
+signs	O
+and	O
+terms	O
+are	O
+influenced	O
+by	O
+etymology	O
+,	O
+language	O
+,	O
+and	O
+history	O
+.	O
+
+Eponyms	O
+also	O
+make	O
+dermatology	O
+a	O
+fascinating	O
+but	O
+linguistically	O
+challenging	O
+subject	O
+.	O
+
+This	O
+article	O
+reviews	O
+dermatological	O
+conditions	O
+described	O
+in	O
+relation	O
+to	O
+fashion	O
+,	O
+and	O
+what	O
+we	O
+wear	O
+in	O
+everyday	O
+life	O
+from	O
+top	O
+to	O
+toe	O
+,	O
+demonstrating	O
+that	O
+dermatology	O
+can	O
+be	O
+inspired	O
+even	O
+in	O
+the	O
+most	O
+common	O
+things	O
+.	O
+
+Previous	O
+research	O
+has	O
+demonstrated	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+Coxiella	O
+burnetii	O
+in	O
+the	O
+bulk	O
+tank	O
+milk	O
+on	O
+large	O
+industrial	O
+dairy	O
+farms	O
+of	O
+the	O
+central	O
+and	O
+eastern	O
+European	O
+region	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+survey	O
+was	O
+to	O
+estimate	O
+the	O
+prevalence	B-EPI
+of	O
+specific	O
+IgG	O
+antibodies	O
+to	O
+C.	O
+burnetii	O
+proving	O
+previous	O
+infection	O
+among	O
+dairy	O
+farm	O
+workers	O
+and	O
+to	O
+determine	O
+the	O
+possible	O
+risk	O
+factors	O
+.	O
+
+Serum	O
+samples	O
+from	O
+veterinarians	O
+,	O
+inseminators	O
+,	O
+animal	O
+caretakers	O
+,	O
+milking	O
+parlor	O
+workers	O
+,	O
+and	O
+herd	O
+managers	O
+working	O
+on	O
+dairy	O
+farms	O
+were	O
+tested	O
+for	O
+the	O
+presence	O
+of	O
+IgG	O
+to	O
+phase	O
+I	O
+and	O
+phase	O
+II	O
+of	O
+C.	O
+burnetii	O
+using	O
+an	O
+indirect	O
+microimmunofluorescence	O
+assay	O
+.	O
+
+Antibodies	O
+phase	O
+II	O
+to	O
+C.	O
+burnetii	O
+were	O
+detected	O
+in	O
+59	O
+out	O
+of	O
+70	O
+individuals	O
+tested	O
+(	O
+84.3	O
+%	O
+)	O
+.	O
+
+All	O
+occupational	O
+groups	O
+are	O
+highly	O
+exposed	O
+to	O
+C.	O
+burnetii	O
+infection	O
+.	O
+
+Veterinarians	O
+,	O
+inseminators	O
+,	O
+and	O
+animal	O
+caretakers	O
+had	O
+100	O
+%	O
+seropositivity	O
+rate	O
+of	O
+phase	O
+II	O
+,	O
+whereas	O
+the	O
+seropositivity	O
+rate	O
+found	O
+among	O
+herd	O
+managers	O
+and	O
+milking	O
+parlor	O
+workers	O
+was	O
+71.4	O
+%	O
+and	O
+47	O
+%	O
+,	O
+respectively	O
+.	O
+
+The	O
+findings	O
+of	O
+this	O
+survey	O
+suggest	O
+that	O
+the	O
+risk	O
+of	O
+C.	O
+burnetii	O
+infection	O
+is	O
+correlated	O
+with	O
+cattle	O
+density	O
+in	O
+the	O
+large	O
+dairy	O
+farms	O
+and	O
+also	O
+with	O
+occupational	O
+groups	O
+.	O
+
+Craniofacial	O
+anomalies	O
+are	O
+among	O
+the	O
+most	O
+common	O
+birth	O
+defects	O
+and	O
+are	O
+associated	O
+with	O
+increased	O
+mortality	O
+and	O
+,	O
+in	O
+many	O
+cases	O
+,	O
+the	O
+need	O
+for	O
+lifelong	O
+treatment	O
+.	O
+
+Over	O
+the	O
+past	O
+few	O
+decades	O
+,	O
+dramatic	O
+advances	O
+in	O
+the	O
+surgical	O
+and	O
+medical	O
+care	O
+of	O
+these	O
+patients	O
+have	O
+led	O
+to	O
+marked	O
+improvements	O
+in	O
+patient	O
+outcomes	O
+.	O
+
+However	O
+,	O
+none	O
+of	O
+the	O
+treatments	O
+currently	O
+in	O
+clinical	O
+use	O
+address	O
+the	O
+underlying	O
+molecular	O
+causes	O
+of	O
+these	O
+disorders	O
+.	O
+
+Fortunately	O
+,	O
+the	O
+field	O
+of	O
+craniofacial	O
+developmental	O
+biology	O
+provides	O
+a	O
+strong	O
+foundation	O
+for	O
+improved	O
+diagnosis	O
+and	O
+for	O
+therapies	O
+that	O
+target	O
+the	O
+genetic	O
+causes	O
+of	O
+birth	O
+defects	O
+.	O
+
+In	O
+this	O
+chapter	O
+,	O
+we	O
+discuss	O
+recent	O
+advances	O
+in	O
+our	O
+understanding	O
+of	O
+the	O
+embryology	O
+of	O
+craniofacial	O
+conditions	O
+,	O
+and	O
+we	O
+focus	O
+on	O
+the	O
+use	O
+of	O
+animal	O
+models	O
+to	O
+guide	O
+rational	O
+therapies	O
+anchored	O
+in	O
+genetics	O
+and	O
+biochemistry	O
+.	O
+
+Objective	O
+Classic	O
+congenital	O
+adrenal	O
+hyperplasia	O
+(	O
+CAH	O
+)	O
+secondary	O
+to	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+is	O
+characterized	O
+by	O
+increased	O
+prenatal	O
+adrenal	O
+androgen	O
+secretion	O
+.	O
+
+There	O
+are	O
+a	O
+small	O
+number	O
+of	O
+reports	O
+in	O
+the	O
+literature	O
+showing	O
+higher	O
+birth	O
+weight	O
+and	O
+length	O
+in	O
+CAH	O
+newborns	O
+.	O
+
+Methods	O
+We	O
+analyzed	O
+birth	O
+weight	O
+and	O
+length	O
+data	O
+of	O
+116	O
+German	O
+newborns	O
+(	O
+48	O
+boys	O
+,	O
+68	O
+girls	O
+)	O
+with	O
+classic	O
+CAH	O
+who	O
+were	O
+born	O
+during	O
+the	O
+period	O
+from	O
+1990	O
+to	O
+2017	O
+.	O
+
+All	O
+children	O
+have	O
+been	O
+followed	O
+or	O
+are	O
+currently	O
+treated	O
+as	O
+outpatients	O
+in	O
+our	O
+clinic	O
+.	O
+
+All	O
+children	O
+were	O
+born	O
+at	O
+term	O
+.	O
+
+The	O
+mothers	O
+were	O
+healthy	O
+and	O
+their	O
+pregnancies	O
+were	O
+uneventful	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+CAH	O
+was	O
+confirmed	O
+by	O
+molecular	O
+analyses	O
+of	O
+the	O
+CYP21A2	O
+gene	O
+.	O
+
+Birth	O
+data	O
+were	O
+calculated	O
+as	O
+standard	O
+deviation	O
+(	O
+SD	O
+)	O
+scores	O
+according	O
+to	O
+German	O
+reference	O
+values	O
+.	O
+
+Results	O
+Weight	O
+and	O
+length	O
+in	O
+male	O
+CAH	O
+newborns	O
+(	O
+mean	O
+±	O
+SD	O
+)	O
+(	O
+3601±576	O
+g	O
+;	O
+52.4±2.85	O
+cm	O
+)	O
+were	O
+significantly	O
+higher	O
+than	O
+in	O
+female	O
+CAH	O
+newborns	O
+(	O
+3347±442	O
+g	O
+;	O
+51.2±2.55	O
+cm	O
+)	O
+,	O
+but	O
+male	O
+-	O
+female	O
+differences	O
+in	O
+the	O
+CAH	O
+cohort	O
+were	O
+lost	O
+when	O
+the	O
+data	O
+were	O
+converted	O
+into	O
+SD	O
+scores	O
+.	O
+
+The	O
+birth	O
+sizes	O
+of	O
+the	O
+CAH	O
+newborns	O
+did	O
+not	O
+differ	O
+from	O
+the	O
+reference	O
+group	O
+.	O
+
+The	O
+birth	O
+sizes	O
+also	O
+did	O
+not	O
+differ	O
+between	O
+the	O
+different	O
+CAH	O
+genotypes	O
+.	O
+
+Maternal	O
+age	O
+,	O
+mode	O
+of	O
+delivery	O
+and	O
+maternal	O
+parity	O
+had	O
+no	O
+influence	O
+on	O
+birth	O
+size	O
+.	O
+
+Conclusion	O
+Our	O
+data	O
+show	O
+that	O
+prenatal	O
+hyperandrogenism	O
+does	O
+not	O
+affect	O
+fetal	O
+growth	O
+.	O
+
+Clinical	O
+disorders	O
+known	O
+to	O
+affect	O
+inherited	O
+gamma	O
+-	O
+amino	O
+butyric	O
+acid	O
+(	O
+GABA	O
+)	O
+metabolism	O
+are	O
+autosomal	O
+recessively	O
+inherited	O
+succinic	O
+semialdehyde	O
+dehydrogenase	O
+and	O
+GABA	O
+-	O
+transaminase	O
+deficiency	O
+.	O
+
+The	O
+clinical	O
+presentation	O
+of	O
+succinic	O
+semialdehyde	O
+dehydrogenase	O
+deficiency	O
+includes	O
+intellectual	O
+disability	O
+,	O
+ataxia	O
+,	O
+obsessive	O
+-	O
+compulsive	O
+disorder	O
+and	O
+epilepsy	O
+with	O
+a	O
+nonprogressive	O
+course	O
+in	O
+typical	O
+cases	O
+,	O
+although	O
+a	O
+progressive	O
+form	O
+in	O
+early	O
+childhood	O
+as	O
+well	O
+as	O
+deterioration	O
+in	O
+adulthood	O
+with	O
+worsening	O
+epilepsy	O
+are	O
+reported	O
+.	O
+
+GABA	O
+-	O
+transaminase	O
+deficiency	O
+is	O
+associated	O
+with	O
+a	O
+severe	O
+neonatal	O
+-	O
+infantile	O
+epileptic	O
+encephalopathy	O
+.	O
+
+Purpose	O
+To	O
+describe	O
+the	O
+molecular	O
+epidemiology	O
+of	O
+nonsyndromic	O
+retinitis	O
+pigmentosa	O
+(	O
+RP	O
+)	O
+and	O
+Usher	O
+syndrome	O
+(	O
+US	B-LOC
+)	O
+in	O
+Italian	O
+patients	O
+.	O
+
+Methods	O
+A	O
+total	O
+of	O
+591	O
+probands	O
+(	O
+315	O
+with	O
+family	O
+history	O
+and	O
+276	O
+sporadics	O
+)	O
+were	O
+analyzed	O
+.	O
+
+For	O
+155	O
+of	O
+them	O
+,	O
+we	O
+performed	O
+a	O
+family	O
+segregation	O
+study	O
+,	O
+considering	O
+a	O
+total	O
+of	O
+382	O
+relatives	O
+.	O
+
+Probands	O
+were	O
+analyzed	O
+by	O
+a	O
+customized	O
+multigene	O
+panel	O
+approach	O
+.	O
+
+Sanger	O
+sequencing	O
+was	O
+used	O
+to	O
+validate	O
+all	O
+genetic	O
+variants	O
+and	O
+to	O
+perform	O
+family	O
+segregation	O
+studies	O
+.	O
+
+Copy	O
+number	O
+variants	O
+of	O
+selected	O
+genes	O
+were	O
+analyzed	O
+by	O
+multiplex	O
+ligation	O
+-	O
+dependent	O
+probe	O
+amplification	O
+.	O
+
+Four	O
+patients	O
+who	O
+tested	O
+negative	O
+to	O
+targeted	O
+next	O
+-	O
+generation	O
+sequencing	O
+analysis	O
+underwent	O
+clinical	O
+exome	O
+sequencing	O
+.	O
+
+Results	O
+The	O
+mean	O
+diagnostic	O
+yield	O
+of	O
+molecular	O
+testing	O
+among	O
+patients	O
+with	O
+a	O
+family	O
+history	O
+of	O
+retinal	O
+disorders	O
+was	O
+55.2	O
+%	O
+while	O
+the	O
+diagnostic	O
+yield	O
+including	O
+sporadic	O
+cases	O
+was	O
+37.4	B-STAT
+%	I-STAT
+.	O
+
+We	O
+found	O
+468	O
+potentially	O
+pathogenic	O
+variants	O
+,	O
+147	O
+of	O
+which	O
+were	O
+unpublished	O
+,	O
+in	O
+308	O
+probands	O
+and	O
+66	O
+relatives	O
+.	O
+
+Mean	O
+ages	O
+of	O
+onset	O
+of	O
+the	O
+different	O
+classes	O
+of	O
+RP	O
+were	O
+autosomal	O
+dominant	O
+RP	O
+,	O
+19.3	O
+±	O
+12.6	O
+years	O
+;	O
+autosomal	O
+recessive	O
+RP	O
+,	O
+23.2	O
+±	O
+16.6	O
+years	O
+;	O
+X	O
+-	O
+linked	O
+RP	O
+,	O
+13.9	O
+±	O
+9.9	O
+years	O
+;	O
+and	O
+Usher	O
+syndrome	O
+,	O
+18.9	O
+±	O
+9.5	O
+years	O
+.	O
+
+We	O
+reported	O
+potential	O
+new	O
+genotype	O
+-	O
+phenotype	O
+correlations	O
+in	O
+three	O
+probands	O
+,	O
+two	O
+revealed	O
+by	O
+TruSight	O
+One	O
+testing	O
+.	O
+
+All	O
+three	O
+probands	O
+showed	O
+isolated	O
+RP	O
+caused	O
+by	O
+biallelic	O
+variants	O
+in	O
+genes	O
+usually	O
+associated	O
+with	O
+syndromes	O
+such	O
+as	O
+PERCHING	O
+and	O
+Senior	O
+-	O
+Loken	O
+or	O
+with	O
+retinal	O
+dystrophy	O
+,	O
+iris	O
+coloboma	O
+,	O
+and	O
+comedogenic	O
+acne	O
+syndrome	O
+.	O
+
+Conclusions	O
+This	O
+is	O
+the	O
+largest	O
+molecular	O
+study	O
+of	O
+Italian	O
+patients	O
+with	O
+RP	O
+in	O
+the	O
+literature	O
+,	O
+thus	O
+reflecting	O
+the	O
+epidemiology	O
+of	O
+the	O
+disease	O
+in	O
+Italy	B-LOC
+with	O
+reasonable	O
+accuracy	O
+.	O
+
+Nontuberculous	O
+mycobacterial	O
+(	O
+NTM	O
+)	O
+infections	O
+in	O
+humans	O
+have	O
+increased	O
+in	O
+prevalence	B-EPI
+in	O
+recent	O
+decades	O
+.	O
+
+Mycobacterium	O
+kansasii	O
+is	O
+one	O
+of	O
+the	O
+most	O
+prevalent	B-EPI
+human	O
+pathogenic	O
+NTM	O
+species	O
+worldwide	B-LOC
+.	O
+
+Herein	O
+,	O
+we	O
+report	O
+the	O
+first	O
+isolation	O
+of	O
+M.	O
+kansasii	O
+from	O
+an	O
+indoor	O
+domestic	O
+cat	O
+in	O
+Japan	B-LOC
+.	O
+
+Comparative	O
+genome	O
+sequence	O
+analysis	O
+of	O
+the	O
+feline	O
+isolate	O
+showed	O
+this	O
+pathogen	O
+is	O
+genetically	O
+identical	O
+to	O
+human	O
+pathogenic	O
+M.	O
+kansasii	O
+.	O
+
+This	O
+finding	O
+suggests	O
+that	O
+M.	O
+kansasii	O
+has	O
+a	O
+potential	O
+risk	O
+of	O
+zoonoses	O
+and	O
+requires	O
+the	O
+	O
+One	O
+Health	O
+	O
+approach	O
+to	O
+control	O
+NTM	O
+infection	O
+.	O
+
+Hearing	O
+loss	O
+is	O
+highly	O
+prevalent	B-EPI
+and	O
+may	O
+significantly	O
+affect	O
+how	O
+we	O
+age	O
+.	O
+
+Although	O
+the	O
+population	O
+is	O
+aging	O
+,	O
+relatively	O
+few	O
+adults	O
+receive	O
+treatment	O
+for	O
+hearing	O
+loss	O
+.	O
+
+Internists	O
+are	O
+a	O
+critical	O
+partner	O
+to	O
+audiologists	O
+and	O
+otolaryngologists	O
+in	O
+caring	O
+for	O
+the	O
+adult	O
+population	O
+with	O
+hearing	O
+loss	O
+.	O
+
+This	O
+review	O
+provides	O
+a	O
+primer	O
+on	O
+diagnosing	O
+and	O
+managing	O
+hearing	O
+loss	O
+.	O
+
+Q	O
+fever	O
+can	O
+present	O
+as	O
+a	O
+fever	O
+of	O
+unknown	O
+aetiology	O
+and	O
+can	O
+be	O
+challenging	O
+to	O
+diagnose	O
+because	O
+of	O
+the	O
+rare	O
+incidence	B-EPI
+.	O
+
+It	O
+can	O
+present	O
+as	O
+an	O
+acute	O
+illness	O
+with	O
+manifestations	O
+,	O
+including	O
+influenza	O
+-	O
+like	O
+symptoms	O
+,	O
+hepatitis	O
+,	O
+pneumonia	O
+or	O
+chronic	O
+disease	O
+involving	O
+the	O
+cardiovascular	O
+system	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+a	O
+39	O
+-	O
+year	O
+-	O
+old	O
+woman	O
+in	O
+the	O
+USA	B-LOC
+,	O
+who	O
+developed	O
+acute	O
+Q	O
+fever	O
+with	O
+associated	O
+sepsis	O
+and	O
+severe	O
+hepatitis	O
+.	O
+
+She	O
+received	O
+treatment	O
+with	O
+recovery	O
+from	O
+acute	O
+infection	O
+but	O
+currently	O
+has	O
+symptoms	O
+of	O
+post	O
+Q	O
+fever	O
+syndrome	O
+.	O
+
+Background	O
+Approximately	O
+70	O
+%	O
+of	O
+congenital	O
+deafness	O
+is	O
+attributable	O
+to	O
+genetic	O
+causes	O
+.	O
+
+Incidence	B-EPI
+of	O
+congenital	O
+deafness	O
+is	O
+known	O
+to	O
+be	O
+higher	O
+in	O
+families	O
+with	O
+consanguineous	O
+marriage	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+investigated	O
+the	O
+genetic	O
+causes	O
+in	O
+three	O
+consanguineous	O
+Pakistani	O
+families	O
+segregating	O
+with	O
+prelingual	O
+,	O
+severe	O
+-	O
+to	O
+-	O
+profound	O
+deafness	O
+.	O
+
+Results	O
+Through	O
+targeted	O
+next	O
+-	O
+generation	O
+sequencing	O
+of	O
+414	O
+genes	O
+known	O
+to	O
+be	O
+associated	O
+with	O
+deafness	O
+,	O
+homozygous	O
+variants	O
+c.536del	O
+(	O
+p.	O
+Leu180Serfs∗20	O
+)	O
+in	O
+TECTA	O
+,	O
+c.3719	O
+G	O
+>	O
+A	O
+(	O
+p.	O
+Arg1240Gln	O
+)	O
+in	O
+MYO7A	B-LOC
+,	O
+and	O
+c.482	O
++	O
+1986_1988del	O
+in	O
+HGF	O
+were	O
+identified	O
+as	O
+the	O
+pathogenic	O
+causes	O
+of	O
+enrolled	O
+families	O
+.	O
+
+Interestingly	O
+,	O
+in	O
+one	O
+large	O
+consanguineous	O
+family	O
+,	O
+an	O
+additional	O
+c.706G	O
+>	O
+A	O
+(	O
+p.	O
+Glu236Lys	O
+)	O
+variant	O
+in	O
+the	O
+X	O
+-	O
+linked	O
+POU3F4	O
+gene	O
+was	O
+also	O
+identified	O
+in	O
+multiple	O
+affected	O
+family	O
+members	O
+causing	O
+deafness	O
+.	O
+
+Genotype	O
+-	O
+phenotype	O
+cosegregation	O
+was	O
+confirmed	O
+in	O
+all	O
+participating	O
+family	O
+members	O
+by	O
+Sanger	O
+sequencing	O
+.	O
+
+Conclusions	O
+Our	O
+results	O
+showed	O
+that	O
+the	O
+genetic	O
+causes	O
+of	O
+deafness	O
+are	O
+highly	O
+heterogeneous	O
+.	O
+
+Even	O
+within	O
+a	O
+single	O
+family	O
+,	O
+the	O
+affected	O
+members	O
+with	O
+apparently	O
+indistinguishable	O
+clinical	O
+phenotypes	O
+may	O
+have	O
+different	O
+pathogenic	O
+variants	O
+.	O
+
+Diseases	O
+of	O
+the	O
+retina	O
+are	O
+major	O
+causes	O
+of	O
+visual	O
+impairment	O
+and	O
+blindness	O
+in	O
+developed	O
+countries	O
+and	O
+,	O
+due	O
+to	O
+an	O
+ageing	O
+population	O
+,	O
+their	O
+prevalence	B-EPI
+is	O
+continually	O
+rising	O
+.	O
+
+The	O
+lack	O
+of	O
+effective	O
+therapies	O
+and	O
+the	O
+limitations	O
+of	O
+those	O
+currently	O
+in	O
+use	O
+highlight	O
+the	O
+importance	O
+of	O
+continued	O
+research	O
+into	O
+the	O
+pathogenesis	O
+of	O
+these	O
+diseases	O
+.	O
+
+Vascular	O
+endothelial	O
+growth	O
+factor	O
+(	O
+VEGF	O
+)	O
+plays	O
+a	O
+major	O
+role	O
+in	O
+driving	O
+vascular	O
+dysfunction	O
+in	O
+retinal	O
+disease	O
+and	O
+has	O
+therefore	O
+become	O
+a	O
+key	O
+therapeutic	O
+target	O
+.	O
+
+Recent	O
+evidence	O
+also	O
+points	O
+to	O
+a	O
+potentially	O
+similarly	O
+important	O
+role	O
+of	O
+galectins	O
+,	O
+a	O
+family	O
+of	O
+β	O
+-	O
+galactoside	O
+-	O
+binding	O
+proteins	O
+.	O
+
+Indeed	O
+,	O
+they	O
+have	O
+been	O
+implicated	O
+in	O
+regulating	O
+fundamental	O
+processes	O
+,	O
+including	O
+vascular	O
+hyperpermeability	O
+,	O
+angiogenesis	O
+,	O
+neuroinflammation	O
+,	O
+and	O
+oxidative	O
+stress	O
+,	O
+all	O
+of	O
+which	O
+also	O
+play	O
+a	O
+prominent	O
+role	O
+in	O
+retinopathies	O
+.	O
+
+Here	O
+,	O
+we	O
+review	O
+direct	O
+evidence	O
+for	O
+pathological	O
+roles	O
+of	O
+galectins	O
+in	O
+retinal	O
+disease	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+extrapolate	O
+potential	O
+roles	O
+of	O
+galectins	O
+in	O
+the	O
+retina	O
+from	O
+evidence	O
+in	O
+cancer	O
+,	O
+immune	O
+and	O
+neuro	O
+-	O
+biology	O
+.	O
+
+We	O
+conclude	O
+that	O
+there	O
+is	O
+value	O
+in	O
+increasing	O
+understanding	O
+of	O
+galectin	O
+function	O
+in	O
+retinal	O
+biology	O
+,	O
+in	O
+particular	O
+in	O
+the	O
+context	O
+of	O
+the	O
+retinal	O
+vasculature	O
+and	O
+microglia	O
+.	O
+
+With	O
+greater	O
+insight	O
+,	O
+recent	O
+clinical	O
+developments	O
+of	O
+galectin	O
+-	O
+targeting	O
+drugs	O
+could	O
+potentially	O
+also	O
+be	O
+of	O
+benefit	O
+to	O
+the	O
+clinical	O
+management	O
+of	O
+many	O
+blinding	O
+diseases	O
+.	O
+
+Introduction	O
+Classic	O
+bladder	O
+exstrophy	O
+(	O
+BE	O
+)	O
+is	O
+regarded	O
+as	O
+an	O
+isolated	O
+malformation	O
+without	O
+any	O
+further	O
+anomalies	O
+,	O
+but	O
+some	O
+studies	O
+have	O
+indicated	O
+a	O
+higher	O
+incidence	B-EPI
+of	O
+cardiac	O
+anomalies	O
+.	O
+
+This	O
+cross	O
+-	O
+sectional	O
+study	O
+is	O
+planned	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+of	O
+congenital	O
+heart	O
+defects	O
+(	O
+CHDs	O
+)	O
+and	O
+the	O
+clinical	O
+relevance	O
+for	O
+patients	O
+with	O
+BE	O
+admitted	O
+for	O
+primary	O
+closure	O
+.	O
+
+Materials	O
+and	O
+methods	O
+Patients	O
+were	O
+prospectively	O
+recruited	O
+between	O
+March	O
+2012	O
+and	O
+January	O
+2019	O
+.	O
+
+Patients	O
+'	O
+profiles	O
+including	O
+demographic	O
+data	O
+,	O
+results	O
+of	O
+transthoracic	O
+echocardiography	O
+(	O
+TTE	O
+)	O
+,	O
+as	O
+well	O
+as	O
+essential	O
+peri-	O
+and	O
+postoperative	O
+data	O
+were	O
+assessed	O
+.	O
+
+Results	O
+Thirty	O
+-	O
+nine	O
+(	O
+25	O
+boys	O
+and	O
+14	O
+girls	O
+)	O
+patients	O
+with	O
+BE	O
+(	O
+median	O
+age	O
+61	O
+days	O
+)	O
+underwent	O
+delayed	O
+primary	O
+bladder	O
+closure	O
+.	O
+
+Thirty	O
+-	O
+seven	O
+(	O
+24	O
+boys	O
+and	O
+13	O
+girls	O
+)	O
+patients	O
+had	O
+received	O
+TTE	O
+1	O
+day	O
+before	O
+surgery	O
+.	O
+
+CHD	O
+was	O
+detected	O
+in	O
+7	B-STAT
+(	O
+18.9	O
+%	O
+)	O
+out	O
+of	O
+the	O
+39	O
+patients	O
+,	O
+but	O
+no	O
+clinical	O
+differences	O
+between	O
+patients	O
+with	O
+and	O
+without	O
+CHD	O
+were	O
+observed	O
+peri-	O
+or	O
+postoperatively	O
+.	O
+
+Discussion	O
+and	O
+conclusion	O
+This	O
+prospective	O
+systematic	O
+evaluation	O
+shows	O
+an	O
+even	O
+higher	O
+rate	O
+of	O
+CHD	O
+in	O
+patients	O
+with	O
+BE	O
+than	O
+assumed	O
+previously	O
+.	O
+
+Although	O
+peri-	O
+and	O
+postoperative	O
+outcome	O
+did	O
+not	O
+differ	O
+between	O
+patients	O
+with	O
+and	O
+without	O
+CHD	O
+,	O
+we	O
+consider	O
+TTE	O
+an	O
+important	O
+additional	O
+method	O
+for	O
+ensuring	O
+a	O
+safe	O
+peri-	O
+and	O
+postoperative	O
+courses	O
+and	O
+a	O
+short-	O
+and	O
+long	O
+-	O
+term	O
+care	O
+for	O
+patients	O
+with	O
+CHD	O
+.	O
+
+Oculomotor	O
+abnormalities	O
+are	O
+common	O
+in	O
+the	O
+spinocerebellar	O
+ataxias	O
+(	O
+SCAs	O
+)	O
+.	O
+
+In	O
+studies	O
+of	O
+SCAs	O
+1	B-STAT
+,	I-STAT
+2	I-STAT
+,	O
+3	O
+,	O
+and	O
+6	O
+,	O
+eye	O
+movement	O
+abnormalities	O
+correlate	O
+with	O
+disease	O
+severity	O
+.	O
+
+Oculomotor	O
+abnormalities	O
+may	O
+be	O
+the	O
+sole	O
+motor	O
+manifestation	O
+of	O
+early	O
+and/or	O
+premanifest	O
+disease	O
+;	O
+however	O
+,	O
+not	O
+all	O
+ataxia	O
+rating	O
+scales	O
+include	O
+oculomotor	O
+assessment	O
+.	O
+
+We	O
+sought	O
+to	O
+identify	O
+the	O
+prevalence	B-EPI
+and	O
+characteristics	O
+of	O
+oculomotor	O
+abnormalities	O
+at	O
+first	O
+presentation	O
+in	O
+a	O
+large	O
+SCA	O
+cohort	O
+,	O
+including	O
+those	O
+in	O
+earlier	O
+stages	O
+of	O
+disease	O
+.	O
+
+We	O
+performed	O
+a	O
+retrospective	O
+assessment	O
+of	O
+initial	O
+clinical	O
+examinations	O
+of	O
+SCA	O
+patients	O
+followed	O
+in	O
+the	O
+Massachusetts	O
+General	O
+Hospital	O
+Ataxia	O
+Unit	O
+and	O
+assessed	O
+with	O
+the	O
+Brief	O
+Ataxia	O
+Rating	O
+Scale	O
+(	O
+BARS	O
+)	O
+.	O
+
+One	O
+hundred	O
+thirty	O
+-	O
+four	O
+SCA	O
+patients	O
+were	O
+assessed	O
+:	O
+17	O
+SCA1	O
+,	O
+13	O
+SCA2	O
+,	O
+55	O
+SCA3	O
+,	O
+2	O
+SCA5	O
+,	O
+22	O
+SCA6	O
+,	O
+11	O
+SCA7	O
+,	O
+9	O
+SCA8	O
+,	O
+and	O
+5	O
+SCA17	O
+,	O
+mainly	O
+in	O
+the	O
+early	O
+stages	O
+of	O
+disease	O
+(	O
+67.2	O
+%	O
+stage	O
+0	O
+-	O
+1	O
+)	O
+.	O
+
+Oculomotor	O
+abnormalities	O
+were	O
+present	O
+on	O
+initial	O
+assessment	O
+in	O
+94.8	O
+%	O
+,	O
+including	O
+7/9	B-STAT
+stage	O
+0	B-STAT
+and	I-STAT
+77/81	I-STAT
+stage	O
+1	O
+patients	O
+.	O
+
+Stage	O
+0/1	B-STAT
+patients	O
+had	O
+frequent	O
+saccadic	O
+intrusions	O
+,	O
+nystagmus	O
+,	O
+and	O
+hypo	O
+/	O
+hypermetric	O
+saccades	O
+.	O
+
+Saccadic	O
+slowing	O
+was	O
+present	O
+even	O
+in	O
+early	O
+stage	O
+SCA7	O
+and	O
+SCA2	O
+,	O
+eventually	O
+leading	O
+to	O
+ophthalmoplegia	O
+.	O
+
+The	O
+burden	O
+of	O
+oculomotor	O
+abnormalities	O
+correlated	O
+with	O
+disease	O
+stage	O
+,	O
+duration	O
+,	O
+and	O
+severity	O
+,	O
+remaining	O
+highly	O
+significant	O
+even	O
+when	O
+controlling	O
+for	O
+age	O
+.	O
+
+The	O
+ubiquitous	O
+presence	O
+of	O
+oculomotor	O
+abnormalities	O
+in	O
+the	O
+SCAs	O
+,	O
+particularly	O
+early	O
+in	O
+the	O
+course	O
+,	O
+underscores	O
+the	O
+importance	O
+of	O
+oculomotor	O
+assessment	O
+in	O
+ataxia	O
+rating	O
+scales	O
+such	O
+as	O
+BARS	O
+.	O
+
+These	O
+findings	O
+highlight	O
+the	O
+potential	O
+for	O
+quantitative	O
+physiological	O
+oculomotor	O
+measures	O
+as	O
+clinical	O
+biomarkers	O
+in	O
+natural	O
+history	O
+studies	O
+and	O
+clinical	O
+trials	O
+.	O
+
+Carbimazole	O
+(	O
+CMZ	O
+)	O
+and	O
+its	O
+active	O
+metabolite	O
+methimazole	O
+(	O
+MMI	O
+)	O
+are	O
+antithyroid	O
+medications	O
+,	O
+which	O
+can	O
+result	O
+in	O
+MMI	O
+/	O
+CMZ	O
+embryopathy	O
+in	O
+susceptible	O
+individuals	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+birth	O
+defects	O
+related	O
+to	O
+MMI	O
+/	O
+CMZ	O
+embryopathy	O
+remains	O
+unclear	O
+as	O
+several	O
+epidemiologic	O
+studies	O
+failed	O
+to	O
+prove	O
+a	O
+correlation	O
+,	O
+despite	O
+positive	O
+case	O
+-	O
+control	O
+studies	O
+and	O
+numerous	O
+case	O
+reports	O
+.	O
+
+Malformations	O
+reported	O
+in	O
+exposed	O
+individuals	O
+and	O
+commonly	O
+recognized	O
+as	O
+MMI	O
+/	O
+CMZ	O
+embryopathy	O
+include	O
+cutis	O
+aplasia	O
+of	O
+the	O
+scalp	O
+,	O
+choanal	O
+atresia	O
+,	O
+esophageal	O
+atresia	O
+(	O
+EA	O
+)	O
+,	O
+tracheo	O
+-	O
+esophageal	O
+fistula	O
+(	O
+TEF	O
+)	O
+,	O
+persistent	O
+vitelline	O
+duct	O
+,	O
+athelia	O
+/	O
+hypothelia	O
+,	O
+and	O
+subtle	O
+facial	O
+dysmorphisms	O
+including	O
+sparse	O
+or	O
+arched	O
+eyebrows	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+on	O
+individuals	O
+with	O
+early	O
+pregnancy	O
+exposure	O
+to	O
+MMI	O
+,	O
+with	O
+microtia	O
+and	O
+various	O
+other	O
+anomalies	O
+associated	O
+with	O
+MMI	O
+embryopathy	O
+,	O
+suggesting	O
+that	O
+microtia	O
+is	O
+also	O
+seen	O
+with	O
+increased	O
+frequency	O
+after	O
+prenatal	O
+MMI	O
+exposure	O
+.	O
+
+Additional	O
+unusual	O
+malformations	O
+among	O
+our	O
+patients	O
+include	O
+a	O
+previously	O
+unreported	O
+type	O
+of	O
+TEF	O
+with	O
+three	O
+separate	O
+esophageal	O
+pouches	O
+and	O
+a	O
+fistula	O
+connecting	O
+the	O
+middle	O
+pouch	O
+to	O
+the	O
+trachea	O
+in	O
+one	O
+child	O
+,	O
+and	O
+absence	O
+of	O
+the	O
+gall	O
+bladder	O
+in	O
+another	O
+.	O
+
+An	O
+enlarged	O
+anterior	O
+fontanel	O
+was	O
+seen	O
+in	O
+three	O
+patients	O
+,	O
+and	O
+clinodactyly	O
+of	O
+the	O
+fifth	O
+finger	O
+was	O
+noted	O
+in	O
+three	O
+.	O
+
+The	O
+similarities	O
+between	O
+our	O
+three	O
+patients	O
+with	O
+microtia	O
+after	O
+MMI	O
+exposure	O
+and	O
+the	O
+two	O
+previously	O
+reported	O
+with	O
+microtia	O
+after	O
+CMZ	O
+exposure	O
+support	O
+the	O
+concept	O
+of	O
+microtia	O
+being	O
+related	O
+to	O
+the	O
+MMI	O
+/	O
+CMZ	O
+exposure	O
+.	O
+
+Recognition	O
+of	O
+microtia	O
+as	O
+a	O
+manifestation	O
+of	O
+MMI	O
+/	O
+CMZ	O
+embryopathy	O
+will	O
+likely	O
+increase	O
+the	O
+number	O
+of	O
+diagnosed	O
+cases	O
+and	O
+thus	O
+affect	O
+ascertainment	O
+.	O
+
+We	O
+propose	O
+diagnostic	O
+criteria	O
+for	O
+MMI	O
+/	O
+CMZ	O
+embryopathy	O
+,	O
+including	O
+the	O
+presence	O
+of	O
+at	O
+least	O
+one	O
+major	O
+characteristic	O
+finding	O
+.	O
+
+Distal	O
+renal	O
+tubular	O
+acidosis	O
+(	O
+dRTA	O
+)	O
+,	O
+or	O
+RTA	O
+type	O
+1	O
+,	O
+a	O
+rare	O
+inherited	O
+or	O
+acquired	O
+disease	O
+,	O
+is	O
+a	O
+disorder	O
+of	O
+the	O
+distal	O
+tubule	O
+caused	O
+by	O
+impaired	O
+urinary	O
+acid	O
+secretion	O
+.	O
+
+Due	O
+to	O
+associated	O
+conditions	O
+and	O
+nonspecific	O
+symptoms	O
+,	O
+dRTA	O
+may	O
+go	O
+undetected	O
+.	O
+
+This	O
+analysis	O
+aims	O
+to	O
+estimate	O
+the	O
+prevalence	B-EPI
+of	O
+dRTA	O
+in	O
+the	O
+UK	O
+Clinical	O
+Practice	O
+Research	O
+Datalink	O
+(	O
+CPRD	O
+)	O
+databases	O
+and	O
+extrapolate	O
+it	O
+to	O
+European	O
+Union	O
+Five	O
+(	O
+EU5	O
+)	O
+populations	O
+.	O
+
+A	O
+retrospective	O
+analysis	O
+was	O
+conducted	O
+using	O
+the	O
+CPRD	O
+GOLD	O
+database	O
+and	O
+linked	O
+Hospital	O
+Episode	O
+Statistics	O
+(	O
+HES	O
+)	O
+data	O
+to	O
+identify	O
+diagnosed	O
+and	O
+potentially	O
+undiagnosed	O
+or	O
+miscoded	O
+patients	O
+(	O
+suspected	O
+patients	O
+)	O
+.	O
+
+Patients	O
+'	O
+records	O
+with	O
+at	O
+least	O
+one	O
+diagnosis	O
+code	O
+for	O
+dRTA	O
+,	O
+RTA	O
+,	O
+specific	O
+autoimmune	O
+diseases	O
+,	O
+or	O
+renal	O
+disorders	O
+recorded	O
+between	O
+January	O
+1987	O
+and	O
+November	O
+2017	O
+were	O
+obtained	O
+and	O
+analyzed	O
+.	O
+
+An	O
+algorithm	O
+was	O
+developed	O
+to	O
+detect	O
+potentially	O
+undiagnosed	O
+/	O
+miscoded	O
+dRTA	O
+,	O
+based	O
+on	O
+associated	O
+conditions	O
+and	O
+prescriptions	O
+.	O
+
+A	O
+total	O
+of	O
+216	O
+patients	O
+with	O
+diagnosis	O
+of	O
+RTA	O
+or	O
+dRTA	O
+were	O
+identified	O
+(	O
+with	O
+98	O
+linked	O
+to	O
+hospital	O
+data	O
+)	O
+,	O
+and	O
+447	O
+patients	O
+were	O
+identified	O
+as	O
+having	O
+suspected	O
+dRTA	O
+.	O
+
+dRTA	O
+prevalence	B-EPI
+for	O
+2017	O
+was	O
+estimated	O
+between	O
+0.46	O
+(	O
+recorded	O
+cases	O
+,	O
+of	O
+which	O
+22.1	O
+%	O
+were	O
+considered	O
+primary	O
+)	O
+and	O
+1.60	O
+when	O
+including	O
+suspected	O
+cases	O
+(	O
+7.6	O
+%	O
+primary	O
+)	O
+per	I-STAT
+10,000	I-STAT
+people	I-STAT
+.	O
+
+Prescription	O
+and	O
+clinical	O
+records	O
+of	O
+diagnosed	O
+patients	O
+revealed	O
+a	O
+wide	O
+range	O
+of	O
+comorbidities	O
+and	O
+a	O
+need	O
+for	O
+pharmacological	O
+treatment	O
+to	O
+manage	O
+associated	O
+symptoms	O
+.	O
+
+The	O
+study	O
+provides	O
+new	O
+estimates	O
+of	O
+dRTA	O
+prevalence	B-EPI
+in	O
+Europe	B-LOC
+and	O
+suggests	O
+that	O
+patients	O
+may	O
+often	O
+be	O
+unreported	O
+or	O
+miscoded	O
+,	O
+potentially	O
+confounding	O
+appropriate	O
+disease	O
+management	O
+.	O
+
+It	O
+has	O
+been	O
+well	O
+-	O
+established	O
+that	O
+cancer	O
+cells	O
+are	O
+under	O
+constant	O
+oxidative	O
+stress	O
+,	O
+as	O
+reflected	O
+by	O
+elevated	O
+basal	O
+level	O
+of	O
+reactive	O
+oxygen	O
+species	O
+(	O
+ROS	O
+)	O
+,	O
+due	O
+to	O
+increased	O
+metabolism	O
+driven	O
+by	O
+aberrant	O
+cell	O
+growth	O
+.	O
+
+Cancer	O
+cells	O
+can	O
+adapt	O
+to	O
+maintain	O
+redox	O
+homeostasis	O
+through	O
+a	O
+variety	O
+of	O
+mechanisms	O
+.	O
+
+The	O
+prevalent	B-EPI
+perception	O
+about	O
+ROS	O
+is	O
+that	O
+they	O
+are	O
+one	O
+of	O
+the	O
+key	O
+drivers	O
+promoting	O
+tumor	O
+initiation	O
+,	O
+progression	O
+,	O
+metastasis	O
+,	O
+and	O
+drug	O
+resistance	O
+.	O
+
+Based	O
+on	O
+this	O
+notion	O
+,	O
+numerous	O
+antioxidants	O
+that	O
+aim	O
+to	O
+mitigate	O
+tumor	O
+oxidative	O
+stress	O
+have	O
+been	O
+tested	O
+for	O
+cancer	O
+prevention	O
+or	O
+treatment	O
+,	O
+although	O
+the	O
+effectiveness	O
+of	O
+this	O
+strategy	O
+has	O
+yet	O
+to	O
+be	O
+established	O
+.	O
+
+In	O
+recent	O
+years	O
+,	O
+it	O
+has	O
+been	O
+increasingly	O
+appreciated	O
+that	O
+ROS	O
+have	O
+a	O
+complex	O
+,	O
+multifaceted	O
+role	O
+in	O
+the	O
+tumor	O
+microenvironment	O
+(	O
+TME	O
+)	O
+,	O
+and	O
+that	O
+tumor	O
+redox	O
+can	O
+be	O
+targeted	O
+to	O
+amplify	O
+oxidative	O
+stress	O
+inside	O
+the	O
+tumor	O
+to	O
+cause	O
+tumor	O
+destruction	O
+.	O
+
+Accumulating	O
+evidence	O
+indicates	O
+that	O
+cancer	O
+immunotherapies	O
+can	O
+alter	O
+tumor	O
+redox	O
+to	O
+intensify	O
+tumor	O
+oxidative	O
+stress	O
+,	O
+resulting	O
+in	O
+ROS	O
+-	O
+dependent	O
+tumor	O
+rejection	O
+.	O
+
+Herein	O
+we	O
+review	O
+the	O
+recent	O
+progresses	O
+regarding	O
+the	O
+impact	O
+of	O
+ROS	O
+on	O
+cancer	O
+cells	O
+and	O
+various	O
+immune	O
+cells	O
+in	O
+the	O
+TME	O
+,	O
+and	O
+discuss	O
+the	O
+emerging	O
+ROS	O
+-	O
+modulating	O
+strategies	O
+that	O
+can	O
+be	O
+used	O
+in	O
+combination	O
+with	O
+cancer	O
+immunotherapies	O
+to	O
+achieve	O
+enhanced	O
+antitumor	O
+effects	O
+.	O
+
+The	O
+recent	O
+discovery	O
+of	O
+genes	O
+involved	O
+in	O
+familial	O
+forms	O
+of	O
+nephrotic	O
+syndrome	O
+represents	O
+a	O
+break	O
+-	O
+through	O
+in	O
+nephrology	O
+.	O
+
+To	O
+date	O
+,	O
+15	O
+genes	O
+have	O
+been	O
+characterized	O
+and	O
+several	O
+new	O
+loci	O
+have	O
+been	O
+identified	O
+,	O
+with	O
+a	O
+potential	O
+for	O
+discovery	O
+of	O
+new	O
+genes	O
+.	O
+
+Overall	O
+,	O
+these	O
+genes	O
+account	O
+for	O
+a	O
+large	O
+fraction	O
+of	O
+familial	O
+forms	O
+of	O
+nephrotic	O
+syndrome	O
+,	O
+but	O
+they	O
+can	O
+also	O
+be	O
+recognized	O
+in	O
+10	B-STAT
+-	O
+20	O
+%	O
+of	O
+sporadic	O
+cases	O
+.	O
+
+These	O
+advances	O
+increase	O
+diagnostic	O
+and	O
+therapeutic	O
+potentials	O
+,	O
+but	O
+also	O
+add	O
+higher	O
+complexity	O
+to	O
+the	O
+scenario	O
+,	O
+requiring	O
+clear	O
+definitions	O
+of	O
+clinical	O
+,	O
+histopathological	O
+and	O
+molecular	O
+signatures	O
+.	O
+
+In	O
+general	O
+,	O
+genetic	O
+forms	O
+of	O
+nephrotic	O
+syndrome	O
+are	O
+resistant	O
+to	O
+common	O
+therapeutic	O
+approaches	O
+(	O
+that	O
+include	O
+steroids	O
+and	O
+calcineurin	O
+inhibitors	O
+)	O
+but	O
+,	O
+in	O
+a	O
+few	O
+cases	O
+,	O
+drug	O
+response	O
+or	O
+spontaneous	O
+remission	O
+suggest	O
+a	O
+complex	O
+pathogenesis	O
+.	O
+
+Finally	O
+,	O
+syndromic	O
+variants	O
+can	O
+be	O
+recognized	O
+on	O
+the	O
+basis	O
+of	O
+the	O
+associated	O
+extra	O
+-	O
+renal	O
+manifestations	O
+.	O
+
+In	O
+this	O
+educational	O
+review	O
+,	O
+clinical	O
+,	O
+histological	O
+and	O
+molecular	O
+aspects	O
+of	O
+various	O
+forms	O
+of	O
+familial	O
+nephrotic	O
+syndrome	O
+have	O
+been	O
+reviewed	O
+in	O
+an	O
+attempt	O
+to	O
+define	O
+a	O
+rational	O
+diagnostic	O
+approach	O
+.	O
+
+The	O
+proposed	O
+model	O
+focuses	O
+on	O
+practical	O
+and	O
+economic	O
+issues	O
+,	O
+taking	O
+into	O
+consideration	O
+the	O
+impossibility	O
+of	O
+using	O
+genetic	O
+testing	O
+as	O
+starting	O
+diagnostic	O
+tool	O
+.	O
+
+The	O
+final	O
+objective	O
+of	O
+this	O
+review	O
+is	O
+to	O
+outline	O
+a	O
+diagnostic	O
+flow	O
+-	O
+chart	O
+for	O
+clinicians	O
+and	O
+geneticists	O
+and	O
+to	O
+generate	O
+a	O
+rational	O
+scheme	O
+for	O
+molecular	O
+testing	O
+.	O
+
+Pyridoxine	O
+-	O
+dependent	O
+epilepsy	O
+(	O
+PDE	O
+)	O
+is	O
+a	O
+recessive	O
+genetic	O
+disease	O
+characterized	O
+by	O
+epileptic	O
+encephalopathy	O
+with	O
+therapeutic	O
+response	O
+to	O
+pharmacological	O
+doses	O
+of	O
+pyridoxine	O
+and	O
+resistance	O
+to	O
+anti	O
+-	O
+epileptic	O
+treatments	O
+.	O
+
+The	O
+recent	O
+discovery	O
+in	O
+2006	O
+of	O
+the	O
+genetic	O
+defect	O
+antiquitin	O
+(	O
+ALDH7A1	O
+,	O
+OMIM	O
+#	O
+266100	O
+)	O
+has	O
+helped	O
+to	O
+understand	O
+the	O
+underlying	O
+mechanism	O
+,	O
+which	O
+is	O
+the	O
+accumulation	O
+of	O
+neurotoxic	O
+intermediates	O
+in	O
+the	O
+lysine	O
+catabolic	O
+pathway	O
+.	O
+
+The	O
+goal	O
+of	O
+the	O
+new	O
+therapeutic	O
+approach	O
+,	O
+termed	O
+triple	O
+therapy	O
+(	O
+TT	O
+)	O
+(	O
+pyridoxine	O
+,	O
+lysine	O
+-	O
+restricted	O
+diet	O
+and	O
+arginine	O
+supplementation	O
+)	O
+,	O
+is	O
+to	O
+improve	O
+epilepsy	O
+control	O
+and	O
+neurocognitive	O
+development	O
+in	O
+patients	O
+with	O
+PDE	O
+.	O
+
+We	O
+present	O
+the	O
+3	O
+-	O
+year	O
+treatment	O
+outcome	O
+for	O
+a	O
+child	O
+with	O
+PDE	O
+on	O
+pyridoxine	O
+treatment	O
+(	O
+started	O
+at	O
+age	O
+5	O
+months	O
+)	O
+,	O
+lysine	O
+-	O
+restricted	O
+diet	O
+(	O
+started	O
+at	O
+age	O
+17	O
+months	O
+)	O
+and	O
+arginine	O
+supplementation	O
+therapy	O
+(	O
+started	O
+at	O
+age	O
+19	O
+months	O
+)	O
+.	O
+
+The	O
+TT	O
+was	O
+well	O
+-	O
+tolerated	O
+with	O
+good	O
+compliance	O
+.	O
+
+No	O
+adverse	O
+events	O
+were	O
+reported	O
+.	O
+
+We	O
+observed	O
+a	O
+neurodevelopmental	O
+improvement	O
+,	O
+significantly	O
+fewer	O
+seizures	O
+,	O
+and	O
+a	O
+reduction	O
+of	O
+pipecolic	O
+acid	O
+(	O
+PA	O
+)	O
+as	O
+a	O
+biomarker	O
+of	O
+the	O
+illness	O
+.	O
+
+Our	O
+results	O
+show	O
+an	O
+improving	O
+clinical	O
+evolution	O
+,	O
+supporting	O
+and	O
+extending	O
+previous	O
+studies	O
+reporting	O
+efficacy	O
+of	O
+TT	O
+.	O
+
+Objectives	O
+To	O
+review	O
+the	O
+data	O
+of	O
+infants	O
+and	O
+children	O
+with	O
+suspected	O
+monogenic	O
+diabetes	O
+who	O
+underwent	O
+genetic	O
+testing	O
+.	O
+
+Methods	O
+Monogenic	O
+diabetes	O
+is	O
+a	O
+rare	O
+form	O
+of	O
+diabetes	O
+resulting	O
+from	O
+mutations	O
+in	O
+a	O
+single	O
+gene	O
+.	O
+
+It	O
+can	O
+be	O
+caused	O
+by	O
+dominant	O
+as	O
+well	O
+as	O
+recessive	O
+modes	O
+of	O
+inheritance	O
+.	O
+
+In	O
+a	O
+country	O
+like	O
+Pakistan	B-LOC
+where	O
+interfamily	O
+marriages	O
+are	O
+common	O
+the	O
+incidence	B-EPI
+of	O
+genetic	O
+disorders	O
+is	O
+increased	O
+.	O
+
+As	O
+Pakistan	B-LOC
+a	O
+resource	O
+-	O
+poor	O
+country	O
+,	O
+the	O
+diagnosis	O
+of	O
+insulin	O
+-	O
+dependent	O
+diabetes	O
+is	O
+often	O
+delayed	O
+and	O
+a	O
+genetic	O
+diagnosis	O
+of	O
+monogenic	O
+diabetes	O
+is	O
+extremely	O
+difficult	O
+.	O
+
+Children	O
+with	O
+clinical	O
+diagnosis	O
+of	O
+monogenic	O
+and	O
+syndromic	O
+diabates	O
+were	O
+recruited	O
+and	O
+blood	O
+samples	O
+were	O
+sent	O
+for	O
+genetic	O
+analysis	O
+.	O
+
+Results	O
+One	O
+thousand	O
+sixty	O
+four	O
+new	O
+cases	O
+diagnosed	O
+with	O
+type	O
+1	O
+diabetes	O
+were	O
+registered	O
+at	O
+the	O
+National	O
+Institute	O
+of	O
+Child	O
+Health	O
+,	O
+Karachi	B-LOC
+,	O
+in	O
+the	O
+last	O
+10	O
+years	O
+.	O
+
+Of	O
+these	O
+39	O
+patients	O
+were	O
+selected	O
+for	O
+genetic	O
+testing	O
+who	O
+were	O
+diagnosed	O
+with	O
+diabetes	O
+/	O
+had	O
+a	O
+sibling	O
+diagnosed	O
+with	O
+diabetes	O
+before	O
+the	O
+age	O
+of	O
+nine	O
+months	O
+(	O
+n	O
+=	O
+27	O
+)	O
+or	O
+had	O
+extra	O
+pancreatic	O
+features	O
+(	O
+n=	O
+12	O
+)	O
+.	O
+
+We	O
+identified	O
+mutations	O
+in	O
+18/27	B-STAT
+cases	O
+diagnosed	O
+with	O
+diabetes	O
+before	O
+nine	O
+months	O
+of	O
+age	O
+.	O
+
+The	O
+most	O
+common	O
+genetic	O
+subtype	O
+was	O
+WolcottRallison	O
+syndrome	O
+caused	O
+by	O
+EIF2AK3	O
+mutations	O
+(	O
+seven	O
+cases	O
+)	O
+.	O
+
+KCNJ11	O
+mutations	O
+were	O
+identified	O
+in	O
+two	O
+cases	O
+,	O
+ABCC8	O
+mutations	O
+were	O
+identified	O
+in	O
+four	O
+cases	O
+from	O
+three	O
+families	O
+,	O
+GCK	O
+and	O
+INS	O
+mutations	O
+were	O
+each	O
+identified	O
+in	O
+two	O
+cases	O
+,	O
+and	O
+one	O
+SLC2A2	O
+mutation	O
+was	O
+identified	O
+in	O
+one	O
+case	O
+.	O
+
+A	O
+genetic	O
+diagnosis	O
+was	O
+made	O
+in	O
+12/12	B-STAT
+children	O
+from	O
+six	O
+families	O
+with	O
+diabetes	O
+diagnosed	O
+after	O
+the	O
+age	O
+of	O
+nine	O
+months	O
+who	O
+had	O
+extrapancreatic	O
+features	O
+.	O
+
+Six	O
+patients	O
+had	O
+genetically	O
+confirmed	O
+Wolfram	O
+syndrome	O
+(	O
+WFS1	O
+)	O
+,	O
+three	O
+had	O
+thiamine	O
+-	O
+responsive	O
+megaloblastic	O
+anemia	O
+(	O
+SLC19A2	O
+)	O
+and	O
+three	O
+were	O
+diagnosed	O
+with	O
+histocytosis	O
+lymphadenopathy	O
+plus	O
+syndrome	O
+(	O
+SLC29A3	O
+)	O
+.	O
+
+Conclusions	O
+Genetic	O
+testing	O
+is	O
+essential	O
+to	O
+confirm	O
+a	O
+diagnosis	O
+of	O
+monogenic	O
+diabetes	O
+which	O
+guides	O
+clinical	O
+management	O
+and	O
+future	O
+counselling	O
+.	O
+
+Our	O
+study	O
+highlights	O
+the	O
+importance	O
+of	O
+diagnosing	O
+monogenic	O
+diabetes	O
+in	O
+the	O
+largely	O
+consanguineously	O
+-	O
+married	O
+population	O
+of	O
+Pakistan	B-LOC
+.	O
+
+Frontal	O
+fibrosing	O
+alopecia	O
+(	O
+FFA	O
+)	O
+is	O
+a	O
+variant	O
+of	O
+lichen	O
+planopilaris	O
+(	O
+LPP	O
+)	O
+with	O
+characteristic	O
+band	O
+-	O
+like	O
+frontotemporal	O
+hairline	O
+involvement	O
+and	O
+eyebrow	O
+loss	O
+.	O
+
+It	O
+most	O
+commonly	O
+occurs	B-EPI
+in	O
+post	O
+-	O
+menopausal	O
+White	O
+women	O
+.	O
+
+1	O
+In	O
+skin	O
+of	O
+color	O
+(	O
+SOC	O
+)	O
+individuals	O
+,	O
+FFA	O
+is	O
+often	O
+misdiagnosed	O
+as	O
+traction	O
+alopecia	O
+(	O
+TA	O
+)	O
+,	O
+2	O
+and	O
+little	O
+data	O
+exists	O
+regarding	O
+the	O
+presentation	O
+of	O
+FFA	O
+in	O
+the	O
+SOC	O
+patient	O
+population	O
+.	O
+
+3	O
+As	O
+FFA	O
+incidence	B-EPI
+continues	O
+to	O
+increase	O
+,	O
+4	O
+we	O
+aim	O
+to	O
+understand	O
+differences	O
+in	O
+the	O
+presentation	O
+of	O
+FFA	O
+between	O
+White	O
+and	O
+Black	O
+women	O
+in	O
+order	O
+to	O
+aid	O
+in	O
+the	O
+accurate	O
+and	O
+timely	O
+diagnosis	O
+as	O
+well	O
+as	O
+help	O
+inform	O
+prognosis	O
+and	O
+management	O
+.	O
+
+Unilateral	O
+lung	O
+agenesis	O
+is	O
+a	O
+relatively	O
+rare	O
+congenital	O
+anomaly	O
+with	O
+a	O
+reported	O
+incidence	B-EPI
+of	O
+1	B-STAT
+in	I-STAT
+15	I-STAT
+000	I-STAT
+births	I-STAT
+.	O
+
+It	O
+is	O
+frequently	O
+associated	O
+with	O
+other	O
+congenital	O
+malformations	O
+.	O
+
+Some	O
+of	O
+the	O
+sequelae	O
+of	O
+lung	O
+agenesis	O
+are	O
+potentially	O
+life	O
+-	O
+threatening	O
+.	O
+
+Here	O
+,	O
+we	O
+report	O
+a	O
+case	O
+of	O
+left	O
+lung	O
+agenesis	O
+in	O
+association	O
+with	O
+hiatal	O
+hernia	O
+and	O
+atrioventricular	O
+septal	O
+defect	O
+,	O
+a	O
+rare	O
+combination	O
+of	O
+anomalies	O
+which	O
+have	O
+not	O
+been	O
+described	O
+previously	O
+in	O
+the	O
+literature	O
+.	O
+
+Li	O
+-	O
+Fraumeni	O
+syndrome	O
+(	O
+LFS	O
+)	O
+is	O
+a	O
+hereditary	O
+cancer	O
+predisposition	O
+syndrome	O
+,	O
+with	O
+the	O
+characteristics	O
+of	O
+early	O
+onset	O
+of	O
+cancer	O
+and	O
+high	O
+cancer	O
+incidence	B-EPI
+.	O
+
+TP53	O
+is	O
+widely	O
+accepted	O
+as	O
+a	O
+pathogenic	O
+gene	O
+of	O
+LFS	O
+.	O
+
+A	O
+2	O
+years	O
+and	O
+6	O
+months	O
+old	O
+boy	O
+is	O
+reported	O
+in	O
+this	O
+article	O
+,	O
+who	O
+was	O
+diagnosed	O
+with	O
+embryonal	O
+rhabdomyosarcoma	O
+(	O
+RMS	O
+)	O
+in	O
+the	O
+left	O
+submandibular	O
+region	O
+.	O
+
+His	O
+brother	O
+died	O
+of	O
+RMS	O
+,	O
+and	O
+his	O
+grandmother	O
+was	O
+diagnosed	O
+with	O
+breast	O
+cancer	O
+.	O
+
+TP53	O
+gene	O
+mutation	O
+detection	O
+was	O
+performed	O
+in	O
+this	O
+patient	O
+and	O
+some	O
+family	O
+members	O
+,	O
+indicating	O
+a	O
+missense	O
+mutation	O
+in	O
+exon	O
+8	O
+of	O
+the	O
+patient	O
+:	O
+c.844C	O
+>	O
+T	O
+(	O
+p.	O
+Arg282Trp	O
+,	O
+heterozygous	O
+)	O
+.	O
+
+TP53	O
+mutation	O
+was	O
+also	O
+found	O
+in	O
+his	O
+mother	O
+and	O
+sister	O
+.	O
+
+The	O
+boy	O
+met	O
+the	O
+diagnostic	O
+criteria	O
+for	O
+LFS	O
+.	O
+
+Among	O
+pediatric	O
+patients	O
+,	O
+the	O
+most	O
+common	O
+LFS	O
+diseases	O
+include	O
+osteosarcoma	O
+,	O
+adrenocortical	O
+cancer	O
+,	O
+central	O
+nervous	O
+system	O
+tumor	O
+,	O
+and	O
+soft	O
+tissue	O
+tumor	O
+.	O
+
+Additionally	O
+,	O
+leukemia	O
+and	O
+lymphoma	O
+are	O
+also	O
+involved	O
+.	O
+
+LFS	O
+patients	O
+have	O
+a	O
+high	O
+risk	O
+to	O
+suffer	O
+secondary	O
+or	O
+even	O
+multiple	O
+cancers	O
+.	O
+
+Therefore	O
+,	O
+it	O
+is	O
+necessary	O
+to	O
+perform	O
+genetic	O
+detection	O
+for	O
+pediatric	O
+cancer	O
+patients	O
+,	O
+especially	O
+those	O
+with	O
+hereditary	O
+predisposition	O
+cancers	O
+.	O
+
+TP53	O
+mutation	O
+often	O
+indicates	O
+poor	O
+prognosis	O
+,	O
+so	O
+it	O
+is	O
+important	O
+to	O
+take	O
+active	O
+treatment	O
+and	O
+systematic	O
+monitoring	O
+for	O
+LFS	O
+family	O
+.	O
+
+The	O
+escalating	O
+prevalence	B-EPI
+of	O
+coronavirus	O
+disease	O
+2019	O
+(	O
+COVID-19	O
+)	O
+worldwide	B-LOC
+,	O
+with	O
+an	O
+increased	O
+rate	O
+of	O
+morbidity	O
+and	O
+mortality	O
+,	O
+highlights	O
+an	O
+urgent	O
+need	O
+to	O
+develop	O
+more	O
+effective	O
+therapeutic	O
+interventions	O
+.	O
+
+Despite	O
+the	O
+authorized	O
+treatment	O
+against	O
+COVID-19	O
+by	O
+the	O
+European	O
+Union	O
+(	O
+EU	O
+)	O
+,	O
+the	O
+safety	O
+and	O
+effectiveness	O
+of	O
+this	O
+therapeutic	O
+strategy	O
+for	O
+a	O
+wide	O
+variety	O
+of	O
+patients	O
+have	O
+remained	O
+a	O
+significant	O
+challenge	O
+.	O
+
+In	O
+this	O
+respect	O
+,	O
+micronutrients	O
+such	O
+as	O
+vitamins	O
+and	O
+minerals	O
+,	O
+as	O
+essential	O
+factors	O
+,	O
+can	O
+be	O
+considered	O
