Most O
amyotrophic O
lateral O
sclerosis O
( O
ALS O
) O
cases O
are O
considered O
sporadic O
, O
without O
a O
known O
genetic O
basis O
, O
and O
lifestyle O
factors O
are O
suspected O
to O
play O
an O
etiologic O
role O
. O

We O
previously O
observed O
increased O
risk O
of O
ALS O
associated O
with O
high O
nail O
mercury O
levels O
as O
an O
exposure O
biomarker O
and O
thus O
hypothesized O
that O
mercury O
exposure O
via O
fish O
consumption O
patterns O
increases O
ALS O
risk O
. O

Lifestyle O
surveys O
were O
obtained O
from O
ALS O
patients O
( O
n O
= O
165 O
) O
and O
n O
= O
330 O
age- O
and O
sex O
- O
matched O
controls O
without O
ALS O
enrolled O
in O
New B-LOC
Hampshire I-LOC
, O
Vermont B-LOC
, O
or O
Ohio B-LOC
, O
USA I-LOC
. O

We O
estimated O
their O
annual O
intake O
of O
mercury O
and O
omega-3 O
polyunsaturated O
fatty O
acid O
( O
PUFA O
) O
via O
self O
- O
reported O
seafood O
consumption O
habits O
, O
including O
species O
and O
frequency O
. O

In O
our O
multivariable O
model O
, O
family O
income O
showed O
a O
significant O
positive O
association O
with O
ALS O
risk O
( O
p O
= O
0.0003 O
, O
adjusted O
for O
age O
, O
sex O
, O
family O
history O
, O
education O
, O
and O
race O
) O
. O

Neither O
the O
estimated O
annual O
mercury O
nor O
omega-3 O
PUFA O
intakes O
via O
seafood O
were O
associated O
with O
ALS O
risk O
. O

ALS O
incidence B-EPI
is O
associated O
with O
socioeconomic O
status O
; O
however O
, O
consistent O
with O
a O
prior O
international O
study O
, O
this O
relationship O
is O
not O
linked O
to O
mercury O
intake O
estimated O
via O
fish O
or O
seafood O
consumption O
patterns O
. O

Background O
Plague O
is O
a O
re O
- O
emerging O
flea O
- O
borne O
infectious O
disease O
of O
global O
importance O
and O
in O
recent O
years O
, O
Zambia B-LOC
has O
periodically O
experienced O
increased O
incidence B-EPI
of O
outbreaks O
of O
this O
disease O
. O

However O
, O
there O
are O
currently O
no O
studies O
in O
the O
country O
that O
provide O
a O
quantitative O
assessment O
of O
the O
ability O
of O
the O
disease O
to O
spread O
during O
these O
outbreaks O
. O

This O
limits O
our O
understanding O
of O
the O
epidemiology O
of O
the O
disease O
especially O
for O
planning O
and O
implementing O
quantifiable O
and O
cost O
- O
effective O
control O
measures O
. O

To O
fill O
this O
gap O
, O
the O
basic O
reproduction O
number O
, O
R0 O
, O
for O
bubonic O
plague O
was O
estimated O
in O
this O
study O
, O
using O
data O
from O
the O
2015 B-DATE
Nyimba B-LOC
district I-LOC
outbreak O
, O
in O
the O
Eastern I-LOC
province I-LOC
of O
Zambia B-LOC
. O

R0 O
is O
the O
average O
number O
of O
secondary O
infections O
arising O
from O
a O
single O
infectious O
individual O
during O
their O
infectious O
period O
in O
an O
entirely O
susceptible O
population O
. O

Methodology O
/ O
principal O
findings O
Secondary O
epidemic O
data O
for O
the O
most O
recent O
2015 B-DATE
Nyimba B-LOC
district I-LOC
bubonic O
plague O
outbreak O
in O
Zambia B-LOC
was O
analyzed O
. O

R0 O
was O
estimated O
as O
a O
function O
of O
the O
average O
epidemic O
doubling O
time O
based O
on O
the O
initial O
exponential O
growth O
rate O
of O
the O
outbreak O
and O
the O
average O
infectious O
period O
for O
bubonic O
plague O
. O

R0 O
was O
estimated O
to O
range O
between O
1.5599 O
[ O
95 O
% O
CI O
: O
1.382 O
- O
1.7378 O
] O
and O
1.9332 O
[ O
95 O
% O
CI O
: O
1.6366 O
- O
2.2297 O
] O
, O
with O
average O
of O
1.7465 O
[ O
95 O
% O
CI O
: O
1.5093 O
- O
1.9838 O
] O
. O

Further O
, O
an O
SIR O
deterministic O
mathematical O
model O
was O
derived O
for O
this O
infection O
and O
this O
estimated O
R0 O
to O
be O
between O
1.4 O
to O
1.5 O
, O
which O
was O
within O
the O
range O
estimated O
above O
. O

Conclusions O
/ O
significance O
This O
estimated O
R0 O
for O
bubonic O
plague O
is O
an O
indication O
that O
each O
bubonic O
plague O
case O
can O
typically O
give O
rise O
to O
almost O
two O
new O
cases O
during O
these O
outbreaks O
. O

This O
R0 O
estimate O
can O
now O
be O
used O
to O
quantitatively O
analyze O
and O
plan O
measurable O
interventions O
against O
future O
plague O
outbreaks O
in O
Zambia B-LOC
. O

Background O
Mucopolysaccharidoses O
( O
MPS O
) O
are O
rare O
, O
inherited O
lysosomal O
storage O
disorders O
characterized O
by O
progressive O
multiorgan O
involvement O
. O

Previous O
studies O
on O
incidence B-EPI
and O
prevalence B-EPI
of O
MPS O
mainly O
focused O
on O
countries O
other O
than O
the B-LOC
United I-LOC
States I-LOC
( O
US B-LOC
) O
, O
showing O
considerable O
variation O
by O
country O
. O

This O
study O
aimed O
to O
identify O
MPS O
incidence B-EPI
and O
prevalence B-EPI
in O
the O
US B-LOC
at O
a O
national O
and O
state O
level O
to O
guide O
clinicians O
and O
policy O
makers O
. O

Methods O
This O
retrospective O
study O
examined O
all O
diagnosed O
cases O
of O
MPS O
from O
1995 B-DATE
to I-DATE
2015 I-DATE
in O
the O
US B-LOC
using O
the O
National O
MPS O
Society O
database O
records O
. O

Data O
included O
year O
of O
birth O
, O
patient O
geographic O
location O
, O
and O
MPS O
variant O
type O
. O

US O
population O
information O
was O
obtained O
from O
the O
National O
Center O
for O
Health O
Statistics O
. O

The O
incidence B-EPI
and O
prevalence B-EPI
rates I-EPI
were O
calculated O
for O
each O
disease O
. O

Incidence B-EPI
rates I-EPI
were O
calculated O
for O
each O
state O
. O

Results O
We O
obtained O
information O
from O
789 O
MPS O
patients O
during O
a O
20 O
- O
year O
period O
. O

Incidence B-EPI
of O
MPS O
in O
the O
US B-LOC
was O
found O
to O
be O
0.98 B-STAT
per I-STAT
100,000 I-STAT
live I-STAT
births I-STAT
. O

Prevalence B-EPI
was O
found O
to O
be O
2.67 B-STAT
per I-STAT
1 I-STAT
million I-STAT
. O

MPS O
I O
, O
II O
, O
and O
III O
had O
the O
highest O
incidence B-EPI
rate I-EPI
at O
birth B-EPI
( O
0.26/100,000 B-STAT
) O
and O
prevalence B-EPI
rates I-EPI
of O
0.70 B-STAT
- I-STAT
0.71 I-STAT
per I-STAT
million I-STAT
. O

Birth B-EPI
incidences I-EPI
of O
MPS O
IV O
, O
VI O
, O
and O
VII O
were O
0.14 B-STAT
, I-STAT
0.04 I-STAT
and I-STAT
0.027 I-STAT
per I-STAT
100,000 I-STAT
live I-STAT
births I-STAT
. O

Conclusions O
This O
is O
the O
most O
comprehensive O
review O
of O
MPS O
incidence B-EPI
and O
prevalence B-EPI
rates I-EPI
in O
the O
US B-LOC
. O

Due O
to O
the O
large O
US O
population O
and O
state O
fragmentation O
, O
US O
incidence B-EPI
and O
prevalence B-EPI
were O
found O
to O
be O
lower O
than O
other O
countries O
. O

Nonetheless O
, O
state O
- O
level O
studies O
in O
the O
US B-LOC
supported O
these O
figures O
. O

Efforts O
should O
be O
focused O
in O
the O
establishment O
of O
a O
national O
rare O
disease O
registry O
with O
mandated O
reporting O
from O
every O
state O
as O
well O
as O
newborn O
screening O
of O
MPS O
. O

Purpose O
of O
review O
Obstructive O
sleep O
apnea O
syndrome O
( O
OSAS O
) O
has O
a O
high O
prevalence B-EPI
in O
western O
countries O
. O

Many O
papers O
have O
been O
published O
with O
the O
purpose O
of O
demonstrating O
that O
OSAS O
acts O
as O
an O
arrhythmia O
trigger O
and O
is O
responsible O
for O
an O
increase O
in O
cardiovascular O
morbidity O
and O
mortality O
. O

The O
aim O
of O
this O
study O
was O
to O
review O
our O
knowledge O
on O
this O
topic O
. O

Recent O
findings O
There O
is O
a O
lot O
of O
evidence O
demonstrating O
the O
relationship O
between O
OSAS O
and O
arrhythmias O
, O
but O
there O
remains O
a O
lack O
of O
an O
interventional O
randomized O
trial O
to O
demonstrate O
that O
by O
treating O
OSAS O
we O
can O
reduce O
arrhythmia O
burden O
. O

OSAS O
is O
a O
highly O
prevalent B-EPI
illness O
in O
western O
countries O
and O
is O
clearly O
related O
to O
an O
increase O
in O
cardiovascular O
mortality O
and O
morbidity O
. O

Cardiac O
arrhythmias O
are O
triggered O
by O
a O
repetitive O
hypoxemia O
, O
hypercapnia O
, O
acidosis O
, O
intrathoracic O
pressure O
fluctuations O
, O
reoxygenation O
, O
and O
arousals O
during O
apnea O
and O
hypopnea O
episodes O
. O

Early O
diagnosis O
and O
treatment O
of O
these O
patients O
can O
reduce O
further O
cardiovascular O
morbidity O
and O
mortality O
. O

Objective O
We O
sought O
to O
determine O
the O
risk O
factors O
, O
incidence B-EPI
, O
and O
mortality O
of O
very O
late O
onset O
bacterial O
infection O
( O
blood O
, O
urine O
, O
or O
cerebrospinal O
fluid O
culture O
positive O
occurring O
after O
day O
of O
life O
120 O
) O
in O
preterm O
infants O
. O

Study O
design O
A O
retrospective O
observational O
cohort O
study O
of O
all O
very O
low O
birth O
weight O
infants O
cared O
for O
between O
day O
of O
life O
120 O
and O
365 O
in O
292 O
neonatal O
intensive O
care O
units O
in O
the B-LOC
United I-LOC
States I-LOC
from O
1997 B-DATE
to I-DATE
2008 I-DATE
. O

Results O
We O
identified O
3918 O
infants O
who O
were O
hospitalized O
beyond O
120 O
days O
of O
life O
. O

Of O
these O
, O
1027 O
( O
26 O
% O
) O
were O
evaluated O
with O
at O
least O
1 O
culture O
( O
blood O
, O
urine O
, O
or O
cerebrospinal O
fluid O
) O
, O
and O
276 O
( O
27 O
% O
) O
of O
the O
evaluated O
infants O
had O
414 O
episodes O
of O
culture O
- O
positive O
infection O
. O

Gram O
- O
positive O
organisms O
caused O
most O
of O
the O
infections O
( O
48 O
% O
) O
. O

The O
risk O
of O
death O
was O
higher O
in O
infants O
with O
positive O
cultures O
( O
odds O
ratio O
; O
10.5 O
, O
95 O
% O
confidence O
interval O
[ O
7.2 O
- O
15.5 O
] O
) O
or O
negative O
cultures O
( O
4.8 O
, O
[ O
3.5 O
- O
6.7 O
] O
) O
compared O
to O
infants O
that O
were O
never O
evaluated O
with O
a O
culture O
( O
p<0.001 O
) O
. O

Mortality O
was O
highest O
with O
fungal O
infections O
( O
8/24 O
, O
33 O
% O
) O
followed O
by O
Gram O
- O
positive O
cocci O
( O
40/142 O
, O
28 O
% O
) O
. O

Conclusions O
Important O
predictive O
risk O
factors O
for O
early O
and O
late O
onset O
sepsis O
( O
birth O
weight O
and O
gestational O
age O
) O
did O
not O
contribute O
to O
risk O
of O
developing O
very O
late O
onset O
infection O
. O

Evaluation O
for O
infection O
( O
whether O
positive O
or O
negative O
) O
was O
a O
significant O
risk O
factor O
for O
death O
. O

GPC O
and O
fungal O
infections O
were O
associated O
with O
high O
mortality O
. O

Background O
In O
this O
nationwide O
study O
, O
we O
used O
the O
unique O
Danish O
registries O
to O
estimate O
the O
risk O
of O
suicide O
and O
deliberate O
self O
- O
harm O
in O
patients O
with O
congenital O
heart O
disease O
( O
CHD O
) O
. O

Methods O
and O
Results O
We O
identified O
all O
Danish B-ETHN
citizens O
receiving O
a O
diagnosis O
of O
CHD O
between B-DATE
1977 I-DATE
and I-DATE
2007 I-DATE
. O

As O
a O
reference O
cohort O
, O
we O
randomly O
selected O
10 O
citizens O
for O
each O
patient O
, O
matched O
by O
sex O
and O
birth O
year O
. O

Using O
the O
Fine O
and O
Gray O
competing O
risk O
regression O
, O
we O
estimated O
the O
cumulative B-EPI
incidences I-EPI
of O
suicide O
and O
self O
- O
harm O
, O
and O
Cox O
proportional O
regression O
analysis O
was O
used O
to O
compare O
the O
risk O
of O
suicide O
and O
deliberate O
self O
- O
harm O
in O
patients O
with O
CHD O
with O
the O
reference O
cohort O
. O

We O
identified O
14 O
433 O
patients O
with O
CHD O
. O

Mean O
follow O
- O
up O
was O
21.3 O
years O
, O
with O
a O
maximum O
follow O
- O
up O
of O
42 O
years O
. O

Since O
the O
time O
of O
diagnosis O
, O
2659 O
patients O
had O
died O
, O
with O
a O
median O
age O
of O
death O
of O
23 O
years O
. O

A O
total O
of O
15 O
patients O
had O
died O
by O
suicide O
, O
compared O
with O
232 O
suicides O
in O
the O
reference O
cohort O
. O

Patients O
with O
CHD O
had O
a O
low O
and O
similar O
risk O
of O
dying O
by O
suicide O
when O
compared O
with O
the O
reference O
cohort O
( O
cause O
- O
specific O
hazard O
ratio O
, O
0.81 O
; O
95 O
% O
CI O
, O
0.48 O
- O
1.37 O
; O
and O
subhazard O
ratio O
, O
0.68 O
; O
95 O
% O
CI O
, O
0.41 O
- O
1.16 O
) O
. O

We O
identified O
336 O
events O
of O
self O
- O
harm O
among O
patients O
with O
CHD O
, O
and O
3484 O
events O
in O
the O
reference O
group O
. O

The O
overall O
risk O
of O
deliberate O
self O
- O
harm O
was O
not O
increased O
in O
patients O
with O
CHD O
when O
compared O
with O
the O
reference O
group O
( O
subhazard O
ratio O
, O
0.95 O
; O
95 O
% O
CI O
, O
0.85 O
- O
1.06 O
) O
. O

Conclusions O
This O
is O
the O
first O
study O
to O
estimate O
the O
risk O
of O
suicide O
and O
deliberate O
self O
- O
harm O
in O
patients O
with O
CHD O
. O

We O
found O
that O
patients O
with O
CHD O
do O
not O
have O
an O
increased O
risk O
of O
suicide O
or O
deliberate O
self O
- O
harm O
when O
compared O
with O
a O
large O
reference O
cohort O
. O

Introduction O
A O
congenital O
lung O
abnormality O
( O
CLA O
) O
is O
often O
found O
in O
conjunction O
with O
other O
abnormalities O
but O
screening O
guidelines O
for O
newborns O
with O
CLA O
have O
not O
yet O
been O
reported O
. O

We O
aimed O
to O
assess O
the O
incidence B-EPI
of O
associated O
anomalies O
in O
CLA O
patients O
born O
or O
followed O
up O
at O
our O
centre O
and O
the O
need O
for O
additional O
screening O
of O
newborns O
with O
a O
CLA O
. O

Methods O
From O
a O
retrospective O
chart O
review O
of O
all O
patients O
born O
with O
a O
CLA O
between B-DATE
January I-DATE
1999 I-DATE
and I-DATE
January I-DATE
2019 I-DATE
, O
we O
identified O
patients O
diagnosed O
with O
a O
congenital O
pulmonary O
airway O
malformation O
, O
bronchopulmonary O
sequestration O
, O
congenital O
lobar O
overinflation O
, O
bronchogenic O
cyst O
, O
or O
lung O
agenesis O
. O

Associated O
anomalies O
were O
noted O
and O
categorized O
according O
to O
the O
affected O
organ O
system O
. O

Results O
Twenty O
- O
eight O
( O
14 O
% O
) O
of O
196 O
CLA O
patients O
had O
a O
major O
associated O
anomaly O
. O

This O
was O
most O
frequent O
in O
conjunction O
with O
a O
lung O
agenesis O
( O
100 O
% O
) O
or O
bronchogenic O
cyst O
( O
29 O
% O
) O
. O

Congenital O
heart O
defects O
( O
32 O
% O
) O
and O
gastrointestinal O
defects O
( O
18 O
% O
) O
were O
the O
most O
frequently O
associated O
anomalies O
. O

Examination O
of O
newborns O
with O
a O
CLA O
should O
focus O
on O
the O
cardiovascular O
and O
gastrointestinal O
tract O
, O
and O
a O
chest O
and O
abdominal O
radiograph O
may O
be O
useful O
to O
assess O
signs O
of O
major O
associated O
anomalies O
, O
regardless O
of O
the O
clinical O
course O
. O

A O
molecular O
epidemiological O
study O
was O
conducted O
in O
a O
population O
of O
9422 O
blood O
donors O
in O
the O
province O
of O
Corrientes B-LOC
, O
Northeastern B-LOC
Argentina I-LOC
, O
to O
determine O
the O
prevalence B-EPI
of O
Human O
T O
- O
cell O
lymphotropic O
virus O
types O
1 O
and O
2 O
( O
HTLV-1/2 O
) O
, O
the O
phylogenetic O
identification O
of O
HTLV-1 O
and O
2 O
subtypes O
/ O
subgroups O
and O
perform O
a O
mutation O
analysis O
. O

Based O
on O
the O
results O
obtained O
, O
it O
was O
shown O
that O
both O
HTLV-1 O
and O
HTLV-2 O
are O
circulating O
in O
a O
low O
- O
risk O
population O
of O
Corrientes B-LOC
, O
although O
with O
a O
similar O
prevalence B-EPI
to O
that O
of O
non O
- O
endemic O
areas O
. O

Phylogenetic O
studies O
identified O
the O
HTLV-1 O
Cosmopolitan O
subtype O
Transcontinental O
subgroup O
( O
Aa O
) O
, O
and O
the O
HTLV-2 O
subtype O
b. O

Infected O
donors O
reported O
neither O
a O
history O
of O
risk O
factors O
such O
as O
transfusions O
, O
intravenous O
drug O
use O
, O
nor O
risky O
or O
HTLV-1/2 O
seropositive O
sexual O
partners O
. O

These O
results O
suggest O
that O
these O
viruses O
were O
transmitted O
from O
mother B-SEX
to O
child O
, O
possibly O
from O
generation O
to O
generation O
, O
and O
that O
these O
strains O
were O
introduced O
into O
the O
Caucasian B-ETHN
population O
of O
this O
region O
from O
ancestors O
originating O
from O
endemic O
areas O
of O
the O
country O
either O
from O
or O
through O
contact O
with O
individuals O
from O
other O
countries O
years O
ago O
. O

Our O
results O
demonstrate O
for O
the O
first O
time O
the O
presence O
of O
HTLV-1 O
and O
HTLV-2 O
in O
the O
province O
of O
Corrientes B-LOC
. O

Moreover O
, O
although O
the O
province O
can O
be O
considered O
a O
non O
- O
endemic O
area O
, O
the O
need O
to O
include O
these O
retroviruses O
in O
a O
national O
Public O
Health O
program O
is O
highlighted O
, O
in O
order O
to O
have O
qualified O
professionals O
duly O
trained O
to O
make O
their O
diagnosis O
and O
provide O
the O
necessary O
information O
in O
relation O
to O
primary O
care O
and O
patient O
follow O
- O
up O
. O

Background O
Entamoeba O
species O
harbored O
by O
humans O
have O
different O
degrees O
of O
pathogenicity O
. O

The O
present O
study O
explores O
the O
intra- O
and O
interspecific O
diversity O
, O
phylogenetic O
relationships O
, O
prevalence B-EPI
and O
distribution O
of O
tetra- O
and O
octonucleated O
cyst O
- O
producing O
Entamoeba O
in O
different O
Brazilian B-ETHN
regions O
. O

Methods O
Cross O
- O
sectional O
studies O
were O
performed O
to O
collect O
fecal O
samples O
( O
n O
= O
1728 O
) O
and O
sociodemographic O
data O
in O
communities O
located O
in O
four O
Brazilian B-ETHN
biomes O
: O
Atlantic B-LOC
Forest I-LOC
, O
Caatinga B-LOC
, O
Cerrado B-LOC
, O
and O
Amazon B-LOC
. O

Fecal O
samples O
were O
subjected O
to O
molecular O
analysis O
by O
partial O
small O
subunit O
ribosomal O
DNA O
sequencing O
( O
SSU O
rDNA O
) O
and O
phylogenetic O
analysis O
. O

Results O
Light O
microscopy O
analysis O
revealed O
that O
tetranucleated O
cysts O
were O
found O
in O
all O
the O
studied O
biomes O
. O

The O
highest O
positivity O
rates O
were O
observed O
in O
the O
age O
group O
6 O
- O
10 O
years O
( O
23.21 O
% O
) O
. O

For O
octonucleated O
cysts O
, O
positivity O
rates O
ranged O
from O
1 O
to O
55.1 O
% O
. O

Sixty O
SSU O
rDNA O
Entamoeba O
sequences O
were O
obtained O
, O
and O
four O
different O
species O
were O
identified O
: O
the O
octonucleated O
E. O
coli O
, O
and O
the O
tetranucleated O
E. O
histolytica O
, O
E. O
dispar O
, O
and O
E. O
hartmanni O
. O

Novel O
haplotypes O
( O
n O
= O
32 O
) O
were O
characterized O
; O
however O
, O
new O
ribosomal O
lineages O
were O
not O
identified O
. O

The O
Entamoeba O
coli O
ST1 O
subtype O
predominated O
in O
Atlantic B-LOC
Forest O
and O
Caatinga B-LOC
, O
and O
the O
ST2 O
subtype O
was O
predominant O
in O
the O
Amazon B-LOC
biome O
. O

E. O
histolytica O
was O
detected O
only O
in O
the O
Amazon B-LOC
biome O
. O

In O
phylogenetic O
trees O
, O
sequences O
were O
grouped O
in O
two O
groups O
, O
the O
first O
containing O
uni- O
and O
tetranucleated O
and O
the O
second O
containing O
uni- O
and O
octonucleated O
cyst O
- O
producing O
Entamoeba O
species O
. O

Molecular O
diversity O
indexes O
revealed O
a O
high O
interspecific O
diversity O
for O
tetra- O
and O
octonucleated O
Entamoeba O
spp O
. O

( O
H O
± O
SD O
= O
0.9625 O
± O
0.0126 O
) O
. O

The O
intraspecific O
diversity O
varied O
according O
to O
species O
or O
subtype O
: O
E. O
dispar O
and O
E. O
histolytica O
showed O
lower O
diversity O
than O
E. O
coli O
subtypes O
ST1 O
and O
ST2 O
and O
E. O
hartmanni O
. O

Conclusions O
Tetra- O
and O
octonucleated O
cyst O
- O
producing O
Entamoeba O
are O
endemic O
in O
the O
studied O
communities O
; O
E. O
histolytica O
was O
found O
in O
a O
low O
proportion O
and O
only O
in O
the O
Amazon B-LOC
biome O
. O

With O
regard O
to O
E. O
coli O
, O
subtype O
ST2 O
was O
predominant O
in O
the O
Amazon B-LOC
biome O
. O

The O
molecular O
epidemiology O
of O
Entamoeba O
spp O
. O

is O
a O
field O
to O
be O
further O
explored O
and O
provides O
information O
with O
important O
implications O
for O
public O
health O
. O

Genetic O
predisposition O
has O
been O
always O
noted O
in O
the O
context O
of O
familial O
hematological O
malignancies O
. O

Epidemiological O
studies O
have O
provided O
evidence O
consisting O
of O
an O
increased O
risk O
to O
develop O
blood O
cancer O
in O
relatives O
diagnosed O
with O
the O
same O
pathology O
and O
characterized O
by O
early O
age O
at O
diagnosis O
and O
higher O
severity O
compared O
to O
sporadic O
forms O
. O

With O
the O
emergence O
of O
new O
genomic O
testing O
approaches O
, O
the O
prevalence B-EPI
of O
familial O
aggregations O
of O
hematological O
malignancies O
seems O
to O
be O
under O
estimated O
. O

The O
heterogeneity O
of O
clinical O
features O
explains O
the O
wide O
number O
of O
genes O
' O
mutations O
reported O
to O
date O
and O
the O
variable O
penetrance O
of O
variants O
. O

Nevertheless O
, O
the O
genetic O
basis O
of O
familial O
hematological O
malignancies O
is O
still O
not O
well O
understood O
. O

Identifying O
the O
genetic O
background O
in O
familial O
aggregations O
provides O
a O
valuable O
tool O
for O
prognostic O
evaluation O
, O
personalized O
treatment O
and O
better O
genetic O
counseling O
in O
high O
- O
risk O
families O
. O

Herein O
, O
we O
provide O
an O
overview O
of O
genes O
reported O
in O
the O
last O
few O
years O
in O
association O
to O
hematological O
malignancies O
including O
familial O
form O
of O
Hodgkin O
Lymphoma O
, O
Non O
- O
Hodgkin O
Lymphoma O
, O
Chronic O
Lymphocytic O
Leukemia O
, O
acute O
Myeloid O
Leukemia O
and O
acute O
Lymphoblastic O
Leukemia O
. O

Objective O
To O
determine O
whether O
the O
two O
most O
common O
genetic O
mutations O
seen O
in O
Stickler O
Syndrome O
( O
SS O
) O
( O
COL2A1 O
and O
COL11A1 O
) O
affect O
the O
incidence B-EPI
of O
mandibular O
distraction O
osteogenesis O
( O
MDO O
) O
and O
what O
impact O
Robin O
sequence O
( O
RS O
) O
has O
on O
diagnosis O
. O

SS O
is O
an O
autosomal O
dominant O
connective O
tissue O
disorder O
characterized O
by O
almost O
complete O
penetrance O
. O

