test.tsv

Context	O
Patients	O
with	O
pseudohypoparathyroidism	O
type	O
1b	O
(	O
PHP1b	O
)	O
show	O
disordered	O
imprinting	O
of	O
the	O
maternal	O
GNAS	O
allele	O
or	O
paternal	O
uniparental	O
disomy	O
(	O
UPD	O
)	O
.	O

Genetic	O
deletions	O
in	O
STX16	O
or	O
in	O
upstream	O
exons	O
of	O
GNAS	O
are	O
present	O
in	O
many	O
familial	O
but	O
not	O
sporadic	O
cases	O
.	O

Objective	O
Characterization	O
of	O
epigenetic	O
and	O
genetic	O
defects	O
in	O
patients	O
with	O
PHP1b	O
.	O

Design	O
and	O
patients	O
DNA	O
from	O
84	O
subjects	O
,	O
including	O
26	O
subjects	O
with	O
sporadic	O
PHP1b	O
,	O
27	O
affected	O
subjects	O
and	O
17	O
unaffected	O
and/or	O
obligate	O
gene	O
carriers	O
from	O
12	O
PHP1b	O
families	O
,	O
11	O
healthy	O
individuals	O
,	O
and	O
3	O
subjects	O
with	O
PHP1a	O
was	O
subjected	O
to	O
quantitative	O
pyrosequencing	O
of	O
GNAS	O
differentially	O
methylated	O
regions	O
(	O
DMRs	O
)	O
,	O
microarray	O
analysis	O
,	O
and	O
microsatellite	O
haplotype	O
analysis	O
.	O

Setting	O
Academic	O
medical	O
center	O
.	O

Main	O
outcome	O
measurements	O
Molecular	O
pathology	O
of	O
PHP1b	O
.	O

Results	O
Healthy	O
subjects	O
,	O
unaffected	O
family	O
members	O
and	O
obligate	O
carriers	O
of	O
paternal	O
PHP1b	O
alleles	O
,	O
and	O
subjects	O
with	O
PHP1a	O
showed	O
normal	O
methylation	O
of	O
all	O
DMRs	O
.	O

All	O
PHP1b	O
subjects	O
showed	O
loss	O
of	O
methylation	O
(	O
LOM	O
)	O
at	O
the	O
exon	O
A	O
/	O
B	O
DMR	O
.	O

Affected	O
members	O
of	O
nine	O
PHP1b	O
kindreds	O
showed	O
LOM	O
only	O
at	O
the	O
exon	O
A	O
/	O
B	O
DMR	O
,	O
which	O
was	O
associated	O
with	O
a	O
3	O
-	O
kb	O
deletion	O
of	O
STX16	O
exons	O
4	O
-	O
6	O
in	O
seven	O
families	O
and	O
a	O
novel	O
deletion	O
of	O
STX16	O
and	O
adjacent	O
NEPEPL1	O
in	O
one	O
family	O
.	O

A	O
novel	O
NESP	O
deletion	O
was	O
found	O
in	O
one	O
of	O
two	O
other	O
families	O
with	O
more	O
extensive	O
methylation	O
defects	O
.	O

One	O
sporadic	O
PHP1b	O
had	O
UPD	O
of	O
20q	O
,	O
two	O
had	O
3	O
-	O
kb	O
STX16	O
deletions	O
,	O
and	O
five	O
had	O
apparent	O
epigenetic	O
mosaicism	O
.	O

Conclusions	O
We	O
found	O
diverse	O
patterns	O
of	O
defective	O
methylation	O
and	O
identified	O
novel	O
or	O
previously	O
known	O
mutations	O
in	O
9	O
of	O
12	O
PHP1b	O
families	O
.	O

Malignancy	O
must	O
be	O
considered	O
in	O
the	O
management	O
of	O
adrenal	O
lesions	O
,	O
including	O
those	O
incidentally	O
identified	O
on	O
imaging	O
studies	O
.	O

Adrenocortical	O
carcinomas	O
(	O
ACCs	O
)	O
are	O
rare	O
tumors	O
with	O
an	O
estimated	O
annual	B-EPI
incidence	I-EPI
of	O
0.7	B-STAT
-	I-STAT
2	I-STAT
cases	I-STAT
per	I-STAT
year	I-STAT
and	O
a	O
worldwide	B-LOC
prevalence	B-EPI
of	O
4	B-STAT
-	I-STAT
12	I-STAT
cases	I-STAT
per	I-STAT
million	I-STAT
/	I-STAT
year	I-STAT
.	O

However	O
,	O
a	O
much	O
higher	O
incidence	B-EPI
of	O
these	O
tumors	O
(	O
>	O
15	O
times	O
)	O
has	O
been	O
demonstrated	O
in	O
south	O
and	O
southeastern	O
Brazil	B-LOC
.	O

Most	O
ACCs	O
cause	O
hypersecretion	O
of	O
steroids	O
including	O
glucocorticoids	O
and	O
androgens	O
.	O

ACC	O
patients	O
have	O
a	O
very	O
poor	O
prognosis	O
with	O
a	O
5	O
-	O
year	O
overall	O
survival	O
(	O
OS	O
)	O
below	O
30	O
%	O
in	O
most	O
series	O
.	O

Pheochromocytoma	O
or	O
paraganglioma	O
(	O
PPGL	O
)	O
is	O
a	O
metabolically	O
active	O
tumor	O
originating	O
from	O
the	O
chromaffin	O
cells	O
of	O
the	O
adrenal	O
medulla	O
.	O

The	O
incidence	B-EPI
of	O
PPGL	O
is	O
0.2	B-STAT
to	I-STAT
0.9	I-STAT
cases	I-STAT
per	I-STAT
100,000	I-STAT
individuals	I-STAT
per	I-STAT
year	I-STAT
.	O

Pheochromocytomas	O
are	O
present	B-EPI
in	O
approximately	B-STAT
4	I-STAT
-	I-STAT
7	I-STAT
%	I-STAT
of	I-STAT
patients	I-STAT
with	I-STAT
adrenal	I-STAT
incidentalomas	I-STAT
.	O

Classically	O
,	O
PPGL	O
manifests	O
as	O
paroxysmal	O
attacks	O
of	O
the	O
following	O
4	O
symptoms	O
:	O
headaches	O
,	O
diaphoresis	O
,	O
palpitations	O
,	O
and	O
severe	O
hypertensive	O
episodes	O
.	O

The	O
diagnosis	O
of	O
malignant	O
PPGL	O
relies	O
on	O
the	O
presence	O
of	O
local	O
invasion	O
or	O
metastasis	O
.	O

In	O
this	O
review	O
,	O
we	O
present	O
the	O
clinical	O
and	O
biochemical	O
characteristics	O
and	O
pathogenesis	O
of	O
malignant	O
primary	O
lesions	O
that	O
affect	O
the	O
cortex	O
and	O
medulla	O
of	O
human	O
adrenal	O
glands	O
.	O

Background	O
.	O

Human	O
T	O
-	O
cell	O
lymphotropic	O
virus	O
type	O
1	O
(	O
HTLV-1	O
)	O
is	O
responsible	O
for	O
tropical	O
spastic	O
paraparesis	O
and	O
HTLV-1	O
-	O
associated	O
leukemia	O
/	O
lymphoma	O
.	O

The	O
infection	O
is	O
endemic	O
in	O
some	O
areas	O
of	O
Peru	B-LOC
,	O
but	O
its	O
prevalence	B-EPI
in	O
the	O
Peruvian	B-LOC
Amazon	I-LOC
is	O
not	O
well	O
established	O
.	O

We	O
aimed	O
to	O
assess	O
the	O
seroprevalence	O
of	O
HTLV-1	O
infection	O
in	O
pregnant	O
women	O
in	O
the	O
Peruvian	B-LOC
Amazon	I-LOC
.	O

Moreover	O
,	O
we	O
performed	O
a	O
systematic	O
literature	O
review	O
and	O
meta	O
-	O
analysis	O
of	O
the	O
seroprevalence	O
of	O
HTLV	O
infection	O
in	O
Peru	B-LOC
.	O

(	O
2	O
)	O
Methods	O
.	O

This	O
is	O
a	O
prospective	O
cross	O
-	O
sectional	O
study	O
involving	O
pregnant	O
women	O
attending	O
health	O
centers	O
in	O
the	O
city	O
of	O
Iquitos	B-LOC
,	I-LOC
Peru	I-LOC
,	O
in	O
May	O
and	O
June	O
2019	O
.	O

The	O
presence	O
of	O
antibodies	O
against	O
HTLV-1	O
was	O
assessed	O
using	O
ELISA	O
(	O
HTLV	O
I	O
+	O
II	O
ELISA	O
recombinant	O
v.4.0	O
,	O
Wiener	O
lab	O
,	O
Rosario	B-LOC
,	I-LOC
Argentina	I-LOC
)	O
.	O

Positive	O
cases	O
were	O
confirmed	O
by	O
Western	O
Blot	O
and	O
HTLV-1	O
proviral	O
load	O
.	O

(	O
3	O
)	O
Results	O
.	O

The	O
study	O
included	O
300	O
pregnant	O
women	O
with	O
a	O
mean	O
age	O
of	O
26	O
years	O
(	O
standard	O
deviation	O
[	O
SD	O
]	O
6.4	O
)	O
.	O

Five	O
patients	O
were	O
diagnosed	O
with	O
HTLV-1	O
infection	O
(	O
prevalence	B-EPI
1.7	B-STAT
%	I-STAT
,	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
0.7	O
%	O
to	O
3.8	O
%	O
)	O
.	O

Pregnant	O
women	O
with	O
HTLV-1	O
infection	O
were	O
discretely	O
younger	O
(	O
mean	O
age	O
22.6	O
[	O
SD	O
22.6	O
]	O
vs	O
26.8	O
[	O
SD	O
6.3	O
]	O
;	O
p	O
=	O
0.128	O
)	O
.	O

None	O
of	O
the	O
five	O
women	O
had	O
been	O
transfused	O
,	O
and	O
all	O
were	O
asymptomatic	O
.	O

Two	O
(	O
40	O
%	O
)	O
also	O
had	O
a	O
positive	O
serology	O
for	O
Strongyloides	O
,	O
but	O
larvae	O
were	O
not	O
detected	O
in	O
any	O
of	O
the	O
parasitological	O
stool	O
studies	O
.	O

The	O
systematic	O
review	O
component	O
identified	O
40	O
studies	O
,	O
which	O
showed	O
that	O
the	O
prevalence	B-EPI
of	O
HTLV	O
infection	O
in	O
the	O
general	B-STAT
population	I-STAT
was	I-STAT
2.9	I-STAT
%	I-STAT
(	O
95	O
%	O
CI	O
1.2	O
%	O
to	O
5.3	O
%	O
)	O
and	O
in	O
women	O
of	O
childbearing	O
age	O
,	O
2.5	O
%	O
(	O
95	O
%	O
CI	O
1.2	O
%	O
to	O
4.0	O
%	O
)	O
.	O

(	O
4	O
)	O
Conclusion	O
.	O

The	O
prevalence	B-EPI
of	O
HTLV-1	O
in	O
the	O
Peruvian	B-LOC
Amazon	I-LOC
basin	I-LOC
is	O
about	B-STAT
1.7	I-STAT
%	I-STAT
,	O
indicating	O
an	O
endemic	O
presence	O
.	O

Screening	O
for	O
HTLV-1	O
in	O
prenatal	O
care	O
is	O
warranted	O
.	O

Background	O
Comorbidity	O
may	O
influence	O
clinical	O
aspects	O
of	O
neuromyelitis	O
optica	O
spectrum	O
disorder	O
(	O
NMOSD	O
)	O
.	O

We	O
estimated	O
the	O
prevalence	B-EPI
of	O
comorbidities	O
to	O
assess	O
their	O
association	O
with	O
outcomes	O
.	O

Methods	O
This	O
retrospective	O
study	O
assessed	O
records	O
of	O
NMOSD	O
patients	O
from	O
2008	O
to	O
2019	O
,	O
categorizing	O
comorbidities	O
into	O
three	O
groups	O
:	O
somatic	O
,	O
psychiatric	O
and	O
autoimmune	O
.	O

Severity	O
of	O
disease	O
was	O
evaluated	O
by	O
the	O
Expanded	O
Disability	O
Status	O
Scale	O
,	O
progression	O
index	O
(	O
PI	O
)	O
and	O
annualized	O
relapse	O
rate	O
.	O

The	O
frequency	O
of	O
comorbidities	O
was	O
compared	O
between	O
anti	O
-	O
aquaporin	O
4	O
antibody	O
(	O
AQP4	O
-	O
IgG	O
)	O
seropositive	O
and	O
seronegative	O
patients	O
.	O

Results	O
A	O
total	O
of	O
67	O
NMOSD	O
patients	O
were	O
enrolled	O
.	O

Thirty	O
-	O
five	O
(	O
52.2	O
%	O
)	O
patients	O
reported	O
at	O
least	O
one	O
comorbidity	O
.	O

In	O
total	O
,	O
44	O
comorbidities	O
were	O
found	O
,	O
of	O
which	O
24	O
occurred	O
prior	O
to	O
NMOSD	O
onset	O
:	O
29	O
somatic	O
,	O
13	O
psychiatric	O
and	O
2	O
autoimmune	O
entities	O
.	O

The	O
most	O
common	O
comorbidities	O
were	O
anxiety	O
disorders	O
7/67	O
(	O
10.4	O
%	O
)	O
,	O
followed	O
by	O
migraine	O
6/67	O
(	O
8.9	O
%	O
)	O
major	O
depression	O
disorder	O
6/67	O
(	O
8.9	O
%	O
)	O
,	O
iron	O
deficiency	O
anemia	O
8/54	O
(	O
14.8	O
%	O
)	O
,	O
and	O
non	O
-	O
autoimmune	O
hypothyroidism	O
4/67	O
(	O
6.0	O
%	O
)	O
.	O

Psychiatric	O
comorbidities	O
associated	O
with	O
PI	O
in	O
unadjusted	O
(	O
OR=0.538	O
,	O
95	O
%	O
CI=0.141	O
,	O
0.935	O
,	O
P=0.009	O
)	O
and	O
adjusted	O
models	O
(	O
OR=0.386	O
,	O
95	O
%	O
CI=0.022	O
,	O
0.751	O
,	O
P=0.038	O
)	O
.	O

A	O
significantly	O
higher	O
frequency	O
of	O
psychiatric	O
comorbidities	O
was	O
observed	O
in	O
the	O
AQP4	O
-	O
IgG	O
positive	O
patients	O
(	O
P=0.031	O
)	O
.	O

Conclusion	O
Half	O
of	O
the	O
patients	O
had	O
comorbidities	O
,	O
suggesting	O
screening	O
for	O
comorbidity	O
as	O
part	O
of	O
NMOSD	O
care	O
.	O

The	O
psychiatric	O
comorbidities	O
had	O
impact	O
on	O
clinical	O
outcome	O
.	O

Aberrant	O
right	O
subclavian	O
artery	O
(	O
ARSA	O
)	O
,	O
the	O
most	O
common	O
aortic	O
arch	O
abnormality	O
,	O
occurs	B-EPI
in	O
approximately	B-STAT
0.5	I-STAT
to	I-STAT
1.8	I-STAT
%	I-STAT
of	I-STAT
the	I-STAT
general	I-STAT
population	I-STAT
,	O
with	O
prevalence	B-EPI
of	O
up	B-STAT
to	I-STAT
25	I-STAT
%	I-STAT
in	I-STAT
those	I-STAT
with	I-STAT
esophageal	I-STAT
atresia	I-STAT
.	O

Although	O
ARSA	O
is	O
often	O
asymptomatic	O
,	O
a	O
fistulous	O
tract	O
into	O
esophagus	O
may	O
develop	O
with	O
prolonged	O
nasogastric	O
tube	O
placement	O
or	O
endotracheal	O
intubation	O
and	O
lead	O
to	O
potentially	O
fatal	O
hematemesis	O
.	O

We	O
present	O
a	O
first	O
case	O
of	O
ARSA	O
-	O
esophageal	O
fistula	O
in	O
a	O
20	O
-	O
year	O
-	O
old	O
woman	O
with	O
VATER	O
association	O
in	O
the	O
absence	O
of	O
an	O
esophageal	O
anomaly	O
and	O
review	O
28	O
cases	O
of	O
ARSA	O
-	O
esophageal	O
fistula	O
reported	O
in	O
the	O
literature	O
to	O
date	O
.	O

Requiring	O
nasogastric	O
and	O
endotracheal	O
tube	O
placement	O
for	O
approximately	O
4	O
months	O
,	O
the	O
patient	O
had	O
a	O
prolonged	O
hospital	O
course	O
and	O
died	O
after	O
sudden	O
hematemesis	O
.	O

An	O
autopsy	O
demonstrated	O
an	O
ARSA	O
-	O
esophageal	O
fistula	O
and	O
no	O
other	O
source	O
of	O
upper	O
gastrointestinal	O
bleeding	O
.	O

In	O
patients	O
with	O
esophageal	O
atresia	O
requiring	O
prolonged	O
placement	O
of	O
an	O
endotracheal	O
or	O
nasogastric	O
tube	O
,	O
a	O
screening	O
imaging	O
study	O
and	O
corrective	O
surgery	O
may	O
be	O
indicated	O
.	O

Although	O
the	O
mortality	O
rate	O
is	O
still	O
high	O
,	O
timely	O
recognition	O
and	O
repair	O
of	O
ARSA	O
-	O
esophageal	O
fistula	O
appear	O
to	O
be	O
improving	O
.	O

Given	O
the	O
potentially	O
prolonged	O
latency	O
for	O
its	O
development	O
with	O
occasional	O
presence	O
of	O
heralding	O
symptoms	O
,	O
increased	O
awareness	O
may	O
facilitate	O
surgical	O
intervention	O
to	O
prevent	O
a	O
catastrophic	O
exsanguination	O
.	O

The	O
reported	O
incidence	B-EPI
of	O
COVID-19	O
among	O
cohorts	O
of	O
patients	O
with	O
inflammatory	O
bowel	O
and	O
skin	O
diseases	O
under	O
treatment	O
with	O
biologicals	O
is	O
low	O
.	O

Treatment	O
may	O
further	O
modify	O
disease	O
severity	O
as	O
some	O
biological	O
modifiers	O
,	O
such	O
as	O
anakinra	O
,	O
are	O
also	O
proposed	O
for	O
the	O
management	O
of	O
COVID-19	O
patients	O
potentially	O
providing	O
HS	O
patients	O
with	O
an	O
advantage	O
.	O

The	O
above	O
preliminary	O
evidence	O
suggests	O
that	O
hidradenitis	O
suppurativa	O
(	O
HS	O
)	O
does	O
probably	O
not	O
provide	O
an	O
increased	O
susceptibility	O
for	O
COVID-19	O
and	O
that	O
any	O
susceptibility	O
is	O
unlikely	O
to	O
be	O
modified	O
negatively	O
by	O
treatment	O
with	O
biologicals	O
.	O

On	O
the	O
occasion	O
of	O
its	O
10th	O
International	O
Conference	O
,	O
experts	O
of	O
the	O
European	O
Hidradenitis	O
Suppurativa	O
Foundation	O
e.	O
V.	O

have	O
prepared	O
a	O
consensus	O
statement	O
regarding	O
anti	O
-	O
COVID-19	O
measurements	O
for	O
HS	O
patients	O
.	O

Based	O
on	O
the	O
available	O
knowledge	O
,	O
patients	O
with	O
HS	O
may	O
be	O
vaccinated	O
against	O
SARS	O
-	O
CoV2	O
and	O
patients	O
affected	O
by	O
metabolic	O
syndrome	O
constitute	O
a	O
high	O
-	O
risk	O
group	O
for	O
COVID-19	O
and	O
should	O
be	O
vaccinated	O
at	O
the	O
earliest	O
convenient	O
point	O
in	O
time	O
.	O

HS	O
patients	O
on	O
treatment	O
with	O
adalimumab	O
can	O
be	O
vaccinated	O
with	O
non	O
-	O
living	O
virus	O
anti	O
-	O
SARS	O
-	O
CoV2	O
vaccines	O
.	O

A	O
possible	O
suboptimal	O
effect	O
of	O
the	O
vaccine	O
may	O
be	O
suspected	O
but	O
might	O
not	O
be	O
expected	O
universally	O
.	O

The	O
management	O
of	O
the	O
biological	O
treatment	O
in	O
HS	O
patients	O
is	O
at	O
the	O
discretion	O
of	O
the	O
dermatologist	O
/	O
responsible	O
physician	O
.	O

Over	O
the	O
last	O
two	O
decades	O
,	O
improvements	O
in	O
perinatology	O
have	O
led	O
to	O
increased	O
survival	O
rates	O
of	O
preterm	O
infants	O
.	O

A	O
large	O
number	O
of	O
studies	O
and	O
meta	O
-	O
analyses	O
have	O
investigated	O
of	O
preterm	O
infants	O
and/or	O
the	O
influence	O
of	O
developmental	O
care	O
.	O

However	O
,	O
the	O
combined	O
influence	O
of	O
the	O
most	O
frequent	O
risk	O
factors	O
and	O
developmental	O
care	O
on	O
the	O
long	O
-	O
term	O
somatic	O
,	O
motor	O
,	O
and	O
cognitive	O
outcome	O
of	O
preterm	O
infants	O
remains	O
unclear	O
.	O