+for	O
+improving	O
+the	O
+function	O
+of	O
+the	O
+immune	O
+system	O
+and	O
+accelerating	O
+the	O
+treatment	O
+procedure	O
+.	O
+
+Dietary	O
+supplements	O
+can	O
+attenuate	O
+vascular	O
+and	O
+inflammatory	O
+manifestations	O
+related	O
+to	O
+infectious	O
+diseases	O
+in	O
+large	O
+part	O
+due	O
+to	O
+their	O
+anti	O
+-	O
+inflammatory	O
+and	O
+antioxidant	O
+properties	O
+.	O
+
+Recently	O
+,	O
+it	O
+has	O
+been	O
+revealed	O
+that	O
+poor	O
+nutritional	O
+status	O
+may	O
+be	O
+one	O
+of	O
+the	O
+notable	O
+risk	O
+factors	O
+in	O
+severe	O
+COVID-19	O
+infections	O
+.	O
+
+In	O
+the	O
+current	O
+review	O
+,	O
+we	O
+focus	O
+on	O
+the	O
+micronutrient	O
+therapy	O
+of	O
+COVID-19	O
+patients	O
+and	O
+provide	O
+a	O
+comprehensive	O
+insight	O
+into	O
+the	O
+essential	O
+vitamins	O
+/	O
+minerals	O
+and	O
+their	O
+role	O
+in	O
+controlling	O
+the	O
+severity	O
+of	O
+the	O
+COVID-19	O
+infection	O
+.	O
+
+We	O
+also	O
+discuss	O
+the	O
+recent	O
+advancements	O
+,	O
+challenges	O
+,	O
+negative	O
+and	O
+positive	O
+outcomes	O
+in	O
+relevance	O
+to	O
+this	O
+approach	O
+.	O
+
+The	O
+Xp22.31	O
+segment	O
+of	O
+the	O
+short	O
+arm	O
+of	O
+the	O
+human	O
+X	O
+chromosome	O
+is	O
+a	O
+region	O
+of	O
+high	O
+instability	O
+with	O
+frequent	O
+rearrangement	O
+.	O
+
+The	O
+duplication	O
+of	O
+this	O
+region	O
+has	O
+been	O
+found	O
+in	O
+healthy	O
+people	O
+as	O
+well	O
+as	O
+in	O
+individuals	O
+with	O
+varying	O
+degrees	O
+of	O
+neurological	O
+impairment	O
+.	O
+
+The	O
+incidence	B-EPI
+has	O
+been	O
+reported	O
+in	O
+a	O
+range	O
+of	O
+0.4	B-STAT
+-	I-STAT
+0.44	I-STAT
+%	I-STAT
+of	O
+the	O
+patients	O
+with	O
+neurological	O
+impairment	O
+.	O
+
+Moreover	O
+,	O
+there	O
+is	O
+evidence	O
+that	O
+Xp22.31	O
+duplication	O
+may	O
+cause	O
+a	O
+common	O
+phenotype	O
+including	O
+developmental	O
+delay	O
+,	O
+intellectual	O
+disability	O
+,	O
+feeding	O
+difficulty	O
+,	O
+autistic	O
+spectrum	O
+disorders	O
+,	O
+hypotonia	O
+,	O
+seizures	O
+,	O
+and	O
+talipes	O
+.	O
+
+We	O
+report	O
+on	O
+a	O
+patient	O
+with	O
+microcephaly	O
+and	O
+trigonocephaly	O
+,	O
+moderate	O
+intellectual	O
+disability	O
+,	O
+speech	O
+and	O
+language	O
+delay	O
+,	O
+and	O
+poor	O
+social	O
+interaction	O
+in	O
+addition	O
+to	O
+minor	O
+but	O
+atypical	O
+dysmorphic	O
+features	O
+.	O
+
+This	O
+report	O
+provides	O
+further	O
+insight	O
+into	O
+the	O
+pathogenicity	O
+of	O
+the	O
+Xp22.31	O
+duplication	O
+by	O
+extending	O
+knowledge	O
+of	O
+its	O
+clinical	O
+features	O
+.	O
+
+This	O
+case	O
+,	O
+in	O
+association	O
+with	O
+those	O
+reported	O
+in	O
+the	O
+literature	O
+,	O
+indicates	O
+that	O
+the	O
+Xp22.31	O
+duplication	O
+may	O
+contribute	O
+to	O
+cause	O
+pathological	O
+phenotypes	O
+with	O
+minor	O
+facial	O
+dysmorphisms	O
+,	O
+microcephaly	O
+,	O
+and	O
+intellectual	O
+disability	O
+as	O
+main	O
+features	O
+.	O
+
+We	O
+examined	O
+the	O
+potential	O
+benefits	O
+of	O
+neuroimaging	O
+measurements	O
+across	O
+the	O
+first	O
+5	O
+years	O
+of	O
+life	O
+in	O
+detecting	O
+early	O
+comorbid	O
+or	O
+etiological	O
+signs	O
+of	O
+autism	O
+spectrum	O
+disorder	O
+(	O
+ASD	O
+)	O
+.	O
+
+In	O
+particular	O
+,	O
+we	O
+analyzed	O
+the	O
+prevalence	B-EPI
+of	O
+neuroradiologic	O
+findings	O
+in	O
+routine	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+scans	O
+of	O
+a	O
+group	O
+of	O
+117	O
+ASD	O
+children	O
+younger	O
+than	O
+5	O
+years	O
+old	O
+.	O
+
+These	O
+data	O
+were	O
+compared	O
+to	O
+those	O
+reported	O
+in	O
+typically	O
+developing	O
+(	O
+TD	O
+)	O
+children	O
+.	O
+
+MRI	O
+findings	O
+in	O
+children	O
+with	O
+ASD	O
+were	O
+analyzed	O
+in	O
+relation	O
+to	O
+their	O
+cognitive	O
+level	O
+,	O
+severity	O
+of	O
+autistic	O
+symptoms	O
+,	O
+and	O
+the	O
+presence	O
+of	O
+electroencephalogram	O
+(	O
+EEG	O
+)	O
+abnormalities	O
+.	O
+
+The	O
+MRI	O
+was	O
+rated	O
+abnormal	O
+in	O
+55	O
+%	O
+of	O
+children	O
+with	O
+ASD	O
+with	O
+a	O
+significant	O
+prevalence	B-EPI
+in	O
+the	O
+high	O
+-	O
+functioning	O
+subgroup	O
+compared	O
+to	O
+TD	O
+children	O
+.	O
+
+We	O
+report	O
+significant	O
+incidental	O
+findings	O
+of	O
+mega	O
+cisterna	O
+magna	O
+,	O
+ventricular	O
+anomalies	O
+and	O
+abnormal	O
+white	O
+matter	O
+signal	O
+intensity	O
+in	O
+ASD	O
+without	O
+significant	O
+associations	O
+between	O
+these	O
+MRI	O
+findings	O
+and	O
+EEG	O
+features	O
+.	O
+
+Based	O
+on	O
+these	O
+results	O
+we	O
+discuss	O
+the	O
+role	O
+that	O
+brain	O
+MRI	O
+may	O
+play	O
+in	O
+the	O
+diagnostic	O
+procedure	O
+of	O
+ASD	O
+.	O
+
+Diabetes	O
+is	O
+a	O
+chronic	O
+illness	O
+.	O
+
+Hyperglycemia	O
+is	O
+the	O
+characteristic	O
+of	O
+this	O
+disorder	O
+.	O
+
+Diabetes	O
+is	O
+a	O
+global	O
+crisis	O
+which	O
+affects	O
+the	O
+economy	O
+and	O
+health	O
+of	O
+all	O
+nations	O
+.	O
+
+Over	O
+the	O
+last	O
+decades	O
+,	O
+the	O
+number	O
+of	O
+individuals	O
+living	O
+with	O
+diabetes	O
+has	O
+significantly	O
+increased	O
+worldwide	B-LOC
+.	O
+
+Asia	B-LOC
+is	O
+a	O
+key	O
+epicenter	O
+of	O
+the	O
+emerging	O
+diabetes	O
+epidemic	O
+,	O
+with	O
+China	B-LOC
+and	O
+India	B-LOC
+the	O
+two	O
+nations	O
+having	O
+the	O
+highest	O
+number	O
+of	O
+diabetic	O
+people	O
+.	O
+
+Economic	O
+development	O
+,	O
+modernization	O
+,	O
+unhealthy	O
+diet	O
+,	O
+population	O
+aging	O
+,	O
+and	O
+sedentary	O
+lifestyles	O
+are	O
+the	O
+major	O
+factors	O
+responsible	O
+for	O
+the	O
+increasing	O
+diabetes	O
+epidemic	O
+.	O
+
+Diabetes	O
+is	O
+associated	O
+with	O
+several	O
+complications	O
+,	O
+and	O
+cardiovascular	O
+disease	O
+is	O
+the	O
+most	O
+important	O
+cause	O
+of	O
+morbidity	O
+and	O
+mortality	O
+among	O
+people	O
+with	O
+diabetes	O
+.	O
+
+These	O
+life	O
+-	O
+threatening	O
+problems	O
+can	O
+be	O
+prevented	O
+or	O
+delayed	O
+by	O
+proper	O
+management	O
+of	O
+diabetes	O
+.	O
+
+Lifestyle	O
+modification	O
+is	O
+an	O
+important	O
+factor	O
+to	O
+decrease	O
+the	O
+diabetes	O
+risk	O
+.	O
+
+The	O
+frequency	O
+of	O
+diabetic	O
+complications	O
+will	O
+rise	O
+if	O
+there	O
+is	O
+a	O
+lack	O
+of	O
+cost	O
+-	O
+effective	O
+and	O
+sustainable	O
+interventions	O
+.	O
+
+Hence	O
+,	O
+prevention	O
+of	O
+diabetes	O
+and	O
+its	O
+complications	O
+such	O
+as	O
+diabetic	O
+retinopathy	O
+and	O
+cardiovascular	O
+disease	O
+should	O
+be	O
+a	O
+crucial	O
+part	O
+of	O
+all	O
+future	O
+health	O
+-	O
+related	O
+public	O
+policies	O
+among	O
+all	O
+nations	O
+.	O
+
+This	O
+review	O
+summarizes	O
+current	O
+epidemiological	O
+aspects	O
+of	O
+diabetes	O
+in	O
+the	O
+world	O
+along	O
+with	O
+its	O
+complications	O
+,	O
+preventive	O
+measures	O
+,	O
+and	O
+treatment	O
+.	O
+
+Purpose	O
+of	O
+review	O
+The	O
+goal	O
+of	O
+the	O
+review	O
+is	O
+to	O
+provide	O
+a	O
+comprehensive	O
+overview	O
+of	O
+the	O
+current	O
+understanding	O
+of	O
+the	O
+mechanisms	O
+underlying	O
+variation	O
+in	O
+human	O
+stature	O
+.	O
+
+Recent	O
+findings	O
+Human	O
+height	O
+is	O
+an	O
+anthropometric	O
+trait	O
+that	O
+varies	O
+considerably	O
+within	O
+human	O
+populations	O
+as	O
+well	O
+as	O
+across	O
+the	O
+globe	O
+.	O
+
+Historically	O
+,	O
+much	O
+research	O
+focus	O
+was	O
+placed	O
+on	O
+understanding	O
+the	O
+biology	O
+of	O
+growth	O
+plate	O
+chondrocytes	O
+and	O
+how	O
+modifications	O
+to	O
+core	O
+chondrocyte	O
+proliferation	O
+and	O
+differentiation	O
+pathways	O
+potentially	O
+shaped	O
+height	O
+attainment	O
+in	O
+normal	O
+as	O
+well	O
+as	O
+pathological	O
+contexts	O
+.	O
+
+Recently	O
+,	O
+much	O
+progress	O
+has	O
+been	O
+made	O
+to	O
+improve	O
+our	O
+understanding	O
+regarding	O
+the	O
+mechanisms	O
+underlying	O
+the	O
+normal	O
+and	O
+pathological	O
+range	O
+of	O
+height	O
+variation	O
+within	O
+as	O
+well	O
+as	O
+between	O
+human	O
+populations	O
+,	O
+and	O
+today	O
+,	O
+it	O
+is	O
+understood	O
+to	O
+reflect	O
+complex	O
+interactions	O
+among	O
+a	O
+myriad	O
+of	O
+genetic	O
+,	O
+environmental	O
+,	O
+and	O
+evolutionary	O
+factors	O
+.	O
+
+Indeed	O
+,	O
+recent	O
+improvements	O
+in	O
+genetics	O
+(	O
+e.g.	O
+,	O
+GWAS	O
+)	O
+and	O
+breakthroughs	O
+in	O
+functional	O
+genomics	O
+(	O
+e.g.	O
+,	O
+whole	O
+exome	O
+sequencing	O
+,	O
+DNA	O
+methylation	O
+analysis	O
+,	O
+ATAC	O
+-	O
+sequencing	O
+,	O
+and	O
+CRISPR	O
+)	O
+have	O
+shed	O
+light	O
+on	O
+previously	O
+unknown	O
+pathways	O
+/	O
+mechanisms	O
+governing	O
+pathological	O
+and	O
+common	O
+height	O
+variation	O
+.	O
+
+Additionally	O
+,	O
+the	O
+use	O
+of	O
+an	O
+evolutionary	O
+perspective	O
+has	O
+also	O
+revealed	O
+important	O
+mechanisms	O
+that	O
+have	O
+shaped	O
+height	O
+variation	O
+across	O
+the	O
+planet	O
+.	O
+
+This	O
+review	O
+provides	O
+an	O
+overview	O
+of	O
+the	O
+current	O
+knowledge	O
+of	O
+the	O
+biological	O
+mechanisms	O
+underlying	O
+height	O
+variation	O
+by	O
+highlighting	O
+new	O
+research	O
+findings	O
+on	O
+skeletal	O
+growth	O
+control	O
+with	O
+an	O
+emphasis	O
+on	O
+previously	O
+unknown	O
+pathways	O
+/	O
+mechanisms	O
+influencing	O
+pathological	O
+and	O
+common	O
+height	O
+variation	O
+.	O
+
+In	O
+this	O
+context	O
+,	O
+this	O
+review	O
+also	O
+discusses	O
+how	O
+evolutionary	O
+forces	O
+likely	O
+shaped	O
+the	O
+genomic	O
+architecture	O
+of	O
+height	O
+across	O
+the	O
+globe	O
+.	O
+
+Background	O
+21	O
+-	O
+Hydroxylase	O
+deficiency	O
+(	O
+21	O
+-	O
+OHD	O
+)	O
+caused	O
+by	O
+the	O
+CYP21A2	O
+gene	O
+mutations	O
+is	O
+the	O
+most	O
+common	O
+form	O
+of	O
+congenital	O
+adrenal	O
+hyperplasia	O
+.	O
+
+It	O
+is	O
+an	O
+autosomal	O
+recessive	O
+disorder	O
+that	O
+results	O
+in	O
+defective	O
+synthesis	O
+of	O
+cortisol	O
+and	O
+aldosterone	O
+.	O
+
+The	O
+incidences	B-EPI
+of	O
+various	O
+CYP21A2	O
+gene	O
+mutations	O
+and	O
+the	O
+genotype	O
+-	O
+phenotype	O
+correlations	O
+vary	O
+among	O
+different	O
+populations	O
+.	O
+
+Materials	O
+and	O
+methods	O
+The	O
+clinical	O
+and	O
+molecular	O
+data	O
+of	O
+22	O
+patients	O
+were	O
+analyzed	O
+in	O
+this	O
+study	O
+.	O
+
+All	O
+patients	O
+were	O
+recruited	O
+from	O
+the	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+.	O
+
+Locus	O
+-	O
+specific	O
+polymerase	O
+chain	O
+reaction	O
+and	O
+Sanger	O
+sequencing	O
+were	O
+applied	O
+to	O
+identify	O
+gene	O
+micro	O
+-	O
+conversions	O
+,	O
+and	O
+multiplex	O
+ligation	O
+-	O
+dependent	O
+probe	O
+amplification	O
+was	O
+used	O
+to	O
+detect	O
+large	O
+fragment	O
+deletions	O
+/	O
+conversions	O
+.	O
+
+Then	O
+,	O
+the	O
+genotypes	O
+were	O
+categorized	O
+in	O
+to	O
+Null	O
+,	O
+A	O
+,	O
+B	O
+,	O
+C	O
+,	O
+and	O
+D	O
+groups	O
+to	O
+analyze	O
+the	O
+relationships	O
+between	O
+genotypes	O
+and	O
+phenotypes	O
+.	O
+
+Results	O
+All	O
+22	O
+patients	O
+were	O
+classified	O
+into	O
+classic	O
+salt	O
+wasting	O
+form	O
+of	O
+21	O
+-	O
+OHD	O
+.	O
+
+Molecular	O
+defects	O
+were	O
+detected	O
+in	O
+44	O
+alleles	O
+(	O
+100	O
+%	O
+)	O
+.	O
+
+Micro	O
+-	O
+conversion	O
+mutation	O
+IVS2	O
+-	O
+13A	O
+/	O
+C	O
+>	O
+G	O
+(	O
+70.5	O
+%	O
+)	O
+is	O
+most	O
+common	O
+in	O
+our	O
+cohort	O
+,	O
+followed	O
+by	O
+large	O
+gene	O
+deletions	O
+and	O
+conversions	O
+(	O
+22.7	O
+%	O
+)	O
+.	O
+
+The	O
+other	O
+mutations	O
+present	O
+were	O
+p.	O
+R357	O
+W	O
+(	O
+4.5	O
+%	O
+)	O
+and	O
+E6	O
+Cluster	O
+(	O
+2.3	O
+%	O
+)	O
+.	O
+
+Genotypes	O
+of	O
+22	O
+patients	O
+(	O
+100	O
+%	O
+)	O
+were	O
+consistent	O
+with	O
+the	O
+predictive	O
+phenotypes	O
+.	O
+
+Conclusion	O
+In	O
+this	O
+study	O
+,	O
+we	O
+identified	O
+the	O
+mutation	O
+spectrum	O
+of	O
+CYP21A2	O
+gene	O
+in	O
+Chinese	O
+patients	O
+,	O
+especially	O
+the	O
+younger	O
+age	O
+cohort	O
+in	O
+pediatrics	O
+.	O
+
+Micro	O
+-	O
+conversions	O
+were	O
+the	O
+most	O
+popular	O
+mutations	O
+.	O
+
+Moreover	O
+,	O
+the	O
+genotypes	O
+and	O
+phenotypes	O
+were	O
+well	O
+correlated	O
+in	O
+this	O
+cohort	O
+of	O
+salt	O
+wasting	O
+21	O
+-	O
+OHD	O
+recruited	O
+from	O
+neonatal	O
+intensive	O
+care	O
+unit	O
+.	O
+
+Background	O
+Vitamin	O
+C	O
+deficiency	O
+is	O
+common	O
+in	O
+chronic	O
+kidney	O
+disease	O
+(	O
+CKD	O
+)	O
+due	O
+to	O
+losses	O
+through	O
+dialysis	O
+and	O
+dietary	O
+intake	O
+below	O
+requirement	O
+.	O
+
+We	O
+investigated	O
+prevalence	B-EPI
+of	O
+vitamin	O
+C	O
+deficiency	O
+and	O
+impact	O
+of	O
+vitamin	O
+C	O
+treatment	O
+in	O
+deficient	O
+/	O
+insufficient	O
+patients	O
+.	O
+
+Methods	O
+A	O
+prospective	O
+cohort	O
+study	O
+in	O
+patients	O
+aged	O
+1	B-STAT
+-	I-STAT
+18	I-STAT
+years	O
+with	O
+CKD	O
+stages	O
+4	O
+and	O
+5D	O
+collected	O
+demographic	O
+data	O
+including	O
+underlying	O
+disease	O
+,	O
+treatment	O
+,	O
+and	O
+anthropometric	O
+assessment	O
+.	O
+
+Vitamin	O
+C	O
+intake	O
+was	O
+assessed	O
+using	O
+24	O
+-	O
+h	O
+dietary	O
+recall	O
+.	O
+
+Hemoglobin	O
+,	O
+iron	O
+status	O
+,	O
+serum	O
+vitamin	O
+C	O
+,	O
+and	O
+serum	O
+oxalate	O
+were	O
+measured	O
+at	O
+baseline	O
+and	O
+after	O
+treatment	O
+.	O
+
+Vitamin	O
+C	O
+(	O
+250	O
+mg	O
+/	O
+day	O
+)	O
+was	O
+given	O
+orally	O
+for	O
+3	O
+months	O
+to	O
+deficient	O
+/	O
+insufficient	O
+patients	O
+.	O
+
+Results	O
+Nineteen	O
+patients	O
+(	O
+mean	O
+age	O
+12.00	O
+±	O
+4.1	O
+years	O
+)	O
+showed	O
+prevalence	B-EPI
+of	O
+10.6	O
+%	O
+vitamin	O
+C	O
+insufficiency	O
+and	O
+78.9	O
+%	O
+deficiency	O
+.	O
+
+There	O
+were	O
+no	O
+associations	O
+between	O
+vitamin	O
+C	O
+level	O
+and	O
+daily	O
+vitamin	O
+C	O
+intake	O
+(	O
+p	O
+=	O
+0.64	O
+)	O
+or	O
+nutritional	O
+status	O
+(	O
+p	O
+=	O
+0.87	O
+)	O
+.	O
+
+Median	O
+serum	O
+vitamin	O
+C	O
+was	O
+1.51	O
+(	O
+0.30	O
+-	O
+1.90	O
+)	O
+mg	O
+/	O
+L.	O
+
+In	O
+16	O
+patients	O
+receiving	O
+treatment	O
+,	O
+median	O
+serum	O
+vitamin	O
+C	O
+increased	O
+from	O
+1.30	O
+(	O
+0.23	O
+-	O
+1.78	O
+)	O
+to	O
+3.22	O
+(	O
+1.77	O
+-	O
+5.96	O
+)	O
+mg	O
+/	O
+L	O
+(	O
+p	O
+=	O
+0.008	O
+)	O
+without	O
+increasing	O
+serum	O
+oxalate	O
+(	O
+79.92	O
+(	O
+56.6	O
+-	O
+106.84	O
+)	O
+vs.	O
+80.47	O
+(	O
+56.88	O
+-	O
+102.95	O
+)	O
+μmol	O
+/	O
+L	O
+,	O
+p	O
+=	O
+0.82	O
+)	O
+.	O
+
+However	O
+,	O
+62.5	O
+%	O
+failed	O
+to	O
+achieve	O
+normal	O
+vitamin	O
+C	O
+levels	O
+.	O
+
+Ordinal	O
+regression	O
+analysis	O
+revealed	O
+patients	O
+with	O
+non	O
+-	O
+oligoanuric	O
+CKD	O
+were	O
+less	O
+likely	O
+to	O
+achieve	O
+normal	O
+vitamin	O
+C	O
+levels	O
+(	O
+β	O
+=	O
+-	O
+3.41	O
+,	O
+p	O
+=	O
+0.03	O
+)	O
+.	O
+
+Conclusion	O
+We	O
+describe	O
+high	O
+prevalence	B-EPI
+of	O
+vitamin	O
+C	O
+insufficiency	O
+/	O
+deficiency	O
+among	O
+pediatric	O
+CKD	O
+patients	O
+.	O
+
+Vitamin	O
+C	O
+levels	O
+could	O
+not	O
+be	O
+solely	O
+predicted	O
+by	O
+nutritional	O
+status	O
+or	O
+daily	O
+intake	O
+.	O
+
+The	O
+treatment	O
+regimen	O
+raised	O
+serum	O
+vitamin	O
+C	O
+without	O
+increasing	O
+serum	O
+oxalate	O
+;	O
+however	O
+,	O
+it	O
+was	O
+largely	O
+insufficient	O
+to	O
+normalize	O
+levels	O
+,	O
+particularly	O
+in	O
+non	O
+-	O
+oligoanuric	O
+CKD	O
+.	O
+
+Graphical	O
+abstract	O
+.	O
+
+While	O
+the	O
+epidemiology	O
+of	O
+Flaviviruses	O
+has	O
+been	O
+extensively	O
+studied	O
+in	O
+most	O
+of	O
+the	B-LOC
+Mediterranean	I-LOC
+basin	I-LOC
+,	O
+little	O
+is	O
+known	O
+about	O
+the	O
+current	O
+situation	O
+in	O
+Algeria	B-LOC
+.	O
+
+In	O
+order	O
+to	O
+detect	O
+the	O
+circulation	O
+of	O
+West	B-LOC
+Nile	I-LOC
+(	O
+WNV	O
+)	O
+and	O
+Usutu	O
+viruses	O
+(	O
+USUV	O
+)	O
+in	O
+Kabylia	B-LOC
+,	O
+165	O
+sera	O
+were	O
+collected	O
+from	O
+two	O
+wild	O
+birds	O
+species	O
+,	O
+namely	O
+the	O
+long	O
+distance	O
+migrant	O
+Turdus	O
+philomelos	O
+(	O
+song	O
+thrush	O
+)	O
+(	O
+n	O
+=	O
+92	O
+)	O
+and	O
+the	O
+resident	O
+Passer	O
+domesticus	O
+(	O
+house	O
+sparrow	O
+)	O
+(	O
+n	O
+=	O
+73	O
+)	O
+.	O
+
+A	O
+total	O
+of	O
+154	O
+sera	O
+were	O
+first	O
+analyzed	O
+by	O
+commercial	O
+competition	O
+ELISA	O
+.	O
+
+WNV	O
+and	O
+USUV	O
+micro	O
+-	O
+neutralization	O
+tests	O
+were	O
+performed	O
+on	O
+all	O
+c	O
+-	O
+ELISA	O
+positive	O
+sera	O
+and	O
+all	O
+samples	O
+with	O
+poor	O
+volume	O
+.	O
+
+Overall	O
+,	O
+7.8	O
+%	O
+(	O
+CI95	O
+%	O
+:	O
+3.5	O
+-	O
+11.9	O
+)	O
+were	O
+positive	O
+by	O
+c	O
+-	O
+ELISA	O
+.	O
+
+Positive	O
+results	O
+were	O
+detected	O
+in	O
+12.5	O
+%	O
+(	O
+CI95	O
+%	O
+:	O
+5.6	O
+-	O
+19.4	O
+)	O
+of	O
+song	O
+thrushes	O
+and	O
+1.5	O
+%	O
+(	O
+CI95	O
+%	O
+:	O
+0.0	O
+-	O
+4.5	O
+)	O
+for	O
+sparrow	O
+.	O
+
+Micro	O
+-	O
+neutralization	O
+tests	O
+revealed	O
+an	O
+overall	O
+seroprevalence	O
+of	O
+6.7	O
+%	O
+for	O
+WNV	O
+(	O
+CI95	O
+%	O
+:	O
+2.9	O
+-	O
+10.3	O
+)	O
+,	O
+Neutralizing	O
+antibodies	O
+were	O
+found	O
+in	O
+8.7	O
+%	O
+(	O
+CI95	O
+%	O
+:	O
+3.0	O
+-	O
+14.4	O
+)	O
+for	O
+song	O
+thrushes	O
+and	O
+in	O
+4.1	O
+%	O
+(	O
+CI95	O
+%	O
+:	O
+0.0	O
+-	O
+8.7	O
+)	O
+of	O
+sparrows	O
+.	O
+
+The	O
+current	O
+study	O
+demonstrates	O
+significant	O
+seroprevalence	O
+of	O
+WNV	O
+antibodies	O
+in	O
+wild	O
+birds	O
+in	O
+Algeria	B-LOC
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+congenital	O
+hydrocephalus	O
+has	O
+been	O
+estimated	O
+at	O
+1.1	B-STAT
+per	I-STAT
+1000	I-STAT
+infants	I-STAT
+when	O
+including	O
+cases	O
+diagnosed	O
+before	O
+1	O
+year	O
+of	O
+age	O
+after	O
+exclusion	O
+of	O
+neural	O
+tube	O
+defects	O
+.	O
+
+Classification	O
+criteria	O
+are	O
+based	O
+either	O
+on	O
+CSF	O
+dynamics	O
+,	O
+pathophysiological	O
+mechanisms	O
+or	O
+associated	O
+lesions	O
+.	O
+
+Whereas	O
+inherited	O
+syndromic	O
+hydrocephalus	O
+has	O
+been	O
+associated	O
+with	O
+more	O
+than	O
+100	O
+disease	O
+-	O
+causing	O
+genes	O
+,	O
+only	O
+four	O
+genes	O
+are	O
+currently	O
+known	O
+to	O
+be	O
+linked	O
+to	O
+congenital	O
+hydrocephalus	O
+either	O
+isolated	O
+or	O
+as	O
+a	O
+major	O
+clinical	O
+feature	O
+:	O
+L1CAM	O
+,	O
+AP1S2	O
+,	O
+MPDZ	O
+and	O
+CCDC88C.	O
+
+In	O
+the	O
+past	O
+10	O
+years	O
+,	O
+pathogenic	O
+variants	O
+in	O
+CCDC88C	O
+have	O
+been	O
+documented	O
+but	O
+the	O
+neuropathology	O
+remains	O
+virtually	O
+unknown	O
+.	O
+
+We	O
+report	O
+the	O
+neuropathology	O
+of	O
+two	O
+foetuses	O
+from	O
+one	O
+family	O
+harbouring	O
+two	O
+novel	O
+compound	O
+heterozygous	O
+pathogenic	O
+variants	O
+in	O
+the	O
+CCDC88C	O
+gene	O
+:	O
+a	O
+maternally	O
+inherited	O
+indel	O
+in	O
+exon	O
+22	O
+,	O
+c.3807_3809delinsACCT;p.(Gly1270Profs*53	O
+)	O
+and	O
+a	O
+paternally	O
+inherited	O
+deletion	O
+of	O
+exon	O
+23	O
+,	O
+c.3967-?_c.4112-?;p.(Leu1323Argfs*10	O
+)	O
+.	O
+
+Medical	O
+termination	O
+of	O
+pregnancy	O
+was	O
+performed	O
+at	O
+18	O
+and	O
+23	O
+weeks	O
+of	O
+gestation	O
+for	O
+severe	O
+bilateral	O
+ventriculomegaly	O
+.	O
+
+In	O
+both	O
+fetuses	O
+,	O
+brain	O
+lesions	O
+consisted	O
+of	O
+multifocal	O
+atresia	O
+-	O
+forking	O
+along	O
+the	O
+aqueduct	O
+of	O
+Sylvius	O
+and	O
+the	O
+central	O
+canal	O
+of	O
+the	O
+medulla	O
+,	O
+periventricular	O
+neuronal	O
+heterotopias	O
+and	O
+choroid	O
+plexus	O
+hydrops	O
+.	O
+
+The	O
+second	O
+fetus	O
+also	O
+presented	O
+lumbar	O
+myelomeningocele	O
+,	O
+left	O
+diaphragmatic	O
+hernia	O
+and	O
+bilateral	O
+renal	O
+agenesis	O
+.	O
+
+CCDC88C	O
+encodes	O
+the	O
+protein	O
+DAPLE	O
+which	O
+contributes	O
+to	O
+ependymal	O
+cell	O
+planar	O
+polarity	O
+by	O
+inhibiting	O
+the	O
+non	O
+-	O
+canonical	O
+Wnt	O
+signaling	O
+pathway	O
+and	O
+interacts	O
+with	O
+MPDZ	O
+and	O
+PARD3	O
+.	O
+
+Interestingly	O
+,	O
+heterozygous	O
+variants	O
+in	O
+PARD3	O
+result	O
+in	O
+neural	O
+tube	O
+defects	O
+by	O
+defective	O
+tight	O
+junction	O
+formation	O
+and	O
+polarization	O
+process	O
+of	O
+the	O
+neuroepithelium	O
+.	O
+
+Besides	O
+,	O
+during	O
+organ	O
+formation	O
+Wnt	O
+signalling	O
+is	O
+a	O
+prerequisite	O
+for	O
+planar	O
+cell	O
+polarity	O
+pathway	O
+activation	O
+,	O
+and	O
+mutations	O
+in	O
+planar	O
+cell	O
+polarity	O
+genes	O
+lead	O
+to	O
+heart	O
+,	O
+lung	O
+and	O
+kidney	O
+malformations	O
+.	O
+
+Hence	O
+,	O
+candidate	O
+variants	O
+in	O
+CCDC88C	O
+should	O
+be	O
+carefully	O
+considered	O
+whether	O
+brain	O
+lesions	O
+are	O
+isolated	O
+or	O
+associated	O
+with	O
+malformations	O
+suspected	O
+to	O
+result	O
+from	O
+disorders	O
+of	O
+planar	O
+cell	O
+polarity	O
+.	O
+
+Background	O
+Vitamin	O
+D	O
+deficiency	O
+is	O
+highly	O
+prevalent	B-EPI
+in	O
+children	O
+with	O
+intestinal	O
+failure	O
+(	O
+IF	O
+)	O
+who	O
+receive	O
+parenteral	O
+nutrition	O
+(	O
+PN	O
+)	O
+,	O
+but	O
+data	O
+on	O
+vitamin	O
+D	O
+status	O
+after	O
+achieving	O
+enteral	O
+autonomy	O
+(	O
+EA	O
+)	O
+are	O
+limited	O
+.	O
+
+We	O
+aimed	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+of	O
+vitamin	O
+D	O
+deficiency	O
+in	O
+this	O
+population	O
+while	O
+exploring	O
+clinical	O
+variables	O
+that	O
+may	O
+be	O
+associated	O
+with	O
+its	O
+development	O
+.	O
+
+Methods	O
+A	O
+retrospective	O
+review	O
+was	O
+performed	O
+on	O
+29	O
+children	O
+with	O
+IF	O
+who	O
+had	O
+achieved	O
+EA	O
+.	O
+
+Deficiency	O
+was	O
+defined	O
+as	O
+a	O
+mean	O
+serum	O
+25	O
+-	O
+hydroxyvitamin	O
+D	O
+<	O
+30	O
+ng	O
+/	O
+ml	O
+.	O
+
+Data	O
+results	O
+Sixty	B-STAT
+-	O
+six	O
+percent	O
+of	O
+children	O
+had	O
+at	O
+least	O
+one	O
+deficient	O
+level	O
+during	O
+the	O
+study	O
+period	O
+,	O
+with	O
+38	O
+%	O
+being	O
+deficient	O
+based	O
+on	O
+the	O
+mean	O
+vitamin	O
+D	O
+levels	O
+.	O
+
+Eighty	B-STAT
+-	O
+four	O
+percent	O
+had	O
+radiologic	O
+evidence	O
+of	O
+osteopenia	O
+.	O
+
+Compared	O
+with	O
+the	O
+sufficient	O
+group	O
+(	O
+n=18	O
+)	O
+,	O
+the	O
+deficient	O
+group	O
+(	O
+n=11	O
+)	O
+received	O
+higher	O
+daily	O
+mean	O
+vitamin	O
+D	O
+doses	O
+(	O
+2246	O
+vs	O
+920	O
+IU	O
+;	O
+P=.02	O
+)	O
+,	O
+had	O
+shorter	O
+remnant	O
+small	O
+-	O
+bowel	O
+length	O
+(	O
+53.8	O
+vs	O
+82.1	O
+cm	O
+;	O
+P=.03	O
+)	O
+,	O
+and	O
+were	O
+PN	O
+dependent	O
+for	O
+a	O
+longer	O
+duration	O
+(	O
+1.3	O
+vs	O
+0.58	O
+years	O
+;	O
+P=.01	O
+)	O
+.	O
+
+Univariate	O
+analyses	O
+revealed	O
+longer	O
+remnant	O
+gut	O
+length	O
+(	O
+odds	O
+ratio	O
+[	O
+OR	O
+]	O
+=	O
+1.03	O
+;	O
+P=.04	O
+)	O
+and	O
+shorter	O
+duration	O
+of	O
+PN	O
+(	O
+OR	O
+=	O
+0.26	O
+;	O
+P=.04	O
+)	O
+to	O
+be	O
+significantly	O
+associated	O
+with	O
+sufficient	O
+vitamin	O
+D	O
+status	O
+.	O
+
+Conclusion	O
+Vitamin	O
+D	O
+deficiency	O
+and	O
+osteopenia	O
+are	O
+highly	O
+prevalent	B-EPI
+in	O
+pediatric	O
+patients	O
+with	O
+a	O
+history	O
+of	O
+IF	O
+who	O
+have	O
+achieved	O
+EA	O
+,	O
+despite	O
+enteral	O
+supplementation	O
+with	O
+higher	O
+than	O
+standard	O
+doses	O
+.	O
+
+Shorter	O
+remnant	O
+small	O
+-	O
+bowel	O
+length	O
+and	O
+longer	O
+duration	O
+of	O
+PN	O
+were	O
+associated	O
+with	O
+vitamin	O
+D	O
+deficiency	O
+.	O
+
+These	O
+findings	O
+emphasize	O
+the	O
+importance	O
+of	O
+prolonged	O
+surveillance	O
+and	O
+highlight	O
+the	O
+need	O
+for	O
+alternate	O
+dosing	O
+regimens	O
+.	O
+
+Enshi	O
+prefecture	O
+of	O
+Hubei	B-LOC
+Province	I-LOC
+is	O
+well	O
+known	O
+for	O
+human	O
+selenium	O
+(	O
+Se	O
+)	O
+poisoning	O
+in	O
+the	O
+early	O
+1960s	O
+in	O
+China	B-LOC
+.	O
+
+Sporadic	O
+cases	O
+of	O
+Se	O
+poisoning	O
+in	O
+livestocks	O
+are	O
+still	O
+being	O
+found	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+Se	O
+levels	O
+in	O
+water	O
+,	O
+cropland	O
+soils	O
+and	O
+various	O
+crops	O
+from	O
+high	O
+-	O
+Se	O
+areas	O
+of	O
+Enshi	O
+were	O
+measured	O
+to	O
+investigate	O
+the	O
+distribution	O
+and	O
+bioavailability	O
+of	O
+Se	O
+in	O
+the	O
+environments	O
+,	O
+as	O
+well	O
+as	O
+probable	O
+daily	O
+intake	O
+(	O
+PDI	O
+)	O
+of	O
+Se	O
+for	O
+local	O
+residents	O
+.	O
+
+The	O
+total	O
+Se	O
+in	O
+surface	O
+water	O
+ranged	O
+from	O
+2.0	O
+to	O
+519.3μg	O
+/	O
+L	O
+with	O
+a	O
+geometric	O
+mean	O
+of	O
+46.0±127.8	O
+μg	O
+/	O
+L	O
+(	O
+n=48	O
+)	O
+,	O
+70.5	O
+-	O
+99.5	O
+%	O
+of	O
+which	O
+was	O
+present	O
+in	O
+the	O
+form	O
+of	O
+Se(VI	O
+)	O
+.	O
+
+The	O
+soil	O
+Se	O
+concentration	O
+varied	O
+from	O
+2.89	O
+to	O
+87.3	O
+μg	O
+/	O
+g	O
+with	O
+a	O
+geometric	O
+mean	O
+of	O
+9.36±18.6	O
+μg	O
+/	O
+g	O
+(	O
+n=45	O
+)	O
+,	O
+and	O
+most	O
+of	O
+Se	O
+was	O
+associated	O
+with	O
+organic	O
+matter	O
+(	O
+OM	O
+-	O
+Se	O
+)	O
+.	O
+
+The	O
+total	O
+Se	O
+in	O
+rice	O
+,	O
+corn	O
+,	O
+and	O
+vegetable	O
+samples	O
+were	O
+2.11±2.87	O
+μg	O
+/	O
+g	O
+(	O
+n=21	O
+)	O
+,	O
+3.76±11.6	O
+μg	O
+/	O
+g	O
+(	O
+n=16	O
+)	O
+,	O
+and	O
+2.09±3.38	O
+μg	O
+/	O
+g	O
+(	O
+n=25	O
+)	O
+,	O
+respectively	O
+.	O
+
+Stream	O
+water	O
+Se	O
+is	O
+likely	O
+leached	O
+from	O
+carbonaceous	O
+shale	O
+and	O
+mine	O
+wastes	O
+,	O
+leading	O
+to	O
+Se	O
+accumulation	O
+in	O
+paddy	O
+soils	O
+.	O
+
+OM	O
+-	O
+Se	O
+may	O
+play	O
+an	O
+important	O
+role	O
+in	O
+Se	O
+uptake	O
+by	O
+rice	O
+plant	O
+in	O
+high	O
+-	O
+Se	O
+area	O
+of	O
+Enshi	O
+.	O
+
+The	O
+PDI	O
+of	O
+Se	O
+is	O
+approximately	O
+2144	O
+μg	O
+/	O
+day	O
+,	O
+and	O
+Se	O
+concentration	O
+in	O
+blood	O
+is	O
+estimated	O
+at	O
+about	O
+3248	O
+μg	O
+/	O
+L	O
+,	O
+posing	O
+a	O
+potential	O
+chronic	O
+Se	O
+poisoning	O
+risk	O
+to	O
+local	O
+residents	O
+.	O
+
+Cereal	O
+consumption	O
+(	O
+48.5	O
+%	O
+)	O
+makes	O
+a	O
+great	O
+contribution	O
+to	O
+human	O
+daily	O
+Se	O
+intake	O
+,	O
+followed	O
+by	O
+vegetables	O
+(	O
+36.6	O
+%	O
+)	O
+,	O
+meats	O
+(	O
+8.5	O
+%	O
+)	O
+,	O
+and	O
+drinking	O
+water	O
+(	O
+6.4	O
+%	O
+)	O
+.	O
+
+However	O
+,	O
+when	O
+assessing	O
+health	O
+risk	O
+on	O
+human	O
+in	O
+high	O
+-	O
+Se	O
+areas	O
+,	O
+the	O
+contribution	O
+of	O
+drinking	O
+water	O
+to	O
+daily	O
+Se	O
+intake	O
+can	O
+not	O
+be	O
+ignored	O
+due	O
+to	O
+high	O
+Se	O
+content	O
+and	O
+dominant	O
+Se(VI	O
+)	O
+species	O
+.	O
+
+Local	O
+inhabitants	O
+should	O
+be	O
+advised	O
+not	O
+to	O
+grow	O
+crops	O
+in	O
+high	O
+-	O
+Se	O
+lands	O
+or	O
+irrigate	O
+using	O
+high	O
+-	O
+Se	O
+water	O
+.	O
+
+If	O
+possible	O
+,	O
+they	O
+should	O
+drink	O
+pipe	O
+water	O
+and	O
+consume	O
+foods	O
+mixed	O
+with	O
+those	O
+from	O
+outside	O
+the	O
+high	O
+-	O
+Se	O
+areas	O
+.	O
+
+Hearing	O
+loss	O
+(	O
+HL	O
+)	O
+is	O
+an	O
+extra	O
+-	O
+skeletal	O
+manifestation	O
+of	O
+the	O
+connective	O
+tissue	O
+disorder	O
+osteogenesis	O
+imperfecta	O
+(	O
+OI	O
+)	O
+.	O
+
+Systematic	O
+evaluation	O
+of	O
+the	O
+prevalence	B-EPI
+and	O
+characteristics	O
+of	O
+HL	O
+in	O
+COL1A1	O
+/	O
+COL1A2	O
+-	O
+related	O
+OI	O
+will	O
+contribute	O
+to	O
+a	O
+better	O
+clinical	O
+management	O
+of	O
+individuals	O
+with	O
+OI	O
+.	O
+
+We	O
+collected	O
+and	O
+analyzed	O
+pure	O
+-	O
+tone	O
+audiometry	O
+data	O
+from	O
+312	O
+individuals	O
+with	O
+OI	O
+who	O
+were	O
+enrolled	O
+in	O
+the	O
+Linked	O
+Clinical	O
+Research	O
+Centers	O
+and	O
+the	O
+Brittle	O
+Bone	O
+Disorders	O
+Consortium	O
+.	O
+
+The	O
+prevalence	B-EPI
+,	O
+type	O
+,	O
+and	O
+severity	O
+of	O
+HL	O
+in	O
+COL1A1	O
+/	O
+COL1A2	O
+-	O
+related	O
+OI	O
+are	O
+reported	O
+.	O
+
+We	O
+show	O
+that	O
+the	O
+prevalence	B-EPI
+of	O
+HL	O
+in	O
+OI	O
+is	O
+28	O
+%	O
+and	O
+increased	O
+with	O
+age	O
+in	O
+Type	O
+I	O
+OI	O
+but	O
+not	O
+in	O
+Types	O
+III	O
+and	O
+IV	O
+.	O
+
+Individuals	O
+with	O
+OI	O
+Types	O
+III	O
+and	O
+IV	O
+are	O
+at	O
+a	O
+higher	O
+risk	O
+to	O
+develop	O
+HL	O
+in	O
+the	O
+first	O
+decade	O
+of	O
+life	O
+when	O
+compared	O
+to	O
+OI	O
+Type	O
+I.	O
+
+We	O
+also	O
+show	O
+that	O
+the	O
+prevalence	B-EPI
+of	O
+SNHL	O
+is	O
+higher	O
+in	O
+females	O
+with	O
+OI	O
+compared	O
+to	O
+males	O
+.	O
+
+This	O
+study	O
+reveals	O
+new	O
+insights	O
+regarding	O
+prevalence	B-EPI
+of	O
+HL	O
+in	O
+OI	O
+including	O
+a	O
+lower	O
+general	O
+prevalence	B-EPI
+of	O
+HL	O
+in	O
+COL1A1	O
+/	O
+COL1A2	O
+-	O
+related	O
+OI	O
+than	O
+previously	O
+reported	O
+(	O
+28.3	O
+vs.	O
+65	O
+%	O
+)	O
+and	O
+high	O
+prevalence	B-EPI
+of	O
+SNHL	O
+in	O
+females	O
+.	O
+
+Our	O
+data	O
+support	O
+the	O
+need	O
+in	O
+early	O
+routine	O
+hearing	O
+evaluation	O
+in	O
+all	O
+types	O
+of	O
+OI	O
+that	O
+can	O
+be	O
+adjusted	O
+to	O
+the	O
+severity	O
+of	O
+the	O
+skeletal	O
+disease	O
+.	O
+
+Introduction	O
+:	O
+'	O
+Chronic	O
+inflammatory	O
+immune	O
+-	O
+related	O
+skin	O
+disease	O
+'	O
+(	O
+ISDs	O
+)	O
+is	O
+an	O
+umbrella	O
+term	O
+grouping	O
+together	O
+heterogeneous	O
+entities	O
+characterized	O
+by	O
+chronic	O
+inflammation	O
+potentially	O
+involving	O
+the	O
+whole	O
+skin	O
+.	O
+
+We	O
+are	O
+not	O
+covering	O
+all	O
+ISDs	O
+in	O
+this	O
+review	O
+,	O
+but	O
+take	O
+a	O
+few	O
+as	O
+the	O
+most	O
+representative	O
+,	O
+including	O
+nonbullous	O
+and	O
+bullous	O
+diseases	O
+.	O
+
+The	O
+question	O
+we	O
+are	O
+aiming	O
+to	O
+address	O
+can	O
+be	O
+summarized	O
+as	O
+follows	O
+:	O
+'	O
+despite	O
+the	O
+differences	O
+,	O
+is	O
+it	O
+possible	O
+to	O
+define	O
+some	O
+unifying	O
+epidemiologic	O
+characteristics	O
+and	O
+shared	O
+progression	O
+pathways	O
+which	O
+can	O
+guide	O
+the	O
+organization	O
+of	O
+healthcare	O
+?	O
+'	O
+
+Areas	O
+covered	O
+:	O
+This	O
+review	O
+covers	O
+incidence	B-EPI
+,	O
+prevalence	B-EPI
+,	O
+risk	O
+factors	O
+and	O
+prognosis	O
+of	O
+psoriasis	O
+,	O
+atopic	O
+dermatitis	O
+(	O
+AD	O
+)	O
+,	O
+pemphigus	O
+and	O
+pemphigoid	O
+.	O
+
+Medline	O
+,	O
+Embase	O
+and	O
+the	O
+Cochrane	O
+Library	O
+were	O
+searched	O
+for	O
+papers	O
+published	O
+between	O
+January	O
+2005	O
+and	O
+December	O
+2019	O
+.	O
+
+Expert	O
+opinion	O
+:	O
+ISDs	O
+epidemiology	O
+varies	O
+according	O
+to	O
+the	O
+ISD	O
+type	O
+,	O
+age	O
+,	O
+sex	O
+,	O
+climate	O
+,	O
+and	O
+sociodemographic	O
+variables	O
+.	O
+
+AD	O
+and	O
+psoriasis	O
+pose	O
+a	O
+considerable	O
+public	O
+health	O
+burden	O
+owing	O
+to	O
+their	O
+high	O
+prevalence	B-EPI
+worldwide	B-LOC
+and	O
+morbidity	O
+.	O
+
+Their	O
+secular	O
+trend	O
+of	O
+increasing	O
+incidence	B-EPI
+points	O
+to	O
+a	O
+role	O
+for	O
+environmental	O
+factors	O
+and	O
+gene	O
+-	O
+environment	O
+interactions	O
+.	O
+
+Bullous	O
+diseases	O
+are	O
+much	O
+rarer	O
+,	O
+with	O
+limited	O
+data	O
+available	O
+.	O
+
+Worldwide	O
+,	O
+the	O
+leading	O
+cause	O
+of	O
+skin	O
+disease	O
+disability	O
+-	O
+adjusted	O
+life	O
+-	O
+years	O
+(	O
+DALYs	O
+)	O
+is	O
+attributable	O
+to	O
+AD	O
+.	O
+
+Future	O
+research	O
+should	O
+focus	O
+on	O
+risk	O
+factors	O
+and	O
+prevention	O
+at	O
+the	O
+global	O
+level	O
+.	O
+
+Background	O
+Neurological	O
+involvement	O
+due	O
+to	O
+intraspinal	O
+extension	O
+in	O
+sacrococcygeal	O
+malignant	O
+germ	O
+cell	O
+tumors	O
+(	O
+SC	O
+-	O
+MGCTs	O
+)	O
+has	O
+rarely	O
+been	O
+reported	O
+.	O
+
+Aim	O
+To	O
+evaluate	O
+the	O
+incidence	B-EPI
+,	O
+presentation	O
+,	O
+management	O
+and	O
+the	O
+outcome	O
+of	O
+patients	O
+of	O
+SC	O
+-	O
+MGCT	O
+with	O
+intraspinal	O
+extension	O
+.	O
+
+Materials	O
+and	O
+methods	O
+Case	O
+records	O
+of	O
+all	O
+cases	O
+of	O
+SC	O
+-	O
+MGCT	O
+from	O
+2001	O
+to	O
+2008	O
+,	O
+were	O
+reviewed	O
+to	O
+identify	O
+cases	O
+with	O
+vertebral	O
+involvement	O
+and	O
+intraspinal	O
+extension	O
+.	O
+
+They	O
+were	O
+evaluated	O
+in	O
+terms	O
+of	O
+their	O
+presentation	O
+,	O
+response	O
+to	O
+therapy	O
+,	O
+extent	O
+of	O
+surgical	O
+resection	O
+,	O
+recovery	O
+of	O
+neurological	O
+symptoms	O
+and	O
+outcome	O
+.	O
+
+Results	O
+Of	O
+the	O
+31	O
+cases	O
+of	O
+SC	O
+-	O
+MGCT	O
+,	O
+5	B-STAT
+(	O
+16	O
+%	O
+)	O
+had	O
+intraspinal	O
+extension	O
+.	O
+
+Age	O
+ranged	O
+from	O
+12	O
+to	O
+84	O
+months	O
+(	O
+median	O
+24	O
+months	O
+)	O
+.	O
+
+Four	O
+patients	O
+had	O
+Altman	O
+type	O
+4	O
+disease	O
+(	O
+stage	O
+4	O
+)	O
+and	O
+1	O
+had	O
+Altman	O
+type	O
+3	O
+(	O
+stage	O
+3	O
+)	O
+disease	O
+.	O
+
+The	O
+intraspinal	O
+extension	O
+in	O
+all	O
+patients	O
+was	O
+detected	O
+on	O
+contrast	O
+CT	O
+scan	O
+.	O
+
+Patients	O
+presented	O
+with	O
+neurological	O
+symptoms	O
+in	O
+the	O
+form	O
+of	O
+lower	O
+limb	O
+paresis	O
+(	O
+80	O
+%	O
+)	O
+,	O
+bowel	O
+and	O
+bladder	O
+(	O
+20	O
+%	O
+)	O
+incontinence	O
+.	O
+
+All	O
+the	O
+tumors	O
+responded	O
+to	O
+pre	O
+-	O
+operative	O
+chemotherapy	O
+.	O
+
+Gross	O
+complete	O
+local	O
+resection	O
+could	O
+be	O
+achieved	O
+in	O
+4(80	O
+%	O
+)	O
+.	O
+
+Neurological	O
+recovery	O
+was	O
+complete	O
+in	O
+all	O
+except	O
+for	O
+persisting	O
+neurogenic	O
+bladder	O
+in	O
+one	O
+.	O
+
+During	O
+follow	O
+up	O
+of	O
+3	O
+-	O
+32	O
+months	O
+,	O
+all	O
+were	O
+alive	O
+with	O
+no	O
+recurrence	O
+.	O
+
+Conclusions	O
+SC	O
+-	O
+MGCT	O
+presenting	O
+with	O
+neurological	O
+deficits	O
+due	O
+to	O
+intraspinal	O
+extension	O
+is	O
+usually	O
+advanced	O
+disease	O
+.	O
+
+These	O
+patients	O
+respond	O
+to	O
+chemotherapy	O
+and	O
+surgical	O
+resection	O
+and	O
+most	O
+have	O
+complete	O
+neurological	O
+improvement	O
+.	O
+
+Middle	O
+ear	O
+barotrauma	O
+(	O
+MEB	O
+)	O
+is	O
+a	O
+common	O
+complication	O
+of	O
+hyperbaric	O
+oxygen	O
+(	O
+HBO2	O
+)	O
+therapy	O
+.	O
+
+It	O
+has	O
+been	O
+reported	O
+in	O
+more	O
+than	O
+40	B-STAT
+%	O
+of	O
+HBO2	O
+treatments	O
+and	O
+can	O
+interrupt	O
+the	O
+sequence	O
+of	O
+HBO2	O
+.	O
+
+MEB	O
+may	O
+lead	O
+to	O
+pain	O
+,	O
+tympanic	O
+membrane	O
+rupture	O
+,	O
+and	O
+even	O
+hearing	O
+loss	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+if	O
+pretreatment	O
+with	O
+intranasal	O
+fluticasone	O
+and	O
+oxymetazoline	O
+affected	O
+the	O
+incidence	B-EPI
+of	O
+MEB	O
+.	O
+
+We	O
+conducted	O
+a	O
+retrospective	O
+chart	O
+review	O
+of	O
+subjects	O
+undergoing	O
+HBO2	O
+at	O
+our	O
+institution	O
+between	O
+February	O
+1	O
+,	O
+2014	O
+,	O
+and	O
+May	O
+31	O
+,	O
+2019	O
+.	O
+
+Subjects	O
+in	O
+the	O
+fluticasone	O
+/	O
+oxymetazoline	O
+(	O
+FOT	O
+)	O
+treatment	O
+group	O
+used	O
+intranasal	O
+fluticasone	O
+50	B-STAT
+mcg	I-STAT
+two	I-STAT
+times	I-STAT
+per	I-STAT
+day	I-STAT
+and	I-STAT
+oxymetazoline	O
+0.05	B-STAT
+%	I-STAT
+one	O
+spray	O
+two	B-STAT
+times	I-STAT
+per	I-STAT
+day	I-STAT
+beginning	I-STAT
+48	I-STAT
+hours	O
+prior	O
+to	O
+initial	O
+HBO2	O
+.	O
+
+Oxymetazoline	O
+was	O
+discontinued	O
+after	O
+four	O
+days	O
+.	O
+
+Fluticasone	O
+was	O
+continued	O
+for	O
+the	O
+duration	O
+of	O
+HBO2	O
+therapy	O
+.	O
+
+A	O
+total	O
+of	O
+154	O
+unique	O
+subjects	O
+underwent	O
+5,683	O
+HBO2	O
+treatments	O
+:	O
+39	O
+unique	O
+subjects	O
+in	O
+the	O
+FOT	O
+group	O
+underwent	O
+1,501	O
+HBO2	O
+;	O
+115	O
+unique	O
+subjects	O
+in	O
+the	O
+nFOT	O
+(	O
+no	O
+oxymetazoline	O
+or	O
+fluticasone	O
+treatment	O
+)	O
+group	O
+underwent	O
+4,182	O
+HBO2	O
+treatments	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+MEB	O
+was	O
+15.4	O
+%	O
+in	O
+the	O
+FOT	O
+group	O
+and	O
+16.2	O
+%	O
+in	O
+the	O
+nFOT	O
+group	O
+.	O
+
+This	O
+was	O
+not	O
+a	O
+statistically	O
+significant	O
+difference	O
+(	O
+OR	O
+=	O
+0.77	O
+;	O
+p	O
+=	O
+0.636	O
+)	O
+.	O
+
+Treatment	O
+pressure	O
+,	O
+age	O
+over	O
+65	O
+years	O
+,	O
+male	O
+sex	O
+,	O
+and	O
+BMI	O
+were	O
+not	O
+associated	O
+with	O
+a	O
+difference	O
+in	O
+MEB	O
+incidence	B-EPI
+.	O
+
+In	O
+summary	O
+,	O
+pretreatment	O
+with	O
+intranasal	O
+oxymetazoline	O
+and	O
+fluticasone	O
+in	O
+patients	O
+undergoing	O
+HBO2	O
+did	O
+not	O
+significantly	O
+reduce	O
+MEB	O
+.	O
+
+More	O
+investigation	O
+with	O
+larger	O
+numbers	O
+of	O
+participants	O
+and	O
+prospective	O
+studies	O
+could	O
+further	O
+clarify	O
+this	O
+issue	O
+.	O
+
+BACKGROUND	O
+:	O
+The	O
+incidence	B-EPI
+of	O
+Taralomyces	O
+marneffei	O
+infection	O
+in	O
+HIV	O
+-	O
+infected	O
+individuals	O
+has	O
+been	O
+decreasing	O
+,	O
+whereas	O
+its	O
+rate	O
+is	O
+rising	O
+among	O
+non	O
+-	O
+HIV	O
+immunodeficient	O
+persons	O
+,	O
+particularly	O
+patients	O
+with	O
+anti	O
+-	O
+interferon	O
+-	O
+gamma	O
+autoantibodies	O
+.	O
+
+T.	O
+marneffei	O
+usually	O
+causes	O
+invasive	O
+and	O
+disseminated	O
+infections	O
+,	O
+including	O
+fungemia	O
+.	O
+
+T.	O
+marneffei	O
+oro	O
+-	O
+pharyngo	O
+-	O
+laryngitis	O
+is	O
+an	O
+unusual	O
+manifestation	O
+of	O
+talaromycosis	O
+.	O
+
+CASE	O
+PRESENTATION	O
+:	O
+A	O
+52	O
+-	O
+year	O
+-	O
+old	O
+Thai	O
+woman	O
+had	O
+been	O
+diagnosed	O
+anti	O
+-	O
+IFNɣ	O
+autoantibodies	O
+for	O
+4	O
+years	O
+.	O
+
+She	O
+had	O
+a	O
+sore	O
+throat	O
+,	O
+odynophagia	O
+,	O
+and	O
+hoarseness	O
+for	O
+3	O
+weeks	O
+.	O
+
+She	O
+also	O
+had	O
+febrile	O
+symptoms	O
+and	O
+lost	O
+5	O
+kg	O
+in	O
+weight	O
+.	O
+
+Physical	O
+examination	O
+revealed	O
+marked	O
+swelling	O
+and	O
+hyperemia	O
+of	O
+both	O
+sides	O
+of	O
+the	O
+tonsils	O
+,	O
+the	O
+uvula	O
+and	O
+palatal	O
+arches	O
+including	O
+a	O
+swelling	O
+of	O
+the	O
+epiglottis	O
+,	O
+and	O
+arytenoid	O
+.	O
+
+The	O
+right	O
+tonsillar	O
+biopsy	O
+exhibited	O
+a	O
+few	O
+intracellular	O
+oval	O
+and	O
+elongated	O
+yeast	O
+-	O
+like	O
+organisms	O
+with	O
+some	O
+central	O
+transverse	O
+septum	O
+seen	O
+,	O
+which	O
+subsequently	O
+grew	O
+a	O
+few	O
+colonies	O
+of	O
+T.	O
+marneffei	O
+on	O
+fungal	O
+cultures	O
+.	O
+
+The	O
+patient	O
+received	O
+amphotericin	O
+B	O
+deoxycholate	O
+45	O
+mg	O
+/	O
+dayfor	O
+1	B-STAT
+weeks	O
+,	O
+followed	O
+by	O
+oral	O
+itraconazole	O
+400	O
+mg	O
+/	O
+day	O
+for	O
+several	O
+months	O
+.	O
+
+Her	O
+symptoms	O
+completely	O
+resolved	O
+without	O
+complication	O
+.	O
+
+CONCLUSION	O
+:	O
+In	O
+patients	O
+with	O
+anti	O
+-	O
+IFN	O
+-	O
+ɣ	O
+autoantibodies	O
+,	O
+T.	O
+marneffei	O
+can	O
+rarely	O
+cause	O
+a	O
+local	O
+infection	O
+involving	O
+oropharynx	O
+and	O
+larynx	O
+.	O
+
+Fungal	O
+culture	O
+and	O
+pathological	O
+examination	O
+are	O
+warranted	O
+for	O
+diagnosis	O
+T.	O
+marneffei	O
+oro	O
+-	O
+pharyngo	O
+-	O
+laryngitis	O
+.	O
+
+This	O
+condition	O
+requires	O
+a	O
+long	O
+term	O
+antifungal	O
+therapy	O
+.	O
+
+Background	O
+and	O
+objective	O
+To	O
+understand	O
+the	O
+microvascular	O
+abnormalities	O
+in	O
+cystoid	O
+macular	O
+edema	O
+(	O
+CME	O
+)	O
+in	O
+gyrate	O
+atrophy	O
+.	O
+
+Patients	O
+and	O
+methods	O
+Spectral	O
+-	O
+domain	O
+optical	O
+coherence	O
+tomography	O
+(	O
+SD	O
+-	O
+OCT	O
+)	O
+and	O
+OCT	O
+angiography	O
+(	O
+OCTA	O
+)	O
+were	O
+used	O
+in	O
+four	O
+consecutive	O
+female	O
+patients	O
+(	O
+eight	O
+eyes	O
+)	O
+with	O
+clinically	O
+and	O
+biochemistry	O
+-	O
+confirmed	O
+cases	O
+of	O
+gyrate	O
+atrophy	O
+and	O
+associated	O
+CME	O
+.	O
+
+Foveal	O
+avascular	O
+zone	O
+(	O
+FAZ	O
+)	O
+area	O
+and	O
+macular	O
+vessel	O
+density	O
+percentage	O
+were	O
+calculated	O
+and	O
+compared	O
+with	O
+normal	O
+subjects	O
+.	O
+
+Results	O
+The	O
+average	O
+age	O
+was	O
+20	O
+years	O
+(	O
+range	O
+:	O
+13	O
+years	O
+to	O
+32	O
+years	O
+)	O
+.	O
+
+The	O
+mean	O
+refractive	O
+error	O
+was	O
+-6.5	O
+diopters	O
+(	O
+D	O
+)	O
+(	O
+range	O
+:	O
+-1.0	O
+D	O
+to	O
+-11.0	O
+D	O
+)	O
+.	O
+
+The	O
+average	O
+central	O
+macular	O
+thickness	O
+was	O
+509	O
+μm	O
+(	O
+range	O
+:	O
+291	O
+μm	O
+to	O
+750	O
+μm	O
+)	O
+.	O
+
+OCTA	O
+showed	O
+an	O
+enlarged	O
+FAZ	O
+in	O
+the	O
+deep	O
+capillary	O
+plexus	O
+(	O
+DCP	O
+)	O
+with	O
+presence	O
+of	O
+hyporeflective	O
+cysts	O
+in	O
+both	O
+the	O
+superficial	O
+and	O
+deep	O
+capillary	O
+layers	O
+corresponding	O
+to	O
+CME	O
+.	O
+
+Compared	O
+to	O
+the	O
+normal	O
+subjects	O
+,	O
+the	O
+mean	O
+FAZ	O
+area	O
+was	O
+enlarged	O
+and	O
+macular	O
+vessel	O
+density	O
+was	O
+reduced	O
+in	O
+both	O
+the	O
+superficial	O
+capillary	O
+plexus	O
+and	O
+DCP	O
+;	O
+this	O
+was	O
+statistically	O
+significant	O
+(	O
+P	O
+<	O
+.05	O
+)	O
+.	O
+
+En	O
+face	O
+OCT	O
+of	O
+the	O
+DCPs	O
+showed	O
+classical	O
+hyporeflective	O
+honeycomb	O
+pattern	O
+delineating	O
+the	O
+structural	O
+pattern	O
+of	O
+CME	O
+in	O
+the	O
+inner	O
+plexiform	O
+and	O
+outer	O
+plexiform	O
+layer	O
+.	O
+
+Conclusion	O
+OCTA	O
+helps	O
+understand	O
+the	O
+basic	O
+pathophysiologic	O
+mechanisms	O
+in	O
+gyrate	O
+atrophy	O
+of	O
+choroid	O
+as	O
+well	O
+as	O
+etiology	O
+for	O
+CME	O
+and	O
+macular	O
+schisis	O
+.	O
+
+[	O
+Ophthalmic	O
+Surg	O