COL2A1 O
and O
COL11A1 O
are O
the O
two O
most O
common O
mutations O
seen O
in O
SS O
patients O
. O

SS O
often O
presents O
at O
birth O
with O
RS O
, O
which O
is O
characterized O
by O
the O
triad O
of O
micrognathia O
, O
glossoptosis O
, O
and O
tongue O
- O
based O
airway O
obstruction O
. O

MDO O
is O
one O
surgical O
intervention O
that O
has O
been O
shown O
to O
be O
successful O
in O
relieving O
tongue O
base O
obstruction O
and O
is O
the O
surgical O
intervention O
of O
choice O
for O
this O
condition O
. O

Methods O
A O
retrospective O
chart O
review O
was O
performed O
on O
all O
patients O
with O
a O
diagnosis O
of O
SS O
at O
a O
tertiary O
pediatric O
hospital O
between B-DATE
January I-DATE
1 I-DATE
, I-DATE
2003 I-DATE
and I-DATE
December I-DATE
31 I-DATE
, I-DATE
2018 I-DATE
. O

The O
included O
patient O
charts O
were O
reviewed O
for O
demographic O
information O
, O
SS O
mutation O
, O
and O
history O
of O
MDO O
. O

Forty O
- O
six O
patients O
had O
a O
clinical O
diagnosis O
of O
SS O
. O

Of O
those O
, O
31 O
met O
inclusion O
criteria O
which O
involved O
having O
a O
molecular O
diagnosis O
of O
SS O
and O
sufficient O
follow O
up O
information O
to O
determine O
if O
MDO O
was O
indicated O
or O
performed O
. O

Twenty O
- O
two O
of O
the O
31 O
included O
patients O
had O
a O
diagnosis O
of O
RS O
( O
70.96 O
% O
) O
. O

Thirteen O
of O
the O
31 O
patients O
( O
41.94 O
% O
) O
included O
in O
this O
study O
required O
MDO O
as O
a O
neonate O
. O

Results O
Fifty O
- O
percent O
of O
patients O
with O
type O
I O
( O
COL2A1 O
) O
required O
MDO O
as O
a O
neonate O
compared O
to O
only O
31 O
% O
of O
patients O
with O
type O
II O
( O
COL11A1 O
) O
, O
though O
the O
difference O
between O
the O
two O
groups O
was O
not O
statistically O
significant O
. O

Conclusion O
The O
findings O
of O
this O
study O
suggest O
that O
patients O
with O
type O
I O
mutation O
may O
have O
a O
higher O
incidence B-EPI
of O
MDO O
than O
patients O
with O
a O
type O
II O
mutation O
, O
though O
further O
research O
with O
larger O
sample O
sizes O
is O
needed O
. O

This O
information O
is O
helpful O
in O
counseling O
those O
with O
SS O
or O
family O
history O
of O
SS O
about O
what O
they O
can O
expect O
related O
to O
RS O
and O
need O
for O
MDO O
based O
on O
genetic O
findings O
. O

Level O
of O
evidence O
3 O
. O

Glucose-6 O
- O
phosphate O
dehydrogenase O
( O
G6PD O
) O
deficiency O
is O
the O
most O
common O
enzymatic O
disorder O
of O
red O
blood O
cells O
worldwide B-LOC
. O

The O
severity O
of O
hemolytic O
anemia O
varies O
among O
individuals O
with O
G6PD O
deficiency O
, O
depending O
on O
the O
genetic O
variant O
in O
the O
G6PD O
gene O
; O
this O
makes O
the O
diagnosis O
of O
the O
condition O
more O
challenging O
in O
some O
cases O
. O

In O
this O
report O
, O
we O
present O
a O
case O
of O
severe O
hemolytic O
anemia O
and O
methemoglobinemia O
in O
a O
patient O
with O
G6PD O
deficiency O
who O
had O
been O
exposed O
to O
hydroxychloroquine O
prescribed O
for O
severe O
acute O
respiratory O
syndrome O
coronavirus O
2 O
( O
SARS O
- O
CoV-2 O
) O
infection O
. O

To O
the O
best O
of O
our O
knowledge O
and O
based O
on O
a O
literature O
search O
, O
this O
is O
one O
of O
the O
first O
case O
reports O
in O
the O
literature O
about O
hemolytic O
crisis O
and O
methemoglobinemia O
in O
a O
patient O
with O
critical O
illness O
due O
to O
severe O
coronavirus O
disease O
2019 O
( O
COVID-19 O
) O
who O
was O
exposed O
to O
hydroxychloroquine O
. O

It O
is O
critical O
for O
physicians O
and O
caregivers O
to O
recognize O
the O
effects O
of O
oxidative O
stressors O
such O
as O
hydroxychloroquine O
, O
particularly O
in O
this O
era O
of O
the O
COVID-19 O
pandemic O
and O
in O
regions O
with O
a O
high O
prevalence B-EPI
of O
G6PD O
deficiency O
, O
for O
the O
appropriate O
management O
of O
this O
unique O
subset O
of O
patients O
. O

Background O
Many O
studies O
have O
been O
conducted O
to O
assess O
the O
incidence B-EPI
of O
congenital O
heart O
disease O
( O
CHD O
) O
. O

However O
, O
results O
were O
greatly O
inconsistent O
among O
these O
studies O
with O
a O
broad O
range O
of O
findings O
. O

Methods O
A O
prospective O
census O
- O
based O
cohort O
study O
was O
conducted O
in O
Qingdao B-LOC
, I-LOC
China I-LOC
, O
from O
August B-DATE
1 I-DATE
, I-DATE
2018 I-DATE
to I-DATE
April I-DATE
30 I-DATE
, I-DATE
2019 I-DATE
. O

All O
of O
the O
local O
registered O
pregnant O
women B-SEX
were O
continuously O
investigated O
and O
followed O
from O
15 O
to O
20 O
weeks O
of O
gestation O
to O
delivery O
, O
tracking O
the O
CHD O
cases O
in O
both O
the O
fetal O
and O
neonatal O
stages O
. O

A O
logistic O
regression O
model O
was O
applied O
to O
assess O
the O
association O
between O
CHD O
and O
possible O
risk O
factors O
. O

Results O
The O
positive O
rate O
of O
prenatal O
CHD O
screening O
was O
14.36 B-STAT
per I-STAT
1000 I-STAT
fetuses I-STAT
and O
the O
incidence B-EPI
of O
CHD O
was O
9.38 B-STAT
per I-STAT
1000 I-STAT
live I-STAT
births I-STAT
. O

Results O
from O
logistic O
regression O
indicated O
that O
, O
living O
in O
the O
countryside O
( O
odds O
ratio O
, O
( O
OR O
): O
0.771 O
; O
95 O
% O
confidence O
interval O
, O
( O
CI O
): O
0.628 O
- O
0.946 O
) O
and O
having O
a O
childbearing O
history O
( O
OR O
: O
0.802 O
; O
95%CI O
: O
0.676 O
- O
0.951 O
) O
were O
negatively O
associated O
with O
CHD O
. O

However O
, O
twin O
pregnancy O
( O
OR O
: O
1.957 O
, O
95 O
% O
CI O
: O
1.245 O
- O
3.076 O
) O
, O
illness O
in O
the O
first O
trimester O
( O
OR O
: O
1.306 O
; O
95 O
% O
CI O
: O
1.048 O
- O
1.628 O
) O
, O
a O
family O
history O
of O
CHD O
( O
OR O
: O
7.156 O
; O
95 O
% O
CI O
: O
3.293 O
- O
15.552 O
) O
, O
and O
having O
a O
child O
with O
a O
birth O
defect O
( O
OR O
: O
2.086 O
; O
95 O
% O
CI O
: O
1.167 O
- O
3.731 O
) O
were O
positively O
associated O
with O
CHD O
. O

Conclusion O
CHD O
is O
a O
serious O
health O
problem O
in O
Qingdao B-LOC
. O

The O
CHD O
incidence B-EPI
found O
in O
this O
study O
was O
similar O
to O
existing O
research O
. O

The O
positive O
rate O
of O
prenatal O
CHD O
screening O
was O
higher O
than O
the O
incidence B-EPI
of O
neonatal O
CHD O
. O

Moreover O
, O
CHD O
risk O
factors O
were O
identified O
in O
our O
study O
, O
and O
our O
findings O
may O
have O
great O
implications O
for O
formation O
CHD O
intervention O
strategies O
. O

The O
Global O
Atmospheric O
Passive O
Sampling O
( O
GAPS O
) O
network O
, O
initiated O
in O
2005 B-DATE
across O
55 O
global O
sites O
, O
supports O
the O
global O
monitoring O
plan O
( O
GMP O
) O
of O
the O
Stockholm O
Convention O
on O
Persistent O
Organic O
Pollutants O
( O
POPs O
) O
by O
providing O
information O
on O
POP O
concentrations O
in O
air O
on O
a O
global O
scale O
. O

These O
data O
inform O
assessments O
of O
the O
long O
- O
range O
transport O
potential O
of O
POPs O
and O
the O
effectiveness O
evaluation O
of O
chemical O
regulation O
efforts O
, O
by O
observing O
changes O
in O
concentrations O
over O
time O
. O

Currently O
, O
measurements O
spanning O
5 O
- O
10 O
sampling O
years O
are O
available O
for O
40 O
sites O
from O
the O
GAPS O
Network O
. O

This O
study O
was O
the O
first O
time O
that O
POP O
concentrations O
in O
air O
were O
reported O
on O
a O
global O
scale O
for O
an O
extended O
time O
period O
and O
the O
first O
to O
evaluate O
worldwide B-LOC
trends O
with O
an O
internally O
consistent O
sample O
set O
. O

For O
consistency O
between O
sampling O
years O
, O
site- O
and O
sample O
specific O
sampling O
rates O
were O
calculated O
with O
a O
new O
, O
public O
online O
model O
, O
which O
accounts O
for O
the O
effects O
of O
wind O
speed O
variability O
. O

Concentrations O
for O
legacy O
POPs O
in O
air O
between B-DATE
2005 I-DATE
and I-DATE
2014 I-DATE
show O
different O
trends O
for O
different O
organochlorine O
pesticides O
( O
OCPs O
) O
and O
polychlorinated O
biphenyls O
( O
PCBs O
) O
. O

The O
POPs O
discussed O
in O
this O
study O
were O
chosen O
due O
to O
being O
the O
most O
frequently O
detected O
, O
with O
detection O
at O
the O
majority O
of O
sites O
. O

PCB O
, O
endosulfan O
, O
and O
hexachlorocyclohexane O
( O
HCH O
) O
concentrations O
in O
air O
are O
decreasing O
at O
most O
sites O
. O

The O
global O
trends O
reflect O
global O
sources O
and O
recycling O
of O
HCH O
, O
ongoing O
emissions O
from O
old O
stockpiles O
for O
PCBs O
, O
and O
recent O
use O
restrictions O
for O
endosulfan O
. O

These O
chlorinated O
OCPs O
continue O
to O
present O
exposure O
threat O
to O
humans O
and O
ecosystems O
worldwide B-LOC
. O

Concentrations O
of O
other O
OCPs O
, O
such O
as O
chlordanes O
, O
heptachlor O
and O
dieldrin O
, O
are O
steady O
and/or O
declining O
slowly O
at O
the O
majority O
of O
sites O
, O
reflecting O
a O
transition O
from O
primary O
to O
secondary O
sources O
( O
i.e. O
, O
re O
- O
emission O
from O
reservoirs O
where O
these O
POPs O
have O
accumulated O
historically O
) O
which O
now O
control O
ambient O
air O
burdens O
. O

Background O
The O
increase O
of O
chronic O
diseases O
prevalence B-EPI
has O
created O
the O
need O
to O
adapt O
care O
models O
and O
to O
provide O
greater O
home O
supervision O
. O

Objective O
The O
objective O
of O
our O
study O
was O
to O
evaluate O
the O
impact O
of O
telemonitoring O
on O
patients O
with O
long O
- O
term O
conditions O
at O
high O
risk O
for O
rehospitalization O
or O
an O
emergency O
department O
visit O
, O
in O
terms O
of O
target O
disease O
control O
( O
diabetes O
, O
hypertension O
, O
heart O
failure O
, O
and O
chronic O
obstructive O
pulmonary O
disease O
) O
. O

Methods O
We O
conducted O
a O
quasi O
- O
experimental O
study O
with O
a O
before O
- O
and O
- O
after O
analysis O
to O
assess O
the O
effectiveness O
of O
the O
ValCrònic O
program O
after O
1 O
year O
of O
primary O
care O
monitoring O
. O

The O
study O
included O
high O
- O
risk O
patients O
with O
1 O
or O
more O
of O
the O
following O
conditions O
: O
diabetes O
, O
high O
blood O
pressure O
, O
heart O
failure O
, O
and O
chronic O
obstructive O
pulmonary O
disease O
. O

We O
assessed O
risk O
according O
to O
the O
Community O
Assessment O
Risk O
Screen O
. O

Participants O
used O
an O
electronic O
device O
( O
tablet O
) O
to O
self O
- O
report O
relevant O
health O
information O
, O
which O
was O
then O
automatically O
entered O
into O
their O
eHealth O
record O
for O
consultation O
. O

Results O
The O
total O
sample O
size O
was O
521 O
patients O
. O

Compared O
with O
the O
preintervention O
year O
, O
there O
were O
significant O
reductions O
in O
weight O
( O
82.3 O
kg O
before O
vs O
80.1 O
kg O
after O
; O
P=.001 O
) O
and O
in O
the O
proportion O
of O
people O
with O
high O
systolic O
( O
≥140 O
mmHg O
; O
190 O
, O
36.5 O
% O
vs O
170 O
, O
32.6 O
% O
; O
P=.001 O
) O
and O
diastolic O
( O
≥90 O
mmHg O
; O
72 O
, O
13.8 O
% O
vs O
40 O
, O
7.7 O
% O
; O
P=.01 O
) O
blood O
pressures O
, O
and O
hemoglobin O
A O
1c O
≥8 O
% O
( O
186 O
, O
35.7 O
% O
vs O
104 O
, O
20.0 O

% O
; O
P=.001 O
) O
. O

There O
was O
also O
a O
decrease O
in O
the O
proportion O
of O
participants O
who O
used O
emergency O
services O
in O
primary O
care O
( O
68 O
, O
13.1 O
% O
vs O
33 O
, O
6.3 O
% O
; O
P<.001 O
) O
and O
in O
hospital O
( O
98 O
, O
18.8 O
% O
vs O
67 O
, O
12.8 O
% O
; O
P<.001 O
) O
. O

Likewise O
, O
fewer O
participants O
required O
hospital O
admission O
due O
to O
an O
emergency O
( O
105 O
, O
20.2 O
% O
vs O
71 O
, O
13.6 O
% O
; O
P<.001 O
) O
or O
disease O
exacerbation O
( O
55 O
, O
10.5 O
% O
vs O
42 O
, O
8.1 O
% O
; O
P<.001 O
) O
. O

Conclusions O
The O
ValCrònic O
telemonitoring O
program O
in O
patients O
at O
high O
risk O
for O
rehospitalization O
or O
an O
emergency O
department O
visit O
appears O
to O
be O
useful O
to O
improve O
target O
disease O
control O
and O
to O
reduce O
the O
use O
of O
resources O
. O

Alport O
syndrome O
is O
an O
inherited O
disorder O
characterized O
by O
the O
association O
of O
a O
progressive O
haematuric O
nephropathy O
with O
ultrastructural O
abnormalities O
of O
the O
glomerular O
basement O
membranes O
, O
a O
progressive O
sensorineural O
hearing O
loss O
and O
sometimes O
ocular O
involvement O
. O

Its O
incidence B-EPI
is O
less B-STAT
than I-STAT
1 I-STAT
per I-STAT
5000 I-STAT
individuals I-STAT
and O
the O
disease O
is O
the O
cause O
of O
about O
2 O
% O
of O
end O
stage O
renal O
disease O
in O
Europe B-LOC
and O
the B-LOC
United I-LOC
States I-LOC
. O

Alport O
syndrome O
is O
clinically O
and O
genetically O
heterogeneous O
. O

It O
is O
related O
to O
mutations O
in O
the O
genes O
encoding O
one O
of O
three O
chains O
, O
[alpha]3 O
, O
[alpha]4 O
[alpha]5 O
of O
type O
IV O
collagen O
, O
the O
main O
component O
of O
basement O
membranes O
, O
expressed O
in O
the O
glomerular O
basement O
membrane O
. O

COL4A5 O
mutations O
are O
associated O
with O
X O
- O
linked O
Alport O
syndrome O
, O
which O
represents O
80 O
to O
85 O
% O
of O
cases O
and O
is O
more O
severe O
in O
boys B-SEX
than O
in O
girls B-SEX
. O

Mutations O
in O
COL4A3 O
or O
COL4A4 O
are O
associated O
with O
autosomal O
Alport O
syndrome O
. O

The O
expression O
of O
collagen O
chains O
in O
skin O
and O
kidney O
basement O
membranes O
allows O
for O
the O
diagnosis O
and O
characterization O
of O
the O
mode O
of O
transmission O
in O
most O
patients O
. O

It O
is O
necessary O
to O
diagnose O
this O
syndrome O
because O
its O
family O
involvement O
, O
its O
severity O
, O
and O
the O
importance O
of O
genetic O
counseling O
. O

Angiotensin O
blockers O
are O
increasingly O
prescribed O
in O
proteinuric O
patients O
. O

Prospective O
studies O
are O
needed O
to O
assess O
the O
effectiveness O
of O
these O
treatments O
on O
proteinuria O
and O
progression O
of O
kidney O
failure O
, O
and O
to O
specify O
indications O
. O

Animal O
studies O
have O
shown O
the O
potential O
value O
of O
different O
molecules O
( O
protease O
inhibitors O
, O
chemokine O
receptor O
blockers O
, O
transforming O
growth O
factor O
- O
[beta]01 O
inhibitors O
, O
hydroxy O
- O
methyl O
- O
coenzyme O
A O
reductase O
inhibitors O
, O
bone O
morphogenetic O
protein-7 O
inhibitors O
) O
, O
hematopoietic O
stem O
cells O
, O
and O
of O
a O
anti O
- O
micro O
- O
RNA O
. O

Introduction O
Globally B-LOC
, O
eye O
diseases O
are O
considered O
as O
one O
of O
the O
major O
contributors O
of O
nonfatal O
disabling O
conditions O
. O

In O
Bangladesh B-LOC
, O
1.5 O
% O
of O
adults O
are O
blind O
and O
21.6 O
% O
have O
low O
vision O
. O

Therefore O
, O
this O
paper O
aimed O
to O
identify O
the O
community O
- O
based O
prevalence B-EPI
and O
associated O
risk O
factors O
of O
eye O
diseases O
among O
slum O
dwellers O
of O
Dhaka B-LOC
city I-LOC
. O

Methods O
The O
study O
was O
carried O
out O
in O
two O
phases O
. O

In O
the O
first O
phase O
, O
a O
survey O
was O
conducted O
using O
multistage O
cluster O
sampling O
among O
1320 O
households O
of O
three O
purposively O
selected O
slums O
in O
Dhaka B-LOC
city I-LOC
. O

From O
each O
household O
, O
one O
family O
member O
( O
≥ O
18 O
years O
old O
) O
was O
randomly O
interviewed O
by O
trained O
data O
collectors O
using O
a O
structured O
questionnaire O
. O

After O
that O
, O
each O
of O
the O
participants O
was O
requested O
to O
take O
part O
in O
the O
second O
phase O
of O
the O
study O
. O

Following O
the O
request O
, O
432 O
participants O
out O
of O
1320 O
participants O
came O
into O
the O
tertiary O
care O
hospitals O
where O
they O
were O
clinically O
assessed O
by O
ophthalmologist O
for O
presence O
of O
eye O
diseases O
. O

A O
number O
of O
descriptive O
and O
inferential O
statistics O
were O
performed O
using O
Stata O
13 O
. O

Result O
The O
majority O
of O
total O
432 O
study O
participants O
were O
female B-SEX
( O
68.6 O
% O
) O
, O
married O
( O
82.6 O
% O
) O
and O
Muslim B-ETHN
( O
98.8 O
% O
) O
. O

Among O
them O
almost O
all O
( O
92.8 O
% O
) O
were O
clinically O
diagnosed O
with O
eye O
disease O
. O

The O
most O
prevalent O
eye O
diseases O
were O
refractive O
error O
( O
63.2 O
% O
) O
, O
conjunctivitis O
( O
17.1 O
% O
) O
, O
visual O
impairment O
( O
16.4 O
% O
) O
and O
cataract O
( O
7.2 O
% O
) O
. O

Refractive O
error O
was O
found O
significantly O
associated O
with O
older O
age O
, O
female B-SEX
gender O
and O
income O
generating O
work O
. O

Cataract O
was O
found O
negatively O
associated O
with O
the O
level O
of O
education O
, O
however O
, O
opposite O
relationship O
was O
found O
between O
cataract O
and O
visual O
impairment O
. O

Conclusion O
Our O
study O
provides O
epidemiologic O
data O
on O
the O
prevalence B-EPI
of O
eye O
diseases O
among O
adult O
population O
in O
low O
- O
income O
urban O
community O
of O
Dhaka B-LOC
city I-LOC
. O

The O
high O
prevalence B-EPI
of O
refractive O
error O
, O
allergic O
conjunctivitis O
, O
visual O
impairment O
, O
and O
cataract O
among O
this O
group O
of O
people O
suggests O
the O
importance O
of O
increasing O
access O
to O
eye O
care O
services O
. O

Epidemiological O
data O
on O
the O
14 O
cases O
of O
adrenal O
cortical O
tumour O
registered O
with O
the O
Manchester B-LOC
Children O
's O
Tumour O
Registry O
from O
1954 B-DATE
and I-DATE
1985 I-DATE
are O
presented O
. O

The O
incidence B-EPI
of O
adrenal O
cortical O
carcinomas O
was O
0.3 O
% O
, O
mainly O
in O
girls B-SEX
, O
most O
of O
whom O
presented O
with O
virilisation O
. O

The O
incidence B-EPI
of O
neoplastic O
disease O
among O
close O
relatives O
was O
ascertained O
, O
but O
, O
except O
in O
siblings O
, O
this O
was O
not O
significantly O
higher O
than O
would O
be O
expected O
. O

Evidence O
from O
extended O
pedigrees O
, O
however O
, O
indicates O
that O
at O
least O
four O
of O
the O
children O
could O
be O
members O
of O
families O
with O
the O
SBLA O
( O
sarcoma O
, O
breast O
and O
brain O
tumour O
, O
leukaemia O
, O
laryngeal O
and O
lung O
cancer O
, O
and O
adrenal O
cortical O
carcinoma O
) O
cancer O
family O
syndrome O
, O
and O
that O
other O
relatives O
may O
be O
at O
risk O
of O
developing O
such O
neoplasms O
. O

Background O
The O
prevalence B-EPI
of O
developmental O
alterations O
associated O
with O
in O
- O
utero O
Zika O
virus O
( O
ZIKV O
) O
exposure O
in O
children O
is O
not O
well O
understood O
. O

Furthermore O
, O
estimation O
of O
the O
Population O
Attributable O
Fraction O
( O
PAF O
) O
of O
developmental O
alterations O
attributed O
to O
ZIKV O
has O
not O
been O
performed O
due O
to O
lack O
of O
population O
- O
based O
cohorts O
with O
data O
on O
symptomatic O
and O
asymptomatic O
ZIKV O
exposures O
and O
an O
appropriate O
control O
group O
. O

The O
aim O
of O
this O
study O
was O
to O
characterize O
neurodevelopmental O
outcomes O
of O
children O
at O
11 O
to O
32 O
months O
of O
age O
with O
intrauterine O
ZIKV O
exposure O
and O
estimate O
the O
PAF O
of O
alterations O
secondary O
to O
ZIKV O
exposure O
. O

Methodology O
/ O
principal O
findings O
We O
performed O
a O
cohort O
of O
biannual O
community O
- O
based O
prospective O
serosurveys O
in O
a O
slum O
community O
in O
Salvador B-LOC
, I-LOC
Brazil I-LOC
. O

We O
recruited O
women B-SEX
participating O
in O
our O
cohort O
, O
with O
a O
documented O
pregnancy O
from O
January B-DATE
2015 I-DATE
to I-DATE
December I-DATE
2016 I-DATE
and O
children O
born O
to O
those O
mothers O
. O

Children O
were O
classified O
as O
ZIKV O
exposed O
in O
utero O
( O
born O
from O
women B-SEX
with O
ZIKV O
seroconversion O
during O
pregnancy O
) O
or O
unexposed O
( O
born O
from O
women B-SEX
without O
ZIKV O
seroconversion O
or O
that O
seroconverted O
before O
/ O
after O
pregnancy O
) O
by O
using O
an O
IgG O
monoclonal O
antibody O
blockade O
- O
of O
- O
binding O
( O
BoB O
) O
. O

We O
interviewed O
mothers O
and O
performed O
anthropometric O
, O
audiometric O
, O
ophthalmological O
, O
neurologic O
, O
and O
neurodevelopmental O
evaluations O
of O
their O
children O
at O
11 O
to O
32 O
months O
of O
age O
. O

Among O
the O
655 O
women B-SEX
participating O
in O
the O
cohort O
, O
66 O
( O
10 O
% O
) O
were O
pregnant O
during O
the O
study O
period O
. O

46 O
( O
70 O
% O
) O
of O
them O
completed O
follow O
- O
up O
, O
of O
whom O
ZIKV O
seroconversion O
occurred O
before O
, O
during O
, O
and O
after O
pregnancy O
in O
25 O
( O
54 O
% O
) O
, O
13 O
( O
28 O
% O
) O
, O
and O
1 O
( O
2 O
% O
) O
, O
respectively O
. O

The O
rest O
of O
women B-SEX
, O
7 O
( O
21.2 O
% O
) O
, O
did O
not O
present O
ZIKV O
seroconversion O
. O

At O
11 O
to O
32 O
months O
of O
life O
, O
the O
13 O
ZIKV O
- O
exposed O
children O
had O
increased O
risk O
of O
mild O
cognitive O
delay O
( O
RR O
5.1 O
; O
95%CI O
1.1 O
- O
24.4 O
) O
compared O
with O
the O
33 O
children O
unexposed O
, O
with O
a O
PAF O
of O
53.5 O
% O
. O

Exposed O
children O
also O
had O
increased O
risk O
of O
altered O
auditory O
behavior O
( O
RR O
6.0 O
; O
95%CI O
1.3 O
- O
26.9 O
) O
, O
with O
a O
PAF O
of O
59.5 O
% O
. O

Conclusions O
A O
significant O
proportion O
of O
children O
exposed O
in O
utero O
to O
ZIKV O
developed O
mild O
cognitive O
delay O
and O
auditory O
behavioral O
abnormalities O
even O
in O
the O
absence O
of O
gross O
birth O
defects O
such O
as O
microcephaly O
and O
other O
neurodevelopmental O
domains O
. O

Furthermore O
, O
our O
findings O
suggest O
that O
over O
half O
of O
these O
abnormalities O
could O
be O
attributed O
to O
intrauterine O
ZIKV O
exposure O
. O

Cone O
- O
rod O
dystrophy O
( O
CORD O
) O
is O
one O
of O
the O
inherited O
retinal O
diseases O
that O
result O
in O
central O
visual O
field O
deterioration O
and O
decreased O
visual O
acuity O
( O
VA O
) O
. O