This	O
retrospective	O
,	O
single	O
-	O
center	O
cohort	O
study	O
includes	O
256	O
children	O
treated	O
in	O
a	O
tertiary	O
neonatal	O
intensive	O
care	O
unit	O
in	O
Rostock	B-LOC
,	I-LOC
Germany	I-LOC
,	O
between	O
2008	O
and	O
2013	O
.	O

Follow	O
-	O
up	O
examinations	O
(	O
somatic	O
,	O
psychomotor	O
,	O
and	O
mental	O
development	O
)	O
were	O
performed	O
at	O
(	O
corrected	O
)	O
24	O
months	O
using	O
Bayley	O
Scales	O
of	O
Infant	O
Development	O
II	O
(	O
BSID	O
-	O
II	O
)	O
.	O

Developmental	O
care	O
was	O
carried	O
out	O
according	O
to	O
the	O
legal	O
framework	O
and	O
national	O
guidelines	O
(	O
physiotherapy	O
and/or	O
early	O
education	O
)	O
.	O

Bronchopulmonary	O
dysplasia	O
(	O
BPD	O
)	O
and	O
an	O
exclusive	O
formula	O
feeding	O
showed	O
a	O
2.8	O
-	O
4.6	O
-	O
fold	O
higher	O
risk	O
(	O
95	O
%	O
Confidence	O
Interval	O
:	O
Mental	O
Developmental	O
Index	O
1.73	O
-	O
7.58	O
;	O
Psychomotor	O
Developmental	O
Index	O
1.44	O
-	O
14.54	O
;	O
body	O
length	O
1.20	O
-	O
6.41	O
)	O
for	O
developmental	O
deficits	O
(	O
mental	O
and	O
psychomotor	O
developmental	O
index	O
;	O
body	O
length	O
)	O
.	O

Developmental	O
care	O
after	O
discharge	O
according	O
to	O
national	O
guidelines	O
did	O
not	O
prevent	O
this	O
.	O

Since	O
this	O
is	O
a	O
retrospective	O
pilot	O
study	O
,	O
no	O
recommendations	O
can	O
be	O
made	O
based	O
on	O
this	O
analysis	O
.	O

Therefore	O
,	O
future	O
research	O
should	O
evaluate	O
whether	O
standard	O
developmental	O
care	O
should	O
be	O
extended	O
by	O
tailored	O
measures	O
depending	O
on	O
individual	O
risk	O
factors	O
.	O

Abstract	O
Previous	O
studies	O
have	O
suggested	O
that	O
human	O
T	O
-	O
cell	O
leukemia	O
virus	O
type	O
1	O
(	O
HTLV-1	O
)	O
might	O
act	O
as	O
a	O
pathogen	O
in	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
,	O
but	O
epidemiological	O
evidence	O
of	O
an	O
association	O
is	O
scarce	O
.	O

We	O
measured	O
anti	O
-	O
HTLV-1	O
antibodies	O
among	O
Nagasaki	B-LOC
atomic	O
bomb	O
survivors	O
to	O
determine	O
whether	O
HTLV-1	O
is	O
related	O
to	O
RA	O
and	O
whether	O
radiation	O
exposure	O
is	O
associated	O
with	O
HTLV-1	O
and	O
RA	O
prevalence	B-EPI
.	O
This	O
is	O
a	O
cross	O
-	O
sectional	O
study	O
among	O
atomic	O
bomb	O
survivors	O
who	O
participated	O
in	O
biennial	O
health	O
examinations	O
from	O
2006	O
to	O
2010	O
.	O

Serum	O
levels	O
of	O
anti	O
-	O
HTLV-1	O
antibodies	O
were	O
measured	O
using	O
a	O
chemiluminescent	O
enzyme	O
immunoassay	O
and	O
confirmed	O
by	O
Western	O
blotting	O
.	O

Association	O
between	O
HTLV-1	O
and	O
RA	O
was	O
analyzed	O
by	O
a	O
logistic	O
regression	O
model	O
.	O
Of	O
2091	O
participants	O
(	O
women	O
61.5	O
%	O
;	O
median	O
age	O
,	O
73	O
years	O
)	O
,	O
215	O
(	O
10.3	O
%	O
)	O
had	O
anti	O
-	O
HTLV-1	O
antibodies	O
.	O

HTLV-1	O
prevalence	B-EPI
was	O
higher	O
among	O
women	O
(	O
13.1	O
%	O
vs	O
5.8	O
%	O
;	O
P	O
<	O
.001	O
)	O
.	O

Twenty	O
-	O
two	O
participants	O
(	O
1.1	B-STAT
%	I-STAT
)	I-STAT
were	I-STAT
diagnosed	I-STAT
with	I-STAT
RA	I-STAT
.	O

HTLV-1	O
prevalence	B-EPI
among	O
RA	O
participants	O
was	O
significantly	O
higher	O
than	O
that	O
among	O
non	O
-	O
RA	O
participants	O
(	O
27.3	O
%	O
vs	O
10.1	O
%	O
;	O
P	O
=	O
.020	O
)	O
.	O

After	O
adjustment	O
for	O
age	O
,	O
sex	O
,	O
and	O
hepatitis	O
C	O
virus	O
infection	O
,	O
HTLV-1	O
was	O
significantly	O
associated	O
with	O
prevalent	O
RA	O
(	O
odds	O
ratio	O
,	O
2.89	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
1.06	O
,	O
7.03	O
)	O
.	O

There	O
was	O
no	O
association	O
between	O
radiation	O
dose	O
and	O
either	O
the	O
prevalence	B-EPI
of	O
HTLV-1	O
or	O
RA.This	O
study	O
,	O
among	O
a	O
well	O
-	O
defined	O
group	O
of	O
atomic	O
bomb	O
survivors	O
,	O
suggests	O
that	O
HTLV-1	O
is	O
associated	O
with	O
RA	O
.	O

A	O
study	O
of	O
parental	O
cancer	O
in	O
326	O
children	O
referred	O
to	O
a	O
single	O
Paediatric	O
Oncology	O
Unit	O
found	O
a	O
significant	O
increase	O
in	O
breast	O
cancer	O
in	O
mothers	O
of	O
children	O
with	O
solid	O
tumours	O
.	O

The	O
5	O
tumours	O
found	O
were	O
8.9	O
times	O
the	O
expected	O
number	O
.	O

This	O
increase	O
could	O
not	O
be	O
accounted	O
for	O
by	O
any	O
of	O
the	O
known	O
risk	O
factors	O
for	O
breast	O
cancer	O
.	O

The	O
incidence	B-EPI
of	O
cancer	O
in	O
mothers	O
of	O
leukaemic	O
children	O
and	O
in	O
all	O
groups	O
of	O
fathers	O
was	O
not	O
significantly	O
raised	O
.	O

Further	O
prospective	O
studies	O
in	O
the	O
mothers	O
of	O
young	O
children	O
with	O
soft	O
tissue	O
tumours	O
are	O
needed	O
to	O
clarify	O
the	O
groups	O
at	O
risk	O
and	O
to	O
determine	O
whether	O
counselling	O
and	O
surveillance	O
of	O
these	O
mothers	O
is	O
appropriate	O
.	O

Background	O
Vitamin	O
C	O
has	O
anti	O
-	O
oxidant	O
properties	O
and	O
acts	O
as	O
a	O
cofactor	O
for	O
several	O
enzymes	O
.	O

Hypovitaminosis	O
C	O
has	O
been	O
associated	O
with	O
bleeding	O
,	O
endothelial	O
dysfunction	O
and	O
death	O
.	O

The	O
prevalence	B-EPI
of	O
hypovitaminosis	O
C	O
is	O
unknown	B-STAT
in	O
Australian	O
hospitalised	O
patients	O
,	O
and	O
its	O
clinical	O
relevance	O
is	O
uncertain	O
.	O

Aims	O
To	O
determine	O
the	O
prevalence	B-EPI
,	O
characteristics	O
and	O
clinical	O
outcomes	O
of	O
hospitalised	O
patients	O
with	O
hypovitaminosis	O
C.	O
Methods	O
This	O
observational	O
study	O
included	O
general	O
-	O
medical	O
inpatients	O
in	O
a	O
tertiary	O
-	O
level	O
hospital	O
in	O
Australia	B-LOC
.	O

High	O
-	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
was	O
used	O
to	O
determine	O
plasma	O
vitamin	O
C	O
levels	O
.	O

As	O
per	O
Johnston	O
's	O
criteria	O
,	O
vitamin	O
C	O
levels	O
of	O
≥28	O
μmol	O
/	O
L	O
were	O
classified	O
as	O
normal	O
and	O
<	O
28	O
μmol	O
/	O
L	O
as	O
low	O
.	O

Clinical	O
outcomes	O
determined	O
included	O
length	O
of	O
hospital	O
stay	O
(	O
LOS	O
)	O
,	O
nosocomial	O
complications	O
,	O
intensive	O
care	O
unit	O
admission	O
and	O
in	O
-	O
hospital	O
mortality	O
.	O

Results	O
A	O
total	O
of	O
200	O
patients	O
participated	O
in	O
this	O
study	O
,	O
and	O
vitamin	O
C	O
levels	O
were	O
available	O
for	O
149	O
patients	O
,	O
of	O
whom	O
35	O
(	O
23.5	O
%	O
)	O
had	O
normal	O
vitamin	O
C	O
levels	O
,	O
and	O
114	O
(	O
76.5	O
%	O
)	O
had	O
hypovitaminosis	O
C.	O
Patients	O
with	O
hypovitaminosis	O
C	O
were	O
older	O
and	O
had	O
higher	O
C	O
-	O
reactive	O
protein	O
(	O
CRP	O
)	O
levels	O
.	O

Median	O
LOS	O
was	O
2	O
days	O
longer	O
in	O
patients	O
with	O
hypovitaminosis	O
C	O
(	O
6	O
days	O
(	O
interquartile	O
range	O
(	O
IQR	O
)	O
4	O
,	O
8)	O
vs	O
4	O
days	O
(	O
IQR	O
3	O
,	O
6	O
)	O
,	O
P	O
=	O
0.02	O
)	O
,	O
and	O
they	O
had	O
fourfold	O
higher	O
odds	O
of	O
staying	O
in	O
hospital	O
for	O
>	O
5	O
days	O
than	O
those	O
with	O
normal	O
vitamin	O
C	O
levels	O
.	O

Other	O
clinical	O
outcomes	O
were	O
similar	O
between	O
the	O
two	O
groups	O
.	O

Conclusions	O
Hypovitaminosis	O
C	O
is	O
common	O
in	O
hospitalised	O
patients	O
and	O
is	O
associated	O
with	O
prolonged	O
LOS	O
.	O

Further	O
research	O
is	O
needed	O
to	O
ascertain	O
the	O
benefits	O
of	O
vitamin	O
C	O
supplementation	O
in	O
vitamin	O
C	O
-	O
depleted	O
patients	O
.	O

We	O
have	O
previously	O
shown	O
that	O
67	O
%	O
of	O
patients	O
with	O
newly	O
diagnosed	O
coeliac	O
disease	O
(	O
CD	O
)	O
presenting	O
to	O
gastroenterologists	O
have	O
evidence	O
of	O
neurological	O
dysfunction	O
.	O

This	O
manifested	O
with	O
headache	O
and	O
loss	O
of	O
co	O
-	O
ordination	O
.	O

Furthermore	O
60	O
%	O
of	O
these	O
patients	O
had	O
abnormal	O
brain	O
imaging	O
.	O

In	O
this	O
follow	O
-	O
up	O
study	O
,	O
we	O
re	O
-	O
examined	O
and	O
re	O
-	O
scanned	O
30	O
patients	O
from	O
the	O
original	O
cohort	O
of	O
100	O
,	O
seven	O
years	O
later	O
.	O

There	O
was	O
significant	O
reduction	O
in	O
the	O
prevalence	O
of	O
headaches	O
(	O
47	O
%	O
to	O
20	O
%	O
)	O
but	O
an	O
increase	O
in	O
the	O
prevalence	O
of	O
incoordination	O
(	O
27	O
%	O
to	O
47	O
%	O
)	O
.	O

Although	O
those	O
patients	O
with	O
coordination	O
problems	O
at	O
baseline	O
reported	O
improvement	O
on	O
the	O
gluten	O
free	O
diet	O
(	O
GFD	O
)	O
,	O
there	O
were	O
7	O
patients	O
reporting	O
incoordination	O
not	O
present	O
at	O
baseline	O
.	O

All	O
7	O
patients	O
had	O
positive	O
serology	O
for	O
one	O
or	O
more	O
gluten	O
-	O
sensitivity	O
related	O
antibodies	O
at	O
follow	O
-	O
up	O
.	O

In	O
total	O
,	O
50	O
%	O
of	O
the	O
whole	O
follow	O
-	O
up	O
cohort	O
were	O
positive	O
for	O
one	O
or	O
more	O
gluten	O
-	O
related	O
antibodies	O
.	O

A	O
comparison	O
between	O
the	O
baseline	O
and	O
follow	O
-	O
up	O
brain	O
imaging	O
showed	O
a	O
greater	O
rate	O
of	O
cerebellar	O
grey	O
matter	O
atrophy	O
in	O
the	O
antibody	O
positive	O
group	O
compared	O
to	O
the	O
antibody	O
negative	O
group	O
.	O

Patients	O
with	O
CD	O
who	O
do	O
not	O
adhere	O
to	O
a	O
strict	O
GFD	O
and	O
are	O
serological	O
positive	O
are	O
at	O
risk	O
of	O
developing	O
ataxia	O
,	O
and	O
have	O
a	O
significantly	O
higher	O
rate	O
of	O
cerebellar	O
atrophy	O
when	O
compared	O
to	O
patients	O
with	O
negative	O
serology	O
.	O

This	O
highlights	O
the	O
importance	O
of	O
regular	O
review	O
and	O
close	O
monitoring	O
.	O

Background	O
To	O
evaluate	O
the	O
relationship	O
between	O
gender	O
,	O
ethnicity	O
/	O
citizenship	O
,	O
clinical	O
phenotype	O
,	O
total	O
prevalence	B-EPI
,	O
and	O
the	O
various	O
congenital	O
malformations	O
associated	O
with	O
oral	O
clefts	O
(	O
OC	O
)	O
in	O
Italy	B-LOC
across	O
the	O
period	O
2001	O
-	O
2014	O
.	O

Methods	O
A	O
retrospective	O
analysis	O
(	O
2001	O
-	O
2014	O
)	O
was	O
conducted	O
based	O
on	O
the	O
National	O
Congenital	O
Malformation	O
Registries	O
network	O
of	O
Italy	B-LOC
(	O
Emilia	O
-	O
Romagna	O
Registry	O
of	O
Birth	O
Defects	O
[	O
IMER	O
]	O
and	O
Registro	O
Toscano	O
Difetti	O
Congeniti	O
[	O
RTDC	O
]	O
)	O
,	O
which	O
were	O
analyzed	O
to	O
investigate	O
time	O
trends	O
,	O
geographical	O
/	O
ethnic	O
clusters	O
,	O
topography	O
,	O
sex	O
ratio	O
,	O
and	O
associated	O
congenital	O
anomalies	O
of	O
OC	O
phenotypes	O
.	O

Results	O
Among	O
739	O
registered	O
cases	O
,	O
29.8	O
%	O
were	O
syndromic	O
or	O
had	O
multi	O
-	O
malformed	O
associated	O
anomalies	O
,	O
compared	O
with	O
70.2	O
%	O
having	O
isolated	O
orofacial	O
cleft	O
.	O

Cleft	O
lip	O
(	O
CL	O
)	O
was	O
observed	O
in	O
22	O
%	O
,	O
cleft	O
palate	O
(	O
CP	O
)	O
in	O
40	O
%	O
,	O
and	O
cleft	O
lip	O
and	O
palate	O
(	O
CLP	O
)	O
in	O
38	O
%	O
of	O
live	O
births	O
,	O
stillbirths	O
,	O
and	O
terminations	O
of	O
pregnancy	O
for	O
fetal	O
anomaly	O
cases	O
.	O

Other	O
associated	O
conditions	O
were	O
major	O
anomalies	O
of	O
cardiovascular	O
defects	O
(	O
39	O
%	O
)	O
,	O
followed	O
by	O
defects	O
of	O
the	O
limbs	O
(	O
28	O
%	O
)	O
,	O
neuroectodermal	O
defects	O
(	O
23	O
%	O
)	O
,	O
and	O
urogenital	O
malformations	O
(	O
10	O
%	O
)	O
.	O

Male	O
-	O
to	O
-	O
female	O
sex	O
ratio	O
was	O
1:1.14	O
in	O
CP	O
,	O
1.22:1	O
in	O
CL	O
,	O
and	O
1.9:1	O
in	O
CLP	O
.	O

Foreigners	O
were	O
represented	O
by	O
29	O
%	O
from	O
Southeast	B-LOC
Asia	I-LOC
,	O
25	O
%	O
from	O
Balkans	B-LOC
,	O
25	O
%	O
from	O
North	B-LOC
-	I-LOC
Central	I-LOC
Africa	I-LOC
,	O
9	O
%	O
from	O
the	O
East	B-LOC
,	O
7	O
%	O
from	O
Western	B-LOC
Europe	I-LOC
,	O
and	O
5	O
%	O
from	O
South	B-LOC
America	I-LOC
.	O

Total	O
prevalence	B-EPI
of	O
OC	O
cases	O
ranged	O
from	O
0.9	B-STAT
(	I-STAT
RTDC	I-STAT
)	I-STAT
to	I-STAT
1.1	I-STAT
(	I-STAT
IMER	I-STAT
)	I-STAT
of	I-STAT
1000	I-STAT
births	I-STAT
.	O

Conclusions	O
This	O
retrospective	O
study	O
provides	O
a	O
population	O
-	O
based	O
,	O
clinical	O
-	O
epidemiological	O
description	O
of	O
the	O
orofacial	O
cleft	O
phenomenon	O
.	O

As	O
a	O
relatively	O
frequent	O
congenital	O
malformation	O
,	O
its	O
social	O
and	O
economic	O
impact	O
is	O
worthy	O
of	O
further	O
study	O
.	O

These	O
abnormalities	O
can	O
cause	O
significant	O
problems	O
that	O
may	O
be	O
solved	O
or	O
minimized	O
by	O
early	O
diagnosis	O
and	O
treatment	O
.	O

Rates	O
of	O
eating	O
disorders	O
(	O
EDs	O
)	O
are	O
increasing	O
in	O
Australia	B-LOC
,	O
as	O
are	O
rates	O
of	O
bariatric	O
and	O
cosmetic	O
surgery	O
including	O
weight	O
-	O
related	O
procedures	O
.	O

It	O
is	O
known	O
that	O
binge	O
eating	O
disorder	O
(	O
BED	O
)	O
is	O
common	O
in	O
bariatric	O
surgery	O
candidates	O
and	O
that	O
people	O
with	O
EDs	O
are	O
likely	O
to	O
undergo	O
weight	O
-	O
related	O
cosmetic	O
procedures	O
,	O
however	O
,	O
most	O
of	O
the	O
literature	O
is	O
based	O
on	O
clinic	O
samples	O
and	O
focuses	O
on	O
young	O
women	O
and	O
BED	O
.	O

Aims	O
of	O
this	O
study	O
were	O
to	O
determine	O
the	O
prevalence	B-EPI
of	O
(	O
1	O
)	O
actual	O
or	O
intended	O
bariatric	O
surgery	O
and	O
(	O
2	O
)	O
actual	O
or	O
intended	O
cosmetic	O
surgery	O
including	O
weight	O
-	O
related	O
procedures	O
in	O
people	O
with	O
a	O
current	O
ED	O
and	O
a	O
lifetime	O
history	O
of	O
BED	O
or	O
bulimia	O
nervosa	O
(	O
BN	O
)	O
,	O
and	O
the	O
associations	O
with	O
actual	O
or	O
intended	O
bariatric	O
or	O
cosmetic	O
surgery	O
and	O
demographic	O
features	O
.	O

Using	O
a	O
general	O
population	O
survey	O
,	O
2977	O
individuals	O
were	O
interviewed	O
regarding	O
sociodemographic	O
status	O
,	O
ED	O
symptoms	O
,	O
mental	O
health	O
-	O
related	O
quality	O
of	O
life	O
(	O
MHRQoL	O
)	O
and	O
actual	O
or	O
intended	O
use	O
of	O
bariatric	O
and	O
cosmetic	O
surgery	O
,	O
prevalence	O
estimates	O
of	O
which	O
were	O
2.0	O
%	O
and	O
1.1	O
%	O
,	O
respectively	O
.	O

People	O
who	O
had	O
planned	O
or	O
received	O
either	O
type	O
of	O
surgery	O
were	O
more	O
likely	O
to	O
be	O
(	O
1	O
)	O
women	O
and	O
(	O
2	O
)	O
have	O
a	O
higher	O
BMI	O
,	O
(	O
3	O
)	O
poorer	O
MHRQoL	O
and	O
(	O
4	O
)	O
a	O
current	O
ED	O
,	O
lifetime	O
BN	O
or	O
BED	O
or	O
features	O
of	O
EDs	O
(	O
all	O
p	O
<	O
0.05	O
)	O
.	O