+Lasers	O
+Imaging	O
+Retina	O
+.	O
+
+2019;50:423	O
+-	O
+427	O
+.	O
+
+]	O
+.	O
+
+Larsen	O
+syndrome	O
+(	O
+OMIM	O
+150250	O
+)	O
+was	O
+first	O
+described	O
+in	O
+1950	O
+as	O
+an	O
+entity	O
+characterized	O
+by	O
+distinct	O
+facial	O
+features	O
+and	O
+dislocations	O
+of	O
+the	O
+multiple	O
+large	O
+joint	O
+,	O
+and	O
+cleft	O
+palate	O
+,	O
+hearing	O
+loss	O
+,	O
+and	O
+spinal	O
+abnormalities	O
+were	O
+occasionally	O
+observed	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+Larsen	O
+syndrome	O
+is	O
+estimated	O
+to	O
+be	O
+one	O
+in	O
+100,000	O
+live	O
+births	O
+.	O
+
+Management	O
+of	O
+multiple	O
+large	O
+-	O
+joint	O
+dislocations	O
+often	O
+proves	O
+difficult	O
+with	O
+a	O
+tendency	O
+toward	O
+recurrence	O
+,	O
+particularly	O
+if	O
+a	O
+patient	O
+has	O
+complete	O
+dislocation	O
+of	O
+the	O
+knee	O
+.We	O
+treated	O
+a	O
+boy	O
+with	O
+the	O
+clinical	O
+phenotype	O
+of	O
+Larsen	O
+syndrome	O
+using	O
+10	O
+orthopedic	O
+procedures	O
+,	O
+but	O
+failed	O
+to	O
+achieve	O
+a	O
+satisfactory	O
+outcome	O
+.	O
+The	O
+aim	O
+of	O
+this	O
+report	O
+is	O
+to	O
+review	O
+the	O
+surgical	O
+course	O
+and	O
+report	O
+results	O
+of	O
+surgical	O
+treatments	O
+for	O
+this	O
+patient	O
+with	O
+12	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+Objective	O
+Dominant	O
+optic	O
+atrophy	O
+(	O
+DOA	O
+)	O
+is	O
+the	O
+most	O
+common	O
+inherited	O
+optic	O
+neuropathy	O
+,	O
+with	O
+a	O
+prevalence	B-EPI
+of	O
+1:12,000	B-STAT
+to	O
+1:25,000	O
+.	O
+
+OPA1	O
+mutations	O
+are	O
+found	O
+in	O
+70	O
+%	O
+of	O
+DOA	O
+patients	O
+,	O
+with	O
+a	O
+significant	O
+number	O
+remaining	O
+undiagnosed	O
+.	O
+
+Methods	O
+We	O
+screened	O
+286	O
+index	O
+cases	O
+presenting	O
+optic	O
+atrophy	O
+,	O
+negative	O
+for	O
+OPA1	O
+mutations	O
+,	O
+by	O
+targeted	O
+next	O
+generation	O
+sequencing	O
+or	O
+whole	O
+exome	O
+sequencing	O
+.	O
+
+Pathogenicity	O
+and	O
+molecular	O
+mechanisms	O
+of	O
+the	O
+identified	O
+variants	O
+were	O
+studied	O
+in	O
+yeast	O
+and	O
+patient	O
+-	O
+derived	O
+fibroblasts	O
+.	O
+
+Results	O
+Twelve	O
+cases	O
+(	O
+4	O
+%	O
+)	O
+were	O
+found	O
+to	O
+carry	O
+novel	O
+variants	O
+in	O
+AFG3L2	O
+,	O
+a	O
+gene	O
+that	O
+has	O
+been	O
+associated	O
+with	O
+autosomal	O
+dominant	O
+spinocerebellar	O
+ataxia	O
+28	O
+(	O
+SCA28	O
+)	O
+.	O
+
+Half	O
+of	O
+cases	O
+were	O
+familial	O
+with	O
+a	O
+dominant	O
+inheritance	O
+,	O
+whereas	O
+the	O
+others	O
+were	O
+sporadic	O
+,	O
+including	O
+de	O
+novo	O
+mutations	O
+.	O
+
+Biallelic	O
+mutations	O
+were	O
+found	O
+in	O
+3	O
+probands	O
+with	O
+severe	O
+syndromic	O
+optic	O
+neuropathy	O
+,	O
+acting	O
+as	O
+recessive	O
+or	O
+phenotype	O
+-	O
+modifier	O
+variants	O
+.	O
+
+All	O
+the	O
+DOA	O
+-	O
+associated	O
+AFG3L2	O
+mutations	O
+were	O
+clustered	O
+in	O
+the	O
+ATPase	O
+domain	O
+,	O
+whereas	O
+SCA28	O
+-	O
+associated	O
+mutations	O
+mostly	O
+affect	O
+the	O
+proteolytic	O
+domain	O
+.	O
+
+The	O
+pathogenic	O
+role	O
+of	O
+DOA	O
+-	O
+associated	O
+AFG3L2	O
+mutations	O
+was	O
+confirmed	O
+in	O
+yeast	O
+,	O
+unraveling	O
+a	O
+mechanism	O
+distinct	O
+from	O
+that	O
+of	O
+SCA28	O
+-	O
+associated	O
+AFG3L2	O
+mutations	O
+.	O
+
+Patients	O
+'	O
+fibroblasts	O
+showed	O
+abnormal	O
+OPA1	O
+processing	O
+,	O
+with	O
+accumulation	O
+of	O
+the	O
+fission	O
+-	O
+inducing	O
+short	O
+forms	O
+leading	O
+to	O
+mitochondrial	O
+network	O
+fragmentation	O
+,	O
+not	O
+observed	O
+in	O
+SCA28	O
+patients	O
+'	O
+cells	O
+.	O
+
+Interpretation	O
+This	O
+study	O
+demonstrates	O
+that	O
+mutations	O
+in	O
+AFG3L2	O
+are	O
+a	O
+relevant	O
+cause	O
+of	O
+optic	O
+neuropathy	O
+,	O
+broadening	O
+the	O
+spectrum	O
+of	O
+clinical	O
+manifestations	O
+and	O
+genetic	O
+mechanisms	O
+associated	O
+with	O
+AFG3L2	O
+mutations	O
+,	O
+and	O
+underscores	O
+the	O
+pivotal	O
+role	O
+of	O
+OPA1	O
+and	O
+its	O
+processing	O
+in	O
+the	O
+pathogenesis	O
+of	O
+DOA	O
+.	O
+
+ANN	O
+NEUROL	O
+2020	O
+ANN	O
+NEUROL	O
+2020;88:18	O
+-	O
+32	O
+.	O
+
+Objective	O
+To	O
+analyze	O
+the	O
+results	O
+and	O
+follow	O
+up	O
+data	O
+of	O
+screening	O
+for	O
+newborn	O
+organic	O
+aciduria	O
+in	O
+Zhejiang	B-LOC
+province	I-LOC
+.	O
+
+Methods	O
+The	O
+results	O
+and	O
+follow	O
+-	O
+up	O
+data	O
+of	O
+1	B-STAT
+861	I-STAT
+262	I-STAT
+newborns	O
+from	O
+Zhejiang	B-LOC
+province	O
+undergoing	O
+screening	O
+for	O
+organic	O
+aciduria	O
+during	O
+January	O
+2009	O
+and	O
+December	O
+2016	O
+were	O
+retrospectively	O
+analyzed	O
+.	O
+
+The	O
+acylcarnitine	O
+spectrum	O
+in	O
+urine	O
+samples	O
+was	O
+detected	O
+by	O
+tandem	O
+mass	O
+spectrum	O
+(	O
+MS	O
+/	O
+MS	O
+)	O
+and	O
+the	O
+positive	O
+patients	O
+were	O
+confirmed	O
+by	O
+urine	O
+gas	O
+chromatography	O
+mass	O
+spectrometry	O
+and/or	O
+gene	O
+analysis	O
+.	O
+
+Results	O
+Ninety	O
+two	O
+cases	O
+of	O
+organic	O
+aciduria	O
+were	O
+confirmed	O
+with	O
+a	O
+prevalence	B-EPI
+of	O
+1:20	B-STAT
+200	I-STAT
+.	I-STAT
+
+Among	O
+40	O
+cases	O
+of	O
+methylmalonic	O
+academia	O
+(	O
+MMA	O
+)	O
+,	O
+13	B-STAT
+(	O
+32.5	O
+%	O
+)	O
+were	O
+of	O
+MMA	O
+simple	O
+type	O
+and	O
+27	B-STAT
+(	O
+67.5	O
+%	O
+)	O
+were	O
+combined	O
+type	O
+.	O
+
+Genetic	O
+analysis	O
+showed	O
+6	O
+cases	O
+of	O
+MUT	O
+type	O
+and	O
+1	O
+case	O
+of	O
+CblB	O
+type	O
+out	O
+of	O
+7	O
+patients	O
+with	O
+MMA	O
+simple	O
+type	O
+,	O
+10	O
+cases	O
+of	O
+CblC	O
+and	O
+1	O
+case	O
+of	O
+CblF	O
+out	O
+of	O
+11	O
+patients	O
+with	O
+combined	O
+type	O
+,	O
+respectively	O
+.	O
+
+Six	O
+patients	O
+had	O
+propionic	O
+academia	O
+with	O
+a	O
+prevalence	B-EPI
+of	O
+1:310	B-STAT
+200	I-STAT
+,	I-STAT
+7	I-STAT
+had	O
+isovaleric	O
+academia	O
+(	O
+1:265	B-STAT
+900	I-STAT
+)	I-STAT
+,	O
+6	O
+had	O
+glutaric	O
+academia	O
+type	O
+1	B-STAT
+(	I-STAT
+1:310	B-STAT
+200	I-STAT
+)	I-STAT
+,	O
+27	O
+had	O
+3	O
+-	O
+methylcrotonyl	O
+-	O
+CoA	O
+carboxylase	O
+deficiency	O
+(	O
+MCC	O
+,	O
+1:68	B-STAT
+900	I-STAT
+)	I-STAT
+,	O
+1	B-STAT
+had	I-STAT
+3	I-STAT
+-	O
+hydroxy-3	O
+-	O
+methylglutaric	O
+aciduria	O
+(	O
+1:1	B-STAT
+861	I-STAT
+300	I-STAT
+)	I-STAT
+,	O
+2	O
+had	O
+β	O
+-	O
+ketothiolase	O
+deficiency	O
+(	O
+1:960	B-STAT
+600	I-STAT
+)	I-STAT
+,	O
+and	O
+3	O
+had	O
+biotinidase	O
+deficiency	O
+/	O
+holocarboxylase	O
+synthetase	O
+deficiency	O
+(	O
+1:620	B-STAT
+400	I-STAT
+)	I-STAT
+.	O
+
+Thirty	O
+-	O
+one	O
+patients	O
+had	O
+a	O
+disease	O
+onset	O
+at	O
+neonatal	O
+period	O
+,	O
+and	O
+15	O
+at	O
+post	O
+-	O
+neonatal	O
+period	O
+.	O
+
+Thirty	O
+-	O
+three	O
+patients	O
+had	O
+brain	O
+involvements	O
+or	O
+cranial	O
+imaging	O
+disorders	O
+.	O
+
+Three	O
+patients	O
+with	O
+MMA	O
+had	O
+kidney	O
+diseases	O
+or	O
+heomlytic	O
+uremic	O
+syndrome	O
+,	O
+and	O
+3	O
+had	O
+myocardial	O
+impairments	O
+.	O
+
+Twenty	O
+patients	O
+died	O
+during	O
+the	O
+follow	O
+-	O
+up	O
+.	O
+
+Conclusions	O
+MMA	O
+is	O
+the	O
+most	O
+common	O
+newborn	O
+organic	O
+aciduria	O
+in	O
+Zhejiang	B-LOC
+province	I-LOC
+.	O
+
+Except	O
+MCC	O
+,	O
+most	O
+organic	O
+aciduria	O
+may	O
+lead	O
+to	O
+metabolism	O
+decompensation	O
+,	O
+complications	O
+or	O
+even	O
+death	O
+.	O
+
+Oral	O
+dexamethasone	O
+mini	O
+pulse	O
+(	O
+OMP	O
+)	O
+is	O
+an	O
+established	O
+treatment	O
+modality	O
+for	O
+active	O
+vitiligo	O
+.	O
+
+Cyclosporine	O
+may	O
+have	O
+therapeutic	O
+role	O
+in	O
+active	O
+vitiligo	O
+but	O
+current	O
+evidence	O
+supporting	O
+its	O
+role	O
+is	O
+scarce	O
+.	O
+
+The	O
+objective	O
+of	O
+study	O
+was	O
+to	O
+compare	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+oral	O
+cyclosporine	O
+with	O
+OMP	O
+in	O
+patients	O
+of	O
+active	O
+vitiligo	O
+.	O
+
+Fifty	O
+patients	O
+with	O
+active	O
+vitiligo	O
+were	O
+randomized	O
+into	O
+two	O
+groups	O
+of	O
+25	O
+patients	O
+.	O
+
+Group	O
+1	O
+was	O
+treated	O
+with	O
+OMP	O
+(	O
+2.5	O
+mg	O
+dexamethasone	O
+)	O
+on	O
+two	O
+consecutive	O
+days	O
+/	O
+week	O
+for	O
+4	O
+months	O
+while	O
+group	O
+2	O
+was	O
+treated	O
+with	O
+cyclosporine	O
+(	O
+3	O
+mg	O
+/	O
+kg	O
+/	O
+day	O
+)	O
+for	O
+4	O
+months	O
+.	O
+
+Laboratory	O
+monitoring	O
+was	O
+performed	O
+as	O
+per	O
+the	O
+prevalent	B-EPI
+protocol	O
+.	O
+
+The	O
+patients	O
+were	O
+followed	O
+up	O
+for	O
+another	O
+2	O
+months	O
+after	O
+stopping	O
+treatment	O
+.	O
+
+Arrest	O
+of	O
+disease	O
+progression	O
+(	O
+ADP	O
+)	O
+was	O
+defined	O
+as	O
+change	O
+of	O
+vitiligo	O
+disease	O
+activity	O
+score	O
+from	O
+4	O
++	O
+to	O
+3	O
++	O
+(	O
+time	O
+elapsed	O
+since	O
+last	O
+disease	O
+activity	O
+being	O
+more	O
+than	O
+6	O
+weeks	O
+upto	O
+3	O
+months	O
+)	O
+during	O
+the	O
+study	O
+period	O
+(	O
+6	O
+months	O
+)	O
+.	O
+
+ADP	O
+was	O
+attained	O
+in	O
+21	O
+patients	O
+in	O
+group	O
+1	B-STAT
+and	I-STAT
+22	I-STAT
+patients	O
+in	O
+group	O
+2	B-STAT
+(	O
+84	O
+%	O
+vs.	O
+88	O
+%	O
+,	O
+p	O
+=	O
+1.00	O
+)	O
+at	O
+the	O
+end	O
+of	O
+6	O
+months	O
+.	O
+
+However	O
+,	O
+mean	O
+time	O
+to	O
+achieve	O
+ADP	O
+was	O
+significantly	O
+lower	O
+in	O
+group	O
+2	O
+as	O
+compared	O
+to	O
+group	O
+1	O
+(	O
+10.92	O
+[	O
+4.12	O
+]	O
+weeks	O
+vs.	O
+13.90	O
+[	O
+3.92	O
+]	O
+weeks	O
+,	O
+p	O
+=	O
+0.01	O
+)	O
+.	O
+
+Extent	O
+of	O
+repigmentation	O
+,	O
+improvement	O
+in	O
+patient	O
+assessment	O
+score	O
+,	O
+vitiligo	O
+quality	O
+of	O
+life	O
+and	O
+clinical	O
+markers	O
+of	O
+disease	O
+activity	O
+were	O
+marginal	O
+and	O
+comparable	O
+in	O
+both	O
+groups	O
+.	O
+
+Cyclosporine	O
+leads	O
+to	O
+earlier	O
+disease	O
+stabilization	O
+in	O
+active	O
+vitiligo	O
+as	O
+compared	O
+to	O
+OMP	O
+.	O
+
+Although	O
+considered	O
+a	O
+rescue	O
+drug	O
+in	O
+dermatology	O
+,	O
+low	O
+dose	O
+cyclosporine	O
+can	O
+be	O
+an	O
+effective	O
+therapeutic	O
+alternative	O
+in	O
+vitiligo	O
+patients	O
+.	O
+
+Methylmalonic	O
+acidemia	O
+(	O
+MMA	O
+)	O
+is	O
+a	O
+lethal	O
+,	O
+severe	O
+heterogeneous	O
+disorder	O
+of	O
+methylmalonate	O
+and	O
+cobalamin	O
+(	O
+cbl	O
+;	O
+vitamin	O
+B12	O
+)	O
+metabolism	O
+with	O
+poor	O
+prognosis	O
+.	O
+
+Two	O
+main	O
+forms	O
+of	O
+the	O
+disease	O
+have	O
+been	O
+identified	O
+,	O
+isolated	O
+methylmalonic	O
+acidurias	O
+and	O
+combined	O
+methylmalonic	O
+aciduria	O
+and	O
+homocystinuria	O
+,	O
+which	O
+is	O
+respectively	O
+caused	O
+by	O
+different	O
+gene	O
+mutations	O
+.	O
+
+Here	O
+,	O
+we	O
+review	O
+the	O
+improvement	O
+of	O
+pathogenesis	O
+,	O
+diagnosis	O
+and	O
+treatment	O
+in	O
+MMA	B-LOC
+.	O
+
+Importantly	O
+,	O
+the	O
+reported	O
+epidemiological	O
+data	O
+of	O
+MMA	O
+patients	O
+in	O
+China	B-LOC
+and	O
+the	O
+hot	O
+mutation	O
+sites	O
+in	O
+Chinese	O
+patients	O
+are	O
+listed	O
+,	O
+which	O
+will	O
+aid	O
+in	O
+improving	O
+healthcare	O
+of	O
+Chinese	O
+patients	O
+in	O
+the	O
+future	O
+.	O
+
+c.729_730insTT	O
+was	O
+the	O
+most	O
+common	O
+mutation	O
+in	O
+Chinese	O
+isolated	O
+MMA	O
+patients	O
+,	O
+while	O
+c.609G	O
+>	O
+A	O
+and	O
+c.658_660delAAG	O
+were	O
+in	O
+Chinese	O
+cblC	O
+type	O
+patients	O
+according	O
+to	O
+unrelated	O
+studies	O
+.	O
+
+The	O
+estimated	O
+newborn	O
+screening	O
+incidence	B-EPI
+was	O
+reported	O
+to	O
+be	O
+1:26,000	B-STAT
+,	O
+1:3,920	B-STAT
+,	O
+1:11,160	B-STAT
+,	O
+1:6,032	B-STAT
+respectively	I-STAT
+in	I-STAT
+Beijing	B-LOC
+and	O
+Shanghai	B-LOC
+,	O
+Shandong	B-LOC
+province	I-LOC
+,	O
+Taian	B-LOC
+district	I-LOC
+,	O
+and	O
+Henan	B-LOC
+province	I-LOC
+of	I-LOC
+China	B-LOC
+.	O
+
+Alternatively	O
+,	O
+when	O
+patients	O
+with	O
+suspected	O
+inherited	O
+metabolic	O
+diseases	O
+were	O
+used	O
+as	O
+the	O
+screened	O
+sample	O
+,	O
+the	O
+relatively	O
+high	O
+incidence	B-EPI
+0.3	B-STAT
+%	I-STAT
+and	O
+1.32	O
+%	O
+were	O
+respectively	O
+obtained	O
+in	O
+southern	O
+China	B-LOC
+and	O
+throughout	O
+all	O
+the	O
+provinces	O
+of	O
+mainland	O
+China	B-LOC
+and	O
+Macao	B-LOC
+with	O
+the	O
+exception	O
+of	O
+five	O
+provinces	O
+(	O
+Hainan	B-LOC
+,	O
+Neimenggu	B-LOC
+,	O
+Tibet	B-LOC
+,	O
+Ningxia	B-LOC
+,	O
+and	O
+Hong	B-LOC
+Kong	I-LOC
+)	O
+.	O
+
+The	O
+establishing	O
+of	O
+46	O
+chromosomes	O
+as	O
+the	O
+normal	O
+complement	O
+in	O
+man	O
+and	O
+the	O
+report	O
+of	O
+the	O
+sex	O
+chromatin	O
+bodies	O
+in	O
+buccal	O
+smears	O
+were	O
+followed	O
+by	O
+reports	O
+of	O
+trisomies	O
+and	O
+other	O
+abnormal	O
+patterns	O
+of	O
+the	O
+X	O
+and	O
+Y	O
+chromosomes	O
+in	O
+Klinefelter	O
+'s	O
+and	O
+Turner	O
+'s	O
+syndromes	O
+.	O
+
+Abnormal	O
+autosomal	O
+complements	O
+were	O
+described	O
+in	O
+mongolism	O
+,	O
+in	O
+the	O
+E	O
+-	O
+trisomy	O
+syndrome	O
+,	O
+the	O
+D	O
+-	O
+trisomy	O
+syndrome	O
+,	O
+in	O
+the	O
+Sturge	O
+-	O
+Weber	O
+syndrome	O
+,	O
+Waldenstrom	O
+'s	O
+macroglobulinemia	O
+,	O
+benign	O
+congenital	O
+hypotonia	O
+,	O
+atrial	O
+septal	O
+defect	O
+and	O
+in	O
+the	O
+schizoid	O
+personality	O
+.	O
+
+Certain	O
+of	O
+these	O
+conditions	O
+,	O
+as	O
+well	O
+as	O
+the	O
+	O
+oral	O
+-	O
+facial	O
+-	O
+digital	O
+	O
+syndrome	O
+,	O
+were	O
+also	O
+found	O
+to	O
+exist	O
+as	O
+partial	O
+trisomies	O
+.	O
+
+The	O
+mechanism	O
+of	O
+a	O
+trisomy	O
+is	O
+one	O
+of	O
+non	O
+-	O
+disjunction	O
+and	O
+of	O
+partial	O
+trisomy	O
+translocation	O
+or	O
+insertion	O
+.	O
+
+Two	O
+cases	O
+of	O
+the	O
+partial	O
+trisomy	O
+in	O
+the	O
+E	O
+group	O
+are	O
+described	O
+;	O
+these	O
+are	O
+of	O
+especial	O
+interest	O
+because	O
+of	O
+the	O
+familial	O
+incidence	B-EPI
+,	O
+longer	O
+survival	O
+and	O
+male	O
+sex	O
+occurrence	B-EPI
+,	O
+features	O
+which	O
+are	O
+rarely	O
+seen	O
+in	O
+the	O
+full	O
+E	O
+-	O
+trisomy	O
+syndrome	O
+.	O
+
+Background	O
+Consanguineous	O
+families	O
+have	O
+a	O
+relatively	O
+high	O
+prevalence	B-EPI
+of	O
+genetic	O
+disorders	O
+caused	O
+by	O
+bi	O
+-	O
+allelic	O
+mutations	O
+in	O
+recessive	O
+genes	O
+.	O
+
+This	O
+study	O
+aims	O
+to	O
+evaluate	O
+the	O
+effectiveness	O
+and	O
+efficiency	O
+of	O
+a	O
+consanguinity	O
+-	O
+based	O
+exome	O
+sequencing	O
+approach	O
+to	O
+capturing	O
+genetic	O
+mutations	O
+in	O
+inherited	O
+retinal	O
+dystrophy	O
+families	O
+with	O
+consanguineous	O
+marriages	O
+.	O
+
+Methods	O
+Ten	O
+unrelated	O
+consanguineous	O
+families	O
+with	O
+a	O
+proband	O
+affected	O
+by	O
+inherited	O
+retinal	O
+dystrophy	O
+were	O
+recruited	O
+in	O
+this	O
+study	O
+.	O
+
+All	O
+participants	O
+underwent	O
+comprehensive	O
+ophthalmic	O
+examinations	O
+.	O
+
+Whole	O
+exome	O
+sequencing	O
+was	O
+performed	O
+,	O
+followed	O
+by	O
+a	O
+homozygote	O
+-	O
+prior	O
+strategy	O
+to	O
+rapidly	O
+filter	O
+disease	O
+-	O
+causing	O
+mutations	O
+.	O
+
+Bioinformatic	O
+prediction	O
+of	O
+pathogenicity	O
+,	O
+Sanger	O
+sequencing	O
+and	O
+co	O
+-	O
+segregation	O
+analysis	O
+were	O
+carried	O
+out	O
+for	O
+further	O
+validation	O
+.	O
+
+Results	O
+In	O
+ten	O
+consanguineous	O
+families	O
+,	O
+a	O
+total	O
+of	O
+10	O
+homozygous	O
+mutations	O
+in	O
+8	O
+IRD	O
+genes	O
+were	O
+identified	O
+,	O
+including	O
+2	O
+novel	O
+mutations	O
+,	O
+c.1654_1655delAG	O
+(	O
+p.	O
+R552Afs*5	O
+)	O
+in	O
+gene	O
+FAM161A	O
+in	O
+a	O
+patient	O
+diagnosed	O
+with	O
+retinitis	O
+pigmentosa	O
+,	O
+and	O
+c.830	O
+T	O
+>	O
+C	O
+(	O
+p.	O
+L277P	O
+)	O
+in	O
+gene	O
+CEP78	O
+in	O
+a	O
+patient	O
+diagnosed	O
+with	O
+cone	O
+and	O
+rod	O
+dystrophy	O
+.	O
+
+Conclusion	O
+The	O
+genetic	O
+etiology	O
+in	O
+consanguineous	O
+families	O
+with	O
+IRD	O
+were	O
+successfully	O
+identified	O
+using	O
+consanguinity	O
+-	O
+based	O
+analysis	O
+of	O
+exome	O
+sequencing	O
+data	O
+,	O
+suggesting	O
+that	O
+this	O
+approach	O
+could	O
+provide	O
+complementary	O
+insights	O
+into	O
+genetic	O
+diagnoses	O
+in	O
+consanguineous	O
+families	O
+with	O
+variant	O
+genetic	O
+disorders	O
+.	O
+
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+(	O
+CMT	O
+)	O
+disease	O
+is	O
+a	O
+common	O
+inherited	O
+peripheral	O
+neuropathy	O
+.	O
+
+The	O
+CMT2	O
+K	O
+axonal	O
+form	O
+is	O
+associated	O
+with	O
+GDAP1	O
+dominant	O
+mutations	O
+,	O
+which	O
+according	O
+to	O
+the	O
+affected	O
+domain	O
+cause	O
+a	O
+gradient	O
+of	O
+severity	O
+.	O
+
+Indeed	O
+,	O
+the	O
+p.	O
+C240Y	O
+mutation	O
+,	O
+located	O
+within	O
+GDAP1	O
+glutathione	O
+S	O
+-	O
+transferase	O
+(	O
+GST	O
+)	O
+domain	O
+and	O
+associated	O
+to	O
+a	O
+mitochondrial	O
+complex	O
+I	O
+defect	O
+,	O
+is	O
+related	O
+to	O
+a	O
+faster	O
+disease	O
+progression	O
+,	O
+compared	O
+to	O
+other	O
+mutations	O
+,	O
+such	O
+as	O
+the	O
+p.	O
+R120W	O
+located	O
+outside	O
+the	O
+GST	O
+domain	O
+.	O
+
+Here	O
+,	O
+we	O
+analysed	O
+the	O
+pathophysiology	O
+of	O
+six	O
+CMT2	O
+K	O
+fibroblast	O
+cell	O
+lines	O
+,	O
+carrying	O
+either	O
+the	O
+p.	O
+C240Y	O
+or	O
+p.	O
+R120W	O
+mutations	O
+.	O
+
+We	O
+show	O
+that	O
+complex	O
+I	O
+deficiency	O
+leads	O
+to	O
+a	O
+redox	O
+potential	O
+alteration	O
+and	O
+a	O
+significant	O
+reduction	O
+of	O
+sirtuin	O
+1	O
+(	O
+SIRT1	O
+)	O
+expression	O
+,	O
+a	O
+major	O
+deacetylase	O
+sensitive	O
+to	O
+the	O
+cellular	O
+redox	O
+state	O
+,	O
+and	O
+NRF1	O
+the	O
+downstream	O
+target	O
+of	O
+SIRT1	O
+.	O
+
+In	O
+addition	O
+,	O
+we	O
+disclosed	O
+that	O
+the	O
+p.	O
+C240Y	O
+mutation	O
+is	O
+associated	O
+with	O
+a	O
+greater	O
+mitochondrial	O
+oxidative	O
+stress	O
+than	O
+the	O
+p.	O
+R120W	O
+mutation	O
+.	O
+
+Moreover	O
+,	O
+complex	O
+I	O
+activity	O
+is	O
+further	O
+restored	O
+in	O
+CMT2	O
+K	O
+mutant	O
+cell	O
+lines	O
+exposed	O
+to	O
+resveratrol	O
+.	O
+
+Together	O
+,	O
+these	O
+results	O
+suggest	O
+that	O
+the	O
+reduction	O
+of	O
+oxidative	O
+stress	O
+may	O
+constitute	O
+a	O
+promising	O
+therapeutic	O
+strategy	O
+for	O
+CMT2K.	O
+
+Purpose	O
+Graves	O
+'	O
+orbitopathy	O
+(	O
+GO	O
+)	O
+is	O
+an	O
+inflammatory	O
+autoimmune	O
+disorder	O
+of	O
+the	O
+orbit	O
+and	O
+while	O
+the	O
+antiphospholipid	O
+antibodies	O
+(	O
+aPL	O
+)	O
+Abs	O
+were	O
+associated	O
+with	O
+the	O
+markers	O
+of	O
+inflammation	O
+in	O
+the	O
+antiphospholipid	O
+syndrome	O
+(	O
+APS	O
+)	O
+,	O
+there	O
+is	O
+no	O
+literature	O
+that	O
+investigate	O
+the	O
+presence	O
+of	O
+aPL	O
+Abs	O
+in	O
+GO	O
+.	O
+
+We	O
+analyzed	O
+the	O
+prevalence	B-EPI
+of	O
+aPL	O
+Abs	O
+and	O
+the	O
+differences	O
+between	O
+aPL	O
+(	O
++	O
+)	O
+and	O
+aPL	O
+(	O
+-	O
+)	O
+subgroups	O
+of	O
+GO	O
+patients	O
+.	O
+
+Methods	O
+Study	O
+included	O
+consecutive	O
+patients	O
+with	O
+GO	O
+(	O
+66	O
+with	O
+Graves	O
+'	O
+(	O
+GD	O
+)	O
+,	O
+10	O
+with	O
+Hashimoto	O
+(	O
+HD	O
+)	O
+,	O
+and	O
+8	O
+were	O
+euthyroid	O
+)	O
+.	O
+
+Anticardiolipin	O
+(	O
+aCL	O
+)	O
+and	O
+anti	O
+-	O
+beta	O
+2glycoprotein	O
+I	O
+(	O
+aβ2gpI	O
+)	O
+Abs	O
+were	O
+measured	O
+by	O
+ELISA	O
+.	O
+
+Results	O
+aPL	O
+Abs	O
+were	O
+present	O
+in	O
+9/84	B-STAT
+(	O
+10.71	O
+%	O
+)	O
+patients	O
+.	O
+
+The	O
+IgM	O
+aβ2gpI	O
+Abs	O
+were	O
+present	O
+in	O
+8/66	B-STAT
+and	O
+in	O
+1/10	B-STAT
+patients	O
+with	O
+GD	O
+and	O
+HD	O
+.	O
+
+The	O
+IgG	O
+aCL	O
+Abs	O
+were	O
+present	O
+in	O
+one	O
+GD	O
+patient	O
+,	O
+and	O
+IgM	O
+aCL	O
+were	O
+present	O
+in	O
+3/66	B-STAT
+GD	O
+and	O
+in	O
+1/10	B-STAT
+patients	O
+with	O
+HD	O
+.	O
+
+In	O
+GD	O
+group	O
+,	O
+anti	O
+-	O
+Tg	O
+Abs	O
+were	O
+in	O
+positive	O
+correlation	O
+with	O
+aβ2gpI	O
+IgG	O
+(	O
+p	O
+=	O
+0.000	O
+)	O
+and	O
+with	O
+anti	O
+-	O
+TPO	O
+Abs	O
+(	O
+p	O
+=	O
+0.016	O
+)	O
+.	O
+
+In	O
+HD	O
+group	O
+,	O
+anti	O
+-	O
+Tg	O
+Abs	O
+were	O
+in	O
+positive	O
+correlation	O
+with	O
+IgM	O
+aCL	O
+(	O
+p	O
+=	O
+0.042	O
+)	O
+,	O
+while	O
+anti	O
+-	O
+TPO	O
+Abs	O
+were	O
+in	O
+positive	O
+correlation	O
+with	O
+aβ2gpI	O
+IgM	O
+(	O
+p	O
+=	O
+0.014	O
+)	O
+.	O
+
+Conclusion	O
+This	O
+study	O
+is	O
+the	O
+first	O
+report	O
+of	O
+the	O
+aPL	O
+Abs	O
+presence	O
+in	O
+GO	O
+patients	O
+.	O
+
+The	O
+anti	O
+-	O
+thyroid	O
+Abs	O
+were	O
+linked	O
+to	O
+aPL	O
+suggesting	O
+that	O
+their	O
+presence	O
+is	O
+not	O
+the	O
+sole	O
+consequence	O
+of	O
+hyperstimulation	O
+of	O
+autoreactive	O
+B	O
+-	O
+lymphocytes	O
+.	O
+
+Larger	O
+studies	O
+are	O
+necessary	O
+to	O
+confirm	O
+potential	O
+cause	O
+-	O
+effect	O
+relations	O
+.	O
+
+Since	O
+1984	O
+,	O
+we	O
+have	O
+diagnosed	O
+at	O
+the	O
+La	O
+Paz	O
+University	O
+Hospital	O
+,	O
+Madrid	B-LOC
+,	O
+Spain	B-LOC
+,	O
+41	O
+patients	O
+with	O
+hypoxanthine	O
+phosphoribosyltransferase	O
+(	O
+HPRT	O
+)	O
+activity	O
+deficiency	O
+.	O
+
+These	O
+patients	O
+belonged	O
+to	O
+34	O
+families	O
+.	O
+
+We	O
+have	O
+also	O
+performed	O
+molecular	O
+and	O
+enzymatic	O
+diagnosis	O
+in	O
+three	O
+patients	O
+from	O
+India	B-LOC
+,	O
+one	O
+from	O
+Belgium	B-LOC
+,	O
+and	O
+three	O
+from	O
+Colombia	B-LOC
+.	O
+
+About	O
+1/3	B-STAT
+of	O
+these	O
+patients	O
+were	O
+followed	O
+up	O
+at	O
+La	O
+Paz	O
+University	O
+Hospital	O
+at	O
+least	O
+every	O
+year	O
+.	O
+
+This	O
+fact	O
+has	O
+allowed	O
+us	O
+to	O
+examine	O
+the	O
+complete	O
+spectrum	O
+of	O
+HPRT	O
+deficiency	O
+as	O
+well	O
+as	O
+to	O
+perform	O
+a	O
+more	O
+accurate	O
+diagnosis	O
+and	O
+treatment	O
+.	O
+
+In	O
+the	O
+present	O
+review	O
+,	O
+we	O
+also	O
+summarized	O
+our	O
+studies	O
+on	O
+the	O
+basis	O
+of	O
+physiopathology	O
+of	O
+the	O
+neurological	O
+manifestation	O
+of	O
+Lesch	O
+Nyhan	O
+disease	O
+(	O
+LND	O
+)	O
+.	O
+
+Background	O
+Community	O
+-	O
+acquired	O
+pneumonia	O
+(	O
+CAP	O
+)	O
+is	O
+the	O
+major	O
+manifestation	O
+of	O
+Q	O
+fever	O
+,	O
+an	O
+emerging	O
+disease	O
+in	O
+French	O
+Guiana	B-LOC
+.	O
+
+Consequently	O
+,	O
+the	O
+empirical	O
+antibiotherapy	O
+used	O
+for	O
+the	O
+treatment	O
+of	O
+CAP	O
+combines	O
+doxycycline	O
+and	O
+the	O
+recommended	O
+amoxicillin	O
+.	O
+
+Our	O
+objectives	O
+were	O
+to	O
+estimate	O
+the	O
+prevalence	B-EPI
+of	O
+Q	O
+fever	O
+pneumonia	O
+and	O
+to	O
+build	O
+a	O
+prediction	O
+rule	O
+to	O
+identify	O
+patients	O
+with	O
+Q	O
+fever	O
+pneumonia	O
+for	O
+empirical	O
+antibiotic	O
+guidance	O
+.	O
+
+Methods	O
+A	O
+retrospective	O
+case	O
+-	O
+control	O
+study	O
+was	O
+conducted	O
+on	O
+inpatients	O
+admitted	O
+with	O
+CAP	O
+in	O
+the	O
+Department	O
+of	O
+Infectious	O
+Diseases	O
+of	O
+Cayenne	O
+Hospital	O
+from	O
+2004	O
+to	O
+2007	O
+.	O
+
+Serodiagnosis	O
+for	O
+Coxiella	O
+burnetii	O
+was	O
+performed	O
+for	O
+all	O
+patients	O
+.	O
+
+Risk	O
+factor	O
+analysis	O
+was	O
+performed	O
+using	O
+multivariate	O
+logistic	O
+regression	O
+,	O
+and	O
+a	O
+prognostic	O
+score	O
+was	O
+computed	O
+using	O
+bootstrap	O
+procedures	O
+.	O
+
+The	O
+score	O
+performance	O
+characteristics	O
+were	O
+used	O
+to	O
+choose	O
+the	O
+best	O
+prediction	O
+rule	O
+to	O
+identify	O
+patients	O
+with	O
+Q	O
+fever	O
+pneumonia	O
+.	O
+
+Results	O
+One	O
+hundred	O
+thirty	O
+-	O
+one	O
+patients	O
+with	O
+CAP	O
+were	O
+included	O
+and	O
+the	O
+Q	O
+fever	O
+pneumonia	O
+prevalence	B-EPI
+was	O
+24.4	O
+%	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+,	O
+17.1	O
+-	O
+31.9	O
+)	O
+.	O
+
+In	O
+multivariate	O
+analysis	O
+,	O
+male	O
+sex	O
+,	O
+middle	O
+age	O
+(	O
+age	O
+,	O
+30	O
+-	O
+60	O
+years	O
+)	O
+,	O
+headache	O
+,	O
+leukocyte	O
+count	O
+<	O
+10	B-STAT
+×	I-STAT
+10(9)/L	I-STAT
+and	O
+C	O
+-	O
+reactive	O
+protein	O
+level	O
+>	O
+185	O
+mg	O
+/	O
+L	O
+were	O
+independently	O
+associated	O
+with	O
+Q	O
+fever	O
+pneumonia	O
+.	O
+
+Patients	O
+with	O
+a	O
+predictive	O
+score	O
+≤3	O
+had	O
+a	O
+low	O
+risk	O
+of	O
+Q	O
+fever	O
+pneumonia	O
+with	O
+a	O
+negative	O
+predictive	O
+value	O
+of	O
+0.97	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+.90	O
+-	O
+1	O
+)	O
+and	O
+a	O
+sensitivity	O
+of	O
+0.97	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+.89	O
+-	O
+1	O
+)	O
+.	O
+
+Conclusions	O
+The	O
+prediction	O
+rule	O
+described	O
+here	O
+accurately	O
+identifies	O
+patients	O
+with	O
+low	O
+risk	O
+of	O
+Q	O
+fever	O
+pneumonia	O
+and	O
+may	O
+help	O
+physicians	O
+to	O
+make	O
+more	O
+rational	O
+decisions	O
+about	O
+the	O
+empirical	O
+use	O
+of	O
+antibiotherapy	O
+.	O
+
+Further	O
+prospective	O
+studies	O
+should	O
+be	O
+performed	O
+to	O
+validate	O
+this	O
+score	O
+.	O
+
+Introduction	O
+Neuromyelitis	O
+optica	O
+spectrum	O
+disorders	O
+(	O
+NMOSD	O
+)	O
+is	O
+an	O
+inflammatory	O
+and	O
+heterogeneous	O
+astrocyte	O
+disorder	O
+of	O
+the	O
+central	O
+nervous	O
+system	O
+with	O
+the	O
+characteristic	O
+of	O
+higher	O
+incidence	B-EPI
+in	O
+women	O
+and	O
+Asian	O
+people	O
+.	O
+
+Most	O
+patients	O
+with	O
+NMOSD	O
+have	O
+a	O
+course	O
+of	O
+recurrence	O
+and	O
+remission	O
+that	O
+is	O
+prone	O
+to	O
+cause	O
+paralysis	O
+and	O
+blindness	O
+.	O
+
+Several	O
+studies	O
+have	O
+confirmed	O
+the	O
+efficacy	O
+and	O
+promising	O
+prospect	O
+of	O
+mycophenolate	O
+mofetil	O
+(	O
+MMF	O
+)	O
+in	O
+the	O
+treatment	O
+of	O
+NMOSD	O
+.	O
+
+Yet	O
+its	O
+therapeutic	O
+effect	O
+and	O
+safety	O
+are	O
+controversial	O
+.	O
+
+Although	O
+there	O
+has	O
+been	O
+two	O
+published	O
+literature	O
+that	O
+is	O
+relevant	O
+to	O
+the	O
+topic	O
+of	O
+this	O
+study	O
+,	O
+both	O
+of	O
+them	O
+have	O
+certain	O
+defects	O
+,	O
+and	O
+they	O
+can	O
+only	O
+provide	O
+answers	O
+about	O
+the	O
+efficacy	O
+or	O
+safety	O
+of	O
+MMF	O
+in	O
+the	O
+treatment	O
+of	O
+NMOSD	O
+from	O
+partial	O
+perspectives	O
+or	O
+conclusions	O
+.	O
+
+This	O
+research	O
+aims	O
+to	O
+perform	O
+a	O
+direct	O
+and	O
+comprehensive	O
+systematic	O
+review	O
+and	O
+meta	O
+-	O
+analysis	O
+to	O
+evaluate	O
+MMF	O
+'s	O
+effectiveness	O
+and	O
+safety	O
+in	O
+treating	O
+NMOSD	O
+.	O
+
+Methods	O
+and	O
+analysis	O
+This	O
+systematic	O
+review	O
+will	O
+cover	O
+all	O
+comparative	O
+researches	O
+,	O
+from	O
+randomised	O
+controlled	O
+trials	O
+to	O
+cohort	O
+studies	O
+,	O
+and	O
+case	O
+-	O
+control	O
+study	O
+.	O
+
+A	O
+relevant	O
+literature	O
+search	O
+will	O
+be	O
+conducted	O
+in	O
+PubMed	O
+,	O
+Web	O
+of	O
+Science	O
+,	O
+EMBASE	O
+,	O
+the	O
+Cochrane	O
+Library	O
+,	O
+China	O
+National	O
+Knowledge	O
+Infrastructure	O
+,	O
+Wanfang	O
+Database	O
+,	O
+China	O
+Science	O
+and	O
+Technology	O
+Journal	O
+Database	O
+and	O
+Chinese	O
+Biomedical	O
+Literature	O
+Database	O
+from	O
+their	O
+inception	O
+to	O
+31	O
+June	O
+2020	O
+.	O
+
+We	O
+will	O
+also	O
+search	O
+registers	O
+of	O
+clinical	O
+trials	O
+,	O
+potential	O
+grey	O
+literature	O
+and	O
+abstracts	O
+from	O
+conferences	O
+.	O
+
+There	O
+are	O
+no	O
+limits	O
+on	O
+language	O
+and	O
+publication	O
+status	O
+.	O
+
+The	O
+reporting	O
+quality	O
+and	O
+risk	O
+of	O
+bias	O
+will	O
+be	O
+assessed	O
+by	O
+two	O
+researchers	O
+independently	O
+.	O
+
+Expanded	O
+Disability	O
+Status	O
+Scales	O
+and	O
+annualised	O
+relapse	O
+rate	O
+will	O
+be	O
+evaluated	O
+as	O
+the	O
+primary	O
+outcome	O
+.	O
+
+The	O
+secondary	O
+outcomes	O
+will	O
+consist	O
+of	O
+the	O
+frequency	O
+and	O
+severity	O
+of	O
+adverse	O
+events	O
+,	O
+best	O
+-	O
+corrected	O
+visual	O
+acuity	O
+,	O
+relapse	O
+-	O
+free	O
+rate	O
+and	O
+time	O
+to	O
+the	O
+next	O
+attack	O
+.	O
+
+A	O
+meta	O
+-	O
+analysis	O
+will	O
+be	O
+performed	O
+using	O
+RevMan	O
+V.5.3	O
+software	O
+provided	O
+by	O
+the	O
+Cochrane	O
+Collaboration	O
+and	O
+Stata	O
+V.12.0	O
+.	O
+
+Ethics	O
+and	O
+dissemination	O
+Because	O
+the	O
+data	O
+used	O
+for	O
+this	O
+systematic	O
+review	O
+will	O
+be	O
+exclusively	O
+extracted	O
+from	O
+published	O
+studies	O
+,	O
+ethical	O
+approval	O
+and	O
+informed	O
+consent	O
+of	O
+patients	O
+will	O
+not	O
+be	O
+required	O
+.	O
+
+The	O
+systematic	O
+review	O
+will	O
+be	O
+published	O
+in	O
+a	O
+peer	O
+-	O
+reviewed	O
+journal	O
+,	O
+presented	O
+at	O
+conferences	O
+and	O
+will	O
+be	O
+shared	O
+on	O
+social	O
+media	O
+platforms	O
+.	O
+
+Prospero	O
+registration	O
+number	O
+CRD42020164179	O
+.	O
+
+Purpose	O
+/	O
+aim	O
+of	O
+the	O
+study	O
+:	O
+We	O
+report	O
+a	O
+rare	O
+case	O
+of	O
+autosomal	O
+dominant	O
+genetic	O
+syndrome	O
+	O
+Pfeiffer	O
+	O
+,	O
+which	O
+is	O
+part	O
+of	O
+the	O
+group	O
+of	O
+acrocephalosyndactyly	O
+,	O
+with	O
+an	O
+annual	B-EPI
+incidence	I-EPI
+<	B-STAT
+1/100,000	I-STAT
+.	O
+
+Three	O
+forms	O
+are	O
+known	O
+.	O
+
+Type	O
+I	O
+is	O
+the	O
+less	O
+common	O
+form	O
+and	O
+it	O
+is	O
+characterized	O
+by	O
+moderate	O
+-	O
+severe	O
+mediofacial	O
+hypoplasia	O
+usually	O
+with	O
+normal	O
+cognitive	O
+development	O
+.	O
+
+Conversely	O
+,	O
+types	O
+2	O
+and	O
+3	O
+are	O
+more	O
+common	O
+and	O
+they	O
+are	O
+associated	O
+with	O
+more	O
+severe	O
+signs	O
+and	O
+complications	O
+with	O
+a	O
+more	O
+unfavorable	O
+prognosis	O
+.	O
+
+The	O
+type	O
+3	O
+form	O
+due	O
+to	O
+the	O
+presence	O
+of	O
+a	O
+cloverleaf	O
+skull	O
+distinguishes	O
+type	O
+2	O
+.	O
+
+Materials	O
+and	O
+methods	O
+:	O
+Thirty	O
+-	O
+eight	O
+-	O
+year	O
+-	O
+old	O
+primigravida	O
+was	O
+referred	O
+to	O
+our	O
+center	O
+,	O
+at	O
+28	O
+weeks	O
+of	O
+gestation	O
+due	O
+to	O
+borderline	O
+ventriculomegaly	O
+,	O
+macrocrania	O
+,	O
+and	O
+a	O
+short	O
+femur	O
+.	O
+
+First	O
+trimester	O
+screening	O
+for	O
+chromosomopathies	O
+and	O
+CF	O
+-	O
+DNA	O
+was	O
+low	O
+risk	O
+;	O
+II	O
+trimester	O
+screening	O
+ultrasound	O
+showed	O
+the	O
+presence	O
+of	O
+	O
+short	O
+femur	O
+	O
+and	O
+macrocrania	O
+.	O
+
+Result	O
+:	O
+Our	O
+ultrasound	O
+evaluation	O
+,	O
+assisted	O
+by	O
+3D	O
+ultrasound	O
+,	O
+showed	O
+cloverleaf	O
+skull	O
+,	O
+turricephaly	O
+,	O
+moderate	O
+ventriculomegaly	O
+(	O
+13	O
+mm	O
+)	O
+,	O
+hypertelorism	O
+and	O
+exophthalmos	O
+,	O
+low	O
+ear	O
+implantation	O
+,	O
+mild	O
+rhizomelia	O
+.	O
+
+Ultrasound	O
+depicts	O
+Pfeiffer	O
+syndrome	O
+or	O
+other	O
+acrocephalosyndactyly	O
+syndromes	O
+(	O
+Apert	O
+syndromes	O
+,	O
+Saethre	O
+-	O
+Chotzen	O
+)	O
+or	O
+other	O
+syndromic	O
+forms	O
+of	O
+craniosynostosis	O
+like	O
+Crouzon	O
+syndrome	O
+.	O
+
+The	O
+NGS	O
+panel	O
+for	O
+molecular	O
+analysis	O
+of	O
+genes	O
+involved	O
+in	O
+skeletal	O
+dysplasias	O
+showed	O
+the	O
+mutation	O
+of	O
+the	O
+FGFR2	O
+gene	O
+,	O
+de	O
+novo	O
+.	O
+
+Conclusions	O
+:	O
+Using	O
+three	O
+-	O
+dimensional	O
+(	O
+3D	O
+)	O
+ultrasound	O
+,	O
+it	O
+is	O
+easier	O
+to	O
+distinguish	O
+rare	O
+syndromes	O
+characterized	O
+by	O
+facial	O
+dysmorphisms	O
+such	O
+as	O
+exophthalmos	O
+,	O
+mediofacial	O
+hypoplasia	O
+,	O
+and	O
+craniosynostosis	O
+.	O
+
+Genetic	O
+testing	O
+is	O
+used	O
+to	O
+optimise	O
+the	O
+management	O
+of	O
+inherited	O
+cardiovascular	O
+disorders	O
+that	O
+can	O
+cause	O
+sudden	O
+cardiac	O
+death	O
+.	O
+
+Yet	O
+more	O
+genotype	O
+-	O
+phenotype	O
+correlation	O
+studies	O
+from	O
+populations	O
+not	O
+ascertained	O
+on	O
+clinical	O
+symptoms	O
+or	O
+family	O
+history	O
+of	O
+disease	O
+are	O
+required	O
+to	O
+improve	O
+understanding	O
+of	O
+gene	O
+penetrance	O
+.	O
+
+We	O
+performed	O
+targeted	O
+sequencing	O
+of	O
+25	O
+genes	O
+used	O
+routinely	O
+in	O
+clinical	O
+genetic	O
+testing	O
+for	O
+inherited	O
+cardiovascular	O
+disorders	O
+in	O
+a	O
+population	O
+of	O
+13,131	O
+asymptomatic	O
+older	O
+individuals	O
+(	O
+mean	O
+age	O
+75	O
+years	O
+)	O
+enrolled	O
+in	O
+the	O
+ASPREE	O
+trial	O
+.	O
+
+Participants	O
+had	O
+no	O
+prior	O
+history	O
+of	O
+cardiovascular	O
+disease	O
+events	O
+,	O
+dementia	O
+or	O
+physical	O
+disability	O
+at	O
+enrolment	O
+.	O
+
+Variants	O
+were	O
+classified	O
+following	O
+ACMG	O
+/	O
+AMP	O
+standards	O
+.	O
+
+Sudden	O
+and	O
+rapid	O
+cardiac	O
+deaths	O
+were	O
+clinically	O
+adjudicated	O
+as	O
+ASPREE	O
+trial	O
+endpoints	O
+,	O
+and	O
+assessed	O
+during	O
+mean	O
+4.7	O
+years	O
+of	O
+follow	O
+-	O
+up	O
+.	O
+
+In	O
+total	O
+,	O
+119	O
+participants	O
+had	O
+pathogenic	O
+/	O
+deleterious	O
+variants	O
+in	O
+one	B-STAT
+of	I-STAT
+the	I-STAT
+25	I-STAT
+genes	O
+analysed	O
+(	O
+carrier	O
+rate	O
+of	O
+1	B-STAT
+in	I-STAT
+110	B-STAT
+or	I-STAT
+0.9	I-STAT
+%	I-STAT
+)	O
+.	O
+
+Participants	O
+carried	O
+variants	O
+associated	O
+with	O
+hypertrophic	O
+cardiomyopathy	O
+(	O
+N	O
+=	O
+24	O
+)	O
+,	O
+dilated	O
+cardiomyopathy	O
+(	O
+N	O
+=	O
+29	O
+)	O
+,	O
+arrhythmogenic	O
+right	O
+-	O
+ventricular	O
+cardiomyopathy	O
+(	O
+N	O
+=	O
+22	O
+)	O
+,	O
+catecholaminergic	O
+polymorphic	O
+ventricular	O
+tachycardia	O
+(	O
+N	O
+=	O
+4	O
+)	O
+,	O
+aortopathies	O
+(	O
+N	O
+=	O
+1	B-STAT
+)	I-STAT
+,	O
+and	O
+long	O
+-	O
+QT	O
+syndrome	O
+(	O
+N	O
+=	O
+39	O
+)	O
+.	O
+
+Among	O
+119	O
+carriers	O
+,	O
+two	O
+died	O
+from	O
+presumed	O
+sudden	O
+/	O
+rapid	O
+cardiac	O
+deaths	O
+during	O
+follow	O
+-	O
+up	O
+(	O
+1.7	O
+%	O
+)	O
+;	O
+both	O
+with	O
+pathogenic	O
+variants	O
+in	O
+long	O
+-	O
+QT	O
+syndrome	O
+genes	O
+(	O
+KCNQ1	O
+,	O
+SCN5A	O
+)	O
+.	O
+
+Among	O
+non	O
+-	O
+carriers	O
+,	O
+the	O
+rate	O
+of	O
+sudden	O
+/	O
+rapid	O
+cardiac	O
+deaths	O
+was	O
+significantly	O
+lower	O
+(	O
+0.08	B-STAT
+%	I-STAT
+,	O
+11/12936	B-STAT
+,	O
+p	O
+<	O
+0.001	O
+)	O
+.	O
+
+Variants	O
+associated	O
+with	O
+inherited	O
+cardiovascular	O
+disorders	O
+are	O
+found	O
+in	O
+asymptomatic	O
+individuals	O
+aged	O
+70	O
+years	O
+and	O
+older	O
+without	O
+a	O
+history	O
+of	O
+cardiovascular	O
+disease	O
+.	O
+
+Adrenal	O
+insufficiency	O
+may	O
+result	O
+from	O
+a	O
+wide	O
+variety	O
+of	O
+congenital	O
+or	O
+acquired	O
+disorders	O
+of	O
+hypothalamus	O
+,	O
+pituitary	O
+,	O
+or	O
+adrenal	O
+cortex	O
+.	O
+
+Destruction	O
+or	O
+dysfunction	O
+of	O
+the	O
+adrenal	O
+cortex	O
+is	O
+the	O
+cause	O
+of	O
+primary	O
+adrenal	O
+insufficiency	O
+,	O
+while	O
+secondary	O
+adrenal	O
+insufficiency	O
+is	O
+a	O
+result	O
+of	O
+pituitary	O
+or	O
+hypothalamic	O
+disease	O
+.	O
+
+Timely	O
+diagnosis	O
+and	O
+clinical	O
+management	O
+of	O
+adrenal	O
+insufficiency	O
+are	O
+critical	O
+to	O
+prevent	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+This	O
+review	O
+summarizes	O
+the	O
+etiologies	O
+,	O
+presentation	O
+,	O
+and	O
+diagnosis	O
+of	O
+adrenal	O
+insufficiency	O
+utilizing	O
+different	O
+dynamic	O
+hormone	O
+testing	O
+and	O
+describes	O
+current	O
+treatment	O
+recommendations	O
+and	O
+new	O
+therapies	O
+.	O
+
+Objective	O
+To	O
+determine	O
+the	O
+prevalence	B-EPI
+of	O
+Barth	O
+syndrome	O
+in	O
+the	O
+pediatric	O
+population	O
+.	O
+
+Study	O
+design	O
+Data	O
+were	O
+collected	O
+from	O
+the	O
+Barth	O
+Syndrome	O
+Foundation	O
+Registry	O
+and	O
+relevant	O
+literature	O
+.	O
+
+With	O
+the	O
+advent	O
+of	O
+genetic	O
+testing	O
+and	O
+whole	O
+-	O
+exome	O
+sequencing	O
+,	O
+a	O
+multipronged	O
+Bayesian	O
+analysis	O
+was	O
+used	O
+to	O
+estimate	O
+the	O
+prevalence	B-EPI
+of	O
+Barth	O
+syndrome	O
+based	O
+on	O
+published	O
+data	O
+on	O
+the	O
+incidence	B-EPI
+and	O
+prevalence	B-EPI
+of	O
+cardiomyopathy	O
+and	O
+neutropenia	O
+,	O
+and	O
+the	O
+respective	O
+subpopulations	O
+of	O
+patients	O
+with	O
+Barth	O
+syndrome	O
+indicated	O
+in	O
+these	O
+publications	O
+.	O
+
+Results	O
+Based	O
+on	O
+7	O
+published	O
+studies	O
+of	O
+cardiomyopathy	O
+and	O
+2	O
+published	O
+studies	O
+of	O
+neutropenia	O
+,	O
+the	O
+estimated	B-EPI
+prevalence	I-EPI
+of	O
+Barth	O
+syndrome	O
+is	O
+approximately	O
+1	B-STAT
+case	I-STAT
+per	I-STAT
+million	I-STAT
+male	I-STAT
+population	O
+.	O
+
+This	O
+contrasts	O
+with	O
+99	O
+cases	O
+in	O
+the	O
+Barth	O
+Syndrome	O
+Foundation	O
+Registry	O
+,	O
+58	O
+of	O
+which	O
+indicate	O
+a	O
+US	B-LOC
+location	O
+,	O
+and	O
+only	O
+230	O
+-	O
+250	O
+cases	O
+known	O
+worldwide	B-LOC
+.	O
+
+Conclusions	O
+It	O
+appears	O
+that	O
+Barth	O
+syndrome	O
+is	O
+greatly	O
+underdiagnosed	O
+.	O
+
+There	O
+is	O
+a	O
+need	O
+for	O
+better	O
+education	O
+and	O
+awareness	O
+of	O
+this	O
+rare	O
+disease	O
+to	O
+move	O
+toward	O
+early	O
+diagnosis	O
+and	O
+treatment	O
+.	O
+
+Ogilvie	O
+syndrome	O
+is	O
+a	O
+clinical	O
+condition	O
+in	O
+which	O
+there	O
+is	O
+a	O
+colorectal	O
+distention	O
+in	O
+the	O
+absence	O
+of	O
+mechanical	O
+obstacles	O
+.	O
+
+Early	O
+diagnosis	O
+and	O
+appropriate	O
+therapy	O
+significantly	O
+reduce	O
+mortality	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+this	O
+is	O
+not	O
+known	O
+.	O
+
+This	O
+paper	O
+presents	O
+the	O
+course	O
+of	O
+diagnosis	O
+and	O
+treatment	O
+,	O
+both	O
+conservative	O
+and	O
+operational	O
+,	O
+of	O
+an	O
+82	O
+year	O
+old	O
+patient	O
+with	O
+pulmonary	O
+embolism	O
+,	O
+burdened	O
+with	O
+coronary	O
+artery	O
+disease	O
+,	O
+hypertension	O
+,	O
+heart	O
+failure	O
+and	O
+chronic	O
+kidney	O
+failure	O
+,	O
+in	O
+which	O
+the	O
+hospital	O
+diagnosed	O
+Ogilvie	O
+syndrome	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+examine	O
+the	O
+incidence	B-EPI
+,	O
+mortality	O
+,	O
+and	O
+health	O
+care	O
+use	O
+related	O
+to	O
+neonatal	O
+herpes	O
+simplex	O
+virus	O
+(	O
+HSV	O
+)	O
+infection	O
+.	O
+
+METHODS	O
+:	O
+A	O
+retrospective	O
+longitudinal	O
+cohort	O
+study	O
+using	O
+a	O
+multistate	O
+Medicaid	O
+claims	O
+database	O
+.	O
+
+We	O
+identified	O
+neonates	O
+hospitalized	O
+with	O
+HSV	O
+infection	O
+from	O
+2009	O
+to	O
+2015	O
+by	O
+using	O
+discharge	O
+diagnosis	O
+codes	O
+and	O
+managed	O
+them	O
+for	O
+6	O
+months	O
+after	O
+discharge	O
+.	O
+
+Incidence	B-EPI
+rates	O
+were	O
+corrected	O
+for	O
+the	O
+imperfect	O
+sensitivity	O
+and	O
+specificity	O
+of	O
+thediagnosis	O
+codes	O
+for	O
+identifying	O
+HSV	O
+infection	O
+.	O
+
+RESULTS	O
+:	O
+Of	O
+2	O
+107	O
+124	O
+births	O
+from	O
+2009	O
+to	O
+2015	O
+,	O
+900	O
+neonates	O
+were	O
+identified	O
+with	O
+HSV	O
+infection	O
+,	O
+with	O
+a	O
+corrected	O
+incidence	B-EPI
+rate	O
+of	O
+4.5	O
+(	O
+95	O
+%	O
+confidence	O
+interval	O
+[	O
+CI	O
+]	O
+:	O
+4.2	B-STAT
+-	I-STAT
+4.8	I-STAT
+)	I-STAT
+per	I-STAT
+10	I-STAT
+000	I-STAT
+births	I-STAT
+.	O
+
+The	O
+yearly	O
+disease	O
+incidence	B-EPI
+increased	O
+by	O
+56	O
+%	O
+,	O
+from	O
+3.4	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+2.8	B-STAT
+-	I-STAT
+4.2	I-STAT
+)	I-STAT
+per	I-STAT
+10	I-STAT
+000	I-STAT
+births	I-STAT
+(	O
+or	O
+1	B-STAT
+in	I-STAT
+2941	I-STAT
+births	I-STAT
+)	O
+in	O
+2009	O
+to	O
+5.3	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+4.6	B-STAT
+-	I-STAT
+6.1	I-STAT
+)	I-STAT
+per	I-STAT
+10	I-STAT
+000	I-STAT
+births	I-STAT
+(	O
+or	O
+1	B-STAT
+in	I-STAT
+1886	I-STAT
+births	I-STAT
+)	O
+in	O
+2015	O
+(	O
+P	O
+<	O
+.001	O
+)	O
+.	O
+
+Of	O
+the	O
+900	O
+neonates	O
+with	O
+HSV	O
+infection	O
+,	O
+54	B-STAT
+(	O
+6.0	O
+%	O
+[	O
+95	O
+%	O
+CI	O
+:	O
+4.4%-7.6	O
+%	O
+]	O
+)	O
+died	O
+during	O
+the	O
+index	O
+hospitalization	O
+;	O
+there	O
+was	O
+no	O
+increase	O
+in	O
+the	O
+yearly	O
+mortality	O
+rate	O
+.	O
+
+Of	O
+the	O
+692	B-STAT
+(	O
+81.2	O
+%	O
+)	O
+infants	O
+with	O
+follow	O
+-	O
+up	O
+data	O
+,	O
+316	B-STAT
+(	O
+45.7	O
+%	O
+)	O
+had	O
+an	O
+emergency	O
+department	O
+visit	O
+,	O
+and	O
+112	B-STAT
+(	O
+16.2	O
+%	O
+)	O
+had	O
+a	O
+hospital	O
+readmission	O
+.	O
+
+Total	O
+payments	O
+at	O
+6	O
+months	O
+amounted	O
+to	O
+$	O
+60	O
+620	O
+431	O
+,	O
+a	O
+median	O
+of	O
+$	O
+87	B-STAT
+602	I-STAT
+per	I-STAT
+case	I-STAT
+of	I-STAT
+neonatal	O
+HSV	O
+infection	O
+.	O
+
+CONCLUSIONS	O
+:	O
+We	O
+observed	O
+an	O
+increase	O
+in	O
+neonatal	O
+HSV	O
+infection	O
+incidence	B-EPI
+over	O
+a	O
+recent	O
+7	O
+-	O
+year	O
+period	O
+in	O
+a	O
+Medicaid	O
+population	O
+.	O
+
+Associated	O
+health	O
+care	O
+use	O
+and	O
+payments	O
+were	O
+substantial	O
+.	O
+
+Public	O
+health	O
+interventions	O
+targeting	O
+disease	O
+prevention	O
+and	O
+early	O
+diagnosis	O
+are	O
+needed	O
+.	O
+
+Despite	O
+the	O
+prevalence	B-EPI
+of	O
+preterm	O
+brain	O
+injury	O
+,	O
+there	O
+are	O
+no	O
+established	O
+neuroprotective	O
+strategies	O
+to	O
+prevent	O
+or	O
+alleviate	O
+mild	O
+-	O
+to	O
+-	O
+moderate	O
+inflammation	O
+-	O
+related	O
+brain	O
+injury	O
+.	O
+
+Perinatal	O
+infection	O
+and	O
+inflammation	O
+have	O
+been	O
+shown	O
+to	O
+trigger	O
+acute	O
+neuroinflammation	O
+,	O
+including	O
+proinflammatory	O