In O
CORD O
patients O
, O
impaired O
photoreceptor O
cells O
are O
observed O
as O
the O
disruption O
of O
ellipsoid O
zone O
( O
EZ O
) O
on O
optical O
coherence O
tomography O
( O
OCT O
) O
images O
. O

In O
the O
present O
study O
, O
we O
calculated O
the O
index O
of O
residual O
EZ O
( O
rEZ O
) O
to O
quantify O
the O
function O
of O
photoreceptor O
cells O
and O
investigated O
the O
correlation O
between O
rEZ O
index O
and O
visual O
functions O
. O

Twenty O
- O
six O
eyes O
of O
13 O
patients O
with O
clinical O
suspicion O
of O
CORD O
were O
examined O
. O

Visual O
field O
was O
tested O
with O
the O
Humphrey O
Visual O
Field O
Analyzer O
( O
HFA O
10 O
- O
2 O
program O
) O
. O

We O
simultaneously O
obtained O
OCT O
images O
and O
calculated O
the O
area O
of O
decreased O
EZ O
intensity O
( O
EZa O
) O
. O

Using O
the O
binarized O
OCT O
images O
, O
the O
percentage O
of O
the O
rEZ O
in O
a O
3 O
× O
3 O
mm O
area O
surrounding O
the O
macula O
was O
analyzed O
. O

To O
clarify O
interrator O
reproducibility O
, O
intraclass O
correlation O
coefficient O
( O
ICC O
) O
was O
calculated O
. O

Moreover O
, O
we O
investigated O
the O
association O
between O
OCT O
parameters O
and O
VA O
as O
well O
as O
the O
mean O
deviation O
( O
MD O
) O
value O
measured O
with O
HFA O
. O

The O
mean O
age O
of O
the O
patients O
was O
48.5 O
± O
16.9 O
years O
. O

The O
mean O
central O
retinal O
thickness O
was O
122.7 O
± O
73.2 O
[mu]m O
. O

The O
mean O
EZa O
and O
rEZ O
were O
22.2 O
± O
23.6 O
[mu]m O
2 O
and O
0.35 O
± O
0.31 O
, O
respectively O
. O

The O
ICC O
of O
each O
rEZ O
index O
was O
0.91 O
( O
95 O
% O
CI O
: O
0.89 O
< O
ICC O
< O
0.93 O
) O
. O

Multivariate O
analysis O
indicated O
rEZ O
was O
significantly O
related O
to O
logMAR O
VA O
( O
p O
= O
0.05 O
) O
and O
rEZ O
and O
EZa O
were O
associated O
with O
the O
MD O
value O
( O
p O
= O
0.014 O
and O
p O
= O
0.009 O
, O
linear O
mixed O
model O
) O
. O

Furthermore O
, O
rEZ O
was O
also O
associated O
with O
photopic O
a- O
and O
b O
- O
wave O
amplitudes O
( O
p O
= O
0.027 O
and O
p O
= O
0.0024 O
, O
respectively O
, O
linear O
mixed O
model O
) O
. O

Taken O
together O
, O
the O
current O
results O
suggested O
the O
usefulness O
of O
rEZ O
quantification O
for O
predicting O
visual O
functions O
in O
CORD O
patients O
. O

The O
relationship O
between O
smoking O
and O
illness O
perceptions O
among O
congenital O
heart O
disease O
( O
CHD O
) O
survivors O
is O
unknown O
. O

The O
primary O
aims O
of O
the O
present O
study O
were O
to O
compare O
the O
smoking O
prevalence B-EPI
among O
CHD O
survivors O
to O
a O
nationally O
representative O
U.S. B-LOC
sample O
and O
examine O
the O
relationship O
between O
smoking O
and O
illness O
perceptions O
. O

CHD O
survivors O
( O
N O
= O
744 O
) O
from O
six O
U.S. O
sites O
participated O
in O
the O
study O
. O

The O
smoking O
prevalence B-EPI
among O
CHD O
survivors O
( O
9.3 O
% O
) O
was O
lower O
than O
the O
general O
population O
( O
15.3 O
% O
) O
. O

However O
, O
23.3 O
% O
of O
CHD O
survivors O
with O
severe O
functional O
limitations O
smoked O
. O

Smoking O
prevalence B-EPI
differed O
by O
U.S. O
region O
, O
with O
a O
greater O
proportion O
of O
those O
attending O
CHD O
care O
in O
the O
Midwest O
reporting O
smoking O
( O
11.8 O
% O
) O
. O

The O
illness O
perception O
dimensions O
of O
Concern O
and O
Emotional O
Response O
were O
independently O
associated O
with O
smoking O
. O

Differences O
in O
illness O
perceptions O
enhance O
our O
understanding O
of O
smoking O
among O
CHD O
survivors O
and O
may O
guide O
interventions O
promoting O
positive O
health O
behaviors O
. O

The O
protocol O
for O
the O
study O
from O
which O
the O
present O
analyses O
were O
conducted O
was O
recorded O
at O
ClinicalTrials.gov O
: O
NCT02150603 O
. O

Since O
2013 B-DATE
, O
a O
high O
incidence B-EPI
of O
bilateral O
symmetrical O
alopecia O
has O
been O
observed O
in O
free O
- O
ranging O
Formosan O
macaques O
( O
Macaca O
cyclopis O
) O
in O
Mt. O
Longevity O
, O
Taiwan B-LOC
. O

We O
hypothesized O
that O
stress O
induces O
alopecia O
in O
this O
population O
. O

To O
verify O
our O
hypothesis O
, O
we O
evaluated O
the O
histopathological O
characteristics O
of O
skin O
biopsy O
and O
used O
a O
validated O
enzyme O
immunoassay O
( O
EIA O
) O
for O
fecal O
glucocorticoid O
metabolite O
( O
FGM O
) O
analysis O
, O
which O
act O
as O
an O
indicator O
of O
stress O
experienced O
by O
the O
individual O
. O

Follicular O
densities O
were O
lower O
( O
2.1 O
- O
3.0 O
mm O
2 O
) O
in O
individuals O
with O
symmetrical O
alopecia O
than O
in O
those O
with O
normal O
hair O
conditions O
( O
4.7 O
mm O
2 O
) O
. O

Furthermore O
, O
anagen O
to O
catagen O
/ O
telogen O
ratios O
were O
lower O
in O
individuals O
with O
alopecia O
( O
0 O
- O
1.4 O
) O
than O
in O
those O
with O
normal O
hair O
( O
4.0 O
) O
. O

The O
histopathological O
characteristics O
of O
alopecia O
were O
similar O
to O
those O
of O
telogen O
effluvium O
, O
which O
indicates O
that O
stress O
is O
one O
of O
the O
possible O
etiologies O
. O

On O
the O
basis O
of O
the O
analytical O
and O
biological O
validation O
of O
EIAs O
for O
FGM O
analysis O
, O
11[beta]0 O
- O
hydroxyetiocholanolone O
was O
considered O
suitable O
for O
monitoring O
adrenocortical O
activity O
in O
both O
sexes O
of O
Formosan B-ETHN
macaques O
. O

The O
mean O
concentrations O
( O
standard O
error O
; O
sample O
size O
) O
of O
11[beta]0 O
- O
hydroxyetiocholanolone O
were O
2.02 O
( O
0.17 O
; O
n O
= O
10 O
) O
and O
1.41 O
( O
0.10 O
; O
n O
= O
31 O
) O
[mu]g O
/ O
g O
for O
individuals O
with O
and O
without O
alopecia O
, O
respectively O
. O

Furthermore O
, O
the O
results O
of O
logistic O
regression O
analysis O
show O
that O
11[beta]0 O
- O
hydroxyetiocholanolone O
( O
p O
= O
0.012 O
) O
concentration O
was O
positively O
associated O
with O
alopecia O
. O

Thus O
, O
stress O
was O
the O
most O
likely O
to O
trigger O
symmetrical O
alopecia O
in O
Formosan B-ETHN
macaques O
in O
Mt. O
Longevity O
. O

Although O
stress O
can O
decrease O
the O
fitness O
of O
an O
individual O
, O
considering O
the O
population O
status O
of O
Formosan O
macaques O
in O
Taiwan B-LOC
is O
stable O
and O
alopecia O
was O
only O
observed O
in O
our O
study O
area O
, O
which O
is O
isolated O
from O
other O
populations O
, O
the O
impact O
on O
the O
total O
population O
of O
Formosan O
macaque O
in O
Taiwan B-LOC
is O
limited O
. O

Nonetheless O
, O
stress O
- O
induced O
immunosuppression O
and O
alopecia O
might O
affect O
the O
local O
abundance O
and O
increase O
zoonosis O
risk O
due O
to O
frequent O
human O
- O
macaque O
contact O
in O
Mt. O
Longevity O
. O

Future O
studies O
are O
suggested O
to O
focus O
on O
the O
causative O
factor O
of O
stress O
and O
the O
effects O
of O
stress O
and O
alopecia O
on O
the O
health O
and O
welfare O
in O
the O
Formosan B-ETHN
macaques O
. O

Incidence B-EPI
of O
nontuberculous O
mycobacterial O
infections O
has O
increased O
during O
the O
past O
decades O
. O

Disseminated O
infections O
are O
relatively O
rare O
and O
associated O
with O
immunocompromised O
status O
. O

We O
report O
a O
case O
of O
disseminated O
Mycobacterium O
szulgai O
infection O
of O
cervical O
lymphadenitis O
and O
pulmonary O
involvement O
with O
positive O
anti O
- O
interferon O
- O
gamma O
autoantibodies O
. O

The O
patient O
was O
successfully O
treated O
with O
rifampin O
, O
ethambutol O
, O
and O
clarithromycin O
. O

The O
case O
reports O
and O
series O
through O
search O
engines O
of O
Pubmed O
and O
Google O
with O
the O
keyword O
of O
disseminated O
infection O
of O
M. O
szulgai O
were O
reviewed O
. O

Fifteen O
patients O
of O
disseminated O
M. O
szulgai O
infection O
were O
reviewed O
and O
included O
. O

Disseminated O
M. O
szulgai O
infection O
involves O
bone O
, O
skin O
and O
lymph O
node O
more O
common O
instead O
of O
pulmonary O
involvement O
, O
and O
most O
are O
associated O
with O
immunocompromised O
status O
with O
neoplastic O
hematologic O
disorders O
. O

In O
patients O
with O
disseminated O
M. O
szulgai O
infection O
, O
long O
term O
anti O
- O
mycobacterial O
agents O
are O
necessary O
. O

Most O
patients O
will O
respond O
to O
rifampin O
and O
ethambutol O
combination O
regimens O
. O

Kuwait B-LOC
has O
a O
cosmopolitan B-ETHN
population O
of O
1.7 O
million O
, O
mostly O
Arabs B-ETHN
. O

This O
population O
is O
a O
mosaic O
of O
large O
and O
small O
minorities O
representing O
most O
Arab B-ETHN
communities O
. O

In O
general O
, O
Kuwait B-LOC
's O
population O
is O
characterized O
by O
a O
rapid O
rate O
of O
growth O
, O
large O
family O
size O
, O
high O
rates O
of O
consanguineous O
marriages O
within O
the O
Arab B-ETHN
communities O
with O
low O
frequency O
of O
intermarriage O
between O
them O
, O
and O
the O
presence O
of O
genetic O
isolates O
and O
semi O
- O
isolates O
in O
some O
extended O
families O
and O
Bedouin B-ETHN
tribes O
. O

Genetic O
services O
have O
been O
available O
in O
Kuwait B-LOC
for O
over O
a O
decade O
. O

During O
this O
time O
it O
has O
become O
clear O
that O
Arabs O
have O
a O
high O
frequency O
of O
genetic O
disorders O
, O
and O
in O
particular O
autosomal O
recessive O
traits O
. O

Their O
pattern O
is O
unique O
and O
some O
disorders O
are O
relatively O
common O
. O

Examples O
are O
Bardet O
- O
Biedl O
and O
Meckel O
syndromes O
, O
phenylketonuria O
, O
and O
familial O
Mediterranean O
fever O
. O

A O
relatively O
large O
number O
of O
new O
syndromes O
and O
variants O
have O
been O
delineated O
in O
Kuwait B-LOC
's O
population O
, O
many O
being O
the O
result O
of O
homozygosity O
for O
autosomal O
recessive O
genes O
that O
occurred O
because O
of O
inbreeding O
. O

Some O
of O
these O
syndromes O
have O
subsequently O
been O
found O
in O
other O
parts O
of O
the O
world O
, O
negating O
the O
concept O
of O
the O
private O
syndrome O
. O

This O
paper O
provides O
an O
overview O
of O
autosomal O
recessive O
disorders O
among O
the O
Arabs O
in O
Kuwait B-LOC
from O
a O
personal O
perspective O
and O
published O
studies O
, O
and O
highlights O
the O
need O
for O
genetic O
services O
in O
Arab B-ETHN
countries O
with O
the O
goal O
of O
prevention O
and O
treatment O
of O
genetic O
disorders O
. O

Introduction O
Niemann O
- O
Pick O
type O
C O
( O
NPC O
) O
is O
a O
lysosomal O
storage O
disease O
that O
is O
progressive O
and O
life O
- O
limiting O
, O
with O
an O
estimated B-EPI
incidence I-EPI
of O
1:120,000 B-STAT
live I-STAT
births I-STAT
. O

In O
addition O
to O
systemic O
manifestation O
with O
( O
hepato-)splenomegaly O
, O
there O
are O
a O
number O
of O
neurological O
manifestations O
( O
ataxia O
, O
dysarthria O
, O
dementia O
, O
cataplexy O
, O
epileptic O
seizures O
, O
and O
psychiatric O
disorders O
) O
. O

Characteristic O
is O
vertical O
supranuclear O
gaze O
palsy O
, O
which O
is O
often O
overlooked O
. O

Early O
diagnosis O
and O
start O
of O
therapy O
improve O
quality O
of O
life O
. O

This O
study O
aimed O
to O
characterize O
oculomotor O
dysfunction O
of O
NPC O
patients O
, O
and O
to O
provide O
ophthalmologic O
data O
including O
retinal O
imaging O
. O

Methods O
Eighteen O
patients O
with O
biochemically O
or O
genetically O
diagnosed O
NPC O
completed O
oculomotor O
and O
ophthalmologic O
examination O
. O

Ten O
of O
them O
performed O
saccadometry O
by O
infrared O
based O
video O
- O
oculography O
. O

Saccadic O
parameters O
were O
compared O
to O
100 O
healthy O
controls O
, O
and O
were O
correlated O
with O
clinical O
variables O
. O

Another O
subgroup O
of O
eight O
patients O
received O
optical O
coherence O
tomography O
( O
OCT O
) O
of O
the O
optic O
disc O
and O
the O
macula O
, O
of O
which O
the O
segmented O
layers O
were O
analysed O
using O
a O
crude O
linear O
mixed O
model O
, O
and O
one O
adjusted O
for O
age O
, O
sex O
, O
and O
spherical O
equivalent O
. O

Results O
Saccadometry O
revealed O
slowed O
peak O
velocity O
compared O
to O
controls O
most O
evident O
vertically O
. O

Peak O
velocity O
correlated O
negatively O
with O
SARA O
- O
Score O
, O
but O
correlation O
with O
clinical O
assessment O
of O
saccades O
was O
not O
significant O
. O

Clinical O
features O
in O
the O
assessment O
of O
vertical O
saccades O
were O
intensive O
blinking O
and O
head O
movements O
to O
initiate O
gaze O
changes O
, O
and O
lateral O
trajectory O
of O
the O
eyes O
. O

Macular O
OCT O
revealed O
significant O
total O
retinal O
thinning O
in O
the O
fovea O
, O
specifically O
of O
the O
outer O
nuclear O
layer O
and O
outer O
retinal O
layer O
. O

Para- O
and O
perifoveal O
retinal O
thicknesses O
, O
as O
well O
as O
peripapillary O
retinal O
nerve O
fibre O
layer O
were O
normal O
. O

Conclusions O
Foveal O
thinning O
was O
revealed O
in O
NPC O
. O

It O
remains O
to O
be O
shown O
, O
whether O
OCT O
will O
prove O
to O
be O
useful O
to O
monitor O
progression O
. O

Saccadic O
impairment O
reflects O
CNS O
involvement O
and O
therefore O
is O
a O
parameter O
to O
demonstrate O
the O
progression O
of O
NPC O
, O
and O
potentially O
also O
the O
efficacy O
of O
new O
therapies O
. O

Saccadometry O
, O
in O
contrast O
to O
clinical O
investigation O
, O
allows O
the O
precise O
evaluation O
of O
saccades O
. O

Summary O
Emerging O
and O
re O
- O
emerging O
infectious O
disease O
in O
otorhinolaryngology O
( O
ENT O
) O
are O
an O
area O
of O
growing O
epidemiological O
and O
clinical O
interest O
. O

The O
aim O
of O
this O
section O
is O
to O
comprehensively O
report O
on O
the O
epidemiology O
of O
key O
infectious O
disease O
in O
otorhinolaryngology O
, O
reporting O
on O
their O
burden O
at O
the O
national O
and O
international O
level O
, O
expanding O
of O
the O
need O
of O
promoting O
and O
implementing O
preventive O
interventions O
, O
and O
the O
rationale O
of O
applying O
evidence O
- O
based O
, O
effective O
and O
cost- O
effective O
diagnostic O
, O
curative O
and O
preventive O
approaches O
. O

In O
particular O
, O
we O
focus O
on O
i O
) O
ENT O
viral O
infections O
( O
HIV O
, O
Epstein O
- O
Barr O
virus O
, O
Human O
Papilloma O
virus O
) O
, O
retrieving O
the O
available O
evidence O
on O
their O
oncogenic O
potential O
; O
ii O
) O
typical O
and O
atypical O
mycobacteria O
infections O
; O
iii O
) O
non O
- O
specific O
granulomatous O
lymphadenopathy O
; O
iv O
) O
emerging O
paediatric O
ENT O
infectious O
diseases O
and O
the O
prevention O
of O
their O
complications O
; O
v O
) O
the O
growing O
burden O
of O
antimicrobial O
resistance O
in O
ENT O
and O
the O
strategies O
for O
its O
control O
in O
different O
clinical O
settings O
. O

We O
conclude O
by O
outlining O
knowledge O
gaps O
and O
action O
needed O
in O
ENT O
infectious O
diseases O
research O
and O
clinical O
practice O
and O
we O
make O
references O
to O
economic O
analysis O
in O
the O
field O
of O
ENT O
infectious O
diseases O
prevention O
and O
care O
. O

Background O
The O
prevalence B-EPI
of O
metabolic O
disease O
in O
Nepal B-LOC
is O
largely O
unknown B-STAT
. O

Some O
consideration O
has O
been O
given O
by O
the O
nepalese B-ETHN
government O
for O
high O
prevalence B-EPI
of O
congenital O
disorders O
in O
some O
populations O
, O
but O
disorders O
due O
to O
enzymatic O
deficiencies O
have O
not O
been O
considered O
as O
a O
class O
of O
diseases O
where O
timely O
diagnosis O
and O
intervention O
might O
be O
possible O
. O

No O
case O
for O
these O
disorders O
has O
been O
made O
so O
far O
, O
however O
, O
findings O
of O
many O
rare O
metabolic O
diseases O
have O
been O
reported O
in O
literature O
by O
the O
nepalese B-ETHN
medical O
fraternity O
. O

Methods O
A O
search O
for O
case O
reports O
on O
metabolic O
disorders O
listed O
according O
to O
International O
Classification O
of O
Diseases O
-11 O
was O
performed O
using O
the O
google O
search O
engine O
. O

Results O
A O
total O
of O
443 O
cases O
have O
been O
discovered O
presented O
in O
the O
literature O
. O

This O
does O
not O
include O
disorders O
that O
might O
be O
due O
to O
lifestyle O
and O
behaviour O
. O

Most O
of O
the O
reported O
cases O
have O
been O
identified O
based O
on O
clinical O
acumen O
, O
radiological O
and O
histopathological O
findings O
. O

Conclusions O
Glucose O
6 O
phosphate O
dehydrogenase O
deficiency O
, O
Wilson O
's O
disease O
and O
lysosomal O
disorders O
should O
be O
considered O
for O
early O
diagnosis O
through O
newborn O
screening O
along O
with O
the O
acknowledged O
disorders O
hypothyroidism O
and O
hemoglobinopathies O
in O
Nepal O
. O

Early O
intervention O
in O
these O
disorders O
can O
significantly O
reduce O
morbidity O
and O
mortality O
in O
infancy O
. O

Rare O
diseases O
are O
usually O
genetic O
, O
chronic O
and O
incurable O
disorders O
with O
a O
relatively O
low O
incidence B-EPI
. O

Developments O
in O
the O
diagnosis O
and O
management O
of O
rare O
diseases O
have O
been O
relatively O
slow O
due O
to O
a O
lack O
of O
sufficient O
profit O
motivation O
and O
market O
to O
attract O
research O
by O
companies O
. O

However O
, O
due O
to O
the O
attention O
of O
government O
and O
society O
as O
well O
as O
economic O
development O
, O
rare O
diseases O
have O
been O
gradually O
become O
an O
increasing O
concern O
. O

As O
several O
dental O
- O
craniofacial O
manifestations O
are O
associated O
with O
rare O
diseases O
, O
we O
summarize O
them O
in O
this O
study O
to O
help O
dentists O
and O
oral O
maxillofacial O
surgeons O
provide O
an O
early O
diagnosis O
and O
subsequent O
management O
for O
patients O
with O
these O
rare O
diseases O
. O

Osteoporosis O
, O
characterized O
by O
reduced O
bone O
mass O
and O
increased O
bone O
fragility O
, O
is O
a O
disease O
prevalent B-EPI
in O
women B-SEX
. O

Likewise O
, O
breast O
cancer O
is O
a O
multifactorial O
disease O
and O
considered O
the O
major O
cause O
of O
mortality O
in O
premenopausal O
and O
postmenopausal O
women B-SEX
worldwide B-LOC
. O

Our O
data O
demonstrated O
the O
association O
of O
the O
MYLK O
gene O
and O
PTGS1 O
gene O
variants O
with O
osteoporosis O
and O
benign O
breast O
tumor O
risk O
and O
the O
impact O
of O
ovariectomy O
on O
osteoporosis O
in O
Korean B-ETHN
women B-SEX
. O

We O
performed O
a O
genome O
- O
wide O
association O
study O
( O
GWAS O
) O
of O
women B-SEX
with O
osteoporosis O
and O
benign O
breast O
tumors O
. O

There O
were O
60 O
single O
nucleotide O
polymorphisms O
( O
SNPs O
) O
and O
12 O
SNPs O
in O
the O
MYLK O
and O
PTGS1 O
genes O
, O
associated O
with O
benign O
breast O
tumors O
and O
osteoporosis O
. O

Our O
study O
showed O
that O
women B-SEX
with O
homozygous O
MYLK O
rs12163585 O
major O
alleles O
had O
an O
increased O
risk O
of O
osteoporosis O
following O
ovariectomy O
compared O
to O
those O
with O
minor O
alleles O
. O

Women B-SEX
carrying O
the O
minor O
PTGS1 O
rs1213265 O
allele O
and O
not O
treated O
via O
ovariectomy O
carried O
a O
higher O
risk O
of O
osteoporosis O
than O
those O
who O
underwent O
ovariectomy O
with O
a O
homozygous O
genotype O
at O
the O
major O
alleles O
. O

Our O
results O
suggest O
that O
both O
the O
MYLK O
and O
PTGS1 O
genes O
are O
genetic O
factors O
associated O
with O
the O
phenotypes O
, O
and O
these O
associations O
appear O
to O
be O
modulated O
by O
ovariectomy O
. O

Transient O
congenital O
hypothyroidism O
( O
CH O
) O
refers O
to O
a O
temporary O
deficiency O
of O
thyroid O
hormone O
identified O
after O
birth O
, O
with O
low O
thyroxine O
( O
T4 O
) O
and O
elevated O
thyrotropin O
( O
TSH O
) O
, O
which O
later O
recovers O
to O
improved O
thyroxine O
production O
, O
typically O
in O
first O
few O
months O
of O
infancy O
. O

Approximately O
17 O
% O
to O
40 O
% O
of O
children O
diagnosed O
with O
CH O
by O
newborn O
screening O
( O
NBS O
) O
programs O
were O
later O
determined O
to O
have O
transient O
hypothyroidism O
. O

Causes O
of O
transient O
CH O
are O
prematurity O
, O
iodine O
deficiency O
, O
maternal O
thyrotropin O
receptor O
blocking O
antibodies O
, O
maternal O
intake O
of O
anti O
- O
thyroid O
drugs O
, O
maternal O
or O
neonatal O
iodine O
exposure O
, O
loss O
of O
function O
mutations O
and O
hepatic O
hemangiomas O
. O

The O
classic O
clinical O
symptoms O
and O
signs O
of O
CH O
are O
usually O
absent O
immediately O
after O
birth O
in O
vast O
majority O
of O
infants O
due O
to O
temporary O
protection O
from O
maternal O
thyroxine O
. O

NBS O
has O
been O
largely O
successful O
in O
preventing O
intellectual O
disability O
by O
early O
detection O
of O
CH O
by O
performing O
thyroid O
function O
tests O
in O
infants O
with O
abnormal O
screening O
results O
. O

In O
this O
review O
we O
present O
the O
evidence O
for O
decision O
making O
regarding O
treatment O
vs. O
withholding O
treatment O
in O
infants O
with O
transient O
CH O
and O
present O
a O
rational O
approach O
to O
identifying O
transient O
CH O
based O
on O
American B-ETHN
Academy O
of O
Pediatrics O
( O
AAP O
) O
recommendation O
. O

Orthostatic O
tremor O
is O
a O
rare O
condition O
, O
though O
its O
exact B-EPI
prevalence B-EPI
is O
unknown B-STAT
, O
which O
is O
clinically O
characterized O
by O
a O
feeling O
of O
unsteadiness O
or O
being O
about O
to O
fall O
on O
standing O
and O
which O
disappears O
on O
walking O
, O
sitting O
, O
or O
lying O
down O
. O

It O
is O
generally O
accepted O
that O
classic O
orthostatic O
tremor O
manifests O
with O
a O
high O
- O
frequency O
tremor O
( O
> O
13 O
Hz O
) O
of O
the O
legs O
when O
standing O
. O

However O
, O
a O
number O
of O
patients O
initially O
reported O
as O
orthostatic O
tremor O
did O
not O
actually O
have O
such O
electrophysiological O
features O
. O

It O
is O
our O
experience O
that O
there O
is O
a O
clinical O
spectrum O
of O
different O
conditions O
presenting O
as O
shaking O
on O
standing O
, O
and O
this O
highlights O
the O
importance O
of O
the O
electrophysiology O
to O
aid O
the O
differential O
diagnosis O
of O
these O
disorders O
. O

Here O
, O
we O
provide O
a O
critical O
review O
of O
the O
clinical O
spectrum O
of O
shaking O
on O
standing O
, O
along O
with O
demonstrative O
electrophysiological O
recordings O
of O
some O
of O
these O
conditions O
. O

The O
number O
of O
patients O
with O
spinocerebellar O
degeneration O
( O
SCD O
) O
has O
recently O
exceeds O
20,000 O
in O
Japan B-LOC
. O

Among O
them O
, O
sporadic O
form O
is O
the O
most O
common O
form O
( O
67.2 O
% O
) O
. O

Among O
the O
hereditary O
forms O
of O
SCD O
, O
autosomal O
dominant O
( O
AD O
) O
form O
comprises O
27.0 O
% O
, O
while O
autosomal O
recessive O
( O
AR O
) O
form O
is O
rare O
( O
1.8 O
% O
) O
. O