Age	O
and	O
household	O
income	O
were	O
not	O
significantly	O
associated	O
with	O
increased	O
use	O
of	O
either	O
type	O
of	O
surgery	O
.	O

Given	O
the	O
potential	O
for	O
an	O
ED	O
to	O
affect	O
outcomes	O
of	O
surgery	O
,	O
screening	O
and	O
treatment	O
for	O
EDs	O
should	O
be	O
considered	O
in	O
such	O
surgical	O
candidates	O
.	O

Congenital	O
adrenal	O
hyperplasia	O
(	O
CAH	O
)	O
was	O
the	O
fourth	O
disorder	O
added	O
to	O
the	O
national	O
Swedish	O
neonatal	O
screening	O
program	O
in	O
1986	O
,	O
and	O
approximately	O
115,000	O
newborns	O
are	O
screened	O
annually	O
.	O

Dried	O
blood	O
spot	O
(	O
DBS	O
)	O
screening	O
with	O
measurement	O
of	O
17	O
-	O
hydroxyprogesterone	O
(	O
17OHP	O
)	O
is	O
also	O
offered	O
to	O
older	O
children	O
moving	O
to	O
Sweden	B-LOC
from	O
countries	O
lacking	O
a	O
national	O
DBS	O
screening	O
program	O
.	O

Here	O
,	O
we	O
report	O
an	O
update	O
on	O
the	O
CAH	O
screening	O
from	O
January	O
2011	O
until	O
December	O
2019	O
.	O

Results	O
:	O
During	O
the	O
study	O
period	O
,	O
1,030,409	O
newborns	O
and	O
34,713	O
older	O
children	O
were	O
screened	O
.	O

In	O
total	O
,	O
87	O
newborns	O
were	O
verified	O
to	O
have	O
CAH	O
,	O
which	O
gives	O
an	O
overall	O
positive	O
predictive	O
value	O
(	O
PPV	O
)	O
of	O
11	O
%	O
and	O
21	O
%	O
for	O
term	O
infants	O
.	O

Including	O
the	O
five	O
missed	O
CAH	O
cases	O
identified	O
during	O
this	O
period	O
,	O
this	O
gives	O
an	O
incidence	B-EPI
of	O
1:11,200	B-STAT
of	O
CAH	O
in	O
Sweden	B-LOC
.	O

Among	O
the	O
older	O
children	O
,	O
12	O
of	O
14	O
recalled	O
cases	O
were	O
found	O
to	O
be	O
true	O
positive	O
for	O
CAH	O
.	O

All	O
patients	O
were	O
genotyped	O
as	O
part	O
of	O
the	O
clinical	O
follow	O
-	O
up	O
and	O
70	O
%	O
of	O
the	O
newborns	O
had	O
salt	O
wasting	O
(	O
SW	O
)	O
CAH	O
and	O
92	B-STAT
%	I-STAT
had	O
classic	O
CAH	O
(	O
i.e.	O
,	O
SW	O
and	O
simple	O
virilizing	O
(	O
SV	O
)	O
CAH	O
)	O
.	O

In	O
the	O
group	O
of	O
12	O
older	O
children	O
,	O
none	O
had	O
SW	O
CAH	O
and	O
two	O
had	O
SV	O
CAH	O
.	O

Conclusion	O
:	O
The	O
incidence	B-EPI
of	O
classic	O
CAH	O
is	O
relatively	O
high	O
in	O
Sweden	B-LOC
.	O

Early	O
genetic	O
confirmation	O
with	O
CYP21A2	O
genotyping	O
has	O
been	O
a	O
valuable	O
complement	O
to	O
the	O
analysis	O
of	O
17OHP	O
to	O
predict	O
disease	O
severity	O
,	O
make	O
treatment	O
decisions	O
and	O
for	O
the	O
follow	O
-	O
up	O
and	O
evaluation	O
of	O
the	O
screening	O
program	O
.	O

Background	O
Juvenile	O
idiopathic	O
arthritis	O
(	O
JIA	O
)	O
is	O
a	O
heterogeneous	O
group	O
of	O
chronic	O
arthritides	O
presenting	O
in	O
patients	O
aged	O
≤16	O
years	O
,	O
with	O
a	O
prevalence	B-EPI
of	O
16	B-STAT
to	I-STAT
150	I-STAT
per	I-STAT
100,000	I-STAT
.	O

Juvenile	O
osteochondritis	O
dissecans	O
(	O
OCD	O
)	O
is	O
an	O
idiopathic	O
disease	O
of	O
articular	O
cartilage	O
and	O
subchondral	O
bone	O
,	O
has	O
an	O
onset	O
age	O
of	O
10	O
to	O
16	O
years	O
,	O
and	O
often	O
affects	O
the	O
knee	O
,	O
with	O
a	O
prevalence	B-EPI
of	O
2	B-STAT
to	I-STAT
18	I-STAT
per	I-STAT
100,000	I-STAT
.	O

Currently	O
,	O
there	O
are	O
few	O
studies	O
that	O
have	O
evaluated	O
the	O
relationship	O
between	O
JIA	O
and	O
OCD	O
.	O

Hypothesis	O
OCD	O
is	O
more	O
prevalent	O
in	O
children	O
with	O
JIA	O
,	O
and	O
when	O
diagnosed	O
in	O
such	O
patients	O
,	O
OCD	O
often	O
presents	O
at	O
an	O
advanced	O
state	O
.	O

Study	O
design	O
Case	O
series	O
;	O
Level	O
of	O
evidence	O
,	O
4	O
.	O

Methods	O
The	O
medical	O
records	O
of	O
patients	O
with	O
diagnoses	O
of	O
both	O
JIA	O
and	O
OCD	O
treated	O
between	O
January	O
2008	O
and	O
March	O
2019	O
at	O
a	O
single	O
children	O
's	O
hospital	O
were	O
retrospectively	O
reviewed	O
.	O

Associations	O
between	O
timing	O
of	O
diagnoses	O
,	O
number	O
and	O
types	O
of	O
corticosteroid	O
treatments	O
,	O
category	O
of	O
arthritis	O
,	O
timing	O
of	O
diagnoses	O
,	O
and	O
lesion	O
stability	O
were	O
examined	O
with	O
Spearman	O
correlation	O
coefficients	O
.	O

Results	O
A	O
total	O
of	O
2021	O
patients	O
with	O
JIA	O
were	O
identified	O
,	O
20	O
of	O
whom	O
(	O
19	O
female	O
,	O
1	O
male	O
)	O
had	O
OCD	O
of	O
the	O
knee	O
and/or	O
talus	O
for	O
a	O
prevalence	B-EPI
of	O
1	B-STAT
in	I-STAT
100	I-STAT
or	O
1000	B-STAT
in	I-STAT
100,000	I-STAT
,	O
or	O
approximately	O
50	O
to	O
500	O
times	O
that	O
of	O
the	O
general	O
population	O
.	O

These	O
20	O
patients	O
had	O
a	O
total	O
of	O
28	O
OCD	O
lesions	O
:	O
43	O
%	O
(	O
9	O
femur	O
,	O
3	O
talus	O
)	O
were	O
radiographically	O
stable	O
over	O
time	O
,	O
50	O
%	O
(	O
10	O
femur	O
,	O
2	O
patella	O
,	O
2	O
talus	O
)	O
were	O
unstable	O
at	O
initial	O
diagnosis	O
,	O
and	O
7	O
%	O
(	O
2	O
femur	O
)	O
were	O
initially	O
stable	O
but	O
progressed	O
to	O
unstable	O
lesions	O
despite	O
drilling	O
.	O

Twelve	O
patients	O
(	O
60	O
%	O
)	O
underwent	O
surgery	O
:	O
4	O
(	O
20	O
%	O
)	O
with	O
stable	O
femoral	O
lesions	O
for	O
persistent	O
symptoms	O
despite	O
prolonged	O
nonoperative	O
treatment	O
and	O
8	O
(	O
40	O
%	O
)	O
for	O
treatment	O
of	O
their	O
unstable	O
lesions	O
(	O
femoral	O
and	O
patellar	O
)	O
.	O

Within	O
our	O
study	O
design	O
,	O
we	O
could	O
identify	O
no	O
significant	O
associations	O
between	O
lesion	O
stability	O
and	O
timing	O
of	O
diagnoses	O
,	O
number	O
of	O
joint	O
injections	O
,	O
or	O
limb	O
deformities	O
,	O
nor	O
were	O
there	O
associations	O
between	O
timing	O
of	O
JIA	O
and	O
OCD	O
diagnoses	O
and	O
category	O
of	O
arthritis	O
.	O

Conclusion	O
In	O
our	O
population	O
of	O
patients	O
with	O
JIA	O
,	O
OCD	O
lesions	O
were	O
found	O
to	O
be	O
50	O
to	O
500	O
times	O
more	O
prevalent	O
when	O
compared	O
with	O
published	O
rates	O
in	O
the	O
general	O
population	O
and	O
often	O
presented	O
at	O
an	O
advanced	O
state	O
,	O
with	O
instability	O
or	O
delayed	O
healing	O
requiring	O
surgery	O
for	O
stabilization	O
or	O
resolution	O
of	O
symptoms	O
.	O

Background	O
Insight	O
into	O
type	O
6	O
long	O
-	O
QT	O
syndrome	O
(	O
LQT6	O
)	O
,	O
stemming	O
from	O
mutations	O
in	O
the	O
KCNE2	O
-encoded	O
voltage	O
-	O
gated	O
channel	O
β	O
-	O
subunit	O
,	O
is	O
limited	O
.	O

We	O
sought	O
to	O
further	O
characterize	O
its	O
clinical	O
phenotype	O
.	O

Methods	O
and	O
results	O
Individuals	O
with	O
reported	O
pathogenic	O
KCNE2	O
mutations	O
identified	O
during	O
arrhythmia	O
evaluation	O
were	O
collected	O
from	O
inherited	O
arrhythmia	O
clinics	O
and	O
the	O
Rochester	O
long	O
-	O
QT	O
syndrome	O
(	O
LQTS	O
)	O
registry	O
.	O

Previously	O
reported	O
LQT6	O
cases	O
were	O
identified	O
through	O
a	O
search	O
of	O
the	O
MEDLINE	O
database	O
.	O

Clinical	O
features	O
were	O
assessed	O
,	O
while	O
reported	O
KCNE2	O
mutations	O
were	O
evaluated	O
for	O
genotype	O
-	O
phenotype	O
segregation	O
and	O
classified	O
according	O
to	O
the	O
contemporary	O
American	O
College	O
of	O
Medical	O
Genetics	O
guidelines	O
.	O

Twenty	O
-	O
seven	O
probands	O
possessed	O
reported	O
pathogenic	O
KCNE2	O
mutations	O
,	O
while	O
a	O
MEDLINE	O
search	O
identified	O
17	O
additional	O
LQT6	O
cases	O
providing	O
clinical	O
and	O
genetic	O
data	O
.	O

Sixteen	O
probands	O
had	O
normal	O
resting	O
QTc	O
values	O
and	O
only	O
developed	O
QT	O
prolongation	O
and	O
malignant	O
arrhythmias	O
after	O
exposure	O
to	O
QT	O
-	O
prolonging	O
stressors	O
,	O
10	O
had	O
other	O
LQTS	O
pathogenic	O
mutations	O
,	O
and	O
10	O
did	O
not	O
have	O
an	O
LQTS	O
phenotype	O
.	O

Although	O
the	O
remaining	O
8	O
subjects	O
had	O
an	O
LQTS	O
phenotype	O
,	O
evidence	O
suggested	O
that	O
the	O
KCNE2	O
variant	O
was	O
not	O
the	O
underlying	O
culprit	O
.	O

The	O
collective	O
frequency	B-EPI
of	O
KCNE2	O
variants	O
implicated	O
in	O
LQT6	O
in	O
the	O
Exome	O
Aggregation	O
Consortium	O
database	O
was	O
1.4	B-STAT
%	I-STAT
,	O
in	O
comparison	O
with	O
a	O
0.0005	B-STAT
%	I-STAT
estimated	B-EPI
clinical	I-EPI
prevalence	I-EPI
for	O
LQT6	O
.	O

Conclusions	O
On	O
the	O
basis	O
of	O
clinical	O
phenotype	O
,	O
the	O
high	O
allelic	O
frequencies	O
of	O
LQT6	O
mutations	O
in	O
the	O
Exome	O
Aggregation	O
Consortium	O
database	O
,	O
and	O
absence	O
of	O
previous	O
documentation	O
of	O
genotype	O
-	O
phenotype	O
segregation	O
,	O
our	O
findings	O
suggest	O
that	O
many	O
KCNE2	O
variants	O
,	O
and	O
perhaps	O
all	O
,	O
have	O
been	O
erroneously	O
designated	O
as	O
LQTS	O
-	O
causative	O
mutations	O
.	O

Instead	O
,	O
KCNE2	O
variants	O
may	O
confer	O
proarrhythmic	O
susceptibility	O
when	O
provoked	O
by	O
additional	O
environmental	O
/	O
acquired	O
or	O
genetic	O
factors	O
,	O
or	O
both	O
.	O

Purpose	O
To	O
compare	O
clinical	O
outcomes	O
between	O
pars	O
plana	O
vitrectomy	O
(	O
PPV	O
)	O
,	O
scleral	O
buckling	O
(	O
SB	O
)	O
,	O
and	O
PPV+SB	O
for	O
rhegmatogenous	O
retinal	O
detachment	O
in	O
the	O
Japan	B-LOC
-	O
RD	O
Registry	O
.	O

Methods	O
This	O
is	O
a	O
nation	O
-	O
wide	O
,	O
multicenter	O
,	O
observational	O
study	O
based	O
on	O
the	O
registry	O
data	O
between	O
2016	O
and	O
2017	O
.	O

The	O
failure	O
levels	O
were	O
defined	O
as	O
Level	O
1	O
(	O
a	O
failure	O
of	O
retinal	O
detachment	O
repair	O
)	O
,	O
Level	O
2	O
(	O
remaining	O
silicone	O
oil	O
)	O
,	O
and	O
Level	O
3	O
(	O
multiple	O
surgeries	O
to	O
achieve	O
reattachment	O
)	O
.	O

We	O
compared	O
cases	O
treated	O
by	O
SB	O
or	O
PPV	O
in	O
the	O
subgroup	O
of	O
simple	O
rhegmatogenous	O
retinal	O
detachment	O
using	O
multivariate	O
Cox	O
proportional	O
hazard	O
models	O
.	O

Results	O
A	O
total	O
of	O
2,775	O
cases	O
were	O
included	O
.	O

Overall	O
,	O
6	O
months	O
any	O
levels	O
of	O
failure	O
in	O
total	O
,	O
SB	O
,	O
PPV	O
,	O
and	O
PPV+SB	O
were	O
9.2	O
%	O
(	O
n	O
=	O
256	O
)	O
,	O
6.9	O
%	O
(	O
n	O
=	O
48	O
)	O
,	O
8.2	O
%	O
(	O
n	O
=	O
157	O
)	O
,	O
and	O
21.3	O
%	O
(	O
n	O
=	O
51	O
)	O
,	O
respectively	O
.	O

Poor	O
visual	O
acuity	O
at	O
baseline	O
in	O
SB	O
and	O
inferior	O
rhegmatogenous	O
retinal	O
detachment	O
and	O
larger	O
retinal	O
tear	O
in	O
PPV	O
were	O
associated	O
with	O
a	O
higher	O
risk	O
of	O
failure	O
.	O

Pars	O
plana	O
vitrectomy	O
was	O
associated	O
with	O
a	O
higher	O
chance	O
of	O
achieving	O
primary	O
success	O
in	O
cases	O
with	O
simple	O
RRD	O
,	O
especially	O
for	O
cases	O
with	O
superior	O
RRD	O
(	O
adjusted	O
hazard	O
ratio	O
3.61	O
,	O
95	O
%	O
confidence	O
interval	O
2.22	O
-	O
5.94	O
,	O
P	O
<	O
0.001	O
)	O
.	O

Conclusion	O
In	O
this	O
nationwide	O
study	O
,	O
surgical	O
anatomic	O
outcomes	O
were	O
equally	O
successful	O
in	O
either	O
SB	O
or	O
PPV	O
.	O

There	O
were	O
different	O
baseline	O
characteristics	O
associated	O
with	O
primary	O
success	O
between	O
SB	O
and	O
PPV	O
.	O

Uveal	O
melanoma	O
(	O
UM	O
)	O
represents	O
the	O
most	O
prominent	O
primary	O
eye	O
cancer	O
in	O
adults	O
.	O

With	O
an	O
incidence	B-EPI
of	O
approximately	B-STAT
5	I-STAT
cases	I-STAT
per	I-STAT
million	I-STAT
individuals	I-STAT
annually	I-STAT
in	O
the	B-LOC
United	I-LOC
States	I-LOC
,	O
UM	O
could	O
be	O
considered	O
a	O
relatively	O
rare	O
cancer	O
.	O

The	O
90-95	O
%	O
of	O
UM	O
cases	O
arise	O
from	O
the	O
choroid	O
.	O

Diagnosis	O
is	O
based	O
mainly	O
on	O
a	O
clinical	O
examination	O
and	O
ancillary	O
tests	O
,	O
with	O
ocular	O
ultrasonography	O
being	O
of	O
greatest	O
value	O
.	O

Differential	O
diagnosis	O
can	O
prove	O
challenging	O
in	O
the	O
case	O
of	O
indeterminate	O
choroidal	O
lesions	O
and	O
,	O
sometimes	O
,	O
monitoring	O
for	O
documented	O
growth	O
may	O
be	O
the	O
proper	O
approach	O
.	O

Fine	O
needle	O
aspiration	O
biopsy	O
tends	O
to	O
be	O
performed	O
with	O
a	O
prognostic	O
purpose	O
,	O
often	O
in	O
combination	O
with	O
radiotherapy	O
.	O

Gene	O
expression	O
profiling	O
has	O
allowed	O
for	O
the	O
grading	O
of	O
UMs	O
into	O
two	O
classes	O
,	O
which	O
feature	O
different	O
metastatic	O
risks	O
.	O

Patients	O
with	O
UM	O
require	O
a	O
specialized	O
multidisciplinary	O
management	O
.	O

Primary	O
tumor	O
treatment	O
can	O
be	O
either	O
enucleation	O
or	O
globe	O
preserving	O
.	O

Usually	O
,	O
enucleation	O
is	O
reserved	O
for	O
larger	O
tumors	O
,	O
while	O
radiotherapy	O
is	O
preferred	O
for	O
small	O
/	O
medium	O
melanomas	O
.	O

The	O
prognosis	O
is	O
unfavorable	O
due	O
to	O
the	O
high	O
mortality	O
rate	O
and	O
high	O
tendency	O
to	O
metastasize	O
.	O

Following	O
the	O
development	O
of	O
metastatic	O
disease	O
,	O
the	O
mortality	O
rate	O
increases	O
to	O
80	O
%	O
within	O
one	O
year	O
,	O
due	O
to	O
both	O
the	O
absence	O
of	O
an	O
effective	O
treatment	O
and	O
the	O
aggressiveness	O
of	O
the	O
condition	O
.	O

Novel	O
molecular	O
studies	O
have	O
allowed	O
for	O
a	O
better	O
understanding	O
of	O
the	O
genetic	O
and	O
epigenetic	O
mechanisms	O
involved	O
in	O
UM	O
biological	O
activity	O
,	O
which	O
differs	O
compared	O
to	O
skin	O
melanomas	O
.	O

The	O
most	O
commonly	O
mutated	O
genes	O
are	O
GNAQ	O
,	O
GNA11	O
and	O
BAP1	O
.	O

Research	O
in	O
this	O
field	O
could	O
help	O
to	O
identify	O
effective	O
diagnostic	O
and	O
prognostic	O
biomarkers	O
,	O
as	O
well	O
as	O
novel	O
therapeutic	O
targets	O
.	O

Marine	O
mammals	O
are	O
important	O
sources	O
of	O
food	O
for	O
indigenous	O
residents	O
of	O
northern	B-LOC
Alaska	I-LOC
.	O

Changing	O
sea	O
ice	O
patterns	O
affect	O
the	O
animals	O
themselves	O
as	O
well	O
as	O
access	O
to	O
them	O
by	O
hunters	O
.	O

Documenting	O
the	O
traditional	O
knowledge	O
of	O
Iñupiaq	O
and	O
Yupik	O
hunters	O
concerning	O
marine	O
mammals	O
and	O
sea	O
ice	O
makes	O
accessible	O
a	O
wide	O
range	O
of	O
information	O
relevant	O
to	O
understanding	O
the	O
ecosystem	O
to	O
which	O
humans	O
belong	O
.	O

We	O
interviewed	O
hunters	O
in	O
11	B-LOC
coastal	I-LOC
villages	I-LOC
from	I-LOC
the	I-LOC
northern	I-LOC
Bering	I-LOC
Sea	I-LOC
to	I-LOC
the	I-LOC
Beaufort	I-LOC
Sea	I-LOC
.	O

Hunters	O
reported	O
extensive	O
changes	O
in	O
sea	O
ice	O
and	O
weather	O
that	O
have	O
affected	O
the	O
timing	O
of	O
marine	O
mammal	O
migrations	O
,	O
their	O
distribution	O
and	O
behaviour	O
and	O
the	O
efficacy	O
of	O
certain	O
hunting	O
methods	O
.	O

