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 I-STAT
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 B-LOC
and O
southeastern B-LOC
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 O
in O
approximately B-STAT
4 O
- O
7 O
% O
of O
patients O
with O
adrenal O
incidentalomas O
. 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 O
Amazon O
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 O
Amazon O
. 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
, O
Peru B-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
, O
Argentina B-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 O
% O
, O
95 O
% O
confidence O
interval O
( O
CI O
) O
0.7 O
% I-STAT
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 O
population O
was O
2.9 O
% O
( 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 O
Amazon O
basin O
is O
about O
1.7 O
% O
, 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 B-STAT
( O
10.4 O
% O
) O
, O
followed O
by O
migraine O
6/67 B-STAT
( O
8.9 O
% O
) O
major O
depression O
disorder O
6/67 B-STAT
( O
8.9 O
% O
) O
, O
iron O
deficiency O
anemia O
8/54 B-STAT
( O
14.8 O
% O
) O
, O
and O
non O
- O
autoimmune O
hypothyroidism O
4/67 B-STAT
( 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 O
1.8 O
% O
of O
the O
general O
population O
, O
with O
prevalence B-EPI
of O
up O
to O
25 B-STAT
% O
in O
those O
with O
esophageal O
atresia O
. 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
, O
Germany B-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 O
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 B-STAT
( 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 O
% O
) O
were O
diagnosed O
with O
RA O
. 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 B-EPI
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 O
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 B-STAT
( O
23.5 O
% O
) O
had O
normal O
vitamin O
C O
levels O
, O
and O
114 B-STAT
( 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 B-EPI
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 B-EPI
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 O
- O
Central O
Africa B-LOC
, O
9 O
% O
from O
the O
East I-LOC
, O
7 O
% O
from O
Western O
Europe B-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 O
( O
RTDC O
) O
to O
1.1 O
( O
IMER O
) O
of O
1000 O
births O
. 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 B-EPI
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 I-STAT
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 O
% O
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 B-EPI
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 O
in O
100,000 O
, 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 B-STAT
( 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 B-STAT
( 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 B-EPI
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 B-LOC
-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 O
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 O
% O
, O
in O
comparison O
with O
a O
0.0005 B-STAT
% I-STAT
estimated O
clinical O
prevalence B-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 O
- 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 O
5 B-STAT
cases I-STAT
per I-STAT
million I-STAT
individuals I-STAT
annually O
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 B-STAT
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 O
coastal O
villages O
from O
the O
northern O
Bering B-LOC
Sea I-LOC
to O
the O
Beaufort B-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 B-LOC
. 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 O
than O
80 O
individuals O
with O
ADSL O
deficiency O
have O
been O
identified O
, O
but O
incidence B-EPI
of O
the O
disease O
remains O
unknown O
. 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 O
0.4 I-STAT
% I-STAT
of O
new O
patients O
presenting O
to O
dermatologists O
, 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 B-EPI
incidence I-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 B-EPI
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 O
incidence I-EPI
of O
granuloma O
annulare O
was O
0.04 B-STAT
% I-STAT
, O
or O
37.9 O
( O
95 O
% O
CI O
, O
36.9 O
- I-STAT
38.9 I-STAT
) I-STAT
per I-STAT
100 I-STAT
000 I-STAT
, I-STAT
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 O
( O
95 O
% O
CI O
, O
57.1 O
- I-STAT
59.5 O
) I-STAT
per I-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 O
than O
1 B-STAT
out I-STAT
of I-STAT
10 O
women O
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 B-EPI
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 O
areas O
in O
Cachoeiras B-LOC
de I-LOC
Macacu B-LOC
, O
Rio B-LOC
de I-LOC
Janeiro I-LOC
, O
Brazil B-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 O
% O
( O
n O
= O
41 O
) O
and O
13.4 O
% O
( 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 O
among O
children O
living O
in O
poor O
families O
( O
24/187 B-STAT
( O
12.8 O
% O
) O
vs. O
16/272 B-STAT
( O
5.9 O
% O
) O
; O
prevalence B-EPI
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 B-STAT
( O
23 O
% O
) O
vs. O
40/272 B-STAT
( O
14/7 O
% O
) 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 B-STAT
( O
15.9 O
% O
) O
vs. O
16/311 B-STAT
( 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 B-STAT
( O
23.2 O
% O
) O
vs. O
30/311 B-STAT
( 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 O
individuals O
were O
registered O
with O
CS O
, O
of O
whom O
104 B-STAT
( 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 B-STAT
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 B-STAT
( 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 B-STAT
% I-STAT
. 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 O
) O
than O
in O
other O
Australian O
States O
. 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 B-STAT
and I-STAT
2 I-STAT
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 B-STAT
( O
70.3 O
% O
) O
with O
HSV O
1 O
. O

Of O
104 B-STAT
( O
60.5 O
% O
) O
infants O
with O
signs O
of O
HSV O
disease O
, O
76 B-STAT
( 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 O
( O
95 O
% O
confidence O
interval O
, O
7.0 B-STAT
- I-STAT
11.5 I-STAT
) I-STAT
per I-STAT
100,000 I-STAT
live I-STAT
births I-STAT
] O
and O
28 B-STAT
( 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 O
( O
95 O
% O
confidence O
interval O
, O
2.4 B-STAT
- I-STAT
5.4 I-STAT
) I-STAT
per I-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 B-STAT
( 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 B-STAT
( O
22.4 O
% O
) O
with O
HSV O
encephalitis O
and O
11 B-STAT
( 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 B-STAT
, O
75.0 O
% O
) O
or O
HSV O
encephalitis O
( O
6 B-STAT
, O
21.4 O
% O
) O
. O

Death O
occurred O
in O
12/104 B-STAT
( 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 O
times O
the O
national O
reported O
incidence B-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 O
from O
1.3 O
% O
to O
8.8 O
% O
of O
all O
cholecystectomies O
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 B-STAT
and I-STAT
20 I-STAT
% I-STAT
) 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 O
countries O
. 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 O
countries O
. 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 B-STAT
% I-STAT
( 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
- O
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 O
. O

Interestingly O
, O
9/10 B-STAT
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 B-STAT
( 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 B-LOC
. 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 B-STAT
per I-STAT
100 I-STAT
000 I-STAT
infants I-STAT
( O
n O
= O
4663 O
) O
. O

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

Fall O
accidents O
were O
reported O
among O
71·4 B-STAT
% I-STAT
. 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 B-STAT
( 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 B-STAT
( 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 B-STAT
. 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 B-LOC
. 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 B-STAT
( 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 B-STAT
( 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 O
6.0 O
% I-STAT
in O
the O
normal O
population O
) 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 B-EPI
in O
MPS O
disorders O
( O
72 B-STAT
- 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 O
in O
1:50,000 B-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 O
% O
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 B-STAT
and I-STAT
18 I-STAT
. 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 B-STAT
( 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 O
COVID-19 O
patients O
have O
been O
identified O
in O
161 O
countries O
. O

By O
then O
, O
over O
700 O
pediatric O
patients O
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