Because O
of O
the O
rare O
occurrence B-EPI
of O
AR O
- O
SCD O
, O
the O
molecular O
genetic O
studies O
have O
been O
difficult O
to O
conduct O
. O

Recent O
progresses O
in O
molecular O
genetics O
, O
however O
, O
have O
enabled O
identification O
of O
causative O
genes O
for O
the O
majority O
of O
AR O
- O
SCD O
. O

Although O
Friedreich O
's O
ataxia O
is O
the O
most O
representative O
form O
of O
AR O
- O
SCD O
, O
patients O
with O
molecular O
diagnosis O
of O
Friedreich O
's O
ataxia O
have O
not O
been O
described O
in O
the O
Japanese B-ETHN
population O
. O

Among O
the O
various O
forms O
of O
AR O
- O
SCD O
, O
early O
- O
onset O
ataxia O
with O
ocular O
motor O
apraxia O
and O
hypoalbuminemia O
( O
EAOH O
) O
seems O
to O
be O
the O
most O
common O
form O
in O
the O
Japanese B-ETHN
population O
. O

Aprataxin O
, O
the O
causative O
gene O
for O
EAOH O
, O
has O
been O
suggested O
to O
play O
a O
role O
in O
the O
single O
strand O
DNA O
break O
repair O
. O

Interestingly O
, O
abnormalities O
in O
DNA O
break O
repair O
processes O
have O
been O
implicated O
in O
several O
forms O
of O
AR O
- O
SCD O
including O
AOA2 O
, O
SCAN1 O
and O
ataxia O
telangiectasia O
. O

In O
this O
group O
of O
AR O
- O
SCD O
, O
cerebellar O
atrophy O
is O
more O
marked O
compared O
to O
that O
observed O
in O
Friedreich O
's O
ataxia O
. O

Taken O
together O
, O
abnormalities O
in O
DNA O
break O
repair O
processes O
may O
play O
an O
essential O
role O
in O
cerebellar O
degeneration O
in O
this O
group O
of O
AR O
- O
SCD O
. O

Background O
Acute O
colonic O
pseudo O
- O
obstruction O
( O
ACPO O
) O
or O
Ogilvie O
's O
syndrome O
occurs B-EPI
in O
0.22%-7 O
% O
of O
patients O
undergoing O
surgery O
, O
with O
a O
mortality O
of O
up O
to O
46 O
% O
. O

ACPO O
increased O
median O
hospital O
days O
versus O
control O
in O
spinal O
surgery O
( O
14 O
vs. O
6 O
days O
; O
P O
< O
0.001 O
) O
. O

If O
defined O
as O
postoperative O
ileus O
, O
the O
incidence B-EPI
was O
7%-13.4 B-STAT
% I-STAT
. O

Postoperative O
ileus O
is O
associated O
with O
2.9 O
additional O
hospital O
days O
and O
an O
$ O
80,000 O
increase O
in O
cost O
per O
patient O
. O

We O
present O
a O
case O
of O
ACPO O
in O
an O
adult O
patient O
undergoing O
spinal O
fusion O
for O
correction O
of O
scoliosis O
and O
review O
the O
available O
literature O
to O
outline O
clinical O
characteristics O
and O
surgical O
outcomes O
. O

Case O
description O
The O
patient O
was O
a O
31 O
- O
year O
- O
old O
woman B-SEX
with O
untreated O
advanced O
scoliosis O
with O
no O
history O
of O
neurologic O
issues O
. O

T2 O
- O
L3 O
spinal O
instrumentation O
and O
fusion O
was O
completed O
. O

Plain O
abdominal O
radiography O
showed O
of O
dilated O
cecum O
11 O
cm O
and O
the O
department O
of O
general O
surgery O
was O
consulted O
. O

Neostigmine O
administration O
was O
planned O
after O
conservative O
treatment O
failure O
after O
transfer O
to O
the O
intensive O
care O
unit O
. O

The O
patient O
was O
discharged O
home O
with O
no O
recurrence O
> O
60 O
days O
. O

Thirty O
cases O
were O
found O
in O
our O
literature O
review O
using O
PubMed O
and O
Embase O
databases O
and O
summarized O
. O

Conclusions O
Of O
30 O
cases O
reviewed O
, O
only O
3 O
cases O
of O
ACPO O
were O
specific O
to O
patients O
undergoing O
spinal O
fusion O
for O
scoliosis O
. O

According O
to O
the O
literature O
, O
20 O
% O
of O
patients O
had O
resolution O
with O
conservative O
treatment O
, O
40 O
% O
with O
neostigmine O
, O
and O
30 O
% O
with O
surgical O
intervention O
. O

Other O
noninvasive O
treatments O
may O
have O
similar O
efficacy O
in O
preventing O
complications O
leading O
to O
surgical O
invention O
. O

Sixty O
clinical O
trials O
and O
9 O
systematic O
reviews O
were O
summarized O
with O
an O
updated O
management O
algorithm O
. O

Background O
/ O
aims O
Pseudohypoparathyroidism O
type O
1a O
( O
PHP1a O
) O
is O
a O
rare O
genetic O
disorder O
. O

This O
study O
aimed O
to O
determine O
the O
prevalence B-EPI
of O
sleep O
apnea O
in O
children O
with O
PHP1a O
. O

Methods O
Nineteen O
patients O
with O
PHP1a O
between O
the O
age O
of O
2 O
and O
21 O
years O
were O
enrolled O
prospectively O
using O
online O
advertisements O
. O

Parents O
completed O
a O
medical O
history O
and O
surveys O
to O
assess O
sleep O
behavior O
. O

Polysomnography O
records O
were O
obtained O
when O
available O
. O

In O
addition O
, O
18 O
subjects O
were O
identified O
in O
a O
retrospective O
chart O
review O
of O
de O
- O
identified O
medical O
records O
with O
2.3 O
million O
patient O
charts O
. O

Results O
Parents O
reported O
sleep O
disturbance O
( O
94 O
% O
) O
and O
daytime O
somnolence O
( O
81 O
% O
) O
in O
their O
children O
with O
PHP1a O
. O

In O
the O
retrospective O
chart O
review O
, O
39 O
% O
had O
a O
history O
of O
sleep O
apnea O
versus O
8.8 O
% O
of O
a O
similarly O
obese O
control O
group O
. O

In O
the O
combined O
analysis O
( O
n O
= O
31 O
) O
, O
52 O
% O
had O
a O
history O
of O
snoring O
and O
45 O
% O
had O
a O
diagnosis O
of O
sleep O
apnea O
. O

Patients O
were O
obese O
with O
a O
mean O
BMI O
z O
- O
score O
of O
2.20 O
± O
0.59 O
. O

Patients O
with O
sleep O
apnea O
were O
significantly O
younger O
than O
those O
without O
a O
diagnosis O
( O
8.1 O
± O
5.4 O
vs. O
12.8 O
± O
5.0 O
years O
, O
p O
= O
0.02 O
) O
. O

Conclusions O
Children O
with O
PHP1a O
have O
a O
4.4 O
- O
fold O
greater O
relative O
risk O
of O
sleep O
apnea O
than O
similarly O
obese O
children O
. O

Screening O
for O
sleep O
apnea O
in O
this O
population O
may O
be O
warranted O
to O
prevent O
adverse O
health O
outcomes O
. O

Background O
Methylmalonic O
acidemia O
( O
MMA O
) O
and O
propionic O
acidemia O
( O
PA O
) O
are O
two O
kinds O
of O
diseases O
caused O
by O
inborn O
errors O
of O
metabolism O
. O

So O
far O
, O
the O
epidemiological O
data O
on O
them O
are O
limited O
in O
China B-LOC
. O

The O
aim O
of O
our O
study O
is O
to O
investigate O
the O
proportion O
and O
characteristics O
of O
hospitalized O
pediatric O
patients O
with O
MMA O
and O
PA O
in O
China B-LOC
. O

Methods O
The O
data O
in O
this O
study O
were O
obtained O
from O
the O
Hospital O
Quality O
Monitoring O
System O
, O
a O
national O
inpatient O
database O
in O
China B-LOC
, O
with O
information O
on O
the O
patients O
hospitalized O
during O
the O
period O
from O
2013 B-DATE
to I-DATE
2017 I-DATE
. O

We O
identified O
the O
data O
related O
to O
the O
patients O
who O
were O
under O
18 O
years O
old O
and O
were O
diagnosed O
with O
MMA O
/ O
PA O
, O
and O
extracted O
the O
information O
on O
demographic O
characteristics O
, O
hospital O
location O
, O
total O
cost O
and O
other O
related O
clinical O
presentations O
from O
the O
data O
. O

Results O
Among O
all O
hospitalized O
pediatric O
patients O
with O
liver O
diseases O
, O
there O
were O
increasing O
trends O
in O
the O
proportion O
of O
individuals O
diagnosed O
with O
MMA O
or O
PA O
during O
the O
period O
from O
2013 B-DATE
( O
0.76 O
% O
for O
MMA O
; O
0.13 O
% O
for O
PA O
) O
to I-DATE
2017 I-DATE
( O
1.61 O
% O
for O
MMA O
; O
0.32 O
% O
for O
PA O
) O
. O

For O
both O
MMA O
and O
PA O
, O
children O
under O
2 O
- O
year O
- O
old O
accounted O
for O
the O
highest O
proportion O
. O

The O
median O
of O
total O
cost O
per O
hospitalization O
was O
relatively O
high O
( O
RMB O
7388.53 O
for O
MMA O
; O
RMB O
4999.66 O
for O
PA O
) O
. O

Moreover O
, O
most O
patients O
hospitalized O
in O
tertiary O
class O
A O
hospitals O
( O
MMA O
: O
80.96 O
% O
, O
PA O
: O
76.21 O
% O
) O
; O
and O
a O
majority O
of O
pediatric O
patients O
admitted O
in O
the O
hospitals O
in O
Shanghai B-LOC
and O
Beijing B-LOC
are O
from O
outside O
districts O
. O

Manifestations O
of O
nervous O
system O
- O
related O
symptoms O
, O
and O
metabolic O
acidosis O
or O
anemia O
in O
laboratory O
findings O
were O
more O
common O
during O
hospitalization O
. O

Conclusions O
The O
study O
is O
the O
first O
nationwide O
one O
in O
providing O
epidemiological O
and O
clinical O
information O
on O
hospitalized O
pediatric O
patients O
with O
MMA O
/ O
PA O
. O

An O
increasing O
hospitalization O
with O
various O
presentations O
and O
a O
heavy O
financial O
burden O
were O
observed O
. O

In O
addition O
, O
geographically O
, O
the O
medical O
resources O
in O
China B-LOC
have O
been O
unevenly O
distributed O
. O

Objective O
This O
study O
was O
undertaken O
to O
measure O
the O
incidence B-EPI
and O
prevalence B-EPI
of O
active O
psychogenic O
nonepileptic O
seizures O
( O
PNES O
) O
in O
a O
Norwegian B-ETHN
county I-LOC
. O

Methods O
Using O
the O
Norwegian B-ETHN
patient O
registry O
, O
we O
identified O
patients O
in O
Møre B-LOC
and I-LOC
Romsdal I-LOC
County I-LOC
in O
Norway B-LOC
diagnosed O
with O
F44.5 O
( O
conversion O
disorder O
with O
seizures O
or O
convulsions O
) O
or O
R56.8 O
( O
convulsions O
, O
not O
elsewhere O
classified O
) O
in O
the O
period O
January B-DATE
2010 I-DATE
to I-DATE
January I-DATE
2020 I-DATE
. O

A O
review O
of O
the O
patients O
' O
medical O
records O
and O
an O
assessment O
of O
diagnostic O
validity O
were O
performed O
. O

PNES O
were O
diagnosed O
according O
to O
the O
recommendations O
by O
the O
International O
League O
Against O
Epilepsy O
Nonepileptic O
Seizures O
Task O
Force O
. O

Point B-EPI
prevalence I-EPI
of O
PNES O
on O
January B-DATE
1 I-DATE
, I-DATE
2020 I-DATE
and O
incidence B-EPI
rates I-EPI
for O
the O
period O
2010 B-DATE
- I-DATE
2019 I-DATE
were O
determined O
. O

Results O
Based O
on O
PNES O
within O
the O
past O
5 O
years O
, O
we O
found O
a O
PNES O
prevalence B-EPI
of O
23.8/100000 B-STAT
( O
95 O
% O
confidence O
interval O
[ O
CI O
] O
= O
17.9 O
- O
29.6 O
) O
, O
including O
all O
levels O
of O
diagnostic O
certainty O
. O

For O
the O
highest O
level O
of O
diagnostic O
certainty O
( O
video O
- O
electroencephalographically O
confirmed O
) O
, O
the O
prevalence B-EPI
was O
10.6/100000 B-STAT
( O
95 O
% O
CI O
= O
6.7 O
- O
14.5 O
) O
. O

The O
highest O
prevalence B-EPI
was O
found O
in O
the O
age O
group O
15 O
- O
19 O
years O
, O
at O
59.5/100000 B-STAT
( O
95 O
% O
CI O
= O
22.6 O
- O
96.3 O
) O
. O

The O
mean O
annual B-EPI
incidence I-EPI
rate I-EPI
between B-DATE
2010 I-DATE
and I-DATE
2019 I-DATE
was O
3.1/100000 B-STAT
/ I-STAT
year I-STAT
( O
95 O
% O
CI O
= O
2.4 O
- O
3.7 O
) O
. O

Significance O
We O
report O
for O
the O
first O
time O
a O
population O
- O
based O
estimate O
of O
the O
prevalence B-EPI
of O
PNES O
. O

Our O
findings O
suggest O
that O
the O
prevalence B-EPI
of O
PNES O
is O
within O
the O
range O
of O
estimates O
from O
non O
- O
population O
- O
based O
data O
. O

We O
found O
a O
strikingly O
high O
prevalence B-EPI
of O
PNES O
in O
the O
15 O
- O
19 O
- O
year O
age O
group O
. O

With O
increasing O
maternal O
age O
in O
this O
decade O
, O
there O
is O
a O
parallel O
rise O
in O
the O
number O
of O
pregnant O
and O
lactating O
women B-SEX
affected O
by O
glaucoma O
worldwide B-LOC
. O

Understanding O
the O
diagnosis O
and O
management O
of O
glaucoma O
during O
pregnancy O
and O
lactation O
is O
essential O
to O
preventing O
blindness O
from O
glaucoma O
in O
this O
vulnerable O
population O
. O

This O
report O
provides O
a O
review O
of O
the O
current O
literature O
and O
offers O
effective O
strategies O
that O
will O
overcome O
the O
challenges O
in O
managing O
glaucoma O
during O
pregnancy O
and O
lactation O
. O

Practically O
, O
glaucoma O
management O
during O
pregnancy O
and O
lactation O
presents O
a O
unique O
challenge O
for O
the O
physician O
, O
as O
the O
benefit O
of O
any O
treatment O
must O
be O
weighed O
against O
the O
potential O
risks O
to O
the O
fetus O
. O

Prior O
to O
initiating O
or O
continuing O
treatment O
, O
the O
physician O
should O
be O
familiar O
with O
the O
various O
treatment O
options O
to O
manage O
intraocular O
pressure O
during O
pregnancy O
and O
lactation O
, O
including O
the O
safety O
of O
various O
anti O
- O
glaucoma O
medications O
as O
supported O
by O
the O
existing O
literature O
and O
based O
on O
the O
food O
and O
drug O
administration O
guidelines O
. O

A O
collaborative O
team O
effort O
between O
the O
ophthalmologist O
, O
obstetrician O
, O
and O
neonatologist O
in O
high O
- O
risk O
pregnancies O
is O
recommended O
to O
optimize O
care O
for O
the O
mother O
and O
fetus O
. O

Background O
The O
incidence B-EPI
of O
contralateral O
occult O
hernia O
( O
COH O
) O
varies O
from O
4.2 O
% O
to I-STAT
57.5 O
% O
. O

Total O
extraperitoneal O
( O
TEP O
) O
gives O
us O
opportunity O
to O
visualize O
contralateral O
groin O
for O
occult O
hernia O
and O
its O
simultaneous O
repair O
. O

Ultrasonography O
( O
USG O
) O
helps O
to O
diagnose O
occult O
hernia O
preoperatively O
with O
detection O
rate O
of O
96.6 O
% O
with O
specificity O
84.4 O
% O
. O

Objective O
The O
aims O
of O
this O
study O
were O
to O
identify O
the O
incidence B-EPI
of O
contralateral O
occult O
inguinal O
hernia O
in O
clinically O
diagnosed O
unilateral O
inguinal O
hernia O
patients O
using O
USG O
as O
diagnostic O
modality O
and O
to O
compare O
the O
clinical O
outcomes O
of O
unilateral O
TEP O
vs. O
bilateral O
TEP O
with O
respect O
to O
pain O
, O
duration O
of O
hospital O
stay O
, O
time O
for O
return O
to O
normal O
work O
, O
and O
postoperative O
complications O
. O

Setting O
and O
design O
This O
was O
a O
prospective O
observational O
, O
single O
- O
center O
study O
. O

Materials O
and O
methods O
A O
total O
of O
30 O
male B-SEX
patients O
were O
included O
in O
the O
study O
who O
was O
having O
clinically O
diagnosed O
unilateral O
hernia O
. O

All O
patients O
were O
assessed O
by O
USG O
for O
contralateral O
occult O
inguinal O
hernia O
. O

Results O
Incidence B-EPI
of O
COH O
was O
10 O
% O
, O
two O
( O
6.7 O
% O
) O
had O
indirect O
defect O
, O
and O
1 O
( O
3.3 O
% O
) O
had O
direct O
defect O
. O

Two O
( O
6.7 O
% O
) O
patients O
underwent O
bilateral O
TEP O
and O
28 O
( O
93.3 O
% O
) O
underwent O
unilateral O
TEP O
. O

No O
significant O
difference O
was O
observed O
in O
terms O
of O
mean O
duration O
of O
hospital O
stay O
, O
duration O
of O
surgery O
, O
and O
visual O
analog O
scale O
score O
for O
pain O
in O
both O
unilateral O
and O
bilateral O
TEP O
. O

The O
mean O
for O
resuming O
daily O
work O
in O
unilateral O
TEP O
was O
4.86 O
± O
0.833 O
days O
and O
in O
bilateral O
TEP O
the O
mean O
was O
7.50 O
± O
0.70 O
days O
and O
this O
showed O
statistically O
significant O
difference O
( O
P O
< O
0.001 O
) O
. O

Conclusion O
Patients O
with O
COH O
should O
be O
counselled O
for O
synchronous O
repair O
as O
there O
is O
no O
significant O
difference O
in O
clinical O
outcomes O
of O
unilateral O
and O
bilateral O
TEP O
. O

On O
the O
basis O
of O
this O
pilot O
study O
, O
it O
can O
be O
concluded O
that O
preoperative O
USG O
is O
mandatory O
for O
diagnosis O
and O
simultaneous O
management O
of O
preexisting O
contralateral O
hernia O
. O

Autosomal O
dominant O
cerebellar O
ataxia O
type O
I O
is O
a O
heterogeneous O
group O
of O
spinocerebellar O
ataxias O
with O
variable O
neurologic O
presentations O
, O
with O
age O
of O
onset O
varying O
from O
infancy O
to O
adulthood O
. O

Autosomal O
dominant O
cerebellar O
ataxia O
type O
I O
is O
composed O
mainly O
of O
3 O
prevalent B-EPI
spinocerebellar O
ataxia O
types O
with O
different O
pathogenic O
loci O
, O
specifically O
spinocerebellar O
ataxia O
1 O
( O
6p24 O
- O
p23 O
) O
, O
spinocerebellar O
ataxia O
2 O
( O
12q24.1 O
) O
, O
and O
spinocerebellar O
ataxia O
3 O
( O
14q32.1 O
) O
. O

The O
shared O
pathogenic O
mutational O
event O
is O
the O
expansion O
of O
the O
CAG O
repeat O
that O
results O
in O
polyglutamine O
extended O
stretches O
in O
the O
encoded O
proteins O
. O

CAG O
repeat O
disorders O
generally O
show O
the O
phenomenon O
of O
anticipation O
, O
which O
is O
more O
often O
associated O
with O
paternal O
transmission O
. O

In O
this O
report O
, O
we O
describe O
a O
patient O
with O
infantile O
- O
onset O
spinocerebellar O
ataxia O
type O
2 O
( O
~320 O
CAG O
repeat O
) O
who O
inherited O
the O
disease O
from O
his O
father O
( O
47 O
CAG O
repeats O
) O
. O

We O
have O
summarized O
the O
clinical O
, O
neuroimaging O
, O
electroencephalographic O
( O
EEG O
) O
, O
and O
molecular O
data O
of O
previous O
cases O
and O
attempt O
to O
highlight O
the O
most O
consistent O
findings O
. O

Our O
intent O
is O
to O
help O
treating O
clinicians O
to O
suspect O
this O
disorder O
and O
to O
offer O
timely O
genetic O
counseling O
for O
a O
currently O
potentially O
untreatable O
disorder O
. O

Intellectual O
disability O
( O
ID O
) O
has O
an O
estimated B-EPI
prevalence I-EPI
of O
1.5%-2 B-STAT
% I-STAT
. O

Whole O
exome O
sequencing O
( O
WES O
) O
studies O
have O
identified O
a O
multitude O
of O
novel O
causative O
gene O
defects O
and O
have O
shown O
that O
sporadic O
ID O
cases O
result O
from O
de O
novo O
mutations O
in O
genes O
associated O
with O
ID O
. O

Here O
, O
we O
report O
on O
a O
10 O
- O
year O
- O
old O
girl B-SEX
, O
who O
has O
been O
regularly O
presented O
in O
our O
neuropediatric O
and O
genetic O
outpatient O
clinic O
. O

A O
median O
cleft O
palate O
and O
a O
heart O
defect O
were O
surgically O
corrected O
in O
infancy O
. O

Apart O
from O
ID O
, O
she O
has O
behavioral O
anomalies O
, O
muscular O
hypotonia O
, O
scoliosis O
, O
and O
hypermobile O
joints O
. O

The O
facial O
phenotype O
is O
characterized O
by O
arched O
eyebrows O
, O
mildly O
upslanting O
long O
palpebral O
fissures O
, O
prominent O
nasal O
tip O
, O
and O
large O
, O
protruding O
ears O
. O

Trio O
WES O
revealed O
a O
de O
novo O
missense O
variant O
in O
MEIS2 O
( O
c.998G O
> O
A O
; O
p. O
Arg333Lys O
) O
. O

Haploinsufficiency O
of O
MEIS2 O
had O
been O
discussed O
as O
the O
most O
likely O
mechanism O
of O
the O
microdeletion O
5q14 O
- O
associated O
complex O
phenotype O
with O
ID O
, O
cleft O
palate O
, O
and O
heart O
defect O
. O

Recently O
, O
four O
studies O
including O
in O
total O
17 O
individuals O
with O
intragenic O
MEIS2 O
variants O
were O
reported O
. O

Here O
we O
present O
the O
evolution O
of O
the O
clinical O
phenotype O
and O
compare O
with O
the O
data O
of O
known O
individuals O
. O

Background O
Given O
recent O
reports O
of O
percutaneous O
closure O
of O
sinus O
venosus O
atrial O
septal O
defects O
, O
we O
reviewed O
our O
experience O
with O
surgical O
repair O
. O

Owing O
to O
the O
high O
incidence B-EPI
of O
arrhythmias O
with O
the O
two O
- O
patch O
technique O
, O
since O
2001 B-DATE
we O
have O
used O
either O
one O
- O
patch O
repairs O
or O
the O
Warden O
procedure O
. O

Methods O
A O
retrospective O
review O
was O
performed O
of O
pediatric O
patients O
undergoing O
sinus O
venosus O
atrial O
septal O
defect O
repair O
at O
our O
institution O
from O
January B-DATE
1 I-DATE
, I-DATE
1990 I-DATE
, I-DATE
to I-DATE
July I-DATE
1 I-DATE
, I-DATE
2018 I-DATE
. O

Standard O
demographic O
data O
such O
as O
echocardiographic O
and O
cross O
- O
sectional O
imaging O
along O
with O
operative O
details O
and O
clinical O
echocardiographic O
outcomes O
were O
collected O
. O

Results O
The O
cohort O
included O
144 O
patients O
with O
a O
median O
age O
of O
4.3 O
years O
( O
interquartile O
range O
, O
8.5 O
) O
. O

Inferior O
SVASD O
was O
present O
in O
24 O
patients O
( O
17 O
% O
) O
. O

A O
single O
autologous O
untreated O
pericardial O
patch O
was O
used O
for O
114 O
patients O
( O
79 O
% O
) O
, O
a O
two O
- O
patch O
technique O
for O
20 O
patients O
( O
14 O
% O
, O
last O
performed O
in O
2000 B-DATE
) O
, O
and O
a O
Warden O
procedure O
in O
10 O
patients O
( O
7 O
% O
) O
. O

Median O
length O
of O
stay O
was O
4 O
days O
( O
interquartile O
range O
, O
2 O
) O
. O

On O
echocardiogram O
follow O
- O
up O
, O
no O
patient O
had O
pulmonary O
vein O
stenosis O
. O

One O
patient O
who O
had O
the O
Warden O
procedure O
required O
a O
balloon O
dilation O
of O
the O
superior O
caval O
vein O
2 O
years O
postoperatively O
and O
a O
stent O
3 O
years O
later O
. O

Two O
- O
patch O
patients O
were O
substantially O
less O
likely O
to O
be O
in O
normal O
sinus O
rhythm O
( O
41 O
% O
) O
on O
postoperative O
electrocardiograms O
compared O
with O
the O
other O
two O
techniques O
( O
81 O
% O
one O
- O
patch O
and O
89 O
% O
Warden O
, O
P O
= O
.02 O
) O
. O

Conclusions O
The O
great O
majority O
of O
patients O
with O
sinus O
venosus O
atrial O
septal O
defects O
can O
be O
successfully O
repaired O
with O
a O
single O
patch O
of O
autologous O
pericardium O
. O

We O
transitioned O
to O
using O
either O
a O
single O
pericardial O
patch O
or O
the O
Warden O
procedure O
, O
resulting O
in O
a O
higher O
frequency O
of O
normal O
sinus O
rhythm O
on O
postoperative O
electrocardiograms O
. O

Background O
Antiretroviral O
chemoprophylaxis O
before O
exposure O
is O
a O
promising O
approach O
for O
the O
prevention O
of O
human O
immunodeficiency O
virus O
( O
HIV O
) O
acquisition O
. O

Methods O
We O
randomly O
assigned O
2499 O
HIV O
- O
seronegative O
men B-SEX
or O
transgender O
women B-SEX
who O
have O
sex O
with O
men B-SEX
to O
receive O
a O
combination O
of O
two O
oral O
antiretroviral O
drugs O
, O
emtricitabine O
and O
tenofovir O
disoproxil O
fumarate O
( O
FTC O
- O
TDF O
) O
, O
or O
placebo O
once O
daily O
. O

All O
subjects O
received O
HIV O
testing O
, O
risk O
- O
reduction O
counseling O
, O
condoms O
, O
and O
management O
of O
sexually O
transmitted O
infections O
. O

Results O
The O
study O
subjects O
were O
followed O
for O
3324 O
person O
- O
years O
( O
median O
, O
1.2 O
years O
; O
maximum O
, O
2.8 O
years O
) O
. O

