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
of	O
genetic	O
obesity	O
.	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
that	O
patients	O
with	O
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
treatment	O
with	O
synthetic	O
antithyroid	O
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
the	O
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
with	O
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
term	O
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
with	O
established	O
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
commoner	O
in	O
people	O
with	O
shorter	O
disease	O
duration	O
.	O

The	O
clinical	O
significance	O
of	O
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
of	O
the	O
disease	O
.	O

Long	O
-	O
COVID	O
is	O
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
AF	O
)	O
.	O

Results	O
are	O
inconsistent	O
regarding	O
the	O
risk	O
of	O
dementia	O
when	O
patients	O
with	O
AF	O
use	O
different	O
anticoagulants	O
.	O

We	O
aimed	O
to	O
investigate	O
the	O
risk	O
of	O
dementia	O
in	O
patients	O
with	O
AF	O
receiving	O
non	O
-	O
vitamin	O
K	O
antagonist	O
oral	O
anticoagulants	O
(	O
NOACs	O
)	O
compared	O
with	O
those	O
receiving	O
warfarin	O
.	O

Methods	O
and	O
Results	O
We	O
conducted	O
a	O
nationwide	O
population	O
-	O
based	O
cohort	O
study	O
of	O
incident	O
cases	O
using	O
the	O
Taiwan	O
National	O
Health	O
Insurance	O
Research	O
Database	O
.	O

We	O
initially	O
enlisted	O
all	O
incident	O
cases	O
of	O
AF	O
and	O
then	O
selected	O
those	O
treated	O
with	O
either	O
NOACs	O
or	O
warfarin	O
for	O
at	O
least	O
90	O
days	O
between	O
2012	O
and	O
2016	O
.	O

First	O
-	O
ever	O
diagnosis	O
of	O
dementia	O
was	O
the	O
primary	O
outcome	O
.	O

We	O
performed	O
propensity	O
score	O
matching	O
to	O
minimize	O
the	O
difference	O
between	O
each	O
cohort	O
.	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
the	O
hazard	O
ratio	O
(	O
HR	O
)	O
for	O
dementia	O
.	O

We	O
recruited	O
12	O
068	O
patients	O
with	O
AF	O
(	O
6034	O
patients	O
in	O
each	O
cohort	O
)	O
.	O

The	O
mean	O
follow	O
-	O
up	O
time	O
was	O
3.27	O
and	O
3.08	O
years	O
in	O
the	O
groups	O
using	O
NOACs	O
and	O
warfarin	O
,	O
respectively	O
.	O

Compared	O
with	O
the	O
HR	O
for	O
the	O
group	O
using	O
warfarin	O
,	O
the	O
HR	O
for	O
dementia	O
was	O
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
in	O
the	O
group	O
using	O
NOACs	O
.	O

Subgroup	O
analysis	O
demonstrated	O
that	O
users	O
of	O
NOAC	O
aged	O
65	O
to	O
74	O
years	O
,	O
with	O
a	O
high	O
risk	O
of	O
stroke	O
or	O
bleeding	O
were	O
associated	O
with	O
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
with	O
a	O
lower	O
risk	O
of	O
dementia	O
than	O
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