+cytokine	O
+release	O
+and	O
+gliosis	O
+,	O
+which	O
+are	O
+associated	O
+with	O
+acute	O
+and	O
+chronic	O
+disturbances	O
+in	O
+brain	O
+cell	O
+survival	O
+and	O
+maturation	O
+.	O
+
+These	O
+findings	O
+suggest	O
+the	O
+hypothesis	O
+that	O
+the	O
+inhibition	O
+of	O
+peripheral	O
+immune	O
+responses	O
+following	O
+infection	O
+or	O
+nonspecific	O
+inflammation	O
+may	O
+be	O
+a	O
+therapeutic	O
+strategy	O
+to	O
+reduce	O
+the	O
+associated	O
+brain	O
+injury	O
+and	O
+neurobehavioral	O
+deficits	O
+.	O
+
+This	O
+review	O
+provides	O
+an	O
+overview	O
+of	O
+the	O
+neonatal	O
+immunity	O
+,	O
+neuroinflammation	O
+,	O
+and	O
+mechanisms	O
+of	O
+inflammation	O
+-	O
+related	O
+brain	O
+injury	O
+in	O
+preterm	O
+infants	O
+and	O
+explores	O
+the	O
+safety	O
+and	O
+efficacy	O
+of	O
+anti	O
+-	O
+inflammatory	O
+agents	O
+as	O
+potentially	O
+neurotherapeutics	O
+.	O
+
+Inferior	O
+vena	O
+cava	O
+(	O
+IVC	O
+)	O
+agenesis	O
+is	O
+a	O
+rare	O
+congenital	O
+abnormality	O
+affecting	O
+the	O
+infrarenal	O
+segment	O
+,	O
+the	O
+suprarenal	O
+or	O
+the	O
+whole	O
+of	O
+the	O
+IVC	O
+.	O
+
+It	O
+has	O
+an	O
+estimated	B-EPI
+prevalence	I-EPI
+of	O
+up	O
+to	O
+1	B-STAT
+%	O
+in	O
+the	O
+general	O
+population	O
+that	O
+can	O
+rise	B-STAT
+to	O
+8.7	O
+%	O
+when	O
+abnormalities	O
+of	O
+the	O
+left	O
+renal	O
+vein	O
+are	O
+considered	O
+.	O
+
+Most	O
+IVC	O
+malformations	O
+are	O
+asymptomatic	O
+but	O
+may	O
+be	O
+associated	O
+with	O
+nonspecific	O
+symptoms	O
+or	O
+present	O
+as	O
+deep	O
+vein	O
+thrombosis	O
+(	O
+DVT	O
+)	O
+.	O
+
+Up	B-STAT
+to	O
+5	O
+%	O
+of	O
+young	O
+individuals	O
+under	O
+30	O
+years	O
+of	O
+age	O
+with	O
+unprovoked	O
+DVT	O
+are	O
+found	O
+to	O
+have	O
+this	O
+condition	O
+.	O
+
+Regarding	O
+the	O
+treatment	O
+of	O
+IVC	O
+agenesis	O
+-	O
+associated	O
+DVT	O
+,	O
+there	O
+are	O
+no	O
+standard	O
+guidelines	O
+.	O
+
+Treatment	O
+is	O
+directed	O
+towards	O
+preventing	O
+thrombosis	O
+or	O
+its	O
+recurrence	O
+.	O
+
+Low	O
+molecular	O
+weight	O
+heparin	O
+and	O
+oral	O
+anticoagulation	O
+medication	O
+,	O
+in	O
+particular	O
+vitamin	O
+K	O
+antagonists	O
+(	O
+VKAs	O
+)	O
+are	O
+the	O
+mainstay	O
+of	O
+therapy	O
+.	O
+
+Given	O
+the	O
+high	O
+risk	O
+of	O
+DVT	O
+recurrence	O
+in	O
+these	O
+patients	O
+,	O
+oral	O
+anticoagulation	O
+therapy	O
+is	O
+suggested	O
+to	O
+be	O
+pursued	O
+indefinitely	O
+.	O
+
+As	O
+far	O
+as	O
+we	O
+know	O
+,	O
+this	O
+is	O
+the	O
+first	O
+case	O
+reporting	O
+the	O
+use	O
+of	O
+a	O
+direct	O
+factor	O
+Xa	O
+inhibitor	O
+in	O
+IVC	O
+agenesis	O
+-	O
+associated	O
+DVT	O
+.	O
+
+Given	O
+VKA	O
+monitoring	O
+limitations	O
+,	O
+the	O
+use	O
+of	O
+a	O
+direct	O
+Xa	O
+inhibitor	O
+could	O
+be	O
+an	O
+alternative	O
+in	O
+young	O
+individuals	O
+with	O
+anatomical	O
+defects	O
+without	O
+thrombophilia	O
+,	O
+but	O
+further	O
+studies	O
+will	O
+be	O
+needed	O
+to	O
+confirm	O
+its	O
+efficacy	O
+and	O
+safety	O
+.	O
+
+LEARNING	O
+POINTS	O
+:	O
+Up	O
+to	O
+5	B-STAT
+%	O
+of	O
+young	O
+individuals	O
+under	O
+30	O
+years	O
+of	O
+age	O
+with	O
+unprovoked	O
+deep	O
+vein	O
+thrombosis	O
+(	O
+DVT	O
+)	O
+are	O
+found	O
+to	O
+have	O
+this	O
+condition	O
+.	O
+
+Therefore	O
+,	O
+these	O
+types	O
+of	O
+anomalies	O
+should	O
+be	O
+actively	O
+looked	O
+for	O
+,	O
+particularly	O
+in	O
+young	O
+patients	O
+with	O
+DVT.Treatment	O
+with	O
+low	O
+molecular	O
+weight	O
+heparin	O
+or	O
+oral	O
+anticoagulation	O
+medication	O
+is	O
+the	O
+mainstay	O
+of	O
+therapy	O
+,	O
+directed	O
+towards	O
+preventing	O
+thrombosis	O
+or	O
+its	O
+recurrence	O
+.	O
+A	O
+direct	O
+factor	O
+Xa	O
+inhibitor	O
+could	O
+be	O
+a	O
+possible	O
+alternative	O
+to	O
+vitamin	O
+K	O
+antagonists	O
+in	O
+these	O
+patients	O
+,	O
+despite	O
+the	O
+lack	O
+of	O
+clinical	O
+evidence	O
+supporting	O
+its	O
+use	O
+at	O
+the	O
+moment	O
+.	O
+
+BACKGROUND	O
+:	O
+Lesch	O
+-	O
+Nyhan	O
+syndrome	O
+(	O
+LNS	O
+)	O
+is	O
+a	O
+congenital	O
+X	O
+-	O
+linked	O
+recessive	O
+neurogenetic	O
+disorder	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+hypoxanthine	O
+-	O
+guanine	O
+phosphoribosyltransferase	O
+(	O
+HPRT	O
+)	O
+gene	O
+.	O
+
+The	O
+main	O
+clinical	O
+manifestation	O
+includes	O
+hyperuricemia	O
+,	O
+juvenile	O
+-	O
+onset	O
+gouty	O
+arthritis	O
+,	O
+and	O
+neurological	O
+developmental	O
+disorders	O
+.	O
+
+Studies	O
+have	O
+reported	O
+more	O
+than	O
+400	O
+HPRT	O
+gene	O
+mutation	O
+sites	O
+,	O
+but	O
+the	O
+incidence	B-EPI
+of	O
+LNS	O
+in	O
+the	O
+Chinese	O
+population	O
+is	O
+extremely	O
+low	O
+.	O
+
+METHODS	O
+:	O
+Here	O
+we	O
+report	O
+a	O
+16	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+suffered	O
+neurological	O
+dysfunction	O
+at	O
+an	O
+early	O
+age	O
+and	O
+gouty	O
+arthritis	O
+in	O
+his	O
+youth	O
+.	O
+
+RESULTS	O
+:	O
+No	O
+activity	O
+of	O
+the	O
+HPRT	O
+enzyme	O
+was	O
+detected	O
+in	O
+the	O
+erythrocytes	O
+.	O
+
+Furthermore	O
+,	O
+we	O
+found	O
+a	O
+mutation	O
+on	O
+exon	O
+3	O
+of	O
+the	O
+HPRT	O
+gene	O
+in	O
+the	O
+patient	O
+and	O
+his	O
+mother	O
+(	O
+exon	O
+3	O
+:	O
+c.143G	O
+>	O
+A	O
+)	O
+,	O
+which	O
+resulted	O
+in	O
+arginine	O
+to	O
+histidine	O
+(	O
+p.	O
+R48H	O
+)	O
+substitution	O
+in	O
+the	O
+encoded	O
+protein	O
+.	O
+
+The	O
+same	O
+mutation	O
+was	O
+reported	O
+in	O
+several	O
+European	O
+families	O
+,	O
+but	O
+was	O
+found	O
+for	O
+the	O
+first	O
+time	O
+in	O
+a	O
+Chinese	O
+family	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Clinicians	O
+in	O
+China	B-LOC
+have	O
+poor	O
+experience	O
+in	O
+diagnosing	O
+LNS	O
+cases	O
+due	O
+to	O
+the	O
+low	O
+incidence	B-EPI
+in	O
+China	B-LOC
+.	O
+
+Therefore	O
+,	O
+LNS	O
+screening	O
+for	O
+infants	O
+or	O
+adolescents	O
+with	O
+hyperuricemia	O
+,	O
+gouty	O
+arthritis	O
+,	O
+and	O
+neurological	O
+dysfunction	O
+should	O
+be	O
+performed	O
+.	O
+
+Objectives	O
+Few	O
+studies	O
+have	O
+investigated	O
+the	O
+prognostic	O
+factors	O
+for	O
+idiopathic	O
+inflammatory	O
+myopathy	O
+-	O
+associated	O
+interstitial	O
+lung	O
+disease	O
+(	O
+IIM	O
+-	O
+ILD	O
+)	O
+across	O
+different	O
+clinical	O
+/	O
+serological	O
+phenotypes	O
+.	O
+
+Methods	O
+We	O
+conducted	O
+a	O
+retrospective	O
+analysis	O
+of	O
+patients	O
+diagnosed	O
+with	O
+IIM	O
+between	O
+January	O
+2012	O
+and	O
+December	O
+2017	O
+.	O
+
+Results	O
+Of	O
+the	O
+760	O
+IIM	O
+cases	O
+registered	O
+,	O
+679	O
+adult	O
+cases	O
+were	O
+included	O
+in	O
+this	O
+study	O
+.	O
+
+ILD	O
+was	O
+present	O
+in	O
+508	O
+cases	O
+,	O
+and	O
+the	O
+presence	O
+of	O
+ILD	O
+in	O
+the	O
+clinically	O
+amyopathic	O
+DM	B-LOC
+,	O
+DM	O
+and	O
+PM	O
+groups	O
+was	O
+92.7	O
+,	O
+73.6	O
+and	O
+55.1	O
+%	O
+,	O
+respectively	O
+(	O
+P	O
+<	O
+0.01	O
+)	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+ILD	O
+in	O
+the	O
+anti	O
+-	O
+synthetase	O
+antibody	O
+(	O
+ASA)+-IIM	O
+group	O
+was	O
+higher	O
+than	O
+that	O
+in	O
+ASA	O
+--	O
+IIM	O
+group	O
+(	O
+95.2	O
+vs	O
+72.4	O
+%	O
+,	O
+P	O
+<	O
+0.01	O
+)	O
+;	O
+no	O
+such	O
+difference	O
+was	O
+found	O
+between	O
+the	O
+anti	O
+-	O
+histidyl	O
+-	O
+tRNA	O
+synthetase	O
+(	O
+Jo-1)+-IIM	O
+and	O
+Jo-1	O
+-	O
+ASA+-IIM	O
+groups	O
+(	O
+93.0	O
+vs	O
+98.5	O
+%	O
+,	O
+P	O
+>	O
+0.05	O
+)	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+ILD	O
+in	O
+the	O
+melanoma	O
+differentiation	O
+-	O
+associated	O
+protein-5	O
+(	O
+MDA-5)+-IIM	O
+group	O
+was	O
+higher	O
+than	O
+that	O
+in	O
+MDA-5	O
+-	O
+-IIM	O
+group	O
+(	O
+97.8	O
+vs	O
+72.1	O
+%	O
+,	O
+P	O
+<	O
+0.01	O
+)	O
+.	O
+
+Among	O
+adults	O
+with	O
+IIM	O
+,	O
+men	O
+with	O
+concurrent	O
+ILD	O
+,	O
+who	O
+were	O
+older	O
+than	O
+50	O
+years	O
+,	O
+were	O
+most	O
+likely	O
+to	O
+die	O
+.	O
+
+No	O
+significant	O
+difference	O
+was	O
+found	O
+in	O
+the	O
+all	O
+-	O
+cause	O
+mortality	O
+rates	O
+between	O
+DM	O
+-	O
+ILD	O
+and	O
+clinically	O
+amyopathic	O
+DM	O
+-	O
+ILD	O
+groups	O
+(	O
+33.3	O
+vs	O
+23	O
+%	O
+,	O
+P	O
+>	O
+0.05	O
+)	O
+,	O
+although	O
+both	O
+were	O
+higher	O
+than	O
+that	O
+in	O
+PM	O
+group	O
+(	O
+13.2	O
+%	O
+,	O
+P	O
+=	O
+0.01	O
+and	O
+P	O
+<	O
+0.05	O
+,	O
+respectively	O
+)	O
+.	O
+
+No	O
+difference	O
+was	O
+found	O
+in	O
+the	O
+all	O
+-	O
+cause	O
+mortality	O
+rates	O
+between	O
+MDA5	O
+-	O
+ASA	O
+--	O
+IM	O
+-	O
+ILD	O
+and	O
+MDA5	O
+-	O
+ASA+-IM	O
+-	O
+ILD	O
+groups	O
+(	O
+17.2	O
+vs	O
+12.8	O
+%	O
+,	O
+P	O
+>	O
+0.05	O
+)	O
+,	O
+and	O
+both	O
+were	O
+lower	O
+than	O
+that	O
+in	O
+MDA5+ASA	O
+--	O
+IM	O
+-	O
+ILD	O
+group	O
+(	O
+33.7	O
+%	O
+,	O
+P	O
+<	O
+0.05	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+prevalence	B-EPI
+of	O
+ILD	O
+in	O
+IIM	O
+and	O
+the	O
+prognosis	O
+of	O
+IIM	O
+-	O
+ILD	O
+patients	O
+may	O
+vary	O
+depending	O
+on	O
+the	O
+statuses	O
+of	O
+the	O
+ASA	O
+and	O
+MDA-5	O
+antibodies	O
+.	O
+
+Background	O
+:	O
+Little	O
+is	O
+known	O
+about	O
+the	O
+surgical	O
+conditions	O
+affecting	O
+the	O
+pediatric	O
+population	O
+in	O
+low	O
+-	O
+income	O
+countries	O
+.	O
+
+In	O
+this	O
+article	O
+we	O
+describe	O
+the	O
+epidemiology	O
+of	O
+pediatric	O
+surgical	O
+diseases	O
+observed	O
+in	O
+Mutoyi	B-LOC
+hospital	O
+,	O
+a	O
+first	O
+-	O
+level	O
+hospital	O
+in	O
+Burundi	B-LOC
+.	O
+
+Methods	O
+and	O
+Findings	O
+:	O
+We	O
+retrospectively	O
+reviewed	O
+the	O
+records	O
+of	O
+all	O
+children	O
+(	O
+0	O
+-	O
+14	O
+years	O
+)	O
+admitted	O
+to	O
+the	O
+Surgery	O
+ward	O
+from	O
+January	O
+2017	O
+to	O
+December	O
+2017	O
+.	O
+
+We	O
+also	O
+reviewed	O
+the	O
+records	O
+of	O
+all	O
+the	O
+patients	O
+admitted	O
+to	O
+the	O
+Neonatology	B-LOC
+ward	O
+in	O
+2017	O
+and	O
+among	O
+them	O
+we	O
+selected	O
+the	O
+ones	O
+in	O
+which	O
+a	O
+surgical	O
+diagnosis	O
+was	O
+present	O
+.	O
+
+Five	O
+hundred	O
+twenty	O
+-	O
+eight	O
+children	O
+were	O
+admitted	O
+to	O
+the	O
+surgical	O
+ward	O
+during	O
+the	O
+study	O
+period	O
+.	O
+
+The	O
+most	O
+common	O
+conditions	O
+requiring	O
+hospitalization	O
+were	O
+abscesses	O
+(	O
+29.09	O
+%	O
+)	O
+,	O
+fractures	O
+(	O
+13.59	O
+%	O
+)	O
+,	O
+osteomyelitis	O
+(	O
+9.76	O
+%	O
+)	O
+,	O
+burns	O
+(	O
+5.40	O
+%	O
+)	O
+and	O
+head	O
+injuries	O
+(	O
+4.36	O
+%	O
+)	O
+.	O
+
+The	O
+average	O
+length	O
+of	O
+stay	O
+was	O
+16	O
+days	O
+.	O
+
+Fifty	O
+-	O
+six	O
+newborns	O
+were	O
+admitted	O
+to	O
+the	O
+Neonatology	B-LOC
+ward	O
+for	O
+a	O
+surgical	O
+condition	O
+;	O
+29	O
+%	O
+of	O
+them	O
+had	O
+an	O
+abscess	O
+.	O
+
+Conclusions	O
+:	O
+Conditions	O
+requiring	O
+surgical	O
+care	O
+are	O
+frequent	O
+in	O
+Burundian	O
+children	O
+and	O
+have	O
+a	O
+completely	O
+different	O
+spectrum	O
+from	O
+the	O
+western	O
+ones	O
+.	O
+
+This	O
+is	O
+due	O
+on	O
+one	O
+side	O
+to	O
+an	O
+under	O
+-	O
+diagnosis	O
+of	O
+certain	O
+conditions	O
+caused	O
+by	O
+the	O
+lack	O
+of	O
+diagnostic	O
+tools	O
+and	O
+on	O
+the	O
+other	O
+to	O
+the	O
+living	O
+conditions	O
+of	O
+the	O
+population	O
+.	O
+
+This	O
+difference	O
+should	O
+lead	O
+to	O
+intervention	O
+plans	O
+tailored	O
+on	O
+the	O
+actual	O
+necessities	O
+of	O
+the	O
+country	O
+and	O
+not	O
+on	O
+the	O
+western	O
+ones	O
+.	O
+
+Introduction	O
+Tinea	O
+capitis	O
+is	O
+the	O
+most	O
+common	O
+form	O
+of	O
+dermatophytosis	O
+among	O
+children	O
+,	O
+contributing	O
+significantly	O
+to	O
+the	O
+global	O
+burden	O
+of	O
+skin	O
+and	O
+hair	O
+infections	O
+.	O
+
+However	O
+,	O
+an	O
+accurate	O
+account	O
+of	O
+its	O
+burden	O
+in	O
+Africa	B-LOC
+,	O
+where	O
+most	O
+cases	O
+are	O
+thought	O
+to	O
+occur	O
+,	O
+is	O
+lacking	O
+.	O
+
+We	O
+aim	O
+to	O
+systematically	O
+evaluate	O
+the	O
+burden	O
+,	O
+aetiology	O
+and	O
+epidemiological	O
+trend	O
+of	O
+tinea	O
+capitis	O
+among	O
+children	O
+over	O
+a	O
+30	O
+-	O
+year	O
+period	O
+in	O
+Africa	B-LOC
+.	O
+
+Methods	O
+and	O
+analysis	O
+A	O
+systematic	O
+review	O
+will	O
+be	O
+conducted	O
+using	O
+Embase	O
+,	O
+PubMed	O
+,	O
+African	O
+Journals	O
+Online	O
+,	O
+Web	O
+of	O
+Science	O
+and	O
+the	O
+Cochrane	O
+Library	O
+of	O
+Systematic	O
+Review	O
+.	O
+
+These	O
+resources	O
+will	O
+be	O
+used	O
+to	O
+identify	O
+studies	O
+published	O
+between	O
+1990	O
+and	O
+December	O
+2020	O
+,	O
+which	O
+report	O
+the	O
+prevalence	B-EPI
+,	O
+aetiology	O
+and	O
+trend	O
+of	O
+tinea	O
+capitis	O
+among	O
+children	O
+younger	O
+than	O
+18	O
+years	O
+in	O
+Africa	B-LOC
+.	O
+
+Articles	O
+in	O
+English	O
+and	O
+French	O
+will	O
+be	O
+considered	O
+.	O
+
+Two	O
+independent	O
+reviewers	O
+will	O
+screen	O
+the	O
+articles	O
+for	O
+eligibility	O
+,	O
+and	O
+any	O
+discrepancies	O
+will	O
+be	O
+resolved	O
+by	O
+discussion	O
+and	O
+consensus	O
+between	O
+the	O
+authors	O
+.	O
+
+Methodological	O
+quality	O
+of	O
+all	O
+studies	O
+will	O
+be	O
+assessed	O
+and	O
+critically	O
+appraised	O
+.	O
+
+We	O
+will	O
+perform	O
+a	O
+metaregression	O
+to	O
+assess	O
+the	O
+impact	O
+of	O
+study	O
+characteristics	O
+on	O
+heterogeneity	O
+and	O
+also	O
+to	O
+correct	O
+the	O
+meta	O
+-	O
+analytical	O
+estimates	O
+for	O
+biases	O
+.	O
+
+A	O
+qualitative	O
+synthesis	O
+will	O
+be	O
+performed	O
+,	O
+and	O
+STATA	O
+V.16.0	O
+software	O
+will	O
+be	O
+used	O
+to	O
+estimate	O
+the	O
+pooled	B-EPI
+prevalence	I-EPI
+and	O
+aetiology	O
+of	O
+tinea	O
+capitis	O
+.	O
+
+The	O
+Mann	O
+-	O
+Kendall	O
+trend	O
+test	O
+will	O
+be	O
+use	O
+to	O
+evaluate	O
+the	O
+trend	O
+in	O
+the	O
+prevalence	B-EPI
+of	O
+tinea	O
+capitis	O
+over	O
+the	O
+study	O
+period	O
+.	O
+
+Ethics	O
+and	O
+dissemination	O
+Ethical	O
+approval	O
+from	O
+an	O
+institutional	O
+review	O
+board	O
+or	O
+research	O
+ethics	O
+committee	O
+is	O
+not	O
+required	O
+for	O
+this	O
+systematic	O
+review	O
+and	O
+meta	O
+-	O
+analysis	O
+.	O
+
+The	O
+results	O
+will	O
+be	O
+published	O
+in	O
+a	O
+peer	O
+-	O
+reviewed	O
+journal	O
+and	O
+presented	O
+in	O
+conferences	O
+.	O
+
+Background	O
+:	O
+Previous	O
+research	O
+has	O
+suggested	O
+that	O
+vigorous	O
+physical	O
+activity	O
+(	O
+VPA	O
+)	O
+during	O
+adolescence	O
+and	O
+early	O
+adulthood	O
+is	O
+associated	O
+with	O
+ALS	O
+.	O
+
+The	O
+National	O
+ALS	O
+Registry	O
+(	O
+Registry	O
+)	O
+collects	O
+physical	O
+activity	O
+data	O
+from	O
+persons	O
+with	O
+ALS	O
+.	O
+
+Objective	O
+:	O
+To	O
+examine	O
+the	O
+association	O
+between	O
+vigorous	O
+VPA	O
+and	O
+early	O
+onset	O
+ALS	O
+,	O
+defined	O
+as	O
+a	O
+diagnosis	O
+before	O
+age	O
+60	O
+,	O
+among	O
+patients	O
+enrolled	O
+in	O
+the	O
+Registry	O
+.	O
+
+VPA	O
+was	O
+defined	O
+as	O
+engaging	O
+in	O
+dynamic	O
+exercise	O
+for	O
+at	O
+least	O
+10	O
+minutes	O
+in	O
+a	O
+session	O
+that	O
+caused	O
+heavy	O
+sweating	O
+or	O
+large	O
+increases	O
+in	O
+breathing	O
+or	O
+heart	O
+rate	O
+.	O
+
+Methods	O
+:	O
+A	O
+cross	O
+-	O
+sectional	O
+study	O
+was	O
+conducted	O
+of	O
+5463	O
+ALS	O
+patients	O
+with	O
+VPA	O
+history	O
+and	O
+956	O
+ALS	O
+patients	O
+who	O
+never	O
+engaged	O
+in	O
+VPA	O
+.	O
+
+Patient	O
+characteristics	O
+were	O
+collected	O
+via	O
+online	O
+surveys	O
+in	O
+the	O
+following	O
+areas	O
+:	O
+demographic	O
+,	O
+lifetime	O
+VPA	O
+history	O
+,	O
+and	O
+initial	O
+onset	O
+of	O
+symptoms	O
+.	O
+
+General	O
+linear	O
+modeling	O
+was	O
+used	O
+to	O
+estimate	O
+mean	O
+age	O
+of	O
+diagnosis	O
+and	O
+to	O
+compute	O
+95	O
+%	O
+confidence	O
+intervals	O
+.	O
+
+Results	O
+:	O
+Patients	O
+who	O
+reported	O
+engaging	O
+in	O
+VPA	O
+at	O
+least	O
+moderately	O
+(	O
+three	O
+times	O
+a	O
+week	O
+)	O
+during	O
+early	O
+adulthood	O
+were	O
+more	O
+likely	O
+to	O
+have	O
+an	O
+ALS	O
+diagnosis	O
+earlier	O
+compared	O
+to	O
+patients	O
+who	O
+did	O
+not	O
+(	O
+p	O
+<	O
+0.0001	O
+)	O
+.	O
+
+After	O
+controlling	O
+for	O
+year	O
+of	O
+birth	O
+,	O
+statistically	O
+significant	O
+associations	O
+between	O
+those	O
+reporting	O
+VPA	O
+at	O
+age	O
+15	O
+-	O
+24	O
+and	O
+25	O
+-	O
+34	O
+and	O
+diagnosis	O
+of	O
+ALS	O
+earlier	O
+(	O
+p	O
+=	O
+0.0009	O
+,	O
+p	O
+=	O
+0.0144	O
+respectively	O
+)	O
+.	O
+
+Conclusion	O
+:	O
+Patients	O
+with	O
+ALS	O
+who	O
+had	O
+a	O
+history	O
+of	O
+VPA	O
+before	O
+age	O
+35	O
+,	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+be	O
+diagnosed	O
+with	O
+ALS	O
+before	O
+age	O
+60	O
+compared	O
+to	O
+patients	O
+with	O
+ALS	O
+who	O
+never	O
+engaged	O
+vigorously	O
+.	O
+
+More	O
+research	O
+is	O
+needed	O
+in	O
+the	O
+relationship	O
+between	O
+VPA	O
+and	O
+early	O
+onset	O
+ALS	O
+.	O
+
+Despite	O
+numerous	O
+studies	O
+in	O
+the	O
+field	O
+of	O
+congenital	O
+adrenal	O
+hyperplasia	O
+(	O
+CAH	O
+)	O
+due	O
+to	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+,	O
+some	O
+clinical	O
+variability	O
+of	O
+the	O
+presentation	O
+and	O
+discrepancies	O
+in	O
+the	O
+genotype	O
+/	O
+phenotype	O
+correlation	O
+are	O
+still	O
+unexplained	O
+.	O
+
+Some	O
+,	O
+but	O
+not	O
+all	O
+,	O
+discordant	O
+phenotypes	O
+caused	O
+by	O
+mutations	O
+with	O
+known	O
+enzyme	O
+activity	O
+have	O
+been	O
+explained	O
+by	O
+in	O
+silico	O
+structural	O
+changes	O
+in	O
+the	O
+21	O
+-	O
+hydroxylase	O
+protein	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+P30L	O
+mutation	O
+varies	O
+in	O
+different	O
+populations	O
+and	O
+is	O
+most	O
+frequently	O
+found	O
+in	O
+several	O
+Central	O
+and	O
+Southeast	O
+European	O
+countries	O
+as	O
+well	O
+as	O
+Mexico	B-LOC
+.	O
+
+Patients	O
+carrying	O
+P30L	O
+mutation	O
+present	O
+predominantly	O
+as	O
+non	O
+-	O
+classical	O
+CAH	O
+;	O
+however	O
+,	O
+simple	O
+virilizing	O
+forms	O
+are	O
+found	O
+in	O
+up	O
+to	O
+50	B-STAT
+%	O
+of	O
+patients	O
+.	O
+
+Taking	O
+into	O
+consideration	O
+the	O
+residual	O
+21	O
+-	O
+hydroxulase	O
+activity	O
+present	O
+with	O
+P30L	O
+mutation	O
+this	O
+is	O
+unexpected	O
+.	O
+
+Different	O
+mechanisms	O
+for	O
+increased	O
+androgenization	O
+in	O
+patients	O
+carrying	O
+P30L	O
+mutation	O
+have	O
+been	O
+proposed	O
+including	O
+influence	O
+of	O
+different	O
+residues	O
+,	O
+accompanying	O
+promotor	O
+allele	O
+variability	O
+or	O
+mutations	O
+,	O
+and	O
+individual	O
+androgene	O
+sensitivity	O
+.	O
+
+Early	O
+diagnosis	O
+of	O
+patients	O
+who	O
+would	O
+present	O
+with	O
+SV	O
+is	O
+important	O
+in	O
+order	O
+to	O
+improve	O
+outcome	O
+.	O
+
+Outcome	O
+studies	O
+of	O
+CAH	O
+have	O
+confirmed	O
+the	O
+uniqueness	O
+of	O
+this	O
+mutation	O
+such	O
+as	O
+difficulties	O
+in	O
+phenotype	O
+classification	O
+,	O
+different	O
+fertility	O
+,	O
+growth	O
+,	O
+and	O
+psychologic	O
+issues	O
+in	O
+comparison	O
+with	O
+other	O
+genotypes	O
+.	O
+
+Additional	O
+studies	O
+of	O
+P30L	O
+mutation	O
+are	O
+warranted	O
+.	O
+
+Background	O
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+disease	O
+type	O
+1A	O
+(	O
+CMT1A	O
+)	O
+is	O
+the	O
+most	O
+common	O
+form	O
+of	O
+hereditary	O
+neuropathy	O
+.	O
+
+Objective	O
+To	O
+investigate	O
+the	O
+prevalence	B-EPI
+and	O
+characteristics	O
+of	O
+pain	O
+in	O
+patients	O
+with	O
+CMT1A.	O
+
+Methods	O
+Nineteen	O
+patients	O
+with	O
+a	O
+diagnosis	O
+of	O
+CMT1A	O
+were	O
+evaluated	O
+between	O
+September	O
+2018	O
+and	O
+October	O
+2019	O
+,	O
+and	O
+other	O
+causes	O
+of	O
+neuropathy	O
+were	O
+ruled	O
+out	O
+.	O
+
+The	O
+following	O
+tools	O
+were	O
+used	O
+for	O
+the	O
+pain	O
+assessment	O
+:	O
+neurological	O
+assessment	O
+,	O
+LANSS	O
+,	O
+DN4	O
+,	O
+clinical	O
+evaluation	O
+,	O
+VAS	O
+,	O
+CMTNS2	O
+and	O
+SF-36	O
+.	O
+
+Statistical	O
+analysis	O
+was	O
+performed	O
+using	O
+prevalence	B-EPI
+analysis	O
+,	O
+t	O
+test	O
+,	O
+chi	O
+-	O
+square	O
+test	O
+and	O
+Spearman	O
+'s	O
+rho	O
+.	O
+
+Results	O
+The	O
+prevalence	B-EPI
+of	O
+pain	O
+was	O
+84.2	O
+%	O
+in	O
+the	O
+sample	O
+of	O
+this	O
+study	O
+,	O
+with	O
+moderate	O
+intensity	O
+and	O
+nociceptive	O
+characteristics	O
+according	O
+to	O
+the	O
+LANSS	O
+scale	O
+(	O
+75	O
+%	O
+)	O
+and	O
+clinical	O
+evaluation	O
+(	O
+50	O
+%	O
+)	O
+,	O
+but	O
+differing	O
+from	O
+DN4	O
+,	O
+which	O
+found	O
+neuropathic	O
+pain	O
+in	O
+the	O
+majority	O
+of	O
+the	O
+patients	O
+(	O
+56.2	O
+%	O
+)	O
+.	O
+
+Mixed	O
+pain	O
+was	O
+also	O
+observed	O
+in	O
+43.7	O
+%	O
+of	O
+the	O
+patients	O
+,	O
+according	O
+to	O
+clinical	O
+criteria	O
+.	O
+
+There	O
+was	O
+a	O
+statistically	O
+significant	O
+correlation	O
+between	O
+pain	O
+intensity	O
+and	O
+SF-36	O
+,	O
+thus	O
+demonstrating	O
+that	O
+the	O
+lower	O
+the	O
+pain	O
+was	O
+,	O
+the	O
+lower	O
+the	O
+impairment	O
+was	O
+,	O
+in	O
+all	O
+domains	O
+.	O
+
+Conclusion	O
+Pain	O
+is	O
+a	O
+prevalent	B-EPI
+and	O
+important	O
+symptom	O
+in	O
+CMT1A	O
+,	O
+with	O
+moderate	O
+intensity	O
+and	O
+nociceptive	O
+characteristics	O
+according	O
+to	O
+two	O
+tools	O
+,	O
+but	O
+neuropathic	O
+pain	O
+is	O
+also	O
+present	O
+,	O
+and	O
+there	O
+may	O
+even	O
+be	O
+a	O
+mixed	O
+pattern	O
+of	O
+pain	O
+.	O
+
+The	O
+correlation	O
+of	O
+the	O
+pain	O
+with	O
+SF-36	O
+suggests	O
+that	O
+pain	O
+relief	O
+could	O
+provide	O
+improvements	O
+to	O
+the	O
+quality	O
+of	O
+life	O
+of	O
+these	O
+individuals	O
+.	O
+
+Auditory	O
+neuropathy	O
+spectrum	O
+disorder	O
+(	O
+ANSD	O
+)	O
+refers	O
+to	O
+a	O
+range	O
+of	O
+hearing	O
+impairments	O
+characterized	O
+by	O
+deteriorated	O
+speech	O
+perception	O
+,	O
+despite	O
+relatively	O
+preserved	O
+pure	O
+-	O
+tone	O
+detection	O
+thresholds	O
+.	O
+
+Affected	O
+individuals	O
+usually	O
+present	O
+with	O
+abnormal	O
+auditory	O
+brainstem	O
+responses	O
+(	O
+ABRs	O
+)	O
+,	O
+but	O
+normal	O
+otoacoustic	O
+emissions	O
+(	O
+OAEs	O
+)	O
+.	O
+
+These	O
+electrophysiological	O
+characteristics	O
+have	O
+led	O
+to	O
+the	O
+hypothesis	O
+that	O
+ANSD	O
+may	O
+be	O
+caused	O
+by	O
+various	O
+dysfunctions	O
+at	O
+the	O
+cochlear	O
+inner	O
+hair	O
+cell	O
+(	O
+IHC	O
+)	O
+and	O
+spiral	O
+ganglion	O
+neuron	O
+(	O
+SGN	O
+)	O
+levels	O
+,	O
+while	O
+the	O
+activity	O
+of	O
+outer	O
+hair	O
+cells	O
+(	O
+OHCs	O
+)	O
+is	O
+preserved	O
+,	O
+resulting	O
+in	O
+discrepancies	O
+between	O
+pure	O
+-	O
+tone	O
+and	O
+speech	O
+comprehension	O
+thresholds	O
+.	O
+
+The	O
+exact	O
+prevalence	B-EPI
+of	O
+ANSD	O
+remains	O
+unknown	O
+;	O
+clinical	O
+findings	O
+show	O
+a	O
+large	O
+variability	O
+among	O
+subjects	O
+with	O
+hearing	O
+impairment	O
+ranging	O
+from	O
+mild	O
+to	O
+profound	O
+hearing	O
+loss	O
+.	O
+
+A	O
+wide	O
+range	O
+of	O
+prenatal	O
+and	O
+postnatal	O
+etiologies	O
+have	O
+been	O
+proposed	O
+.	O
+
+The	O
+study	O
+of	O
+genetics	O
+and	O
+of	O
+the	O
+implicated	O
+sites	O
+of	O
+lesion	O
+correlated	O
+with	O
+clinical	O
+findings	O
+have	O
+also	O
+led	O
+to	O
+a	O
+better	O
+understanding	O
+of	O
+the	O
+molecular	O
+mechanisms	O
+underlying	O
+the	O
+various	O
+forms	O
+of	O
+ANSD	O
+,	O
+and	O
+may	O
+guide	O
+clinicians	O
+in	O
+better	O
+screening	O
+,	O
+assessment	O
+and	O
+treatment	O
+of	O
+ANSD	O
+patients	O
+.	O
+
+Besides	O
+OAEs	O
+and	O
+ABRs	O
+,	O
+audiological	O
+assessment	O
+includes	O
+stapedial	O
+reflex	O
+measurements	O
+,	O
+supraliminal	O
+psychoacoustic	O
+tests	O
+,	O
+electrocochleography	O
+(	O
+ECochG	O
+)	O
+,	O
+auditory	O
+steady	O
+-	O
+state	O
+responses	O
+(	O
+ASSRs	O
+)	O
+and	O
+cortical	O
+auditory	O
+evoked	O
+potentials	O
+(	O
+CAEPs	O
+)	O
+.	O
+
+Hearing	O
+aids	O
+are	O
+indicated	O
+in	O
+the	O
+treatment	O
+of	O
+ANSD	O
+with	O
+mild	O
+to	O
+moderate	O
+hearing	O
+loss	O
+,	O
+whereas	O
+cochlear	O
+implantation	O
+is	O
+the	O
+first	O
+choice	O
+of	O
+treatment	O
+in	O
+case	O
+of	O
+profound	O
+hearing	O
+loss	O
+,	O
+especially	O
+in	O
+case	O
+of	O
+IHC	O
+presynaptic	O
+disorders	O
+,	O
+or	O
+in	O
+case	O
+of	O
+poor	O
+auditory	O
+outcomes	O
+with	O
+conventional	O
+hearing	O
+aids	O
+.	O
+
+Thyroid	O
+cancer	O
+(	O
+TC	O
+)	O
+represents	O
+a	O
+worldwide	B-LOC
+problem	O
+,	O
+the	O
+consistent	O
+growth	O
+of	O
+the	O
+incidence	B-EPI
+increment	O
+issues	O
+about	O
+management	O
+of	O
+risk	O
+factors	O
+and	O
+curative	O
+treatment	O
+.	O
+
+Updated	O
+statistical	O
+data	O
+are	O
+not	O
+complete	O
+in	O
+the	O
+North	B-LOC
+East	I-LOC
+region	O
+of	O
+Romania	B-LOC
+and	O
+need	O
+to	O
+be	O
+improved	O
+.	O
+
+Therefore	O
+,	O
+through	O
+this	O
+study	O
+,	O
+we	O
+aim	O
+to	O
+renew	O
+the	O
+existing	O
+data	O
+on	O
+thyroid	O
+cancer	O
+.	O
+
+We	O
+conducted	O
+a	O
+retrospective	O
+study	O
+covering	O
+a	O
+period	O
+of	O
+10	O
+years	O
+.	O
+
+Data	O
+were	O
+collected	O
+from	O
+a	O
+hospital	O
+information	O
+system	O
+(	O
+InfoWorld	O
+)	O
+between	O
+2009	O
+and	O
+2019	O
+.	O
+
+Patients	O
+'	O
+age	O
+groups	O
+were	O
+stratified	O
+in	O
+relation	O
+with	O
+the	O
+age	O
+at	O
+the	O
+moment	O
+of	O
+the	O
+Chernobyl	B-LOC
+event	O
+.	O
+
+A	O
+database	O
+was	O
+obtained	O
+(	O
+Microsoft	O
+Excel	O
+)	O
+and	O
+statistical	O
+correlations	O
+were	O
+applied	O
+.	O
+
+In	O
+the	O
+studied	O
+period	O
+,	O
+1159	O
+patients	O
+were	O
+diagnosed	O
+:	O
+968	O
+females	O
+and	O
+191	O
+males	O
+,	O
+distributed	O
+by	O
+region	O
+,	O
+with	O
+the	O
+highest	O
+addressability	O
+in	O
+Iasi	B-LOC
+(	O
+529	O
+)	O
+,	O
+followed	O
+by	O
+neighboring	O
+counties	O
+.	O
+
+Age	O
+distribution	O
+displayed	O
+that	O
+most	O
+of	O
+the	O
+thyroid	O
+cancers	O
+were	O
+in	O
+the	O
+range	O
+4060	O
+years	O
+old	O
+(	O
+50.94	O
+%	O
+)	O
+,	O
+followed	O
+by	O
+60	O
+-	O
+80	O
+years	O
+old	O
+(	O
+32.41	O
+%	O
+)	O
+.	O
+
+Most	O
+patients	O
+were	O
+diagnosed	O
+with	O
+papillary	O
+carcinoma	O
+63.10	O
+%	O
+,	O
+then	O
+follicular	O
+14.7	O
+%	O
+,	O
+medullary	O
+6.74	O
+%	O
+and	O
+undifferentiated	O
+1.02	B-STAT
+%	I-STAT
+.	O
+
+Romania	B-LOC
+was	O
+in	O
+the	O
+vicinity	O
+of	O
+the	O
+radioactive	O
+cloud	O
+at	O
+Chernobyl	B-LOC
+fallout	O
+,	O
+so	O
+we	O
+must	O
+deliberate	O
+whether	O
+the	O
+increased	O
+incidence	B-EPI
+of	O
+thyroid	O
+cancer	O
+in	O
+the	O
+age	O
+group	O
+40	O
+-	O
+60	O
+years	O
+is	O
+associated	O
+with	O
+radiogenicity	O
+(	O
+iodine	O
+131	O
+)	O
+given	O
+the	O
+fact	O
+that	O
+over	O
+has	O
+35	O
+years	O
+and	O
+the	O
+half	O
+-	O
+life	O
+of	O
+other	O
+radioisotopes	O
+like	O
+Caesium-137	O
+and	O
+Strontium	O
+-90	O
+is	O
+completed	O
+.	O
+
+The	O
+field	O
+of	O
+Cardio	O
+-	O
+oncology	O
+is	O
+rapidly	O
+growing	O
+with	O
+significant	O
+advances	O
+in	O
+research	O
+leading	O
+to	O
+better	O
+understanding	O
+of	O
+the	O
+underlying	O
+pathogenesis	O
+with	O
+implications	O
+in	O
+the	O
+diagnosis	O
+and	O
+management	O
+of	O
+cancer	O
+-	O
+related	O
+cardiomyopathy	O
+.	O
+
+Parallel	O
+to	O
+advancement	O
+in	O
+cardio	O
+-	O
+oncology	O
+is	O
+an	O
+increased	O
+awareness	O
+of	O
+the	O
+incidence	B-EPI
+of	O
+congestive	O
+heart	O
+failure	O
+and	O
+cardiomyopathy	O
+associated	O
+with	O
+malignancy	O
+.	O
+
+While	O
+specific	O
+cardiotoxic	O
+profiles	O
+exist	O
+for	O
+certain	O
+chemotherapeutic	O
+agents	O
+,	O
+there	O
+is	O
+increasing	O
+evidence	O
+of	O
+unexpected	O
+cardiotoxic	O
+side	O
+effects	O
+of	O
+some	O
+therapeutic	O
+modalities	O
+,	O
+combination	O
+chemo-	O
+and	O
+radiotherapy	O
+with	O
+large	O
+analyses	O
+identifying	O
+a	O
+strong	O
+association	O
+between	O
+malignancy	O
+and	O
+Takotsubo	O
+cardiomyopathy	O
+.	O
+
+Takotsubo	O
+Cardiomyopathy	O
+,	O
+also	O
+known	O
+as	O
+	O
+broken	O
+-	O
+heart	O
+	O
+syndrome	O
+or	O
+stress	O
+cardiomyopathy	O
+,	O
+is	O
+characterized	O
+by	O
+transient	O
+and	O
+reversible	O
+,	O
+regional	O
+or	O
+global	O
+,	O
+myocardial	O
+dysfunction	O
+without	O
+inciting	O
+ischemic	O
+perfusion	O
+defect	O
+from	O
+obstructive	O
+coronary	O
+artery	O
+disease	O
+.	O
+
+While	O
+direct	O
+causative	O
+pathophysiologic	O
+mechanisms	O
+continue	O
+to	O
+be	O
+investigated	O
+,	O
+much	O
+of	O
+the	O
+postulated	O
+pathways	O
+center	O
+on	O
+the	O
+high	O
+emotional	O
+and	O
+physical	O
+burdens	O
+of	O
+cancer	O
+and	O
+the	O
+related	O
+emotional	O
+stress	O
+associated	O
+with	O
+the	O
+diagnosis	O
+of	O
+cancer	O
+as	O
+well	O
+as	O
+the	O
+corporal	O
+effects	O
+of	O
+anti	O
+-	O
+neoplastic	O
+therapies	O
+,	O
+radiation	O
+,	O
+and	O
+oncologic	O
+surgery	O
+.	O
+
+In	O
+this	O
+manuscript	O
+we	O
+review	O
+the	O
+most	O
+current	O
+data	O
+in	O
+this	O
+rapidly	O
+emerging	O
+field	O
+highlighting	O
+the	O
+epidemiology	O
+,	O
+the	O
+postulated	O
+pathogenetic	O
+mechanisms	O
+as	O
+well	O
+as	O
+the	O
+current	O
+guidelines	O
+by	O
+major	O
+societies	O
+addressing	O
+malignancy	O
+-associated	O
+heart	O
+failure	O
+and	O
+cardiomyopathy	O
+,	O
+a	O
+rather	O
+complex	O
+disease	O
+entity	O
+with	O
+high	O
+morbidity	O
+and	O
+mortality	O
+.	O
+
+Mutations	O
+in	O
+the	O
+genes	O
+for	O
+extracellular	O
+matrix	O
+(	O
+ECM	O
+)	O
+components	O
+cause	O
+a	O
+wide	O
+range	O
+of	O
+genetic	O
+connective	O
+tissues	O
+disorders	O
+throughout	O
+the	O
+body	O
+.	O
+
+The	O
+elucidation	O
+of	O
+mutations	O
+and	O
+their	O
+correlation	O
+with	O
+pathology	O
+has	O
+been	O
+instrumental	O
+in	O
+understanding	O
+the	O
+roles	O
+of	O
+many	O
+ECM	O
+components	O
+.	O
+
+The	O
+pathological	O
+consequences	O
+of	O
+ECM	O
+protein	O
+mutations	O
+depend	O
+on	O
+its	O
+tissue	O
+distribution	O
+,	O
+tissue	O
+function	O
+,	O
+and	O
+on	O
+the	O
+nature	O
+of	O
+the	O
+mutation	O
+.	O
+
+The	O
+prevalent	B-EPI
+paradigm	O
+for	O
+the	O
+molecular	O
+pathology	O
+has	O
+been	O
+that	O
+there	O
+are	O
+two	O
+global	O
+mechanisms	O
+.	O
+
+First	O
+,	O
+mutations	O
+that	O
+reduce	O
+the	O
+production	O
+of	O
+ECM	O
+proteins	O
+impair	O
+matrix	O
+integrity	O
+largely	O
+due	O
+to	O
+quantitative	O
+ECM	O
+defects	O
+.	O
+
+Second	O
+,	O
+mutations	O
+altering	O
+protein	O
+structure	O
+may	O
+reduce	O
+protein	O
+secretion	O
+but	O
+also	O
+introduce	O
+dominant	O
+negative	O
+effects	O
+in	O
+ECM	O
+formation	O
+,	O
+structure	O
+and/or	O
+stability	O
+.	O
+
+Recent	O
+studies	O
+show	O
+that	O
+endoplasmic	O
+reticulum	O
+(	O
+ER	O
+)	O
+stress	O
+,	O
+caused	O
+by	O
+mutant	O
+misfolded	O
+ECM	O
+proteins	O
+,	O
+makes	O
+a	O
+significant	O
+contribution	O
+to	O
+the	O
+pathophysiology	O
+.	O
+
+This	O
+suggests	O
+that	O
+targeting	O
+ER	O
+-	O
+stress	O
+may	O
+offer	O
+a	O
+new	O
+therapeutic	O
+strategy	O
+in	O
+a	O
+range	O
+of	O
+ECM	O
+disorders	O
+caused	O
+by	O
+protein	O
+misfolding	O
+mutations	O
+.	O
+
+Anat	O
+Rec	O
+,	O
+2019	O
+.	O
+
+©	O
+2019	O
+The	O
+Authors	O
+.	O
+
+The	O
+Anatomical	O
+Record	O
+published	O
+by	O
+Wiley	O
+Periodicals	O
+,	O
+Inc.	O
+on	O
+behalf	O
+of	O
+American	O
+Association	O
+of	O
+Anatomists	O
+.	O
+
+E.	O
+histolytica	O
+is	O
+an	O
+intestinal	O
+parasite	O
+that	O
+causes	O
+asymptomatic	O
+infection	O
+mostly	O
+;	O
+however	O
+,	O
+it	O
+may	O
+also	O
+cause	O
+amoebic	O
+dysentery	O
+and	O
+liver	O
+abscess	O
+.	O
+
+Molecular	O
+identification	O
+is	O
+required	O
+in	O
+epidemiological	O
+studies	O
+due	O
+to	O
+the	O
+presence	O
+of	O
+morphologically	O
+identical	O
+nonpathogenic	O
+species	O
+.	O
+
+Therefore	O
+,	O
+this	O
+study	O
+was	O
+conducted	O
+to	O
+first	O
+evaluate	O
+the	O
+prevalence	B-EPI
+rate	O
+of	O
+E.	O
+histolytica	O
+among	O
+symptomatic	O
+individuals	O
+of	O
+Erbil	B-LOC
+city	O
+,	O
+and	O
+to	O
+investigate	O
+the	O
+genetic	O
+diversity	O
+of	O
+the	O
+parasite	O
+in	O
+a	O
+limited	O
+geographic	O
+area	O
+.	O
+
+Accordingly	O
+,	O
+a	O
+total	O
+of	O
+2026	O
+samples	O
+were	O
+examined	O
+microscopically	O
+,	O
+and	O
+confirmed	O
+by	O
+nested	O
+PCR	O
+for	O
+18s	O
+rRNA	O
+gene	O
+.	O
+
+The	O
+results	O
+showed	O
+that	O
+the	O
+prevalence	B-EPI
+rate	O
+of	O
+E.	O
+histolytica	O
+was	O
+1.97	O
+%	O
+(	O
+40	O
+samples	O
+)	O
+among	O
+symptomatic	O
+patients	O
+.	O
+
+The	O
+SREHP	O
+gene	O
+was	O
+used	O
+as	O
+a	O
+marker	O
+to	O
+show	O
+the	O
+genetic	O
+polymorphism	O
+of	O
+E.	O
+histolytica	O
+;	O
+however	O
+,	O
+to	O
+compare	O
+the	O
+genetic	O
+diversity	O
+of	O
+symptomatic	O
+with	O
+asymptomatic	O
+isolates	O
+,	O
+57	O
+asymptomatic	O
+samples	O
+were	O
+obtained	O
+from	O
+our	O
+previous	O
+study	O
+.	O
+
+The	O
+amplified	O
+products	O
+of	O
+the	O
+SREHP	O
+gene	O
+were	O
+digested	O
+by	O
+AluI	O
+endonuclease	O
+,	O
+and	O
+DNA	O
+banding	O
+patterns	O
+were	O
+analysed	O
+.	O
+
+Results	O
+showed	O
+29	O
+different	O
+DNA	O
+patterns	O
+among	O
+the	O
+97	O
+symptomatic	O
+and	O
+asymptomatic	O
+samples	O
+,	O
+62	O
+of	O
+which	O
+shared	O
+similar	O
+DNA	O
+patterns	O
+.	O
+
+However	O
+,	O
+8	O
+different	O
+DNA	O
+patterns	O
+were	O
+observed	O
+among	O
+asymptomatic	O
+samples	O
+,	O
+whereas	O
+15	O
+distinct	O
+patterns	O
+were	O
+observed	O
+among	O
+symptomatic	O
+isolates	O
+.	O
+
+In	O
+conclusion	O
+,	O
+this	O
+study	O
+found	O
+that	O
+the	O
+prevalence	B-EPI
+rate	O
+of	O
+E.	O
+histolytica	O
+was	O
+relatively	O
+low	O
+;	O
+relatively	O
+high	O
+genetic	O
+diversity	O
+was	O
+observed	O
+in	O
+a	O
+restricted	O
+endemic	O
+area	O
+;	O
+with	O
+higher	O
+rates	O
+of	O
+variability	O
+in	O
+symptomatic	O
+rather	O
+than	O
+in	O
+asymptomatic	O
+isolates	O
+,	O
+indicating	O
+a	O
+possible	O
+correlation	O
+between	O
+the	O
+genotype	O
+of	O
+E.	O
+histolytica	O
+and	O
+their	O
+clinical	O
+outcome	O
+.	O
+
+Background	O
+Nonclassical	O
+congenital	O
+adrenal	O
+hyperplasia	O
+due	O
+to	O
+21	O
+-	O
+hydroxylase	O
+deficiency	O
+is	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+active	O
+21	O
+-	O
+hydroxylase	O
+gene	O
+(	O
+CYP21A2	O
+)	O
+.	O
+
+The	O
+clinical	O
+symptoms	O
+can	O
+vary	O
+greatly	O
+.	O
+
+To	O
+date	O
+,	O
+no	O
+systematic	O
+studies	O
+have	O
+been	O
+undertaken	O
+in	O
+Germany	B-LOC
+.	O
+
+Aims	O
+Description	O
+of	O
+the	O
+phenotype	O
+,	O
+evaluation	O
+of	O
+the	O
+diagnostics	O
+and	O
+genotype	O
+-	O
+phenotype	O
+correlation	O
+PATIENTS	O
+AND	O
+METHODOLOGY	O
+:	O
+Retrospective	O
+analysis	O
+of	O
+the	O
+data	O
+of	O
+134	O
+patients	O
+(	O
+age	O
+range	O
+0.1	O
+-	O
+18.6	O
+years	O
+)	O
+in	O
+a	O
+multicentre	O
+study	O
+covering	O
+10	O
+paediatric	O
+endocrinology	O
+centres	O
+in	O
+Bavaria	B-LOC
+and	O
+Baden	B-LOC
+-	I-LOC
+Württemberg	I-LOC
+.	O
+
+The	O
+data	O
+was	O
+gathered	O
+on	O
+site	O
+from	O
+the	O
+medical	O
+records	O
+.	O
+
+Two	O
+hundred	O
+and	O
+thirty	O
+-	O
+three	O
+alleles	O
+with	O
+a	O
+mutation	O
+of	O
+the	O
+CYP21A2	O
+gene	O
+were	O
+identified	O
+in	O
+126	O
+patients	O
+.	O
+
+A	O
+genotype	O
+-	O
+phenotype	O
+correlation	O
+of	O
+the	O
+mutation	O
+findings	O
+was	O
+undertaken	O
+(	O
+C1	O
+,	O
+severe	O
+/	O
+mild	O
+;	O
+C2	O
+,	O
+mild	O
+/	O
+mild	O
+)	O
+.	O
+
+Individuals	O
+with	O
+a	O
+heterozygous	O
+mutation	O
+of	O
+the	O
+CYP21A2	O
+were	O
+also	O
+included	O
+(	O
+C3	O
+)	O
+.	O
+
+The	O
+data	O
+was	O
+collected	O
+with	O
+the	O
+approval	O
+of	O
+the	O
+ethics	O
+committee	O
+of	O
+the	O
+University	O
+Hospital	O
+of	O
+Erlangen	O
+during	O
+the	O
+period	O
+of	O
+2014	O
+and	O
+2015	O
+.	O
+
+RESULTS	O
+(	O
+MW	O
+±	O
+SD	O
+):	O
+One	O
+hundred	O
+and	O
+seventeen	O
+out	O
+of	O
+134	O
+patients	O
+(	O
+115	O
+f	O
+,	O
+29	O
+m	O
+)	O
+were	O
+symptomatic	O
+.	O
+
+The	O
+chronological	O
+age	O
+(	O
+CA	O
+)	O
+at	O
+diagnosis	O
+was	O
+7.1	O
+±	O
+4.4	O
+years	O
+.	O
+
+The	O
+most	O
+frequent	O
+symptom	O
+(	O
+73.5	O
+%	O
+)	O
+was	O
+premature	O
+pubarche	O
+.	O
+
+The	O
+height	O
+-	O
+SDS	O
+on	O
+diagnosis	O
+was	O
+0.8	O
+±	O
+1.3	O
+and	O
+the	O
+BMI	O
+-	O
+SDS	O
+was	O
+0.8	O
+±	O
+1.2	O
+.	O
+
+Bone	O
+age	O
+(	O
+BA	O
+)	O
+was	O
+ascertained	O
+in	O
+82.9	O
+%	O
+of	O
+the	O
+symptomatic	O
+patients	O
+.	O
+
+The	O
+difference	O
+between	O
+BA	O
+and	O
+CA	O
+was	O
+1.9	O
+±	O
+1.4	O
+years	O
+.	O
+
+Basal	O
+17OHP	O
+concentrations	O
+were	O
+14.5	O
+±	O
+19.1	O
+ng	O
+/	O
+ml	O
+(	O
+18	O
+patients	O
+<	O
+2	O
+ng	O
+/	O
+ml	O
+)	O
+.	O
+
+In	O
+total	O
+,	O
+58.1	O
+%	O
+mild	O
+and	O
+34.7	O
+%	O
+severe	O
+mutations	O
+were	O
+found	O
+.	O
+
+The	O
+most	O
+common	O
+mutation	O
+was	O
+p.	O
+Val281Leu	O
+(	O
+39.1	O
+%	O
+)	O
+;	O
+65.8	O
+%	O
+of	O
+the	O
+patients	O
+could	O
+be	O
+allocated	O
+to	O
+group	O
+C1	O
+.	O
+
+No	O
+phenotypical	O
+differences	O
+were	O
+found	O
+between	O
+the	O
+3	O
+mutation	O
+groups	O
+.	O
+
+The	O
+17OHP	O
+levels	O
+(	O
+basal	O
+and	O
+after	O
+ACTH	O
+)	O
+in	O
+the	O
+standard	O
+ACTH	O
+stimulation	O
+test	O
+were	O
+highest	O
+in	O
+group	O
+C1	O
+and	O
+also	O
+significantly	O
+higher	O
+in	O
+group	O
+C2	O
+as	O
+in	O
+C3	O
+,	O
+the	O
+ACTH	O
+-	O
+stimulated	O
+cortisol	O
+levels	O
+(	O
+ng	O
+/	O
+ml	O
+)	O
+were	O
+significantly	O
+lower	O
+in	O
+groups	O
+C1	O
+(	O
+192.1	O
+±	O
+62.5	O
+)	O
+and	O
+C2	O
+(	O
+218	O
+±	O
+50	O
+)	O
+than	O
+in	O
+C3	O
+(	O
+297.3	O
+±	O
+98.7	O
+)	O
+.	O
+
+Conclusion	O
+Most	O
+of	O
+the	O
+patients	O
+have	O
+symptoms	O
+of	O
+mild	O
+androgenisation	O
+.	O
+
+Male	O
+patients	O
+are	O
+underdiagnosed	O
+.	O
+
+Diagnostics	O
+are	O
+not	O
+standardised	O
+.	O
+
+Differences	O
+between	O
+the	O
+types	O
+of	O
+mutations	O
+are	O
+found	O
+in	O
+the	O
+hormone	O
+concentrations	O
+but	O
+not	O
+in	O
+phenotype	O
+.	O
+
+We	O
+speculate	O
+that	O
+further	O
+,	O
+as	O
+yet	O
+not	O
+clearly	O
+defined	O
+,	O
+factors	O
+are	O
+responsible	O
+for	O
+the	O
+development	O
+of	O
+the	O
+respective	O
+phenotypes	O
+.	O
+
+Standardized	O
+screening	O
+assessments	O
+and	O
+sex	O
+differences	O
+in	O
+autism	O
+spectrum	O
+disorder	O
+(	O
+ASD	O
+)	O
+are	O
+still	O
+under	O
+-	O
+explored	O
+in	O
+Poland	B-LOC
+.	O
+
+This	O
+study	O
+investigated	O
+the	O
+differences	O
+between	O
+Polish	O
+ASD	O
+females	O
+and	O
+males	O
+based	O
+on	O
+the	O
+responses	O
+provided	O
+by	O
+parents	O
+/	O
+caregivers	O
+to	O
+a	O
+Polish	O
+adaptation	O
+of	O
+the	O
+Social	O
+Communication	O
+Questionnaire	O
+,	O
+SCQ	O
+Lifetime	O
+and	O
+SCQ	O
+Current	O
+.	O
+
+The	O
+study	O
+included	O
+90	O
+ASD	O
+participants	O
+from	O
+Mental	O
+Health	O
+Services	O
+and	O
+Autism	O
+Clinics	O
+in	O
+Poland	B-LOC
+with	O
+no	O
+intellectual	O
+disability	O
+and	O
+no	O
+profound	O
+communication	O
+difficulties	O
+.	O
+
+Parents	O
+provided	O
+information	O
+on	O
+the	O
+SCQ	O
+items	O
+which	O
+were	O
+compared	O
+under	O
+three	O
+domains	O
+of	O
+the	O
+Autism	O
+Diagnostic	O
+Interview	O
+-	O
+Revised	O
+(	O
+ADI	O
+-	O
+R	O
+)	O
+.	O
+
+Four	O
+SCQ	O
+items	O
+with	O
+the	O
+examples	O
+were	O
+investigated	O
+.	O
+
+No	O
+significant	O
+differences	O
+were	O
+found	O
+between	O
+the	O
+two	O
+sexes	O
+in	O
+the	O
+three	O
+domains	O
+.	O
+
+The	O
+repetitive	O
+use	O
+of	O
+objects	O
+declined	O
+with	O
+age	O
+in	O
+ASD	O
+males	O
+.	O
+
+Although	O
+the	O
+findings	O
+of	O
+the	O
+present	O
+study	O
+did	O
+not	O
+reveal	O
+substantial	O
+gender	O
+biases	O
+in	O
+the	O
+Polish	O
+adaptation	O
+of	O
+the	O
+SCQ	O
+,	O
+it	O
+is	O
+necessary	O
+to	O
+take	O
+into	O
+account	O
+potential	O
+gender	O
+differences	O
+in	O
+the	O
+clinical	O
+presentation	O
+of	O
+ASD	O
+and	O
+in	O
+the	O
+adaptation	O
+of	O
+screening	O
+and	O
+diagnostic	O
+tools	O
+.	O
+
+Congenital	O
+disorders	O
+of	O
+glycosylation	O
+(	O
+CDG	O
+)	O
+are	O
+rare	O
+diseases	O
+with	O
+variable	O
+phenotypes	O
+and	O
+severity	O
+.	O
+
+Immunological	O
+involvement	O
+remains	O
+a	O
+largely	O
+uncharted	O
+topic	O
+in	O
+CDG	O
+,	O
+mainly	O
+due	O
+to	O
+lack	O
+of	O
+robust	O
+data	O
+.	O
+
+To	O
+better	O
+characterize	O
+immune	O
+-	O
+related	O
+manifestations	O
+'	O
+prevalence	B-EPI
+,	O
+relevance	O
+,	O
+and	O
+quality	O
+-	O
+of	O
+-	O
+life	O
+(	O
+QoL	O
+)	O
+impact	O
+,	O
+we	O
+developed	O
+electronic	O
+questionnaires	O
+targeting	O
+(	O
+1	O
+)	O
+CDG	O
+patients	O
+and	O
+(	O
+2	O
+)	O
+the	O
+general	O
+	O
+healthy	O
+	O
+population	O
+.	O
+
+Two	O
+-	O
+hundred	O
+and	O
+nine	O
+CDG	O
+patients	O
+/	O
+caregivers	O
+and	O
+349	O
+healthy	O
+participants	O
+were	O
+included	O
+in	O
+this	O
+study	O
+.	O
+
+PMM2	O
+-	O
+CDG	O
+was	O
+the	O
+most	O
+represented	O
+CDG	O
+(	O
+n	O
+=	O
+122/209	B-STAT
+)	O
+.	O
+
+About	O
+half	O
+of	O
+these	O
+participants	O
+(	O
+n	O
+=	O
+65/122	B-STAT
+)	O
+described	O
+relevant	O