Of O
these O
subjects O
, O
10 O
were O
found O
to O
have O
been O
infected O
with O
HIV O
at O
enrollment O
, O
and O
100 O
became O
infected O
during O
follow O
- O
up O
( O
36 O
in O
the O
FTC O
- O
TDF O
group O
and O
64 O
in O
the O
placebo O
group O
) O
, O
indicating O
a O
44 O
% O
reduction O
in O
the O
incidence B-EPI
of O
HIV O
( O
95 O
% O
confidence O
interval O
, O
15 O
to O
63 O
; O
P=0.005 O
) O
. O

In O
the O
FTC O
- O
TDF O
group O
, O
the O
study O
drug O
was O
detected O
in O
22 O
of O
43 O
of O
seronegative O
subjects O
( O
51 O
% O
) O
and O
in O
3 O
of O
34 O
HIV O
- O
infected O
subjects O
( O
9 O
% O
) O
( O
P<0.001 O
) O
. O

Nausea O
was O
reported O
more O
frequently O
during O
the O
first O
4 O
weeks O
in O
the O
FTC O
- O
TDF O
group O
than O
in O
the O
placebo O
group O
( O
P<0.001 O
) O
. O

The O
two O
groups O
had O
similar O
rates O
of O
serious O
adverse O
events O
( O
P=0.57 O
) O
. O

Conclusions O
Oral O
FTC O
- O
TDF O
provided O
protection O
against O
the O
acquisition O
of O
HIV O
infection O
among O
the O
subjects O
. O

Detectable O
blood O
levels O
strongly O
correlated O
with O
the O
prophylactic O
effect O
. O

( O
Funded O
by O
the O
National O
Institutes O
of O
Health O
and O
the O
Bill O
and O
Melinda O
Gates O
Foundation O
; O
ClinicalTrials.gov O
number O
, O
NCT00458393 O
. O

Coronavirus O
2019 O
( O
COVID-19 O
) O
is O
responsible O
for O
the O
current O
pandemic O
which O
has O
already O
resulted O
in O
considerable O
mortality O
worldwide B-LOC
. O

This O
systematic O
review O
was O
conducted O
to O
summarize O
the O
results O
of O
the O
published O
articles O
assessing O
the O
incidence B-EPI
of O
heart O
diseases O
in O
patients O
infected O
with O
COVID-19 O
. O

The O
electronic O
databases O
Scopus O
, O
Web O
of O
Science O
, O
Pubmed O
, O
Science O
Direct O
, O
and O
ProQuest O
were O
used O
to O
search O
for O
potentially O
relevant O
articles O
. O

Articles O
published O
from O
Dec B-DATE
2019 I-DATE
to I-DATE
April I-DATE
2020 I-DATE
were O
included O
. O

All O
cross O
- O
sectional O
, O
retrospective O
or O
prospective O
observational O
cohort O
and O
case O
- O
control O
studies O
were O
selected O
which O
reported O
the O
incidence B-EPI
or O
prevalence B-EPI
of O
myocardial O
injury O
, O
myocardial O
infarction O
, O
or O
cardiovascular O
disease O
in O
patients O
with O
confirmed O
COVID-19 O
infection O
. O

Based O
on O
the O
inclusion O
criteria O
, O
12 O
articles O
were O
selected O
. O

The O
incidence B-EPI
of O
cardiac O
injury O
was O
reported O
in O
8 O
articles O
and O
8 O
articles O
focused O
on O
the O
cardiovascular O
outcomes O
of O
COVID-19 O
infection O
. O

The O
incidence B-EPI
of O
new O
cardiac O
injury O
was O
reported O
to O
be O
7.2 O
- O
77 O
% O
in O
live O
and O
dead O
patients O
, O
respectively O
. O

The O
results O
showed O
that O
patients O
with O
cardiac O
injury O
had O
worse O
outcomes O
including O
higher O
mortality O
than O
those O
without O
cardiac O
injury O
. O

The O
most O
common O
cardiac O
injury O
outcomes O
were O
shock O
and O
malignant O
arrhythmias O
. O

The O
most O
common O
radiographic O
findings O
in O
patients O
with O
cardiac O
injury O
were O
multiple O
mottling O
and O
ground O
- O
glass O
opacities O
in O
the O
lungs O
( O
64.6 O
% O
) O
. O

A O
significant O
number O
of O
patients O
with O
cardiac O
injury O
required O
noninvasive O
mechanical O
ventilation O
( O
46.3 O
% O
) O
or O
invasive O
mechanical O
ventilation O
( O
22.0 O
% O
) O
. O

Acute O
respiratory O
distress O
syndrome O
was O
seen O
in O
58.5 O
% O
, O
acute O
kidney O
injury O
in O
8.5 O
% O
, O
electrolyte O
disturbances O
in O
15.9 O
% O
, O
hypoproteinemia O
in O
13.4 O
% O
, O
and O
coagulation O
disorders O
in O
7.3 O
% O
of O
patients O
with O
cardiac O
injuries O
. O

In O
addition O
, O
survival O
days O
were O
negatively O
correlated O
with O
cardiac O
troponin O
I O
levels O
( O
r O
= O
-0.42 O
, O
95 O
% O
, O
p O
= O
0.005 O
) O
. O

The O
results O
of O
this O
review O
showed O
that O
myocardial O
injury O
in O
patients O
with O
COVID O
19 O
has O
a O
poor O
prognosis O
. O

Hence O
, O
cardiac O
investigation O
and O
management O
in O
these O
patients O
are O
crucial O
. O

Diarrhoea O
lasting O
longer O
than O
14 O
days O
and O
failing O
to O
respond O
to O
conventional O
management O
is O
defined O
as O
severe O
and O
protracted O
diarrhoea O
( O
SD O
) O
. O

In O
this O
study O
, O
we O
investigated O
the O
prevalence B-EPI
, O
pathogens O
and O
prognosis O
of O
SD O
in O
primary O
immunodeficiency O
diseases O
( O
PIDs O
) O
. O

Among O
246 O
patients O
with O
predominantly O
paediatric O
- O
onset O
PIDs O
from O
2003 B-DATE
- I-DATE
2015 I-DATE
, O
21 O
[ O
Btk O
( O
six O
) O
, O
IL2RG O
( O
four O
) O
, O
WASP O
, O
CD40L O
, O
gp91 O
( O
three O
each O
) O
, O
gp47 O
, O
RAG2 O
( O
one O
each O
) O
] O
and O
five O
[ O
CVID O
( O
four O
) O
, O
SCID O
( O
one O
) O
] O
without O
identified O
mutations O
had O
SD O
before O
prophylactic O
treatment O
. O

Detectable O
pathogens O
included O
pseudomonas O
, O
salmonella O
( O
six O
each O
) O
, O
E. O
coli O
, O
cytomegalovirus O
, O
coxsackie O
virus O
and O
cryptosporidium O
( O
one O
each O
) O
, O
all O
of O
whom O
improved O
after O
a O
mean O
17 O
days O
of O
antibiotics O
and/or O
IVIG O
treatment O
. O

Seven O
( O
7/26 O
; O
27.0 O
% O
) O
patients O
died O
[ O
respiratory O
failure O
( O
four O
) O
, O
lymphoma O
, O
sepsis O
and O
intracranial O
haemorrhage O
( O
one O
each O
) O
] O
. O

The O
patients O
with O
WAS O
, O
CGD O
and O
CD40L O
and O
SD O
had O
a O
higher O
mortality O
rate O
than O
those O
without O
. O

Another O
five O
males B-SEX
with O
mutant O
XIAP O
, O
STAT1 O
, O
FOXP3 O
( O
one O
each O
) O
and O
STAT3 O
( O
two O
) O
had O
undetectable O
- O
pathogenic O
refractory O
diarrhoea O
( O
RD O
) O
that O
persisted O
> O
21 O
days O
despite O
aggressive O
antibiotic O
/ O
steroid O
treatment O
and O
directly O
resulted O
in O
mortality O
. O

For O
the O
patients O
with O
RD O
without O
anti O
- O
inflammatory O
optimization O
, O
those O
with O
mutant O
XIAP O
and O
FOXP3 O
died O
of O
Crohn's O
- O
like O
colitis O
and O
electrolyte O
exhaustion O
in O
awaiting O
transplantation O
, O
while O
transplantation O
cured O
the O
STAT1 O
patient O
. O

Background O
Hereditary O
cancer O
susceptibility O
syndrome O
( O
HCSS O
) O
contributes O
to O
the O
cancer O
predisposition O
at O
an O
early O
age O
, O
therefore O
, O
identification O
of O
HCSS O
has O
found O
to O
be O
crucial O
for O
surveillance O
, O
managing O
therapeutic O
interventions O
and O
refer O
the O
patients O
and O
their O
families O
for O
genetic O
counselling O
. O

The O
study O
aimed O
to O
identify O
ALL O
patients O
who O
meet O
the O
American B-ETHN
College O
of O
Medical O
Genetics O
( O
ACMG O
) O
criteria O
and O
refer O
them O
for O
the O
genetic O
testing O
for O
HCSS O
as O
hereditary O
leukemia O
and O
hematologic O
malignancy O
syndrome O
, O
and O
to O
elucidate O
the O
significance O
of O
high O
consanguinity O
with O
the O
prevalence B-EPI
of O
inherited O
leukemia O
in O
Pakistani B-ETHN
population O
. O

Methods O
A O
total O
of O
300 O
acute O
lymphoblastic O
leukemia O
patients O
were O
recruited O
from O
the O
Children O
's O
Hospital O
, O
Lahore B-LOC
, I-LOC
Pakistan B-LOC
from O
December B-DATE
2018 I-DATE
to I-DATE
September I-DATE
2019 I-DATE
. O

A O
structured O
self O
- O
reporting O
questionnaire O
based O
on O
family O
and O
medical O
history O
of O
the O
disease O
was O
utilized O
for O
the O
data O
collection O
. O

Results O
In O
our O
cohort O
, O
60.40 O
% O
of O
ALL O
patients O
were O
identified O
to O
meet O
ACMG O
criteria O
. O

Among O
them O
, O
a O
large O
number O
of O
patients O
( O
40.65 O
% O
) O
solely O
fulfil O
the O
criteria O
due O
to O
the O
presence O
of O
parental O
consanguinity O
. O

However O
, O
parental O
consanguinity O
showed O
protective O
impact O
on O
the O
onset O
at O
early O
age O
of O
disease O
[ O
OD O
= O
0.44 O
( O
0.25 O
- O
0.77 O
) O
, O
p O
- O
value O
= O
0.00 O
] O
while O
, O
a O
family O
history O
of O
cancer O
increased O
the O
risk O
of O
cardiotoxicity O
[ O
OD O
= O
2.46 O
( O
1.15 O
- O
5.24 O
) O
, O
p O
- O
value O
= O
0.02 O
] O
. O

Parental O
consanguinity O
shows O
no O
significant O
impact O
on O
the O
family O
history O
of O
cancer O
and O
the O
number O
of O
relatives O
with O
cancer O
. O

Conclusions O
More O
than O
50 O
% O
of O
the O
ALL O
patients O
were O
considered O
the O
strong O
candidates O
' O
for O
genetic O
testing O
of O
HCSS O
in O
the O
Pakistani B-ETHN
population O
, O
and O
parental O
consanguinity O
was O
the O
leading O
criteria O
fulfilled O
by O
the O
individuals O
when O
assessed O
through O
ACMG O
guidelines O
. O

Our O
study O
suggests O
revisiting O
ACMG O
guidelines O
, O
especially O
for O
the O
criterion O
of O
parental O
consanguinity O
, O
and O
formulating O
the O
score O
based O
criteria O
based O
on O
; O
genetic O
research O
, O
the O
toxicology O
profile O
, O
physical O
features O
, O
personal O
and O
family O
history O
of O
cancer O
for O
the O
identification O
of O
patients O
for O
the O
genetic O
testing O
. O

Background O
The O
majority O
of O
active O
tuberculosis O
( O
TB O
) O
cases O
develop O
from O
latent O
tuberculosis O
infection O
( O
LTBI O
) O
. O

Since O
the O
risk O
of O
TB O
in O
hemodialysis O
( O
HD O
) O
patients O
is O
particularly O
high O
, O
interferon O
- O
gamma O
release O
assay O
( O
IGRA O
) O
for O
LTBI O
screening O
in O
HD O
patients O
is O
considered O
important O
. O

However O
, O
the O
prevalence B-EPI
and O
characteristics O
of O
LTBI O
in O
Japanese B-ETHN
HD O
patients O
remain O
obscure O
. O

Methods O
We O
performed O
an O
observational O
cross O
- O
sectional O
study O
of O
LTBI O
using O
IGRA O
QFT-3 O
G O
tests O
in O
118 O
HD O
outpatients O
enrolled O
at O
3 O
hospitals O
of O
varying O
location O
and O
function O
. O

Results O
Of O
the O
118 O
patients O
, O
96 O
were O
QFT O
negative O
, O
7 O
were O
QFT O
indeterminate O
, O
14 O
were O
QFT O
positive O
, O
and O
1 O
was O
QFT O
judgment O
impossible O
. O

No O
patient O
had O
active O
TB O
. O

Confirmed O
( O
QFT O
positive O
) O
and O
possible O
( O
QFT O
positive O
+ O
indeterminate O
) O
LTBI O
patients O
totaled O
14 O
( O
11.9 O
% O
) O
and O
21 O
( O
17.8 O
% O
) O
, O
respectively O
. O

The O
LTBI O
possible O
group O
was O
significantly O
older O
and O
had O
a O
significantly O
higher O
rate O
of O
nephrosclerosis O
versus O
the O
QFT O
- O
negative O
group O
. O

The O
indeterminate O
group O
had O
a O
significantly O
longer O
HD O
period O
. O

The O
QFT O
results O
were O
not O
remarkably O
affected O
by O
other O
clinical O
data O
, O
including O
hospital O
characteristics O
. O

The O
possible O
LTBI O
rate O
increased O
age O
- O
dependently O
, O
with O
higher O
values O
from O
60 O
years O
of O
age O
. O

Conclusions O
The O
prevalence B-EPI
of O
LTBI O
is O
high O
in O
Japanese B-ETHN
HD O
patients O
, O
especially O
from O
the O
age O
of O
60 O
years O
. O

Older O
age O
was O
a O
significant O
risk O
factor O
for O
LTBI O
, O
with O
prediction O
difficult O
using O
other O
clinical O
data O
. O

Extended O
HD O
may O
mask O
IGRA O
results O
. O

Therefore O
, O
aggressive O
screening O
for O
LTBI O
is O
advised O
in O
all O
HD O
patients O
regardless O
of O
hospital O
region O
or O
type O
, O
especially O
in O
patients O
over O
60 O
years O
of O
age O
or O
newly O
commencing O
HD O
. O

In O
the O
year O
2000 B-DATE
, O
the O
discovery O
of O
OPA1 O
mutations O
as O
causative O
for O
dominant O
optic O
atrophy O
( O
DOA O
) O
was O
pivotal O
to O
rapidly O
expand O
the O
field O
of O
mitochondrial O
dynamics O
and O
describe O
the O
complex O
machinery O
governing O
this O
pathway O
, O
with O
a O
multitude O
of O
other O
genes O
and O
encoded O
proteins O
involved O
in O
neurodegenerative O
disorders O
of O
the O
optic O
nerve O
. O

OPA1 O
turned O
out O
to O
be O
a O
much O
more O
complex O
protein O
than O
initially O
envisaged O
, O
connecting O
multiple O
pathways O
beyond O
its O
strict O
role O
in O
mitochondrial O
fusion O
, O
such O
as O
sensing O
of O
OXPHOS O
needs O
and O
mitochondrial O
DNA O
maintenance O
. O

As O
a O
consequence O
, O
an O
increasing O
need O
to O
investigate O
OPA1 O
functions O
at O
multiple O
levels O
has O
imposed O
the O
development O
of O
multiple O
tools O
and O
models O
that O
are O
here O
reviewed O
. O

Translational O
mitochondrial O
medicine O
, O
with O
the O
ultimate O
objective O
of O
translating O
basic O
science O
necessary O
to O
understand O
pathogenic O
mechanisms O
into O
therapeutic O
strategies O
, O
requires O
disease O
modeling O
at O
multiple O
levels O
: O
from O
the O
simplest O
, O
like O
in O
yeast O
, O
to O
cell O
models O
, O
including O
the O
increasing O
use O
of O
reprogrammed O
stem O
cells O
( O
iPSCs O
) O
from O
patients O
, O
to O
animal O
models O
. O

In O
the O
present O
review O
, O
we O
thoroughly O
examine O
and O
provide O
the O
state O
of O
the O
art O
of O
all O
these O
approaches O
. O

Sexual O
activity O
during O
adolescence O
can O
lead O
to O
unwanted O
pregnancy O
, O
which O
in O
turn O
can O
result O
in O
serious O
maternal O
and O
fetal O
complications O
. O

The O
present O
study O
aimed O
to O
evaluate O
the O
complications O
related O
to O
adolescent O
pregnancy O
, O
through O
a O
systematic O
review O
using O
the O
Medical O
Subject O
Headings O
: O
pregnancy O
complication O
AND O
adolescent O
OR O
pregnancy O
in O
adolescence O
. O

Only O
full O
original O
articles O
in O
English B-ETHN
or O
Portuguese B-ETHN
with O
a O
clearly O
described O
methodology O
, O
were O
included O
. O

No O
qualitative O
studies O
, O
reviews O
or O
meta O
- O
analyses O
, O
editorials O
, O
case O
series O
, O
or O
case O
reports O
were O
included O
. O

The O
sample O
consisted O
of O
15 O
articles O
; O
in O
that O
10 O
were O
cross O
- O
sectional O
and O
5 O
were O
cohort O
studies O
. O

The O
overall B-EPI
prevalence I-EPI
of O
adolescent O
pregnancy O
was O
10 O
% O
, O
and O
among O
the O
Brazilian B-ETHN
studies O
, O
the O
adolescent O
pregnancy O
rate O
was O
26 O
% O
. O

The O
cesarean O
delivery O
rate O
was O
lower O
than O
that O
reported O
in O
the O
general O
population O
. O

The O
main O
maternal O
and O
neonatal O
complications O
were O
hypertensive O
disorders O
of O
pregnancy O
, O
prematurity O
and O
low O
birth O
weight O
, O
respectively O
. O

Adolescent O
pregnancy O
is O
related O
to O
increased O
frequency O
of O
neonatal O
and O
maternal O
complications O
and O
lower O
prevalence B-EPI
of O
cesarean O
delivery O
. O

Excessive O
daytime O
sleepiness O
( O
EDS O
) O
is O
a O
highly O
prevalent B-EPI
condition O
that O
is O
associated O
with O
significant O
morbidity O
. O

The O
causes O
of O
EDS O
are O
varied O
, O
and O
include O
inadequate O
sleep O
, O
sleep O
disordered O
breathing O
, O
circadian O
rhythm O
sleep O
- O
wake O
disorders O
, O
and O
central O
disorders O
of O
hypersomnolence O
( O
narcolepsy O
, O
idiopathic O
hypersomnia O
, O
and O
Kleine O
- O
Levin O
syndrome O
) O
. O

Additionally O
, O
EDS O
could O
represent O
a O
symptom O
of O
an O
underlying O
medical O
or O
psychiatric O
disorder O
. O

Assessment O
of O
EDS O
includes O
a O
thorough O
sleep O
, O
medical O
, O
and O
psychiatric O
history O
, O
targeted O
clinical O
examination O
, O
and O
appropriate O
use O
of O
actigraphy O
to O
measure O
sleep O
duration O
and O
sleep O
- O
wake O
patterns O
, O
polysomnography O
to O
assess O
for O
associated O
conditions O
such O
as O
sleep O
- O
related O
breathing O
disorders O
or O
other O
factors O
that O
might O
disrupt O
nighttime O
sleep O
, O
multiple O
sleep O
latency O
testing O
to O
ascertain O
objective O
sleepiness O
and O
diagnose O
central O
disorders O
of O
hypersomnolence O
, O
and O
measurement O
of O
cerebrospinal O
fluid O
hypocretin-1 O
concentration O
. O

Treatment O
of O
EDS O
secondary O
to O
central O
disorders O
of O
hypersomnolence O
is O
primarily O
pharmacologic O
with O
wakefulness O
- O
promoting O
agents O
such O
as O
modafinil O
, O
stimulants O
such O
as O
methylphenidate O
and O
amphetamines O
, O
and O
newer O
agents O
specifically O
designed O
to O
improve O
wakefulness O
; O
behavioral O
interventions O
can O
provide O
a O
useful O
adjunct O
to O
pharmacologic O
treatment O
. O

When O
excessive O
sleepiness O
is O
secondary O
to O
other O
conditions O
, O
the O
treatment O
should O
focus O
on O
targeting O
the O
primary O
disorder O
. O

This O
review O
discusses O
current O
epidemiology O
, O
provides O
guidance O
on O
clinical O
assessments O
and O
testing O
, O
and O
discusses O
the O
latest O
treatment O
options O
. O

For O
this O
review O
, O
we O
collated O
the O
latest O
evidence O
using O
the O
search O
terms O
excessive O
sleepiness O
, O
hypersomnia O
, O
hypersomnolence O
, O
treatment O
from O
PubMed O
and O
MEDLINE O
and O
the O
latest O
practice O
parameters O
from O
the O
American B-ETHN
Academy O
of O
Sleep O
Medicine O
. O

Aim O
To O
evaluate O
the O
risk O
factors O
and O
incidence B-EPI
of O
Asherman O
Syndrome O
in O
women B-SEX
with O
post O
- O
abortion O
uterine O
evacuation O
and O
curettage O
. O

Methods O
A O
total O
of O
2546 O
patients O
who O
had O
surgical O
abortion O
( O
uterine O
evacuation O
and O
curettage O
) O
before O
the O
20th O
gestational O
week O
with O
indications O
of O
missed O
abortion O
, O
anembryonic O
pregnancy O
, O
incomplete O
abortion O
, O
and O
elective O
curettage O
in O
a O
tertiary O
antenatal O
care O
center O
were O
recruited O
. O

The O
patients O
were O
called O
and O
surveyed O
for O
their O
symptoms O
; O
including O
infertility O
, O
oligo O
- O
amenorrhea O
and O
recurrent O
pregnancy O
loss O
, O
preterm O
birth O
and O
intrauterine O
growth O
retardation O
and O
abnormal O
placentation O
as O
criteria O
of O
Asherman O
Syndrome O
. O

Diagnostic O
( O
office O
) O
hysteroscopy O
was O
performed O
for O
177 O
who O
had O
one O
of O
those O
complaints O
. O

Results O
The O
incidence B-EPI
of O
Asherman O
Syndrome O
was O
1.6 O
% O
( O
n O
= O
43/2546 O
) O
. O

History O
of O
≥3 O
abortions O
was O
the O
main O
factor O
that O
increased O
the O
risk O
of O
Asherman O
Syndrome O
for O
by O
4.6 O
times O
. O

Use O
of O
vacuum O
aspiration O
or O
sharp O
curettage O
, O
premedication O
for O
cervical O
priming O
, O
and O
having O
a O
pregnancy O
> O
10th O
gestational O
weeks O
were O
not O
risk O
factors O
for O
Asherman O
Syndrome O
. O

Conclusion O
When O
the O
diagnosis O
was O
based O
on O
presence O
of O
symptoms O
who O
underwent O
uterine O
instrumentation O
, O
the O
incidence B-EPI
of O
Asherman O
Syndrome O
was O
found O
to O
be O
1.6 O
% O
. O

Repeated O
abortions O
were O
the O
main O
risk O
factor O
for O
Asherman O
Syndrome O
and O
avoiding O
from O
repeated O
uterine O
instrumentations O
may O
have O
a O
role O
in O
prevention O
. O

Background O
Xanthogranulomatous O
pyelonephritis O
( O
XGP O
) O
is O
an O
inflammatory O
condition O
of O
the O
kidney O
and O
its O
treatment O
most O
often O
involves O
a O
combination O
of O
antibiotics O
and O
nephrectomy O
. O

This O
study O
aimed O
to O
define O
the O
clinical O
features O
and O
management O
of O
XGP O
, O
focusing O
on O
microbiological O
aspects O
and O
antibiotic O
therapy O
. O

Methods O
We O
performed O
a O
retrospective O
study O
of O
27 O
cases O
of O
XGP O
diagnosed O
between B-DATE
January I-DATE
2001 I-DATE
and I-DATE
January I-DATE
2020 I-DATE
to O
analyse O
their O
clinical O
and O
management O
characteristics O
. O

In O
addition O
, O
a O
literature O
review O
was O
conducted O
of O
XGP O
case O
series O
covering O
the O
period O
from O
2000 B-DATE
- I-DATE
2020 I-DATE
. O

We O
searched O
PubMed O
for O
case O
series O
through O
April I-DATE
2020 I-DATE
without O
language O
restrictions O
. O

Studies O
reporting O
case O
series O
of O
XGP O
( O
more O
than O
ten O
cases O
) O
were O
included O
if O
they O
were O
relevant O
to O
this O
study O
. O

Results O
Twenty O
- O
seven O
patients O
were O
diagnosed O
with O
XGP O
, O
and O
26 O
of O
them O
were O
histologically O
proven O
to O
have O
XGP O
. O

A O
total O
of O
81.5 O
% O
of O
the O
patients O
were O
female B-SEX
and O
the O
mean O
age O
was O
59.6 O
years O
( O
SD O
19.2 O
) O
. O

The O
most O
frequent O
symptoms O
were O
flank O
pain O
( O
70.4 O
% O
) O
and O
fever O
( O
59.3 O
% O
) O
, O
while O
77.8 O
% O
of O
patients O
had O
renal O
stones O
. O

Proteus O
mirabilis O
was O
detected O
in O
the O
urine O
culture O
in O
18.5 O
% O
of O
patients O
, O
followed O
by O
detection O
of O
Escherichia O
coli O
in O
14.8 O
% O
of O
patients O
. O

The O
computed O
tomography O
( O
CT O
) O
findings O
included O
perirenal O
( O
29.6 O
% O
) O
or O
pararenal O
( O
29.6 O
% O
) O
involvement O
in O
the O
majority O
of O
patients O
. O

Twenty O
- O
six O
patients O
underwent O
nephrectomy O
. O

Piperacillin O
/ O
tazobactam O
and O
ceftriaxone O
were O
the O
most O
commonly O
prescribed O
antibiotics O
for O
treatment O
. O

The O
reported O
piperacillin O
/ O
tazobactam O
and O
ceftriaxone O
resistance O
rates O
were O
14.3 O
% O
and O
16.6 O
% O
, O
respectively O
. O

Twenty O
- O
six O
case O
series O
were O
included O
in O
the O
literature O
review O
, O
reporting O
693 O
cases O
in O
total O
. O

Conclusion O
We O
found O
well O
- O
established O
characteristics O
of O
XGP O
patients O
among O
series O
in O
terms O
of O
previous O
history O
, O
clinical O
, O
laboratory O
and O
imaging O
findings O
, O
and O
operative O
and O
postoperative O
outcomes O
. O

It O
is O
important O
to O
know O
the O
clinical O
presentation O
and O
potential O
severity O
of O
XGP O
, O
as O
well O
as O
the O
most O
frequently O
involved O
microorganisms O
and O
their O
antibiotic O
resistance O
profiles O
, O
to O
select O
the O
most O
appropriate O
antibiotic O
therapy O
. O