Amidst	O
these	O
changes	O
,	O
however	O
,	O
hunters	O
cited	O
offsetting	O
technological	O
benefits	O
,	O
such	O
as	O
more	O
powerful	O
and	O
fuel	O
-	O
efficient	O
outboard	O
engines	O
.	O

Other	O
concerns	O
included	O
potential	O
impacts	O
to	O
subsistence	O
hunting	O
from	O
industrial	O
activity	O
such	O
as	O
shipping	O
and	O
oil	O
and	O
gas	O
development	O
.	O

While	O
hunters	O
have	O
been	O
able	O
to	O
adjust	O
to	O
some	O
changes	O
,	O
continued	O
environmental	O
changes	O
and	O
increased	O
disturbance	O
from	O
human	O
activity	O
may	O
further	O
challenge	O
their	O
ability	O
to	O
acquire	O
food	O
in	O
the	O
future	O
.	O

There	O
are	O
indications	O
,	O
however	O
,	O
that	O
innovation	O
and	O
flexibility	O
provide	O
sources	O
of	O
resilience	O
.	O

The	O
field	O
of	O
gene	O
therapy	O
is	O
striving	O
more	O
than	O
ever	O
to	O
define	O
a	O
path	O
to	O
the	O
clinic	O
and	O
the	O
market	O
.	O

Twenty	O
gene	O
therapy	O
products	O
have	O
already	O
been	O
approved	O
and	O
over	O
two	O
thousand	O
human	O
gene	O
therapy	O
clinical	O
trials	O
have	O
been	O
reported	O
worldwide	O
.	O

These	O
advances	O
raise	O
great	O
hope	O
to	O
treat	O
devastating	O
rare	O
and	O
inherited	O
diseases	O
as	O
well	O
as	O
incurable	O
illnesses	O
.	O

Understanding	O
of	O
the	O
precise	O
pathomechanisms	O
of	O
diseases	O
as	O
well	O
as	O
the	O
development	O
of	O
efficient	O
and	O
specific	O
gene	O
targeting	O
and	O
delivery	O
tools	O
are	O
revolutionizing	O
the	O
global	O
market	O
.	O

Currently	O
,	O
human	O
cancers	O
and	O
monogenic	O
disorders	O
are	O
indications	O
number	O
one	O
.	O

The	O
elevated	O
prevalence	B-EPI
of	O
genetic	O
disorders	O
and	O
cancers	O
,	O
clear	O
gene	O
manipulation	O
guidelines	O
and	O
increasing	O
financial	O
support	O
for	O
gene	O
therapy	O
in	O
clinical	O
trials	O
are	O
major	O
trends	O
.	O

Gene	O
therapy	O
is	O
presently	O
starting	O
to	O
become	O
commercially	O
profitable	O
as	O
a	O
number	O
of	O
gene	O
and	O
cell	O
-	O
based	O
gene	O
therapy	O
products	O
have	O
entered	O
the	O
market	O
and	O
the	O
clinic	O
.	O

This	O
article	O
reviews	O
the	O
history	O
and	O
development	O
of	O
twenty	O
approved	O
human	O
gene	O
and	O
cell	O
-	O
based	O
gene	O
therapy	O
products	O
that	O
have	O
been	O
approved	O
up	O
-	O
to	O
-	O
now	O
in	O
clinic	O
and	O
markets	O
of	O
mainly	O
North	B-LOC
America	I-LOC
,	O
Europe	B-LOC
and	O
Asia	B-LOC
.	O

The	O
term	O
NBIA	O
encompasses	O
a	O
heterogeneous	O
group	O
of	O
inherited	O
disorders	O
characterized	O
clinically	O
by	O
progressive	O
extra	O
pyramidal	O
syndrome	O
and	O
pathologically	O
by	O
excessive	O
iron	O
deposition	O
in	O
brain	O
,	O
primarily	O
affecting	O
the	O
basal	O
ganglia	O
(	O
globus	O
pallidus	O
mainly	O
)	O
.	O

The	O
hallmark	O
of	O
this	O
syndrome	O
is	O
the	O
age	O
specific	O
phenotypic	O
presentation	O
and	O
intraphenotypic	O
heterogeneity	O
.	O

NBIAs	O
at	O
present	O
include	O
ten	O
subtypes	O
with	O
genes	O
identified	O
in	O
nine	O
subtypes	O
.	O

They	O
form	O
an	O
important	O
differential	O
diagnosis	O
for	O
the	O
phenotype	O
of	O
global	O
developmental	O
delay	O
in	O
infancy	O
/	O
childhood	O
to	O
dystonia	O
-	O
parkinsonism	O
or	O
isolated	O
parkinsonism	O
at	O
all	O
ages	O
and	O
also	O
for	O
the	O
isolated	O
craniocervical	O
dystonia	O
of	O
adult	O
onset	O
.	O

There	O
needs	O
to	O
be	O
a	O
high	O
index	O
of	O
clinical	O
suspicion	O
for	O
this	O
syndrome	O
and	O
the	O
evaluation	O
includes	O
MRI	O
brain	O
T2	O
*	O
weighted	O
imaging	O
which	O
reveal	O
symmetrical	O
iron	O
deposition	O
in	O
bilateral	O
globus	O
pallidi	O
and	O
other	O
basal	O
ganglia	O
.	O

The	O
T2	O
*	O
imaging	O
pattern	O
of	O
iron	O
deposition	O
varies	O
amongst	O
the	O
different	O
subtypes	O
and	O
the	O
combination	O
of	O
clinical	O
phenotype	O
and	O
MRI	O
signature	O
makes	O
it	O
easier	O
to	O
confidently	O
make	O
a	O
diagnosis	O
of	O
NBIA	O
and	O
to	O
recommend	O
genetic	O
testing	O
.	O

The	O
treatment	O
to	O
date	O
is	O
mostly	O
symptomatic	O
with	O
targeted	O
therapies	O
on	O
the	O
horizon	O
.	O

Adenylosuccinate	O
lyase	O
ADSL	O
)	O
deficiency	O
is	O
a	O
defect	O
of	O
purine	O
metabolism	O
affecting	O
purinosome	O
assembly	O
and	O
reducing	O
metabolite	O
fluxes	O
through	O
purine	O
de	O
novo	O
synthesis	O
and	O
purine	O
nucleotide	O
recycling	O
pathways	O
.	O

Biochemically	O
this	O
defect	O
manifests	O
by	O
the	O
presence	O
in	O
the	O
biologic	O
fluids	O
of	O
two	O
dephosphorylated	O
substrates	O
of	O
ADSL	O
enzyme	O
:	O
succinylaminoimidazole	O
carboxamide	O
riboside	O
(	O
SAICAr	O
)	O
and	O
succinyladenosine	O
(	O
S	O
-	O
Ado	O
)	O
.	O

More	B-STAT
than	I-STAT
80	I-STAT
individuals	I-STAT
with	O
ADSL	O
deficiency	O
have	O
been	O
identified	B-EPI
,	O
but	O
incidence	B-EPI
of	O
the	O
disease	O
remains	O
unknown	B-STAT
.	O

The	O
disorder	O
shows	O
a	O
wide	O
spectrum	O
of	O
symptoms	O
from	O
slowly	O
to	O
rapidly	O
progressing	O
forms	O
.	O

The	O
fatal	O
neonatal	O
form	O
has	O
onset	O
from	O
birth	O
and	O
presents	O
with	O
fatal	O
neonatal	O
encephalopathy	O
with	O
a	O
lack	O
of	O
spontaneous	O
movement	O
,	O
respiratory	O
failure	O
,	O
and	O
intractable	O
seizures	O
resulting	O
in	O
early	O
death	O
within	O
the	O
first	O
weeks	O
of	O
life	O
.	O

Patients	O
with	O
type	O
I	O
(	O
severe	O
form	O
)	O
present	O
with	O
a	O
purely	O
neurologic	O
clinical	O
picture	O
characterized	O
by	O
severe	O
psychomotor	O
retardation	O
,	O
microcephaly	O
,	O
early	O
onset	O
of	O
seizures	O
,	O
and	O
autistic	O
features	O
.	O

A	O
more	O
slowly	O
progressing	O
form	O
has	O
also	O
been	O
described	O
(	O
type	O
II	O
,	O
moderate	O
or	O
mild	O
form	O
)	O
,	O
as	O
having	O
later	O
onset	O
,	O
usually	O
within	O
the	O
first	O
years	O
of	O
life	O
,	O
slight	O
to	O
moderate	O
psychomotor	O
retardation	O
and	O
transient	O
contact	O
disturbances	O
.	O

Diagnosis	O
is	O
facilitated	O
by	O
demonstration	O
of	O
SAICAr	O
and	O
S	O
-	O
Ado	O
in	O
extracellular	O
fluids	O
such	O
as	O
plasma	O
,	O
cerebrospinal	O
fluid	O
and/or	O
followed	O
by	O
genomic	O
and/or	O
cDNA	O
sequencing	O
and	O
characterization	O
of	O
mutant	O
proteins	O
.	O

Over	O
50	O
ADSL	O
mutations	O
have	O
been	O
identified	O
and	O
their	O
effects	O
on	O
protein	O
biogenesis	O
,	O
structural	O
stability	O
and	O
activity	O
as	O
well	O
as	O
on	O
purinosome	O
assembly	O
were	O
characterized	O
.	O

To	O
date	O
there	O
is	O
no	O
specific	O
and	O
effective	O
therapy	O
for	O
ADSL	O
deficiency	O
.	O

Importance	O
Although	O
several	O
single	O
-	O
center	O
studies	O
have	O
estimated	O
that	O
granuloma	O
annulare	O
may	O
account	O
for	O
approximately	B-STAT
0.1	I-STAT
%	I-STAT
to	I-STAT
0.4	I-STAT
%	I-STAT
of	I-STAT
new	I-STAT
patients	I-STAT
presenting	I-STAT
to	I-STAT
dermatologists	I-STAT
,	O
large	O
-	O
scale	O
population	O
-	O
based	O
studies	O
estimating	O
the	O
prevalence	B-EPI
and	O
incidence	B-EPI
of	O
granuloma	O
annulare	O
are	O
lacking	O
.	O

Objectives	O
To	O
estimate	O
the	O
population	O
-	O
based	O
incidence	B-EPI
and	O
prevalence	B-EPI
of	O
granuloma	O
annulare	O
in	O
the	B-LOC
United	I-LOC
States	I-LOC
and	O
to	O
identify	O
the	O
most	O
commonly	O
prescribed	O
treatments	O
.	O

Design	O
,	O
setting	O
,	O
and	O
participants	O
This	O
cross	O
-	O
sectional	O
study	O
used	O
deidentified	O
data	O
from	O
the	O
Optum	O
Clinformatics	O
Data	O
Mart	O
Database	O
from	O
January	O
1	O
,	O
2017	O
,	O
to	O
December	O
31	O
,	O
2018	O
,	O
to	O
identify	O
patients	O
with	O
granuloma	O
annulare	O
.	O

Main	O
outcomes	O
and	O
measures	O
After	O
validating	O
an	O
approach	O
to	O
classify	O
patients	O
with	O
granuloma	O
annulare	O
using	O
International	O
Statistical	O
Classification	O
of	O
Diseases	O
and	O
Related	O
Health	O
Problems	O
,	O
Tenth	O
Revision	O
codes	O
,	O
the	O
primary	O
outcomes	O
were	O
age-	O
,	O
sex-	O
,	O
and	O
race	O
/	O
ethnicity	O
-	O
specific	O
annualized	O
incidence	B-EPI
and	O
prevalence	B-EPI
estimates	O
for	O
granuloma	O
annulare	O
.	O

In	O
addition	O
,	O
treatment	O
use	O
within	O
6	O
to	O
12	O
months	O
after	O
the	O
first	O
diagnosis	O
of	O
granuloma	O
annulare	O
was	O
examined	O
.	O

Confidence	O
intervals	O
for	O
prevalence	B-EPI
and	O
incidence	B-EPI
estimates	O
were	O
computed	O
assuming	O
a	O
binomial	O
distribution	O
using	O
the	O
Wilson	O
score	O
method	O
.	O

Age-	O
,	O
sex-	O
,	O
and	O
race	O
/	O
ethnicity	O
-	O
specific	O
incidence	B-EPI
and	O
prevalence	B-EPI
estimates	O
were	O
compared	O
using	O
the	O
χ2	O
test	O
.	O

Results	O
A	O
total	O
of	O
11	O
608	O
patients	O
with	O
incident	O
granuloma	O
annulare	O
(	O
8680	O
female	O
patients	O
[	O
74.8	O
%	O
]	O
;	O
mean	O
[	O
SD	O
]	O
age	O
,	O
56.5	O
[	O
18.8	O
]	O
years	O
)	O
and	O
17	O
862	O
patients	O
with	O
prevalent	O
granuloma	O
annulare	O
(	O
13	O
548	O
female	O
patients	O
[	O
75.8	O
%	O
]	O
;	O
mean	O
[	O
SD	O
]	O
age	O
,	O
56.6	O
[	O
18.5	O
]	O
years	O
)	O
were	O
identified	O
during	O
the	O
study	O
period	O
.	O

The	O
overall	O
annualized	B-EPI
incidence	I-EPI
of	O
granuloma	O
annulare	O
was	O
0.04	B-STAT
%	I-STAT
,	O
or	O
37.9	B-STAT
(	O
95	O
%	O
CI	O
,	O
36.9	O
-	O
38.9	O
)	O
per	B-STAT
100	I-STAT
000	I-STAT
,	O
and	O
the	O
overall	O
annualized	B-EPI
prevalence	I-EPI
of	O
granuloma	O
annulare	O
was	O
0.06	B-STAT
%	I-STAT
,	O
or	O
58.3	B-STAT
(	O
95	O
%	O
CI	O
,	O
57.1	O
-	O
59.5	O
)	O
per	B-STAT
100	I-STAT
000	I-STAT
.	O

The	O
incidence	B-EPI
and	O
prevalence	B-EPI
of	O
granuloma	O
annulare	O
were	O
highest	O
in	O
the	O
fifth	O
decade	O
of	O
life	O
.	O

The	O
incidence	B-EPI
and	O
prevalence	B-EPI
of	O
granuloma	O
annulare	O
were	O
higher	O
among	O
women	O
(	O
incidence	B-EPI
:	O
female	O
to	O
male	O
ratio	O
,	O
2.8:1	O
;	O
prevalence	B-EPI
:	O
female	O
to	O
male	O
ratio	O
,	O
3.0:1	O
)	O
.	O

Within	O
6	O
months	O
of	O
their	O
first	O
diagnosis	O
,	O
4822	O
patients	O
(	O
41.5	O
%	O
)	O
filled	O
a	O
prescription	O
for	O
a	O
topical	O
corticosteroid	O
,	O
and	O
1087	O
patients	O
(	O
9.4	O
%	O
)	O
received	O
an	O
intralesional	O
injection	O
.	O

Within	O
6	O
months	O
of	O
their	O
first	O
diagnosis	O
,	O
oral	O
tetracycline	O
prescriptions	O
were	O
filled	O
by	O
820	O
patients	O
(	O
7.1	O
%	O
)	O
,	O
and	O
hydroxychloroquine	O
prescriptions	O
were	O
filled	O
by	O
268	O
patients	O
(	O
2.3	O
%	O
)	O
.	O

Conclusions	O
and	O
relevance	O
Granuloma	O
annulare	O
is	O
a	O
rare	O
disease	O
in	O
the	B-LOC
United	I-LOC
States	I-LOC
that	O
is	O
more	O
common	O
among	O
women	O
and	O
middle	O
-	O
aged	O
to	O
older	O
individuals	O
.	O

The	O
findings	O
of	O
this	O
cross	O
-	O
sectional	O
study	O
provide	O
important	O
background	O
regarding	O
the	O
basic	O
epidemiology	O
and	O
overall	O
burden	O
of	O
granuloma	O
annulare	O
in	O
the	B-LOC
United	I-LOC
States	I-LOC
.	O

Future	O
studies	O
are	O
needed	O
to	O
better	O
understand	O
the	O
association	O
of	O
granuloma	O
annulare	O
with	O
quality	O
of	O
life	O
and	O
the	O
most	O
optimal	O
treatment	O
approaches	O
for	O
this	O
condition	O
.	O

Purpose	O
We	O
investigated	O
the	O
prevalence	B-EPI
of	O
Modic	O
changes	O
(	O
MCs	O
)	O
and	O
associated	O
pathologies	O
in	O
pediatric	O
patients	O
.	O

Methods	O
A	O
total	O
of	O
368	O
MRI	O
obtained	O
for	O
240	O
male	O
and	O
128	O
female	O
patients	O
under	O
the	O
age	O
of	O
18	O
years	O
with	O
complaints	O
of	O
low	O
back	O
/	O
leg	O
pain	O
were	O
retrospectively	O
examined	O
.	O

All	O
changes	O
in	O
signal	O
intensity	O
in	O
the	O
vertebral	O
endplate	O
and	O
subchondral	O
bone	O
on	O
MRI	O
were	O
defined	O
as	O
MCs	O
.	O

We	O
investigated	O
the	O
relationship	O
between	O
MCs	O
and	O
underlying	O
diseases	O
,	O
including	O
lumbar	O
spondylolysis	O
/	O
spondylolisthesis	O
,	O
and	O
conditions	O
of	O
the	O
growth	O
plate	O
in	O
cases	O
with	O
MCs	O
.	O

The	O
degree	O
of	O
disc	O
degeneration	O
in	O
patients	O
with	O
MCs	O
was	O
evaluated	O
using	O
the	O
Pfirrmann	O
grading	O
system	O
.	O

Results	O
MCs	O
were	O
identified	O
in	O
six	O
patients	O
(	O
1.6	O
%	O
)	O
.	O

In	O
five	O
of	O
the	O
six	O
patients	O
,	O
the	O
signal	O
intensity	O
changes	O
were	O
localized	O
to	O
the	O
anterosuperior	O
endplate	O
of	O
the	O
affected	O
vertebra	O
;	O
the	O
MCs	O
were	O
associated	O
with	O
anterior	O
apophyseal	O
ring	O
fracture	O
and	O
an	O
open	O
growth	O
plate	O
in	O
all	O
these	O
cases	O
.	O

Disc	O
degeneration	O
was	O
classified	O
as	O
Pfirrmann	O
grade	O
I	O
in	O
three	O
patients	O
and	O
grade	O
II	O
and	O
III	O
in	O
one	O
patient	O
each	O
.	O

One	O
patient	O
had	O
type	O
I	O
changes	O
associated	O
with	O
grade	O
IV	O
disc	O
degeneration	O
and	O
herniation	O
and	O
no	O
sign	O
of	O
an	O
open	O
growth	O
plate	O
.	O

Conclusion	O
The	O
prevalence	B-EPI
of	O
MCs	O
in	O
pediatrics	O
patients	O
was	O
much	O
lower	O
than	O
the	O
rates	O
reported	O
in	O
adults	O
.	O

Most	O
MCs	O
were	O
associated	O
with	O
an	O
anterior	O
apophyseal	O
ring	O
fracture	O
.	O

If	O
Modic	O
type	O
changes	O
are	O
seen	O
in	O
immature	O
vertebrae	O
of	O
pediatric	O
patients	O
,	O
growth	O
plate	O
lesions	O
such	O
as	O
apophyseal	O
ring	O
fractures	O
should	O
be	O
considered	O
.	O

Level	O
of	O
evidence	O
Diagnostic	O
:	O
individual	O
l	O
cross	O
-	O
sectional	O
studies	O
with	O
consistently	O
applied	O
reference	O
standard	O
and	O
blinding	O
.	O

Background	O
Ehlers	O
-	O
Danlos	O
syndrome	O
(	O
EDS	O
)	O
represents	O
a	O
group	O
of	O
connective	O
tissue	O
disorders	O
characterized	O
by	O
the	O
fragility	O
of	O
the	O
soft	O
connective	O
tissues	O
resulting	O
in	O
widespread	O
skin	O
,	O
ligament	O
,	O
joint	O
,	O
blood	O
vessel	O
and	O
internal	O
organ	O
involvement	O
.	O

The	O
clinical	O
spectrum	O
is	O
highly	O
variable	O
in	O
terms	O
of	O
clinical	O
features	O
,	O
complications	O
,	O
severity	O
,	O
biochemical	O
characteristics	O
and	O
genes	O
mutations	O
.	O

The	O
kyphoscoliotic	O
type	O
EDS	O
(	O
EDS	O
VIA	O
)	O
is	O
a	O
rare	O
variant	O
of	O
the	O
disease	O
,	O
with	O
an	O
incidence	B-EPI
of	O
1:100.000	B-STAT
live	I-STAT
births	I-STAT
.	O

EDS	O
VIA	O
presents	O
at	O
birth	O
as	O
severe	O
muscular	O
hypotonia	O
,	O
early	O
onset	O
of	O
progressive	O
kyphoscoliosis	O
,	O
marked	O
hyperelasticity	O
and	O
fragility	O
of	O
the	O
skin	O
with	O
abnormal	O
scarring	O
,	O
severe	O
joint	O
hypermobility	O
,	O
luxations	O
and	O
osteopenia	O
without	O
a	O
tendency	O
to	O
fractures	O
.	O