+infections	O
+with	O
+a	O
+noteworthy	O
+prevalence	B-EPI
+of	O
+those	O
+affecting	O
+the	O
+gastrointestinal	O
+tract	O
+(	O
+GI	O
+)	O
+(	O
+63.1	O
+%	O
+,	O
+n	O
+=	O
+41/65	B-STAT
+)	O
+.	O
+
+Infection	O
+burden	O
+and	O
+QoL	O
+impact	O
+were	O
+shown	O
+as	O
+infections	O
+correlated	O
+with	O
+more	O
+severe	O
+clinical	O
+phenotypes	O
+and	O
+with	O
+a	O
+set	O
+of	O
+relevant	O
+non	O
+-	O
+immune	O
+PMM2	O
+-	O
+CDG	O
+signs	O
+.	O
+
+Autoimmune	O
+diseases	O
+had	O
+only	O
+a	O
+marginal	O
+presence	O
+in	O
+PMM2	O
+-	O
+CDG	O
+(	O
+2.5	O
+%	O
+,	O
+n	O
+=	O
+3/122	B-STAT
+)	O
+,	O
+all	O
+being	O
+GI	O
+-	O
+related	O
+.	O
+
+Allergy	O
+prevalence	B-EPI
+was	O
+also	O
+low	O
+in	O
+PMM2	O
+-	O
+CDG	O
+(	O
+33	O
+%	O
+,	O
+n	O
+=	O
+41/122	B-STAT
+)	O
+except	O
+for	O
+food	O
+allergies	O
+(	O
+26.8	O
+%	O
+,	O
+n	O
+=	O
+11/41	B-STAT
+,	O
+of	O
+PMM2	O
+-	O
+CDG	O
+and	O
+10.8	O
+%	O
+,	O
+n	O
+=	O
+17/158	B-STAT
+,	O
+of	O
+controls	O
+)	O
+.	O
+
+High	O
+vaccination	O
+compliance	O
+with	O
+greater	O
+perceived	O
+ineffectiveness	O
+(	O
+28.3	O
+%	O
+,	O
+n	O
+=	O
+17/60	B-STAT
+)	O
+and	O
+more	O
+severe	O
+adverse	O
+reactions	O
+were	O
+described	O
+in	O
+PMM2	O
+-	O
+CDG	O
+.	O
+
+This	O
+people	O
+-	O
+centric	O
+approach	O
+not	O
+only	O
+confirmed	O
+literature	O
+findings	O
+,	O
+but	O
+created	O
+new	O
+insights	O
+into	O
+immunological	O
+involvement	O
+in	O
+CDG	O
+,	O
+namely	O
+by	O
+highlighting	O
+the	O
+possible	O
+link	O
+between	O
+the	O
+immune	O
+and	O
+GI	O
+systems	O
+in	O
+PMM2	O
+-	O
+CDG	O
+.	O
+
+Finally	O
+,	O
+our	O
+results	O
+emphasized	O
+the	O
+importance	O
+of	O
+patient	O
+/	O
+caregiver	O
+knowledge	O
+and	O
+raised	O
+several	O
+red	O
+flags	O
+about	O
+immunological	O
+management	O
+.	O
+
+Isolated	O
+cleft	O
+palate	O
+(	O
+CPO	O
+)	O
+is	O
+the	O
+rarest	O
+form	O
+of	O
+oral	O
+clefting	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+CPO	O
+varies	O
+substantially	O
+by	O
+geography	O
+from	O
+1.3	B-STAT
+to	I-STAT
+25.3	I-STAT
+per	I-STAT
+10,000	I-STAT
+live	I-STAT
+births	I-STAT
+,	O
+with	O
+the	O
+highest	O
+rates	O
+in	O
+British	B-LOC
+Columbia	I-LOC
+,	O
+Canada	B-LOC
+and	O
+the	O
+lowest	O
+rates	O
+in	O
+Nigeria	B-LOC
+,	O
+Africa	B-LOC
+.	O
+
+Stratified	O
+by	O
+ethnicity	O
+/	O
+race	O
+,	O
+the	O
+highest	O
+rates	O
+of	O
+CPO	O
+are	O
+observed	O
+in	O
+non	O
+-	O
+Hispanic	O
+Whites	O
+and	O
+the	O
+lowest	O
+in	O
+Africans	O
+;	O
+nevertheless	O
+,	O
+rates	O
+of	O
+CPO	O
+are	O
+consistently	O
+higher	O
+in	O
+females	O
+compared	O
+to	O
+males	O
+.	O
+
+Approximately	O
+fifty	O
+percent	O
+of	O
+cases	O
+born	O
+with	O
+cleft	O
+palate	O
+occur	O
+as	O
+part	O
+of	O
+a	O
+known	O
+genetic	O
+syndrome	O
+or	O
+with	O
+another	O
+malformation	O
+(	O
+e.g.	O
+,	O
+congenital	O
+heart	O
+defects	O
+)	O
+and	O
+the	O
+other	O
+half	O
+occur	O
+as	O
+solitary	O
+defects	O
+,	O
+referred	O
+to	O
+often	O
+as	O
+non	O
+-	O
+syndromic	O
+clefts	O
+.	O
+
+The	O
+etiology	O
+of	O
+CPO	O
+is	O
+multifactorial	O
+involving	O
+genetic	O
+and	O
+environmental	O
+risk	O
+factors	O
+.	O
+
+Several	O
+animal	O
+models	O
+have	O
+yielded	O
+insight	O
+into	O
+the	O
+molecular	O
+pathways	O
+responsible	O
+for	O
+proper	O
+closure	O
+of	O
+the	O
+palate	O
+,	O
+including	O
+the	O
+BMP	O
+,	O
+TGF	O
+-	O
+β	O
+,	O
+and	O
+SHH	O
+signaling	O
+pathways	O
+.	O
+
+In	O
+terms	O
+of	O
+environmental	O
+exposures	O
+,	O
+only	O
+maternal	O
+tobacco	O
+smoke	O
+has	O
+been	O
+found	O
+to	O
+be	O
+strongly	O
+associated	O
+with	O
+CPO	O
+.	O
+
+Some	O
+studies	O
+have	O
+suggested	O
+that	O
+maternal	O
+glucocorticoid	O
+exposure	O
+may	O
+also	O
+be	O
+important	O
+.	O
+
+Clearly	O
+,	O
+there	O
+is	O
+a	O
+need	O
+for	O
+larger	O
+epidemiologic	O
+studies	O
+to	O
+further	O
+investigate	O
+both	O
+genetic	O
+and	O
+environmental	O
+risk	O
+factors	O
+and	O
+gene	O
+-	O
+environment	O
+interactions	O
+.	O
+
+In	O
+terms	O
+of	O
+treatment	O
+,	O
+there	O
+is	O
+a	O
+need	O
+for	O
+long	O
+-	O
+term	O
+comprehensive	O
+care	O
+including	O
+surgical	O
+,	O
+dental	O
+and	O
+speech	O
+pathology	O
+.	O
+
+Overall	O
+,	O
+five	O
+main	O
+themes	O
+emerge	O
+as	O
+critical	O
+in	O
+advancing	O
+research	O
+:	O
+(	O
+1	O
+)	O
+monitoring	O
+of	O
+the	O
+occurrence	B-EPI
+of	O
+CPO	O
+(	O
+capacity	O
+building	O
+)	O
+;	O
+(	O
+2	O
+)	O
+detailed	O
+phenotyping	O
+of	O
+the	O
+severity	O
+(	O
+biology	O
+)	O
+;	O
+(	O
+3	O
+)	O
+understanding	O
+of	O
+the	O
+genetic	O
+and	O
+environmental	O
+risk	O
+factors	O
+(	O
+primary	O
+prevention	O
+)	O
+;	O
+(	O
+4	O
+)	O
+access	O
+to	O
+early	O
+detection	O
+and	O
+multidisciplinary	O
+treatment	O
+(	O
+clinical	O
+services	O
+)	O
+;	O
+and	O
+(	O
+5	O
+)	O
+understanding	O
+predictors	O
+of	O
+recurrence	O
+and	O
+possible	O
+interventions	O
+among	O
+families	O
+with	O
+a	O
+child	O
+with	O
+CPO	O
+(	O
+secondary	O
+prevention	O
+)	O
+.	O
+
+Introduction	O
+Psoriatic	O
+arthritis	O
+(	O
+PsA	O
+)	O
+is	O
+a	O
+chronic	O
+immune	O
+-	O
+mediated	O
+inflammatory	O
+spondyloarthropathy	O
+associated	O
+with	O
+psoriasis	O
+.	O
+
+PsA	O
+is	O
+frequently	O
+associated	O
+with	O
+metabolic	O
+disorders	O
+including	O
+,	O
+obesity	O
+,	O
+metabolic	O
+syndrome	O
+,	O
+and	O
+diabetes	O
+mellitus	O
+(	O
+DM	O
+)	O
+.	O
+
+Type	O
+2	O
+DM	O
+is	O
+among	O
+the	O
+most	O
+common	O
+metabolic	O
+disorders	O
+,	O
+with	O
+a	O
+prevalence	B-EPI
+ranging	O
+from	O
+2.4	B-STAT
+to	O
+14.8	O
+%	O
+in	O
+the	O
+general	O
+population	O
+.	O
+
+Methods	O
+We	O
+conducted	O
+a	O
+narrative	O
+review	O
+of	O
+the	O
+English	O
+-	O
+language	O
+studies	O
+from	O
+January	O
+1989	O
+to	O
+September	O
+2019	O
+investigating	O
+the	O
+risk	O
+of	O
+type	O
+2	O
+DM	O
+in	O
+patients	O
+with	O
+PsA	O
+,	O
+the	O
+pathogenic	O
+mechanism	O
+linking	O
+DM	O
+to	O
+PsA	O
+,	O
+and	O
+the	O
+effects	O
+on	O
+insulin	O
+sensitivity	O
+exerted	O
+by	O
+systemic	O
+therapies	O
+for	O
+PsA.	O
+
+Results	O
+The	O
+prevalence	B-EPI
+of	O
+type	O
+2	O
+DM	O
+in	O
+patients	O
+with	O
+PsA	O
+ranges	O
+from	O
+6.1	B-STAT
+to	O
+20.2	O
+%	O
+,	O
+generally	O
+higher	O
+when	O
+compared	O
+to	O
+the	O
+general	O
+population	O
+.	O
+
+The	O
+higher	O
+risk	O
+of	O
+DM	O
+is	O
+reported	O
+in	O
+women	O
+with	O
+more	O
+severe	O
+forms	O
+of	O
+PsA.	O
+
+Elevated	O
+serum	O
+levels	O
+of	O
+adipokines	O
+,	O
+including	O
+TNF	O
+-	O
+α	O
+,	O
+which	O
+inhibits	O
+the	O
+autophosphorylation	O
+of	O
+the	O
+insulin	O
+receptor	O
+and	O
+suppresses	O
+the	O
+expression	O
+of	O
+glucose	O
+transporter	O
+4	O
+,	O
+favor	O
+insulin	O
+resistance	O
+and	O
+could	O
+partially	O
+explain	O
+the	O
+association	O
+between	O
+PsA	O
+and	O
+DM	O
+.	O
+
+Moreover	O
+,	O
+adiponectin	O
+and	O
+omentin	O
+,	O
+with	O
+insulin	O
+-	O
+sensitizing	O
+and	O
+anti	O
+-	O
+atherogenic	O
+properties	O
+,	O
+are	O
+decreased	O
+in	O
+patients	O
+with	O
+PsA.	O
+
+Some	O
+of	O
+the	O
+treatments	O
+for	O
+PsA	O
+could	O
+affect	O
+the	O
+glucose	O
+homeostasis	O
+.	O
+
+Systemic	O
+corticosteroids	O
+are	O
+known	O
+to	O
+impair	O
+insulin	O
+resistance	O
+,	O
+whereas	O
+apremilast	O
+(	O
+phosphodiesterase	O
+type	O
+4	O
+inhibitor	O
+)	O
+and	O
+TNF	O
+-	O
+α	O
+inhibitors	O
+could	O
+exert	O
+neutral	O
+effect	O
+or	O
+reduce	O
+the	O
+insulin	O
+-	O
+resistance	O
+.	O
+
+The	O
+role	O
+of	O
+IL-17	O
+or	O
+IL-23	O
+inhibitors	O
+has	O
+been	O
+marginally	O
+investigated	O
+.	O
+
+Conclusions	O
+Patients	O
+affected	O
+by	O
+PsA	O
+have	O
+a	O
+higher	O
+prevalence	B-EPI
+of	O
+type	O
+2	O
+DM	O
+compared	O
+with	O
+the	O
+general	O
+population	O
+.	O
+
+The	O
+mechanism	O
+linking	O
+PsA	O
+with	O
+DM	O
+has	O
+not	O
+been	O
+completely	O
+clarified	O
+,	O
+but	O
+some	O
+of	O
+the	O
+principal	O
+mediators	O
+could	O
+be	O
+TNF	O
+-	O
+α	O
+and	O
+adipokine	O
+,	O
+especially	O
+adiponectin	O
+and	O
+omentin	O
+.	O
+
+Apremilast	O
+and	O
+TNF	O
+-	O
+α	O
+inhibitor	O
+may	O
+have	O
+a	O
+favorable	O
+effect	O
+and	O
+could	O
+be	O
+safely	O
+used	O
+in	O
+patients	O
+with	O
+DM	O
+.	O
+
+The	O
+life	O
+span	O
+of	O
+patients	O
+with	O
+primary	O
+and	O
+secondary	O
+immunodeficiency	O
+is	O
+increasing	O
+due	O
+to	O
+recent	O
+improvements	O
+in	O
+therapeutic	O
+strategies	O
+.	O
+
+While	O
+the	O
+incidence	B-EPI
+of	O
+primary	O
+immunodeficiencies	O
+(	O
+PIDs	O
+)	O
+is	O
+1:10,000	B-STAT
+births	I-STAT
+,	I-STAT
+that	O
+of	O
+secondary	O
+immunodeficiencies	O
+are	O
+more	O
+common	O
+and	O
+are	O
+associated	O
+with	O
+posttransplantation	O
+immune	O
+dysfunction	O
+,	O
+with	O
+immunosuppressive	O
+medication	O
+for	O
+human	O
+immunodeficiency	O
+virus	O
+or	O
+with	O
+human	O
+T	O
+-	O
+cell	O
+lymphotropic	O
+virus	O
+infection	O
+.	O
+
+After	O
+infection	O
+,	O
+malignancy	O
+is	O
+the	O
+most	O
+prevalent	B-EPI
+cause	O
+of	O
+death	O
+in	O
+both	O
+children	O
+and	O
+adults	O
+with	O
+(	O
+PIDs	O
+)	O
+.	O
+
+PIDs	O
+more	O
+often	O
+associated	O
+with	O
+cancer	O
+include	O
+common	O
+variable	O
+immunodeficiency	O
+(	O
+CVID	O
+)	O
+,	O
+Wiskott	O
+-	O
+Aldrich	O
+syndrome	O
+,	O
+ataxia	O
+-	O
+telangiectasia	O
+,	O
+and	O
+severe	O
+combined	O
+immunodeficiency	O
+.	O
+
+This	O
+suggests	O
+that	O
+a	O
+protective	O
+immune	O
+response	O
+against	O
+both	O
+infectious	O
+non	O
+-	O
+self-(pathogens	O
+)	O
+and	O
+malignant	O
+self	O
+-	O
+challenges	O
+(	O
+cancer	O
+)	O
+exists	O
+.	O
+
+The	O
+increased	O
+incidence	B-EPI
+of	O
+cancer	O
+has	O
+been	O
+attributed	O
+to	O
+defective	O
+elimination	O
+of	O
+altered	O
+or	O
+	O
+transformed	O
+	O
+cells	O
+and/or	O
+defective	O
+immunity	O
+towards	O
+cancer	O
+cells	O
+.	O
+
+The	O
+concept	O
+of	O
+aberrant	O
+immune	O
+surveillance	O
+occurring	O
+in	O
+PIDs	O
+is	O
+supported	O
+by	O
+evidence	O
+in	O
+mice	O
+and	O
+from	O
+patients	O
+undergoing	O
+immunosuppression	O
+after	O
+transplantation	O
+.	O
+
+Here	O
+,	O
+we	O
+discuss	O
+the	O
+importance	O
+of	O
+PID	O
+defects	O
+in	O
+the	O
+development	O
+of	O
+malignancies	O
+and	O
+the	O
+current	O
+limitations	O
+associated	O
+with	O
+molecular	O
+pathogenesis	O
+of	O
+these	O
+diseases	O
+and	O
+emphasize	O
+the	O
+need	O
+for	O
+further	O
+knowledge	O
+of	O
+how	O
+specific	O
+mutations	O
+can	O
+modulate	O
+the	O
+immune	O
+system	O
+to	O
+alter	O
+immunosurveillance	O
+and	O
+thereby	O
+play	O
+a	O
+key	O
+role	O
+in	O
+the	O
+etiology	O
+of	O
+malignancies	O
+in	O
+PID	O
+patients	O
+.	O
+
+Purpose	O
+of	O
+review	O
+The	O
+aim	O
+was	O
+to	O
+review	O
+evidence	O
+about	O
+diabetes	O
+secondary	O
+to	O
+hereditary	O
+pancreatitis	O
+,	O
+seeking	O
+novel	O
+diagnostic	O
+and	O
+treatment	O
+features	O
+.	O
+
+Recent	O
+findings	O
+Hereditary	O
+pancreatitis	O
+(	O
+HP	O
+)	O
+is	O
+an	O
+autosomal	O
+dominant	O
+condition	O
+,	O
+characterized	O
+by	O
+recurrent	O
+episodes	O
+of	O
+acute	O
+pancreatitis	O
+,	O
+progression	O
+to	O
+fibrosis	O
+,	O
+and	O
+chronic	O
+pancreatitis	O
+.	O
+
+Clinical	O
+presentation	O
+includes	O
+diabetes	O
+of	O
+the	O
+exocrine	O
+pancreas	O
+(	O
+DEP	O
+)	O
+.	O
+
+HP	O
+prevalence	B-EPI
+ranges	O
+from	O
+0.3	B-STAT
+to	I-STAT
+0.57	I-STAT
+per	I-STAT
+100,000	I-STAT
+people	I-STAT
+,	O
+with	O
+up	O
+to	O
+80	B-STAT
+%	O
+of	O
+these	O
+develop	O
+DEP	O
+.	O
+
+This	O
+condition	O
+often	O
+requires	O
+specific	O
+interventions	O
+:	O
+with	O
+regard	O
+to	O
+metabolic	O
+control	O
+,	O
+metformin	O
+is	O
+the	O
+first	O
+choice	O
+for	O
+those	O
+with	O
+mild	O
+DEP	O
+,	O
+and	O
+for	O
+those	O
+in	O
+advanced	O
+disease	O
+,	O
+insulin	O
+is	O
+considered	O
+the	O
+first	O
+-	O
+line	O
+therapy	O
+.	O
+
+Insulin	O
+analogues	O
+and	O
+insulin	O
+pump	O
+therapy	O
+are	O
+preferred	O
+due	O
+to	O
+the	O
+brittle	O
+glycemic	O
+pattern	O
+and	O
+risk	O
+of	O
+hypoglycemia	O
+.	O
+
+In	O
+case	O
+of	O
+exocrine	O
+insufficiency	O
+,	O
+pancreatic	O
+enzyme	O
+replacement	O
+therapy	O
+is	O
+recommended	O
+.	O
+
+Pancreatic	O
+polypeptide	O
+administration	O
+is	O
+a	O
+promising	O
+novel	O
+treatment	O
+feature	O
+.	O
+
+DEP	O
+due	O
+to	O
+HP	O
+appears	O
+to	O
+be	O
+a	O
+misdiagnosed	O
+condition	O
+.	O
+
+The	O
+requirement	O
+of	O
+specific	O
+management	O
+demonstrates	O
+the	O
+importance	O
+of	O
+this	O
+matter	O
+;	O
+therefore	O
+,	O
+appropriate	O
+recognition	O
+and	O
+classification	O
+are	O
+important	O
+.	O
+
+Background	O
+.	O
+
+Vitamin	O
+C	O
+,	O
+E	O
+,	O
+D	O
+,	O
+A	O
+,	O
+zinc	O
+are	O
+considered	O
+to	O
+be	O
+essential	O
+in	O
+preventing	O
+and	O
+treating	O
+of	O
+acute	O
+respiratory	O
+infections	O
+(	O
+ARI	O
+)	O
+including	O
+COVID-19	O
+.	O
+
+Methods	O
+.	O
+
+We	O
+reviewed	O
+published	O
+studies	O
+evaluating	O
+the	O
+potential	O
+roles	O
+of	O
+these	O
+vitamin	O
+and	O
+zinc	O
+for	O
+ARIs	O
+and	O
+COVID-19	O
+using	O
+Medline	O
+database	O
+,	O
+medRxiv	O
+,	O
+and	O
+bibliographic	O
+references	O
+.	O
+
+Results	O
+.	O
+
+Vitamins	O
+C	O
+,	O
+D	O
+,	O
+and	O
+E	O
+did	O
+not	O
+reduce	O
+incidence	B-EPI
+of	O
+common	O
+cold	O
+in	O
+general	O
+,	O
+but	O
+vitamin	O
+C	O
+reduced	O
+by	O
+half	O
+in	O
+population	O
+with	O
+physical	O
+and	O
+environment	O
+stresses	O
+.	O
+
+Vitamins	O
+C	O
+and	O
+E	O
+shortened	O
+duration	O
+and	O
+reduced	O
+severity	O
+of	O
+common	O
+cold	O
+.	O
+
+A	O
+large	O
+-	O
+dose	O
+vitamin	O
+A	O
+had	O
+no	O
+effect	O
+on	O
+recovery	O
+from	O
+pneumonia	O
+.	O
+
+Zinc	O
+improved	O
+clinical	O
+deterioration	O
+and	O
+pneumonia	O
+duration	O
+in	O
+under	O
+five	O
+.	O
+
+The	O
+effect	O
+on	O
+preventing	O
+COVID-19	O
+morbidity	O
+and	O
+related	O
+-	O
+death	O
+was	O
+lacking	O
+.	O
+
+Conclusions	O
+.	O
+
+Although	O
+the	O
+effects	O
+of	O
+vitamins	O
+and	O
+zinc	O
+on	O
+ARIs	O
+including	O
+COVID-19	O
+were	O
+inconclusive	O
+,	O
+taking	O
+these	O
+for	O
+a	O
+short	O
+period	O
+during	O
+pandemic	O
+may	O
+be	O
+beneficial	O
+when	O
+there	O
+is	O
+risks	O
+of	O
+deficiency	O
+.	O
+
+Infection	O
+of	O
+a	O
+maternal	O
+urachal	O
+cyst	O
+during	O
+pregnancy	O
+is	O
+rare	O
+;	O
+Sonography	O
+is	O
+an	O
+important	O
+diagnostic	O
+tool	O
+that	O
+can	O
+help	O
+minimize	O
+maternal	O
+and	O
+fetal	O
+complications	O
+.	O
+
+We	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+35	O
+-	O
+year	O
+-	O
+old	O
+multiparous	O
+woman	O
+presenting	O
+in	O
+the	O
+third	O
+trimester	O
+with	O
+2	O
+weeks	O
+of	O
+fever	O
+,	O
+abdominal	O
+pain	O
+,	O
+and	O
+urinary	O
+symptoms	O
+.	O
+
+Imaging	O
+showed	O
+a	O
+5	O
+-	O
+cm	O
+complex	O
+anterior	O
+midline	O
+mass	O
+,	O
+found	O
+intraoperatively	O
+to	O
+be	O
+eroding	O
+into	O
+the	O
+uterus	O
+.	O
+
+Sonographic	O
+imaging	O
+aided	O
+in	O
+the	O
+diagnosis	O
+and	O
+management	O
+of	O
+the	O
+urachal	O
+cyst	O
+,	O
+and	O
+antepartum	O
+sonographic	O
+measurements	O
+of	O
+the	O
+lower	O
+uterine	O
+segment	O
+helped	O
+to	O
+counsel	O
+regarding	O
+a	O
+trial	O
+of	O
+labor	O
+.	O
+
+Following	O
+treatment	O
+,	O
+the	O
+patient	O
+stabilized	O
+and	O
+had	O
+an	O
+uncomplicated	O
+vaginal	O
+delivery	O
+.	O
+
+Context	O
+Because	O
+the	O
+skin	O
+and	O
+modified	O
+mucosal	O
+surfaces	O
+of	O
+the	O
+vulvar	O
+region	O
+contain	O
+dense	O
+apocrine	O
+glands	O
+and	O
+anogenital	O
+mammary	O
+-	O
+like	O
+glands	O
+,	O
+in	O
+addition	O
+to	O
+eccrine	O
+glands	O
+and	O
+folliculosebaceous	O
+units	O
+,	O
+benign	O
+as	O
+well	O
+as	O
+malignant	O
+lesions	O
+derived	O
+from	O
+these	O
+adnexal	O
+structures	O
+are	O
+,	O
+not	O
+surprisingly	O
+,	O
+found	O
+in	O
+the	O
+vulva	O
+.	O
+
+However	O
+,	O
+their	O
+incidence	B-EPI
+occurring	O
+in	O
+the	O
+vulva	O
+has	O
+not	O
+been	O
+reported	O
+,	O
+to	O
+our	O
+knowledge	O
+.	O
+
+Objective	O
+To	O
+determine	O
+the	O
+incidence	B-EPI
+of	O
+various	O
+vulvar	O
+adnexal	O
+lesions	O
+.	O
+
+Design	O
+We	O
+performed	O
+a	O
+retrospective	O
+review	O
+(	O
+1978	O
+-	O
+2010	O
+)	O
+of	O
+the	O
+cases	O
+at	O
+our	O
+institution	O
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+189	O
+vulvar	O
+adnexal	O
+lesions	O
+were	O
+identified	O
+.	O
+
+Most	O
+of	O
+these	O
+lesions	O
+were	O
+benign	O
+(	O
+133	O
+of	O
+189	B-STAT
+;	O
+70	O
+%	O
+)	O
+,	O
+with	O
+hidradenoma	O
+papilliferum	O
+being	O
+the	O
+most	O
+common	O
+,	O
+followed	O
+by	O
+syringoma	O
+and	O
+various	O
+types	O
+of	O
+cysts	O
+.	O
+
+Rare	O
+cases	O
+of	O
+tubular	O
+adenoma	O
+,	O
+poroma	O
+,	O
+spiradenoma	O
+,	O
+hidradenoma	O
+,	O
+cylindroma	O
+,	O
+sebaceoma	O
+,	O
+and	O
+trichoepithelioma	O
+were	O
+identified	O
+.	O
+
+Malignant	O
+adnexal	O
+neoplasms	O
+comprised	O
+the	O
+remaining	O
+30	O
+%	O
+(	O
+56	O
+of	O
+189	O
+)	O
+of	O
+the	O
+cases	O
+.	O
+
+Extramammary	O
+Paget	O
+disease	O
+was	O
+the	O
+most	O
+common	O
+(	O
+49	O
+of	O
+56	O
+)	O
+,	O
+and	O
+29	O
+%	O
+(	O
+14	O
+of	O
+49	O
+)	O
+demonstrated	O
+an	O
+invasive	O
+component	O
+.	O
+
+Rare	O
+cases	O
+of	O
+basal	O
+cell	O
+carcinoma	O
+,	O
+sebaceous	O
+carcinoma	O
+,	O
+apocrine	O
+carcinoma	O
+,	O
+adenoid	O
+cystic	O
+carcinoma	O
+,	O
+and	O
+spiradenocarcinoma	O
+were	O
+identified	O
+.	O
+
+Conclusions	O
+In	O
+this	O
+retrospective	O
+review	O
+,	O
+we	O
+identified	O
+several	O
+benign	O
+entities	O
+that	O
+have	O
+not	O
+been	O
+previously	O
+reported	O
+on	O
+the	O
+vulva	O
+,	O
+namely	O
+pilomatricoma	O
+,	O
+poroma	O
+,	O
+spiradenoma	O
+,	O
+and	O
+sebaceoma	O
+.	O
+
+Hidradenoma	O
+papilliferum	O
+and	O
+extramammary	O
+Paget	O
+disease	O
+were	O
+the	O
+most	O
+common	O
+benign	O
+and	O
+malignant	O
+adnexal	O
+neoplasms	O
+,	O
+respectively	O
+.	O
+
+The	O
+spectrum	O
+of	O
+various	O
+vulvar	O
+adnexal	O
+lesions	O
+appears	O
+to	O
+reflect	O
+the	O
+frequency	O
+of	O
+the	O
+underlying	O
+glandular	O
+elements	O
+.	O
+
+Background	O
+Primary	O
+and	O
+secondary	O
+aortopathy	O
+are	O
+frequently	O
+encountered	O
+in	O
+patients	O
+with	O
+congenital	O
+heart	O
+disease	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+present	O
+our	O
+experience	O
+and	O
+the	O
+incidence	B-EPI
+of	O
+primary	O
+and	O
+secondary	O
+adult	O
+CHD	O
+-	O
+associated	O
+aortopathy	O
+.	O
+
+Methods	O
+The	O
+cohort	O
+is	O
+comprised	O
+of	O
+adult	O
+patients	O
+with	O
+congenital	O
+heart	O
+disease	O
+from	O
+the	O
+registry	O
+of	O
+the	O
+Eastern	O
+Slovakia	O
+Institute	O
+of	O
+Cardiovascular	O
+Diseases	O
+.	O
+
+Data	O
+from	O
+the	O
+last	O
+follow	O
+-	O
+up	O
+examinations	O
+are	O
+included	O
+in	O
+this	O
+study	O
+.	O
+
+In	O
+the	O
+primary	O
+and	O
+secondary	O
+aortopathy	O
+groups	O
+were	O
+35	O
+and	O
+12	O
+patients	O
+respectively	O
+.	O
+
+As	O
+a	O
+control	O
+group	O
+were	O
+selected	O
+64	O
+patients	O
+with	O
+non	O
+aortopathy	O
+associated	O
+congenital	O
+heart	O
+disease	O
+(	O
+atrial	O
+and	O
+ventricular	O
+septal	O
+defect	O
+)	O
+.	O
+
+Results	O
+Patients	O
+with	O
+primary	O
+and	O
+secondary	O
+aortopathy	O
+had	O
+larger	O
+ascending	O
+aorta	O
+/	O
+aortic	O
+root	O
+diameters	O
+than	O
+the	O
+control	O
+group	O
+(	O
+36.28	O
+(	O
+26	O
+-	O
+49	O
+)	O
+mm	O
+vs	O
+30.25	O
+(	O
+21	O
+-	O
+41	O
+)	O
+mm	O
+p	O
+=	O
+0.000113	O
+,	O
+33.82	O
+27	O
+-	O
+49	O
+)	O
+mm	O
+vs	O
+29.03	O
+(	O
+19	O
+-	O
+38)mm	O
+p	O
+=	O
+0.000366	O
+and	O
+42.1	O
+(	O
+30	O
+-	O
+50	O
+)	O
+mm	O
+vs	O
+30.25	O
+(	O
+21	O
+-	O
+41	O
+)	O
+mm	O
+,	O
+p	O
+=	O
+0.000106	O
+,	O
+35.67	O
+(	O
+27	O
+-	O
+48	O
+)	O
+mm	O
+vs	O
+29.03	O
+(	O
+19	O
+-	O
+38	O
+)	O
+mm	O
+,	O
+p	O
+=	O
+0.000119	O
+respectively	O
+)	O
+.	O
+
+Moreover	O
+,	O
+patients	O
+with	O
+secondary	O
+aortopathy	O
+had	O
+statistically	O
+significant	O
+larger	O
+ascending	O
+aorta	O
+diameter	O
+compared	O
+to	O
+the	O
+patients	O
+with	O
+primary	O
+aortopathy	O
+(	O
+42.1	O
+(	O
+30	O
+-	O
+50	O
+)	O
+mm	O
+vs	O
+36.28	O
+(	O
+26	O
+-	O
+49	O
+)	O
+mm	O
+p	O
+=	O
+0.030	O
+)	O
+.	O
+
+During	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+,	O
+were	O
+performed	O
+only	O
+in	O
+2	O
+patients	O
+(	O
+one	O
+from	O
+each	O
+group	O
+)	O
+operations	O
+on	O
+the	O
+aortic	O
+root	O
+and	O
+the	O
+ascending	O
+aorta	O
+due	O
+to	O
+aortic	O
+root	O
+or	O
+ascending	O
+aorta	O
+dilatation	O
+.	O
+
+Conclusion	O
+More	O
+patients	O
+with	O
+secondary	O
+aortopathy	O
+had	O
+dilated	O
+ascending	O
+aorta/	O
+aortic	O
+root	O
+,	O
+as	O
+well	O
+as	O
+larger	O
+aortic	O
+diameters	O
+compare	O
+to	O
+the	O
+patients	O
+with	O
+primary	O
+aortopathy	O
+.	O
+
+Routine	O
+follow	O
+-	O
+up	O
+of	O
+these	O
+patients	O
+with	O
+attention	O
+to	O
+aortic	O
+diameter	O
+is	O
+necessary	O
+.	O
+
+Amoebiasis	O
+is	O
+a	O
+common	O
+infection	O
+widely	O
+prevalent	B-EPI
+in	O
+tropical	O
+countries	O
+with	O
+low	O
+income	O
+and	O
+poor	O
+sanitation	O
+.	O
+
+The	O
+clinical	O
+picture	O
+is	O
+usually	O
+nonspecific	O
+;	O
+however	O
+,	O
+invasion	O
+of	O
+the	O
+liver	O
+by	O
+Entamoeba	O
+histolytica	O
+could	O
+lead	O
+to	O
+an	O
+amoebic	O
+liver	O
+abscess	O
+(	O
+ALA	O
+)	O
+.	O
+
+It	O
+is	O
+relatively	O
+uncommon	O
+in	O
+women	O
+and	O
+children	O
+.	O
+
+Though	O
+rare	O
+,	O
+extension	O
+of	O
+ALA	O
+into	O
+the	O
+lungs	O
+,	O
+pleural	O
+cavity	O
+,	O
+and	O
+pericardium	O
+may	O
+prove	O
+fatal	O
+.	O
+
+Pericardial	O
+amoebiasis	O
+is	O
+a	O
+rare	O
+complication	O
+which	O
+,	O
+if	O
+not	O
+treated	O
+early	O
+,	O
+could	O
+result	O
+in	O
+cardiac	O
+tamponade	O
+and	O
+subsequent	O
+death	O
+.	O
+
+The	O
+standard	O
+management	O
+option	O
+is	O
+eradication	O
+with	O
+metronidazole	O
+along	O
+with	O
+the	O
+drainage	O
+of	O
+fluid	O
+from	O
+the	O
+liver	O
+abscess	O
+and	O
+pericardial	O
+effusion	O
+.	O
+
+Herein	O
+,	O
+we	O
+present	O
+a	O
+case	O
+of	O
+a	O
+seven	O
+-	O
+year	O
+-	O
+old	O
+male	O
+child	O
+with	O
+ALA	O
+,	O
+who	O
+developed	O
+signs	O
+and	O
+symptoms	O
+suggesting	O
+pericardial	O
+effusion	O
+within	O
+a	O
+few	O
+days	O
+of	O
+hospital	O
+admission	O
+.	O
+
+Early	O
+diagnosis	O
+of	O
+pericardial	O
+complication	O
+and	O
+successful	O
+management	O
+of	O
+abscess	O
+resolved	O
+the	O
+pericardial	O
+effusion	O
+.	O
+
+Background	O
+:	O
+Electrophysiological	O
+examination	O
+plays	O
+an	O
+important	O
+role	O
+in	O
+the	O
+diagnosis	O
+of	O
+X	O
+-	O
+linked	O
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+disease	O
+(	O
+CMTX1	O
+)	O
+with	O
+transient	O
+central	O
+nervous	O
+system	O
+deficits	O
+.	O
+
+However	O
+,	O
+the	O
+electrophysiological	O
+features	O
+are	O
+seldom	O
+reported	O
+.	O
+
+Methods	O
+:	O
+We	O
+reviewed	O
+and	O
+analyzed	O
+published	O
+reports	O
+to	O
+determine	O
+the	O
+electrophysiological	O
+features	O
+of	O
+CMTX1	O
+patients	O
+with	O
+transient	O
+central	O
+nervous	O
+system	O
+deficits	O
+.	O
+
+Results	O
+:	O
+A	O
+total	O
+of	O
+21	O
+CMTX1	O
+patients	O
+with	O
+transient	O
+central	O
+nervous	O
+system	O
+deficits	O
+were	O
+found	O
+in	O
+17	O
+published	O
+case	O
+reports	O
+/	O
+series	O
+.	O
+
+The	O
+age	O
+of	O
+onset	O
+ranged	O
+from	O
+0.5	O
+to	O
+18	O
+years	O
+(	O
+mean	O
+12.02	O
+±	O
+0.78	O
+years	O
+)	O
+.	O
+
+All	O
+patients	O
+were	O
+male	O
+.	O
+
+Recurrent	O
+episodes	O
+of	O
+central	O
+nervous	O
+system	O
+deficits	O
+were	O
+reported	O
+in	O
+all	O
+21	O
+cases	O
+and	O
+resolved	O
+in	O
+periods	O
+ranging	O
+from	O
+several	O
+minutes	O
+to	O
+3	O
+days	O
+.	O
+
+All	O
+20	O
+patients	O
+who	O
+had	O
+MRIs	O
+at	O
+presentation	O
+had	O
+bilaterally	O
+symmetrical	O
+abnormal	O
+T2	O
+/	O
+Diffusion	O
+signals	O
+in	O
+the	O
+white	O
+matter	O
+without	O
+enhancement	O
+of	O
+gadolinium	O
+.	O
+
+All	O
+subsequent	O
+MRIs	O
+showed	O
+improvement	O
+or	O
+were	O
+within	O
+normal	O
+limits	O
+.	O
+
+The	O
+median	O
+motor	O
+nerve	O
+conduction	O
+velocity	O
+(	O
+MNCV	O
+)	O
+,	O
+motor	O
+latencies	O
+,	O
+and	O
+compound	O
+muscle	O
+action	O
+potential	O
+(	O
+CMAP	O
+)	O
+amplitude	O
+were	O
+the	O
+most	O
+commonly	O
+measurable	O
+electrophysiological	O
+parameters	O
+(	O
+85.7	O
+%	O
+)	O
+.	O
+
+All	O
+cases	O
+that	O
+had	O
+MNCV	O
+at	O
+presentation	O
+had	O
+slower	O
+and	O
+significantly	O
+decreased	O
+MNCV	O
+compared	O
+with	O
+the	O
+normal	O
+value	O
+(	O
+34.1	O
+±	O
+1.10	O
+m	O
+/	O
+s	O
+vs.	O
+46.8±2.05	O
+m	O
+/	O
+s	O
+,	O
+P	O
+<	O
+0.0001	O
+;	O
+95	O
+%	O
+CI	O
+,	O
+-17.4	O
+to	O
+-7.92	O
+)	O
+.	O
+
+The	O
+average	O
+variations	O
+of	O
+MNCV	O
+in	O
+median	O
+nerve	O
+,	O
+ulnar	O
+nerve	O
+,	O
+peroneal	O
+nerve	O
+,	O
+and	O
+tibial	O
+nerve	O
+were	O
+22.0	B-STAT
+±	O
+5.96	O
+%	O
+,	O
+27.6	O
+±	O
+11.9	O
+%	O
+,	O
+25.9	O
+±	O
+4.36	O
+%	O
+,	O
+and	O
+27.3	B-STAT
+±	O
+4.30	O
+%	O
+,	O
+respectively	O
+.	O
+
+All	O
+cases	O
+with	O
+measured	O
+sensory	O
+nerve	O
+conduction	O
+velocity	O
+(	O
+SNCV	O
+)	O
+at	O
+presentation	O
+had	O
+slower	O
+and	O
+significantly	O
+decreased	O
+SNCV	O
+compared	O
+with	O
+the	O
+normal	O
+value	O
+(	O
+35.3	O
+±	O
+1.33	O
+m	O
+/	O
+s	O
+vs.	O
+47.7	O
+±	O
+2.40	O
+m	O
+/	O
+s	O
+,	O
+P	O
+<	O
+0.001	O
+;	O
+95	O
+%	O
+CI	O
+-18.2	O
+to	O
+-6.46	O
+)	O
+.	O
+
+The	O
+average	O
+variations	O
+of	O
+SNCV	O
+in	O
+median	O
+nerve	O
+,	O
+ulnar	O
+nerve	O
+,	O
+and	O
+sural	O
+nerve	O
+were	O
+19.9	B-STAT
+±	O
+8.24	O
+%	O
+,	O
+25.2	O
+±	O
+7.75	O
+%	O
+,	O
+and	O
+23.2	O
+±	O
+3.95	O
+%	O
+,	O
+respectively	O
+.	O
+
+Conclusion	O
+:	O
+This	O
+case	O
+series	O
+serves	O
+as	O
+a	O
+reminder	O
+that	O
+electrophysiological	O
+examination	O
+should	O
+be	O
+included	O
+in	O
+the	O
+diagnosis	O
+of	O
+recurrent	O
+and	O
+episodic	O
+neurological	O
+deficit	O
+with	O
+white	O
+matter	O
+lesions	O
+.	O
+
+Median	O
+MNCV	O
+is	O
+a	O
+sensitive	O
+and	O
+valuable	O
+parameter	O
+to	O
+support	O
+the	O
+diagnosis	O
+of	O
+CMTX1	O
+with	O
+transient	O
+central	O
+nervous	O
+system	O
+deficits	O
+.	O
+
+Most	O
+of	O
+the	O
+knowledge	O
+in	O
+pediatric	O
+antiphospholipid	O
+syndrome	O
+(	O
+APS	O
+)	O
+is	O
+derived	O
+from	O
+studies	O
+performed	O
+on	O
+the	O
+adult	O
+population	O
+.	O
+
+As	O
+in	O
+adults	O
+,	O
+antiphospholipid	O
+antibodies	O
+(	O
+aPL	O
+)	O
+can	O
+contribute	O
+to	O
+thrombosis	O
+,	O
+especially	O
+cerebrovascular	O
+thrombosis	O
+,	O
+in	O
+neonates	O
+and	O
+children	O
+.	O
+
+Since	O
+aPL	O
+have	O
+the	O
+potential	O
+to	O
+cross	O
+the	O
+placental	O
+barrier	O
+,	O
+and	O
+since	O
+the	O
+pediatric	O
+population	O
+is	O
+prone	O
+to	O
+infections	O
+,	O
+re	O
+-	O
+testing	O
+for	O
+their	O
+positivity	O
+is	O
+essential	O
+to	O
+specify	O
+their	O
+role	O
+in	O
+cerebrovascular	O
+thrombosis	O
+.	O
+In	O
+this	O
+review	O
+,	O
+we	O
+aimed	O
+at	O
+assessing	O
+the	O
+prevalence	B-EPI
+of	O
+aPL	O
+,	O
+criteria	O
+or	O
+non	O
+-	O
+criteria	O
+,	O
+in	O
+neonatal	O
+and	O
+childhood	O
+ischemic	O
+stroke	O
+and	O
+sinovenous	O
+thrombosis	O
+trying	O
+to	O
+find	O
+an	O
+association	O
+between	O
+aPL	O
+and	O
+cerebrovascular	O
+thrombosis	O
+in	O
+the	O
+neonatal	O
+and	O
+pediatric	O
+population	O
+.	O
+
+Also	O
+,	O
+we	O
+looked	O
+into	O
+the	O
+effect	O
+of	O
+aPL	O
+and	O
+anticoagulants	O
+/	O
+antiplatelets	O
+on	O
+the	O
+long	O
+term	O
+neurological	O
+outcomes	O
+of	O
+affected	O
+neonates	O
+or	O
+children	O
+.	O
+
+The	O
+questions	O
+regarding	O
+the	O
+prevalence	B-EPI
+of	O
+aPL	O
+among	O
+pediatric	O
+patients	O
+with	O
+cerebrovascular	O
+thrombosis	O
+,	O
+the	O
+relationship	O
+between	O
+the	O
+titers	O
+of	O
+aPL	O
+and	O
+incidence	B-EPI
+and	O
+recurrence	O
+of	O
+cerebrovascular	O
+events	O
+,	O
+the	O
+predictability	O
+of	O
+the	O
+long	O
+term	O
+neurological	O
+outcomes	O
+,	O
+and	O
+the	O
+most	O
+optimal	O
+anticoagulation	O
+plan	O
+are	O
+still	O
+to	O
+be	O
+answered	O
+.	O
+
+However	O
+,	O
+it	O
+is	O
+crucial	O
+for	O
+clinicians	O
+to	O
+screen	O
+neonates	O
+and	O
+children	O
+with	O
+cerebrovascular	O
+thrombosis	O
+for	O
+aPL	O
+and	O
+confirm	O
+their	O
+presence	O
+if	O
+positive	O
+.	O
+
+Babies	O
+in	O
+Neonatal	O
+Intensive	O
+Care	O
+Units	O
+(	O
+NICU	O
+)	O
+have	O
+an	O
+additional	O
+risk	O
+for	O
+hearing	O
+loss	O
+due	O
+to	O
+various	O
+risk	O
+factors	O
+like	O
+,	O
+prematurity	O
+,	O
+low	O
+birth	O
+weight	O
+,	O
+mechanical	O
+ventilation	O
+,	O
+hyperbillirubinemia	O
+,	O
+ototoxic	O
+drugs	O
+,	O
+low	O
+APGAR	O
+score	O
+etc	O
+.	O
+
+as	O
+compared	O
+to	O
+the	O
+babies	O
+from	O
+well	O
+baby	O
+nursery	O
+(	O
+WBN	O
+)	O
+who	O
+,	O
+poses	O
+risk	O
+factors	O
+mostly	O
+family	O
+history	O
+,	O
+syndromic	O
+deafness	O
+.	O
+
+So	O
+the	O
+present	O
+study	O
+was	O
+aimed	O
+know	O
+the	O
+risk	O
+factors	O
+responsible	O
+for	O
+hearing	O
+loss	O
+in	O
+NICU	O
+and	O
+WBN	O
+babies	O
+and	O
+to	O
+assess	O
+the	O
+incidence	B-EPI
+of	O
+deafness	O
+.	O
+
+A	O
+total	O
+of	O
+800	O
+babies	O
+from	O
+NICU	O
+(	O
+n	O
+=	O
+402	O
+)	O
+and	O
+WBN	O
+(	O
+n	O
+=	O
+398	O
+)	O
+underwent	O
+hearing	O
+screening	O
+from	O
+a	O
+tertiary	O
+care	O
+center	O
+.	O
+
+Hearing	O
+screening	O
+was	O
+done	O
+using	O
+two	O
+staged	O
+screening	O
+protocol	O
+as	O
+per	O
+JCIH	O
+guidelines	O
+with	O
+Distortion	O
+product	O
+Evoked	O
+Otoacoustic	O
+Emissions	O
+(	O
+DPOAE	O
+)	O
+and	O
+Automated	O
+Auditory	O
+Brainstem	O
+Responses	O
+(	O
+A	O
+-	O
+ABR	O
+)	O
+.	O
+
+According	O
+to	O
+DPOAE	O
+test	O
+,	O
+311	O
+from	O
+NICU	O
+and	O
+383	O
+from	O
+WBN	O
+passed	O
+the	O
+test	O
+and	O
+during	O
+second	O
+screening	O
+,	O
+80	O
+out	O
+of	O
+91	O
+from	O
+NICU	O
+and	O
+11	O
+out	O
+of	O
+13	O
+from	O
+WBN	O
+passed	O
+the	O
+DPOAE	O
+test	O
+.	O
+
+Further	O
+BERA	O
+was	O
+done	O
+at	O
+the	O
+3	O
+rd	O
+month	O
+of	O
+corrected	O
+age	O
+where	O
+6	O
+out	O
+of	O
+11	O
+showed	O
+positive	O
+responses	O
+from	O
+NICU	O
+and	O
+3	O
+babies	O
+from	O
+WBN	O
+had	O
+profound	O
+hearing	O
+loss	O
+.	O
+
+Data	O
+analysis	O
+revealed	O
+that	O
+family	O
+history	O
+of	O
+deafness	O
+,	O
+anemia	O
+and	O
+hypertension	O
+in	O
+ANC	O
+,	O
+TORCH	O
+in	O
+mother	O
+,	O
+low	O
+Apgar	O
+score	O
+and	O
+hyperbillirubinemia	O
+in	O
+newborns	O
+were	O
+a	O
+major	O
+risk	O
+factor	O
+for	O
+hearing	O
+impairment	O
+.	O
+
+We	O
+conclude	O
+that	O
+the	O
+diagnoses	O
+of	O
+auditory	O
+disorders	O
+at	O
+early	O
+stage	O
+due	O
+to	O
+various	O
+risk	O
+factors	O
+are	O
+important	O
+since	O
+appropriate	O
+therapeutic	O
+intervention	O
+and	O
+rehabilitation	O
+would	O
+help	O
+in	O
+better	O
+development	O
+of	O
+children	O
+.	O
+
+Background	O
+As	O
+a	O
+result	O
+of	O
+the	O
+current	O
+global	O
+pandemic	O
+,	O
+the	O
+dental	O
+profession	O
+has	O
+utilized	O
+teledentistry	O
+to	O
+reduce	O
+footfall	O
+in	O
+the	O
+hospitals	O
+and	O
+clinics	O
+where	O
+possible	O
+.	O
+
+Pediatric	O
+dental	O
+consultants	O
+form	O
+a	O
+vital	O
+part	O
+of	O
+a	O
+multidisciplinary	O
+team	O
+and	O
+regularly	O
+monitor	O
+the	O
+dental	O
+growth	O
+and	O
+development	O
+of	O
+patients	O
+with	O
+cleft	O
+lip	O
+and	O
+palate	O
+.	O
+
+Objective	O
+To	O
+assess	O
+the	O
+effectiveness	O
+of	O
+the	O
+service	O
+provided	O
+by	O
+pediatric	O
+dental	O
+consultants	O
+in	O
+the	O
+South	O
+Thames	O
+Cleft	O
+Service	O
+at	O
+Evelina	O
+Children	O
+'s	O
+Hospital	O
+during	O
+the	O
+COVID-19	O
+pandemic	O
+through	O
+virtual	O
+clinics	O
+.	O
+
+Design	O
+Data	O
+were	O
+collected	O
+retrospectively	O
+and	O
+include	O
+all	O
+cleft	O
+patients	O
+contacted	O
+via	O
+the	O
+virtual	O
+clinic	O
+during	O
+May	O
+to	O
+July	O
+2020	O
+.	O
+
+Patients	O
+were	O
+prioritized	O
+by	O
+the	O
+Red	O
+,	O
+Amber	O
+,	O
+Green	O
+(	O
+RAG	O
+)	O
+scale	O
+to	O
+highlight	O
+the	O
+urgency	O
+of	O
+their	O
+next	O
+face	O
+-	O
+to	O
+-	O
+face	O
+appointment	O
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+215	O
+patients	O
+were	O
+contacted	O
+during	O
+this	O
+period	O
+with	O
+a	O
+97	O
+%	O
+response	O
+rate	O
+.	O
+
+Patients	O
+given	O
+a	O
+RAG	O
+score	O
+of	O
+GREEN	O
+(	O
+86	O
+%	O
+)	O
+meant	O
+no	O
+urgent	O
+requirement	O
+for	O
+a	O
+face	O
+-	O
+to	O
+-	O
+face	O
+consultation	O
+and	O
+AMBER	O
+(	O
+8	O
+%	O
+)	O
+patients	O
+required	O
+treatment	O
+that	O
+was	O
+deemed	O
+nonurgent	O
+.	O
+
+However	O
+,	O
+3	O
+%	O
+of	O
+patients	O
+received	O
+a	O
+RED	O
+rating	O
+as	O
+they	O
+required	O
+urgent	O
+input	O
+.	O
+
+Conclusion	O
+Through	O
+these	O
+virtual	O
+clinics	O
+,	O
+the	O
+pediatric	O
+team	O
+was	O
+able	O
+to	O
+reach	O
+208	O
+patients	O
+and	O
+provided	O
+advice	O
+and	O
+reassurance	O
+.	O
+
+The	O
+need	O
+for	O
+face	O
+-	O
+to	O
+-	O
+face	O
+appointment	O
+was	O
+eliminated	O
+for	O
+11	O
+%	O
+of	O
+patients	O
+who	O
+were	O
+discharged	O
+to	O
+their	O
+local	O
+dental	O
+practitioners	O
+,	O
+thereby	O
+reducing	O
+the	O
+risk	O
+of	O
+spreading	O
+COVID-19	O
+.	O
+
+Of	O
+7,028	O
+disorders	O
+with	O
+suspected	O
+Mendelian	O
+inheritance	O
+,	O
+1,139	O
+are	O
+recessive	O
+and	O
+have	O
+an	O
+established	O
+molecular	O
+basis	O
+.	O
+
+Although	O
+individually	O
+uncommon	O
+,	O
+Mendelian	O
+diseases	O
+collectively	O
+account	O
+for	O
+~20	O
+%	O
+of	O
+infant	O
+mortality	O
+and	O
+~18	O
+%	O
+of	O
+pediatric	O
+hospitalizations	O
+.	O
+
+Molecular	O
+diagnostic	O
+testing	O
+is	O
+currently	O
+available	O
+for	O
+only	O
+~300	O
+recessive	O
+disorders	O
+.	O
+
+Preconception	O
+screening	O
+,	O
+together	O
+with	O
+genetic	O
+counseling	O
+of	O
+carriers	O
+,	O
+has	O
+resulted	O
+in	O
+remarkable	O
+declines	O
+in	O
+the	O
+incidence	B-EPI
+of	O
+several	O
+severe	O
+recessive	O
+diseases	O
+including	O
+Tay	O
+-	O
+Sachs	O
+disease	O
+and	O
+cystic	O
+fibrosis	O
+.	O
+
+However	O
+,	O
+extension	O
+of	O
+preconception	O
+screening	O
+and	O
+molecular	O
+diagnostic	O
+testing	O
+to	O
+most	O
+recessive	O
+disease	O
+genes	O
+has	O
+hitherto	O
+been	O
+impractical	O
+.	O
+
+Recently	O
+,	O
+we	O
+reported	O
+a	O
+preconception	O
+carrier	O
+screen	O
+/	O
+molecular	O
+diagnostic	O
+test	O
+for	O
+448	O
+recessive	O
+childhood	O
+diseases	O
+.	O
+
+The	O
+current	O
+status	O
+of	O
+this	O
+test	O
+is	O
+reviewed	O
+here	O
+.	O
+
+Currently	O
+,	O
+this	O
+reports	O
+analytical	O
+validity	O
+of	O
+the	O
+comprehensive	O
+carrier	O
+test	O
+.	O
+
+As	O
+the	O
+clinical	O
+validity	O
+and	O
+clinical	O
+utility	O
+in	O
+the	O
+contexts	O
+described	O
+is	O
+ascertained	O
+,	O
+this	O
+article	O
+will	O
+be	O
+updated	O
+.	O
+
+Introduction	O
+:	O
+Intra	O
+-	O
+uterine	O
+adhesion	O
+(	O
+IUA	O
+)	O
+is	O
+one	O
+of	O
+the	O
+main	O
+causes	O
+of	O
+secondary	O
+infertility	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+of	O
+IUA	O
+developing	O
+in	O
+women	O
+undergoing	O
+hysteroscopic	O
+resection	O
+for	O
+submucous	O
+myomas	O
+,	O
+polyps	O
+,	O
+and	O
+intrauterine	O
+synechiae	O
+and	O
+test	O
+the	O
+efficacy	O
+of	O
+second	O
+look	O
+hysteroscopy	O
+for	O
+diagnosing	O
+and	O
+treating	O
+post	O
+-	O
+surgical	O
+adhesions	O
+.	O
+
+Materials	O
+and	O
+Methods	O
+:	O
+We	O
+retrospectively	O
+collected	O
+data	O
+from	O
+reproductive	O
+age	O
+women	O
+who	O
+had	O
+a	O
+second	O
+look	O
+office	O
+hysteroscopy	O
+following	O
+hysteroscopic	O
+resection	O
+for	O
+myoma	O
+,	O
+polyp	O
+,	O
+or	O
+IUA	O
+at	O
+Foch	O
+hospital	O
+(	O
+Suresnes	O
+,	O
+France	B-LOC
+)	O
+between	O
+2009	O
+and	O
+2017	O
+.	O
+
+Results	O
+:	O
+Six	O
+hundred	O
+and	O
+twenty	O
+two	O
+reproductive	O
+-	O
+age	O
+women	O
+underwent	O
+hysteroscopic	O
+resection	O
+for	O
+myoma	O
+,	O
+polyp	O
+,	O
+and/or	O
+IUA	O
+.	O
+
+Among	O
+them	O
+,	O
+155	O
+women	O
+had	O
+a	O
+second	O
+look	O
+hysteroscopy	O
+.	O
+
+In	O
+this	O
+group	O
+,	O
+29/155	B-STAT
+(	O
+18.7	O
+%	O
+)	O
+had	O
+IUA	O
+formation	O
+:	O
+17/83	B-STAT
+(	O
+20.5	O
+%	O
+)	O
+women	O
+who	O
+underwent	O
+hysteroscopic	O
+myomectomy	O
+,	O
+5/46	B-STAT
+(	O
+10.9	O
+%	O
+)	O
+women	O
+who	O
+underwent	O
+hysteroscopic	O
+polypectomy	O
+,	O
+and	O
+7/26	B-STAT
+(	O
+26.9	O
+%	O
+)	O
+women	O
+who	O
+underwent	O
+hysteroscopic	O
+lysis	O
+of	O
+adhesions	O
+.	O
+
+These	O
+IUA	O
+have	O
+been	O
+lysed	O
+by	O
+the	O
+office	O
+hysteroscopy	O
+procedure	O
+in	O
+16/29	B-STAT
+(	O
+55.2	O
+%	O
+)	O
+patients	O
+:	O
+11/17	B-STAT
+(	O
+64.7	O
+%	O
+)	O
+,	O
+2/5	B-STAT
+(	O
+40	O
+%	O
+)	O
+,	O
+and	O
+3/7	B-STAT
+(	O
+42.9	O
+%	O
+)	O
+in	O
+women	O
+who	O
+underwent	O
+hysteroscopic	O
+myomectomy	O
+,	O
+polypectomy	O
+and	O
+lysis	O
+of	O
+adhesion	O
+,	O
+respectively	O
+.	O
+
+Conclusion	O
+:	O
+IUA	O
+is	O
+a	O
+common	O
+complication	O
+of	O
+hysteroscopic	O
+surgery	O
+.	O
+
+Second	O
+look	O
+office	O
+hysteroscopy	O
+is	O
+an	O
+easy	O
+and	O
+effective	O
+procedure	O
+for	O
+diagnosing	O
+and	O
+removing	O
+newly	O
+formed	O
+IUA	O
+.	O
+
+It	O
+should	O
+be	O
+recommended	O
+for	O
+all	O
+women	O
+undergoing	O
+hysteroscopic	O
+resection	O
+for	O
+myomas	O
+,	O
+polyps	O
+,	O
+or	O
+IUA	O
+.	O
+
+Identifying	O
+which	O
+factors	O
+contribute	O
+to	O
+vitiligo	O
+severity	O
+and	O
+determining	O
+their	O
+individual	O
+weight	O
+are	O
+important	O
+in	O
+the	O
+management	O
+of	O
+vitiligo	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+is	O
+to	O
+investigate	O
+the	O
+predictive	O
+variables	O
+concerning	O
+vitiligo	O
+severity	O
+as	O
+perceived	O
+by	O
+the	O
+patients	O
+.	O
+
+Based	O
+on	O
+a	O
+questionnaire	O
+,	O
+several	O
+factors	O
+that	O
+may	O
+contribute	O
+to	O
+the	O
+Patient	O
+Global	O
+Assessment	O
+(	O
+PtGA	O
+)	O
+of	O
+severity	O
+were	O
+investigated	O
+within	O
+a	O
+Belgian	O
+vitiligo	O
+population	O
+(	O
+n	O
+=	O
+291	O
+)	O
+.	O
+
+In	O
+addition	O
+,	O
+possible	O
+factors	O
+influencing	O
+vitiligo	O
+severity	O
+were	O
+scored	O
+and	O
+ranked	O
+.	O
+
+The	O
+strongest	O
+correlations	O
+with	O
+the	O
+PtGA	O
+of	O
+severity	O
+were	O
+found	O
+for	O
+impact	O
+,	O
+Dermatology	O
+Life	O
+Quality	O
+Index	O
+and	O
+disease	O
+extent	O
+.	O
+
+Based	O
+on	O
+multivariable	O
+regression	O
+analyses	O
+,	O
+64.7	O
+%	O
+of	O
+PtGA	O
+of	O
+severity	O
+could	O
+be	O
+predicted	O
+by	O
+subjective	O
+and	O
+objective	O
+variables	O
+,	O
+while	O
+32	O
+%	O
+could	O
+be	O
+explained	O
+by	O
+objective	O
+clinical	O
+features	O
+only	O
+.	O
+
+Patients	O
+considered	O
+lesion	O
+location	O
+,	O
+extent	O
+and	O
+disease	O
+activity	O
+as	O
+the	O
+most	O
+important	O
+contributing	O
+factors	O
+to	O
+severity	O
+.	O
+
+Vitiligo	O
+severity	O
+is	O
+determined	O
+by	O
+objective	O
+clinical	O
+features	O
+,	O
+but	O
+also	O
+,	O
+for	O
+a	O
+significant	O
+part	O
+,	O
+by	O
+the	O
+perceived	O
+impact	O
+of	O
+the	O
+disease	O
+.	O
+
+Background	O
+Moebius	O
+syndrome	O
+is	O
+a	O
+disorder	O
+characterized	O
+by	O
+facial	O
+and	O
+abducens	O
+nerve	O
+paralysis	O
+.	O
+
+Patients	O
+can	O
+present	O
+a	O
+wide	O
+range	O
+of	O
+upper	O
+extremity	O
+malformations	O
+.	O
+
+Literature	O
+focused	O
+on	O
+orthopedic	O
+manifestations	O
+of	O
+Moebius	O
+syndrome	O
+shows	O
+variability	O
+in	O
+the	O
+prevalence	B-EPI
+and	O
+clinical	O
+presentation	O
+of	O
+upper	O
+extremity	O
+anomalies	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+work	O
+is	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+of	O
+upper	O
+extremity	O
+malformations	O
+in	O
+patients	O
+with	O
+Moebius	O
+syndrome	O
+,	O
+clarify	O
+its	O
+various	O
+clinical	O
+presentations	O
+,	O
+and	O
+present	O
+treatment	O
+strategies	O
+for	O
+their	O
+management	O
+.	O
+
+Methods	O
+This	O
+is	O
+a	O
+retrospective	O
+,	O
+cross	O
+-	O
+sectional	O
+study	O
+including	O
+patients	O
+with	O
+Moebius	O
+syndrome	O
+and	O
+upper	O
+extremity	O
+malformations	O
+between	O
+2012	O
+and	O
+2019	O
+.	O
+
+Data	O
+include	O
+demographic	O
+characteristics	O
+,	O
+Moebius	O
+syndrome	O
+subtype	O
+,	O
+type	O
+of	O
+malformation	O
+,	O
+affected	O
+extremity	O
+,	O
+and	O
+surgical	O
+procedures	O
+underwent	O
+.	O
+
+Quantitative	O
+data	O
+were	O
+recorded	O
+as	O
+mean	O
+(	O
+standard	O
+deviation	O
+[	O
+SD	O
+]	O
+)	O
+,	O
+and	O
+qualitative	O
+data	O
+were	O
+expressed	O
+in	O
+terms	O
+of	O
+totals	O
+and	O
+percentages	O
+.	O
+
+Statistical	O
+association	O
+between	O
+Moebius	O
+syndrome	O
+subtype	O
+and	O
+development	O
+of	O
+upper	O
+extremity	O
+anomalies	O
+was	O
+evaluated	O
+using	O
+binary	O
+logistic	O
+regression	O
+.	O
+
+Results	O
+Twenty	O