Introduction O
Cardiac O
rehabilitation O
( O
CR O
) O
is O
a O
proven O
therapy O
for O
reducing O
cardiovascular O
death O
and O
hospitalization O
. O

Whether O
CR O
participation O
is O
associated O
with O
improved O
outcomes O
in O
patients O
with O
chronic O
kidney O
disease O
( O
CKD O
) O
is O
unknown O
. O

Methods O
We O
obtained O
data O
on O
all O
adult O
patients O
in O
Calgary B-LOC
, O
Alberta B-LOC
, O
Canada B-LOC
with O
angiographically O
proven O
coronary O
artery O
disease O
from O
1996 B-DATE
to I-DATE
2016 I-DATE
referred O
to O
CR O
from O
The O
Alberta B-LOC
Provincial O
Project O
for O
Outcome O
Assessment O
in O
Coronary O
Heart O
Disease O
and O
TotalCardiology O
Rehabilitation O
. O

An O
estimated O
glomerular O
filtration O
rate O
( O
eGFR O
) O
< O
60 O
ml O
/ O
min/1.73 O
m O
2 O
or O
kidney O
replacement O
therapy O
defined O
CKD O
. O

Predictors O
of O
CR O
use O
were O
estimated O
with O
multinomial O
logistic O
regression O
. O

The O
association O
between O
starting O
versus O
not O
starting O
and O
completion O
versus O
noncompletion O
of O
CR O
and O
clinical O
outcomes O
were O
estimated O
using O
multivariable O
Cox O
proportional O
hazards O
models O
. O

Results O
Of O
23,215 O
patients O
referred O
to O
CR O
, O
12,084 O
were O
eligible O
for O
inclusion O
. O

Participants O
with O
CKD O
( O
N O
= O
1322 O
) O
were O
older O
, O
had O
more O
comorbidity O
, O
lower O
exercise O
capacity O
on O
graded O
treadmill O
testing O
, O
and O
took O
longer O
to O
be O
referred O
and O
to O
start O
CR O
than O
those O
without O
CKD O
. O

CKD O
predicted O
not O
starting O
CR O
: O
odds O
ratio O
0.73 O
( O
95 O
% O
confidence O
interval O
[ O
CI O
] O
0.64 O
- O
0.83 O
) O
. O

Over O
a O
median O
1 O
year O
follow O
- O
up O
, O
there O
were O
146 O
deaths O
, O
40 O
( O
0.3 O
% O
) O
from O
CKD O
and O
106 O
( O
1.0 O
% O
) O
not O
from O
CKD O
. O

Similar O
to O
those O
without O
CKD O
, O
the O
risk O
of O
death O
was O
lower O
in O
CR O
completers O
( O
hazard O
ratio O
[ O
HR O
] O
0.24 O
[ O
95 O
% O
CI O
0.06 O
- O
0.91 O
) O
and O
starters O
( O
HR O
0.56 O
[ O
95 O
% O
CI O
0.29- O
1.10 O
] O
) O
with O
CKD O
. O

Conclusion O
CR O
participation O
was O
associated O
with O
comparable O
benefits O
in O
people O
with O
moderate O
CKD O
as O
those O
without O
who O
survived O
to O
CR O
. O

Lower O
rates O
of O
CR O
attendance O
in O
this O
high O
- O
risk O
population O
suggest O
that O
strategies O
to O
increase O
CR O
utilization O
are O
needed O
. O

Background O
Lichen O
scrofulosorum O
( O
LS O
) O
represents O
immunologic O
reaction O
to O
the O
Mycobacterium O
tuberculosis O
antigen O
and O
presents O
with O
subtle O
, O
asymptomatic O
, O
grouped O
follicular O
papules O
over O
the O
trunk O
and O
shows O
good O
therapeutic O
response O
to O
antitubercular O
drugs O
. O

Objective O
To O
study O
the O
clinical O
and O
epidemiological O
characteristics O
of O
patients O
diagnosed O
with O
LS O
. O

Materials O
and O
methods O
A O
single O
- O
center O
retrospective O
review O
of O
patients O
diagnosed O
with O
LS O
from O
1997 B-DATE
to I-DATE
2018 I-DATE
was O
conducted O
. O

The O
data O
pertained O
to O
clinico O
- O
epidemiological O
profile O
, O
BCG O
vaccination O
, O
Mantoux O
positivity O
, O
laboratory O
investigations O
, O
coexistent O
focus O
of O
tuberculosis O
, O
and O
response O
to O
antitubercular O
treatment O
( O
ATT O
) O
. O

Results O
LS O
cases O
constituted O
15.2 O
% O
( O
221/1458 O
) O
of O
all O
the O
patients O
diagnosed O
with O
cutaneous O
tuberculosis O
( O
CTB O
) O
. O

Of O
these O
, O
156 O
( O
70.5 O
% O
) O
were O
pediatric O
patients O
. O

All O
patients O
presented O
with O
multiple O
follicular O
and O
perifollicular O
grouped O
papules O
. O

The O
trunk O
was O
the O
most O
common O
site O
involved O
( O
98.6 O
% O
) O
, O
followed O
by O
lower O
limb O
( O
25.33 O
% O
) O
, O
upper O
limb O
( O
15.83 O
% O
) O
, O
face O
( O
5 O
% O
) O
, O
and O
external O
genitalia O
( O
3.6 O
% O
) O
. O

Evidence O
of O
BCG O
vaccination O
and O
Mantoux O
test O
positivity O
was O
observed O
in O
52.03 O
and O
83.2 O
% O
, O
respectively O
. O

Coexistent O
TB O
focus O
was O
detected O
in O
134 O
( O
60.6 O
% O
) O
patients O
in O
lymph O
nodes O
, O
lungs O
, O
abdomen O
, O
and O
unusual O
sites O
such O
as O
intracranial O
, O
endometrium O
, O
and O
eye O
. O

Twenty O
- O
eight O
patients O
( O
12.66 O
% O
) O
had O
coexistent O
other O
clinical O
forms O
of O
CTB O
. O

Clinical O
diagnosis O
of O
LS O
was O
confirmed O
on O
histology O
that O
revealed O
chiefly O
periappendageal O
epithelioid O
cell O
granuloma O
. O

Response O
to O
ATT O
was O
good O
with O
complete O
resolution O
of O
lesion O
in O
8 O
- O
12 O
weeks O
. O

Conclusion O
LS O
appears O
to O
be O
an O
underdiagnosed O
entity O
. O

Subtle O
and O
asymptomatic O
lesions O
of O
LS O
are O
often O
missed O
, O
thereby O
necessitating O
a O
high O
index O
of O
suspicion O
and O
appropriate O
evaluation O
of O
the O
underlying O
TB O
focus O
. O

Coagulation O
factor O
X O
( O
F10 O
) O
amplifies O
the O
clotting O
reaction O
in O
the O
middle O
of O
the O
coagulation O
cascade O
, O
and O
thus O
F10 O
deficiency O
leads O
to O
a O
bleeding O
tendency O
. O

Isolated O
acquired O
F10 O
deficiency O
is O
widely O
recognized O
in O
patients O
with O
immunoglobulin O
light O
- O
chain O
amyloidosis O
or O
plasma O
cell O
dyscrasias O
. O

However O
, O
its O
occurrence B-EPI
as O
an O
autoimmune O
disorder O
is O
extremely O
rare O
. O

The O
Japanese B-ETHN
Collaborative O
Research O
Group O
has O
been O
conducting O
a O
nationwide O
survey O
on O
autoimmune O
coagulation O
factor O
deficiencies O
( O
AiCFDs O
) O
starting O
in O
the O
last O
decade O
; O
we O
recently O
identified O
three O
patients O
with O
autoimmune O
F10 O
deficiency O
( O
AiF10D O
) O
. O

Furthermore O
, O
an O
extensive O
literature O
search O
was O
performed O
, O
confirming O
26 O
AiF10D O
and O
28 O
possible O
cases O
. O

Our O
study O
revealed O
that O
AiF10D O
patients O
were O
younger O
than O
patients O
with O
other O
AiCFDs O
; O
AiF10D O
patients O
included O
children O
and O
were O
predominantly O
male B-SEX
. O

AiF10D O
was O
confirmed O
as O
a O
severe O
type O
of O
bleeding O
diathesis O
, O
although O
its O
mortality O
rate O
was O
not O
high O
. O

As O
AiF10D O
patients O
showed O
only O
low O
F10 O
inhibitor O
titers O
, O
they O
were O
considered O
to O
have O
nonneutralizing O
anti O
- O
F10 O
autoantibodies O
rather O
than O
their O
neutralizing O
counterparts O
. O

Accordingly O
, O
immunological O
anti O
- O
F10 O
antibody O
detection O
is O
highly O
recommended O
. O

Hemostatic O
and O
immunosuppressive O
therapies O
may O
help O
arrest O
bleeding O
and O
eliminate O
anti O
- O
F10 O
antibodies O
, O
leading O
to O
a O
high O
recovery O
rate O
. O

However O
, O
further O
investigation O
is O
necessary O
to O
understand O
the O
basic O
characteristics O
and O
proper O
management O
of O
AiF10D O
owing O
to O
the O
limited O
number O
of O
patients O
. O

Herpes O
simplex O
virus O
( O
HSV O
) O
1 O
and O
HSV-2 O
infections O
are O
highly O
prevalent B-EPI
worldwide B-LOC
and O
are O
characterized O
by O
establishing O
lifelong O
infection O
with O
periods O
of O
latency O
interspersed O
with O
periodic O
episodes O
of O
reactivation O
. O

Acquisition O
of O
HSV O
by O
an O
infant O
during O
the O
peripartum O
or O
postpartum O
period O
results O
in O
neonatal O
HSV O
disease O
, O
a O
rare O
but O
significant O
infection O
that O
can O
be O
associated O
with O
severe O
morbidity O
and O
mortality O
, O
especially O
if O
there O
is O
dissemination O
or O
central O
nervous O
system O
involvement O
. O

Diagnostic O
and O
therapeutic O
advances O
have O
led O
to O
improvements O
in O
mortality O
and O
, O
to O
a O
lesser O
extent O
, O
neurodevelopmental O
outcomes O
, O
but O
room O
exists O
for O
further O
improvement O
. O

Q O
fever O
is O
a O
zoonotic O
disease O
caused O
by O
Coxiella O
burnetii O
which O
has O
a O
worldwide B-LOC
distribution O
. O

Pneumonia O
occurs B-EPI
in O
almost O
half O
of O
the O
patients O
who O
have O
an O
acute O
C. O
burnetii O
infection O
. O

Less O
than O
5 O
- O
6 O
% O
of O
community O
acquired O
pneumonia O
( O
CAP O
) O
is O
found O
to O
be O
caused O
by O
this O
organism O
. O

Endemicity O
of O
C. O
burnetii O
infection O
has O
been O
recorded O
in O
various O
studies O
carried O
out O
in O
our O
country O
. O

However O
there O
is O
no O
mention O
about O
Q O
fever O
as O
a O
cause O
of O
CAP O
in O
the O
various O
studies O
done O
to O
identify O
the O
aetiological O
agent O
. O

We O
report O
a O
case O
of O
acute O
Q O
fever O
related O
pneumonia O
and O
this O
appears O
to O
be O
the O
first O
reported O
case O
of O
pneumonia O
due O
to O
C. O
burnetii O
infection O
in O
India B-LOC
. O

Objective O
To O
investigate O
the O
prevalence B-EPI
of O
mutations O
in O
domain O
V O
of O
Mycoplasma O
pneumoniae O
( O
MP O
) O
23S O
ribosomal O
RNA O
( O
rRNA O
) O
and O
the O
clinical O
characteristics O
of O
pediatric O
MP O
pneumonia O
( O
MPP O
) O
in O
Nanjing B-LOC
, I-LOC
China I-LOC
. O

Methods O
Domain O
V O
of O
23S O
rRNA O
was O
sequenced O
in O
MP O
strains O
collected O
from O
children O
diagnosed O
with O
MPP O
in O
Nanjing B-LOC
. O

Clinical O
and O
laboratory O
data O
were O
obtained O
. O

Results O
Among O
the O
276 O
MP O
strains O
, O
255 O
( O
92.39 O
% O
) O
harbored O
mutations O
, O
primarily O
A2063 O
G O
in O
domain O
V O
of O
MP O
23S O
rRNA O
. O

When O
children O
were O
stratified O
according O
to O
the O
presence O
or O
absence O
of O
mutations O
, O
no O
significant O
differences O
were O
found O
in O
sex O
, O
age O
, O
the O
MP O
DNA O
load O
at O
enrollment O
, O
lymphocyte O
counts O
, O
pulmonary O
complications O
, O
immunomodulator O
levels O
, O
fever O
duration O
, O
the O
duration O
of O
fever O
after O
macrolide O
therapy O
, O
and O
hospital O
stay O
. O

The O
prevalence B-EPI
of O
refractory O
MPP O
in O
the O
two O
groups O
was O
similar O
. O

Children O
with O
refractory O
MPP O
exhibited O
higher O
MP O
DNA O
loads O
than O
those O
with O
non O
- O
refractory O
MPP O
. O

Conclusions O
Despite O
the O
high O
prevalence B-EPI
of O
the O
A2063 O
G O
mutation O
in O
domain O
V O
of O
MP O
23S O
rRNA O
, O
mutations O
were O
not O
associated O
with O
the O
clinical O
characteristics O
of O
MPP O
. O

The O
MP O
DNA O
load O
significantly O
differed O
between O
refractory O
and O
non O
- O
refractory O
MPP O
. O

The O
MBTPS2 O
gene O
on O
the O
X O
- O
chromosome O
encodes O
the O
membrane O
- O
bound O
transcription O
factor O
protease O
, O
site-2 O
( O
MBTPS2 O
) O
or O
site-2 O
protease O
( O
S2P O
) O
which O
cleaves O
and O
activates O
several O
signaling O
and O
regulatory O
proteins O
from O
the O
membrane O
. O

The O
MBTPS2 O
is O
critical O
for O
a O
myriad O
of O
cellular O
processes O
, O
ranging O
from O
the O
regulation O
of O
cholesterol O
homeostasis O
to O
unfolded O
protein O
responses O
. O

While O
its O
functional O
role O
has O
become O
much O
clearer O
in O
the O
recent O
years O
, O
how O
mutations O
in O
the O
MBTPS2 O
gene O
lead O
to O
several O
human O
disorders O
with O
different O
phenotypes O
including O
Ichthyosis O
Follicularis O
, O
Atrichia O
and O
Photophobia O
syndrome O
( O
IFAP O
) O
with O
or O
without O
BRESHECK O
syndrome O
, O
Keratosis O
Follicularis O
Spinulosa O
Decalvans O
( O
KFSD O
) O
, O
Olmsted O
syndrome O
, O
and O
Osteogenesis O
Imperfecta O
type O
XIX O
remains O
obscure O
. O

This O
review O
presents O
the O
biological O
role O
of O
MBTPS2 O
in O
development O
, O
summarizes O
its O
mutations O
and O
implicated O
disorders O
, O
and O
discusses O
outstanding O
unanswered O
questions O
. O

Group O
B O
Streptococcus O
, O
a O
common O
commensal O
in O
the O
gut O
of O
humans O
and O
in O
the O
lower O
genital O
tract O
in O
women B-SEX
, O
remains O
an O
important O
cause O
of O
neonatal O
mortality O
and O
morbidity O
. O

The O
incidence B-EPI
of O
early O
onset O
disease O
has O
fallen O
markedly O
in O
countries O
that O
test O
women B-SEX
for O
carriage O
at O
35 O
- O
37 O
weeks O
of O
pregnancy O
and O
then O
offer O
intrapartum O
prophylaxis O
with O
penicillin O
during O
labour O
. O

Countries O
that O
do O
not O
test O
, O
but O
instead O
employ O
a O
risk O
factor O
approach O
, O
have O
not O
seen O
a O
similar O
fall O
. O

There O
are O
concerns O
about O
the O
effect O
on O
the O
neonatal O
microbiome O
of O
widespread O
use O
of O
antibiotic O
prophylaxis O
during O
labour O
, O
but O
so O
far O
the O
effects O
seem O
minor O
and O
temporary O
. O

Vaccination O
against O
GBS O
would O
be O
acceptable O
to O
most O
women B-SEX
and O
GBS O
vaccines O
are O
in O
the O
early O
stages O
of O
development O
. O

Tweetable O
abstract O
: O
Group O
B O
Strep O
is O
a O
key O
cause O
of O
infection O
, O
death O
and O
disability O
in O
young O
babies O
. O

Antibiotics O
given O
in O
labour O
remain O
the O
mainstay O
of O
prevention O
, O
until O
a O
vaccine O
is O
available O
. O

BACKGROUND O
: O
Adrenocortical O
carcinoma O
( O
ACC O
) O
is O
a O
rare O
endocrine O
malignancy O
, O
often O
with O
an O
unfavorable O
prognosis O
. O

Radical O
adrenalectomy O
is O
the O
gold O
standard O
of O
treatment O
of O
localized O
disease O
. O

CASE O
DESCRIPTION O
: O
We O
report O
a O
case O
of O
a O
23 O
- O
year O
- O
old O
male B-SEX
patient O
who O
presented O
with O
persistent O
left O
flank O
pain O
and O
urticaria O
for O
3 O
months O
. O

Imaging O
studies O
confirmed O
the O
presence O
of O
a O
large O
left O
adrenal O
mass O
with O
malignant O
features O
. O

The O
biochemical O
workup O
was O
unremarkable O
. O

Open O
left O
radical O
adrenalectomy O
was O
performed O
, O
the O
final O
pathologic O
examination O
showed O
ACC O
with O
negative O
surgical O
margins O
. O

The O
patient O
remained O
disease O
- O
free O
for O
eighteen O
months O
period O
of O
follow O
up O
after O
surgery O
. O

DISCUSSION O
: O
ACC O
is O
a O
rare O
neoplasm O
with O
poor O
prognosis O
and O
with O
an O
incidence B-EPI
of O
one B-STAT
in I-STAT
one I-STAT
million I-STAT
population I-STAT
. O

There O
is O
a O
slight O
female B-SEX
predilection O
. O

The O
ACC O
may O
be O
functional O
with O
a O
clinically O
pure O
endocrine O
syndrome O
like O
Cushing O
syndrome O
. O

Most O
of O
patients O
with O
ACC O
present O
with O
symptoms O
and O
signs O
of O
hormonal O
secretion O
. O

Adrenal O
computed O
tomography O
( O
CT O
) O
scanning O
and O
magnetic O
resonance O
imaging O
( O
MRI O
) O
are O
the O
imaging O
studies O
of O
choice O
in O
ACC O
. O

When O
feasible O
, O
total O
resection O
remains O
the O
treatment O
of O
choice O
for O
the O
definitive O
treatment O
of O
ACC O
. O

The O
benefit O
of O
the O
use O
of O
mitotane O
as O
an O
adjuvant O
treatment O
has O
been O
considered O
controversial O
. O

Adjuvant O
mitotane O
significantly O
decreases O
the O
recurrence O
and O
mortality O
rate O
after O
resection O
of O
ACC O
in O
patients O
without O
distant O
metastasis O
as O
proved O
by O
some O
studies O
, O
but O
these O
findings O
need O
further O
validation O
. O

CONCLUSION O
: O
ACC O
is O
a O
rare O
neoplasm O
characterized O
by O
a O
high O
risk O
of O
recurrence O
after O
surgical O
resection O
. O

The O
high O
prevalence B-EPI
of O
hearing O
loss O
among O
older O
adults O
creates O
a O
perception O
that O
it O
is O
simply O
a O
benign O
consequence O
of O
aging O
, O
which O
leads O
to O
unaddressed O
communication O
needs O
. O

Strategies O
to O
address O
hearing O
loss O
as O
part O
of O
routine O
clinical O
care O
are O
pertinent O
to O
the O
geriatric O
care O
setting O
where O
hearing O
loss O
is O
prevalent B-EPI
in O
two B-STAT
out I-STAT
of O
every I-STAT
three I-STAT
patients O
70 O
years O
and O
older O
. O

Our O
objectives O
are O
to O
briefly O
discuss O
the O
pathophysiology O
of O
hearing O
loss O
, O
describe O
the O
epidemiologic O
prevalence B-EPI
and O
impact O
, O
identify O
statutory O
barriers O
facing O
older O
adults O
in O
accessing O
hearing O
care O
, O
discuss O
current O
progress O
on O
legislation O
to O
address O
accessibility O
issues O
, O
and O
provide O
actionable O
strategies O
for O
addressing O
hearing O
loss O
as O
a O
barrier O
to O
effective O
communication O
. O

Simple O
steps O
can O
be O
taken O
to O
improve O
hearing O
care O
accessibility O
for O
older O
adults O
with O
hearing O
loss O
and O
can O
optimize O
understanding O
in O
daily O
communication O
, O
re O
- O
engage O
patients O
in O
being O
actively O
involved O
in O
their O
care O
, O
and O
promote O
patient O
autonomy O
in O
informed O
decision- O
making O
. O

In O
recent O
years O
the O
number O
of O
disorders O
known O
to O
affect O
amino O
acid O
synthesis O
has O
grown O
rapidly O
. O

Nor O
is O
it O
just O
the O
number O
of O
disorders O
that O
has O
increased O
: O
the O
associated O
clinical O
phenotypes O
have O
also O
expanded O
spectacularly O
, O
primarily O
due O
to O
the O
advances O
of O
next O
generation O
sequencing O
diagnostics O
. O

In O
contrast O
to O
the O
classical O
inborn O
errors O
of O
metabolism O
in O
catabolic O
pathways O
, O
in O
which O
elevated O
levels O
of O
metabolites O
are O
easily O
detected O
in O
body O
fluids O
, O
synthesis O
defects O
present O
with O
low O
values O
of O
metabolites O
or O
, O
confusingly O
, O
even O
completely O
normal O
levels O
of O
amino O
acids O
. O

This O
makes O
the O
biochemical O
diagnosis O
of O
this O
relatively O
new O
group O
of O
metabolic O
diseases O
challenging O
. O

Defects O
in O
the O
synthesis O
pathways O
of O
serine O
metabolism O
, O
glutamine O
, O
proline O
and O
, O
recently O
, O
asparagine O
have O
all O
been O
reported O
. O

Although O
these O
amino O
acid O
synthesis O
defects O
are O
in O
unrelated O
metabolic O
pathways O
, O
they O
do O
share O
many O
clinical O
features O
. O

In O
children O
the O
central O
nervous O
system O
is O
primarily O
affected O
, O
giving O
rise O
to O
( O
congenital O
) O
microcephaly O
, O
early O
onset O
seizures O
and O
varying O
degrees O
of O
mental O
disability O
. O

The O
brain O
abnormalities O
are O
accompanied O
by O
skin O
disorders O
such O
as O
cutis O
laxa O
in O
defects O
of O
proline O
synthesis O
, O
collodion O
- O
like O
skin O
and O
ichthyosis O
in O
serine O
deficiency O
, O
and O
necrolytic O
erythema O
in O
glutamine O
deficiency O
. O

Hypomyelination O
with O
accompanying O
loss O
of O
brain O
volume O
and O
gyration O
defects O
can O
be O
observed O
on O
brain O
MRI O
in O
all O
synthesis O
disorders O
. O

In O
adults O
with O
defects O
in O
serine O
or O
proline O
synthesis O
, O
spastic O
paraplegia O
and O
several O
forms O
of O
polyneuropathy O
with O
or O
without O
intellectual O
disability O
appear O
to O
be O
the O
major O
symptoms O
in O
these O
late O
- O
presenting O
forms O
of O
amino O
acid O
disorders O
. O

This O
review O
provides O
a O
comprehensive O
overview O
of O
the O
disorders O
in O
amino O
acid O
synthesis O
. O

Congenital O
lung O
agenesis O
is O
an O
extremely O
rare O
condition O
with O
an O
estimated B-EPI
prevalence I-EPI
of O
34 B-STAT
in I-STAT
1,000,000 I-STAT
live I-STAT
births I-STAT
. O

It O
is O
often O
associated O
with O
other O
congenital O
malformations O
of O
the O
skeletal O
, O
cardiovascular O
, O
urogenital O
, O
and O
gastrointestinal O
systems O
. O

We O
discuss O
the O
case O
of O
a O
5 O
- O
month O
- O
old O
who O
presented O
with O
increasing O
stridor O
over O
1 O
month O
. O

Imaging O
revealed O
right O
lung O
agenesis O
, O
complete O
dextromalposition O
of O
heart O
, O
and O
compression O
of O
distal O
trachea O
. O

An O
intrathoracic O
saline O
tissue O
expander O
was O
placed O
which O
marked O
improved O
distal O
tracheal O
stenosis O
. O

In O
patients O
who O
are O
symptomatic O
it O
becomes O
imperative O
to O
perform O
surgeries O
to O
increase O
survival O
as O
was O
the O
case O
in O
this O
patient O
. O

Childhood O
wasting O
is O
among O
the O
most O
prevalent B-EPI
forms O
of O
undernutrition O
globally B-LOC
. O

The O
Southeast B-LOC
Asia I-LOC
region O
is O
home O
to O
many O
wasted O
children O
, O
but O
wasting O
is O
not O
recognized O
as O
a O
public O
health O
problem O
and O
its O
epidemiology O
is O
yet O
to O
be O
fully O
examined O
. O

This O
analysis O
aimed O
to O
determine O
the O
burden O
of O
wasting O
, O
its O
predictors O
, O
and O
the O
level O
of O
wasting O
and O
stunting O
concurrence O
. O

Datasets O
from O
Demographic O
and O
Health O
Surveys O
and O
Multiple O
Indicator O
Cluster O
Surveys O
in O
six O
countries O
in O
the O
region O
were O
analyzed O
. O

The O
pooled O
weighted O
prevalence I-EPI
for O
wasting O
and O
concurrent O
wasting O
and O
stunting O
among O
children O
0 O
- O
59 O
months O
in O
the O
six O
countries O
was O
8.9 O
% O
, O
95 O
% O
CI O
( O
8.0 O
- O
9.9 O
) O
and O
1.6 O
% O
, O
95 O
% O
CI O
( O
1.5 O
- O
1.8 O
) O
, O
respectively O
. O

This O
prevalence B-EPI
is O
approximately O
12 O
- O
fold O
higher O
than O
the O
0.7 B-STAT
% I-STAT
prevalence B-EPI
of O
high O
- O
income O
countries O
; O
and O
translated O
into O
an O
absolute O
number O
of O
1,088,747 O
children O
affected O
by O
wasting O
and O
272,563 O
concurrent O
wasting O
and O
stunting O
. O

Wasting O
prevalence B-EPI
was O
50 O
percent O
higher O
in O
the O
0 O
- O
23 O
- O
month O
age O
group O
. O

Predictors O
for O
wasting O
included O
source O
of O
drinking O
water O
, O
wealth O
index O
, O
urban O
residence O
, O
child O
's O
age O
and O
history O
of O
illness O
and O
mother O
's O
body O
mass O
index O
. O

In O
conclusion O
, O
our O
analysis O
showed O
that O
wasting O
is O
a O
serious O
public O
health O
problem O
in O
the O
region O
that O
should O
be O
addressed O
urgently O
using O
both O
preventive O
and O
curative O
approaches O
. O

Q O
fever O
is O
a O
disease O
of O
high O
zoonotic O
potential O
, O
but O
interest O
in O
its O
causative O
agent O
is O
rather O
low O
although O
it O
causes O
some O
public O
health O
problems O
in O
Hungary B-LOC
. O

The O
prevalence B-EPI
of O
Q O
fever O
is O
highly O
variable O
by O
country O
. O