This	O
condition	O
is	O
due	O
to	O
a	O
mutation	O
in	O
the	O
PLOD1	O
gene	O
,	O
and	O
less	O
commonly	O
in	O
FKBP14	O
gene	O
,	O
which	O
results	O
in	O
the	O
erroneous	O
development	O
of	O
collagen	O
molecules	O
with	O
consequent	O
mechanical	O
instability	O
of	O
the	O
affected	O
tissue	O
.	O

Case	O
presentation	O
A	O
female	O
newborn	O
,	O
found	O
to	O
be	O
floppy	O
at	O
birth	O
,	O
presented	O
a	O
remarkable	O
physical	O
examination	O
for	O
joint	O
hypermobility	O
,	O
muscle	O
weakness	O
,	O
hyperelastic	O
skin	O
,	O
a	O
slight	O
curve	O
of	O
the	O
spine	O
,	O
the	O
absence	O
of	O
the	O
inferior	O
labial	O
and	O
lingual	O
frenulum	O
.	O

Due	O
to	O
severe	O
hypotonia	O
,	O
neuromuscular	O
disorders	O
such	O
as	O
Spinal	O
Muscular	O
Atrophy	O
(	O
SMA	O
)	O
,	O
genetic	O
diseases	O
such	O
as	O
Prader	O
Willi	O
syndrome	O
(	O
PWS	O
)	O
,	O
myopathies	O
and	O
connective	O
tissue	O
disorders	O
were	O
considered	O
in	O
the	O
differential	O
diagnosis	O
.	O

Targeted	O
gene	O
sequencing	O
were	O
performed	O
for	O
SMN1	O
,	O
PLOD1	O
,	O
FKBP14	O
,	O
COL6A1	O
,	O
COL6A2	O
,	O
COL6A3	O
.	O

The	O
urinary	O
lysyl	O
and	O
hydroxy	O
-	O
lysyl	O
pyridinoline	O
ratio	O
was	O
diagnostic	O
before	O
discovering	O
the	O
homozygous	O
duplication	O
in	O
the	O
PLOD1	O
gene	O
,	O
which	O
confirmed	O
kyphoscoliotic	O
EDS	O
diagnosis	O
.	O

Conclusion	O
In	O
front	O
of	O
a	O
floppy	O
infant	O
,	O
a	O
large	O
variety	O
of	O
disorders	O
should	O
be	O
considered	O
,	O
including	O
some	O
connective	O
diseases	O
.	O

The	O
presence	O
at	O
the	O
birth	O
of	O
kyphoscoliosis	O
,	O
associated	O
with	O
joint	O
hypermobility	O
and	O
the	O
absence	O
of	O
the	O
lingual	O
and	O
lower	O
lip	O
frenulum	O
,	O
should	O
suggest	O
an	O
EDS	O
.	O

More	B-STAT
than	I-STAT
1	I-STAT
out	I-STAT
of	I-STAT
10	I-STAT
women	I-STAT
worldwide	B-LOC
are	O
diagnosed	O
with	O
polycystic	O
ovary	O
syndrome	O
(	O
PCOS	O
)	O
,	O
the	O
leading	O
cause	O
of	O
female	O
reproductive	O
and	O
metabolic	O
dysfunction	O
.	O

Despite	O
its	O
high	O
prevalence	B-EPI
,	O
PCOS	O
and	O
its	O
accompanying	O
morbidities	O
are	O
likely	O
underdiagnosed	O
,	O
averaging	O
>	O
2	O
years	O
and	O
3	O
physicians	O
before	O
women	O
are	O
diagnosed	O
.	O

Although	O
it	O
has	O
been	O
intensively	O
researched	O
,	O
the	O
underlying	O
cause(s	O
)	O
of	O
PCOS	O
have	O
yet	O
to	O
be	O
defined	O
.	O

In	O
order	O
to	O
understand	O
PCOS	O
pathophysiology	O
,	O
its	O
developmental	O
origins	O
,	O
and	O
how	O
to	O
predict	O
and	O
prevent	O
PCOS	O
onset	O
,	O
there	O
is	O
an	O
urgent	O
need	O
for	O
safe	O
and	O
effective	O
markers	O
and	O
treatments	O
.	O

In	O
this	O
review	O
,	O
we	O
detail	O
which	O
animal	O
models	O
are	O
more	O
suitable	O
for	O
contributing	O
to	O
our	O
understanding	O
of	O
the	O
etiology	O
and	O
pathophysiology	O
of	O
PCOS	O
.	O

We	O
summarize	O
and	O
highlight	O
advantages	O
and	O
limitations	O
of	O
hormonal	O
or	O
genetic	O
manipulation	O
of	O
animal	O
models	O
,	O
as	O
well	O
as	O
of	O
naturally	O
occurring	O
PCOS	O
-	O
like	O
females	O
.	O

Anticancer	O
drug	O
nephrotoxicity	O
is	O
an	O
important	O
and	O
increasing	O
adverse	O
drug	O
event	O
that	O
limits	O
the	O
efficacy	O
of	O
cancer	O
treatment	O
.	O

The	O
kidney	O
is	O
an	O
important	O
elimination	O
pathway	O
for	O
many	O
antineoplastic	O
drugs	O
and	O
their	O
metabolites	O
,	O
which	O
occurs	O
by	O
glomerular	O
filtration	O
and	O
tubular	O
secretion	O
.	O

Chemotherapeutic	O
agents	O
,	O
both	O
conventional	O
cytotoxic	O
agents	O
and	O
molecularly	O
targeted	O
agents	O
,	O
can	O
affect	O
any	O
segment	O
of	O
the	O
nephron	O
including	O
its	O
microvasculature	O
,	O
leading	O
to	O
many	O
clinical	O
manifestations	O
such	O
as	O
proteinuria	O
,	O
hypertension	O
,	O
electrolyte	O
disturbances	O
,	O
glomerulopathy	O
,	O
acute	O
and	O
chronic	O
interstitial	O
nephritis	O
,	O
acute	O
kidney	O
injury	O
and	O
at	O
times	O
chronic	O
kidney	O
disease	O
.	O

The	O
clinician	O
should	O
be	O
alert	O
to	O
recognize	O
several	O
factors	O
that	O
may	O
maximize	O
renal	O
dysfunction	O
and	O
contribute	O
to	O
the	O
increased	O
incidence	B-EPI
of	O
nephrotoxicity	O
associated	O
with	O
these	O
drugs	O
,	O
such	O
as	O
intravascular	O
volume	O
depletion	O
,	O
the	O
associated	O
use	O
of	O
nonchemotherapeutic	O
nephrotoxic	O
drugs	O
(	O
analgesics	O
,	O
antibiotics	O
,	O
proton	O
pump	O
inhibitors	O
,	O
and	O
bone	O
-	O
targeted	O
therapies	O
)	O
,	O
radiographic	O
ionic	O
contrast	O
media	O
or	O
radiation	O
therapy	O
,	O
urinary	O
tract	O
obstruction	O
,	O
and	O
intrinsic	O
renal	O
disease	O
.	O

Identification	O
of	O
patients	O
at	O
higher	O
risk	O
for	O
nephrotoxicity	O
may	O
allow	O
the	O
prevention	O
or	O
at	O
least	O
reduction	O
in	O
the	O
development	O
and	O
severity	O
of	O
this	O
adverse	O
effect	O
.	O

Therefore	O
,	O
the	O
aim	O
of	O
this	O
brief	O
review	O
is	O
to	O
provide	O
currently	O
available	O
evidences	O
on	O
oncologic	O
drug	O
-	O
related	O
nephrotoxicity	O
.	O

Zika	O
virus	O
(	O
ZIKV	O
)	O
is	O
a	O
vectorborne	O
infectious	O
agent	O
of	O
global	O
public	O
health	O
significance	O
due	O
to	O
its	O
potential	O
to	O
cause	O
severe	O
teratogenic	O
outcomes	O
.	O

The	O
question	O
of	O
whether	O
health	O
systems	O
should	O
consider	O
adopting	O
screening	O
programmes	O
for	O
ZIKV	O
infections	O
during	O
pregnancy	O
warrants	O
consideration	O
.	O

In	O
this	O
analysis	O
,	O
we	O
apply	O
the	O
Wilson	O
-	O
Jungner	O
framework	O
to	O
appraise	O
the	O
potential	O
utility	O
of	O
a	O
prenatal	O
ZIKV	O
screening	O
programme	O
,	O
outline	O
potential	O
screening	O
strategies	O
within	O
the	O
case	O
-	O
finding	O
pathway	O
,	O
and	O
consider	O
other	O
epidemiological	O
factors	O
that	O
may	O
influence	O
the	O
planning	O
of	O
such	O
a	O
screening	O
programme	O
.	O

Our	O
evaluation	O
of	O
a	O
potential	O
prenatal	O
ZIKV	O
screening	O
programme	O
highlights	O
factors	O
affirming	O
its	O
usefulness	O
,	O
including	O
the	O
importance	O
of	O
Congenital	O
Zika	O
Syndrome	O
as	O
a	O
public	O
health	O
problem	O
and	O
the	O
existence	O
of	O
analogous	O
congenital	O
prenatal	O
screening	O
programmes	O
for	O
STORCH	O
agents	O
(	O
syphilis	O
,	O
toxoplasmosis	O
,	O
others	O
(	O
eg	O
,	O
human	O
immunodeficiency	O
virus	O
,	O
varicella	O
-	O
zoster	O
virus	O
,	O
parvovirus	O
B19	O
)	O
,	O
rubella	O
,	O
cytomegalovirus	O
,	O
and	O
herpes	O
simplex	O
virus	O
)	O
.	O

However	O
,	O
our	O
assessment	O
also	O
reveals	O
key	O
barriers	O
to	O
implementation	O
,	O
such	O
as	O
the	O
need	O
for	O
more	O
accurate	O
diagnostic	O
tests	O
,	O
effective	O
antiviral	O
treatments	O
,	O
increased	O
social	O
service	O
capacity	O
,	O
and	O
surveillance	O
.	O

Given	O
that	O
the	O
reemergence	O
of	O
ZIKV	O
is	O
likely	O
,	O
we	O
provide	O
a	O
guiding	O
framework	O
for	O
policymakers	O
and	O
public	O
health	O
leaders	O
that	O
can	O
be	O
further	O
elaborated	O
and	O
adapted	O
to	O
different	O
contexts	O
in	O
order	O
to	O
reduce	O
the	O
burden	O
of	O
adverse	O
ZIKV	O
-	O
related	O
birth	O
outcomes	O
during	O
future	O
outbreaks	O
.	O

We	O
aimed	O
to	O
explore	O
the	O
genetic	O
and	O
environmental	O
contributions	O
to	O
variation	O
in	O
the	O
risk	O
of	O
hematologic	O
malignancies	O
and	O
characterize	O
familial	O
dependence	O
within	O
and	O
across	O
hematologic	O
malignancies	O
.	O

The	O
study	O
base	O
included	O
316,397	O
individual	O
twins	O
from	O
the	O
Nordic	O
Twin	O
Study	O
of	O
Cancer	O
with	O
a	O
median	O
of	O
41	O
years	O
of	O
follow	O
-	O
up	O
:	O
88,618	O
(	O
28	O
%	O
)	O
of	O
the	O
twins	O
were	O
monozygotic	O
,	O
and	O
3459	O
hematologic	O
malignancies	O
were	O
reported	O
.	O

We	O
estimated	O
the	O
cumulative	B-EPI
incidence	I-EPI
by	O
age	O
,	O
familial	O
risk	O
,	O
and	O
genetic	O
and	O
environmental	O
variance	O
components	O
of	O
hematologic	O
malignancies	O
accounting	O
for	O
competing	O
risk	O
of	O
death	O
.	O

The	O
lifetime	O
risk	O
of	O
any	O
hematologic	O
malignancy	O
was	O
2.5	O
%	O
(	O
95	O
%	O
CI	O
2.4	O
-	O
2.6	O
%	O
)	O
,	O
as	O
in	O
the	O
background	O
population	O
.	O

This	O
risk	O
was	O
elevated	O
to	O
4.5	O
%	O
(	O
95	O
%	O
CI	O
3.1	O
-	O
6.5	O
%	O
)	O
conditional	O
on	O
hematologic	O
malignancy	O
in	O
a	O
dizygotic	O
co	O
-	O
twin	O
and	O
was	O
even	O
greater	O
at	O
7.6	O
%	O
(	O
95	O
%	O
CI	O
4.8	O
-	O
11.8	O
%	O
)	O
if	O
a	O
monozygotic	O
co	O
-	O
twin	O
had	O
a	O
hematologic	O
malignancy	O
.	O

Heritability	O
of	O
the	O
liability	O
to	O
develop	O
any	O
hematologic	O
malignancy	O
was	O
24	O
%	O
(	O
95	O
%	O
CI	O
14	O
-	O
33	O
%	O
)	O
.	O

This	O
estimate	O
decreased	O
across	O
age	O
,	O
from	O
approximately	O
55	O
%	O
at	O
age	O
40	O
to	O
about	O
20	O
-	O
25	O
%	O
after	O
age	O
55	O
,	O
when	O
it	O
seems	O
to	O
stabilize	O
.	O

In	O
this	O
largest	O
ever	O
studied	O
twin	O
cohort	O
with	O
the	O
longest	O
follow	O
-	O
up	O
,	O
we	O
found	O
evidence	O
for	O
familial	O
risk	O
of	O
hematologic	O
malignancies	O
.	O

The	O
discovery	O
of	O
decreasing	O
familial	O
predisposition	O
with	O
increasing	O
age	O
underscores	O
the	O
importance	O
of	O
cancer	O
surveillance	O
in	O
families	O
with	O
hematological	O
malignancies	O
.	O

A	O
57	O
-	O
year	O
-	O
old	O
male	O
presented	O
to	O
the	O
emergency	O
department	O
with	O
right	O
upper	O
quadrant	O
pain	O
and	O
constitutional	O
symptoms	O
.	O

Initial	O
investigation	O
revealed	O
biliary	O
sepsis	O
with	O
features	O
of	O
chronic	O
cholecystitis	O
,	O
multiple	O
liver	O
abscesses	O
and	O
a	O
fistulous	O
connection	O
between	O
the	O
gallbladder	O
and	O
colon	O
.	O

He	O
was	O
subsequently	O
diagnosed	O
with	O
a	O
cholecysto	O
-	O
colonic	O
fistula	O
,	O
an	O
unusual	O
complication	O
of	O
biliary	O
pathology	O
,	O
with	O
an	O
incidence	B-EPI
of	O
0.06	B-STAT
-	I-STAT
0.14	I-STAT
%	I-STAT
at	O
cholecystectomy	O
.	O

It	O
is	O
the	O
second	O
most	O
common	O
form	O
of	O
cholecystoenteric	O
fistula	O
,	O
the	O
first	O
of	O
which	O
is	O
cholecystoduodenal	O
.	O

A	O
preoperative	O
diagnosis	O
was	O
suggested	O
using	O
computed	O
tomography	O
and	O
sinogram	O
imaging	O
.	O

The	O
associated	O
liver	O
abscesses	O
together	O
with	O
the	O
xanthogranulomatous	O
inflammation	O
found	O
on	O
histopathology	O
,	O
makes	O
the	O
case	O
particularly	O
exceptional	O
.	O

Massachusetts	B-LOC
began	O
newborn	O
screening	O
(	O
NBS	O
)	O
for	O
Spinal	O
Muscular	O
Atrophy	O
(	O
SMA	O
)	O
following	O
the	O
availability	O
of	O
new	O
treatment	O
options	O
.	O

The	O
New	O
England	O
Newborn	O
Screening	O
Program	O
developed	O
,	O
validated	O
,	O
and	O
implemented	O
a	O
screening	O
algorithm	O
for	O
the	O
detection	O
of	O
SMA	O
-	O
affected	O
infants	O
who	O
show	O
absent	O
SMN1	O
Exon	O
7	O
by	O
Real	O
-	O
Time	O
â„¢	O
quantitative	O
PCR	O
(	O
qPCR	O
)	O
.	O

We	O
screened	O
179,467	O
neonates	O
and	O
identified	O
9	O
SMA	O
-	O
affected	O
infants	O
,	O
all	O
of	O
whom	O
were	O
referred	O
to	O
a	O
specialist	O
by	O
day	O
of	O
life	O
6	O
(	O
average	O
and	O
median	O
4	O
days	O
of	O
life	O
)	O
.	O

Another	O
ten	O
SMN1	O
hybrids	O
were	O
observed	O
but	O
never	O
referred	O
.	O

The	O
nine	O
referred	O
infants	O
who	O
were	O
confirmed	O
to	O
have	O
SMA	O
were	O
entered	O
into	O
treatment	O
protocols	O
.	O

Early	O
data	O
show	O
that	O
some	O
SMA	O
-	O
affected	O
children	O
have	O
remained	O
asymptomatic	O
and	O
are	O
meeting	O
developmental	O
milestones	O
and	O
some	O
have	O
mild	O
to	O
moderate	O
delays	O
.	O

The	O
Massachusetts	O
experience	O
demonstrates	O
that	O
SMA	O
NBS	O
is	O
feasible	O
,	O
can	O
be	O
implemented	O
on	O
a	O
population	O
basis	O
,	O
and	O
helps	O
engage	O
infants	O
for	O
early	O
treatment	O
to	O
maximize	O
benefit	O
.	O

This	O
study	O
aims	O
to	O
assess	O
the	O
prevalence	B-EPI
,	O
distribution	O
,	O
and	O
etiological	O
profile	O
of	O
intestinal	O
parasitism	O
in	O
children	O
living	O
in	O
periurban	B-LOC
areas	I-LOC
in	I-LOC
Cachoeiras	I-LOC
de	I-LOC
Macacu	I-LOC
,	I-LOC
Rio	I-LOC
de	I-LOC
Janeiro	I-LOC
,	I-LOC
Brazil	I-LOC
.	O

A	O
community	O
-	O
based	O
cross	O
-	O
sectional	O
survey	O
(	O
n	O
=	O
479	O
)	O
was	O
carried	O
out	O
.	O

Prevalence	B-EPI
of	O
infection	O
with	O
G.	O
duodenalis	O
and	O
E.	O
histolytica	O
/	O
E.	O
dispar	O
was	O
8.6	B-STAT
%	I-STAT
(	O
n	O
=	O
41	O
)	O
and	O
13.4	B-STAT
%	I-STAT
(	O
n	O
=	O
64	O
)	O
,	O
respectively	O
.	O

Infection	O
with	O
G.	O
duodenalis	O
was	O
significantly	O
more	O
frequent	B-EPI
among	O
children	O
living	O
in	O
poor	O
families	O
(	O
24/187	O
(	O
12.8	B-STAT
%	I-STAT
)	O
vs.	O
16/272	O
(	O
5.9	B-STAT
%	I-STAT
)	O
;	O
prevalence	O
ratio	O
(	O
PR	O
)	O
=	O
2.18	O
;	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
=	O
1.19	O
-	O
3.99	O
;	O
p	O
=	O
0.011	O
)	O
.	O

This	O
difference	O
was	O
also	O
significant	O
for	O
infection	O
with	O
any	O
pathogenic	O
parasite	O
(	O
43/187	O
(	O
23	B-STAT
%	I-STAT
)	O
vs.	O
40/272	O
(	O
14/7	B-STAT
%	I-STAT
)	O
;	O
PR	O
=	O
1.56	O
;	O
95	O
%	O
CI	O
=	O
1.06	O
-	O
2.30	O
;	O
p	O
=	O
0.026	O
)	O
.	O

In	O
addition	O
,	O
people	O
residing	O
in	O
houses	O
with	O
more	O
than	O
four	O
inhabitants	O
showed	O
significantly	O
higher	O
positivity	O
for	O
infections	O
with	O
G.	O
duodenalis	O
and	O
with	O
E.	O
histolytica	O
/	O
E.	O
dispar	O
(	O
22/138	O
(	O
15.9	O
%	O
)	O
vs.	O
16/311	O
(	O
5.1	O
%	O
)	O
;	O
PR	O
=	O
3.09	O
;	O
95	O
%	O
CI	O
=	O
1.68	O
-	O
5.71	O
;	O
p	O
<	O
0.001	O
for	O
G.	O
duodenalis	O
and	O
32/138	O
(	O
23.2	O
%	O
)	O
vs.	O
30/311	O
(	O
9.6	O
%	O
)	O
;	O
PR	O
=	O
2.40	O
;	O
95	O
%	O
CI	O
=	O
1.52	O
-	O
3.79	O
;	O
p	O
<	O
0.001	O
for	O
E.	O
histolytica	O
/	O
E.	O
dispar	O
)	O
.	O

Laboratory	O
diagnosis	O
of	O
protozoan	O
enteric	O
infections	O
and	O
effective	O
drugs	O
for	O
their	O
treatment	O
are	O
unmet	O
goals	O
in	O
the	O
primary	O
health	O
care	O
system	O
.	O

Therefore	O
,	O
giardiasis	O
and	O
amebiasis	O
are	O
neglected	O
conditions	O
.	O

An	O
accurate	O
diagnosis	O
of	O
syndromic	O
craniosynostosis	O
(	O
CS	O
)	O
is	O
important	O
for	O
personalized	O
treatment	O
,	O
surveillance	O
,	O
and	O
genetic	O
counselling	O
.	O