+-	O
+five	O
+out	O
+of	O
+153	O
+patients	O
+(	O
+16.3	O
+%	O
+)	O
+presented	O
+upper	O
+extremity	O
+malformations	O
+(	O
+48	O
+%	O
+male	O
+)	O
+.	O
+
+Mean	O
+age	O
+of	O
+presentation	O
+was	O
+9.08	O
+±	O
+9.43	O
+years	O
+.	O
+
+Sixty	B-STAT
+-	O
+eight	O
+percent	O
+of	O
+the	O
+malformations	O
+were	O
+unilateral	O
+.	O
+
+The	O
+most	O
+common	O
+presentations	O
+included	O
+Poland	B-LOC
+syndrome	O
+and	O
+simple	O
+syndactyly	O
+with	O
+8	O
+cases	O
+each	O
+(	O
+32	O
+%	O
+)	O
+,	O
+followed	O
+by	O
+5	O
+cases	O
+of	O
+brachysyndactyly	O
+(	O
+20	O
+%	O
+)	O
+,	O
+3	O
+cases	O
+of	O
+amniotic	O
+band	O
+syndrome	O
+(	O
+12	O
+%	O
+)	O
+,	O
+and	O
+1	O
+case	O
+of	O
+cleft	O
+hand	O
+(	O
+4	O
+%	O
+)	O
+.	O
+
+No	O
+statistical	O
+association	O
+was	O
+found	O
+between	O
+Moebius	O
+syndrome	O
+subtype	O
+and	O
+odds	O
+ratio	O
+for	O
+development	O
+of	O
+upper	O
+extremity	O
+anomalies	O
+.	O
+
+Thirteen	O
+patients	O
+(	O
+52	O
+%	O
+)	O
+underwent	O
+reconstructive	O
+procedures	O
+.	O
+
+Conclusion	O
+Poland	B-LOC
+syndrome	O
+and	O
+syndactyly	O
+are	O
+the	O
+most	O
+common	O
+anomalies	O
+in	O
+patients	O
+with	O
+Moebius	O
+syndrome	O
+.	O
+
+Patients	O
+may	O
+present	O
+with	O
+a	O
+wide	O
+range	O
+of	O
+hand	O
+malformations	O
+,	O
+each	O
+patient	O
+should	O
+be	O
+carefully	O
+evaluated	O
+in	O
+order	O
+to	O
+determine	O
+whether	O
+surgical	O
+treatment	O
+is	O
+needed	O
+and	O
+to	O
+optimize	O
+rehabilitation	O
+protocols	O
+.	O
+
+Neurodegeneration	O
+with	O
+brain	O
+iron	O
+accumulation	O
+(	O
+NBIA	O
+)	O
+is	O
+a	O
+group	O
+of	O
+rare	O
+neurogenetic	O
+degenerative	O
+diseases	O
+caused	O
+by	O
+genetic	O
+mutations	O
+and	O
+characterized	O
+by	O
+iron	O
+deposition	O
+in	O
+the	O
+central	O
+nervous	O
+system	O
+,	O
+especially	O
+in	O
+the	O
+basal	O
+ganglia	O
+,	O
+with	O
+an	O
+overall	B-EPI
+incidence	I-EPI
+rate	O
+of	O
+2/1	B-STAT
+000	O
+000	B-STAT
+-	I-STAT
+3/1	I-STAT
+000	I-STAT
+000	I-STAT
+.	O
+
+Major	O
+clinical	O
+manifestations	O
+are	O
+extrapyramidal	O
+symptoms	O
+.	O
+
+This	O
+disease	O
+is	O
+presently	O
+classified	O
+into	O
+14	O
+different	O
+subtypes	O
+based	O
+on	O
+different	O
+pathogenic	O
+genes	O
+,	O
+and	O
+its	O
+pathogenesis	O
+and	O
+treatment	O
+remain	O
+unclear	O
+.	O
+
+This	O
+article	O
+summarizes	O
+the	O
+research	O
+advances	O
+in	O
+the	O
+pathogenesis	O
+and	O
+treatment	O
+of	O
+NBIA	O
+,	O
+so	O
+as	O
+to	O
+help	O
+pediatricians	O
+understand	O
+this	O
+disease	O
+and	O
+provide	O
+a	O
+reference	O
+for	O
+subsequent	O
+research	O
+on	O
+treatment	O
+.	O
+
+Autoimmune	O
+thyroid	O
+disease	O
+(	O
+ATD	O
+)	O
+is	O
+the	O
+most	O
+frequent	O
+cause	O
+of	O
+acquired	O
+thyroid	O
+dysfunction	O
+,	O
+most	O
+commonly	O
+presenting	O
+either	O
+as	O
+Hashimoto	O
+'s	O
+thyroiditis	O
+or	O
+Graves	O
+'	O
+Disease	O
+.	O
+
+Hashimoto	O
+'s	O
+thyroiditis	O
+is	O
+characterized	O
+by	O
+the	O
+presence	O
+of	O
+thyroid	O
+-	O
+specific	O
+autoantibodies	O
+,	O
+more	O
+commonly	O
+anti	O
+-	O
+thyroperoxidase	O
+antibodies	O
+in	O
+the	O
+serum	O
+and	O
+the	O
+typical	O
+inhomogeneous	O
+echostructure	O
+of	O
+the	O
+thyroid	O
+on	O
+a	O
+thyroid	O
+ultrasound	O
+examination	O
+.	O
+
+Hashimoto	O
+'s	O
+thyroiditis	O
+can	O
+for	O
+a	O
+long	O
+time	O
+be	O
+accompanied	O
+by	O
+normal	O
+thyroid	O
+function	O
+and	O
+hypothyroidism	O
+can	O
+only	O
+progressively	O
+be	O
+established	O
+.	O
+
+Graves	O
+'	O
+disease	O
+is	O
+much	O
+less	O
+frequent	O
+in	O
+childhood	O
+and	O
+adolescence	O
+and	O
+presents	O
+with	O
+overt	O
+hyperthyroidism	O
+.	O
+
+After	O
+the	O
+onset	O
+of	O
+puberty	O
+,	O
+ATD	O
+affects	O
+females	O
+with	O
+a	O
+higher	O
+incidence	B-EPI
+than	O
+males	O
+,	O
+while	O
+during	O
+the	O
+prepubertal	O
+period	O
+there	O
+is	O
+not	O
+such	O
+a	O
+clear	O
+preponderance	O
+of	O
+affected	O
+females	O
+.	O
+
+ATD	O
+can	O
+occur	O
+either	O
+isolated	O
+or	O
+in	O
+the	O
+context	O
+of	O
+other	O
+autoimmune	O
+disorders	O
+,	O
+such	O
+as	O
+type	O
+1	O
+Diabetes	O
+mellitus	O
+(	O
+T1D	O
+)	O
+,	O
+celiac	O
+disease	O
+,	O
+alopecia	O
+areata	O
+,	O
+vitiligo	O
+,	O
+etc	O
+.	O
+
+Especially	O
+at	O
+the	O
+pediatric	O
+age	O
+,	O
+a	O
+higher	O
+incidence	B-EPI
+of	O
+ATD	O
+is	O
+also	O
+observed	O
+in	O
+the	O
+context	O
+of	O
+specific	O
+genetic	O
+syndromes	O
+,	O
+such	O
+as	O
+trisomy	O
+21	O
+(	O
+Down	O
+syndrome	O
+)	O
+,	O
+Klinefelter	O
+syndrome	O
+,	O
+Turner	O
+syndrome	O
+,	O
+or	O
+22q11.2	O
+deletion	O
+syndrome	O
+.	O
+
+Nevertheless	O
+,	O
+although	O
+thyroid	O
+dysfunction	O
+may	O
+also	O
+be	O
+observed	O
+in	O
+other	O
+genetic	O
+syndromes	O
+,	O
+such	O
+as	O
+Prader	O
+-	O
+Willi	O
+or	O
+Williams	O
+syndrome	O
+,	O
+the	O
+thyroid	O
+dysfunction	O
+in	O
+these	O
+syndromes	O
+is	O
+not	O
+the	O
+result	O
+of	O
+thyroid	O
+autoimmunity	O
+.	O
+
+Interestingly	O
+,	O
+there	O
+is	O
+emerging	O
+evidence	O
+supporting	O
+a	O
+possible	O
+link	O
+between	O
+autoimmunity	O
+and	O
+RASopathies	O
+.	O
+
+In	O
+this	O
+review	O
+article	O
+the	O
+incidence	B-EPI
+,	O
+as	O
+well	O
+as	O
+the	O
+clinical	O
+manifestation	O
+and	O
+accompanied	O
+pathologies	O
+of	O
+ATD	O
+in	O
+specific	O
+genetic	O
+syndromes	O
+will	O
+be	O
+presented	O
+and	O
+regular	O
+follow	O
+-	O
+up	O
+for	O
+the	O
+early	O
+identification	O
+of	O
+the	O
+disorder	O
+will	O
+be	O
+proposed	O
+.	O
+
+Objectives	O
+A	O
+low	O
+serum	O
+alkaline	O
+phosphatase	O
+(	O
+ALP	O
+)	O
+level	O
+is	O
+an	O
+uncommon	O
+finding	O
+in	O
+patients	O
+with	O
+chronic	O
+liver	O
+disease	O
+(	O
+CLD	O
+)	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+this	O
+finding	O
+and	O
+whether	O
+low	O
+ALP	O
+expression	O
+influences	O
+CLD	O
+remain	O
+to	O
+be	O
+determined	O
+.	O
+
+The	O
+objectives	O
+of	O
+this	O
+study	O
+were	O
+:	O
+(	O
+1	O
+)	O
+to	O
+document	O
+the	O
+prevalence	B-EPI
+of	O
+low	O
+serum	O
+ALP	O
+levels	O
+in	O
+adult	O
+CLD	O
+patients	O
+and	O
+(	O
+2	O
+)	O
+compare	O
+features	O
+of	O
+CLD	O
+in	O
+patients	O
+with	O
+low	O
+versus	O
+normal	O
+or	O
+elevated	O
+serum	O
+ALP	O
+levels	O
+.	O
+
+Methods	O
+An	O
+adult	O
+,	O
+outpatient	O
+liver	O
+disease	O
+database	O
+was	O
+searched	O
+for	O
+patients	O
+with	O
+low	O
+serum	O
+ALP	O
+levels	O
+(	O
+<	O
+40	O
+IU	O
+/	O
+L	O
+)	O
+.	O
+
+Hepatic	O
+inflammation	O
+,	O
+function	O
+,	O
+fibrosis	O
+and	O
+disease	O
+severity	O
+were	O
+determined	O
+by	O
+serum	O
+aminotransferases	O
+,	O
+albumin	O
+,	O
+bilirubin	O
+and	O
+INR	O
+levels	O
+,	O
+Fib-4	O
+calculations	O
+and	O
+MELD	O
+scores	O
+respectively	O
+.	O
+
+Results	O
+Of	O
+19,037	O
+patients	O
+entered	O
+into	O
+the	O
+database	O
+,	O
+47	B-STAT
+(	I-STAT
+0.25	I-STAT
+%	I-STAT
+)	O
+had	O
+consistently	O
+low	O
+serum	O
+ALP	O
+levels	O
+,	O
+51	B-STAT
+(	I-STAT
+0.27	I-STAT
+%	I-STAT
+)	O
+low	O
+levels	O
+on	O
+the	O
+majority	O
+and	O
+469	B-STAT
+(	O
+2.44	O
+%	O
+)	O
+on	O
+the	O
+minority	O
+of	O
+determinations	O
+.	O
+
+Patients	O
+with	O
+consistently	O
+low	O
+levels	O
+were	O
+matched	O
+(	O
+1:2	B-STAT
+)	O
+by	O
+age	O
+,	O
+gender	O
+and	O
+nature	O
+of	O
+the	O
+underlying	O
+liver	O
+disease	O
+to	O
+patients	O
+with	O
+normal	O
+or	O
+elevated	O
+serum	O
+ALP	O
+levels	O
+.	O
+
+Matched	O
+patients	O
+with	O
+consistently	O
+low	O
+ALP	O
+levels	O
+had	O
+significantly	O
+lower	O
+serum	O
+aminotransferase	O
+and	O
+bilirubin	O
+levels	O
+at	O
+their	O
+initial	O
+visit	O
+and	O
+throughout	O
+the	O
+follow	O
+-	O
+up	O
+period	O
+(	O
+p	O
+<	O
+0.05	O
+respectively	O
+)	O
+while	O
+Fib-4	O
+levels	O
+and	O
+MELD	O
+scores	O
+were	O
+similar	O
+at	O
+the	O
+initial	O
+and	O
+last	O
+follow	O
+-	O
+up	O
+visit	O
+.	O
+
+Conclusions	O
+These	O
+results	O
+establish	O
+the	O
+prevalence	B-EPI
+of	O
+low	O
+serum	O
+ALP	O
+levels	O
+in	O
+adult	O
+CLD	O
+patients	O
+and	O
+describe	O
+a	O
+hitherto	O
+unreported	O
+association	O
+between	O
+low	O
+serum	O
+ALP	O
+levels	O
+and	O
+less	O
+biochemical	O
+evidence	O
+of	O
+active	O
+disease	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+analyze	O
+the	O
+genetic	O
+variants	O
+of	O
+51	O
+Chinese	O
+patients	O
+with	O
+distal	O
+renal	O
+tubular	O
+acidosis	O
+(	O
+dRTA	O
+)	O
+and	O
+explore	O
+the	O
+correlation	O
+between	O
+their	O
+genotype	O
+and	O
+phenotype	O
+.	O
+
+Eight	O
+variants	O
+of	O
+SLC4A1	O
+,	O
+19	O
+variants	O
+of	O
+ATP6V0A4	O
+,	O
+and	O
+16	O
+variants	O
+of	O
+ATP6V1B1	O
+have	O
+been	O
+identified	O
+,	O
+and	O
+of	O
+which	O
+14	O
+were	O
+novel	O
+ones	O
+.	O
+
+Eleven	O
+patients	O
+with	O
+autosomal	O
+dominant	O
+dRTA	O
+,	O
+and	O
+four	O
+patients	O
+with	O
+autosomal	O
+recessive	O
+dRTA	O
+were	O
+caused	O
+by	O
+genetic	O
+defects	O
+in	O
+SLC4A1	O
+;	O
+18	O
+and	O
+nine	O
+patients	O
+with	O
+recessive	O
+dRTA	O
+were	O
+resulted	O
+by	O
+defects	O
+in	O
+ATP6V0A4	O
+and	O
+ATP6V1B1	O
+respectively	O
+;	O
+no	O
+causal	O
+gene	O
+was	O
+identified	O
+in	O
+seven	O
+patients	O
+.	O
+
+Mutation	O
+frequency	O
+of	O
+SLC4A1	O
+in	O
+Chinese	O
+populations	O
+was	O
+more	O
+common	O
+than	O
+Europeans	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+deafness	O
+in	O
+ATP6V0A4	O
+and	O
+ATP6V1B1	O
+groups	O
+was	O
+16.7	O
+%	O
+and	O
+54.5	O
+%	O
+,	O
+respectively	O
+.	O
+
+The	O
+frequency	O
+of	O
+CKD	O
+in	O
+adults	O
+,	O
+children	O
+and	O
+infants	O
+was	O
+100	O
+%	O
+,	O
+51	O
+%	O
+,	O
+and	O
+3	O
+%	O
+,	O
+separately	O
+.	O
+
+Our	O
+study	O
+will	O
+further	O
+expand	O
+the	O
+mutation	O
+spectrum	O
+of	O
+primary	O
+dRTA	O
+and	O
+provide	O
+valuable	O
+references	O
+to	O
+genetic	O
+counseling	O
+of	O
+Chinese	O
+populations	O
+.	O
+
+Introduction	O
+Cerebellar	O
+degeneration	O
+has	O
+been	O
+associated	O
+in	O
+patients	O
+with	O
+epilepsy	O
+,	O
+though	O
+the	O
+exact	O
+pathogenic	O
+mechanisms	O
+are	O
+not	O
+understood	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+systematic	O
+review	O
+was	O
+to	O
+identify	O
+the	O
+prevalence	B-EPI
+of	O
+cerebellar	O
+degeneration	O
+in	O
+patients	O
+with	O
+epilepsy	O
+and	O
+identify	O
+any	O
+pathogenic	O
+mechanisms	O
+.	O
+
+Methodology	O
+A	O
+systematic	O
+computer	O
+-	O
+based	O
+literature	O
+search	O
+was	O
+conducted	O
+using	O
+the	O
+PubMed	O
+database	O
+.	O
+
+Data	O
+extracted	O
+included	O
+prevalence	B-EPI
+,	O
+clinical	O
+,	O
+neuroradiological	O
+,	O
+and	O
+neuropathological	O
+characteristics	O
+of	O
+patients	O
+with	O
+epilepsy	O
+and	O
+cerebellar	O
+degeneration	O
+.	O
+
+Results	O
+We	O
+identified	O
+three	O
+consistent	O
+predictors	O
+of	O
+cerebellar	O
+degeneration	O
+in	O
+the	O
+context	O
+of	O
+epilepsy	O
+in	O
+our	O
+review	O
+:	O
+temporal	O
+lobe	O
+epilepsy	O
+,	O
+poor	O
+seizure	O
+control	O
+,	O
+and	O
+phenytoin	O
+as	O
+the	O
+treatment	O
+modality	O
+.	O
+
+Whole	O
+brain	O
+and	O
+hippocampal	O
+atrophy	O
+were	O
+also	O
+identified	O
+in	O
+patients	O
+with	O
+epilepsy	O
+.	O
+
+Conclusions	O
+Cerebellar	O
+degeneration	O
+is	O
+prevalent	B-EPI
+in	O
+patients	O
+with	O
+epilepsy	O
+.	O
+
+Further	O
+prospective	O
+studies	O
+are	O
+required	O
+to	O
+confirm	O
+if	O
+the	O
+predictors	O
+identified	O
+in	O
+this	O
+review	O
+are	O
+indeed	O
+linked	O
+to	O
+cerebellar	O
+degeneration	O
+and	O
+to	O
+establish	O
+the	O
+pathogenic	O
+mechanisms	O
+that	O
+result	O
+in	O
+cerebellar	O
+insult	O
+.	O
+
+Purpose	O
+Our	O
+goal	O
+was	O
+to	O
+assess	O
+the	O
+prevalence	B-EPI
+of	O
+ipsilateral	O
+distal	O
+femoral	O
+osteochondritis	O
+dissecans	O
+(	O
+OCD)-like	O
+lesions	O
+in	O
+children	O
+with	O
+Blount	O
+disease	O
+,	O
+including	O
+factors	O
+associated	O
+with	O
+this	O
+finding	O
+.	O
+
+Materials	O
+and	O
+methods	O
+Characteristics	O
+of	O
+patients	O
+with	O
+an	O
+OCD	O
+-	O
+like	O
+lesion	O
+on	O
+an	O
+imaging	O
+study	O
+[	O
+(	O
+X	O
+-	O
+ray	O
+and/or	O
+magnetic	O
+resonance	O
+imaging	O
+(	O
+MRI	O
+)	O
+]	O
+were	O
+compared	O
+with	O
+those	O
+without	O
+such	O
+a	O
+finding	O
+.	O
+
+Results	O
+Over	O
+a	O
+12	O
+-	O
+year	O
+period	O
+,	O
+6/63	B-STAT
+(	O
+10	O
+%	O
+)	O
+skeletally	O
+immature	O
+patients	O
+(	O
+9/87	B-STAT
+limbs	O
+)	O
+with	O
+Blount	O
+disease	O
+had	O
+an	O
+OCD	O
+-	O
+like	O
+lesion	O
+visible	O
+on	O
+plain	O
+radiographs	O
+.	O
+
+Based	O
+on	O
+available	O
+MRI	O
+,	O
+7/37	B-STAT
+(	O
+19	O
+%	O
+)	O
+patients	O
+or	O
+10/53	B-STAT
+(	O
+19	O
+%	O
+)	O
+limbs	O
+had	O
+an	O
+OCD	O
+-	O
+like	O
+distal	O
+femoral	O
+lesion	O
+.	O
+
+All	O
+lesions	O
+were	O
+noted	O
+in	O
+the	O
+posterior	O
+third	O
+of	O
+the	O
+weight	O
+-	O
+bearing	O
+portion	O
+of	O
+the	O
+medial	O
+femoral	O
+condyle	O
+with	O
+intact	O
+overlying	O
+articular	O
+cartilage	O
+.	O
+
+All	O
+patients	O
+with	O
+OCD	O
+-	O
+like	O
+lesions	O
+were	O
+followed	O
+for	O
+an	O
+average	O
+of	O
+1.9	O
+years	O
+(	O
+range	O
+:	O
+1	O
+-	O
+2.6	O
+years	O
+)	O
+,	O
+and	O
+complete	O
+radiographic	O
+resolution	O
+of	O
+lesion	O
+was	O
+noted	O
+in	O
+7/9	B-STAT
+limbs	O
+(	O
+78	O
+%	O
+)	O
+.	O
+
+There	O
+was	O
+no	O
+association	O
+of	O
+the	O
+presence	O
+of	O
+OCD	O
+-	O
+like	O
+lesion	O
+with	O
+early-	O
+vs	O
+late	O
+-	O
+onset	O
+disease	O
+,	O
+gender	O
+,	O
+age	O
+at	O
+imaging	O
+,	O
+laterality	O
+,	O
+magnitude	O
+of	O
+deformity	O
+[	O
+mean	O
+mechanical	O
+axis	O
+deviation	O
+(	O
+MAD	O
+)	O
+63.3	O
+vs	O
+71.9	O
+mm	O
+]	O
+,	O
+mean	O
+mechanical	O
+lateral	O
+distal	O
+femoral	O
+angle	O
+(	O
+mLDFA	O
+;	O
+91.3	O
+vs	O
+89.7	O
+°	O
+)	O
+,	O
+and	O
+mean	O
+medial	O
+proximal	O
+tibial	O
+angle	O
+(	O
+MPTA	O
+;	O
+71.7	O
+vs	O
+71.8	O
+°	O
+)	O
+.	O
+
+Children	O
+with	O
+an	O
+OCD	O
+-	O
+like	O
+lesion	O
+tended	O
+to	O
+have	O
+a	O
+lower	O
+mean	O
+body	O
+mass	O
+index	O
+(	O
+BMI	O
+;	O
+21	O
+vs	O
+36	O
+,	O
+p	O
+=	O
+0.003	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+overall	B-EPI
+prevalence	I-EPI
+of	O
+OCD	O
+-	O
+like	O
+lesions	O
+in	O
+the	O
+medial	O
+femoral	O
+condyle	O
+in	O
+children	O
+with	O
+Blount	O
+disease	O
+lesions	O
+is	O
+10	O
+%	O
+using	O
+plain	O
+radiographs	O
+and	O
+at	O
+least	B-STAT
+19	O
+%	O
+on	O
+MRI	O
+.	O
+
+Based	O
+on	O
+the	O
+numbers	O
+available	O
+,	O
+we	O
+were	O
+unable	O
+to	O
+demonstrate	O
+any	O
+associations	O
+between	O
+the	O
+presence	O
+of	O
+such	O
+lesions	O
+and	O
+the	O
+patient	O
+'s	O
+age	O
+,	O
+gender	O
+,	O
+or	O
+magnitude	O
+of	O
+varus	O
+deformity	O
+.	O
+
+Further	O
+research	O
+is	O
+needed	O
+to	O
+fully	O
+ascertain	O
+the	O
+aetiology	O
+and	O
+natural	O
+history	O
+of	O
+these	O
+benign	O
+appearing	O
+osteochondral	O
+imaging	O
+findings	O
+in	O
+children	O
+with	O
+Blount	O
+disease	O
+.	O
+
+Our	O
+current	O
+data	O
+support	O
+that	O
+these	O
+lesions	O
+do	O
+resolve	O
+with	O
+time	O
+and	O
+that	O
+no	O
+surgical	O
+intervention	O
+targeted	O
+at	O
+the	O
+femoral	O
+OCD	O
+-	O
+like	O
+lesion	O
+is	O
+warranted	O
+.	O
+
+Level	O
+of	O
+evidence	O
+Diagnostic	O
+study	O
+Level	O
+III	O
+.	O
+
+How	O
+to	O
+cite	O
+this	O
+article	O
+Edobor	O
+-	O
+Osula	O
+F	O
+,	O
+Wenokor	O
+C	O
+,	O
+Bloom	O
+T	O
+,	O
+et	O
+al	O
+.	O
+
+Ipsilateral	O
+Osteochondritis	O
+Dissecans	O
+-	O
+like	O
+Distal	O
+Femoral	O
+Lesions	O
+in	O
+Children	O
+with	O
+Blount	O
+Disease	O
+:	O
+Prevalence	B-EPI
+and	O
+Associated	O
+Findings	O
+.	O
+
+Strategies	O
+Trauma	O
+Limb	O
+Reconstr	O
+2019;14(3):121	O
+-	O
+125	O
+.	O
+
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+(	O
+CMT	O
+)	O
+disease	O
+is	O
+the	O
+most	O
+common	O
+inherited	O
+neuropathy	O
+and	O
+one	O
+of	O
+the	O
+most	O
+common	O
+inherited	O
+diseases	O
+in	O
+humans	O
+.	O
+
+The	O
+diagnosis	O
+of	O
+CMT	O
+is	O
+traditionally	O
+made	O
+by	O
+the	O
+neurologic	O
+specialist	O
+,	O
+yet	O
+the	O
+optimal	O
+management	O
+of	O
+CMT	O
+patients	O
+includes	O
+genetic	O
+counselors	O
+,	O
+physical	O
+and	O
+occupational	O
+therapists	O
+,	O
+physiatrists	O
+,	O
+orthotists	O
+,	O
+mental	O
+health	O
+providers	O
+,	O
+and	O
+community	O
+resources	O
+.	O
+
+Rapidly	O
+developing	O
+genetic	O
+discoveries	O
+and	O
+novel	O
+gene	O
+discovery	O
+techniques	O
+continue	O
+to	O
+add	O
+a	O
+growing	O
+number	O
+of	O
+genetic	O
+subtypes	O
+of	O
+CMT	O
+.	O
+
+The	O
+first	O
+large	O
+clinical	O
+natural	O
+history	O
+and	O
+therapeutic	O
+trials	O
+have	O
+added	O
+to	O
+our	O
+knowledge	O
+of	O
+each	O
+CMT	O
+subtype	O
+and	O
+revealed	O
+how	O
+CMT	O
+impacts	O
+patient	O
+quality	O
+of	O
+life	O
+.	O
+
+In	O
+this	O
+review	O
+,	O
+we	O
+discuss	O
+several	O
+important	O
+trends	O
+in	O
+CMT	O
+research	O
+factors	O
+that	O
+will	O
+require	O
+a	O
+collaborative	O
+multidisciplinary	O
+approach	O
+.	O
+
+These	O
+include	O
+the	O
+development	O
+of	O
+large	O
+multicenter	O
+patient	O
+registries	O
+,	O
+standardized	O
+clinical	O
+instruments	O
+to	O
+assess	O
+disease	O
+progression	O
+and	O
+disability	O
+,	O
+and	O
+increasing	O
+recognition	O
+and	O
+use	O
+of	O
+patient	O
+-	O
+reported	O
+outcome	O
+measures	O
+.	O
+
+These	O
+developments	O
+will	O
+continue	O
+to	O
+guide	O
+strategies	O
+in	O
+long	O
+-	O
+term	O
+multidisciplinary	O
+efforts	O
+to	O
+maintain	O
+quality	O
+of	O
+life	O
+and	O
+preserve	O
+functionality	O
+in	O
+CMT	O
+patients	O
+.	O
+
+The	O
+human	O
+T	O
+cell	O
+lymphotropic	O
+virus	O
+type	O
+1	O
+(	O
+HTLV-1	O
+)	O
+is	O
+the	O
+first	O
+human	O
+retrovirus	O
+discovered	O
+.	O
+
+Since	O
+then	O
+,	O
+it	O
+has	O
+spread	O
+worldwide	B-LOC
+and	O
+is	O
+mainly	O
+associated	O
+with	O
+adult	O
+T	O
+cell	O
+leukemia	O
+/	O
+lymphoma	O
+(	O
+ATLL	O
+)	O
+and	O
+HTLV1	O
+-	O
+associated	O
+myelopathy	O
+(	O
+HAM	O
+)	O
+.	O
+
+Its	O
+relationship	O
+,	O
+however	O
+,	O
+with	O
+other	O
+types	O
+of	O
+cancer	O
+is	O
+controversial	O
+.	O
+
+We	O
+describe	O
+the	O
+case	O
+of	O
+a	O
+patient	O
+presenting	O
+with	O
+small	O
+cells	O
+lung	O
+epidermoid	O
+carcinoma	O
+who	O
+had	O
+recently	O
+developed	O
+HAM	O
+,	O
+and	O
+a	O
+review	O
+of	O
+the	O
+literature	O
+related	O
+to	O
+these	O
+conditions	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+case	O
+of	O
+this	O
+type	O
+of	O
+lung	O
+cancer	O
+,	O
+the	O
+same	O
+of	O
+the	O
+first	O
+description	O
+in	O
+the	O
+literature	O
+,	O
+associated	O
+with	O
+HAM	O
+outside	O
+Japan	B-LOC
+.	O
+
+BACKGROUND	O
+Vascular	O
+type	O
+of	O
+Ehlers	O
+-	O
+Danlos	O
+syndrome	O
+(	O
+vEDS	O
+)	O
+is	O
+a	O
+rare	O
+connective	O
+tissue	O
+disorder	O
+associated	O
+with	O
+a	O
+high	O
+prevalence	B-EPI
+rate	O
+of	O
+aortic	O
+dissection	O
+(	O
+AD	O
+)	O
+.	O
+
+The	O
+coexistence	O
+of	O
+a	O
+pregnancy	O
+raises	O
+these	O
+rates	O
+and	O
+the	O
+diagnostic	O
+complexity	O
+of	O
+the	O
+situation	O
+.	O
+
+In	O
+this	O
+article	O
+,	O
+we	O
+present	O
+a	O
+different	O
+initial	O
+diagnostic	O
+approach	O
+to	O
+an	O
+acute	O
+aortic	O
+syndrome	O
+.	O
+
+CASE	O
+REPORT	O
+A	O
+young	O
+pregnant	O
+woman	O
+(	O
+29th	O
+week	O
+gestation	O
+)	O
+with	O
+vEDS	O
+was	O
+admitted	O
+to	O
+our	O
+clinic	O
+due	O
+to	O
+sudden	O
+tearing	O
+back	O
+pain	O
+radiating	O
+to	O
+the	O
+left	O
+arm	O
+.	O
+
+Four	O
+years	O
+ago	O
+,	O
+the	O
+same	O
+patient	O
+underwent	O
+a	O
+surgical	O
+aortic	O
+valve	O
+reconstruction	O
+and	O
+replace	O
+of	O
+the	O
+ascending	O
+and	O
+proximal	O
+arch	O
+of	O
+the	O
+aorta	O
+because	O
+of	O
+an	O
+acute	O
+Standford	O
+A	O
+AD	O
+.	O
+
+The	O
+clinical	O
+,	O
+laboratory	O
+as	O
+well	O
+as	O
+transthoracic	O
+echocardiographic	O
+findings	O
+did	O
+not	O
+reveal	O
+any	O
+objective	O
+signs	O
+of	O
+an	O
+acute	O
+aortic	O
+syndrome	O
+.	O
+
+Due	O
+to	O
+the	O
+relative	O
+contraindications	O
+against	O
+computed	O
+tomography	O
+imaging	O
+due	O
+to	O
+pregnancy	O
+,	O
+we	O
+conducted	O
+a	O
+transesophageal	O
+echocardiography	O
+which	O
+revealed	O
+acute	O
+progress	O
+of	O
+pre	O
+-	O
+existing	O
+AD	O
+.	O
+
+A	O
+follow	O
+-	O
+up	O
+computed	O
+tomography	O
+could	O
+verify	O
+our	O
+findings	O
+,	O
+showing	O
+a	O
+Standford	O
+B	O
+dissection	O
+,	O
+which	O
+was	O
+treated	O
+conservatively	O
+.	O
+
+After	O
+2	O
+weeks	O
+,	O
+due	O
+to	O
+a	O
+distal	O
+progression	O
+of	O
+dissection	O
+,	O
+our	O
+patient	O
+underwent	O
+a	O
+cesarean	O
+section	O
+.	O
+
+In	O
+absence	O
+of	O
+new	O
+clinical	O
+findings	O
+,	O
+the	O
+young	O
+patient	O
+was	O
+discharged	O
+the	O
+following	O
+week	O
+.	O
+
+CONCLUSIONS	O
+Patients	O
+with	O
+vEDS	O
+are	O
+at	O
+high	O
+risk	O
+of	O
+an	O
+AD	O
+and	O
+other	O
+life	O
+-	O
+threatening	O
+complications	O
+,	O
+especially	O
+during	O
+pregnancy	O
+.	O
+
+According	O
+to	O
+the	O
+guidelines	O
+of	O
+European	O
+Society	O
+of	O
+Cardiology	O
+(	O
+ESC	O
+)	O
+,	O
+vEDS	O
+-	O
+patients	O
+should	O
+be	O
+thoroughly	O
+screened	O
+.	O
+
+In	O
+the	O
+case	O
+of	O
+pregnancy	O
+,	O
+physicians	O
+should	O
+consider	O
+frequent	O
+follow	O
+-	O
+up	O
+examinations	O
+and	O
+be	O
+prepared	O
+for	O
+diagnosis	O
+and	O
+treatment	O
+of	O
+the	O
+potential	O
+complications	O
+.	O
+
+Objective	O
+The	O
+Global	O
+FKRP	O
+Registry	O
+is	O
+a	O
+database	O
+for	O
+individuals	O
+with	O
+conditions	O
+caused	O
+by	O
+mutations	O
+in	O
+the	O
+Fukutin	O
+-	O
+Related	O
+Protein	O
+(	O
+FKRP	O
+)	O
+gene	O
+:	O
+limb	O
+girdle	O
+muscular	O
+dystrophy	O
+R9	O
+(	O
+LGMDR9	O
+,	O
+formerly	O
+LGMD2I	O
+)	O
+and	O
+congenital	O
+muscular	O
+dystrophies	O
+MDC1C	O
+,	O
+Muscle	O
+-	O
+Eye	O
+-	O
+Brain	O
+Disease	O
+and	O
+Walker	O
+-	O
+Warburg	O
+Syndrome	O
+.	O
+
+The	O
+registry	O
+seeks	O
+to	O
+further	O
+understand	O
+the	O
+natural	O
+history	O
+and	O
+prevalence	B-EPI
+of	O
+FKRP	O
+-	O
+related	O
+conditions	O
+;	O
+aid	O
+the	O
+rapid	O
+identification	O
+of	O
+eligible	O
+patients	O
+for	O
+clinical	O
+studies	O
+;	O
+and	O
+provide	O
+a	O
+source	O
+of	O
+information	O
+to	O
+clinical	O
+and	O
+academic	O
+communities	O
+.	O
+
+Methods	O
+Registration	O
+is	O
+patient	O
+-	O
+initiated	O
+through	O
+a	O
+secure	O
+online	O
+portal	O
+.	O
+
+Data	O
+,	O
+reported	O
+by	O
+both	O
+patients	O
+and	O
+their	O
+clinicians	O
+,	O
+include	O
+:	O
+age	O
+of	O
+onset	O
+,	O
+presenting	O
+symptoms	O
+,	O
+family	O
+history	O
+,	O
+motor	O
+function	O
+and	O
+muscle	O
+strength	O
+,	O
+respiratory	O
+and	O
+cardiac	O
+function	O
+,	O
+medication	O
+,	O
+quality	O
+of	O
+life	O
+and	O
+pain	O
+.	O
+
+Results	O
+Of	O
+663	O
+registered	O
+participants	O
+,	O
+305	O
+were	O
+genetically	O
+confirmed	O
+LGMDR9	O
+patients	O
+from	O
+23	O
+countries	O
+.	O
+
+A	O
+majority	O
+of	O
+LGMDR9	O
+patients	O
+carried	O
+the	O
+common	O
+mutation	O
+c.826C	O
+>	O
+A	O
+on	O
+one	O
+or	O
+both	O
+alleles	O
+;	O
+67.9	O
+%	O
+were	O
+homozygous	O
+and	O
+28.5	O
+%	O
+were	O
+compound	O
+heterozygous	O
+for	O
+this	O
+mutation	O
+.	O
+
+The	O
+mean	O
+ages	O
+of	O
+symptom	O
+onset	O
+and	O
+disease	O
+diagnosis	O
+were	O
+higher	O
+in	O
+individuals	O
+homozygous	O
+for	O
+c.826C	O
+>	O
+A	O
+compared	O
+with	O
+individuals	O
+heterozygous	O
+for	O
+c.826C	O
+>	O
+A.	O
+
+This	O
+divergence	O
+was	O
+replicated	O
+in	O
+ages	O
+of	O
+loss	O
+of	O
+running	O
+ability	O
+,	O
+wheelchair	O
+-	O
+dependence	O
+and	O
+ventilation	O
+assistance	O
+;	O
+consistent	O
+with	O
+the	O
+milder	O
+phenotype	O
+associated	O
+with	O
+individuals	O
+homozygous	O
+for	O
+c.826C	O
+>	O
+A.	O
+
+In	O
+LGMDR9	O
+patients	O
+,	O
+75.1	O
+%	O
+were	O
+currently	O
+ambulant	O
+and	O
+24.6	O
+%	O
+,	O
+nonambulant	O
+(	O
+unreported	O
+in	O
+0.3	B-STAT
+%	I-STAT
+)	O
+.	O
+
+Cardiac	O
+impairment	O
+was	O
+reported	O
+in	O
+23.2	O
+%	O
+(	O
+30/129	O
+)	O
+.	O
+
+Interpretation	O
+The	O
+Global	O
+FKRP	O
+Registry	O
+enables	O
+the	O
+collection	O
+of	O
+patient	O
+natural	O
+history	O
+data	O
+,	O
+which	O
+informs	O
+academics	O
+,	O
+healthcare	O
+professionals	O
+and	O
+industry	O
+.	O
+
+It	O
+represents	O
+a	O
+trial	O
+-	O
+ready	O
+cohort	O
+of	O
+individuals	O
+and	O
+is	O
+centrally	O
+placed	O
+to	O
+facilitate	O
+recruitment	O
+to	O
+clinical	O
+studies	O
+.	O
+
+Background	O
+:	O
+It	O
+has	O
+been	O
+estimated	O
+that	O
+27.8	O
+million	O
+neonates	O
+will	O
+die	O
+worldwide	B-LOC
+between	O
+2018	O
+and	O
+2030	O
+if	O
+no	O
+improvements	O
+in	O
+neonatal	O
+and	O
+maternal	O
+care	O
+take	O
+place	O
+.	O
+
+The	O
+aim	O
+of	O
+this	O
+study	O
+was	O
+to	O
+determine	O
+the	O
+rate	O
+,	O
+risk	O
+factors	O
+,	O
+and	O
+causes	O
+of	O
+neonatal	O
+mortality	O
+in	O
+Jordan	B-LOC
+.	O
+
+Methods	O
+:	O
+In	O
+August	O
+2019	O
+,	O
+an	O
+electronic	O
+stillbirths	O
+and	O
+neonatal	O
+deaths	O
+surveillance	O
+system	O
+(	O
+JSANDS	O
+)	O
+was	O
+established	O
+in	O
+in	O
+three	O
+large	O
+cities	O
+through	O
+five	O
+hospitals	O
+.	O
+
+Data	O
+on	O
+all	O
+births	O
+,	O
+neonatal	O
+mortality	O
+and	O
+their	O
+causes	O
+,	O
+and	O
+other	O
+characteristics	O
+in	O
+the	O
+period	O
+between	O
+August	O
+2019	O
+and	O
+January	O
+2020	O
+were	O
+exported	O
+from	O
+the	O
+JSANDS	O
+and	O
+analyzed	O
+.	O
+
+Results	O
+:	O
+A	O
+total	O
+of	O
+10,328	O
+births	O
+[	O
+10,226	O
+live	O
+births	O
+(	O
+LB	O
+)	O
+and	O
+102	O
+stillbirths	O
+]	O
+were	O
+registered	O
+in	O
+the	O
+study	O
+period	O
+,	O
+with	O
+a	O
+rate	O
+of	O
+14.1	B-STAT
+deaths	I-STAT
+per	I-STAT
+1,000	I-STAT
+LBs	I-STAT
+;	O
+76	O
+%	O
+were	O
+early	O
+neonatal	O
+deaths	O
+and	O
+24	O
+%	O
+were	O
+late	O
+deaths	O
+.	O
+
+The	O
+odds	O
+of	O
+deaths	O
+in	O
+the	O
+Ministry	O
+of	O
+Health	O
+hospitals	O
+were	O
+almost	O
+21	O
+times	O
+(	O
+OR	O
+=	O
+20.8	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+2.8	O
+,	O
+153.1	O
+)	O
+higher	O
+than	O
+that	O
+in	O
+private	O
+hospitals	O
+.	O
+
+Low	O
+birthweight	O
+and	O
+pre	O
+-	O
+term	O
+babies	O
+were	O
+significantly	O
+more	O
+likely	O
+to	O
+die	O
+during	O
+the	O
+neonatal	O
+period	O
+compared	O
+to	O
+full	O
+-	O
+term	O
+babies	O
+.	O
+
+The	O
+odds	O
+of	O
+neonatal	O
+mortality	O
+were	O
+significantly	O
+higher	O
+among	O
+babies	O
+born	O
+to	O
+housewives	O
+compared	O
+to	O
+those	O
+who	O
+were	O
+born	O
+to	O
+employed	O
+women	O
+(	O
+OR	O
+=	O
+2.7	O
+;	O
+95	O
+%	O
+CI	O
+:	O
+1.2	O
+,	O
+6.0	O
+)	O
+.	O
+
+Main	O
+causes	O
+of	O
+neonatal	O
+deaths	O
+that	O
+occurred	O
+pre	O
+-	O
+discharge	O
+were	O
+respiratory	O
+and	O
+cardiovascular	O
+disorders	O
+(	O
+43	O
+%	O
+)	O
+and	O
+low	O
+birthweight	O
+and	O
+pre	O
+-	O
+term	O
+(	O
+33	O
+%	O
+)	O
+.	O
+
+The	O
+main	O
+maternal	O
+conditions	O
+that	O
+attributed	O
+to	O
+these	O
+deaths	O
+were	O
+complications	O
+of	O
+the	O
+placenta	O
+and	O
+cord	O
+,	O
+complications	O
+of	O
+pregnancy	O
+,	O
+and	O
+medical	O
+and	O
+surgical	O
+conditions	O
+.	O
+
+The	O
+main	O
+cause	O
+of	O
+neonatal	O
+deaths	O
+that	O
+occurred	O
+post	O
+-	O
+discharge	O
+were	O
+low	O
+birthweight	O
+and	O
+pre	O
+-	O
+term	O
+(	O
+42	O
+%	O
+)	O
+.	O
+
+Conclusions	O
+:	O
+The	O
+rate	O
+of	O
+neonatal	O
+mortality	O
+have	O
+not	O
+decreased	O
+since	O
+2012	O
+and	O
+the	O
+majority	O
+of	O
+neonatal	O
+deaths	O
+occurred	O
+could	O
+have	O
+been	O
+prevented	O
+.	O
+
+Regular	O
+antenatal	O
+visits	O
+,	O
+in	O
+which	O
+any	O
+possible	O
+diseases	O
+or	O
+complications	O
+of	O
+pregnant	O
+women	O
+or	O
+fetal	O
+anomalies	O
+,	O
+need	O
+to	O
+be	O
+fully	O
+documented	O
+and	O
+monitored	O
+with	O
+appropriate	O
+and	O
+timely	O
+medical	O
+intervention	O
+to	O
+minimize	O
+such	O
+deaths	O
+.	O
+
+Ophiogomphus	O
+howei	O
+Bromley	B-LOC
+is	O
+a	O
+rare	O
+North	O
+American	O
+dragonfly	O
+,	O
+given	O
+a	O
+global	O
+conservation	O
+rank	O
+of	O
+Vulnerable	O
+by	O
+NatureServe	O
+.	O
+
+This	O
+species	O
+inhabits	O
+localized	O
+stretches	O
+of	O
+a	O
+limited	O
+number	O
+of	O
+typically	O
+undisturbed	O
+,	O
+high	O
+-	O
+quality	O
+,	O
+forested	O
+rivers	O
+in	O
+two	O
+disjunct	O
+regions	O
+in	O
+North	B-LOC
+America	I-LOC
+.	O
+
+We	O
+describe	O
+a	O
+new	O
+population	O
+in	O
+between	O
+the	O
+known	O
+ranges	O
+from	O
+an	O
+impaired	O
+river	O
+in	O
+a	O
+largely	O
+urban	O
+watershed	O
+in	O
+southern	O
+Michigan	B-LOC
+,	O
+United	B-LOC
+States	I-LOC
+.	O
+
+We	O
+also	O
+report	O
+a	O
+previously	O
+overlooked	O
+specimen	O
+from	O
+a	O
+new	O
+location	O
+in	O
+Pennsylvania	B-LOC
+,	O
+United	B-LOC
+States	I-LOC
+,	O
+and	O
+provide	O
+current	O
+occurrence	B-EPI
+and	O
+conservation	O
+status	O
+of	O
+the	O
+species	O
+in	O
+North	B-LOC
+America	I-LOC
+.	O
+
+Background	O
+Charcot	O
+-	O
+Marie	O
+-	O
+Tooth	O
+disease	O
+Type	O
+2A	O
+(	O
+CMT2A	O
+)	O
+presents	O
+with	O
+optic	O
+atrophy	O
+in	O
+a	O
+subset	O
+of	O
+patients	O
+,	O
+but	O
+the	O
+prevalence	B-EPI
+and	O
+severity	O
+of	O
+optic	O
+nerve	O
+involvement	O
+in	O
+relation	O
+to	O
+other	O
+CMT	O
+subtypes	O
+has	O
+not	O
+been	O
+explored	O
+.	O
+
+Methods	O
+Patients	O
+with	O
+genetically	O
+confirmed	O
+CMT2A	O
+(	O
+n	O
+=	O
+5	O
+)	O
+,	O
+CMT1A	O
+(	O
+n	O
+=	O
+9	O
+)	O
+and	O
+CMTX1	O
+(	O
+n	O
+=	O
+10	O
+)	O
+underwent	O
+high-	B-LOC
+and	O
+low	O
+-	O
+contrast	O
+acuity	O
+testing	O
+using	O
+Sloan	O
+letter	O
+charts	O
+,	O
+and	O
+circumpapillary	O
+retinal	O
+nerve	O
+fiber	O
+layer	O
+(	O
+RNFL	O
+)	O
+and	O
+macular	O
+total	O
+retinal	O
+,	O
+RNFL	O
+,	O
+and	O
+ganglion	O
+cell	O
+layer	O
+/	O
+inner	O
+plexiform	O
+layer	O
+thickness	O
+was	O
+measured	O
+using	O
+spectral	O
+domain	O
+optical	O
+coherence	O
+tomography	O
+(	O
+OCT	O
+)	O
+.	O
+
+We	O
+used	O
+age-	O
+and	O
+gender	O
+-	O
+adjusted	O
+linear	O
+regression	O
+to	O
+compare	O
+contrast	O
+acuity	O
+and	O
+retinal	O
+thickness	O
+between	O
+CMT	O
+groups	O
+.	O
+
+Results	O
+One	B-STAT
+of	I-STAT
+5	I-STAT
+patients	O
+with	O
+CMT2A	O
+had	O
+optic	O
+nerve	O
+atrophy	O
+(	O
+binocular	O
+high	O
+-	O
+contrast	O
+acuity	O
+equivalent	O
+20/160	B-STAT
+,	O
+mean	O
+circumpapillary	O
+RNFL	O
+47.5	O
+μm	O
+)	O
+.	O
+
+The	O
+other	O
+patients	O
+with	O
+CMT2A	O
+had	O
+normal	O
+high-	O
+and	O
+low	O
+-	O
+contrast	O
+acuity	O
+and	O
+retinal	O
+thickness	O
+,	O
+and	O
+there	O
+were	O
+no	O
+significant	O
+differences	O
+between	O
+patients	O
+with	O
+CMT2A	B-LOC
+,	O
+CMT1A	O
+,	O
+and	O
+CMTX1	O
+.	O
+
+Conclusions	O
+Optic	O
+atrophy	O
+occurs	B-EPI
+in	O
+some	O
+patients	O
+with	O
+CMT2A	O
+,	O
+but	O
+in	O
+others	O
+,	O
+there	O
+is	O
+no	O
+discernible	O
+optic	O
+nerve	O
+involvement	O
+.	O
+
+This	O
+suggests	O
+that	O
+optic	O
+neuropathy	O
+is	O
+specific	O
+to	O
+certain	O
+MFN2	O
+mutations	O
+in	O
+CMT2A	O
+and	O
+that	O
+low	O
+-	O
+contrast	O
+acuity	O
+or	O
+OCT	O
+is	O
+of	O
+limited	O
+value	O
+as	O
+a	O
+disease	O
+-	O
+wide	O
+biomarker	O
+.	O
+
+Coxiella	O
+burnetii	O
+is	O
+an	O
+intracellular	O
+bacterium	O
+and	O
+the	O
+cause	O
+of	O
+the	O
+zoonotic	O
+infection	O
+,	O
+Q	O
+fever	O
+.	O
+
+National	O
+surveillance	O
+data	O
+on	O
+C.	O
+burnetii	O
+seroprevalence	O
+is	O
+currently	O
+not	O
+available	O
+for	O
+any	O
+South	O
+American	O
+country	O
+,	O
+making	O
+efforts	O
+of	O
+public	O
+health	O
+to	O
+implement	O
+strategies	O
+to	O
+mitigate	O
+infections	O
+in	O
+different	O
+at	O
+-	O
+risk	O
+groups	O
+within	O
+the	O
+population	O
+extremely	O
+challenging	O
+.	O
+
+In	O
+the	O
+current	O
+study	O
+,	O
+we	O
+used	O
+two	O
+commercial	O
+anti-	O
+C.	O
+burnetii	O
+immunoassays	O
+to	O
+screen	O
+sera	O
+collected	O
+from	O
+a	O
+sample	O
+of	O
+the	O
+Chilean	O
+population	O
+as	O
+part	O
+of	O
+a	O
+2016	O
+-	O
+2017	O
+national	O
+health	O
+survey	O
+(	O
+n	O
+=	O
+5166	O
+)	O
+,	O
+nationwide	O
+and	O
+age	O
+-	O
+standardized	O
+.	O
+
+The	O
+seroprevalence	O
+for	O
+C.	O
+burnetii	O
+for	O
+persons	O
+≥	O
+15	O
+years	O
+was	O
+estimated	O
+to	O
+be	O
+3.0	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+2.2	O
+-	O
+4.0	O
+)	O
+,	O
+a	O
+level	O
+similar	O
+to	O
+national	O
+surveys	O
+from	O
+The	O
+Netherlands	B-LOC
+(	O
+2.4	O
+%	O
+)	O
+and	O
+USA	B-LOC
+(	O
+3.1	O
+%	O
+)	O
+,	O
+but	O
+lower	O
+than	O
+Australia	B-LOC
+(	O
+5.6	O
+%	O
+)	O
+.	O
+
+A	O
+linear	O
+increase	O
+of	O
+C.	O
+burnetii	O
+seropositivity	O
+was	O
+associated	O
+with	O
+an	O
+individual	O
+'s	O
+age	O
+,	O
+with	O
+the	O
+peak	O
+seroprevalence	O
+5.6	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+3.6	O
+-	O
+8.6	O
+)	O
+observed	O
+in	O
+the	O
+≥65	O
+years	O
+'	O
+group	O
+.	O
+
+C.	O
+burnetii	O
+seropositivity	O
+was	O
+significantly	O
+higher	O
+in	O
+the	O
+southern	O
+macro	O
+-	O
+zone	O
+6.0	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+3.3	O
+-	O
+10.6	O
+)	O
+compared	O
+to	O
+metropolitan	O
+region	O
+1.8	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+0.9	O
+-	O
+3.3	O
+)	O
+,	O
+the	O
+former	O
+region	O
+being	O
+home	O
+to	O
+significant	O
+livestock	O
+industries	O
+,	O
+particularly	O
+dairy	O
+farming	O
+.	O
+
+These	O
+data	O
+will	O
+be	O
+useful	O
+to	O
+inform	O
+targeted	O
+strategies	O
+for	O
+the	O
+prevention	O
+of	O
+Q	O
+fever	O
+in	O
+at	O
+-	O
+risk	O
+populations	O
+in	O
+Chile	B-LOC
+.	O
+
+Factor	O
+X	O
+deficiency	O
+is	O
+a	O
+severe	O
+inherited	O
+coagulation	O
+disorder	O
+,	O
+which	O
+is	O
+characterized	O
+by	O
+severe	O
+systemic	O
+bleeding	O
+manifestations	O
+in	O
+affected	O
+individuals	O
+.	O
+
+It	O
+is	O
+a	O
+rare	O
+disorder	O
+with	O
+a	O
+frequency	O
+of	O
+around	B-STAT
+1:1,000,000	I-STAT
+in	O
+the	O
+general	O
+population	O
+.	O
+
+We	O
+present	O
+the	O
+case	O
+of	O
+an	O
+infant	O
+with	O
+factor	O
+X	O
+deficiency	O
+who	O
+presented	O
+with	O
+complex	O
+febrile	O
+seizure	O
+.	O
+
+Although	O
+febrile	O
+seizures	O
+are	O
+very	O
+common	O
+in	O
+children	O
+,	O
+a	O
+closer	O
+scrutiny	O
+leads	O
+to	O
+neuroimaging	O
+and	O
+finding	O
+of	O
+intracranial	O
+bleed	O
+.	O
+
+Hematologic	O
+and	O
+genetic	O
+investigations	O
+confirmed	O
+the	O
+diagnosis	O
+.	O
+
+A	O
+high	O
+index	O
+of	O
+suspicion	O
+should	O
+be	O
+maintained	O
+to	O
+diagnose	O
+uncommon	O
+bleeding	O
+disorders	O
+in	O
+children	O
+.	O
+
+BACKGROUND	O
+:	O
+Neonatal	O
+herpes	O
+simplex	O
+virus	O
+infection	O
+(	O
+nHSV	O
+)	O
+leads	O
+to	O
+severe	O
+morbidity	O
+and	O
+mortality	O
+,	O
+but	O
+national	O
+incidence	B-EPI
+is	O
+uncertain	O
+.	O
+
+Florida	B-LOC
+regulations	O
+require	O
+that	O
+healthcare	O
+providers	O
+report	O
+cases	O
+,	O
+and	O
+clinical	O
+laboratories	O
+report	O
+test	O
+results	O
+when	O
+herpes	O
+simplex	O
+virus	O
+(	O
+HSV	O
+)	O
+is	O
+detected	O
+.	O
+
+We	O
+estimated	O
+nHSV	O
+incidence	B-EPI
+using	O
+laboratory	O
+-	O
+confirmed	O
+provider	O
+-	O
+reported	O
+cases	O
+and	O
+electronic	O
+laboratory	O
+reports	O
+(	O
+ELR	O
+)	O
+stored	O
+separately	O
+from	O
+provider	O
+-	O
+reported	O
+cases	O
+.	O
+
+Mortality	O
+was	O
+estimated	O
+using	O
+provider	O
+-	O
+reported	O
+cases	O
+,	O
+ELR	O
+,	O
+and	O
+vital	O
+statistics	O
+death	O
+records	O
+.	O
+
+METHODS	O
+:	O
+For	O
+2011	O
+-	O
+2017	O
+,	O
+we	O
+reviewed	O
+:	O
+provider	O
+-	O
+reported	O
+cases	O
+(	O
+infants	O
+<	O
+60	O
+days	O
+of	O
+age	O
+with	O
+HSV	O
+infection	O
+confirmed	O
+by	O
+culture	O
+or	O
+polymerase	O
+chain	O
+reaction	O
+(	O
+PCR	O
+)	O
+)	O
+,	O
+ELR	O
+of	O
+HSV	O
+-	O
+positive	O
+culture	O
+or	O
+PCR	O
+results	O
+in	O
+the	O
+same	O
+age	O
+group	O
+,	O
+and	O
+death	O
+certificates	O
+containing	O
+International	O
+Classification	O
+of	O
+Disease	O
+,	O
+Tenth	O
+Revision	O
+,	O
+codes	O
+for	O
+herpes	O
+infection	O
+:	O
+P35.2	O
+,	O
+B00.0	O
+-	O
+B00.9	O
+,	O
+and	O
+A60.0	O
+-	O
+A60.9	O
+.	O
+
+Provider	O
+-	O
+reported	O
+cases	O
+were	O
+matched	O
+against	O
+ELR	O
+reports	O
+.	O
+
+Death	O
+certificates	O
+were	O
+matched	O
+with	O
+provider	O
+and	O
+ELR	O
+reports	O
+.	O
+
+Chapman	O
+'s	O
+capture	O
+-	O
+recapture	O
+method	O
+was	O
+used	O
+to	O
+estimate	O
+nHSV	O
+incidence	B-EPI
+and	O
+mortality	O
+.	O
+
+Mortality	O
+from	O
+all	O
+three	O
+sources	O
+was	O
+estimated	O
+using	O
+log	O
+-	O
+linear	O
+modelling	O
+.	O
+
+RESULTS	O
+:	O
+Providers	O
+reported	O
+114	O
+nHSV	O
+cases	O
+and	O
+ELR	O
+identified	O
+197	O
+nHSV	O
+cases	O
+.	O
+
+Forty	O
+-	O
+six	O
+cases	O
+were	O
+common	O
+to	O
+both	O
+datasets	O
+,	O
+leaving	O
+265	O
+unique	O
+nHSV	O
+reports	O
+.	O
+
+Chapman	O
+'s	O
+estimate	O
+suggests	O
+483	B-STAT
+(	I-STAT
+95	I-STAT
+%	I-STAT
+C.I.	O
+
+383	O
+-	O
+634	O
+)	O
+nHSV	O
+cases	O
+occurred	O
+(	O
+31.5	B-STAT
+infections	I-STAT
+per	I-STAT
+100,000	I-STAT
+live	I-STAT
+births	I-STAT
+)	O
+.	O
+
+nHSV	O
+deaths	O
+were	O
+reported	O
+by	O
+providers	O
+(	O
+n=9	O
+)	O
+,	O
+ELR	O
+(	O
+n=18	O
+)	O
+,	O
+and	O
+vital	O
+statistics	O
+(	O
+n=31	O
+)	O
+,	O
+totaling	O
+34	O
+unique	O
+reports	O
+.	O
+
+Log	O
+-	O
+linear	O
+modeling	O
+estimates	O
+35.8	O
+fatal	O
+cases	O
+occurred	O
+(	O
+95	O
+%	O
+CI	O
+34	O
+-	O
+40	O
+)	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Chapman	O
+'s	O
+estimates	O
+using	O
+data	O
+collected	O
+over	O
+7	O
+years	O
+in	O
+Florida	B-LOC
+,	O
+conclude	O
+nHSV	O
+infections	O
+occurred	O
+at	O
+a	O
+rate	O
+of	O
+1	B-STAT
+per	I-STAT
+3000	I-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+Background	O
+Congenital	O
+malformations	O
+are	O
+described	O
+in	O
+about	O
+3	O
+%	O
+of	O
+live	O
+births	O
+and	O
+20	O
+%	O
+of	O
+stillbirths	O
+in	O
+the	O
+industrialized	O
+countries	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+congenital	O
+anomalies	O
+in	O
+developing	O
+countries	O
+,	O
+including	O
+Morocco	B-LOC
+,	O
+is	O
+not	O
+well	O
+known	O
+at	O
+the	O
+national	O
+level	O
+.	O
+
+The	O
+aim	O
+of	O
+our	O
+study	O
+is	O
+to	O
+conduct	O
+a	O
+descriptive	O
+exploratory	O
+analysis	O
+of	O
+congenital	O
+malformations	O
+cases	O
+diagnosed	O
+at	O
+the	O
+	O
+Les	O
+Orangers	O
+	O
+Maternity	O
+and	O
+Reproductive	O
+Health	O
+Hospital	O
+in	O
+Rabat	B-LOC
+.	O
+
+Methods	O
+We	O
+collected	O
+all	O
+the	O
+cases	O
+of	O
+congenital	O
+malformations	O
+diagnosed	O
+at	O
+the	O
+	O
+Les	O
+Orangers	O
+	O
+Maternity	O
+and	O
+Reproductive	O
+Health	O
+Hospital	O
+in	O
+Rabat	B-LOC
+,	O
+from	O
+January	O
+1st	O
+,	O
+2011	O
+to	O
+June	O
+31st	O
+,	O
+2016	O
+.	O
+
+Data	O
+were	O
+reported	O
+on	O
+pre	O
+-	O
+established	O
+sheets	O
+and	O
+on	O
+a	O
+registry	O
+of	O
+malformations	O
+.	O
+
+Total	O
+and	O
+specific	O
+prevalences	B-EPI
+were	O
+calculated	O
+for	O
+each	O
+malformation	O
+.	O
+
+A	O
+principal	O
+component	O
+analysis	O
+(	O
+PCA	O
+)	O
+was	O
+then	O
+conducted	O
+followed	O
+by	O
+a	O
+Varimax	O
+rotation	O
+in	O
+order	O
+to	O
+identify	O
+the	O
+different	O
+associations	O
+of	O
+malformations	O
+in	O
+our	O
+series	O
+.	O
+
+Results	O
+We	O
+registred	O
+245	O
+cases	O
+of	O
+congenital	O
+malformations	O
+out	O
+of	O
+a	O
+total	O
+of	O
+43,923	O
+recorded	O
+births	O
+;	O
+a	O
+prevalence	B-EPI
+of	O
+5.58	B-STAT
+per	I-STAT
+thousand	I-STAT
+births	I-STAT
+of	O
+which	O
+19.2	O
+%	O
+were	O
+FDIU	O
+(	O
+fetal	O
+deaths	O
+in	O
+utero	O
+)	O
+.	O
+
+A	O
+polymalformative	O
+syndrome	O
+was	O
+found	O
+in	O
+26.5	O
+%	O
+of	O
+cases	O
+which	O
+makes	O
+a	O
+total	O
+number	O
+of	O
+470	O
+anomalies	O
+.	O
+
+The	O
+musculoskeletal	O
+anomalies	O
+predominate	O
+with	O
+a	O
+rate	O
+of	O
+33	O
+%	O
+,	O
+followed	O
+by	O
+neurological	O
+abnormalities	O
+18	O
+%	O
+,	O
+of	O
+whom	O
+31	O
+%	O
+were	O
+hydrocephalus	O
+,	O
+26.2	O
+%	O
+anencephaly	O
+,	O
+and	O
+20.24	O
+%	O
+spina	O
+bifida	O
+.	O
+
+Malformations	O
+of	O
+the	O
+eye	O
+,	O
+ear	O
+,	O
+face	O
+and	O
+neck	O
+were	O
+described	O
+in	O
+12	O
+%	O
+of	O
+the	O
+cases	O
+,	O
+while	O
+genetic	O
+abnormalities	O
+were	O
+observed	O
+in	O
+8,5	O
+%	O
+of	O
+which	O
+87.5	O
+%	O
+represented	O
+Down	O
+syndrome	O
+.	O
+
+The	O
+antenatal	O
+diagnosis	O
+of	O
+congenital	O
+malformations	O
+was	O
+performed	O
+in	O
+28.6	O
+%	O
+of	O
+cases	O
+.	O
+
+Conclusions	O
+Our	O
+study	O
+provides	O
+a	O
+general	O
+overview	O
+of	O
+the	O
+epidemiological	O
+situation	O
+related	O
+to	O
+different	O
+types	O
+of	O
+congenital	O
+anomalies	O
+for	O
+a	O
+specific	O
+area	O
+in	O
+Morocco	B-LOC
+.	O
+
+It	O
+represents	O
+a	O
+database	O
+that	O
+should	O
+be	O
+complemented	O
+by	O
+other	O
+multicenter	O
+studies	O
+and	O
+the	O