The O
main O
reservoirs O
of O
the O
disease O
are O
the O
same O
domestic O
ruminant O
species O
everywhere O
, O
but O
the O
epidemiological O
profile O
depends O
on O
the O
features O
of O
the O
specific O
reservoir O
. O

The O
aim O
of O
this O
large O
- O
scale O
study O
was O
to O
demonstrate O
the O
importance O
of O
Q O
fever O
in O
different O
species O
as O
a O
possible O
source O
for O
human O
infection O
in O
most O
regions O
of O
Hungary B-LOC
. O

A O
total O
of O
851 O
serum O
samples O
from O
44 O
dairy O
farms O
, O
16 O
sheep O
flocks O
, O
4 O
goat O
farms O
and O
3 O
zoos O
located O
in O
different O
parts O
of O
Hungary B-LOC
were O
tested O
. O

The O
presence O
of O
antibodies O
to O
Coxiella O
burnetii O
was O
surveyed O
in O
dairy O
cattle O
( O
n O
= O
547 O
) O
, O
goats O
( O
n O
= O
71 O
) O
, O
sheep O
( O
n O
= O
200 O
) O
and O
zoo O
animals O
( O
n O
= O
33 O
) O
. O

The O
animal O
species O
tested O
in O
Hungary B-LOC
showed O
different O
seroprevalence O
values O
of O
C. O
burnetii O
infection O
. O

Seropositivity O
by O
the O
enzyme O
- O
linked O
immunosorbent O
assay O
was O
found O
in O
258 O
out O
of O
547 O
( O
47.2 O
% O
) O
cows O
and O
in O
69 O
out O
of O
271 O
( O
25.5 O
% O
) O
small O
ruminants O
, O
among O
them O
in O
47 O
out O
of O
200 O
( O
23.5 O
% O
) O
sheep O
and O
in O
22 O
out O
of O
71 O
( O
31.0 O
% O
) O
goats O
. O

Antibodies O
to O
C. O
burnetii O
were O
not O
detected O
in O
zoo O
animals O
. O

Seropositivity O
was O
demonstrated O
in O
44 O
out O
of O
44 O
( O
100 O
% O
) O
dairy O
cattle O
farms O
, O
with O
at O
least O
one O
serum O
sample O
found O
to O
be O
positive O
on O
each O
farm O
. O

The O
seropositivity O
rate O
of O
small O
ruminant O
farms O
was O
55.0 O
% O
( O
11 O
positive O
out O
of O
20 O
tested O
) O
, O
with O
9 O
out O
of O
16 O
( O
56.3 O
% O
) O
sheep O
flocks O
and O
2 O
out O
of O
4 O
( O
50.0 O
% O
) O
goat O
herds O
showing O
seropositivity O
. O

Microcephaly O
is O
a O
prevalent B-EPI
phenotype O
in O
patients O
with O
neurodevelopmental O
problems O
, O
often O
with O
genetic O
causes O
. O

We O
comprehensively O
investigated O
the O
clinical O
phenotypes O
and O
genetic O
background O
of O
microcephaly O
in O
40 O
Korean B-ETHN
patients O
. O

We O
analyzed O
their O
clinical O
phenotypes O
and O
radiologic O
images O
and O
conducted O
whole O
exome O
sequencing O
( O
WES O
) O
and O
analysis O
of O
copy O
number O
variation O
( O
CNV O
) O
. O

Infantile O
hypotonia O
and O
developmental O
delay O
were O
present O
in O
all O
patients O
. O

Thirty O
- O
four O
patients O
( O
85 O
% O
) O
showed O
primary O
microcephaly O
. O

The O
diagnostic O
yield O
from O
the O
WES O
and O
CNV O
analyses O
was O
47.5 O
% O
. O

With O
WES O
, O
we O
detected O
pathogenic O
or O
likely O
pathogenic O
variants O
that O
were O
previously O
associated O
with O
microcephaly O
in O
12 O
patients O
( O
30 O
% O
) O
; O
nine O
of O
these O
were O
de O
novo O
variants O
with O
autosomal O
dominant O
inheritance O
. O

Two O
unrelated O
patients O
had O
mutations O
in O
the O
KMT2A O
gene O
. O

In O
10 O
other O
patients O
, O
we O
found O
mutations O
in O
the O
GNB1 O
, O
GNAO1 O
, O
TCF4 O
, O
ASXL1 O
, O
SMC1A O
, O
VPS13B O
, O
ACTG1 O
, O
EP300 O
, O
and O
KMT2D O
genes O
. O

Seven O
patients O
( O
17.5 O
% O
) O
were O
diagnosed O
with O
pathogenic O
CNVs O
. O

Korean B-ETHN
patients O
with O
microcephaly O
show O
a O
genetic O
spectrum O
that O
is O
different O
from O
that O
of O
patients O
with O
microcephaly O
of O
other O
ethnicities O
. O

WES O
along O
with O
CNV O
analysis O
represents O
an O
effective O
approach O
for O
diagnosis O
of O
the O
underlying O
causes O
of O
microcephaly O
. O

Renal O
and O
hepatic O
functions O
are O
often O
mingled O
through O
both O
the O
existence O
of O
associated O
primary O
organ O
diseases O
and O
hemodynamic O
co O
- O
relationship O
. O

The O
primary O
objective O
of O
this O
study O
was O
to O
sum O
up O
the O
relationship O
between O
autoimmune O
hepatitis O
( O
AIH O
) O
on O
renal O
tubular O
acidosis O
( O
RTA O
) O
and O
the O
stages O
of O
the O
disease O
. O

A O
systematic O
review O
was O
performed O
for O
24 O
trials O
. O

A O
total O
of O
3687 O
patients O
were O
included O
. O

The O
incidence B-EPI
of O
RTA O
occurring O
and O
short O
- O
term O
mortality O
reduction O
was O
seen O
in O
two O
groups O
; O
for O
an O
overall O
effect O
: O
Z O
= O
2.85 O
( O
P O
= O
0.004 O
) O
a O
total O
95 O
% O
CI O
of O
0.53 O
[ O
0.34 O
, O
0.82 O
] O
. O

Only O
one O
patient O
with O
alcoholic O
liver O
cirrhosis O
was O
found O
to O
have O
an O
incomplete O
type O
of O
RTA O
. O

Test O
for O
overall O
effect O
: O
Z O
= O
2.28 O
( O
P O
= O
0.02 O
) O
95 O
% O
CI O
of O
2.83 O
[ O
1.16 O
, O
6.95 O
] O
. O

A O
reduction O
in O
fatal O
infections O
with O
dual O
therapy O
of O
corticosteroid O
plus O
N O
- O
acetylcysteine O
( O
NAC O
) O
test O
for O
overall O
effect O
: O
Z O
= O
3.07 O
( O
P O
= O
0.002 O
) O
with O
95 O
% O
CI O
of O
0.45 O
[ O
0.27 O
, O
0.75 O
] O
. O

Autoimmune O
diseases O
are O
the O
most O
frequent O
underlying O
cause O
of O
secondary O
RTA O
in O
adults O
. O

The O
primary O
renal O
disease O
must O
be O
actively O
excluded O
in O
all O
patients O
with O
hepatic O
failure O
by O
aggressive O
clinical O
and O
laboratory O
evaluations O
. O

Rhabdomyosarcoma O
( O
RMS O
) O
is O
the O
most O
common O
soft O
- O
tissue O
sarcoma O
in O
children O
, O
yet O
little O
is O
known O
about O
its O
etiology O
. O

Studies O
that O
examine O
either O
environmental O
exposures O
or O
germline O
genetic O
predisposition O
in O
RMS O
have O
begun O
to O
identify O
factors O
that O
contribute O
to O
this O
malignancy O
. O

Here O
, O
we O
summarize O
epidemiological O
reports O
of O
RMS O
incidence B-EPI
in O
terms O
of O
several O
factors O
, O
including O
age O
at O
diagnosis O
, O
biological O
sex O
, O
and O
geographic O
location O
. O

We O
then O
describe O
findings O
from O
association O
studies O
, O
which O
explore O
the O
role O
of O
parental O
exposures O
, O
birth O
and O
perinatal O
characteristics O
, O
and O
childhood O
exposures O
in O
RMS O
. O

Further O
, O
we O
discuss O
RMS O
predisposition O
syndromes O
and O
large O
- O
scale O
sequencing O
studies O
that O
have O
further O
identified O
RMS O
- O
associated O
genes O
. O

Finally O
, O
we O
propose O
future O
directions O
of O
study O
, O
which O
aim O
to O
advance O
our O
understanding O
of O
the O
origin O
of O
RMS O
and O
can O
provide O
knowledge O
for O
novel O
RMS O
therapies O
. O

Objective O
: O
To O
analyze O
the O
prevalence B-EPI
and O
the O
related O
factors O
of O
dyslipidemia O
in O
21 O
- O
hydroxylase O
deficiency O
( O
21 O
- O
OHD O
) O
patients O
. O

Methods O
: O
A O
total O
of O
205 O
patients O
with O
21 O
- O
OHD O
were O
recruited O
in O
Peking B-LOC
Union I-LOC
Medical I-LOC
College I-LOC
Hospital O
from O
January B-DATE
2016 I-DATE
to I-DATE
January I-DATE
2018 I-DATE
. O

The O
basic O
information O
, O
glucocorticoid O
replacement O
therapy O
, O
and O
laboratory O
examination O
results O
of O
patients O
were O
obtained O
from O
medical O
records O
. O

The O
genotypes O
of O
CYP21A2 O
were O
identified O
by O
Sanger O
sequencing O
and O
multiplex O
ligation O
dependent O
probe O
amplification O
. O

The O
prevalence B-EPI
of O
dyslipidemia O
among O
21 O
- O
OHD O
patients O
, O
basic O
information O
and O
related O
hormone O
levels O
of O
21 O
- O
OHD O
patients O
with O
different O
status O
of O
blood O
lipid O
were O
described O
. O

Logistic O
regression O
model O
was O
used O
to O
analyze O
the O
related O
factors O
of O
dyslipidemia O
in O
21 O
- O
OHD O
patients O
. O

Results O
: O
The O
age O
of O
subjects O
was O
17.0 O
( O
8.3 O
, O
25.0 O
) O
years O
old O
, O
including O
51 O
males B-SEX
( O
24.9 O
% O
) O
. O

According O
to O
CYP21A2 O
genotypes O
, O
there O
were O
16 O
cases O
in O
Null O
group O
, O
26 O
cases O
in O
Group O
A O
, O
105 O
cases O
in O
group O
B O
, O
27 O
cases O
in O
group O
C O
, O
and O
31 O
cases O
in O
group O
D. O
The O
incidence B-EPI
of O
dyslipidemia O
was O
29.3 O
% O
( O
60/205 O
) O
, O
among O
which O
37.3 O
% O
( O
19/51 O
) O
in O
male B-SEX
and O
26.6 O
% O
( O
41/154 O
) O
in O
female B-SEX
patients O
, O
respectively O
. O

The O
M O
( O
Q O
1 O
, O
Q O
3 O
) O
of O
total O
cortisol O
level O
( O
nmol O
/ O
L O
) O
and O
body O
mass O
index O
( O
kg O
/ O
m O
2 O
) O
of O
male B-SEX
21 O
- O
OHD O
patients O
with O
dyslipidemia O
were O
0.17 O
( O
0.06 O
, O
0.35 O
) O
and O
25.76 O
( O
17.01 O
, O
30.45 O
) O
, O
respectively O
, O
which O
were O
higher O
than O
those O
with O
ortholiposis O
[ O
0.04 O
( O
0.02 O
, O
0.21 O
) O
and O
18.83 O
( O
16.53 O
, O
23.88 O
) O
] O
( O
all O
P O
0.05 O
) O
. O

The O
M O
( O
Q O
1 O
, O
Q O
3 O
) O
of O
progesterone O
level O
( O
nmol O
/ O
L O
) O
, O
body O
mass O
index O
( O
kg O
/ O
m O
2 O
) O
and O
age O
( O
years O
) O
of O
female B-SEX
21 O
- O
OHD O
patients O
with O
dyslipidemia O
were O
74.40 O
( O
50.97 O
, O
98.52 O
) O
, O
23.09 O
( O
21.78 O
, O
27.78 O
) O
and O
23.00 O
( O
16.50 O
, O
28.00 O
) O
, O
respectively O
, O
which O
were O
higher O
than O
those O
with O
ortholiposis O
[ O
52.81 O
( O
33.41 O
, O
68.85 O
) O
, O
21.55 O
( O
18.63 O
, O
25.71 O

) O
and O
18.00 O
( O
9.50 O
, O
25.00 O
) O
] O
( O
all O
P O
0.05 O
) O
. O

The O
risk O
of O
dyslipidemia O
increased O
by O
5.0 O
% O
[ O
OR O
( O
95 O
% O
CI O
): O
1.05 O
( O
1.01 O
, O
1.09 O
) O
] O
for O
every O
1 O
nmol O
/ O
L O
increase O
of O
progesterone O
. O

Conclusion O
: O
The O
incidence B-EPI
of O
dyslipidemia O
is O
high O
in O
21 O
- O
OHD O
patients O
, O
and O
progesterone O
level O
is O
positively O
correlated O
with O
dyslipidemia O
. O

Lysosomal O
disorders O
are O
diseases O
that O
involve O
mutations O
in O
genes O
responsible O
for O
the O
coding O
of O
lysosomal O
enzymes O
, O
transport O
proteins O
, O
activator O
proteins O
and O
protein O
processing O
enzymes O
. O

These O
defects O
lead O
to O
the O
storage O
of O
specific O
metabolites O
within O
lysosomes O
resulting O
in O
a O
great O
variety O
of O
clinical O
features O
depending O
on O
the O
tissues O
with O
the O
storage O
, O
the O
storage O
products O
and O
the O
extent O
of O
the O
storage O
. O

The O
methods O
for O
rapidly O
diagnosing O
patients O
started O
in O
the O
late O
1960 B-DATE
's O
when O
the O
enzyme O
defects O
were O
identified O
eliminating O
the O
need O
for O
tissue O
biopsies O
. O

The O
first O
requests O
for O
diagnostic O
help O
in O
this O
laboratory O
came O
in O
1973 B-DATE
. O

In O
that O
year O
, O
patients O
with O
Krabbe O
disease O
and O
Niemann O
- O
Pick O
type O
A O
were O
diagnosed O
. O

Since O
that O
time O
samples O
from O
about O
62000.0 O
individuals O
have O
been O
received O
for O
diagnostic O
studies O
, O
and O
4900 O
diagnoses O
have O
been O
made O
. O

The O
largest O
number O
of O
diagnosed O
individuals O
had O
metachromatic O
leukodystrophy O
and O
Krabbe O
disease O
because O
of O
our O
research O
interest O
in O
leukodystrophies O
. O

A O
number O
of O
new O
disorders O
were O
identified O
and O
the O
primary O
defects O
in O
other O
disorders O
were O
clarified O
. O

With O
new O
methods O
for O
diagnosis O
, O
including O
newborn O
screening O
, O
molecular O
analysis O
, O
microarrays O
, O
there O
is O
still O
a O
need O
for O
biochemical O
confirmation O
before O
treatment O
is O
considered O
. O

With O
new O
treatments O
, O
including O
gene O
therapy O
, O
stem O
cell O
transplantation O
, O
enzyme O
replacement O
used O
alone O
or O
in O
combination O
becoming O
more O
available O
, O
the O
need O
for O
rapid O
, O
accurate O
diagnosis O
is O
critical O
. O

Background O
and O
aims O
one O
of O
the O
health O
concerns O
for O
any O
society O
is O
to O
have O
its O
own O
standard O
of O
growth O
. O

The O
aim O
of O
this O
study O
was O
to O
provide O
the O
age- O
and O
sex O
- O
specific O
percentile O
values O
of O
anthropometric O
measures O
for O
adolescents O
of O
developing O
countries O
. O

The O
use O
of O
global O
percentiles O
in O
developing O
countries O
overestimates O
underweight O
and O
stunting O
while O
underestimates O
overweight O
and O
obesity O
. O

Methods O
The O
data O
were O
obtained O
from O
the O
Global O
School O
- O
based O
Student O
Health O
Survey O
( O
GSHS O
) O
. O

This O
study O
was O
conducted O
on O
school O
students O
, O
selected O
by O
multistage O
random O
cluster O
sampling O
from O
73 O
developing O
countries O
. O

A O
parametric O
method O
was O
used O
for O
constructing O
age O
- O
specific O
reference O
intervals O
( O
normal O
ranges O
) O
. O

Results O
In O
general O
, O
210,045 O
11 O
- O
18 O
years O
- O
old O
schoolchildren O
( O
14.38 O
± O
1.39 O
) O
from O
73 O
developing O
countries O
between B-DATE
2003 I-DATE
and I-DATE
2014 I-DATE
were O
included O
in O
this O
study O
, O
among O
which O
103,080 O
( O
49.08 O
% O
) O
were O
male B-SEX
and O
106,965 O
( O
50.92 O
% O
) O
were O
female B-SEX
. O

Calculation O
of O
body O
mass O
index O
( O
BMI O
) O
percentile O
showed O
that O
for O
all O
BMI O
percentile O
curves O
of O
both O
sexes O
, O
there O
was O
a O
gradual O
increase O
up O
to O
the O
age O
of O
around O
15 O
years O
, O
and O
then O
remain O
stable O
( O
except O
for O
95th O
percentile O
) O
. O

Moreover O
in O
all O
weight O
percentile O
curves O
of O
boys B-SEX
, O
except O
90th O
and O
above O
, O
there O
was O
a O
slight O
rise O
until O
the O
age O
of O
18 O
years O
. O

In O
10th O
height O
percentile O
curves O
and O
above O
in O
boys B-SEX
, O
there O
was O
a O
sharp O
increase O
up O
to O
the O
age O
of O
17 O
, O
followed O
by O
a O
decline O
. O

Similarly O
, O
this O
pattern O
was O
found O
for O
50th O
height O
percentile O
and O
above O
in O
girls B-SEX
. O

Conclusion O
The O
use O
of O
global O
percentiles O
in O
developing O
countries O
overestimates O
underweight O
and O
stunting O
while O
underestimates O
overweight O
and O
obesity O
. O

Premature O
loss O
of O
ovarian O
activity O
before O
40 O
years O
of O
age O
is O
known O
as O
primary O
ovarian O
insufficiency O
( O
POI O
) O
and O
occurs B-EPI
in O
~ O
1.0 B-STAT
% I-STAT
of O
women B-SEX
. O

A O
more O
subtle O
decline O
in O
ovarian O
activity O
, O
known O
as O
premature O
ovarian O
ageing O
( O
POA O
) O
, O
occurs B-EPI
in O
~ O
10.0 B-STAT
% I-STAT
of O
women B-SEX
. O

Despite O
the O
high O
prevalence B-EPI
of O
POA O
, O
very O
little O
is O
known O
regarding O
its O
genetic O
causation O
. O

Senataxin O
( O
SETX O
) O
is O
an O
RNA O
/ O
DNA O
helicase O
involved O
in O
repair O
of O
oxidative O
stress O
- O
induced O
DNA O
damage O
. O

Homozygous O
mutation O
of O
SETX O
leads O
to O
the O
neurodegenerative O
disorder O
, O
ataxia O
oculomotor O
apraxia O
type O
2 O
( O
AOA2 O
) O
. O

There O
have O
been O
reports O
of O
POI O
in O
AOA2 O
females B-SEX
suggesting O
a O
link O
between O
SETX O
and O
ovarian O
ageing O
. O

Here O
, O
we O
studied O
female B-SEX
mice O
lacking O
either O
one O
( O
Setx+/- O
) O
or O
both O
( O
Setx-/- O
) O
copies O
of O
SETX O
over O
a O
12- O
to O
14 O
- O
month O
period O
. O

We O
find O
that O
DNA O
damage O
is O
increased O
in O
oocytes O
from O
8 O
- O
month O
- O
old O
Setx+/- O
and O
Setx-/- O
females B-SEX
compared O
with O
Setx+/+ O
oocytes O
leading O
to O
a O
marked O
reduction O
in O
all O
classes O
of O
ovarian O
follicles O
at O
least O
4 O
months O
earlier O
than O
typically O
occurs O
in O
female B-SEX
mice O
. O

Furthermore O
, O
during O
a O
12 O
- O
month O
long O
mating O
trial O
, O
Setx+/- O
and O
Setx-/- O
females B-SEX
produced O
significantly O
fewer O
pups O
than O
Setx+/+ O
females B-SEX
from O
7 O
months O
of O
age O
onwards O
. O

These O
data O
show O
that O
SETX O
is O
critical O
for O
preventing O
POA O
in O
mice O
, O
likely O
by O
preserving O
DNA O
integrity O
in O
oocytes O
. O

Intriguingly O
, O
heterozygous O
Setx O
loss O
causes O
an O
equally O
severe O
impact O
on O
ovarian O
ageing O
as O
homozygous O
Setx O
loss O
. O

Because O
heterozygous O
SETX O
disruption O
is O
less O
likely O
to O
produce O
systemic O
effects O
, O
SETX O
compromise O
could O
underpin O
some O
cases O
of O
insidious O
POA O
. O

Objectives O
The O
objective O
of O
our O
study O
was O
to O
conduct O
a O
systematic O
literature O
review O
of O
estimates O
of O
costs O
of O
illness O
of O
spinal O
muscular O
atrophy O
( O
SMA O
) O
. O

Methods O
We O
searched O
MEDLINE O
( O
through O
PubMed O
) O
, O
CINAHL O
, O
Embase O
, O
Web O
of O
Science O
, O
National O
Health O
Service O
Economic O
Evaluation O
Database O
, O
and O
the O
National O
Health O
Service O
Health O
Technology O
Assessment O
Database O
for O
studies O
published O
from O
inception O
up O
until O
31 B-DATE
August I-DATE
, I-DATE
2020 I-DATE
, O
reporting O
direct O
medical O
, O
direct O
non O
- O
medical O
, O
and/or O
indirect O
costs O
of O
any O
phenotype O
of O
SMA O
. O

Two O
reviewers O
independently O
screened O
records O
for O
eligibility O
, O
extracted O
the O
data O
, O
and O
assessed O
studies O
for O
risk O
of O
bias O
using O
the O
Newcastle B-LOC
- O
Ottawa B-LOC
Scale O
. O

Costs O
were O
adjusted O
and O
converted O
to O
2018 O
US O
dollars O
. O

Results O
The O
search O
identified O
14 O
studies O
from O
eight O
countries O
( O
Australia B-LOC
, O
France B-LOC
, O
Germany B-LOC
, O
Italy B-LOC
, O
Spain B-LOC
, O
Sweden B-LOC
, O
the O
UK B-LOC
, O
and O
the O
USA B-LOC
) O
. O

The O
mean O
per O
- O
patient O
annual O
direct O
medical O
cost O
of O
illness O
was O
estimated O
at O
between O
$ O
3320 O
( O
SMA O
type O
III O
, O
Italy B-LOC
) O
and O
$ O
324,410 O
( O
SMA O
type O
I O
, O
USA B-LOC
) O
, O
mean O
per O
- O
patient O
annual O
direct O
non O
- O
medical O
cost O
between O
$ O
25,880 O
( O
SMA O
types O
I O
- O
III O
, O
Spain O
) O
and O
$ O
136,800 O
( O
SMA O
type O
I O
, O
Sweden B-LOC
) O
, O
and O
mean O
per O
- O
patient O
annual O
indirect O
cost O
between O
$ O
9440 O
( O
SMA O
type O
I O
, O
Germany B-LOC
) O
and O
$ O
74,910 O
( O
SMA O
type O
II O
, O
Australia B-LOC
) O
. O

Most O
studies O
exhibited O
a O
risk O
of O
bias O
. O

Conclusions O
The O
current O
body O
of O
evidence O
of O
costs O
of O
illness O
of O
SMA O
is O
relatively O
scarce O
and O
characterized O
by O
considerable O
variability O
across O
geographical O
settings O
and O
disease O
phenotypes O
. O

Our O
review O
provides O
data O
pertaining O
to O
the O
economic O
impact O
of O
SMA O
, O
which O
is O
of O
particular O
relevance O
in O
light O
of O
emerging O
treatments O
and O
ongoing O
research O
in O
this O
field O
, O
and O
underscores O
the O
substantial O
unmet O
medical O
need O
in O
this O
patient O
population O
. O

Background O
Dominant O
optic O
atrophy O
( O
DOA O
) O
is O
an O
inherited O
optic O
neuropathy O
that O
mainly O
affects O
visual O
acuity O
, O
central O
visual O
fields O
and O
color O
vision O
due O
to O
a O
progressive O
loss O
of O
retinal O
ganglion O
cells O
and O
their O
axons O
that O
form O
the O
optic O
nerve O
. O

Approximately O
45 O
- O
90 O
% O
of O
affected O
individuals O
with O
DOA O
harbor O
pathogenic O
variants O
in O
the O
OPA1 O
gene O
. O

The O
mutation O
spectrum O
of O
OPA1 O
comprises O
nonsense O
, O
canonical O
and O
non O
- O
canonical O
splice O
site O
, O
frameshift O
and O
missense O
as O
well O
as O
copy O
number O
variants O
, O
but O
intragenic O
inversions O
have O
not O
been O
reported O
so O
far O
. O

Case O
presentation O
We O
report O
a O
33 O
- O
year O
- O
old O
male B-SEX
with O
characteristic O
clinical O
features O
of O
DOA O
. O

Whole O
- O
genome O
sequencing O
identified O
a O
structural O
variant O
of O
2.4 O
kb O
comprising O
an O
inversion O
of O
937 O
bp O
at O
the O
OPA1 O
locus O
. O

Fine O
mapping O
of O
the O
breakpoints O
to O
single O
nucleotide O
level O
revealed O
that O
the O
structural O
variation O
was O
an O
inversion O
flanked O
by O
two O
deletions O
. O

As O
this O
rearrangement O
inverts O
the O
entire O
first O
exon O
of O
OPA1 O
, O
it O
was O
classified O
as O
likely O
pathogenic O
. O

Conclusions O
We O
report O
the O
first O
DOA O
case O
harboring O
an O
inversion O
in O
the O
OPA1 O
gene O
. O

Our O
study O
demonstrates O
that O
copy O
- O
neutral O
genomic O
rearrangements O
have O
to O
be O
considered O
as O
a O
possible O
cause O
of O
disease O
in O
DOA O
cases O
. O

Introduction O
/ O
background O
Bladder O
exstrophy O
patients O
have O
a O
high O
prevalence B-EPI
of O
inguinal O
hernia O
that O
often O
become O
clinically O
evident O
following O
bladder O
closure O
. O

Understanding O
when O
the O
bladder O
exstrophy O
patient O
is O
under O
greatest O
risk O
of O
developing O
an O
inguinal O
hernia O
following O
bladder O
closure O
is O
important O
, O
since O
incarceration O
resulting O
in O
strangulation O
of O
intra O
- O
abdominal O
contents O
can O
lead O
to O
significant O
morbidity O
if O
not O
addressed O
in O
a O
timely O
fashion O
. O

Although O
the O
incidence B-EPI
and O
risk O
factors O
of O
inguinal O
hernia O
have O
been O
reported O
, O
the O
timing O
of O
occurrence B-EPI
is O
not O
well O
understood O
. O

Objective O
The O
primary O
objective O
of O
this O
study O
was O
to O
assess O
the O
timing O
of O
inguinal O
hernia O
following O
complete O
primary O
repair O
of O
bladder O
exstrophy O
( O
CPRE O
) O
. O