We	O
describe	O
detailed	O
clinical	O
criteria	O
for	O
syndromic	O
CS	O
and	O
the	O
distribution	O
of	O
genetic	O
diagnoses	O
within	O
the	O
cohort	O
.	O

The	O
prospective	O
registry	O
of	O
the	O
Norwegian	O
National	O
Unit	O
for	O
Craniofacial	O
Surgery	O
was	O
used	O
to	O
retrieve	O
individuals	O
with	O
syndromic	O
CS	O
born	O
between	O
1	O
January	O
2002	O
and	O
30	O
June	O
2019	O
.	O

All	O
individuals	O
were	O
assessed	O
by	O
a	O
clinical	O
geneticist	O
and	O
classified	O
using	O
defined	O
clinical	O
criteria	O
.	O

A	O
stepwise	O
approach	O
consisting	O
of	O
single	O
-	O
gene	O
analysis	O
,	O
comparative	O
genomic	O
hybridization	O
(	O
aCGH	O
)	O
,	O
and	O
exome	O
-	O
based	O
high	O
-	O
throughput	O
sequencing	O
,	O
first	O
filtering	O
for	O
72	O
genes	O
associated	O
with	O
syndromic	O
CS	O
,	O
followed	O
by	O
an	O
extended	O
trio	O
-	O
based	O
panel	O
of	O
1570	O
genes	O
were	O
offered	O
to	O
all	O
syndromic	O
CS	O
cases	O
.	O

A	O
total	O
of	O
381	B-STAT
individuals	I-STAT
were	O
registered	O
with	O
CS	O
,	O
of	O
whom	O
104	O
(	O
27	O
%	O
)	O
were	O
clinically	O
classified	O
as	O
syndromic	O
CS	O
.	O

Using	O
the	O
single	O
-	O
gene	O
analysis	O
,	O
aCGH	O
,	O
and	O
custom	O
-	O
designed	O
panel	O
,	O
a	O
genetic	O
diagnosis	O
was	O
confirmed	O
in	O
73	O
%	O
of	O
the	O
individuals	O
(	O
n	O
=	O
94	O
)	O
.	O

The	O
diagnostic	O
yield	O
increased	O
to	O
84	O
%	O
after	O
adding	O
the	O
results	O
from	O
the	O
extended	O
trio	O
-	O
based	O
panel	O
.	O

Common	O
causes	O
of	O
syndromic	O
CS	O
were	O
found	O
in	O
53	O
individuals	O
(	O
56	O
%	O
)	O
,	O
whereas	O
26	O
(	O
28	O
%	O
)	O
had	O
other	O
genetic	O
syndromes	O
,	O
including	O
17	O
individuals	O
with	O
syndromes	O
not	O
commonly	O
associated	O
with	O
CS	O
.	O

Only	O
15	O
individuals	O
(	O
16	O
%	O
)	O
had	O
negative	O
genetic	O
analyses	O
.	O

Using	O
the	O
defined	O
combination	O
of	O
clinical	O
criteria	O
,	O
we	O
detected	O
among	O
the	O
highest	O
numbers	O
of	O
syndromic	O
CS	O
cases	O
reported	O
,	O
confirmed	O
by	O
a	O
high	O
genetic	O
diagnostic	O
yield	O
of	O
84	O
%	O
.	O

The	O
observed	O
genetic	O
heterogeneity	O
encourages	O
a	O
broad	O
genetic	O
approach	O
in	O
diagnosing	O
syndromic	O
CS	O
.	O

Background	O
National	O
neonatal	O
surveillance	O
for	O
herpes	O
simplex	O
virus	O
(	O
HSV	O
)	O
disease	O
suggests	O
that	O
the	O
incidence	B-EPI
of	O
HSV	O
disease	O
may	O
be	O
higher	O
in	O
Queensland	B-LOC
(	O
QLD	B-LOC
)	O
than	O
in	O
other	B-LOC
Australian	I-LOC
States	I-LOC
.	O

We	O
sought	O
to	O
investigate	O
the	O
incidence	B-EPI
via	O
a	O
retrospective	O
13	O
-	O
year	O
evaluation	O
of	O
statewide	O
laboratory	O
data	O
,	O
autopsy	O
data	O
and	O
linked	O
clinical	O
records	O
of	O
infants	O
with	O
laboratory	O
confirmed	O
infection	O
.	O

Methods	O
All	O
positive	O
polymerase	O
chain	O
reaction	O
HSV	O
1	O
and	O
2	O
results	O
were	O
obtained	O
for	O
infants	O
0	O
-	O
3	O
months	O
of	O
age	O
from	O
January	O
1	O
,	O
2005	O
to	O
December	O
31	O
,	O
2017	O
.	O

Clinical	O
data	O
were	O
obtained	O
from	O
patient	O
records	O
and	O
parent	O
questionnaires	O
were	O
used	O
to	O
evaluate	O
long	O
-	O
term	O
sequelae	O
.	O

Results	O
One	O
hundred	O
seventy	O
-	O
two	O
infants	O
with	O
HSV	O
positive	O
polymerase	O
chain	O
reaction	O
results	O
:	O
121	O
(	O
70.3	O
%	O
)	O
with	O
HSV	O
1	O
.	O

Of	O
104	O
(	O
60.5	O
%	O
)	O
infants	O
with	O
signs	O
of	O
HSV	O
disease	O
,	O
76	O
(	O
73.1	O
%	O
)	O
were	O
neonates	O
(	O
≤28	O
days	O
of	O
age	O
)	O
[	O
incidence	B-EPI
9.6	B-STAT
(	O
95	O
%	O
confidence	O
interval	O
,	O
7.0	O
-	O
11.5	O
)	O
per	B-STAT
100,000	I-STAT
live	I-STAT
births	I-STAT
]	O
and	O
28	O
(	O
26.9	O
%	O
)	O
were	O
young	O
infants	O
(	O
29	O
-	O
90	O
days	O
of	O
age	O
)	O
[	O
3.6	B-STAT
(	O
95	O
%	O
confidence	O
interval	O
,	O
2.4	O
-	O
5.4	O
)	O
per	B-STAT
100,000	I-STAT
live	I-STAT
births	I-STAT
]	O
.	O

The	O
annual	B-EPI
incidence	I-EPI
of	O
neonatal	O
HSV	O
disease	O
increased	O
significantly	O
in	O
Queensland	B-LOC
over	O
the	O
study	O
period	O
(	O
P	O
<	O
0.01	O
)	O
.	O

Of	O
the	O
76	O
neonates	O
with	O
HSV	O
disease	O
,	O
58	O
(	O
76.3	O
%	O
)	O
presented	O
with	O
the	O
skin	O
,	O
eye	O
,	O
mouth	O
(	O
SEM	O
)	O
disease	O
,	O
17	O
(	O
22.4	O
%	O
)	O
with	O
HSV	O
encephalitis	O
and	O
11	O
(	O
14.5	O
%	O
)	O
had	O
disseminated	O
disease	O
.	O

Young	O
infants	O
presented	O
with	O
HSV	O
skin	O
,	O
eye	O
,	O
mouth	O
disease	O
(	O
21	O
,	O
75.0	O
%	O
)	O
or	O
HSV	O
encephalitis	O
(	O
6	O
,	O
21.4	O
%	O
)	O
.	O

Death	O
occurred	O
in	O
12/104	O
(	O
11.5	O
%	O
)	O
infants	O
(	O
all	O
neonates	O
)	O
with	O
10	O
attributable	O
to	O
HSV	O
disease	O
.	O

Conclusion	O
The	O
incidence	B-EPI
of	O
neonatal	O
HSV	O
disease	O
in	O
QLD	B-LOC
is	O
almost	O
3	B-STAT
times	I-STAT
the	O
national	B-EPI
reported	I-EPI
incidence	I-EPI
.	O

Further	O
research	O
is	O
being	O
undertaken	O
to	O
explore	O
reasons	O
for	O
this	O
change	O
and	O
implications	O
for	O
practice	O
.	O

Xanthogranulomatous	O
cholecystitis	O
(	O
XGC	O
)	O
is	O
a	O
rare	O
form	O
of	O
cholecystitis	O
,	O
characterized	O
by	O
the	O
presence	O
of	O
xanthogranuloma	O
,	O
prominent	O
yellow	O
structures	O
within	O
the	O
gallbladder	O
wall	O
that	O
is	O
very	O
often	O
lithiasic	O
.	O

When	O
XGC	O
presents	O
in	O
its	O
pseudo	O
-	O
tumoral	O
form	O
with	O
occasional	O
adjacent	O
organ	O
involvement	O
,	O
it	O
can	O
mimic	O
gallbladder	O
carcinoma	O
(	O
GBC	O
)	O
.	O

The	O
etiopathogenesis	O
of	O
XGC	O
is	O
inflammatory	O
destruction	O
of	O
Rokitansky	O
-	O
Aschoff	O
sinuses	O
containing	O
biliary	O
and	O
cholesterol	O
pigments	O
within	O
the	O
gallbladder	O
wall	O
;	O
this	O
leads	O
to	O
a	O
florid	O
granulomatous	O
histiocytic	O
inflammatory	O
reaction	O
.	O

The	O
prevalence	B-EPI
ranges	B-STAT
from	I-STAT
1.3	I-STAT
%	I-STAT
to	I-STAT
8.8	I-STAT
%	I-STAT
of	I-STAT
all	I-STAT
cholecystectomies	I-STAT
and	O
varies	O
from	O
country	O
to	O
country	O
;	O
XGC	O
occurs	B-EPI
predominantly	O
in	O
patients	O
over	O
50	O
years	O
of	O
age	O
,	O
and	O
is	O
equally	O
distributed	O
between	O
males	O
and	O
females	O
.	O

Its	O
association	O
with	O
GBC	O
remains	O
a	O
topic	O
of	O
debate	O
in	O
the	O
literature	O
(	O
between	O
0	O
and	O
20	O
%	O
)	O
.	O

Symptoms	O
are	O
non	O
-	O
specific	O
and	O
generally	O
similar	O
to	O
those	O
of	O
acute	O
or	O
chronic	O
cholecystitis	O
.	O

XGC	O
,	O
when	O
associated	O
with	O
altered	O
health	O
status	O
,	O
leads	O
to	O
the	O
suspicion	O
of	O
GBC	O
.	O

XGC	O
can	O
also	O
come	O
to	O
light	O
due	O
to	O
an	O
acute	O
complication	O
of	O
cholecystolithiasis	O
,	O
in	O
particular	O
,	O
gallstone	O
migration	O
.	O

Imaging	O
by	O
sonography	O
and	O
CT	O
scan	O
is	O
suggestive	O
,	O
but	O
magnetic	O
resonance	O
imaging	O
is	O
more	O
specific	O
.	O

In	O
difficult	O
cases	O
,	O
biopsy	O
may	O
be	O
necessary	O
to	O
eliminate	O
the	O
diagnosis	O
of	O
tumor	O
.	O

In	O
case	O
of	O
pre-	O
or	O
intra	O
-	O
operative	O
diagnostic	O
doubt	O
,	O
the	O
opinion	O
of	O
a	O
hepatobiliary	O
specialty	O
center	O
can	O
be	O
of	O
help	O
.	O

When	O
diagnosis	O
of	O
GBC	O
has	O
been	O
eliminated	O
,	O
laparoscopic	O
cholecystectomy	O
is	O
recommended	O
,	O
although	O
with	O
a	O
high	O
risk	O
of	O
conversion	O
to	O
laparotomy	O
and	O
complications	O
.	O

Background	O
and	O
Objectives	O
:	O
The	O
incidence	B-EPI
of	O
diverticulitis	O
is	O
increasing	O
in	O
western	B-LOC
countries	I-LOC
.	O

Complicated	O
diverticulitis	O
is	O
defined	O
as	O
diverticulitis	O
associated	O
with	O
localized	O
or	O
generalized	O
perforation	O
,	O
localized	O
or	O
distant	O
abscess	O
,	O
fistula	O
,	O
stricture	O
or	O
obstruction	O
.	O

Colonic	O
symptomatic	O
strictures	O
are	O
often	O
treated	O
with	O
segmental	O
colectomy	O
.	O

The	O
aim	O
of	O
our	O
study	O
is	O
to	O
report	O
our	O
experience	O
with	O
Self	O
Expandable	O
Metal	O
Stents	O
(	O
SEMS	O
)	O
placement	O
to	O
relieve	O
sigmoid	O
obstruction	O
secondary	O
to	O
diverticulitis	O
,	O
either	O
as	O
a	O
permanent	O
solution	O
or	O
as	O
a	O
bridge	O
to	O
elective	O
colectomy	O
.	O

Material	O
and	O
Methods	O
:	O
From	O
January	O
2016	O
to	O
December	O
2018	O
,	O
21	O
patients	O
underwent	O
SEMS	O
placement	O
for	O
sigmoid	O
obstruction	O
secondary	O
to	O
diverticulitis	O
at	O
our	O
institution	O
.	O

In	O
four	O
patients	O
with	O
poor	O
general	O
conditions	O
,	O
SEMS	O
was	O
considered	O
the	O
definitive	O
form	O
of	O
treatment	O
.	O

In	O
17	O
patients	O
,	O
the	O
stent	O
was	O
placed	O
as	O
bridge	O
to	O
elective	O
colectomy	O
.	O

Data	O
were	O
prospectively	O
collected	O
and	O
retrospectively	O
analyzed	O
.	O

Primary	O
outcomes	O
were	O
postoperative	O
mortality	O
and	O
morbidity	O
after	O
SEMS	O
and	O
subsequent	O
elective	O
colectomy	O
.	O

Results	O
:	O
There	O
was	O
no	O
mortality	O
or	O
major	O
morbidity	O
after	O
SEMS	O
placement	O
or	O
subsequent	O
elective	O
colectomy	O
.	O

No	O
stoma	O
was	O
performed	O
.	O

Conclusions	O
:	O
Placement	O
of	O
Colorectal	O
Self	O
Expandable	O
Stent	O
represents	O
a	O
useful	O
tool	O
to	O
relieve	O
obstruction	O
in	O
patients	O
with	O
left	O
-	O
sided	O
colonic	O
diverticulitis	O
.	O

SEMS	O
placement	O
makes	O
it	O
possible	O
to	O
transform	O
an	O
emergency	O
clinical	O
condition	O
into	O
an	O
elective	O
condition	O
,	O
giving	O
time	O
to	O
resolve	O
the	O
inflammation	O
and	O
the	O
infection	O
inevitably	O
associated	O
with	O
complicated	O
diverticulitis	O
.	O

Oculo	O
-	O
auriculo	O
-	O
vertebral	O
spectrum	O
is	O
a	O
complex	O
developmental	O
disorder	O
characterised	O
mainly	O
by	O
anomalies	O
of	O
the	O
ear	O
,	O
hemifacial	O
microsomia	O
,	O
epibulbar	O
dermoids	O
and	O
vertebral	O
anomalies	O
.	O

The	O
aetiology	O
is	O
largely	O
unknown	O
,	O
and	O
the	O
epidemiological	O
data	O
are	O
limited	O
and	O
inconsistent	O
.	O

We	O
present	O
the	O
largest	O
population	O
-	O
based	O
epidemiological	O
study	O
to	O
date	O
,	O
using	O
data	O
provided	O
by	O
the	O
large	O
network	O
of	O
congenital	O
anomalies	O
registries	O
in	O
Europe	B-LOC
.	O

The	O
study	O
population	O
included	O
infants	O
diagnosed	O
with	O
oculo	O
-	O
auriculo	O
-	O
vertebral	O
spectrum	O
during	O
the	O
1990	O
-	O
2009	O
period	O
from	O
34	O
registries	O
active	O
in	O
16	O
European	B-LOC
countries	I-LOC
.	O

Of	O
the	O
355	O
infants	O
diagnosed	O
with	O
oculo	O
-	O
auriculo	O
-	O
vertebral	O
spectrum	O
,	O
there	O
were	O
95.8	O
%	O
(	O
340/355	O
)	O
live	O
born	O
,	O
0.8	O
%	O
(	O
3/355	O
)	O
fetal	O
deaths	O
,	O
3.4	O
%	O
(	O
12/355	O
)	O
terminations	O
of	O
pregnancy	O
for	O
fetal	O
anomaly	O
and	O
1.5	O
%	O
(	O
5/340	O
)	O
neonatal	O
deaths	O
.	O

In	O
18.9	O
%	O
,	O
there	O
was	O
prenatal	O
detection	O
of	O
anomaly	O
/	O
anomalies	O
associated	O
with	O
oculo	O
-	O
auriculo	O
-	O
vertebral	O
spectrum	O
,	O
69.7	O
%	O
were	O
diagnosed	O
at	O
birth	O
,	O
3.9	O
%	O
in	O
the	O
first	O
week	O
of	O
life	O
and	O
6.1	O
%	O
within	O
1	O
year	O
of	O
life	O
.	O

Microtia	O
(	O
88.8	O
%	O
)	O
,	O
hemifacial	O
microsomia	O
(	O
49.0	O
%	O
)	O
and	O
ear	O
tags	O
(	O
44.4	O
%	O
)	O
were	O
the	O
most	O
frequent	O
anomalies	O
,	O
followed	O
by	O
atresia	O
/	O
stenosis	O
of	O
external	O
auditory	O
canal	O
(	O
25.1	O
%	O
)	O
,	O
diverse	O
vertebral	O
(	O
24.3	O
%	O
)	O
and	O
eye	O
(	O
24.3	O
%	O
)	O
anomalies	O
.	O

There	O
was	O
a	O
high	O
rate	O
(	O
69.5	O
%	O
)	O
of	O
associated	O
anomalies	O
of	O
other	O
organs	O
/	O
systems	O
.	O

The	O
most	O
common	O
were	O
congenital	O
heart	O
defects	O
present	O
in	O
27.8	O
%	O
of	O
patients	O
.	O

The	O
prevalence	B-EPI
of	O
oculo	O
-	O
auriculo	O
-	O
vertebral	O
spectrum	O
,	O
defined	O
as	O
microtia	O
/	O
ear	O
anomalies	O
and	O
at	O
least	O
one	O
major	O
characteristic	O
anomaly	O
,	O
was	O
3.8	B-STAT
per	I-STAT
100,000	I-STAT
births	I-STAT
.	O

Twinning	O
,	O
assisted	O
reproductive	O
techniques	O
and	O
maternal	O
pre	O
-	O
pregnancy	O
diabetes	O
were	O
confirmed	O
as	O
risk	O
factors	O
.	O

The	O
high	O
rate	O
of	O
different	O
associated	O
anomalies	O
points	O
to	O
the	O
need	O
of	O
performing	O
an	O
early	O
ultrasound	O
screening	O
in	O
all	O
infants	O
born	O
with	O
this	O
disorder	O
.	O

Background	O
21	O
-	O
hydroxylase	O
deficiency	O
(	O
21OHD	O
)	O
is	O
an	O
autosomal	O
recessive	O
disorder	O
with	O
an	O
incidence	B-EPI
of	O
1:10,000	B-STAT
-	I-STAT
1:20,000	I-STAT
and	O
is	O
the	O
result	O
of	O
various	O
mutations	O
in	O
the	O
CYP21A2	O
gene	O
.	O

21OHD	O
has	O
been	O
described	O
in	O
many	O
different	O
populations	O
,	O
but	O
it	O
has	O
not	O
been	O
studied	O
in	O
Roma	O
individuals	O
so	O
far	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
analyse	O
the	O
genotype	O
in	O
Roma	O
patients	O
with	O
21OHD	O
and	O
the	O
prevalence	B-EPI
of	O
the	O
disease	O
in	O
the	O
Roma	O
population	O
of	O
North	B-LOC
Macedonia	I-LOC
.	O

Methods	O
Molecular	O
analysis	O
of	O
the	O
nine	O
most	O
frequent	O
CYP21A2	O
mutations	O
in	O
all	O
known	O
Roma	O
patients	O
with	O
CAH	O
in	O
North	B-LOC
Macedonia	I-LOC
,	O
relatives	O
and	O
healthy	O
individuals	O
of	O
Roma	O
ancestry	O
,	O
using	O
the	O
PCR	O
/	O
ACRS	O
method	O
.	O

Results	O
Ten	O
Roma	O
patients	O
with	O
21OHD	O
were	O
identified	O
,	O
of	O
which	O
nine	O
had	O
the	O
salt	O
-	O
wasting	O
and	O
one	O
had	O
the	O
simple	O
virilizing	O
form	O
.	O

Calculated	O
incidence	B-EPI
of	O
21OHD	O
in	O
the	O
North	O
Macedonian	O
Roma	O
population	O
was	O
1:3375	B-STAT
.	O

Interestingly	O
,	O
9/10	O
patients	O
(	O
90	O
%	O
)	O
were	O
homozygous	O
for	O
the	O
In2	O
G	O
splicing	O
mutation	O
(	O
293	O
-	O
13A	O
/	O
C	O
>	O
G	O
)	O
.	O

Standard	O
therapy	O
with	O
hydrocortisone	O
and	O
fludrocortisone	O
had	O
been	O
introduced	O
according	O
to	O
the	O
guidelines	O
.	O