+implementation	O
+of	O
+a	O
+national	O
+registry	O
+to	O
+determine	O
+the	O
+prevalence	B-EPI
+of	O
+congenital	O
+malformations	O
+at	O
+a	O
+national	O
+level	O
+.	O
+
+Hearing	O
+loss	O
+is	O
+one	O
+of	O
+the	O
+most	O
+common	O
+birth	O
+disorders	O
+in	O
+humans	O
+,	O
+with	O
+an	O
+estimated	B-EPI
+prevalence	I-EPI
+of	O
+1	B-STAT
+-	I-STAT
+3	I-STAT
+in	O
+every	O
+1000	O
+newborns	O
+.	O
+
+This	O
+study	O
+investigates	O
+the	O
+molecular	O
+etiology	O
+of	O
+a	O
+hearing	O
+loss	O
+cohort	O
+using	O
+a	O
+stepwise	O
+strategy	O
+to	O
+effectively	O
+diagnose	O
+patients	O
+and	O
+address	O
+the	O
+challenges	O
+posed	O
+by	O
+the	O
+genetic	O
+heterogeneity	O
+and	O
+variable	O
+mutation	O
+spectrum	O
+of	O
+hearing	O
+loss	O
+.	O
+
+In	O
+order	O
+to	O
+target	O
+known	O
+pathogenic	O
+variants	O
+,	O
+multiplex	O
+PCR	O
+plus	O
+next	O
+-	O
+generation	O
+sequencing	O
+was	O
+applied	O
+in	O
+the	O
+first	O
+step	O
+;	O
+patients	O
+which	O
+did	O
+not	O
+receive	O
+a	O
+diagnosis	O
+from	O
+this	O
+were	O
+further	O
+referred	O
+for	O
+exome	O
+sequencing	O
+.	O
+
+A	O
+total	O
+of	O
+92	O
+unrelated	O
+patients	O
+with	O
+nonsyndromic	O
+hearing	O
+loss	O
+were	O
+enrolled	O
+in	O
+the	O
+study	O
+.	O
+
+In	O
+total	O
+,	O
+64	O
+%	O
+(	O
+59/92	O
+)	O
+of	O
+the	O
+patients	O
+were	O
+molecularly	O
+diagnosed	O
+,	O
+44	O
+of	O
+them	O
+in	O
+the	O
+first	O
+step	O
+by	O
+multiplex	O
+PCR	O
+plus	O
+sequencing	O
+.	O
+
+Exome	O
+sequencing	O
+resulted	O
+in	O
+eleven	O
+diagnoses	O
+(	O
+23	O
+%	O
+,	O
+11/48	O
+)	O
+and	O
+four	O
+probable	O
+diagnoses	O
+(	O
+8	O
+%	O
+,	O
+4/48	O
+)	O
+among	O
+the	O
+48	O
+patients	O
+who	O
+were	O
+not	O
+diagnosed	O
+in	O
+the	O
+first	O
+step	O
+.	O
+
+The	O
+rate	O
+of	O
+secondary	O
+findings	O
+from	O
+exome	O
+sequencing	O
+in	O
+our	O
+cohort	O
+was	O
+3	O
+%	O
+(	O
+2/58	O
+)	O
+.	O
+
+This	O
+research	O
+presents	O
+a	O
+molecular	O
+diagnosis	O
+spectrum	O
+of	O
+92	O
+non	O
+-	O
+syndromic	O
+hearing	O
+loss	O
+patients	O
+and	O
+demonstrates	O
+the	O
+benefits	O
+of	O
+using	O
+a	O
+stepwise	O
+diagnostic	O
+approach	O
+in	O
+the	O
+genetic	O
+testing	O
+of	O
+nonsyndromic	O
+hearing	O
+loss	O
+.	O
+
+This	O
+study	O
+aimed	O
+to	O
+analyze	O
+the	O
+epidemiology	O
+of	O
+congenital	O
+upper	O
+limb	O
+anomalies	O
+(	O
+CULA	O
+)	O
+in	O
+Korea	B-LOC
+.	O
+
+We	O
+evaluated	O
+the	O
+incidence	B-EPI
+of	O
+each	O
+type	O
+of	O
+CULA	O
+,	O
+the	O
+presence	O
+of	O
+coexisting	O
+anomalies	O
+and	O
+the	O
+surgical	O
+treatment	O
+status	O
+in	O
+CULA	O
+patients	O
+.	O
+
+We	O
+conducted	O
+a	O
+retrospective	O
+cohort	O
+study	O
+of	O
+patients	O
+aged	O
+<	B-STAT
+1	I-STAT
+year	I-STAT
+between	I-STAT
+2007	I-STAT
+and	O
+2016	O
+who	O
+were	O
+registered	O
+with	O
+CULA	O
+in	O
+the	O
+Health	O
+Insurance	O
+Review	O
+and	O
+Assessment	O
+Service	O
+of	O
+Korea	O
+.	O
+
+In	O
+total	O
+,	O
+10,704	O
+patients	O
+had	O
+CULA	O
+,	O
+including	O
+6,174	O
+boys	O
+(	O
+57.7	O
+%	O
+)	O
+and	O
+4,530	O
+girls	O
+(	O
+42.3	O
+%	O
+)	O
+.	O
+
+The	O
+mean	O
+annual	B-EPI
+incidence	I-EPI
+of	O
+CULA	O
+was	O
+23.5	B-STAT
+per	I-STAT
+10,000	I-STAT
+live	I-STAT
+births	I-STAT
+;	O
+it	O
+was	O
+significantly	O
+higher	O
+in	O
+boys	O
+than	O
+in	O
+girls	O
+(	O
+26.3	O
+vs.	O
+20.5	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+.	O
+
+Among	O
+the	O
+four	O
+categories	O
+of	O
+CULA	O
+-	O
+polydactyly	O
+,	O
+syndactyly	O
+,	O
+limb	O
+deficiency	O
+,	O
+and	O
+other	O
+anomalies	O
+-	O
+polydactyly	O
+was	O
+the	O
+most	O
+common	O
+.	O
+
+In	O
+total	O
+,	O
+4,149	O
+patients	O
+(	O
+38.8	O
+%	O
+)	O
+had	O
+other	O
+congenital	O
+anomalies	O
+and	O
+coexisting	O
+anomalies	O
+of	O
+the	O
+circulatory	O
+system	O
+(	O
+24.9	O
+%	O
+)	O
+were	O
+the	O
+most	O
+common	O
+.	O
+
+In	O
+total	O
+4,776	O
+patients	O
+(	O
+44.6	O
+%	O
+)	O
+underwent	O
+operative	O
+treatment	O
+for	O
+CULA	O
+within	O
+minimum	O
+three	O
+years	O
+of	O
+the	O
+diagnosis	O
+.	O
+
+The	O
+proportion	O
+of	O
+patients	O
+who	O
+underwent	O
+surgical	O
+treatment	O
+was	O
+significantly	O
+higher	O
+for	O
+polydactyly	O
+(	O
+73.4	O
+%	O
+vs.	O
+16.8	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+and	O
+syndactyly	O
+(	O
+65.3	O
+%	O
+vs.	O
+41.5	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+but	O
+it	O
+was	O
+significantly	O
+lower	O
+in	O
+limb	O
+deficiency	O
+(	O
+27.6	O
+%	O
+vs.	O
+45.4	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+and	O
+other	O
+anomalies	O
+(	O
+10.0	O
+%	O
+vs.	O
+69.8	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+than	O
+rest	O
+of	O
+CULA	O
+patients	O
+.	O
+
+Among	O
+the	O
+patients	O
+who	O
+had	O
+operations	O
+,	O
+21.5	O
+%	O
+underwent	O
+multiple	O
+operations	O
+.	O
+
+The	O
+proportion	O
+of	O
+patients	O
+who	O
+underwent	O
+multiple	O
+operations	O
+was	O
+significantly	O
+higher	O
+in	O
+syndactyly	O
+(	O
+35.6	O
+%	O
+vs.	O
+18.1	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+,	O
+but	O
+it	O
+was	O
+significantly	O
+lower	O
+in	O
+polydactyly	O
+(	O
+4.0	O
+%	O
+vs.	O
+95.5	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+and	O
+other	O
+anomalies	O
+(	O
+17.9	O
+%	O
+vs.	O
+21.9	O
+%	O
+,	O
+p	O
+<	O
+0.001	O
+)	O
+than	O
+rest	O
+of	O
+CULA	O
+patients	O
+.	O
+
+These	O
+results	O
+could	O
+provide	O
+a	O
+basis	O
+for	O
+estimating	O
+the	O
+national	O
+healthcare	O
+costs	O
+for	O
+CULA	O
+and	O
+the	O
+required	O
+number	O
+of	O
+CULA	O
+specialists	O
+.	O
+
+The	O
+Australian	O
+Cattle	O
+dog	O
+(	O
+ACD	O
+)	O
+is	O
+one	O
+of	O
+many	O
+breeds	O
+predisposed	O
+to	O
+congenital	O
+sensorineural	O
+deafness	O
+(	O
+CSD	O
+)	O
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+estimate	O
+CSD	O
+prevalence	B-EPI
+and	O
+investigate	O
+any	O
+association	O
+with	O
+phenotype	O
+in	O
+the	O
+ACD	O
+in	O
+the	O
+UK	B-LOC
+.	O
+
+The	O
+database	O
+of	O
+the	O
+authors	O
+'	O
+institution	O
+was	O
+searched	O
+for	O
+ACD	O
+puppies	O
+undergoing	O
+brainstem	O
+auditory	O
+evoked	O
+response	O
+(	O
+BAER	O
+)	O
+testing	O
+for	O
+CSD	O
+screening	O
+(	O
+1999	O
+-	O
+2019	O
+)	O
+.	O
+
+Inclusion	O
+criteria	O
+were	O
+BAER	O
+performed	O
+at	O
+4	O
+-	O
+10	O
+weeks	O
+of	O
+age	O
+,	O
+testing	O
+of	O
+complete	O
+litters	O
+and	O
+available	O
+phenotypic	O
+data	O
+.	O
+
+The	O
+age	O
+,	O
+sex	O
+,	O
+coat	O
+and	O
+iris	O
+colour	O
+,	O
+presence	O
+and	O
+location	O
+of	O
+face	O
+and	O
+body	O
+patches	O
+,	O
+hearing	O
+status	O
+and	O
+BAER-	O
+determined	O
+parental	O
+hearing	O
+status	O
+of	O
+each	O
+puppy	O
+were	O
+recorded	O
+.	O
+
+A	O
+multivariable	O
+mixed	O
+-	O
+effects	O
+logistic	O
+regression	O
+model	O
+was	O
+used	O
+to	O
+calculate	O
+odds	O
+ratios	O
+and	O
+95	O
+%	O
+confidence	O
+intervals	O
+to	O
+determine	O
+whether	O
+any	O
+of	O
+these	O
+variables	O
+were	O
+significantly	O
+associated	O
+with	O
+CSD	O
+,	O
+while	O
+adjusting	O
+for	O
+clustering	O
+at	O
+litter	O
+level	O
+.	O
+
+Inclusion	O
+criteria	O
+were	O
+met	O
+for	O
+524	O
+puppies	O
+.	O
+
+Hearing	O
+was	O
+bilaterally	O
+normal	O
+in	O
+464	O
+puppies	O
+(	O
+88.6	O
+%	O
+)	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+unilateral	O
+and	O
+bilateral	O
+CSD	O
+was	O
+9.7	O
+%	O
+and	O
+1.7	O
+%	O
+,	O
+respectively	O
+.	O
+
+On	O
+the	O
+basis	O
+of	O
+multivariable	O
+analysis	O
+,	O
+the	O
+presence	O
+of	O
+a	O
+pigmented	O
+face	O
+patch	O
+was	O
+the	O
+only	O
+phenotypic	O
+variable	O
+significantly	O
+associated	O
+with	O
+CSD	O
+,	O
+and	O
+was	O
+linked	O
+to	O
+a	O
+reduced	O
+risk	O
+of	O
+the	O
+condition	O
+.	O
+
+The	O
+prevalence	B-EPI
+was	O
+similar	O
+to	O
+that	O
+reported	O
+in	O
+an	O
+Australian	O
+population	O
+of	O
+ACDs	O
+.	O
+
+The	O
+key	O
+findings	O
+from	O
+this	O
+study	O
+were	O
+that	O
+overall	O
+CSD	O
+prevalence	B-EPI
+in	O
+the	O
+ACD	O
+population	O
+in	O
+the	O
+UK	B-LOC
+was	O
+11.4	O
+%	O
+,	O
+and	O
+puppies	O
+with	O
+a	O
+face	O
+patch	O
+were	O
+at	O
+reduced	O
+risk	O
+of	O
+the	O
+condition	O
+.	O
+
+Background	O
+The	O
+evidence	O
+of	O
+an	O
+association	O
+between	O
+statins	O
+and	O
+amyotrophic	O
+lateral	O
+sclerosis	O
+(	O
+ALS	O
+)	O
+is	O
+heterogeneous	O
+and	O
+inconclusive	O
+.	O
+
+Methods	O
+We	O
+performed	O
+a	O
+population	O
+-	O
+based	O
+cohort	O
+study	O
+consisting	O
+of	O
+974,304	O
+statin	O
+initiators	O
+aged	O
+≥40	O
+years	O
+and	O
+1,948,606	O
+matched	O
+general	O
+population	O
+comparators	O
+identified	O
+from	O
+Danish	O
+,	O
+nationwide	O
+registries	O
+(	O
+1996	O
+-	O
+2016	O
+)	O
+.	O
+
+We	O
+computed	O
+incidence	B-EPI
+rates	O
+and	O
+hazard	O
+ratios	O
+(	O
+HRs	O
+)	O
+of	O
+a	O
+first	O
+-	O
+time	O
+hospital	O
+-	O
+based	O
+diagnosis	O
+of	O
+ALS	O
+.	O
+
+HRs	O
+were	O
+controlled	O
+for	O
+sex	O
+,	O
+birth	O
+year	O
+,	O
+calendar	O
+year	O
+,	O
+medically	O
+diagnosed	O
+comorbidities	O
+,	O
+and	O
+concomitant	O
+medications	O
+.	O
+
+Results	O
+During	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+7.7	O
+years	O
+,	O
+852	O
+ALS	O
+events	O
+occurred	O
+among	O
+statin	O
+initiators	O
+(	O
+11.3	O
+[	O
+95	O
+%	O
+CI	O
+:	O
+10.6	O
+-	O
+12.1	O
+]	O
+events	B-STAT
+per	I-STAT
+100,000	I-STAT
+person	I-STAT
+-	O
+years	O
+)	O
+and	O
+1,679	O
+among	O
+non	O
+-	O
+initiators	O
+(	O
+11.4	O
+[	O
+95	O
+%	O
+CI	O
+:	O
+10.9	O
+-	O
+12.0	O
+]	O
+events	B-STAT
+per	I-STAT
+100,000	I-STAT
+person	I-STAT
+-	O
+years	O
+)	O
+.	O
+
+The	O
+overall	O
+adjusted	O
+HR	O
+indicated	O
+a	O
+slight	O
+association	O
+between	O
+statin	O
+initiation	O
+and	O
+ALS	O
+(	O
+1.11	O
+[	O
+95	O
+%	O
+CI	O
+:	O
+1.00	O
+-	O
+1.23	O
+]	O
+.	O
+
+In	O
+the	O
+first	O
+year	O
+after	O
+initiation	O
+,	O
+the	O
+HR	O
+was	O
+1.40	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+1.09	O
+-	O
+1.79	O
+)	O
+for	O
+both	O
+sexes	O
+combined	O
+,	O
+1.00	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+0.70	O
+-	O
+1.42	O
+)	O
+for	O
+men	O
+,	O
+and	O
+1.92	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+1.30	O
+-	O
+2.82	O
+)	O
+for	O
+women	O
+.	O
+
+The	O
+associations	O
+diminished	O
+to	O
+approximately	O
+null	O
+after	O
+the	O
+first	O
+year	O
+of	O
+follow	O
+-	O
+up	O
+for	O
+both	O
+sexes	O
+combined	O
+and	O
+for	O
+men	O
+,	O
+but	O
+point	O
+estimates	O
+were	O
+above	O
+1	O
+for	O
+women	O
+until	O
+10	O
+years	O
+after	O
+initiation	O
+.	O
+
+Conclusions	O
+Statin	O
+initiation	O
+was	O
+largely	O
+unassociated	O
+with	O
+ALS	O
+diagnosis	O
+but	O
+was	O
+associated	O
+with	O
+an	O
+elevated	O
+risk	O
+of	O
+ALS	O
+in	O
+women	O
+,	O
+especially	O
+in	O
+the	O
+first	O
+year	O
+after	O
+initiation	O
+.	O
+
+The	O
+association	O
+could	O
+be	O
+explained	O
+by	O
+reverse	O
+causation	O
+,	O
+detection	O
+bias	O
+,	O
+early	O
+neurotoxic	O
+effects	O
+of	O
+statins	O
+that	O
+affect	O
+women	O
+more	O
+than	O
+men	O
+,	O
+or	O
+a	O
+combination	O
+thereof	O
+.	O
+
+Papillon	O
+-	O
+Lefevre	O
+syndrome	O
+(	O
+PLS	O
+)	O
+is	O
+a	O
+rare	O
+disease	O
+characterized	O
+by	O
+skin	O
+lesions	O
+,	O
+which	O
+includes	O
+palmar	O
+-	O
+plantar	O
+hyperkeratosis	O
+and	O
+hyperhidrosis	O
+with	O
+severe	O
+periodontal	O
+destruction	O
+involving	O
+both	O
+the	O
+primary	O
+and	O
+the	O
+permanent	O
+dentitions	O
+.	O
+
+It	O
+is	O
+transmitted	O
+as	O
+an	O
+autosomal	O
+-	O
+recessive	O
+condition	O
+,	O
+and	O
+consanguinity	O
+of	O
+parents	O
+is	O
+evident	O
+in	O
+about	O
+one	O
+-	O
+third	O
+of	O
+the	O
+cases	O
+.	O
+
+This	O
+paper	O
+describes	O
+a	O
+13	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+who	O
+presented	O
+to	O
+the	O
+department	O
+of	O
+pedodontics	O
+,	O
+with	O
+rapidly	O
+progressing	O
+periodontitis	O
+.	O
+
+A	O
+general	O
+physical	O
+examination	O
+revealed	O
+scaling	O
+on	O
+the	O
+hands	O
+and	O
+feet	O
+,	O
+which	O
+had	O
+been	O
+medically	O
+diagnosed	O
+as	O
+PLS	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+this	O
+rare	O
+entity	O
+is	O
+increasing	O
+in	O
+the	O
+recent	O
+times	O
+,	O
+which	O
+is	O
+associated	O
+with	O
+irreparable	O
+periodontal	O
+destruction	O
+at	O
+an	O
+early	O
+age	O
+,	O
+with	O
+not	O
+so	O
+prominent	O
+skin	O
+lesions	O
+in	O
+some	O
+cases	O
+.	O
+
+In	O
+such	O
+instances	O
+,	O
+the	O
+dentist	O
+has	O
+a	O
+more	O
+important	O
+role	O
+in	O
+diagnosing	O
+,	O
+treatment	O
+planning	O
+and	O
+preservation	O
+of	O
+the	O
+periodontal	O
+tissues	O
+and	O
+,	O
+at	O
+the	O
+same	O
+time	O
+,	O
+referring	O
+for	O
+the	O
+treatment	O
+of	O
+the	O
+skin	O
+lesions	O
+.	O
+
+This	O
+paper	O
+emphasizes	O
+the	O
+combined	O
+effort	O
+of	O
+the	O
+two	O
+specialities	O
+in	O
+order	O
+to	O
+maintain	O
+skin	O
+as	O
+well	O
+as	O
+dental	O
+conditions	O
+in	O
+health	O
+by	O
+early	O
+intervention	O
+and	O
+a	O
+synergistic	O
+treatment	O
+approach	O
+.	O
+
+OBJECTIVES	O
+:	O
+To	O
+describe	O
+the	O
+prevalence	B-EPI
+of	O
+the	O
+reduced	O
+ankle	O
+-	O
+brachial	O
+index	O
+(	O
+ABI	O
+)	O
+in	O
+patients	O
+with	O
+heart	O
+failure	O
+(	O
+HF	O
+)	O
+with	O
+preserved	O
+ejection	O
+fraction	O
+(	O
+HFpEF	O
+)	O
+attended	O
+at	O
+a	O
+HF	O
+clinic	O
+in	O
+the	O
+metropolitan	O
+region	O
+of	O
+Porto	B-LOC
+Alegre	I-LOC
+,	O
+and	O
+to	O
+compar	O
+the	O
+patients	O
+to	O
+those	O
+with	O
+reduced	O
+ejection	O
+fraction	O
+(	O
+HFrEF	O
+)	O
+.	O
+
+METHODS	O
+:	O
+A	O
+descriptive	O
+observational	O
+study	O
+,	O
+included	O
+patients	O
+referred	O
+to	O
+the	O
+heart	O
+failure	O
+clinic	O
+in	O
+HU	O
+-	O
+Ulbra	O
+with	O
+HFpEF	O
+or	O
+HFrEF	O
+and	O
+diastolic	O
+dysfunction	O
+,	O
+and	O
+measurements	O
+of	O
+ABIs	O
+using	O
+vascular	O
+Doppler	O
+equipment	O
+were	O
+performed	O
+in	O
+both	O
+groups	O
+.	O
+
+RESULTS	O
+:	O
+The	O
+sample	O
+consisted	O
+of	O
+106	O
+patients	O
+with	O
+HF	O
+,	O
+53.9	O
+%	O
+of	O
+the	O
+patients	O
+had	O
+HFpEF	O
+,	O
+and	O
+19.4	O
+%	O
+had	O
+a	O
+diagnosis	O
+of	O
+peripheral	O
+arterial	O
+disease	O
+(	O
+PAD	O
+)	O
+(	O
+ABI	O
+less	O
+than	O
+0.9	O
+)	O
+.	O
+
+PAD	O
+was	O
+identified	O
+in	O
+24.1	O
+%	O
+of	O
+the	O
+patients	O
+with	O
+HFpEF	O
+,	O
+while15.8	O
+%	O
+of	O
+patients	O
+in	O
+the	O
+HFrEF	O
+group	O
+were	O
+diagnosed	O
+with	O
+PAD	O
+.	O
+
+CONCLUSION	O
+:	O
+Our	O
+results	O
+did	O
+not	O
+identify	O
+a	O
+significantly	O
+different	O
+prevalence	B-EPI
+of	O
+altered	O
+and	O
+compatible	O
+PAD	O
+values	O
+in	O
+patients	O
+with	O
+HFpEF	O
+.	O
+
+However	O
+,	O
+we	O
+showed	O
+a	O
+prevalence	B-EPI
+of	O
+19.4	O
+%	O
+,	O
+a	O
+high	O
+value	O
+if	O
+we	O
+consider	O
+similar	O
+populations	O
+.	O
+
+Enamel	O
+renal	O
+syndrome	O
+is	O
+a	O
+unique	O
+syndrome	O
+associated	O
+with	O
+kidney	O
+agenesis	O
+associated	O
+with	O
+kidney	O
+agenesis	O
+,	O
+amelogenesis	O
+imperfecta	O
+,	O
+and	O
+gingival	O
+hyperplasia	O
+.	O
+
+The	O
+prevalence	B-EPI
+rate	O
+of	O
+this	O
+rare	O
+syndrome	O
+is	O
+<	B-STAT
+1/1,000,000	I-STAT
+.	O
+
+A	O
+17	O
+-	O
+year	O
+-	O
+old	O
+male	O
+patient	O
+came	O
+to	O
+the	O
+department	O
+of	O
+periodontics	O
+,	O
+with	O
+a	O
+chief	O
+complaint	O
+of	O
+dislodged	O
+crown	O
+in	O
+the	O
+anterior	O
+teeth	O
+region	O
+.	O
+
+On	O
+clinical	O
+examination	O
+,	O
+the	O
+patient	O
+had	O
+teeth	O
+with	O
+mottled	O
+enamel	O
+and	O
+gingival	O
+enlargement	O
+.	O
+
+The	O
+orthopantomograph	O
+and	O
+gingival	O
+biopsy	O
+revealed	O
+pulpal	O
+calcification	O
+and	O
+gingival	O
+calcification	O
+,	O
+respectively	O
+.	O
+
+Furthermore	O
+,	O
+the	O
+renal	O
+ultrasonography	O
+revealed	O
+absence	O
+/	O
+agenesis	O
+of	O
+the	O
+left	O
+kidney	O
+.	O
+
+Thus	O
+,	O
+based	O
+on	O
+radiographical	O
+,	O
+histological	O
+,	O
+and	O
+ultrasound	O
+investigations	O
+,	O
+the	O
+patient	O
+was	O
+diagnosed	O
+with	O
+nephrocalcinosis	O
+syndrome	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+periodontal	O
+therapy	O
+and	O
+prosthodontic	O
+full	O
+-	O
+mouth	O
+rehabilitation	O
+.	O
+
+This	O
+case	O
+report	O
+highlights	O
+the	O
+need	O
+of	O
+a	O
+periodontist	O
+to	O
+be	O
+acquainted	O
+about	O
+the	O
+signs	O
+and	O
+symptoms	O
+of	O
+the	O
+syndrome	O
+to	O
+benefit	O
+an	O
+individual	O
+in	O
+the	O
+right	O
+diagnosis	O
+and	O
+treatment	O
+plan	O
+.	O
+
+Mitochondria	O
+are	O
+ubiquitous	O
+intracellular	O
+organelles	O
+found	O
+in	O
+almost	O
+all	O
+eukaryotes	O
+and	O
+involved	O
+in	O
+various	O
+aspects	O
+of	O
+cellular	O
+life	O
+,	O
+with	O
+a	O
+primary	O
+role	O
+in	O
+energy	O
+production	O
+.	O
+
+The	O
+interest	O
+in	O
+this	O
+organelle	O
+has	O
+grown	O
+stronger	O
+with	O
+the	O
+discovery	O
+of	O
+their	O
+link	O
+to	O
+various	O
+pathologies	O
+,	O
+including	O
+cancer	O
+,	O
+aging	O
+and	O
+neurodegenerative	O
+diseases	O
+.	O
+
+Indeed	O
+,	O
+dysfunctional	O
+mitochondria	O
+can	O
+not	O
+provide	O
+the	O
+required	O
+energy	O
+to	O
+tissues	O
+with	O
+a	O
+high	O
+-	O
+energy	O
+demand	O
+,	O
+such	O
+as	O
+heart	O
+,	O
+brain	O
+and	O
+muscles	O
+,	O
+leading	O
+to	O
+a	O
+large	O
+spectrum	O
+of	O
+clinical	O
+phenotypes	O
+.	O
+
+Mitochondrial	O
+defects	O
+are	O
+at	O
+the	O
+origin	O
+of	O
+a	O
+group	O
+of	O
+clinically	O
+heterogeneous	O
+pathologies	O
+,	O
+called	O
+mitochondrial	O
+diseases	O
+,	O
+with	O
+an	O
+incidence	B-EPI
+of	O
+1	B-STAT
+in	I-STAT
+5000	I-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+Primary	O
+mitochondrial	O
+diseases	O
+are	O
+associated	O
+with	O
+genetic	O
+mutations	O
+both	O
+in	O
+nuclear	O
+and	O
+mitochondrial	O
+DNA	O
+(	O
+mtDNA	O
+)	O
+,	O
+affecting	O
+genes	O
+involved	O
+in	O
+every	O
+aspect	O
+of	O
+the	O
+organelle	O
+function	O
+.	O
+
+As	O
+a	O
+consequence	O
+,	O
+it	O
+is	O
+difficult	O
+to	O
+find	O
+a	O
+common	O
+cause	O
+for	O
+mitochondrial	O
+diseases	O
+and	O
+,	O
+subsequently	O
+,	O
+to	O
+offer	O
+a	O
+precise	O
+clinical	O
+definition	O
+of	O
+the	O
+pathology	O
+.	O
+
+Moreover	O
+,	O
+the	O
+complexity	O
+of	O
+this	O
+condition	O
+makes	O
+it	O
+challenging	O
+to	O
+identify	O
+possible	O
+therapies	O
+or	O
+drug	O
+targets	O
+.	O
+
+Although	O
+many	O
+nutritional	O
+deficiencies	O
+are	O
+associated	O
+with	O
+Crohn	O
+'s	O
+disease	O
+(	O
+CD	O
+)	O
+,	O
+vitamin	O
+C	O
+deficiency	O
+is	O
+less	O
+frequently	O
+diagnosed	O
+and	O
+reported	O
+despite	O
+its	O
+prevalence	B-EPI
+.	O
+
+Vitamin	O
+C	O
+deficiency	O
+may	O
+be	O
+more	O
+difficult	O
+to	O
+diagnose	O
+in	O
+patients	O
+with	O
+CD	O
+because	O
+symptoms	O
+from	O
+active	O
+CD	O
+may	O
+overlap	O
+with	O
+scurvy	O
+.	O
+
+Identification	O
+of	O
+the	O
+deficiency	O
+is	O
+vital	O
+,	O
+however	O
+,	O
+because	O
+treatment	O
+can	O
+lead	O
+to	O
+swift	O
+,	O
+marked	O
+resolution	O
+of	O
+symptoms	O
+.	O
+
+We	O
+present	O
+a	O
+patient	O
+with	O
+long	O
+-	O
+standing	O
+CD	O
+who	O
+presented	O
+with	O
+gum	O
+bleeding	O
+and	O
+was	O
+found	O
+to	O
+have	O
+scurvy	O
+.	O
+
+Purpose	O
+:	O
+Cataract	O
+surgery	O
+,	O
+quantity	O
+and	O
+quality	O
+,	O
+is	O
+an	O
+indicator	O
+of	O
+ophthalmic	O
+care	O
+.	O
+
+A	O
+comprehensive	O
+assessment	O
+of	O
+cataract	O
+surgical	O
+services	O
+has	O
+never	O
+been	O
+carried	O
+out	O
+in	O
+Palestine	B-LOC
+,	O
+including	O
+West	B-LOC
+Bank	I-LOC
+,	O
+Gaza	B-LOC
+Strip	I-LOC
+and	O
+East	B-LOC
+Jerusalem	I-LOC
+.	O
+
+The	O
+objective	O
+of	O
+this	O
+study	O
+was	O
+to	O
+estimate	O
+the	O
+cataract	O
+surgical	O
+rate	O
+in	O
+2015	O
+to	O
+and	O
+to	O
+explore	O
+the	O
+modes	O
+of	O
+payment	O
+and	O
+referral	O
+systems	O
+.	O
+
+Methods	O
+:	O
+A	O
+cross	O
+-	O
+sectional	O
+study	O
+conducted	O
+between	O
+June	O
+and	O
+August	O
+2016	O
+.	O
+
+Medical	O
+Directors	O
+from	O
+Cataract	O
+Surgical	O
+Centres	O
+in	O
+Palestine	B-LOC
+were	O
+interviewed	O
+using	O
+a	O
+structured	O
+questionnaire	O
+to	O
+extract	O
+data	O
+on	O
+cataract	O
+output	O
+and	O
+surgical	O
+techniques	O
+.	O
+
+Additionally	O
+,	O
+data	O
+were	O
+collected	O
+on	O
+modes	O
+of	O
+payment	O
+for	O
+cataract	O
+services	O
+.	O
+
+The	O
+cataract	O
+surgical	O
+rate	O
+was	O
+calculated	O
+by	O
+dividing	O
+the	O
+total	O
+cataract	O
+output	O
+in	O
+2015	O
+by	O
+the	O
+estimated	O
+population	O
+of	O
+Palestine	B-LOC
+in	O
+millions	O
+.	O
+
+Results	O
+:	O
+In	O
+2015	O
+,	O
+9908	O
+cataract	O
+surgeries	O
+were	O
+carried	O
+out	O
+in	O
+22	O
+centres	O
+.	O
+
+The	O
+cataract	O
+surgical	O
+rate	O
+was	O
+2,117	B-STAT
+operations	I-STAT
+per	I-STAT
+million	I-STAT
+population	I-STAT
+.	O
+
+Phacoemulsification	O
+was	O
+the	O
+most	O
+common	O
+technique	O
+(	O
+73.4	O
+%	O
+)	O
+,	O
+however	O
+in	O
+government	O
+centres	O
+67	O
+%	O
+were	O
+performed	O
+by	O
+extracapsular	O
+cataract	O
+extraction	O
+.	O
+In	O
+the	B-LOC
+Gaza	I-LOC
+Strip	I-LOC
+,	O
+56.6	O
+%	O
+of	O
+cataract	O
+surgeries	O
+were	O
+operated	O
+at	O
+government	O
+centres	O
+,	O
+and	O
+42.8	O
+%	O
+were	O
+operated	O
+at	O
+NGO	B-LOC
+centres	O
+while	O
+in	O
+West	B-LOC
+Bank	I-LOC
+,	O
+only	O
+12	O
+%	O
+of	O
+cataract	O
+surgeries	O
+were	O
+operated	O
+at	O
+government	O
+centres	O
+,	O
+with	O
+two	O
+-	O
+thirds	O
+of	O
+cataracts	O
+diagnosed	O
+at	O
+governmental	O
+centres	O
+being	O
+referred	O
+to	O
+private	O
+and	O
+NGO	B-LOC
+centres	O
+.	O
+
+Seventy	O
+eight	O
+percent	O
+of	O
+cataract	O
+surgeries	O
+were	O
+funded	O
+by	O
+insurance	O
+,	O
+of	O
+which	O
+the	O
+government	O
+insurance	O
+scheme	O
+contributed	O
+65	B-STAT
+%	I-STAT
+.	O
+
+Conclusion	O
+:	O
+The	O
+cataract	O
+surgical	O
+rate	O
+in	O
+Palestine	B-LOC
+falls	O
+short	O
+of	O
+the	O
+required	O
+WHO	O
+target	O
+.	O
+
+The	O
+majority	O
+of	O
+cataract	O
+surgeries	O
+are	O
+funded	O
+by	O
+insurance	O
+.	O
+
+BACKGROUND	O
+:	O
+Most	O
+patients	O
+with	O
+isolated	O
+methylmalonic	O
+acidemia	O
+(	O
+MMA	O
+)	O
+/propionic	O
+acidemia	O
+(	O
+PA	O
+)	O
+presenting	O
+during	O
+the	O
+neonatal	O
+period	O
+with	O
+acute	O
+metabolic	O
+distress	O
+are	O
+at	O
+risk	O
+for	O
+death	O
+and	O
+significant	O
+neurodevelopmental	O
+disability	O
+.	O
+
+The	O
+nationwide	O
+newborn	O
+screening	O
+for	O
+MMA	O
+/	O
+PA	O
+has	O
+been	O
+in	O
+place	O
+in	O
+Taiwan	B-LOC
+from	O
+January	O
+,	O
+2000	O
+and	O
+data	O
+was	O
+collected	O
+until	O
+December	O
+,	O
+2016	O
+.	O
+
+RESULTS	O
+:	O
+During	O
+the	O
+study	O
+period	O
+,	O
+3,155,263	O
+newborns	O
+were	O
+screened	O
+.	O
+
+The	O
+overall	B-EPI
+incidence	I-EPI
+of	O
+MMA	O
+mutase	O
+type	O
+cases	O
+was	O
+1/121,356	B-STAT
+(	O
+n	O
+=	O
+26	O
+)	O
+,	O
+1	B-STAT
+cobalamin	I-STAT
+B	I-STAT
+was	O
+detected	O
+and	O
+that	O
+for	O
+PA	O
+cases	O
+(	O
+n	O
+=	O
+4	O
+)	O
+was	O
+1/788,816	B-STAT
+.	O
+
+The	O
+time	O
+of	O
+referral	O
+is	O
+8.8	O
+days	O
+for	O
+MMA	O
+patients	O
+,	O
+and	O
+7.5	O
+days	O
+for	O
+PA	O
+patients	O
+.	O
+
+The	O
+MMA	O
+mutase	O
+type	O
+patients	O
+have	O
+higher	O
+AST	O
+,	O
+ALT	O
+,	O
+and	O
+NH3	O
+values	O
+as	O
+well	O
+as	O
+a	O
+lower	O
+pH	O
+value	O
+(	O
+p	O
+<	O
+0.05	O
+)	O
+.	O
+
+The	O
+mean	O
+age	O
+for	O
+liver	O
+transplantation	O
+(	O
+LT	O
+)	O
+is	O
+402	O
+days	O
+(	O
+range	O
+from	O
+0.6	O
+-	O
+6.7	O
+yr	O
+)	O
+with	O
+16	O
+out	O
+of	O
+20	O
+cases	O
+(	O
+80.0	O
+%	O
+)	O
+using	O
+living	O
+donors	O
+.	O
+
+The	O
+mean	O
+admission	O
+length	O
+shortened	O
+from	O
+90.6	O
+days	O
+/	O
+year	O
+(	O
+pre	O
+-	O
+LT	O
+)	O
+to	O
+5.3	O
+days	O
+/	O
+year	O
+(	O
+at	O
+3rd	O
+year	O
+post	O
+-	O
+LT	O
+)	O
+(	O
+p	O
+<	O
+0.0005	O
+)	O
+.	O
+
+Similarly	O
+,	O
+the	O
+tube	O
+feeding	O
+ratio	O
+decreased	O
+from	O
+67.8	B-STAT
+to	I-STAT
+0.50	I-STAT
+%	I-STAT
+(	O
+p	O
+<	O
+0.00005	O
+)	O
+.	O
+
+The	O
+anxiety	O
+level	O
+of	O
+the	O
+caregiver	O
+was	O
+reduced	O
+from	O
+33.4	O
+to	O
+27.2	O
+after	O
+LT	O
+(	O
+p	O
+=	O
+0.001	O
+)	O
+and	O
+the	O
+DQ	O
+/	O
+IQ	O
+performance	O
+of	O
+the	O
+patients	O
+was	O
+improved	O
+after	O
+LT	O
+from	O
+50	O
+to	O
+60.1	O
+(	O
+p	O
+=	O
+0.07	O
+)	O
+.	O
+
+CONCLUSION	O
+:	O
+MMA	O
+/	O
+PA	O
+patients	O
+with	O
+LT	O
+do	O
+survive	O
+and	O
+have	O
+reduced	O
+admission	O
+time	O
+,	O
+reduced	O
+tube	O
+feeding	O
+and	O
+the	O
+caregiver	O
+is	O
+less	O
+anxious	O
+.	O
+
+The	O
+use	O
+of	O
+Drosophila	O
+melanogaster	O
+as	O
+a	O
+model	O
+for	O
+studying	O
+human	O
+disease	O
+is	O
+well	O
+established	O
+,	O
+reflected	O
+by	O
+the	O
+steady	O
+increase	O
+in	O
+both	O
+the	O
+number	O
+and	O
+proportion	O
+of	O
+fly	O
+papers	O
+describing	O
+human	O
+disease	O
+models	O
+in	O
+recent	O
+years	O
+.	O
+
+In	O
+this	O
+article	O
+,	O
+we	O
+highlight	O
+recent	O
+efforts	O
+to	O
+improve	O
+the	O
+availability	O
+and	O
+accessibility	O
+of	O
+the	O
+disease	O
+model	O
+information	O
+in	O
+FlyBase	O
+(	O
+http://flybase.org	O
+)	O
+,	O
+the	O
+model	O
+organism	O
+database	O
+for	O
+Drosophila	O
+.	O
+
+FlyBase	O
+has	O
+recently	O
+introduced	O
+Human	O
+Disease	O
+Model	O
+Reports	O
+,	O
+each	O
+of	O
+which	O
+presents	O
+background	O
+information	O
+on	O
+a	O
+specific	O
+disease	O
+,	O
+a	O
+tabulation	O
+of	O
+related	O
+disease	O
+subtypes	O
+,	O
+and	O
+summaries	O
+of	O
+experimental	O
+data	O
+and	O
+results	O
+using	O
+fruit	O
+flies	O
+.	O
+
+Integrated	O
+presentations	O
+of	O
+relevant	O
+data	O
+and	O
+reagents	O
+described	O
+in	O
+other	O
+sections	O
+of	O
+FlyBase	O
+are	O
+incorporated	O
+into	O
+these	O
+reports	O
+,	O
+which	O
+are	O
+specifically	O
+designed	O
+to	O
+be	O
+accessible	O
+to	O
+non	O
+-	O
+fly	O
+researchers	O
+in	O
+order	O
+to	O
+promote	O
+collaboration	O
+across	O
+model	O
+organism	O
+communities	O
+working	O
+in	O
+translational	O
+science	O
+.	O
+
+Another	O
+key	O
+component	O
+of	O
+disease	O
+model	O
+information	O
+in	O
+FlyBase	O
+is	O
+that	O
+data	O
+are	O
+collected	O
+in	O
+a	O
+consistent	O
+format	O
+---	O
+using	O
+the	O
+evolving	O
+Disease	O
+Ontology	O
+(	O
+an	O
+open	O
+-	O
+source	O
+standardized	O
+ontology	O
+for	O
+human	O
+-	O
+disease	O
+-	O
+associated	O
+biomedical	O
+data	O
+)	O
+-	O
+to	O
+allow	O
+robust	O
+and	O
+intuitive	O
+searches	O
+.	O
+
+To	O
+facilitate	O
+this	O
+,	O
+FlyBase	O
+has	O
+developed	O
+a	O
+dedicated	O
+tool	O
+for	O
+querying	O
+and	O
+navigating	O
+relevant	O
+data	O
+,	O
+which	O
+include	O
+mutations	O
+that	O
+model	O
+a	O
+disease	O
+and	O
+any	O
+associated	O
+interacting	O
+modifiers	O
+.	O
+
+In	O
+this	O
+article	O
+,	O
+we	O
+describe	O
+how	O
+data	O
+related	O
+to	O
+fly	O
+models	O
+of	O
+human	O
+disease	O
+are	O
+presented	O
+in	O
+individual	O
+Gene	O
+Reports	O
+and	O
+in	O
+the	O
+Human	O
+Disease	O
+Model	O
+Reports	O
+.	O
+
+Finally	O
+,	O
+we	O
+discuss	O
+search	O
+strategies	O
+and	O
+new	O
+query	O
+tools	O
+that	O
+are	O
+available	O
+to	O
+access	O
+the	O
+disease	O
+model	O
+data	O
+in	O
+FlyBase	O
+.	O
+
+Seizures	O
+are	O
+the	O
+most	O
+acute	O
+evident	O
+manifestation	O
+of	O
+central	O
+nervous	O
+system	O
+dysfunction	O
+in	O
+neonates	O
+.	O
+
+The	O
+incidence	B-EPI
+is	O
+higher	O
+in	O
+very	O
+low	O
+weight	O
+neonates	O
+,	O
+about	O
+58/100	B-STAT
+live	I-STAT
+births	I-STAT
+,	O
+as	O
+opposed	O
+to	O
+full	O
+-	O
+term	O
+infants	O
+,	O
+estimated	O
+about	O
+3.5/100	B-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+Neonatal	O
+seizures	O
+represent	O
+the	O
+clinical	O
+manifestation	O
+of	O
+a	O
+non	O
+-	O
+specific	O
+disorder	O
+of	O
+cortical	O
+cerebral	O
+dysfunction	O
+,	O
+which	O
+could	O
+lead	O
+to	O
+permanent	O
+brain	O
+injury	O
+.	O
+
+The	O
+etiology	O
+is	O
+multifactorial	O
+and	O
+requires	O
+a	O
+judicious	O
+assessment	O
+of	O
+each	O
+clinical	O
+scenario	O
+.	O
+
+The	O
+diagnosis	O
+and	O
+its	O
+management	O
+are	O
+further	O
+complicated	O
+as	O
+most	O
+neonatal	O
+seizures	O
+may	O
+have	O
+very	O
+subtle	O
+or	O
+no	O
+clinical	O
+changes	O
+and	O
+the	O
+diagnosis	O
+may	O
+be	O
+just	O
+based	O
+on	O
+EEG	O
+findings	O
+,	O
+so	O
+-	O
+called	O
+subclinical	O
+.	O
+
+The	O
+treatment	O
+is	O
+dependent	O
+on	O
+the	O
+etiology	O
+,	O
+but	O
+early	O
+and	O
+opportune	O
+intervention	O
+can	O
+prevent	O
+further	O
+brain	O
+damage	O
+and	O
+improve	O
+prognosis	O
+.	O
+
+Although	O
+early	O
+identification	O
+and	O
+treatment	O
+are	O
+essential	O
+,	O
+the	O
+diagnosis	O
+of	O
+neonatal	O
+seizures	O
+can	O
+be	O
+further	O
+complicated	O
+by	O
+the	O
+clinical	O
+presentations	O
+,	O
+possible	O
+etiologies	O
+,	O
+and	O
+treatments	O
+.	O
+
+Nevertheless	O
+,	O
+research	O
+studies	O
+and	O
+clinical	O
+evidence	O
+have	O
+shown	O
+that	O
+early	O
+treatment	O
+with	O
+anti	O
+-	O
+seizure	O
+medications	O
+can	O
+change	O
+the	O
+outcome	O
+.	O
+
+Urea	O
+cycle	O
+disorders	O
+(	O
+UCDs	O
+)	O
+are	O
+inherited	O
+metabolic	O
+disorders	O
+with	O
+impaired	O
+nitrogen	O
+detoxification	O
+caused	O
+by	O
+defects	O
+in	O
+urea	O
+cycle	O
+enzymes	O
+.	O
+
+They	O
+often	O
+manifest	O
+with	O
+hyperammonemic	O
+attacks	O
+resulting	O
+in	O
+significant	O
+morbidity	O
+or	O
+death	O
+.	O
+
+We	O
+performed	O
+a	O
+nationwide	O
+questionnaire	O
+-	O
+based	O
+study	O
+between	O
+January	O
+2000	O
+and	O
+March	O
+2018	O
+to	O
+document	O
+all	O
+UCDs	O
+in	O
+Japan	B-LOC
+,	O
+including	O
+diagnoses	O
+,	O
+treatments	O
+,	O
+and	O
+outcomes	O
+.	O
+
+A	O
+total	O
+of	O
+229	O
+patients	O
+with	O
+UCDs	O
+were	O
+enrolled	O
+in	O
+this	O
+study	O
+:	O
+73	O
+males	O
+and	O
+53	O
+females	O
+with	O
+ornithine	O
+transcarbamylase	O
+deficiency	O
+(	O
+OTCD	O
+)	O
+,	O
+33	O
+patients	O
+with	O
+carbamoylphosphate	O
+synthetase	O
+1	B-STAT
+deficiency	I-STAT
+,	I-STAT
+48	I-STAT
+with	O
+argininosuccinate	O
+synthetase	O
+deficiency	O
+,	O
+14	O
+with	O
+argininosuccinate	O
+lyase	O
+deficiency	O
+,	O
+and	O
+8	O
+with	O
+arginase	O
+deficiency	O
+.	O
+
+Survival	O
+rates	O
+at	O
+20	O
+years	O
+of	O
+age	O
+of	O
+male	O
+and	O
+female	O
+patients	O
+with	O
+late	O
+-	O
+onset	O
+OTCD	O
+were	O
+100	O
+%	O
+and	O
+97.7	O
+%	O
+,	O
+respectively	O
+.	O
+
+Blood	O
+ammonia	O
+levels	O
+and	O
+time	O
+of	O
+onset	O
+had	O
+a	O
+significant	O
+impact	O
+on	O
+the	O
+neurodevelopmental	O
+outcome	O
+(	O
+P	O
+<	O
+.001	O
+and	O
+P	O
+=	O
+.028	O
+,	O
+respectively	O
+)	O
+.	O
+
+Hemodialysis	O
+and	O
+liver	O
+transplantation	O
+did	O
+not	O
+prevent	O
+poor	O
+neurodevelopmental	O
+outcomes	O
+.	O
+
+While	O
+treatment	O
+including	O
+medication	O
+,	O
+hemodialysis	O
+,	O
+and	O
+liver	O
+transplantation	O
+may	O
+aid	O
+in	O
+decreasing	O
+blood	O
+ammonia	O
+and/or	O
+preventing	O
+severe	O
+hyperammonemia	O
+,	O
+a	O
+blood	O
+ammonia	O
+level	O
+≥	O
+360	O
+μmol	O
+/	O
+L	O
+was	O
+found	O
+to	O
+be	O
+a	O
+significant	O
+indicator	O
+for	O
+a	O
+poor	O
+neurodevelopmental	O
+outcome	O
+.	O
+
+In	O
+conclusion	O
+,	O
+although	O
+current	O
+therapy	O
+for	O
+UCDs	O
+has	O
+advanced	O
+and	O
+helped	O
+saving	O
+lives	O
+,	O
+patients	O
+with	O
+blood	O
+ammonia	O
+levels	O
+≥	O
+360	O
+μmol	O
+/	O
+L	O
+at	O
+onset	O
+often	O
+have	O
+impaired	O
+neurodevelopmental	O
+outcomes	O
+.	O
+
+Novel	O
+neuroprotective	O
+measures	O
+should	O
+therefore	O
+be	O
+developed	O
+to	O
+achieve	O
+better	O
+neurodevelopmental	O
+outcomes	O
+in	O
+these	O
+patients	O
+.	O
+
+Despite	O
+the	O
+importance	O
+of	O
+Culex	O
+species	O
+as	O
+major	O
+vectors	O
+of	O
+Rift	B-LOC
+Valley	I-LOC
+fever	O
+virus	O
+,	O
+West	B-LOC
+Nile	I-LOC
+virus	O
+and	O
+the	O
+microfilariae	O
+that	O
+cause	O
+lymphatic	O
+filariasis	O
+,	O
+information	O
+on	O
+these	O
+mosquitoes	O
+in	O
+Sudan	B-LOC
+is	O
+limited	O
+to	O
+works	O
+published	O
+65	O
+years	O
+ago	O
+in	O
+the	O
+former	O
+Anglo	O
+-	O
+Egyptian	O
+Sudan	B-LOC
+,	O
+where	O
+some	O
+species	O
+were	O
+only	O
+recorded	O
+from	O
+areas	O
+of	O
+the	O
+territory	O
+now	O
+known	O
+as	O
+South	B-LOC
+Sudan	I-LOC
+.	O
+
+In	O
+this	O
+paper	O
+,	O
+we	O
+provide	O
+updated	O
+information	O
+on	O
+Culex	O
+mosquitoes	O
+collected	O
+indoors	O
+during	O
+surveillance	O
+studies	O
+conducted	O
+along	O
+the	B-LOC
+Nile	I-LOC
+River	I-LOC
+in	O
+central	O
+and	O
+northern	O
+areas	O
+of	O
+Sudan	B-LOC
+between	O
+2012	O
+and	O
+2019	O
+.	O
+
+Of	O
+3,411	O
+female	O
+mosquitoes	O
+collected	O
+in	O
+Khartoum	B-LOC
+and	O
+northern	O
+states	O
+along	O
+the	O
+river	O
+,	O
+2,560	O
+(	O
+75	O
+%	O
+)	O
+were	O
+specimens	O
+of	O
+Culex	O
+belonging	O
+to	O
+12	O
+species	O
+:	O
+Cx	O
+.	O
+
+(	O
+Culex	O
+)	O
+antennatus	O
+(	O
+Becker	O
+,	O
+1903	O
+)	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+laticinctus	O
+Edwards	O
+,	O
+1913	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+neavei	O
+Theobald	B-LOC
+,	O
+1906	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+pipiens	O
+Linnaeus	O
+,	O
+1758	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+perexiguus	O
+Theobald	B-LOC
+,	O
+1903	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+poicilipes	O
+(	O
+Theobald	B-LOC
+,	O
+1903	O
+)	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+quinquefasciatus	O
+Say	O
+,	O
+1823	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+simpsoni	O
+Theobald	B-LOC
+,	O
+1905	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+sinaiticus	O
+Kirkpatrick	O
+,	O
+1925	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+theileri	O
+Theobald	B-LOC
+,	O
+1903	O
+,	O
+Cx	O
+.	O
+
+(	O
+Cux	O
+.	O
+)	O
+
+tritaeniorhynchus	O
+Giles	O
+,	O
+1901	O
+and	O
+Cx	O
+.	O
+
+(	O
+Culiciomyia	O
+)	O
+macfiei	O
+Edwards	O
+,	O
+1923	O
+.	O
+
+This	O
+is	O
+the	O
+first	O
+record	O
+for	O
+Cx	O
+.	O
+
+tritaeniorhynchus	O
+and	O
+Cx	O
+.	O
+
+macfiei	O
+in	O
+central	O
+Sudan	B-LOC
+.	O
+
+The	O
+relative	O
+abundance	O
+of	O
+each	O
+species	O
+varied	O
+in	O
+different	O
+areas	O
+and	O
+seasons	O
+,	O
+but	O
+Cx	O
+.	O
+
+antennatus	O
+and	O
+Cx	O
+.	O
+
+quinquefasciatus	O
+were	O
+the	O
+most	O
+abundant	O
+indoor	O
+resting	O
+species	O
+.	O
+
+We	O
+provide	O
+an	O
+updated	O
+dichotomous	O
+key	O
+for	O
+the	O
+identification	O
+of	O
+the	O
+adults	O
+of	O
+Culex	O
+mosquitoes	O
+known	O
+to	O
+occur	O
+in	O
+the	B-LOC
+Republic	I-LOC
+of	I-LOC
+the	I-LOC
+Sudan	I-LOC
+.	O
+
+The	O
+authors	O
+analyse	O
+descriptions	O
+of	O
+Greenlandic	O
+and	O
+Faroese	O
+medicine	O
+found	O
+in	O
+an	O
+Italian	O
+medical	O
+publication	O
+from	O
+the	O
+18th	O
+century	O
+entitled	O
+,	O
+Europae	O
+Medicina	O
+a	O
+Sapientibus	O
+Illustrata	O
+[	O
+…	O
+]	O
+,	O
+which	O
+was	O
+printed	O
+in	O
+Brescia	B-LOC
+,	O
+in	O
+Northern	B-LOC
+Italy	I-LOC
+,	O
+in	O
+1747	O
+.	O
+
+The	O
+author	O
+of	O
+these	O
+descriptions	O
+,	O
+Francesco	O
+Roncalli	O
+Parolino	O
+(	O
+1692	O
+-	O
+1769	O
+)	O
+,	O
+was	O
+a	O
+renowned	O
+European	O
+physician	O
+.	O
+
+Roncalli	O
+Parolino	O
+focused	O
+his	O
+study	O
+on	O
+the	O
+treatment	O
+of	O
+scurvy	O
+and	O
+he	O
+promoted	O
+the	O
+inclusion	O
+of	O
+the	O
+Greenlandic	O
+and	O
+Faroese	O
+therapy	O
+into	O
+the	O
+broader	O
+European	O
+context	O
+.	O
+
+He	O
+was	O
+influenced	O
+to	O
+do	O
+this	O
+due	O
+to	O
+the	O
+already	O
+integrated	O
+European	O
+perspective	O
+of	O
+medicine	O
+which	O
+his	O
+book	O
+follows	O
+.	O
+Like	O
+now	O
+,	O
+medicine	O
+in	O
+18th	O
+-	O
+century	O
+Europe	B-LOC
+was	O
+multicentric	O
+and	O
+characterised	O
+by	O
+rich	O
+intellectual	O
+activity	O
+,	O
+which	O
+contributed	O
+to	O
+the	O
+enhancement	O
+of	O
+clinical	O
+practice	O
+during	O
+this	O
+period	O
+.	O
+
+At	O
+the	O
+time	O
+,	O
+Greenland	B-LOC
+and	O
+Faroe	B-LOC
+Islands	I-LOC
+were	O
+also	O
+integrated	O
+into	O
+this	O
+European	O
+context	O
+because	O
+they	O
+contributed	O
+for	O
+medical	O
+-	O
+scientific	O
+development	O
+that	O
+would	O
+lay	O
+the	O
+foundations	O
+for	O
+modern	O
+medicine	O
+.	O
+
+Francesco	O
+Roncalli	O
+Parolino	O
+obtained	O
+just	O
+recognition	O
+for	O
+these	O
+regions	O
+through	O
+the	O
+advancement	O
+and	O
+defence	O
+of	O
+their	O
+valuable	O
+medical	O
+contributions	O
+.	O
+
+VACTERL	O
+/	O
+VATER	O
+association	O
+is	O
+typically	O
+defined	O
+by	O
+the	O
+presence	O
+of	O
+at	O
+least	O
+three	O
+of	O
+the	O
+following	O
+congenital	O
+malformations	O
+:	O
+vertebral	O
+defects	O
+,	O
+anal	O
+atresia	O
+,	O
+cardiac	O
+defects	O
+,	O
+tracheo	O
+-	O
+esophageal	O
+fistula	O
+,	O
+renal	O
+anomalies	O
+,	O
+and	O
+limb	O
+abnormalities	O
+.	O
+
+In	O
+addition	O
+to	O
+these	O
+core	O
+component	O
+features	O
+,	O
+patients	O
+may	O
+also	O
+have	O
+other	O
+congenital	O
+anomalies	O
+.	O
+
+Although	O
+diagnostic	O
+criteria	O
+vary	O
+,	O
+the	O
+incidence	B-EPI
+is	O
+estimated	O
+at	O
+approximately	O
+1	O
+in	O
+10,000	O
+to	O
+1	O
+in	O
+40,000	O
+live	O
+-	O
+born	O
+infants	O
+.	O
+
+The	O
+condition	O
+is	O
+ascertained	O
+clinically	O
+by	O
+the	O
+presence	O
+of	O
+the	O
+above	O
+-	O
+mentioned	O
+malformations	O
+;	O
+importantly	O
+,	O
+there	O
+should	O
+be	O
+no	O
+clinical	O
+or	O
+laboratory	O
+-	O
+based	O
+evidence	O
+for	O
+the	O
+presence	O
+of	O
+one	O
+of	O
+the	O
+many	O
+similar	O
+conditions	O
+,	O
+as	O
+the	O
+differential	O
+diagnosis	O
+is	O
+relatively	O
+large	O
+.	O
+
+This	O
+differential	O
+diagnosis	O
+includes	O
+(	O
+but	O
+is	O
+not	O
+limited	O
+to	O
+)	O
+Baller	O
+-	O
+Gerold	O
+syndrome	O
+,	O
+CHARGE	O
+syndrome	O
+,	O
+Currarino	O
+syndrome	O
+,	O
+deletion	O
+22q11.2	O
+syndrome	O
+,	O
+Fanconi	O
+anemia	O
+,	O
+Feingold	O
+syndrome	O
+,	O
+Fryns	O
+syndrome	O
+,	O
+MURCS	O
+association	O
+,	O
+oculo	O
+-	O
+auriculo	O
+-	O
+vertebral	O
+syndrome	O
+,	O
+Opitz	O
+G	O
+/	O
+BBB	O
+syndrome	O
+,	O
+Pallister	O
+-	O
+Hall	O
+syndrome	O
+,	O
+Townes	O
+-	O
+Brocks	O
+syndrome	O
+,	O
+and	O
+VACTERL	O
+with	O
+hydrocephalus	O
+.	O
+
+Though	O
+there	O
+are	O
+hints	O
+regarding	O
+causation	O
+,	O
+the	O
+aetiology	O
+has	O
+been	O
+identified	O
+only	O
+in	O
+a	O
+small	O
+fraction	O
+of	O
+patients	O
+to	O
+date	O
+,	O
+likely	O
+due	O
+to	O
+factors	O
+such	O
+as	O
+a	O
+high	O
+degree	O
+of	O
+clinical	O
+and	O
+causal	O
+heterogeneity	O
+,	O
+the	O
+largely	O
+sporadic	O
+nature	O
+of	O
+the	O
+disorder	O
+,	O
+and	O
+the	O
+presence	O
+of	O
+many	O
+similar	O
+conditions	O
+.	O
+
+New	O
+genetic	O
+research	O
+methods	O
+offer	O
+promise	O
+that	O
+the	O
+causes	O
+of	O
+VACTERL	O
+association	O
+will	O
+be	O
+better	O
+defined	O
+in	O
+the	O
+relatively	O
+near	O
+future	O
+.	O
+
+Antenatal	O
+diagnosis	O
+can	O
+be	O
+challenging	O
+,	O
+as	O
+certain	O
+component	O
+features	O
+can	O
+be	O
+difficult	O
+to	O
+ascertain	O
+prior	O
+to	O
+birth	O
+.	O
+
+The	O
+management	O
+of	O
+patients	O
+with	O
+VACTERL	O
+/	O
+VATER	O
+association	O
+typically	O
+centers	O
+around	O
+surgical	O
+correction	O
+of	O
+the	O
+specific	O
+congenital	O
+anomalies	O
+(	O
+typically	O
+anal	O
+atresia	O
+,	O
+certain	O
+types	O
+of	O
+cardiac	O
+malformations	O
+,	O
+and/or	O
+tracheo	O
+-	O
+esophageal	O
+fistula	O
+)	O
+in	O
+the	O
+immediate	O
+postnatal	O
+period	O
+,	O
+followed	O
+by	O
+long	O
+-	O
+term	O
+medical	O
+management	O
+of	O
+sequelae	O
+of	O
+the	O
+congenital	O
+malformations	O
+.	O
+
+If	O
+optimal	O
+surgical	O
+correction	O
+is	O
+achievable	O
+,	O
+the	O
+prognosis	O
+can	O
+be	O
+relatively	O
+positive	O
+,	O
+though	O
+some	O
+patients	O
+will	O
+continue	O
+to	O
+be	O
+affected	O
+by	O
+their	O
+congenital	O
+malformations	O
+throughout	O
+life	O
+.	O
+
+Importantly	O
+,	O
+patients	O
+with	O
+VACTERL	O
+association	O
+do	O
+not	O
+tend	O
+to	O
+have	O
+neurocognitive	O
+impairment	O
+.	O
+
+MYO15A	O
+is	O
+the	O
+third	O
+most	O
+crucial	O
+gene	O
+in	O
+hereditary	O
+sensorineural	O
+hearing	O
+loss	O
+after	O
+GJB2	O
+and	O
+SLC26A4	O
+.	O
+
+In	O
+the	O
+present	O
+study	O
+,	O
+we	O
+reviewed	O
+the	O
+prevalence	B-EPI
+of	O
+MYO15A	O
+mutations	O
+in	O
+patients	O
+with	O
+autosomal	O
+recessive	O
+non	O
+-	O
+syndromic	O
+hearing	O
+loss	O
+(	O
+ARNSHL	O
+)	O
+.	O
+
+In	O
+this	O
+meta	O
+-	O
+analysis	O
+,	O
+we	O
+conducted	O
+a	O
+search	O
+of	O
+PubMed	O
+,	O
+Web	O
+of	O
+Science	O
+,	O
+Excerpta	O
+Medica	O
+Database	O
+,	O
+and	O
+Scopus	O
+,	O
+and	O
+identified	O
+the	O
+articles	O
+up	O
+to	O
+September	O
+2019	O
+without	O
+any	O
+time	O
+limit	O
+.	O
+
+Two	O
+investigators	O
+independently	O
+selected	O
+the	O
+relevant	O
+papers	O
+and	O
+extracted	O