In	O
16	O
healthy	O
relatives	O
investigated	O
for	O
CYP21A2	O
mutations	O
,	O
heterozygosity	O
for	O
the	O
In2	O
G	O
mutation	O
was	O
detected	O
in	O
13/32	O
(	O
40.6	O
%	O
)	O
alleles	O
.	O

In	O
100	O
healthy	O
Roma	O
individuals	O
,	O
none	O
related	O
to	O
the	O
analysed	O
families	O
,	O
no	O
CYP21A2	O
mutations	O
were	O
detected	O
.	O

Conclusion	O
The	O
Roma	O
population	O
in	O
North	B-LOC
Macedonia	I-LOC
had	O
a	O
very	O
high	O
incidence	B-EPI
of	O
classic	O
21OHD	O
.	O

Almost	O
all	O
patients	O
had	O
the	O
severe	O
salt	O
-	O
wasting	O
form	O
and	O
the	O
In2G	O
/	O
In2	O
G	O
genotype	O
.	O

BACKGROUND	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
assess	O
the	O
incidence	B-EPI
of	O
fractures	O
in	O
infancy	O
,	O
overall	O
and	O
by	O
type	O
of	O
fracture	O
,	O
its	O
association	O
with	O
accidents	O
,	O
metabolic	O
bone	O
disease	O
risk	O
factors	O
,	O
and	O
abuse	O
diagnosis	O
.	O

METHODS	O
:	O
The	O
design	O
was	O
a	O
population	O
-	O
based	O
register	O
study	O
in	O
Sweden	B-LOC
.	O

Participants	O
:	O
Children	O
born	O
1997	O
-	O
2014	O
,	O
0	O
-	O
1	O
years	O
of	O
age	O
diagnosed	O
with	O
fracture	O
-	O
diagnosis	O
according	O
to	O
International	O
Classification	O
of	O
Diseases	O
(	O
ICD10	O
)	O
were	O
retrieved	O
from	O
the	O
National	O
Patient	O
Register	O
and	O
linked	O
to	O
the	O
Swedish	O
Medical	O
Birth	O
Register	O
and	O
the	O
Death	O
Cause	O
Register	O
.	O

Main	O
outcome	O
measures	O
were	O
fractures	O
of	O
the	O
skull	O
,	O
long	O
bone	O
,	O
clavicle	O
and	O
ribs	O
,	O
categorized	O
by	O
age	O
(	O
younger	O
or	O
older	O
than	O
6	O
months	O
)	O
,	O
and	O
accident	O
or	O
not	O
.	O

FINDINGS	O
:	O
The	O
incidence	B-EPI
of	O
fractures	O
during	O
infancy	O
was	O
251	O
per	O
100	O
000	O
infants	O
(	O
n	O
=	O
4663	O
)	O
.	O

Major	O
fracture	O
localisations	O
were	O
long	O
bone	O
(	O
44·9	O
%	O
)	O
,	O
skull	O
(	O
31·7	O
%	O
)	O
,	O
and	O
clavicle	O
(	O
18·6	O
%	O
)	O
,	O
while	O
rib	O
fractures	O
were	O
few	O
(	O
1·4	O
%	O
)	O
.	O

Fall	O
accidents	O
were	O
reported	O
among	O
71·4	O
%	O
.	O

One	O
-	O
third	O
occurred	O
during	O
the	O
first	O
6	O
months	O
.	O

Metabolic	O
bone	O
disease	O
risk	O
factors	O
,	O
such	O
as	O
maternal	O
obesity	O
,	O
preterm	O
birth	O
,	O
vitamin	O
D	O
deficiency	O
,	O
rickets	O
,	O
and	O
calcium	O
metabolic	O
disturbances	O
,	O
had	O
increased	O
odds	O
of	O
fractures	O
of	O
long	O
bones	O
and	O
ribs	O
in	O
early	O
infancy	O
(	O
0	O
-	O
6	O
months	O
):	O
birth	O
32	O
-	O
36	O
weeks	O
and	O
long	O
bone	O
fracture	O
[	O
AOR	O
2·13	O
(	O
95%CI	O
1·67	O
-	O
2·93	O
)	O
]	O
and	O
rib	O
fracture	O
[	O
AOR	O
4·24	O
(	O
95%CI	O
1·40	O
-	O
12·8	O
)	O
]	O
.	O

Diagnosis	O
of	O
vitamin	O
D	O
deficiency	O
/	O
rickets	O
/	O
disorders	O
of	O
calcium	O
metabolism	O
had	O
increased	O
odds	O
of	O
long	O
bone	O
fracture	O
[	O
AOR	O
49·5	O
(	O
95%CI	O
18·3	O
-	O
134	O
)	O
]	O
and	O
rib	O
fracture	O
[	O
AOR	O
617	O
(	O
95%CI	O
162	O
-	O
2506	O
)	O
]	O
.	O

Fractures	O
without	O
a	O
reported	O
accident	O
had	O
higher	O
odds	O
of	O
metabolic	O
risk	O
factors	O
than	O
those	O
with	O
reported	O
accidents	O
.	O

Abuse	O
diagnosis	O
was	O
registered	O
in	O
105	O
infants	O
,	O
with	O
overrepresentation	O
of	O
preterm	O
births	O
,	O
multiple	O
births	O
and	O
small	O
-	O
for	O
-	O
gestational	O
age	O
.	O

INTERPRETATION	O
:	O
Metabolic	O
bone	O
disease	O
risk	O
factors	O
are	O
strongly	O
associated	O
with	O
fractures	O
of	O
long	O
bone	O
and	O
ribs	O
in	O
early	O
infancy	O
.	O

Fracture	O
cases	O
with	O
abuse	O
diagnosis	O
had	O
a	O
metabolic	O
bone	O
risk	O
factor	O
profile	O
.	O

End	O
-	O
stage	O
renal	O
disease	O
(	O
ESRD	O
)	O
is	O
associated	O
with	O
a	O
number	O
of	O
serious	O
complications	O
,	O
including	O
increased	O
cardiovascular	O
disease	O
,	O
anaemia	O
and	O
metabolic	O
bone	O
disease	O
.	O

Optic	O
atrophy	O
secondary	O
to	O
chronic	O
anaemia	O
in	O
ESRD	O
is	O
rare	O
.	O

We	O
report	O
a	O
case	O
of	O
bilateral	O
optic	O
atrophy	O
in	O
a	O
young	O
patient	O
with	O
chronic	O
anaemia	O
secondary	O
to	O
ESRD	O
.	O

A	O
23	O
-	O
year	O
-	O
old	O
lady	O
with	O
ESRD	O
,	O
presented	O
with	O
progressive	O
blurring	O
of	O
vision	O
in	O
her	O
left	O
eye	O
for	O
a	O
period	O
of	O
six	O
months	O
.	O

Visual	O
acuity	O
in	O
the	O
left	O
eye	O
was	O
counting	O
finger	O
and	O
the	O
right	O
eye	O
was	O
6/6	O
.	O

Left	O
optic	O
nerve	O
functions	O
were	O
significantly	O
reduced	O
.	O

Bilateral	O
anterior	O
segments	O
and	O
intraocular	O
pressure	O
were	O
normal	O
.	O

Funduscopy	O
showed	O
bilateral	O
pale	O
disc	O
with	O
arteriolar	O
attenuation	O
.	O

The	O
infective	O
,	O
autoimmune	O
and	O
demyelinating	O
screening	O
were	O
negative	O
.	O

Serial	O
full	O
blood	O
count	O
indicated	O
low	O
haemoglobin	O
and	O
haematocrit	O
value	O
.	O

The	O
full	O
blood	O
picture	O
revealed	O
normocytic	O
normochromic	O
anaemia	O
.	O

Neuroimaging	O
was	O
normal	O
.	O

The	O
patient	O
was	O
diagnosed	O
as	O
having	O
bilateral	O
optic	O
atrophy	O
secondary	O
to	O
chronic	O
anaemia	O
due	O
to	O
ESRD	O
.	O

Chronic	O
anaemia	O
is	O
a	O
potential	O
cause	O
of	O
optic	O
atrophy	O
in	O
a	O
young	O
patient	O
with	O
chronic	O
disease	O
.	O

Management	O
of	O
anaemia	O
in	O
such	O
cases	O
is	O
crucial	O
to	O
prevent	O
irreversible	O
complications	O
including	O
optic	O
atrophy	O
and	O
blindness	O
.	O

Pharmacological	O
,	O
technological	O
and	O
educational	O
approaches	O
have	O
advanced	O
the	O
treatment	O
of	O
Type	O
1	O
diabetes	O
in	O
the	O
last	O
four	O
decades	O
and	O
yet	O
diabetic	O
ketoacidosis	O
(	O
DKA	O
)	O
continues	O
to	O
be	O
a	O
leading	O
cause	O
of	O
admission	O
in	O
Type	O
1	O
diabetes	O
.	O

This	O
article	O
begins	O
by	O
reviewing	O
the	O
contemporary	O
epidemiological	O
evidence	O
in	O
DKA	O
.	O

It	O
highlights	O
a	O
rise	O
in	O
DKA	O
episodes	O
in	O
the	O
last	O
two	O
decades	O
,	O
with	O
DKA	O
continuing	O
to	O
be	O
the	O
leading	O
cause	O
of	O
death	O
in	O
young	O
people	O
with	O
Type	O
1	O
diabetes	O
,	O
and	O
that	O
DKA	O
episodes	O
are	O
a	O
marker	O
for	O
subsequent	O
all	O
-	O
cause	O
mortality	O
.	O

It	O
also	O
summarizes	O
the	O
limited	O
evidence	O
base	O
for	O
DKA	O
prevention	O
and	O
associations	O
with	O
psychopathology	O
.	O

To	O
emphasize	O
the	O
importance	O
of	O
this	O
group	O
with	O
high	O
-	O
risk	O
Type	O
1	O
diabetes	O
and	O
the	O
degree	O
to	O
which	O
they	O
have	O
been	O
overlooked	O
in	O
the	O
past	O
two	O
decades	O
,	O
the	O
article	O
summarizes	O
the	O
research	O
literature	O
of	O
recurrent	O
DKA	O
during	O
1976	O
-	O
1991	O
when	O
it	O
was	O
extensively	O
investigated	O
as	O
part	O
of	O
the	O
phenomenon	O
of	O
'	O
brittle	O
diabetes	O
'	O
.	O

This	O
period	O
saw	O
numerous	O
basic	O
science	O
studies	O
investigating	O
the	O
pathophysiology	O
of	O
recurrent	O
DKA	O
.	O

Subsequently	O
,	O
research	O
centres	O
published	O
their	O
experiences	O
of	O
brittle	O
diabetes	O
research	O
participants	O
manipulating	O
their	O
treatment	O
under	O
research	O
conditions	O
.	O

Unfortunately	O
,	O
the	O
driver	O
for	O
this	O
behaviour	O
and	O
whether	O
it	O
was	O
indicative	O
of	O
other	O
people	O
with	O
ketoacidosis	O
was	O
not	O
pursued	O
.	O

In	O
summary	O
,	O
we	O
suggest	O
there	O
has	O
been	O
a	O
stasis	O
in	O
the	O
approach	O
to	O
recurrent	O
DKA	O
prevention	O
,	O
which	O
is	O
likely	O
linked	O
to	O
historical	O
cases	O
of	O
mass	O
sabotage	O
of	O
brittle	O
diabetes	O
research	O
.	O

Further	O
investigation	O
is	O
required	O
to	O
clarify	O
possible	O
psychological	O
characteristics	O
that	O
increase	O
the	O
risk	O
of	O
DKA	O
and	O
thereby	O
targets	O
for	O
DKA	O
prevention	O
.	O

Importance	O
:	O
Congenital	O
retinal	O
macrovessel	O
(	O
CRM	O
)	O
is	O
a	O
rarely	O
reported	O
venous	O
malformation	O
of	O
the	O
retina	O
that	O
is	O
associated	O
with	O
venous	O
anomalies	O
of	O
the	O
brain	O
.	O

Objective	O
:	O
To	O
study	O
the	O
multimodal	O
imaging	O
findings	O
of	O
a	O
series	O
of	O
eyes	O
with	O
congenital	O
retinal	O
macrovessel	O
and	O
describe	O
the	O
systemic	O
associations	O
.	O

Design	O
,	O
Setting	O
,	O
and	O
Participants	O
:	O
In	O
this	O
cross	O
-	O
sectional	O
multicenter	O
study	O
,	O
medical	O
records	O
were	O
retrospectively	O
reviewed	O
from	O
7	O
different	O
retina	O
clinics	O
worldwide	B-LOC
over	O
a	O
10	O
-	O
year	O
period	O
(	O
2007	O
-	O
2017	O
)	O
.	O

Patients	O
with	O
CRM	O
,	O
defined	O
as	O
an	O
abnormal	O
,	O
large	O
,	O
macular	O
vessel	O
with	O
a	O
vascular	O
distribution	O
above	O
and	O
below	O
the	O
horizontal	O
raphe	O
,	O
were	O
identified	O
.	O

Data	O
were	O
analyzed	O
from	O
December	O
2016	O
to	O
August	O
2017	O
.	O

Main	O
Outcomes	O
and	O
Measures	O
:	O
Clinical	O
information	O
and	O
multimodal	O
retinal	O
imaging	O
findings	O
were	O
collected	O
and	O
studied	O
.	O

Pertinent	O
systemic	O
information	O
,	O
including	O
brain	O
magnetic	O
resonance	O
imaging	O
findings	O
,	O
was	O
also	O
noted	O
if	O
available	O
.	O

Results	O
:	O
Of	O
the	O
49	O
included	O
patients	O
,	O
32	O
(	O
65	O
%	O
)	O
were	O
female	O
,	O
and	O
the	O
mean	O
(	O
SD	O
)	O
age	O
at	O
onset	O
was	O
44.0	O
(	O
20.9	O
)	O
years	O
.	O

A	O
total	O
of	O
49	O
eyes	O
from	O
49	O
patients	O
were	O
studied	O
.	O

Macrovessel	O
was	O
unilateral	O
in	O
all	O
patients	O
.	O

Color	O
fundus	O
photography	O
illustrated	O
a	O
large	O
aberrant	O
dilated	O
and	O
tortuous	O
retinal	O
vein	O
in	O
all	O
patients	O
.	O

Early	O
-	O
phase	O
frames	O
of	O
fluorescein	O
angiography	O
further	O
confirmed	O
the	O
venous	O
nature	O
of	O
the	O
macrovessel	O
in	O
40	O
of	O
40	O
eyes	O
.	O

Optical	O
coherence	O
tomography	O
angiography	O
,	O
available	O
in	O
17	O
eyes	O
(	O
35	O
%	O
)	O
,	O
displayed	O
microvascular	O
capillary	O
abnormalities	O
around	O
the	O
CRM	O
,	O
which	O
were	O
more	O
evident	O
in	O
the	O
deep	O
capillary	O
plexus	O
.	O

Of	O
the	O
49	O
patients	O
with	O
CRM	O
,	O
39	O
(	O
80	O
%	O
)	O
did	O
not	O
illustrate	O
any	O
evidence	O
of	O
ophthalmic	O
complications	O
.	O

Ten	O
patients	O
(	O
20	O
%	O
)	O
presented	O
with	O
retinal	O
complications	O
,	O
typically	O
an	O
incidental	O
association	O
with	O
CRM	O
.	O

Twelve	O
patients	O
(	O
24	O
%	O
)	O
were	O
noted	O
to	O
have	O
venous	O
malformations	O
of	O
the	O
brain	O
with	O
associated	O
magnetic	O
resonance	O
imaging	O
.	O

Of	O
these	O
,	O
location	O
of	O
the	O
venous	O
anomaly	O
in	O
the	O
brain	O
was	O
ipsilateral	O
to	O
the	O
CRM	O
in	O
10	O
patients	O
(	O
83	O
%	O
)	O
and	O
contralateral	O
in	O
2	O
patients	O
(	O
17	O
%	O
)	O
,	O
mainly	O
located	O
in	O
the	O
frontal	O
lobe	O
in	O
9	O
patients	O
(	O
75	O
%	O
)	O
.	O

Conclusions	O
and	O
Relevance	O
:	O
Our	O
study	O
has	O
identified	O
an	O
association	O
between	O
macrovessels	O
in	O
the	O
retina	O
and	O
venous	O
anomalies	O
of	O
the	O
brain	O
(	O
24	O
%	O
compared	O
with	O
0.2	B-STAT
%	I-STAT
to	I-STAT
6.0	I-STAT
%	I-STAT
in	I-STAT
the	I-STAT
normal	I-STAT
population	I-STAT
)	O
.	O

Thus	O
,	O
we	O
recommend	O
new	O
guidelines	O
for	O
the	O
systemic	O
workup	O
of	O
patients	O
with	O
CRM	O
to	O
include	O
brain	O
magnetic	O
resonance	O
imaging	O
with	O
contrast	O
.	O

These	O
lesions	O
may	O
be	O
more	O
accurately	O
referred	O
to	O
as	O
retinal	O
venous	O
malformations	O
,	O
which	O
may	O
raise	O
awareness	O
regarding	O
potential	O
cerebral	O
associations	O
.	O

Background	O
Sleep	O
disorders	O
are	O
common	O
in	O
people	O
with	O
intellectual	O
disability	O
(	O
ID	O
)	O
and	O
autism	O
,	O
with	O
growing	O
evidence	O
of	O
diverse	O
sleep	O
profiles	O
across	O
ID	O
associated	O
genetic	O
syndromes	O
.	O

Documenting	O
the	O
prevalence	B-EPI
and	O
profile	O
of	O
specific	O
sleep	O
disorders	O
in	O
syndromes	O
will	O
quantify	O
syndrome	O
-	O
driven	O
'	O
risk	O
'	O
,	O
inform	O
prognosis	O
and	O
enhance	O
understanding	O
of	O
aetiology	O
of	O
sleep	O
disorders	O
.	O

Method	O
Following	O
PRISMA	O
guidelines	O
for	O
meta	O
-	O
analysis	O
,	O
we	O
searched	O
Ovid	O
PsycINFO	O
,	O
Ovid	O
MEDLINE	O
,	O
Ovid	O
Embase	O
,	O
Web	O
of	O
Science	O
and	O
PubMed	O
Central	O
with	O
use	O
of	O
syndrome	O
-	O
specific	O
keywords	O
and	O
60	O
sleep	O
-	O
related	O
search	O
terms	O
.	O

We	O
screened	O
and	O
extracted	O
papers	O
that	O
reported	O
sleep	O
disorder	O
prevalence	B-EPI
data	O
for	O
five	O
or	O
more	O
individuals	O
within	O
a	O
genetic	O
syndrome	O
,	O
and	O
applied	O
quality	O
criteria	O
to	O
produce	O
a	O
quality	O
-	O
effects	O
prevalence	B-EPI
model	O
of	O
six	O
types	O
of	O
sleep	O
disorder	O
across	O
nineteen	O
syndromes	O
.	O

Relative	O
risk	O
estimates	O
were	O
calculated	O
for	O
the	O
prevalence	B-EPI
of	O
each	O
sleep	O
disorder	O
in	O
each	O
syndrome	O
.	O

Results	O
Two	O
hundred	O
and	O
seventy	O
three	O
papers	O
were	O
identified	O
,	O
generating	O
463	O
prevalence	B-EPI
estimates	O
for	O
Angelman	O
,	O
CHARGE	O
,	O
Cornelia	O
de	O
Lange	O
,	O
Down	O
,	O
fragile	O
X	O
,	O
Prader	O
-	O
Willi	O
,	O
Rett	O
,	O
Smith	O
-	O
Magenis	O
and	O
Williams	O
syndromes	O
,	O
mucopolysaccharidoses	O
(	O
MPS	O
disorders	O
)	O
,	O
neurofibromatosis	O
and	O
tuberous	O
sclerosis	O
complex	O
.	O

Prevalence	B-EPI
estimates	O
were	O
higher	O
in	O
genetic	O
syndromes	O
than	O
published	O
equivalents	O
for	O
typically	O
developing	O
individuals	O
,	O
with	O
few	O
exceptions	O
.	O

Between	O
-	O
syndrome	O
differences	O
for	O
some	O
disorders	O
were	O
evident	O
;	O
sleep	O
-	O
disordered	O
breathing	O
was	O
most	O
prevalent	O
in	O
MPS	O
disorders	O
(	O
72	O
-	O
77	O
%	O
)	O
,	O
while	O
excessive	O
daytime	O
sleepiness	O
was	O
highest	O
in	O
Smith	O
-	O
Magenis	O
syndrome	O
(	O
60	O
%	O
)	O
.	O

Conversely	O
,	O
insomnia	O
,	O
which	O
was	O
reported	O
at	O
a	O
higher	O
rate	O
than	O
TD	O
estimates	O
in	O
all	O
syndromes	O
except	O
fragile	O
X	O
,	O
was	O
not	O
associated	O
with	O
specific	O
genetic	O
risk	O
.	O

This	O
suggests	O
insomnia	O
could	O
emerge	O
because	O
of	O
the	O
individual	O
's	O
environment	O
or	O
associated	O
developmental	O
delay	O
,	O
rather	O
than	O
any	O
specific	O
genetic	O
syndromes	O
.	O

Limitations	O
Due	O
to	O
the	O
broad	O
scope	O
of	O
the	O
meta	O
-	O
analysis	O
,	O
only	O
syndromes	O
previously	O
identified	O
as	O
reporting	O
preliminary	O
sleep	O
research	O
were	O
included	O
.	O

Other	O
syndromes	O
may	O
also	O
experience	O
elevated	O
prevalence	B-EPI
rates	O
of	O
specific	O
types	O
of	O
sleep	O
disorder	O
.	O

Only	O
English	O
language	O
papers	O
were	O
included	O
.	O

Conclusions	O
Differing	O
prevalence	B-EPI
rates	O
between	O
types	O
of	O
sleep	O
disorder	O
suggest	O
differing	O
causal	O
mechanisms	O
,	O
such	O
as	O
cranio	O
-	O
facial	O
morphology	O
in	O
Down	O
and	O
Prader	O
-	O
Willi	O
syndromes	O
and	O
the	O
build	O
-	O
up	O
of	O
mucopolysaccharides	O
in	O
MPS	O
disorders	O
.	O

Priorities	O
for	O
clinical	O
assessment	O
and	O
intervention	O
for	O
sleep	O
disorders	O
are	O
discussed	O
.	O

Maternal	O
hypertensive	O
disorders	O
during	O
pregnancy	O
(	O
HDP	O
)	O
have	O
been	O
associated	O
with	O
neuropsychiatric	O
problems	O
in	O
offspring	O
.	O

We	O
aim	O
to	O
investigate	O
the	O
associations	O
between	O
specific	O
types	O
of	O
maternal	O
HDP	O
and	O
offspring	O
neurodevelopmental	O
disorders	O
and	O
further	O
examine	O
whether	O
the	O
timing	O
of	O
onset	O
and	O
severity	O
of	O
HDP	O
would	O
affect	O
these	O
associations	O
.	O

The	O
study	O
population	O
consisted	O
of	O
4,489,044	O
live	O
-	O
born	O
singletons	O
in	O
Denmark	B-LOC
during	O
1978	O
-	O
2012	O
and	O
Sweden	B-LOC
during	O
1987	O
-	O
2010	O
.	O

Maternal	O
HDP	O
was	O
categorized	O
into	O
chronic	O
hypertension	O
,	O
gestational	O
hypertension	O
,	O
and	O
pre	O
-	O
eclampsia	O
;	O
pre	O
-	O
eclampsia	O
was	O
further	O
stratified	O
according	O
to	O
timing	O
(	O
early	O
-	O
onset	O
,	O
late	O
-	O
onset	O
)	O
,	O
or	O
severity	O
(	O
moderate	O
,	O
severe	O
)	O
of	O
the	O
disease	O
.	O

Neurodevelopmental	O
disorders	O
,	O
including	O
attention	O
-	O
deficit	O
/	O
hyperactivity	O
disorder	O
(	O
ADHD	O
)	O
,	O
autism	O
spectrum	O
disorder	O
(	O
ASD	O
)	O
,	O
and	O
intellectual	O
disability	O
(	O
ID	O
)	O
,	O
were	O
defined	O
by	O
ICD	O
-	O
coded	O
register	O
diagnosis	O
.	O

Cox	O
regression	O
was	O
used	O
to	O
calculate	O
hazard	O
ratios	O
(	O
HR	O
)	O
while	O
adjusting	O
for	O
potential	O
confounders	O
,	O
and	O
sibling	O
analyses	O
assessed	O
the	O
influence	O
of	O
unmeasured	O
shared	O
familial	O
factors	O
.	O

Maternal	O
HDP	O
was	O
associated	O
with	O
increased	O
risks	O
of	O
ADHD	O
(	O
HR	O
,	O
1.24	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
,	O
1.20	O
-	O
1.28	O
)	O
,	O
ASD	O
(	O
1.29	O
[	O
1.24	O
-	O
1.34	O
]	O
)	O
,	O
and	O
ID	O
(	O
1.58	O
[	O
1.50	O
-	O
1.66	O
]	O
)	O
in	O
offspring	O
,	O
respectively	O
,	O
which	O
was	O
mostly	O
driven	O
by	O
pre	O
-	O
eclampsia	O
.	O

The	O
strongest	O
associations	O
were	O
observed	O
for	O
early	O
-	O
onset	O
and	O
severe	O
pre	O
-	O
eclampsia	O
,	O
and	O
the	O
corresponding	O
HRs	O
for	O
ADHD	O
,	O
ASD	O
and	O
ID	O
were	O
1.93	O
[	O
1.73	O
-	O
2.16	O
]	O
,	O
1.86	O
[	O
1.61	O
-	O
2.15	O
]	O
,	O
and	O
3.99	O
[	O
3.42	O
-	O
4.65	O
]	O
,	O
respectively	O
.	O

The	O
results	O
were	O
similar	O
in	O
the	O
sibling	O
analyses	O
.	O

The	O
associations	O
between	O
maternal	O
HDP	O
and	O
offspring	O
neurodevelopmental	O
disorders	O
were	O
consistent	O
across	O
the	O
subgroups	O
of	O
sex	O
,	O
preterm	O
status	O
,	O
parity	O
,	O
maternal	O
age	O
and	O
psychiatric	O
disorders	O
.	O

Maternal	O
HDP	O
,	O
especially	O
early	O
-	O
onset	O
pre	O
-	O
eclampsia	O
,	O
are	O
associated	O
with	O
increased	O
risks	O
of	O
ADHD	O
,	O
ASD	O
,	O
and	O
ID	O
in	O
particular	O
,	O
independent	O
of	O
shared	O
familial	O
factors	O
.	O

Central	O
hypothyroidism	O
(	O
CH	O
)	O
occurs	B-EPI
approximately	B-STAT
in	I-STAT
1:50,000	I-STAT
,	O
and	O
therefore	O
is	O
expected	O
to	O
be	O
one	O
thousand	O
times	O
rarer	O
compared	O
with	O
primary	O
hypothyroidism	O
.	O

Despite	O
its	O
rarity	O
in	O
the	O
general	O
population	O
,	O
it	O
is	O
much	O
more	O
common	O
in	O
certain	O
disorders	O
,	O
in	O
which	O
it	O
is	O
frequently	O
associated	O
with	O
other	O
pituitary	O
hormone	O
deficiencies	O
.	O

The	O
aim	O
of	O
this	O
paper	O
is	O
to	O
provide	O
an	O
updated	O
review	O
on	O
the	O
frequency	O
of	O
congenital	O
CH	O
,	O
which	O
is	O
<	B-STAT
1:50,000	I-STAT
,	O
and	O
on	O
its	O
etiology	O
,	O
disregarding	O
CH	O
caused	O
by	O
other	O
genetic	O
defects	O
,	O
such	O
as	O
mutations	O
of	O
transcription	O
factors	O
involved	O
in	O
pituitary	O
organogenesis	O
or	O
mutations	O
of	O
the	O
genes	O
encoding	O
TRH	O
or	O
TRH	O
receptor	O
.	O

Aims	O
Coeliac	O
disease	O
(	O
CD	O
)	O
is	O
an	O
autoimmune	O
disorder	O
with	O
a	O
prevalence	B-EPI
≤2	B-STAT
%	I-STAT
that	O
causes	O
an	O
immune	O
reaction	O
to	O
gluten	O
.	O

Growth	O
retardation	O
(	O
GR	O
)	O
generally	O
accompanies	O
CD	O
due	O
to	O
gastrointestinal	O
complications	O
and	O
should	O
be	O
treated	O
as	O
early	O
as	O
possible	O
along	O
with	O
initiation	O
of	O
a	O
gluten	O
-	O
free	O
diet	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
indicators	O
of	O
GR	O
in	O
patients	O
with	O
CD	O
.	O

Methods	O
This	O
single	O
-	O
centre	O
retrospective	O
study	O
included	O
paediatric	O
outpatients	O
with	O
CD	O
.	O

All	O
patients	O
were	O
diagnosed	O
with	O
CD	O
via	O
serological	O
analysis	O
and	O
upper	O
gastrointestinal	O
endoscopy	O
if	O
necessary	O
.	O

Patient	O
records	O
were	O
obtained	O
from	O
Adana	O
City	O
Training	O
and	O
Research	O
Hospital	O
.	O

Patients	O
that	O
were	O
diagnosed	O
with	O
GR	O
accompanying	O
CD	O
were	O
given	O
oral	O
nutritional	O
supplements	O
and	O
followed	O
-	O
up	O
every	O
3	O
-	O
6	O
months	O
.	O

Statistical	O
relationships	O
between	O
demographics	O
,	O
and	O
anthropometric	O
measurements	O
,	O
duration	O
of	O
breastfeeding	O
,	O
gluten	O
contact	O
time	O
,	O
diet	O
duration	O
,	O
presenting	O
complaints	O
and	O
serological	O
findings	O
were	O
evaluated	O
.	O

Results	O
This	O
study	O
included	O
169	O
paediatric	O
outpatients	O
between	O
ages	O
1	O
and	O
18	O
.	O

Longer	O
symptom	O
duration	O
and	O
shorter	O
breastfeeding	O
duration	O
were	O
significantly	O
correlated	O
with	O
GR	O
accompanying	O
CD	O
(	O
P	O
=	O
0.007	O
and	O
P	O
=	O
0.029	O
,	O
respectively	O
)	O
.	O

Vomiting	O
was	O
the	O
only	O
symptom	O
that	O
was	O
correlated	O
with	O
the	O
presence	O
of	O
GR	O
(	O
P	O
=	O
0.010	O
)	O
.	O

Helicobacter	O
pylori	O
infection	O
was	O
not	O
correlated	O
with	O
the	O
presence	O
of	O
GR	O
(	O
P	O
=	O
0.277	O
)	O
.	O

Conclusions	O
GR	O
should	O
be	O
treated	O
as	O
early	O
as	O
possible	O
to	O
reduce	O
the	O
severity	O
of	O
CD	O
and	O
a	O
6	O
months	O
sole	O
breastfeeding	O
followed	O
by	O
solid	O
foods	O
accompanied	O
by	O
breastfeeding	O
for	O
2	O
years	O
is	O
crucial	O
for	O
preventing	O
GR	O
.	O

Moreover	O
,	O
vomiting	O
as	O
a	O
presenting	O
complaint	O
in	O
patients	O
with	O
CD	O
might	O
be	O
indicative	O
of	O
the	O
presence	O
of	O
GR	O
.	O

Frailty	O
is	O
common	O
in	O
older	O
hospitalised	O
patients	O
and	O
may	O
be	O
associated	O
with	O
micronutrient	O
malnutrition	O
.	O

Only	O
limited	O
studies	O
have	O
explored	O
the	O
relationship	O
between	O
frailty	O
and	O
vitamin	O
C	O
deficiency	O
.	O

This	O
study	O
investigated	O
the	O
prevalence	B-EPI
of	O
vitamin	O
C	O
deficiency	O
and	O
its	O
association	O
with	O
frailty	O
severity	O
in	O
patients	O
≥75	O
years	O
admitted	O
under	O
a	O
geriatric	O
unit	O
.	O

Patients	O
(	O
n	O
=	O
160	O
)	O
with	O
a	O
mean	O
age	O
of	O
84.4	O
±	O
6.4	O
years	O
were	O
recruited	O
and	O
underwent	O
frailty	O
assessment	O
by	O
use	O
of	O
the	O
Edmonton	O
Frail	O
Scale	O
(	O
EFS	O
)	O
.	O

Patients	O
with	O
an	O
EFS	O
score	O
<	O
10	O
were	O
classified	O
as	O
non	O
-	O
frail	O
/	O
vulnerable	O
/	O
mildly	O
frail	O
and	O
those	O
with	O
≥10	O
as	O
moderate	O
-	O
severely	O
frail	O
.	O

Patients	O
with	O
vitamin	O
C	O
levels	O
between	O
11	O
-	O
28	O
μmol	O
/	O
L	O
were	O
classified	O
as	O
vitamin	O
C	O
depleted	O
while	O
those	O
with	O
levels	O
<	O
11	O
μmol	O
/	O
L	O
were	O
classified	O
as	O
vitamin	O
C	O
deficient	O
.	O

A	O
multivariate	O
logistic	O
regression	O
model	O
determined	O
the	O
relationship	O
between	O
vitamin	O
C	O
deficiency	O
and	O
frailty	O
severity	O
after	O
adjustment	O
for	O
various	O
co	O
-	O
variates	O
.	O

Fifty	O
-	O
seven	O
(	O
35.6	O
%	O
)	O
patients	O
were	O
vitamin	O
C	O
depleted	O
,	O
while	O
42	O
(	O
26.3	O
%	O
)	O
had	O
vitamin	O
C	O
deficiency	O
.	O

Vitamin	O
C	O
levels	O
were	O
significantly	O
lower	O
among	O
patients	O
who	O
were	O
moderate	O
-	O
severely	O
frail	O
when	O
compared	O
to	O
those	O
who	O
were	O
non	O
-	O
frail	O
/	O
vulnerable	O
/	O
mildly	O
frail	O
(	O
p	O
<	O
0.05	O
)	O
.	O

After	O
adjusted	O
analysis	O
,	O
vitamin	O
C	O
deficiency	O
was	O
4.3	O
-	O
fold	O
more	O
likely	O
to	O
be	O
associated	O
with	O
moderate	O
-	O
severe	O
frailty	O
(	O
aOR	O
4.30	O
,	O
95	O
%	O
CI	O
1.33	O
-	O
13.86	O
,	O
p	O
=	O
0.015	O
)	O
.	O

Vitamin	O
C	O
deficiency	O
is	O
common	O
and	O
is	O
associated	O
with	O
a	O
greater	O
severity	O
of	O
frailty	O
in	O
older	O
hospitalised	O
patients	O
.	O

Ever	O
since	O
SARS	O
-	O
CoV-2	O
began	O
infecting	O
people	O
by	O
the	O
end	O
of	O
2019	O
,	O
of	O
whom	O
some	O
developed	O
severe	O
pneumonia	O
(	O
about	O
5	O
%	O
)	O
,	O
which	O
could	O
be	O
fatal	O
(	O
case	O
fatality	O
~3.5	O
%	O
)	O
,	O
the	O
extent	O
and	O
speed	O
of	O
the	O
COVID-19	O
outbreak	O
has	O
been	O
phenomenal	O
.	O

Within	O
2.5	O
months	O
(	O
by	O
March	O
18	O
,	O
2020	O
)	O
over	O
191,127	B-STAT
COVID-19	O
patients	O
have	O
been	O
identified	O
in	O
161	B-LOC
countries	I-LOC
.	O

By	O
then	O
,	O
over	O
700	B-STAT
pediatric	I-STAT
patients	I-STAT
were	O
confirmed	O
to	O
have	O
COVID-19	O
in	O
China	B-LOC
,	O
with	O
only	O
about	O
58	O
diagnosed	O
elsewhere	O
.	O

By	O
now	O
,	O
there	O
are	O
thousands	O
of	O
children	O
and	O
adolescents	O
infected	O
.	O

Chinese	O
pediatricians	O
would	O
like	O
to	O
share	O
their	O
experience	O
on	O
how	O
these	O
patients	O
were	O
managed	O
in	O
China	B-LOC
and	O
the	O
key	O
recommendations	O
that	O
had	O
guided	O
them	O
in	O
meeting	O
the	O
evolving	O
challenges	O
.	O

A	O
group	O
of	O
experts	O
were	O
summoned	O
by	O
the	O
Chinese	O
Pediatric	O
Society	O
and	O
Editorial	O
Board	O
of	O
Chinese	O
Journal	O
of	O
Pediatrics	O
to	O
extract	O
informative	O
data	O
from	O
a	O
survey	O
on	O
confirmed	O
COVID-19	O
pediatric	O
patients	O
in	O
China	B-LOC
.	O

Consensus	O
on	O
diagnosis	O
,	O
management	O
,	O
and	O
prevention	O
of	O
pediatric	O
COVID-19	O
were	O
drawn	O
up	O
based	O
on	O
the	O
analysis	O
of	O
such	O
data	O
plus	O
insights	O
gained	O
from	O
the	O
past	O
SARS	O
and	O
MERS	O
coronavirus	O
outbreaks	O
.	O

Relevant	O
cumulating	O
experiences	O
from	O
physicians	O
managing	O
adult	O
patients	O
,	O
expedited	O
reports	O
on	O
clinical	O
and	O
scientific	O
COVID-19	O
and	O
SARS	O
-	O
CoV-2	O
data	O
,	O
and	O
the	O
National	O
Health	O
Committee	O
guidelines	O
on	O
COVID-19	O
management	O
were	O
integrated	O
into	O
this	O
proposal	O
.	O

Rationale	O
Women	O
with	O
congenital	O
adrenal	O
hyperplasia	O
(	O
CAH	O
)	O
can	O
suffer	O
from	O
impaired	O
fertility	O
rates	O
as	O
a	O
result	O
of	O
increased	O
androgen	O
secretion	O
or	O
impaired	O
sex	O
steroid	O
production	O
.	O

CAH	O
patients	O
have	O
lower	O
pregnancy	O
rate	O
compared	O
to	O
normal	O
women	O
.	O

Only	O
a	O
few	O
cases	O
with	O
successful	O
pregnancy	O
have	O
been	O
reported	O
in	O
the	O
literature	O
.	O

This	O
report	O
described	O
a	O
case	O
of	O
CAH	O
with	O
successful	O
pregnancy	O
and	O
live	O
birth	O
.	O

Patient	O
concerns	O
A	O
23	O
-	O
year	O
-	O
old	O
woman	O
visited	O
our	O
endocrinology	O
department	O
for	O
clitoral	O
hypertrophy	O
and	O
primary	O
amenorrhea	O
.	O

Diagnoses	O
The	O
patient	O
was	O
diagnosed	O
as	O
CAH	O
.	O

Intervention	O
Prednisone	O
was	O
initially	O
started	O
to	O
improve	O
the	O
patient	O
's	O
symptoms	O
.	O

Then	O
she	O
underwent	O
clitoral	O
resection	O
and	O
vaginoplasty	O
several	O
months	O
later	O
.	O

She	O
continuously	O
took	O
the	O
prednisolone	O
after	O
the	O
operation	O
and	O
had	O
been	O
undergoing	O
regular	O
checkups	O
.	O

Outcomes	O
She	O
was	O
pregnant	O
spontaneously	O
without	O
assisted	O
reproductive	O
technology	O
and	O
had	O
a	O
successful	O
live	O
birth	O
.	O

Her	O
baby	O
had	O
shown	O
normal	O
external	O
genitalia	O
with	O
normal	O
karyotype	O
and	O
normal	O
development	O
up	O
to	O
6	O
years	O
of	O
age	O
.	O

Lessons	O
Some	O
mild	O
CAH	O
patients	O
with	O
certain	O
types	O
can	O
achieved	O
successful	O
pregnancy	O
without	O
any	O
assisted	O
reproductive	O
technology	O
after	O
treatment	O
with	O
steroid	O
.	O

The	O
pregnancy	O
rate	O
among	O
CAH	O
women	O
who	O
wish	O
to	O
conceive	O
may	O
be	O
much	O
more	O
optimistic	O
than	O
previous	O
researches	O
.	O

Background	O
/	O
aim	O
This	O
study	O
analysed	O
the	O
prevalence	B-EPI
of	O
the	O
characteristics	O
evaluated	O
in	O
dermatoscopy	O
for	O
melanocytic	O
infiltrations	O
of	O
the	O
conjunctiva	O
with	O
various	O
degrees	O
of	O
malignancy	O
.	O

Patients	O
and	O
methods	O
A	O
total	O
of	O
160	O
conjunctival	O
pigmented	O
lesions	O
were	O
studied	O
.	O

Each	O
lesion	O
was	O
scored	O
using	O
dermatoscopic	O
patterns	O
and	O
the	O
characteristics	O
of	O
malignancy	O
described	O
by	O
Kittler	O
.	O

Also	O
,	O
the	O
Authors	O
'	O
own	O
clues	O
were	O
added	O
to	O
the	O
evaluation	O
.	O

Results	O
In	O
melanomas	O
,	O
the	O
following	O
characteristics	O
were	O
identified	O
:	O
asymmetry	O
of	O
the	O
pattern	O
and	O
colour	O
,	O
larger	O
average	O
number	O
of	O
colours	O
,	O
the	O
presence	O
of	O
grey	O
colour	O
,	O
structureless	O
area	O
,	O
polymorphic	O
vessels	O
and	O
feeder	O
vessels	O
.	O

A	O
pattern	O
of	O
black	O
dots	O
and	O
a	O
black	O
colour	O
was	O
typical	O
of	O
malignant	O
lesions	O
and	O
pre	O
-	O
cancerous	O
(	O
premalignant	O
)	O
lesions	O
-	O
primary	O
acquired	O
melanosis	O
(	O
PAM	O
)	O
with	O
atypia	O
.	O

Cysts	O
were	O
observed	O
only	O
in	O
the	O
group	O
of	O
naevi	O
.	O

Conclusion	O
The	O
patterns	O
evaluated	O
with	O
dermatoscopy	O
are	O
present	O
in	O
pigmented	O
lesions	O
of	O
the	O
conjunctiva	O
.	O

There	O
are	O
,	O
however	O
,	O
some	O
characteristics	O
which	O
allow	O
differentiation	O
between	O
melanoma	O
and	O
pigmented	O
naevus	O
and	O
melanosis	O
and	O
also	O
between	O
PAM	O
.	O