+the	O
+required	O
+information	O
+.	O
+
+A	O
+total	O
+of	O
+44	O
+case	O
+-	O
+control	O
+and	O
+case	O
+series	O
+studies	O
+were	O
+considered	O
+,	O
+and	O
+4176	O
+patients	O
+and	O
+3706	O
+healthy	O
+individuals	O
+,	O
+as	O
+the	O
+control	O
+group	O
+,	O
+were	O
+included	O
+.	O
+
+The	O
+pooled	O
+frequency	O
+of	O
+MYO15A	O
+mutations	O
+between	O
+patients	O
+suffering	O
+from	O
+ARNSHL	O
+was	O
+calculated	O
+as	O
+6.2	O
+%	O
+(	O
+95	O
+%	O
+CI	O
+:	O
+4.9	O
+-	O
+7.8	O
+,	O
+P	O
+-value<0.001	O
+)	O
+.	O
+
+There	O
+was	O
+heterogeneity	O
+between	O
+our	O
+studies	O
+(	O
+P	O
+-value<0.001	O
+,	O
+I2=58.1	O
+%	O
+)	O
+;	O
+therefore	O
+,	O
+the	O
+random	O
+-	O
+effects	O
+model	O
+was	O
+utilized	O
+for	O
+analysis	O
+.	O
+
+Given	O
+the	O
+results	O
+,	O
+in	O
+many	O
+countries	O
+,	O
+the	O
+MYO15A	O
+gene	O
+has	O
+a	O
+significant	O
+contribution	O
+to	O
+hearing	O
+loss	O
+.	O
+
+Moreover	O
+,	O
+in	O
+several	O
+regions	O
+,	O
+specific	O
+dominant	O
+mutations	O
+in	O
+this	O
+gene	O
+have	O
+been	O
+reported	O
+.	O
+
+Therefore	O
+,	O
+the	O
+ethnic	O
+background	O
+should	O
+be	O
+considered	O
+to	O
+investigate	O
+the	O
+mutations	O
+of	O
+the	O
+MYO15A	O
+gene	O
+.	O
+
+Encephalocele	O
+is	O
+a	O
+herniation	O
+of	O
+the	O
+brain	O
+(	O
+cranium	O
+bifidum	O
+,	O
+cephalocele	O
+,	O
+craniocele	O
+)	O
+,	O
+formed	O
+during	O
+embryonic	O
+development	O
+,	O
+because	O
+of	O
+the	O
+incomplete	O
+closure	O
+of	O
+Neural	O
+Tube	O
+.	O
+
+It	O
+is	O
+a	O
+rare	O
+skull	O
+defect	O
+,	O
+with	O
+the	O
+incidence	B-EPI
+of	O
+0.8	B-STAT
+to	I-STAT
+5	I-STAT
+per	I-STAT
+10,000	I-STAT
+live	I-STAT
+births	I-STAT
+.	O
+
+The	O
+article	O
+presents	O
+the	O
+medical	O
+history	O
+of	O
+a	O
+four	O
+month	O
+old	O
+patient	O
+,	O
+with	O
+frontoethmoidal	O
+encephalocele	O
+and	O
+multiple	O
+skeletal	O
+anomalies	O
+,	O
+such	O
+as	O
+amniotic	O
+knots	O
+on	O
+limbs	O
+,	O
+foot	O
+deformity	O
+,	O
+sindactilia	O
+and	O
+cleft	O
+palate	O
+.	O
+
+Introduction	O
+Ehlers	O
+-	O
+Danlos	O
+syndrome	O
+(	O
+EDS	O
+)	O
+,	O
+specifically	O
+the	O
+hypermobility	O
+type	O
+(	O
+hEDS	O
+)	O
+,	O
+is	O
+associated	O
+with	O
+a	O
+variety	O
+of	O
+gastrointestinal	O
+(	O
+GI	O
+)	O
+conditions	O
+.	O
+
+This	O
+study	O
+aims	O
+to	O
+evaluate	O
+the	O
+prevalence	B-EPI
+of	O
+and	O
+factors	O
+associated	O
+with	O
+gut	O
+dysmotility	O
+in	O
+patients	O
+with	O
+hEDS	O
+.	O
+
+Methods	O
+This	O
+is	O
+a	O
+retrospective	O
+study	O
+of	O
+hEDS	O
+patients	O
+conducted	O
+at	O
+the	O
+Cleveland	O
+Clinic	O
+'s	O
+Center	O
+for	O
+Personalized	O
+Genetic	O
+Healthcare	O
+between	O
+January	O
+2007	O
+and	O
+December	O
+2017	O
+.	O
+
+Demographics	O
+,	O
+GI	O
+motility	O
+testing	O
+,	O
+endoscopic	O
+,	O
+and	O
+imaging	O
+data	O
+were	O
+extracted	O
+from	O
+the	O
+patients	O
+'	O
+charts	O
+.	O
+
+Results	O
+A	O
+total	O
+of	O
+218	O
+patients	O
+with	O
+hEDS	O
+were	O
+identified	O
+.	O
+
+Among	O
+them	O
+,	O
+136	B-STAT
+(	O
+62.3	O
+%	O
+)	O
+patients	O
+had	O
+at	O
+least	O
+one	O
+GI	O
+symptom	O
+at	O
+the	O
+time	O
+of	O
+EDS	O
+diagnosis	O
+.	O
+
+Motility	O
+testing	O
+was	O
+performed	O
+and	O
+reported	O
+in	O
+42	B-STAT
+(	O
+19.2	O
+%	O
+)	O
+patients	O
+.	O
+
+Out	O
+of	O
+them	O
+,	O
+five	O
+(	O
+11.9	O
+%	O
+)	O
+had	O
+esophageal	O
+dysmotility	O
+,	O
+18	B-STAT
+(	O
+42.8	O
+%	O
+)	O
+had	O
+gastroparesis	O
+,	O
+five	O
+(	O
+11.9	O
+%	O
+)	O
+had	O
+small	O
+bowel	O
+/	O
+colon	O
+altered	O
+transit	O
+time	O
+,	O
+and	O
+four	O
+(	O
+9.5	O
+%	O
+)	O
+had	O
+global	O
+dysmotility	O
+.	O
+
+In	O
+univariable	O
+analysis	O
+,	O
+patients	O
+with	O
+postural	O
+orthostatic	O
+tachycardia	O
+syndrome	O
+(	O
+POTS	O
+)	O
+[	O
+odds	O
+ratio	O
+(	O
+OR	O
+):	O
+8.88	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+3.69	O
+-	O
+24.9	O
+,	O
+p<0.0001	O
+]	O
+,	O
+fibromyalgia	O
+(	O
+OR	O
+:	O
+4.43	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+2.04	O
+-	O
+10.1	O
+,	O
+p=0.0002	O
+)	O
+,	O
+history	O
+of	O
+irritable	O
+bowel	O
+syndrome	O
+(	O
+OR	O
+:	O
+5.01	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+2.31	O
+-	O
+11.2	O
+,	O
+p<0.0001	O
+)	O
+,	O
+and	O
+gastroesophageal	O
+reflux	O
+disease	O
+(	O
+OR	O
+:	O
+3.33	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+1.55	O
+-	O
+7.44	O
+,	O
+p=0.002	O
+)	O
+were	O
+more	O
+likely	O
+to	O
+be	O
+diagnosed	O
+with	O
+GI	O
+dysmotility	O
+.	O
+
+On	O
+multivariable	O
+analysis	O
+,	O
+only	O
+POTS	O
+(	O
+OR	O
+:	O
+5.74	O
+,	O
+95	O
+%	O
+CI	O
+:	O
+2.25	O
+-	O
+16.7	O
+,	O
+p=0.0005	O
+)	O
+was	O
+significantly	O
+associated	O
+with	O
+an	O
+increased	O
+likelihood	O
+of	O
+GI	O
+dysmotility	O
+.	O
+
+Conclusions	O
+This	O
+study	O
+suggests	O
+that	O
+GI	O
+symptoms	O
+are	O
+relatively	O
+common	O
+among	O
+patients	O
+with	O
+hEDS	O
+.	O
+
+Of	O
+the	O
+patients	O
+tested	O
+for	O
+dysmotility	O
+,	O
+76.2	O
+%	O
+were	O
+found	O
+to	O
+have	O
+some	O
+form	O
+of	O
+dysmotility	O
+.	O
+
+POTS	O
+was	O
+found	O
+to	O
+be	O
+an	O
+independent	O
+predictive	O
+factor	O
+for	O
+GI	O
+dysmotility	O
+.	O
+
+The	O
+incidence	B-EPI
+of	O
+neonatal	O
+varicella	O
+has	O
+decreased	O
+dramatically	O
+since	O
+the	O
+introduction	O
+of	O
+the	O
+varicella	O
+vaccination	O
+.	O
+
+Although	O
+the	O
+varicella	O
+zoster	O
+virus	O
+is	O
+often	O
+associated	O
+with	O
+a	O
+mild	O
+infection	O
+,	O
+it	O
+may	O
+cause	O
+severe	O
+morbidity	O
+and	O
+mortality	O
+,	O
+particularly	O
+in	O
+the	O
+neonatal	O
+period	O
+and	O
+immunocompromised	O
+hosts	O
+.	O
+
+We	O
+report	O
+a	O
+case	O
+of	O
+neonatal	O
+varicella	O
+acquired	O
+from	O
+maternal	O
+zoster	O
+in	O
+a	O
+mother	O
+on	O
+biological	O
+immunosuppressive	O
+therapy	O
+.	O
+
+Following	O
+the	O
+diagnosis	O
+,	O
+the	O
+baby	O
+improved	O
+on	O
+antiviral	O
+therapy	O
+without	O
+any	O
+neurological	O
+sequelae	O
+.	O
+
+This	O
+case	O
+highlights	O
+the	O
+limited	O
+published	O
+data	O
+on	O
+neonatal	O
+varicella	O
+following	O
+herpes	O
+zoster	O
+reactivation	O
+to	O
+inform	O
+practice	O
+.	O
+
+This	O
+includes	O
+the	O
+role	O
+of	O
+varicella	O
+zoster	O
+immunoglobulin	O
+in	O
+neonates	O
+exposed	O
+to	O
+maternal	O
+zoster	O
+,	O
+the	O
+degree	O
+of	O
+trans	O
+-	O
+placental	O
+immunity	O
+and	O
+optimum	O
+antiviral	O
+dosing	O
+and	O
+duration	O
+.	O
+
+In	O
+our	O
+previous	O
+studies	O
+,	O
+we	O
+discovered	O
+the	O
+congenital	O
+cold	O
+syndrome	O
+(	O
+CCS	O
+)	O
+,	O
+which	O
+is	O
+characterized	O
+by	O
+'	O
+qi	O
+deficiency	O
+and	O
+qi	O
+stagnation	O
+,	O
+mixed	O
+cold	O
+and	O
+heat	O
+.	O
+'	O
+
+And	O
+there	O
+is	O
+a	O
+type	O
+of	O
+syndrome	O
+with	O
+special	O
+incidence	B-EPI
+characteristic	O
+.	O
+
+However	O
+,	O
+the	O
+diagnosis	O
+of	O
+CCS	O
+still	O
+lacks	O
+an	O
+objective	O
+basis	O
+.	O
+
+In	O
+this	O
+study	O
+,	O
+we	O
+performed	O
+Tandem	O
+Mass	O
+Tag	O
+(	O
+TMT	O
+)	O
+based	O
+on	O
+quantitative	O
+proteomics	O
+technology	O
+to	O
+screen	O
+the	O
+significantly	O
+differentially	O
+expressed	O
+proteins	O
+(	O
+DEPs	O
+)	O
+in	O
+serum	O
+of	O
+patients	O
+with	O
+coronary	O
+heart	O
+disease	O
+(	O
+CHD	O
+)	O
+patients	O
+with	O
+CCS	O
+,	O
+patients	O
+with	O
+heart	O
+and	O
+kidney	O
+yang	O
+deficiency	O
+,	O
+and	O
+healthy	O
+people	O
+.	O
+
+A	O
+total	O
+of	O
+22	O
+DEPs	O
+(	O
+nine	O
+upregulated	O
+and	O
+13	O
+downregulated	O
+)	O
+were	O
+identified	O
+between	O
+patients	O
+with	O
+CCS	O
+and	O
+healthy	O
+subjects	O
+.	O
+
+Next	O
+,	O
+we	O
+performed	O
+GO	O
+and	O
+KEGG	O
+pathway	O
+enrichment	O
+analysis	O
+,	O
+we	O
+found	O
+the	O
+primary	O
+functions	O
+of	O
+DEPs	O
+of	O
+CCS	O
+were	O
+binding	O
+,	O
+catalytic	O
+activity	O
+,	O
+and	O
+molecular	O
+function	O
+regulator	O
+.	O
+
+These	O
+DEPs	O
+were	O
+mainly	O
+involved	O
+in	O
+important	O
+biological	O
+processes	O
+,	O
+such	O
+as	O
+cellular	O
+process	O
+,	O
+response	O
+to	O
+stimulus	O
+,	O
+localization	O
+,	O
+metabolic	O
+process	O
+,	O
+and	O
+biological	O
+regulation	O
+.	O
+
+The	O
+KEGG	O
+analysis	O
+revealed	O
+that	O
+the	O
+DEPs	O
+showed	O
+significant	O
+changes	O
+in	O
+fructose	O
+and	O
+mannose	O
+metabolism	O
+,	O
+Pentose	O
+phosphate	O
+pathway	O
+,	O
+and	O
+Arrhythmogenic	O
+right	O
+ventricular	O
+cardiomyopathy	O
+.	O
+
+After	O
+parallel	O
+reaction	O
+monitoring	O
+(	O
+PRM	O
+)	O
+verification	O
+,	O
+four	O
+upregulated	O
+target	O
+proteins	O
+(	O
+ALDOA	O
+,	O
+PCYOX1	O
+,	O
+Crisp3	O
+and	O
+IGLV4	O
+-	O
+69	O
+)	O
+and	O
+three	O
+downregulated	O
+proteins	O
+(	O
+ALDOC	O
+,	O
+ADAMTSL-2	O
+and	O
+C3	O
+)	O
+were	O
+accurately	O
+identified	O
+.	O
+
+These	O
+proteins	O
+were	O
+mainly	O
+related	O
+to	O
+immune	O
+response	O
+and	O
+glucose	O
+metabolism	O
+.	O
+
+These	O
+DEPs	O
+could	O
+be	O
+the	O
+marker	O
+proteins	O
+of	O
+coronary	O
+heart	O
+disease	O
+with	O
+CCS	O
+.	O
+
+This	O
+findings	O
+help	O
+to	O
+reveal	O
+the	O
+pathogenesis	O
+of	O
+CHD	O
+with	O
+CCS	O
+and	O
+provide	O
+potential	O
+therapeutic	O
+targets	O
+.	O
+
+Objective	O
+We	O
+recently	O
+recorded	O
+a	O
+high	O
+prevalence	B-EPI
+of	O
+inclusion	O
+body	O
+myositis	O
+(	O
+IBM	O
+)	O
+in	O
+patients	O
+with	O
+Sjögren	O
+'s	O
+syndrome	O
+(	O
+SS	O
+)	O
+.	O
+
+Whether	O
+myositis	O
+patients	O
+with	O
+SS	O
+differ	O
+from	O
+myositis	O
+patients	O
+without	O
+SS	O
+in	O
+terms	O
+of	O
+the	O
+characteristics	O
+of	O
+the	O
+myositis	O
+is	O
+currently	O
+unknown	O
+.	O
+
+Anti	O
+-	O
+cytosolic	O
+5'-nucleotidase	O
+1	O
+A	O
+(	O
+cN1A	O
+)	O
+has	O
+recently	O
+been	O
+proposed	O
+as	O
+a	O
+biomarker	O
+for	O
+IBM	O
+but	O
+is	O
+also	O
+frequent	O
+in	O
+SS	B-LOC
+.	O
+
+Whether	O
+anti	O
+-	O
+cN1A	O
+is	O
+independently	O
+associated	O
+with	O
+IBM	O
+is	O
+still	O
+an	O
+open	O
+question	O
+.	O
+
+We	O
+aimed	O
+to	O
+assess	O
+the	O
+significance	O
+of	O
+SS	O
+and	O
+anti	O
+-	O
+cN1A	O
+in	O
+myositis	O
+patients	O
+.	O
+
+Methods	O
+Cumulative	O
+data	O
+on	O
+all	O
+myositis	O
+patients	O
+(	O
+EULAR	O
+/	O
+ACR	O
+2017	O
+criteria	O
+)	O
+screened	O
+for	O
+SS	O
+(	O
+ACR	O
+/	O
+EULAR	O
+2016	O
+criteria	O
+)	O
+in	O
+a	O
+single	O
+center	O
+were	O
+analyzed	O
+.	O
+
+Ninety	O
+-	O
+nine	O
+patients	O
+were	O
+included	O
+,	O
+covering	O
+the	O
+whole	O
+spectrum	O
+of	O
+EULAR	O
+/	O
+ACR	O
+2017	O
+myositis	O
+subgroups	O
+and	O
+with	O
+a	O
+median	O
+follow	O
+-	O
+up	O
+of	O
+6	O
+years	O
+[	O
+range	O
+1.0	O
+-	O
+37.5	O
+]	O
+.	O
+
+The	O
+34	O
+myositis	O
+patients	O
+with	O
+SS	O
+(	O
+myositis	O
+/	O
+SS+	O
+)	O
+were	O
+compared	O
+with	O
+the	O
+65	O
+myositis	O
+patients	O
+without	O
+SS	O
+(	O
+myositis	O
+/	O
+SS-	O
+)	O
+.	O
+
+Results	O
+IBM	O
+was	O
+present	O
+in	O
+24	O
+%	O
+of	O
+the	O
+myositis	O
+/	O
+SS+	O
+patients	O
+vs	O
+6	O
+%	O
+of	O
+the	O
+myositis	O
+/	O
+SS-	O
+group	O
+(	O
+p	O
+=	O
+0.020	O
+)	O
+.	O
+
+None	O
+of	O
+the	O
+IBM	O
+patients	O
+responded	O
+to	O
+treatment	O
+,	O
+whether	O
+they	O
+had	O
+SS	O
+or	O
+not	O
+.	O
+
+Anti	O
+-	O
+cN1A	O
+was	O
+more	O
+frequent	O
+in	O
+myositis	O
+/	O
+SS+	O
+patients	O
+(	O
+38	O
+%	O
+vs	O
+6	O
+%	O
+,	O
+p	O
+=	O
+0.0005	O
+)	O
+,	O
+independently	O
+of	O
+the	O
+higher	O
+prevalence	B-EPI
+of	O
+IBM	O
+in	O
+this	O
+group	O
+(	O
+multivariate	O
+p	O
+-	O
+value	O
+:	O
+0.02	O
+)	O
+.	O
+
+Anti	O
+-	O
+cN1A	O
+antibody	O
+specificity	O
+for	O
+IBM	O
+was	O
+0.96	O
+[	O
+95	O
+%	O
+CI	O
+,	O
+0.87	O
+-	O
+0.99	O
+]	O
+in	O
+the	O
+myositis	O
+SS-	O
+group	O
+but	O
+dropped	O
+to	O
+0.70	O
+[	O
+95	O
+%	O
+CI	O
+,	O
+0.48	O
+-	O
+0.85	O
+]	O
+in	O
+the	O
+myositis	O
+SS/+	O
+group	O
+.	O
+
+Interpretation	O
+In	O
+myositis	O
+patients	O
+,	O
+SS	O
+is	O
+associated	O
+with	O
+IBM	O
+and	O
+with	O
+anti	O
+-	O
+cN1A	O
+antibodies	O
+,	O
+independently	O
+of	O
+the	O
+IBM	O
+diagnosis	O
+.	O
+
+As	O
+a	O
+consequence	O
+,	O
+anti	O
+-	O
+cN1A	O
+has	O
+limited	O
+specificity	O
+for	O
+IBM	O
+in	O
+myositis	O
+patients	O
+with	O
+SS	O
+.	O
+
+Background	O
+Target	O
+organ	O
+damage	O
+(	O
+mainly	O
+cardiac	O
+and	O
+renal	O
+damage	O
+)	O
+is	O
+easy	O
+to	O
+evaluate	O
+in	O
+outpatient	O
+clinics	O
+and	O
+offers	O
+valuable	O
+information	O
+about	O
+patient	O
+'s	O
+cardiovascular	O
+risk	O
+.	O
+
+The	O
+purpose	O
+of	O
+this	O
+study	O
+was	O
+to	O
+evaluate	O
+,	O
+using	O
+simple	O
+methods	O
+,	O
+the	O
+prevalence	B-EPI
+of	O
+cardiac	O
+and	O
+renal	O
+damage	O
+and	O
+its	O
+relationship	O
+to	O
+the	O
+presence	O
+of	O
+established	O
+cardiovascular	O
+disease	O
+(	O
+CVD	O
+)	O
+,	O
+in	O
+patients	O
+with	O
+hypertension	O
+(	O
+HT	O
+)	O
+and	O
+type	O
+2	O
+diabetes	O
+mellitus	O
+(	O
+DM	O
+)	O
+.	O
+
+Methods	O
+The	O
+RICARHD	O
+study	O
+is	O
+a	O
+multicentre	O
+,	O
+cross	O
+-	O
+sectional	O
+study	O
+made	O
+by	O
+293	O
+investigators	O
+in	O
+Nephrology	O
+and	O
+Internal	O
+Medicine	O
+Spanish	O
+outpatient	O
+clinics	O
+,	O
+and	O
+included	O
+patients	O
+aged	O
+55	O
+years	O
+or	O
+more	O
+with	O
+HT	O
+and	O
+type	O
+2	O
+DM	O
+with	O
+more	O
+than	O
+six	O
+months	O
+of	O
+diagnosis	O
+.	O
+
+Demographic	O
+,	O
+clinical	O
+and	O
+biochemical	O
+data	O
+,	O
+and	O
+CVD	O
+were	O
+collected	O
+from	O
+the	O
+clinical	O
+records	O
+.	O
+
+Cardiac	O
+damage	O
+was	O
+defined	O
+by	O
+the	O
+presence	O
+of	O
+electrocardiographic	O
+left	O
+ventricular	O
+hypertrophy	O
+(	O
+ECG	O
+-	O
+LVH	O
+)	O
+,	O
+and	O
+renal	O
+damage	O
+by	O
+a	O
+calculated	O
+glomerular	O
+filtration	O
+rate	O
+(	O
+GFR	O
+)	O
+of	O
+<	O
+60	O
+ml	O
+/	O
+min/1.73	O
+m2	O
+,	O
+and/or	O
+the	O
+presence	O
+of	O
+an	O
+albumin	O
+/	O
+creatinine	O
+ratio	O
+>	O
+or	O
+=	O
+30	O
+mg	O
+/	O
+g	O
+;	O
+or	O
+an	O
+urinary	O
+albumin	O
+excretion	O
+(	O
+UAE	O
+)	O
+>	O
+or	O
+=	O
+30	O
+mg/24	O
+hours	O
+.	O
+
+Results	O
+2339	O
+patients	O
+(	O
+mean	O
+age	O
+68.9	O
+years	O
+,	O
+48.2	O
+%	O
+females	O
+,	O
+51.3	O
+%	O
+with	O
+established	O
+CVD	O
+)	O
+were	O
+included	O
+.	O
+
+ECG	O
+-	O
+LVH	O
+was	O
+present	O
+in	O
+22.9	O
+%	O
+of	O
+the	O
+sample	O
+,	O
+GFR	O
+<	O
+60	O
+ml	O
+/	O
+min/1.73	O
+m2	O
+in	O
+45.1	O
+%	O
+,	O
+and	O
+abnormal	O
+UAE	O
+in	O
+58.7	B-STAT
+%	I-STAT
+.	O
+
+Compared	O
+with	O
+the	O
+reference	O
+patients	O
+(	O
+those	O
+without	O
+neither	O
+cardiac	O
+nor	O
+renal	O
+damage	O
+)	O
+,	O
+patients	O
+with	O
+ECG	O
+-	O
+LVH	O
+alone	O
+(	O
+OR	O
+2.20	O
+,	O
+[	O
+95%CI	O
+1.43	O
+-	O
+3.38	O
+]	O
+)	O
+,	O
+or	O
+kidney	O
+damage	O
+alone	O
+(	O
+OR	O
+1.41	O
+,	O
+[	O
+1.13	O
+-	O
+1.75	O
+]	O
+)	O
+showed	O
+an	O
+increased	O
+prevalence	B-EPI
+of	O
+CVD	O
+.	O
+
+The	O
+presence	O
+of	O
+both	O
+ECG	O
+-	O
+LVH	O
+and	O
+renal	O
+damage	O
+was	O
+associated	O
+with	O
+the	O
+higher	O
+prevalence	B-EPI
+(	O
+OR	O
+3.12	O
+,	O
+[	O
+2.33	O
+-	O
+4.19	O
+]	O
+)	O
+.	O
+
+After	O
+stratifying	O
+by	O
+gender	O
+,	O
+this	O
+relationship	O
+was	O
+present	O
+for	O
+both	O
+,	O
+men	O
+and	O
+women	O
+.	O
+
+Conclusion	O
+In	O
+patients	O
+with	O
+HT	O
+and	O
+type	O
+2	O
+DM	O
+,	O
+ECG	O
+-	O
+LVH	O
+or	O
+renal	O
+damage	O
+,	O
+evaluated	O
+using	O
+simple	O
+methods	O
+,	O
+are	O
+associated	O
+with	O
+an	O
+increased	O
+prevalence	B-EPI
+of	O
+established	O
+CVD	O
+.	O
+
+The	O
+simultaneous	O
+presence	O
+of	O
+both	O
+cardiac	O
+and	O
+renal	O
+damage	O
+was	O
+associated	O
+to	O
+the	O
+higher	O
+prevalence	B-EPI
+of	O
+CVD	O
+,	O
+affording	O
+complementary	O
+information	O
+.	O
+
+A	O
+systematic	O
+assessment	O
+of	O
+cardiac	O
+and	O
+renal	O
+damage	O
+complements	O
+the	O
+risk	O
+assessment	O
+of	O
+these	O
+patients	O
+with	O
+HT	O
+and	O
+type	O
+2	O
+DM	O
+.	O
+
+Objectives	O
+This	O
+study	O
+aimed	O
+to	O
+report	O
+the	O
+prevalence	B-EPI
+and	O
+clinical	O
+characteristics	O
+of	O
+adults	O
+with	O
+cerebral	O
+palsy	O
+(	O
+CP	O
+)	O
+in	O
+a	O
+geographically	O
+defined	O
+region	O
+of	O
+the	O
+UK	B-LOC
+.	O
+
+Design	O
+and	O
+setting	O
+Cross	O
+-	O
+sectional	O
+study	O
+using	O
+the	O
+Northern	O
+Ireland	O
+Cerebral	O
+Palsy	O
+Register	O
+(	O
+NICPR	O
+)	O
+.	O
+
+Participants	O
+All	O
+validated	O
+cases	O
+known	O
+to	O
+the	O
+NICPR	O
+,	O
+born	O
+1981	O
+-	O
+2001	O
+and	O
+alive	O
+and	O
+resident	O
+in	O
+Northern	B-LOC
+Ireland	I-LOC
+at	O
+age	O
+19	O
+years	O
+were	O
+included	O
+.	O
+
+Results	O
+The	O
+study	O
+included	O
+1218	O
+persons	O
+with	O
+CP	O
+aged	O
+19	O
+-	O
+39	O
+years	O
+,	O
+46	O
+of	O
+whom	O
+died	O
+in	O
+adulthood	O
+.	O
+
+The	O
+prevalence	B-EPI
+of	O
+CP	O
+was	O
+2.38	B-STAT
+per	I-STAT
+1000	I-STAT
+.	O
+
+The	O
+majority	O
+of	O
+cases	O
+had	O
+spastic	O
+CP	O
+(	O
+n=1132/1218	O
+,	O
+93	O
+%	O
+)	O
+and	O
+could	O
+walk	O
+(	O
+n=949/1218	O
+,	O
+78	O
+%	O
+)	O
+.	O
+
+Those	O
+that	O
+died	O
+in	O
+adulthood	O
+typically	O
+had	O
+bilateral	O
+spastic	O
+CP	O
+(	O
+n=39/46	O
+)	O
+and	O
+used	O
+a	O
+wheelchair	O
+(	O
+n=40/46	O
+)	O
+.	O
+
+Conclusion	O
+The	O
+prevalence	B-EPI
+of	O
+CP	O
+in	O
+adults	O
+is	O
+similar	O
+to	O
+other	O
+common	O
+neurological	O
+conditions	O
+such	O
+as	O
+multiple	O
+sclerosis	O
+and	O
+Parkinson	O
+'s	O
+disease	O
+.	O
+
+The	O
+needs	O
+of	O
+adults	O
+with	O
+CP	O
+vary	O
+widely	O
+with	O
+almost	O
+half	O
+having	O
+two	O
+or	O
+more	O
+associated	O
+impairments	O
+that	O
+may	O
+require	O
+multiprofessional	O
+and	O
+multiagency	O
+coordination	O
+.	O
+
+Results	O
+from	O
+this	O
+study	O
+can	O
+be	O
+used	O
+to	O
+inform	O
+transformation	O
+of	O
+health	O
+and	O
+care	O
+services	O
+for	O
+adults	O
+with	O
+CP	O
+.	O
+
+Fanconi	O
+anemia	O
+(	O
+FA	O
+)	O
+is	O
+a	O
+recessive	O
+DNA	O
+instability	O
+disorder	O
+associated	O
+with	O
+developmental	O
+abnormalities	O
+,	O
+bone	O
+marrow	O
+failure	O
+,	O
+and	O
+a	O
+predisposition	O
+to	O
+cancer	O
+.	O
+
+Based	O
+on	O
+their	O
+sensitivity	O
+to	O
+DNA	O
+cross	O
+-	O
+linking	O
+agents	O
+,	O
+FA	O
+cells	O
+have	O
+been	O
+assigned	O
+to	O
+15	O
+complementation	O
+groups	O
+,	O
+and	O
+the	O
+associated	O
+genes	O
+have	O
+been	O
+identified	O
+.	O
+
+Founder	O
+mutations	O
+have	O
+been	O
+found	O
+in	O
+different	O
+FA	O
+genes	O
+in	O
+several	O
+populations	O
+.	O
+
+The	O
+majority	O
+of	O
+Dutch	O
+FA	O
+patients	O
+belongs	O
+to	O
+complementation	O
+group	O
+FA	O
+-	O
+C.	O
+
+Here	O
+,	O
+we	O
+report	O
+15	O
+patients	O
+of	O
+Dutch	O
+ancestry	O
+and	O
+a	O
+large	O
+Canadian	O
+Manitoba	B-LOC
+Mennonite	O
+kindred	O
+carrying	O
+the	O
+FANCC	O
+c.67delG	O
+mutation	O
+.	O
+
+Genealogical	O
+investigation	O
+into	O
+the	O
+ancestors	O
+of	O
+the	O
+Dutch	O
+patients	O
+shows	O
+that	O
+these	O
+ancestors	O
+lived	O
+in	O
+four	O
+distinct	O
+areas	O
+in	O
+The	B-LOC
+Netherlands	I-LOC
+.	O
+
+We	O
+also	O
+show	O
+that	O
+the	O
+Dutch	O
+and	O
+Manitoba	B-LOC
+Mennonite	I-LOC
+FANCC	O
+c.67delG	O
+patients	O
+share	O
+the	O
+same	O
+haplotype	O
+surrounding	O
+this	O
+mutation	O
+,	O
+indicating	O
+a	O
+common	O
+founder	O
+.	O
+
+Approximately	O
+one	O
+-	O
+third	O
+of	O
+the	O
+world	O
+'s	O
+population	O
+is	O
+infected	O
+with	O
+Mycobacterium	O
+tuberculosis	O
+,	O
+and	O
+it	O
+is	O
+a	O
+leading	O
+cause	O
+of	O
+infertility	O
+in	O
+endemic	O
+countries	O
+.	O
+
+The	O
+global	B-LOC
+incidence	B-EPI
+of	O
+tuberculosis	O
+(	O
+TB	O
+)	O
+is	O
+growing	O
+at	O
+approximately	B-STAT
+0.4	I-STAT
+%	I-STAT
+per	O
+year	O
+,	O
+and	O
+much	O
+faster	O
+in	O
+sub	O
+-	O
+Saharan	O
+Africa	O
+.	O
+
+TB	O
+causing	O
+fertility	O
+is	O
+rare	O
+in	O
+developed	O
+countries	O
+.	O
+
+We	O
+present	O
+a	O
+case	O
+of	O
+genital	O
+tuberculosis	O
+causing	O
+Asherman	O
+'s	O
+syndrome	O
+and	O
+resultant	O
+infertility	O
+.	O
+
+The	O
+patient	O
+is	O
+a	O
+34	O
+-	O
+year	O
+-	O
+old	O
+P0	O
+who	O
+presented	O
+to	O
+care	O
+after	O
+a	O
+prolonged	O
+period	O
+of	O
+secondary	O
+amenorrhea	O
+and	O
+infertility	O
+.	O
+
+She	O
+underwent	O
+a	O
+hysterosalpingogram	O
+which	O
+demonstrated	O
+no	O
+free	O
+spill	O
+and	O
+a	O
+diagnostic	O
+hysteroscopy	O
+which	O
+had	O
+findings	O
+of	O
+mottled	O
+endometrium	O
+.	O
+
+Pathology	O
+returned	O
+positive	O
+for	O
+Mycobacterium	O
+tuberculosis	O
+.	O
+
+The	O
+patient	O
+was	O
+treated	O
+with	O
+9	O
+months	O
+of	O
+antituberculous	O
+therapy	O
+.	O
+
+While	O
+she	O
+has	O
+not	O
+yet	O
+succeeded	O
+in	O
+becoming	O
+pregnant	O
+,	O
+the	O
+patient	O
+has	O
+started	O
+to	O
+notice	O
+cyclic	O
+spotting	O
+,	O
+indicating	O
+possible	O
+return	O
+of	O
+menses	O
+.	O
+
+This	O
+case	O
+highlights	O
+the	O
+importance	O
+of	O
+TB	O
+treatment	O
+and	O
+considering	O
+TB	O
+in	O
+patients	O
+who	O
+present	O
+with	O
+unexplained	O
+infertility	O
+.	O
+
+Recent	O
+expansion	O
+of	O
+arboviruses	O
+such	O
+as	O
+West	B-LOC
+Nile	I-LOC
+(	O
+WNV	O
+)	O
+,	O
+Usutu	O
+(	O
+USUV	O
+)	O
+,	O
+and	O
+tick	O
+-	O
+borne	O
+encephalitis	O
+(	O
+TBEV	O
+)	O
+over	O
+their	O
+natural	O
+range	O
+of	O
+distribution	O
+needs	O
+strengthening	O
+their	O
+surveillance	O
+.	O
+
+As	O
+common	O
+viral	O
+vertebrate	O
+hosts	O
+,	O
+birds	O
+and	O
+horses	O
+deserve	O
+special	O
+attention	O
+with	O
+routine	O
+serological	O
+surveillance	O
+.	O
+
+Here	O
+,	O
+we	O
+estimated	O
+the	O
+seroprevalence	O
+of	O
+WNV	O
+,	O
+USUV	O
+and	O
+TBEV	O
+in	O
+160	O
+migrating	O
+/	O
+resident	O
+birds	O
+and	O
+60	O
+horses	O
+sampled	O
+in	O
+Mazandaran	B-LOC
+,	O
+Golestan	B-LOC
+,	O
+North	B-LOC
+Khorasan	I-LOC
+,	O
+Kordestan	B-LOC
+provinces	O
+and	O
+Golestan	B-LOC
+province	I-LOC
+of	O
+Iran	B-LOC
+respectively	O
+.	O
+
+ELISA	O
+results	O
+showed	O
+that	O
+of	O
+220	O
+collected	O
+samples	O
+,	O
+32	O
+samples	O
+(	O
+14.54	O
+%	O
+)	O
+,	O
+including	O
+22	O
+birds	O
+and	O
+10	O
+horses	O
+,	O
+were	O
+positive	O
+.	O
+
+Microsphere	O
+immunoassay	O
+results	O
+showed	O
+that	O
+16.7	O
+%	O
+(	O
+10/60	O
+)	O
+of	O
+horse	O
+blood	O
+samples	O
+collected	O
+in	O
+Golestan	B-LOC
+province	I-LOC
+were	O
+seropositive	O
+against	O
+WNV	O
+(	O
+7	B-STAT
+;	O
+11.7	O
+%	O
+)	O
+,	O
+Flavivirus	O
+(	O
+2	B-STAT
+;	O
+3.3	O
+%	O
+)	O
+and	O
+seropositive	O
+for	O
+USUV	O
+or	O
+WNV	O
+(	O
+1	B-STAT
+;	O
+1.7	O
+%	O
+)	O
+.	O
+
+Furthermore	O
+,	O
+micro	O
+virus	O
+neutralization	O
+tests	O
+revealed	O
+that	O
+four	O
+of	O
+seven	O
+ELISA	O
+-	O
+positive	O
+bird	O
+blood	O
+samples	O
+were	O
+seropositive	O
+against	O
+WNV	O
+:	O
+two	O
+Egyptian	O
+vultures	O
+,	O
+and	O
+one	O
+long	O
+-	O
+legged	O
+buzzard	O
+collected	O
+in	O
+Golestan	O
+province	O
+as	O
+well	O
+as	O
+a	O
+golden	O
+eagle	O
+collected	O
+in	O
+North	B-LOC
+Khorasan	I-LOC
+province	O
+.	O
+
+No	O
+evidence	O
+of	O
+seropositivity	O
+with	O
+TBEV	O
+was	O
+observed	O
+in	O
+collected	O
+samples	O
+.	O
+
+We	O
+showed	O
+that	O
+WNV	O
+,	O
+responsible	O
+for	O
+neuroinvasive	O
+infection	O
+in	O
+vertebrates	O
+,	O
+is	O
+circulating	O
+among	O
+birds	O
+and	O
+horses	O
+in	O
+Iran	B-LOC
+,	O
+recommending	O
+a	O
+sustained	O
+surveillance	O
+of	O
+viral	O
+infections	O
+in	O
+animals	O
+,	O
+and	O
+anticipating	O
+future	O
+infections	O
+in	O
+humans	O
+.	O
+
+Past	O
+studies	O
+strongly	O
+connected	O
+stool	O
+consistency	O
+-	O
+as	O
+measured	O
+by	O
+Bristol	O
+Stool	O
+Scale	O
+(	O
+BSS)-with	O
+microbial	O
+gene	O
+richness	O
+and	O
+intestinal	O
+inflammation	O
+,	O
+colonic	O
+transit	O
+time	O
+and	O
+metabolome	O
+characteristics	O
+that	O
+are	O
+of	O
+clinical	O
+relevance	O
+in	O
+numerous	O
+gastro	O
+intestinal	O
+conditions	O
+.	O
+
+While	O
+retention	O
+time	O
+,	O
+defecation	O
+rate	O
+,	O
+BSS	O
+but	O
+not	O
+water	O
+activity	O
+have	O
+been	O
+shown	O
+to	O
+account	O
+for	O
+BSS	O
+-	O
+associated	O
+inflammatory	O
+effects	O
+,	O
+the	O
+potential	O
+correlation	O
+with	O
+the	O
+strength	O
+of	O
+a	O
+gel	O
+in	O
+the	O
+context	O
+of	O
+intestinal	O
+forces	O
+,	O
+abrasion	O
+,	O
+mucus	O
+imprinting	O
+,	O
+fecal	O
+pore	O
+clogging	O
+remains	O
+unexplored	O
+as	O
+a	O
+shaping	O
+factor	O
+for	O
+intestinal	O
+inflammation	O
+and	O
+has	O
+yet	O
+to	O
+be	O
+determined	O
+.	O
+
+Our	O
+study	O
+introduced	O
+a	O
+minimal	O
+pressure	O
+approach	O
+(	O
+MP	O
+)	O
+by	O
+probe	O
+indentation	O
+as	O
+measure	O
+of	O
+stool	O
+material	O
+crosslinking	O
+in	O
+fecal	O
+samples	O
+.	O
+
+Results	O
+reported	O
+here	O
+were	O
+obtained	O
+from	O
+170	O
+samples	O
+collected	O
+in	O
+two	O
+independent	O
+projects	O
+,	O
+including	O
+males	O
+and	O
+females	O
+,	O
+covering	O
+a	O
+wide	O
+span	O
+of	O
+moisture	O
+contents	O
+and	O
+BSS	O
+.	O
+
+MP	O
+values	O
+increased	O
+exponentially	O
+with	O
+increasing	O
+consistency	O
+(	O
+i.e.	O
+,	O
+lower	O
+BSS	O
+)	O
+and	O
+enabled	O
+stratification	O
+of	O
+samples	O
+exhibiting	O
+mixed	O
+BSS	O
+classes	O
+.	O
+
+A	O
+trade	O
+-	O
+off	O
+between	O
+lowest	O
+MP	O
+and	O
+highest	O
+dry	O
+matter	O
+content	O
+delineated	O
+the	O
+span	O
+of	O
+intermediate	O
+healthy	O
+density	O
+of	O
+gel	O
+crosslinks	O
+.	O
+
+The	O
+crossectional	O
+transects	O
+identified	O
+fecal	O
+surface	O
+layers	O
+with	O
+exceptionally	O
+high	O
+MP	O
+and	O
+of	O
+<	O
+5	O
+mm	O
+thickness	O
+followed	O
+by	O
+internal	O
+structures	O
+with	O
+an	O
+order	O
+of	O
+magnitude	O
+lower	O
+MP	O
+,	O
+characteristic	O
+of	O
+healthy	O
+stool	O
+consistency	O
+.	O
+
+The	O
+MP	O
+and	O
+BSS	O
+values	O
+reported	O
+in	O
+this	O
+study	O
+were	O
+coupled	O
+to	O
+reanalysis	O
+of	O
+the	O
+PlanHab	O
+data	O
+and	O
+fecal	O
+1H	O
+-	O
+NMR	O
+metabolomes	O
+reported	O
+before	O
+.	O
+
+The	O
+exponential	O
+association	O
+between	O
+stool	O
+consistency	O
+and	O
+MP	O
+determined	O
+in	O
+this	O
+study	O
+was	O
+mirrored	O
+in	O
+the	O
+elevated	O
+intestinal	O
+and	O
+also	O
+systemic	O
+inflammation	O
+and	O
+other	O
+detrimental	O
+physiological	O
+deconditioning	O
+effects	O
+observed	O
+in	O
+the	O
+PlanHab	O
+participants	O
+reported	O
+before	O
+.	O
+
+The	O
+MP	O
+approach	O
+described	O
+in	O
+this	O
+study	O
+can	O
+be	O
+used	O
+to	O
+better	O
+understand	O
+fecal	O
+hardness	O
+and	O
+its	O
+relationships	O
+to	O
+human	O
+health	O
+as	O
+it	O
+provides	O
+a	O
+simple	O
+,	O
+fine	O
+scale	O
+and	O
+objective	O
+stool	O
+classification	O
+approach	O
+for	O
+the	O
+characterization	O
+of	O
+the	O
+exact	O
+sampling	O
+locations	O
+in	O
+future	O
+microbiome	O
+and	O
+metabolome	O
+studies	O
+.	O
+
+OBJECTIVES	O
+:	O
+The	O
+incidence	B-EPI
+of	O
+neonatal	O
+herpes	O
+simplex	O
+virus	O
+(	O
+nHSV	O
+)	O
+infections	O
+is	O
+monitored	O
+periodically	O
+in	O
+the	O
+Netherlands	B-LOC
+,	O
+yet	O
+management	O
+and	O
+outcome	O
+is	O
+unknown	O
+.	O
+
+Comprehensive	O
+national	O
+guidelines	O
+are	O
+lacking	O
+.	O
+
+We	O
+aim	O
+to	O
+describe	O
+management	O
+and	O
+outcome	O
+in	O
+the	O
+last	O
+decade	O
+to	O
+explore	O
+current	O
+diagnostic	O
+and	O
+therapeutic	O
+challenges	O
+.	O
+
+We	O
+aim	O
+to	O
+identify	O
+possible	O
+variability	O
+in	O
+management	O
+of	O
+patients	O
+with	O
+a	O
+suspected	O
+nHSV	O
+infection	O
+.	O
+
+METHODS	O
+:	O
+We	O
+conducted	O
+a	O
+retrospective	O
+case	O
+series	O
+of	O
+management	O
+and	O
+outcome	O
+of	O
+nHSV	O
+infections	O
+at	O
+2	O
+tertiary	O
+care	O
+center	O
+locations	O
+in	O
+the	O
+Netherlands	B-LOC
+.	O
+
+RESULTS	O
+:	O
+An	O
+nHSV	O
+infection	O
+was	O
+diagnosed	O
+in	O
+1	O
+%	O
+(	O
+12	O
+of	O
+1348	O
+)	O
+of	O
+patients	O
+in	O
+whom	O
+polymerase	O
+chain	O
+reaction	O
+for	O
+HSV	O
+was	O
+performed	O
+.	O
+
+Of	O
+the	O
+patients	O
+with	O
+nHSV	O
+infection	O
+,	O
+3	O
+of	O
+12	O
+died	O
+,	O
+and	O
+4	O
+of	O
+9	B-STAT
+(	O
+44	O
+%	O
+)	O
+survivors	O
+suffered	O
+neurologic	O
+sequelae	O
+.	O
+
+Neurologic	O
+symptoms	O
+at	O
+presentation	O
+were	O
+seen	O
+in	O
+only	O
+2	O
+of	O
+8	O
+patients	O
+with	O
+nHSV	O
+encephalitis	O
+.	O
+
+A	O
+cerebral	O
+spinal	O
+fluid	O
+analysis	O
+was	O
+performed	O
+in	O
+3	O
+of	O
+6	O
+patients	O
+presenting	O
+with	O
+skin	O
+lesions	O
+.	O
+
+Only	O
+3	O
+of	O
+6	O
+patients	O
+with	O
+neurologic	O
+symptoms	O
+received	O
+suppressive	O
+therapy	O
+.	O
+
+nHSV	O
+infection	O
+was	O
+diagnosed	O
+in	O
+8	O
+of	O
+189	B-STAT
+(	O
+4	O
+%	O
+)	O
+patients	O
+who	O
+were	O
+empirically	O
+treated	O
+.	O
+
+CONCLUSIONS	O
+:	O
+Management	O
+of	O
+nHSV	O
+infection	O
+,	O
+particularly	O
+when	O
+presented	O
+with	O
+skin	O
+lesions	O
+,	O
+is	O
+inconsistent	O
+.	O
+
+Many	O
+infants	O
+without	O
+a	O
+HSV	O
+infection	O
+are	O
+exposed	O
+to	O
+antiviral	O
+medication	O
+.	O
+
+There	O
+is	O
+substantial	O
+interhospital	O
+variation	O
+in	O
+diagnostic	O
+and	O
+therapeutic	O
+management	O
+of	O
+a	O
+suspected	O
+infection	O
+.	O
+
+Comprehensive	O
+guidelines	O
+need	O
+to	O
+be	O
+developed	O
+to	O
+standardize	O
+management	O
+of	O
+suspected	O
+nHSV	O
+infection	O
+.	O
+
+Purpose	O
+of	O
+review	O
+The	O
+global	B-LOC
+prevalence	B-EPI
+of	O
+obesity	O
+has	O
+increased	O
+rapidly	O
+over	O
+the	O
+last	O
+decades	O
+,	O
+posing	O
+a	O
+severe	O
+threat	O
+to	O
+human	O
+health	O
+.	O
+
+Currently	O
+,	O
+bariatric	O
+surgery	O
+is	O
+the	O
+most	O
+effective	O
+therapy	O
+for	O
+patients	O
+with	O
+morbid	O
+obesity	O
+.	O
+
+It	O
+is	O
+unknown	O
+whether	O
+this	O
+treatment	O
+is	O
+also	O
+suitable	O
+for	O
+patients	O
+with	O
+obesity	O
+due	O
+to	O
+a	O
+confirmed	O
+genetic	O
+defect	O
+(	O
+genetic	O
+obesity	O
+disorders	O
+)	O
+.	O
+
+Therefore	O
+,	O
+this	O
+review	O
+aims	O
+to	O
+elucidate	O
+the	O
+role	O
+of	O
+bariatric	O
+surgery	O
+in	O
+the	O
+treatment	O
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+genetic	O
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+.	O
+
+Recent	O
+findings	O
+In	O
+monogenic	O
+non	O
+-	O
+syndromic	O
+obesity	O
+,	O
+an	O
+underlying	O
+genetic	O
+defect	O
+seems	O
+to	O
+be	O
+the	O
+most	O
+important	O
+factor	O
+determining	O
+the	O
+efficacy	O
+of	O
+bariatric	O
+surgery	O
+.	O
+
+In	O
+syndromic	O
+obesity	O
+,	O
+bariatric	O
+surgery	O
+result	O
+data	O
+are	O
+scarce	O
+,	O
+and	O
+even	O
+though	O
+some	O
+promising	O
+follow	O
+-	O
+up	O
+results	O
+have	O
+been	O
+reported	O
+,	O
+caution	O
+is	O
+required	O
+as	O
+patients	O
+with	O
+more	O
+severe	O
+behavioral	O
+and	O
+developmental	O
+disorders	O
+might	O
+have	O
+poorer	O
+outcomes	O
+.	O
+
+There	O
+is	O
+limited	O
+evidence	O
+in	O
+support	O
+of	O
+bariatric	O
+surgery	O
+as	O
+a	O
+treatment	O
+option	O
+for	O
+genetic	O
+obesity	O
+disorders	O
+;	O
+hence	O
+,	O
+no	O
+strong	O
+statements	O
+can	O
+be	O
+made	O
+regarding	O
+the	O
+efficacy	O
+and	O
+safety	O
+of	O
+these	O
+procedures	O
+for	O
+these	O
+patients	O
+.	O
+
+However	O
+,	O
+considering	O
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+patients	O
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+genetic	O
+obesity	O
+often	O
+present	O
+with	O
+life	O
+-	O
+threatening	O
+obesity	O
+-	O
+related	O
+comorbidities	O
+,	O
+we	O
+believe	O
+that	O
+bariatric	O
+surgery	O
+could	O
+be	O
+considered	O
+a	O
+last	O
+-	O
+resort	O
+treatment	O
+option	O
+in	O
+selected	O
+patients	O
+.	O
+
+The	O
+treatment	O
+of	O
+Graves	O
+'	O
+disease	O
+is	O
+based	O
+on	O
+three	O
+therapies	O
+:	O
+medical	O
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+agents	O
+,	O
+surgery	O
+and	O
+radioactive	O
+-	O
+iodine	O
+therapy	O
+.	O
+
+The	O
+purpose	O
+of	O
+our	O
+study	O
+was	O
+to	O
+study	O
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+role	O
+and	O
+effectiveness	O
+of	O
+radioactive	O
+-	O
+iodine	O
+therapy	O
+for	O
+the	O
+treatment	O
+of	O
+Graves	O
+'	O
+disease	O
+.	O
+
+We	O
+conducted	O
+a	O
+retrospective	O
+,	O
+descriptive	O
+study	O
+of	O
+the	O
+epidemiological	O
+,	O
+clinical	O
+,	O
+paralclinical	O
+and	O
+therapeutic	O
+features	O
+of	O
+54	O
+patients	O
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+Graves	O
+'	O
+disease	O
+managed	O
+and	O
+treated	O
+with	O
+iodine-131	O
+as	O
+well	O
+as	O
+of	O
+their	O
+short-	O
+and	O
+medium	O
+-	O
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+remission	O
+rate	O
+.	O
+
+The	O
+sex	O
+ratio	O
+was	O
+0.45	O
+.	O
+
+The	O
+average	O
+age	O
+of	O
+patients	O
+was	O
+38,33	O
+±	O
+12.7	O
+years	O
+.	O
+
+The	O
+most	O
+common	O
+functional	O
+signs	O
+were	O
+weight	O
+loss	O
+,	O
+tremors	O
+and	O
+palpitations	O
+.	O
+
+Mean	O
+FT4	O
+was	O
+54,51	O
+±	O
+19,56	O
+ng	O
+/	O
+dl	O
+(	O
+ranging	O
+from	O
+8,90	O
+and	O
+100	O
+)	O
+.	O
+
+Mean	O
+TSHus	O
+was	O
+0,074	O
+±	O
+0,29	O
+µIU	O
+/	O
+ml	O
+.	O
+
+Synthetic	O
+antithyroid	O
+drugs	O
+were	O
+used	O
+in	O
+49	O
+patients	O
+;	O
+83,67	O
+%	O
+of	O
+cases	O
+had	O
+persistent	O
+hyperthyroidism	O
+.	O
+
+Radioactive	O
+-	O
+iodine	O
+therapy	O
+was	O
+used	O
+as	O
+first	O
+-	O
+line	O
+therapy	O
+in	O
+9,3	O
+%	O
+of	O
+cases	O
+and	O
+as	O
+second	O
+-	O
+line	O
+therapy	O
+in	O
+90,7	O
+%	O
+of	O
+cases	O
+.	O
+
+Mean	O
+activity	O
+was	O
+13,29	O
+mCi	O
+±	O
+1,46	O
+ranging	O
+from	O
+10	O
+to	O
+15	O
+mCi	O
+.	O
+
+The	O
+first	O
+assessment	O
+of	O
+hormonal	O
+status	O
+was	O
+performed	O
+after	O
+an	O
+average	O
+post	O
+-	O
+treatment	O
+period	O
+of	O
+1,91	O
+months	O
+;	O
+29	O
+patients	O
+(	O
+53,7	O
+%	O
+)	O
+achieved	O
+remission	O
+(	O
+eu-	O
+or	O
+hypo	O
+-	O
+thyroidism	O
+)	O
+.	O
+
+After	O
+a	O
+12	O
+month	O
+-	O
+follow	O
+-	O
+up	O
+,	O
+patients	O
+'	O
+course	O
+was	O
+marked	O
+by	O
+remission	O
+in	O
+88,88	O
+%	O
+of	O
+cases	O
+(	O
+euthyroidism	O
+in	O
+14,8	O
+%	O
+and	O
+hypothyroidism	O
+in	O
+74	O
+%	O
+of	O
+cases	O
+)	O
+.	O
+
+Radioactive	O
+-	O
+iodine	O
+therapy	O
+is	O
+an	O
+effective	O
+treatment	O
+for	O
+Graves	O
+'	O
+disease	O
+.	O
+
+High	O
+radioactive	O
+iodine	O
+dose	O
+provides	O
+high	O
+remission	O
+rate	O
+.	O
+
+Over	O
+the	O
+last	O
+10	O
+years	O
+,	O
+evidence	O
+has	O
+accumulated	O
+that	O
+autoimmune	O
+Addison	O
+'s	O
+disease	O
+(	O
+AAD	O
+)	O
+is	O
+a	O
+heterogeneous	O
+disease	O
+.	O
+
+Residual	O
+adrenal	O
+function	O
+,	O
+characterised	O
+by	O
+persistent	O
+secretion	O
+of	O
+cortisol	O
+,	O
+other	O
+glucocorticoids	O
+and	O
+mineralocorticoids	O
+is	O
+present	O
+in	O
+around	O
+30	O
+%	O
+of	O
+patients	O
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+AAD	O
+,	O
+and	O
+appears	O
+commoner	O
+in	O
+men	O
+.	O
+
+This	O
+persistent	O
+steroidogenesis	O
+is	O
+present	O
+in	O
+some	O
+patients	O
+with	O
+AAD	O
+for	O
+more	O
+than	O
+20	O
+years	O
+,	O
+but	O
+it	O
+is	O
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+in	O
+people	O
+with	O
+shorter	O
+disease	O
+duration	O
+.	O
+
+The	O
+clinical	O
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+residual	O
+adrenal	O
+function	O
+is	O
+not	O
+fully	O
+clear	O
+at	O
+the	O
+moment	O
+,	O
+but	O
+as	O
+it	O
+signifies	O
+an	O
+intact	O
+adrenocortical	O
+stem	O
+cell	O
+population	O
+,	O
+it	O
+opens	O
+up	O
+the	O
+possibility	O
+of	O
+regeneration	O
+of	O
+adrenal	O
+steroidogenesis	O
+and	O
+improvement	O
+in	O
+adrenal	O
+failure	O
+for	O
+some	O
+patients	O
+.	O
+
+The	O
+global	O
+pandemic	O
+of	O
+COVID-19	O
+has	O
+been	O
+lasting	O
+for	O
+more	O
+than	O
+one	O
+year	O
+and	O
+there	O
+is	O
+little	O
+known	O
+about	O
+the	O
+long	O
+-	O
+term	O
+health	O
+effects	O
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+the	O
+disease	O
+.	O
+
+Long	O
+-	O
+COVID	O
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+a	O
+new	O
+term	O
+that	O
+is	O
+used	O
+to	O
+describe	O
+the	O
+enduring	O
+symptoms	O
+of	O
+COVID-19	O
+survivors	O
+.	O
+
+Huang	O
+et	O
+al	O
+.	O
+
+reported	O
+that	O
+fatigue	O
+,	O
+muscle	O
+weakness	O
+,	O
+sleep	O
+disturbances	O
+,	O
+anxiety	O
+,	O
+and	O
+depression	O
+were	O
+the	O
+most	O
+common	O
+complaints	O
+in	O
+COVID-19	O
+survivors	O
+after	O
+6	O
+months	O
+of	O
+the	O
+infection	O
+.	O
+
+A	O
+recent	O
+meta	O
+-	O
+analysis	O
+showed	O
+that	O
+80	O
+%	O
+of	O
+COVID-19	O
+survivors	O
+have	O
+developed	O
+at	O
+least	O
+one	O
+long	O
+-	O
+term	O
+symptom	O
+and	O
+the	O
+most	O
+common	O
+five	O
+were	O
+fatigue	O
+,	O
+headache	O
+,	O
+attention	O
+deficit	O
+disorder	O
+,	O
+hair	O
+loss	O
+,	O
+and	O
+dyspnea	O
+.	O
+
+In	O
+this	O
+paper	O
+,	O
+we	O
+discuss	O
+the	O
+hypothesis	O
+that	O
+altered	O
+tryptophan	O
+absorption	O
+and	O
+metabolism	O
+could	O
+be	O
+the	O
+main	O
+contributor	O
+to	O
+the	O
+long	O
+-	O
+term	O
+symptoms	O
+in	O
+COVID-19	O
+survivors	O
+.	O
+
+Background	O
+A	O
+higher	O
+risk	O
+of	O
+developing	O
+dementia	O
+is	O
+observed	O
+in	O
+patients	O
+with	O
+atrial	O
+fibrillation	O
+(	O
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+)	O
+.	O
+
+Results	O
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+risk	O
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+dementia	O
+when	O
+patients	O
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+.	O
+
+We	O
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+patients	O
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+receiving	O
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+-	O
+vitamin	O
+K	O
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+oral	O
+anticoagulants	O
+(	O
+NOACs	O
+)	O
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+with	O
+those	O
+receiving	O
+warfarin	O
+.	O
+
+Methods	O
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+Results	O
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+population	O
+-	O
+based	O
+cohort	O
+study	O
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+incident	O
+cases	O
+using	O
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+Taiwan	O
+National	O
+Health	O
+Insurance	O
+Research	O
+Database	O
+.	O
+
+We	O
+initially	O
+enlisted	O
+all	O
+incident	O
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+and	O
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+least	O
+90	O
+days	O
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+2016	O
+.	O
+
+First	O
+-	O
+ever	O
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+primary	O
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+.	O
+
+We	O
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+score	O
+matching	O
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+each	O
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+.	O
+
+We	O
+used	O
+the	O
+Fine	O
+and	O
+Gray	O
+competing	O
+risk	O
+regression	O
+model	O
+to	O
+calculate	O
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+(	O
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+)	O
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+.	O
+
+We	O
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+AF	O
+(	O
+6034	O
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+)	O
+.	O
+
+The	O
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+follow	O
+-	O
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+3.27	O
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+3.08	O
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+warfarin	O
+,	O
+respectively	O
+.	O
+
+Compared	O
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+the	O
+HR	O
+for	O
+the	O
+group	O
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+,	O
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+HR	O
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+dementia	O
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+0.82	O
+(	O
+95	O
+%	O
+CI	O
+,	O
+0.73	O
+-	O
+0.92	O
+;	O
+P	O
+=	O
+0.0004	O
+)	O
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+.	O
+
+Subgroup	O
+analysis	O
+demonstrated	O
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+,	O
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+stroke	O
+or	O
+bleeding	O
+were	O
+associated	O
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+a	O
+lower	O
+risk	O
+of	O
+dementia	O
+than	O
+users	O
+of	O
+warfarin	O
+with	O
+similar	O
+characteristics	O
+.	O
+
+Conclusions	O
+Patients	O
+with	O
+AF	O
+using	O
+NOACs	O
+were	O
+associated	O
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+a	O
+lower	O
+risk	O
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+dementia	O
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+those	O
+using	O
+warfarin	O
+.	O
+
+Further	O
+randomized	O
+clinical	O
+trials	O
+are	O
+greatly	O
+needed	O
+to	O
+prove	O
+these	O
+findings	O
+.	O
+