In O
addition O
, O
we O
aimed O
to O
evaluate O
possible O
risk O
factors O
associated O
with O
inguinal O
hernia O
, O
including O
sex O
, O
age O
at O
bladder O
closure O
and O
iliac O
osteotomy O
status O
. O

Study O
design O
A O
multi O
- O
institutional O
retrospective O
review O
identified O
patients O
with O
bladder O
exstrophy O
repaired O
by O
CPRE O
under O
6 O
months O
of O
age O
while O
excluding O
those O
who O
underwent O
inguinal O
hernia O
repair O
before O
or O
during O
bladder O
closure O
. O

Timing O
of O
inguinal O
hernia O
following O
bladder O
closure O
was O
evaluated O
using O
Kaplan O
- O
Meier O
methods O
. O

Cox O
proportional O
hazards O
model O
was O
used O
to O
investigate O
association O
of O
sex O
, O
age O
at O
bladder O
closure O
, O
and O
osteotomy O
on O
the O
risk O
of O
developing O
of O
inguinal O
hernia O
while O
clustering O
for O
institution O
. O

Results O
91 O
subjects O
were O
included O
in O
our O
analysis O
with O
median O
follow O
- O
up O
time O
of O
6.5 O
years O
. O

34 O
of O
53 O
males B-SEX
( O
64.2 O
% O
) O
and O
2 O
of O
38 O
females B-SEX
( O
5.3 O
% O
) O
underwent O
inguinal O
hernia O
repair O
. O

The O
median O
time O
to O
inguinal O
hernia O
was O
4.7 O
months O
following O
closure O
. O

The O
greatest O
hazard O
of O
inguinal O
hernia O
was O
within O
the O
first O
six O
months O
following O
closure O
. O

In O
multivariate O
analysis O
, O
male B-SEX
sex O
was O
strongly O
associated O
with O
inguinal O
hernia O
( O
HR O
= O
19.00 O
, O
p O
= O
0.0038 O
) O
. O

Osteotomy O
and O
delay O
in O
closure O
were O
not O
significantly O
associated O
with O
inguinal O
hernia O
. O

7 O
of O
36 O
patients O
( O
19.4 O
% O
) O
who O
underwent O
inguinal O
hernia O
repair O
presented O
with O
recurrence O
on O
the O
ipsilateral O
side O
. O

Discussion O
Our O
results O
suggest O
that O
the O
greatest O
risk O
of O
inguinal O
hernia O
is O
within O
the O
first O
six O
months O
following O
bladder O
closure O
. O

The O
decreased O
risk O
of O
inguinal O
hernia O
after O
one O
year O
of O
follow O
- O
up O
may O
reflect O
anatomic O
stability O
that O
is O
reached O
following O
major O
reconstruction O
of O
the O
pelvis O
. O

While O
male B-SEX
bladder O
exstrophy O
patients O
are O
significantly O
more O
susceptible O
to O
inguinal O
hernias O
following O
CPRE O
, O
osteotomy O
and O
delayed O
bladder O
closure O
do O
not O
appear O
to O
be O
protective O
factors O
for O
inguinal O
hernia O
development O
following O
initial O
bladder O
closure O
. O

Conclusions O
There O
is O
a O
heightened O
risk O
of O
inguinal O
hernia O
in O
the O
first O
six O
months O
following O
closure O
. O

The O
rate O
of O
recurrence O
following O
inguinal O
hernia O
repair O
is O
significantly O
elevated O
compared O
to O
the O
general O
pediatric O
population O
. O

Background O
Little O
is O
known O
about O
the O
prognosis O
regarding O
shunt O
revision O
and O
mortality O
among O
hydrocephalus O
patients O
below O
2 O
years O
of O
age O
. O

The O
aims O
of O
this O
study O
were O
to O
investigate O
( O
1 O
) O
the O
cumulative O
risks O
of O
shunt O
revision O
( O
SR O
) O
and O
mortality O
and O
( O
2 O
) O
the O
potential O
associations O
between O
prematurity O
, O
low O
weight O
for O
gestational O
age O
( O
LWGA O
) O
, O
underlying O
aetiology O
, O
sex O
, O
age O
of O
the O
child O
at O
shunt O
placement O
, O
and O
the O
risk O
of O
SR O
. O

Method O
This O
was O
a O
purely O
register O
- O
based O
cohort O
study O
including O
all O
shunted O
hydrocephalic O
infants O
in O
Denmark B-LOC
1996 B-DATE
- I-DATE
2015 I-DATE
. O

The O
cumulative O
risks O
of O
SR O
and O
mortality O
were O
estimated O
using O
the O
Aalen O
- O
Johansen O
and O
Kaplan O
- O
Meier O
estimators O
, O
respectively O
. O

A O
multivariable O
Cox O
- O
regression O
model O
was O
used O
to O
estimate O
hazard O
ratios O
( O
HRs O
) O
for O
SR O
according O
to O
the O
listed O
patient O
- O
related O
risk O
factors O
. O

Results O
Among O
374 O
shunted O
infantile O
hydrocephalus O
patients O
accounting O
for O
1047 O
SRs O
, O
the O
3 O
- O
month O
and O
1 O
- O
year O
cumulative O
risks O
of O
SR O
were O
36 O
% O
and O
50 O
% O
, O
respectively O
. O

The O
overall O
10 O
- O
year O
cumulative O
mortality O
was O
12 O
% O
, O
and O
for O
non O
- O
tumour O
subgroups O
7 O
- O
16 O
% O
( O
isolated O
hydrocephalus O
7 O
% O
) O
. O

The O
10 O
- O
year O
cumulative O
mortality O
for O
children O
born O
with O
LWGA O
was O
21 O
% O
. O

Except O
for O
aetiology O
, O
we O
observed O
no O
strong O
overall O
associations O
between O
the O
investigated O
risk O
factors O
and O
the O
risk O
of O
SR O
but O
interaction O
analyses O
for O
aetiology O
showed O
that O
patients O
with O
Dandy O
- O
Walker O
malformation O
born O
with O
LWGA O
had O
a O
higher O
risk O
of O
SR O
compared O
to O
patients O
of O
similar O
aetiology O
with O
normal O
WGA O
( O
HR O
2.47 O
, O
95 O
% O
CI O
: O
1.39 O
- O
4.40 O
) O
. O

Conclusions O
We O
found O
very O
high O
cumulative O
risks O
of O
SR O
and O
mortality O
among O
this O
youngest O
group O
of O
hydrocephalus O
patients O
, O
disregarding O
aetiology O
, O
but O
none O
of O
them O
were O
strongly O
related O
to O
the O
investigated O
risk O
factors O
. O

Objective O
This O
study O
aimed O
to O
examine O
the O
application O
of O
the O
Objective O
Structured O
Clinical O
Examination O
( O
OSCE O
) O
to O
the O
assessment O
of O
competency O
among O
child O
and O
adolescent O
psychiatry O
( O
CAP O
) O
residents O
and O
to O
analyze O
the O
feedback O
from O
the O
residents O
and O
the O
examiners O
. O

Methods O
The O
OSCE O
was O
administered O
to O
53 O
CAP O
residents O
based O
on O
three O
seniority O
levels O
over O
a O
14 O
- O
year O
period O
. O

The O
results O
of O
147 O
OSCEs O
applied O
to O
residents O
and O
the O
feedback O
received O
were O
evaluated O
. O

OSCE O
scores O
were O
calculated O
based O
on O
the O
scores O
given O
by O
the O
examiners O
and O
standardized O
patients O
( O
SPs O
) O
. O

Results O
Examiners O
' O
communication O
skills O
scores O
were O
significantly O
higher O
than O
examiners O
' O
task O
performance O
scores O
but O
were O
not O
significantly O
different O
than O
the O
SPs O
' O
scores O
. O

Intraclass O
correlation O
coefficients O
indicated O
that O
examiners O
and O
SPs O
were O
very O
consistent O
in O
their O
assessments O
among O
themselves O
. O

The O
scores O
given O
by O
the O
examiners O
and O
the O
SPs O
were O
not O
different O
between O
genders O
except O
for O
female B-SEX
residents O
' O
communication O
skills O
scores O
given O
by O
SPs O
in O
the O
OSCE O
- O
senior O
. O

With O
regard O
to O
the O
feedback O
on O
the O
OSCE O
, O
it O
was O
determined O
that O
examiners O
gave O
significantly O
higher O
scores O
than O
residents O
on O
every O
item O
except O
for O
neutrality O
of O
the O
examiners O
. O

Conclusions O
A O
standard O
OSCE O
including O
different O
station O
types O
was O
structured O
to O
assess O
the O
progressive O
clinical O
skills O
of O
residents O
over O
the O
years O
. O

Using O
the O
OSCE O
contributed O
to O
CAP O
residency O
training O
far O
beyond O
assessment O
, O
creating O
a O
useful O
educational O
experience O
for O
both O
the O
trainers O
and O
the O
residents O
. O

Despite O
the O
challenge O
experienced O
related O
to O
SPs O
, O
the O
OSCE O
was O
found O
to O
be O
useful O
in O
improving O
training O
programs O
. O

Maintaining O
proper O
eye O
alignment O
is O
necessary O
to O
generate O
a O
cohesive O
visual O
image O
. O

This O
involves O
the O
coordination O
of O
complex O
neural O
networks O
, O
which O
can O
become O
impaired O
by O
various O
neurodegenerative O
diseases O
. O

When O
the O
vergence O
system O
is O
affected O
, O
this O
can O
result O
in O
strabismus O
and O
disorienting O
diplopia O
. O

While O
previous O
studies O
have O
detailed O
the O
effect O
of O
these O
disorders O
on O
other O
eye O
movements O
, O
such O
as O
saccades O
, O
relatively O
little O
is O
known O
about O
strabismus O
. O

Here O
, O
we O
focus O
on O
the O
prevalence B-EPI
, O
clinical O
characteristics O
, O
and O
treatment O
of O
strabismus O
and O
disorders O
of O
vergence O
in O
Parkinson O
's O
disease O
, O
spinocerebellar O
ataxia O
, O
Huntington O
disease O
, O
and O
multiple O
system O
atrophy O
. O

We O
find O
that O
vergence O
abnormalities O
may O
be O
more O
common O
in O
these O
disorders O
than O
previously O
thought O
. O

In O
Parkinson O
's O
disease O
, O
the O
evidence O
suggests O
that O
strabismus O
is O
related O
to O
convergence O
insufficiency O
; O
however O
, O
it O
is O
responsive O
to O
dopamine O
replacement O
therapy O
and O
can O
, O
therefore O
, O
fluctuate O
with O
medication O
on O
and O
off O
periods O
throughout O
the O
day O
. O

Diplopia O
is O
also O
established O
as O
a O
side O
effect O
of O
deep O
brain O
stimulation O
and O
is O
thought O
to O
be O
related O
to O
stimulation O
of O
the O
subthalamic O
nucleus O
and O
extraocular O
motor O
nucleus O
among O
other O
structures O
. O

In O
regards O
to O
the O
spinocerebellar O
ataxias O
, O
oculomotor O
symptoms O
are O
common O
in O
many O
subtypes O
, O
but O
diplopia O
is O
most O
common O
in O
SCA3 O
also O
known O
as O
Machado O
- O
Joseph O
disease O
. O

Ophthalmoplegia O
and O
vergence O
insufficiency O
have O
both O
been O
implicated O
in O
strabismus O
in O
these O
patients O
, O
but O
can O
not O
fully O
explain O
the O
properties O
of O
the O
strabismus O
, O
suggesting O
the O
involvement O
of O
other O
structures O
as O
well O
. O

Strabismus O
has O
not O
been O
reported O
as O
a O
common O
finding O
in O
Huntington O
disease O
or O
atypical O
parkinsonian O
syndromes O
and O
more O
studies O
are O
needed O
to O
determine O
how O
these O
disorders O
affect O
binocular O
alignment O
. O

Background O
Lipodystrophy O
syndromes O
are O
a O
group O
of O
disorders O
characterized O
by O
a O
loss O
of O
adipose O
tissue O
once O
other O
situations O
of O
nutritional O
deprivation O
or O
exacerbated O
catabolism O
have O
been O
ruled O
out O
. O

With O
the O
exception O
of O
the O
HIV O
- O
associated O
lipodystrophy O
, O
they O
have O
a O
very O
low O
prevalence B-EPI
, O
which O
together O
with O
their O
large O
phenotypic O
heterogeneity O
makes O
their O
identification O
difficult O
, O
even O
for O
endocrinologists O
and O
pediatricians O
. O

This O
leads O
to O
significant O
delays O
in O
diagnosis O
or O
even O
to O
misdiagnosis O
. O

Our O
group O
has O
developed O
an O
algorithm O
that O
identifies O
the O
more O
than O
40 O
rare O
lipodystrophy O
subtypes O
described O
to O
date O
. O

This O
algorithm O
has O
been O
implemented O
in O
a O
free O
mobile O
application O
, O
LipoDDx O
. O

Our O
aim O
was O
to O
establish O
the O
effectiveness O
of O
LipoDDx O
. O

Forty O
clinical O
records O
of O
patients O
with O
a O
diagnosis O
of O
certainty O
of O
most O
lipodystrophy O
subtypes O
were O
analyzed O
, O
including O
subjects O
without O
lipodystrophy O
. O

The O
medical O
records O
, O
blinded O
for O
diagnosis O
, O
were O
evaluated O
by O
13 O
physicians O
, O
1 O
biochemist O
and O
1 O
dentist O
. O

Each O
evaluator O
first O
gave O
his O
/ O
her O
results O
based O
on O
his O
/ O
her O
own O
criteria O
. O

Then O
, O
a O
second O
diagnosis O
was O
given O
using O
LipoDDx O
. O

The O
results O
were O
analysed O
based O
on O
a O
score O
table O
according O
to O
the O
complexity O
of O
each O
case O
and O
the O
prevalence B-EPI
of O
the O
disease O
. O

Results O
LipoDDx O
provides O
a O
user O
- O
friendly O
environment O
, O
based O
on O
usually O
dichotomous O
questions O
or O
choice O
of O
clinical O
signs O
from O
drop O
- O
down O
menus O
. O

The O
final O
result O
provided O
by O
this O
app O
for O
a O
particular O
case O
can O
be O
a O
low O
/ O
high O
probability O
of O
suffering O
a O
particular O
lipodystrophy O
subtype O
. O

Without O
using O
LipoDDx O
the O
success O
rate O
was O
17 O
± O
20 O
% O
, O
while O
with O
LipoDDx O
the O
success O
rate O
was O
79 O
± O
20 O
% O
( O
p O
< O
0.01 O
) O
. O

Conclusions O
LipoDDx O
is O
a O
free O
app O
that O
enables O
the O
identification O
of O
subtypes O
of O
rare O
lipodystrophies O
, O
which O
in O
this O
small O
cohort O
has O
around O
80 O
% O
effectiveness O
, O
which O
will O
be O
of O
help O
to O
doctors O
who O
are O
not O
experts O
in O
this O
field O
. O

However O
, O
it O
will O
be O
necessary O
to O
analyze O
more O
cases O
in O
order O
to O
obtain O
a O
more O
accurate O
efficiency O
value O
. O

Pierson O
syndrome O
, O
an O
autosomal O
recessive O
disorder O
caused O
by O
a O
mutation O
in O
laminin O
ß2 O
( O
LAMB2 O
) O
gene O
, O
is O
characterized O
by O
congenital O
nephrotic O
syndrome O
and O
various O
ocular O
abnormalities O
. O

The O
ocular O
findings O
in O
Pierson O
syndrome O
are O
not O
well O
understood O
, O
because O
the O
incidence B-EPI
of O
this O
syndrome O
is O
very O
rare O
. O

We O
report O
ocular O
findings O
in O
a O
5 O
- O
month O
- O
old O
boy B-SEX
with O
Pierson O
syndrome O
with O
a O
novel O
mutation O
in O
LAMB2 O
. O

We O
performed O
a O
pupilloplasty O
for O
his O
microcoria O
. O

Ophthalmic O
examinations O
after O
surgery O
revealed O
that O
he O
had O
cataract O
, O
severe O
retinal O
degeneration O
, O
and O
high O
myopia O
. O

Optical O
coherence O
tomography O
showed O
the O
collapse O
of O
retinal O
layer O
structures O
and O
a O
marked O
decrease O
of O
choroidal O
thickness O
. O

Immunohistochemistry O
and O
electron O
microscopy O
examinations O
revealed O
abnormal O
iris O
differentiation O
and O
thinning O
or O
defect O
of O
basal O
membranes O
. O

These O
results O
suggest O
that O
the O
development O
of O
the O
iris O
, O
lens O
, O
retina O
, O
and O
choroid O
are O
affected O
in O
this O
type O
of O
mutation O
. O

Thiamine O
responsive O
megaloblastic O
anemia O
syndrome O
, O
an O
autosomal O
recessive O
inherited O
disorder O
characterized O
by O
a O
triad O
of O
anemia O
, O
diabetes O
mellitus O
and O
sensorineural O
deafness O
is O
caused O
by O
a O
deficiency O
of O
a O
thiamine O
transporter O
protein O
. O

The O
disorder O
is O
rare O
and O
has O
not O
been O
reported O
from O
our O
community O
which O
has O
high O
background O
of O
consanguinity O
. O

We O
report O
a O
six O
years O
old O
girl B-SEX
who O
presented O
with O
diabetes O
mellitus O
which O
remitted O
after O
thiamine O
replacement O
. O

The O
girl B-SEX
in O
addition O
had O
sensorineural O
deafness O
, O
reinopathy O
, O
atrial O
septal O
defect O
and O
megaloblastic O
anemia O
which O
responded O
to O
high O
doses O
of O
thymine O
. O

This O
is O
the O
first O
case O
reported O
from O
Kashmir B-LOC
valley I-LOC
and O
third O
from O
India B-LOC
. O

The O
presentation O
and O
management O
in O
such O
cases O
is O
discussed O
. O

Background O
Obstructive O
sleep O
apnea O
( O
OSA O
) O
is O
prevalent B-EPI
in O
individuals O
with O
Osteogenesis O
imperfecta O
( O
OI O
) O
. O

To O
date O
, O
no O
study O
has O
investigated O
treatment O
of O
OSA O
in O
adult O
individuals O
with O
OI O
using O
positive O
airway O
pressure O
( O
PAP O
) O
. O

This O
observational O
pilot O
study O
examined O
the O
adherence O
of O
adults O
with O
OI O
to O
treatment O
of O
OSA O
with O
PAP O
therapy O
, O
and O
the O
evolution O
of O
self O
- O
experienced O
sleepiness O
and O
depression O
symptoms O
before O
and O
after O
treatment O
. O

Methods O
We O
included O
20 O
patients O
, O
with O
a O
mean O
age O
of O
51 O
years O
, O
who O
represented O
varying O
severity O
of O
OI O
and O
displayed O
an O
apnea O
and O
hypopnea O
index O
≥ O
5 O
/sleeping O
hour O
as O
recorded O
by O
an O
overnight O
polysomnography O
. O

PAP O
therapy O
was O
proposed O
to O
all O
patients O
. O

Epworth O
Sleepiness O
Scale O
( O
ESS O
) O
questionnaire O
to O
evaluate O
daytime O
sleepiness O
, O
and O
a O
validated O
self O
- O
rating O
depression O
questionnaire O
to O
identify O
possible O
depression O
, O
were O
completed O
prior O
to O
PAP O
therapy O
and O
repeated O
after O
a O
minimum O
of O
one O
year O
. O

The O
datasets O
supporting O
the O
conclusions O
of O
this O
article O
are O
included O
within O
the O
article O
. O

Results O
From O
the O
20 O
patients O
, O
15 O
initiated O
PAP O
therapy O
, O
and O
two O
patients O
later O
interrupted O
it O
. O

The O
mean O
PAP O
follow O
- O
up O
period O
was O
1230 O
days O
. O

At O
baseline O
, O
an O
abnormally O
high O
ESS O
score O
was O
reported O
by O
29 O
% O
of O
the O
respondents O
, O
and O
an O
abnormally O
high O
number O
of O
symptoms O
suggesting O
depression O
by O
29 O
% O
. O

Follow O
- O
up O
questionnaires O
were O
completed O
by O
60 O
% O
of O
the O
patients O
, O
of O
whom O
83 O
% O
were O
adherent O
to O
PAP O
treatment O
. O

ESS O
score O
and O
depression O
symptoms O
did O
not O
decrease O
significantly O
with O
PAP O
therapy O
. O

Conclusions O
Patients O
with O
OI O
accepted O
well O
PAP O
therapy O
and O
remained O
compliant O
. O

Sleepiness O
and O
depression O
persisted O
unaltered O
despite O
good O
PAP O
adherence O
. O

These O
unexpectedly O
poor O
improvements O
in O
symptoms O
by O
PAP O
therapy O
may O
be O
due O
to O
subjective O
depression O
symptoms O
and O
the O
complexity O
of O
factors O
underlying O
persisting O
sleepiness O
in O
OI O
. O

Further O
research O
is O
needed O
to O
confirm O
this O
novel O
finding O
. O

Objective O
Tarsal O
coalition O
is O
known O
to O
cause O
abnormal O
talocrural O
stress O
, O
hindfoot O
malalignment O
, O
and O
ankle O
sprains O
. O

These O
can O
all O
be O
associated O
with O
osteochondritis O
dissecans O
( O
OCD O
) O
of O
the O
talar O
dome O
. O

We O
present O
the O
first O
detailed O
description O
of O
a O
series O
of O
talar O
OCDs O
occurring O
in O
patients O
with O
tarsal O
coalition O
, O
with O
the O
goal O
of O
determining O
whether O
there O
is O
an O
increased O
prevalence B-EPI
of O
OCDs O
among O
patients O
with O
tarsal O
coalition O
. O

Materials O
and O
methods O
We O
studied O
ankle O
MRIs O
in O
57 O
patients O
with O
tarsal O
coalitions O
, O
excluding O
those O
with O
a O
reported O
inciting O
traumatic O
event O
. O

The O
MRIs O
were O
performed O
on O
magnetic O
field O
strengths O
ranging O
from O
0.3 O
to O
1.5 O
T O
and O
included O
axial O
, O
coronal O
, O
and O
sagittal O
T1 O
and O
T2 O
or O
PD O
fat O
- O
suppressed O
sequences O
. O

We O
evaluated O
the O
morphology O
and O
location O
of O
classically O
described O
OCDs O
in O
these O
patients O
, O
type O
and O
location O
of O
concomitant O
tarsal O
coalition O
, O
and O
, O
when O
available O
, O
the O
presence O
of O
pes O
planus O
and O
hindfoot O
valgus O
on O
weight O
- O
bearing O
radiographs O
. O

Chi O
- O
squared O
analysis O
was O
used O
to O
compare O
categorical O
variables O
and O
a O
Student O
's O
t O
test O
was O
used O
for O
parametric O
continuous O
variables O
. O

Additionally O
, O
logistic O
regression O
was O
used O
to O
compute O
the O
odds O
ratio O
of O
talar O
OCD O
associated O
with O
patient O
age O
, O
gender O
, O
laterality O
, O
pes O
planus O
status O
, O
hindfoot O
valgus O
status O
, O
and O
coalition O
type O
. O

Results O
Eighty O
- O
nine O
percent O
of O
tarsal O
coalitions O
were O
non O
- O
osseous O
coalitions O
and O
the O
calcaneonavicular O
space O
was O
the O
most O
common O
site O
of O
abnormal O
tarsal O
connection O
( O
54.4 O
% O
) O
. O

In O
the O
29 O
patients O
with O
tarsal O
coalitions O
and O
talar O
OCDs O
, O
OCDs O
commonly O
occurred O
medially O
( O
75.9 O
% O
) O
. O

In O
the O
sagittal O
plane O
, O
talar O
OCDs O
occurred O
centrally O
, O
with O
only O
one O
case O
sparing O
the O
central O
talar O
dome O
. O

The O
mean O
surface O
area O
of O
the O
29 O
OCDs O
was O
89.7 O
mm O
2 O
. O

Both O
osseous O
coalition O
and O
hindfoot O
valgus O
were O
associated O
with O
smaller O
talar O
OCD O
mean O
surface O
area O
( O
p O
= O
0.015 O
and O
p O
= O
0.0001 O
, O
respectively O
) O
. O

There O
was O
no O
association O
between O
depth O
and O
surface O
area O
of O
talar O
OCD O
with O
either O
coalition O
location O
or O
presence O
of O
pes O
planus O
( O
coalition O
location O
: O
p O
= O
0.455 O
for O
depth O
and O
p O
= O
0.295 O
for O
surface O
area O
; O
presence O
of O
pes O
planus O
: O
p O
= O
0.593 O
for O
depth O
and O
p O
= O
0.367 O
for O
surface O
area O
) O
. O

Conclusion O
Talar O
OCD O
prevalence B-EPI
is O
higher O
in O
patients O
with O
tarsal O
coalition O
than O
that O
reported O
for O
the O
general O
population O
. O

This O
occurrence B-EPI
may O
relate O
to O
altered O
biomechanics O
and O
repetitive O
talocrural O
stress O
owing O
to O
altered O
subtalar O
motion O
, O
particularly O
given O
the O
findings O
of O
increased O
odds O
of O
talar O
OCD O
in O
older O
patients O
, O
as O
well O
as O
weak O
associations O
between O
OCD O
surface O
area O
and O
both O
non O
- O
osseous O
coalition O
and O
hindfoot O
alignment O
. O

However O
, O
we O
did O
not O
find O
any O
specific O
OCD O
morphologic O
features O
attributable O
to O
the O
precise O
location O
of O
the O
tarsal O
coalition O
. O

Gyrate O
Atrophy O
( O
GA O
) O
of O
the O
choroid O
and O
retina O
( O
MIM O
# O
258870 O
) O
is O
an O
autosomal O
recessive O
disorder O
due O
to O
mutations O
of O
the O
OAT O
gene O
encoding O
ornithine O
- O
delta O
- O
aminotransferase O
( O
OAT O
) O
, O
associated O
with O
progressive O
retinal O
deterioration O
and O
blindness O
. O

The O
disease O
has O
a O
theoretical O
global B-LOC
incidence B-EPI
of O
approximately B-STAT
1:1,500,000 I-STAT
. O

OAT O
is O
mainly O
involved O
in O
ornithine O
catabolism O
in O
adults O
, O
thus O
explaining O
the O
hyperornithinemia O
as O
hallmark O
of O
the O
disease O
. O

Patients O
are O
treated O
with O
an O
arginine O
- O
restricted O
diet O
, O
to O
limit O
ornithine O
load O
, O
or O
the O
administration O
of O
Vitamin O
B6 O
, O
a O
precursor O
of O
the O
OAT O
coenzyme O
pyridoxal O
phosphate O
. O

Although O
the O
clinical O
and O
genetic O
aspects O
of O
GA O
are O
known O
for O
many O
years O
, O
the O
enzymatic O
phenotype O
of O
pathogenic O
variants O
and O
their O
response O
to O
Vitamin O
B6 O
, O
as O
well O
as O
the O
molecular O
mechanisms O
explaining O
retinal O
damage O
, O
are O
poorly O
clarified O
. O

Herein O
, O
we O
provide O
an O
overview O
of O
the O
current O
knowledge O
on O
the O
biochemical O
properties O
of O
human O
OAT O
and O
on O
the O
molecular O
, O
cellular O
, O
and O
clinical O
aspects O
of O
GA O
. O

As O
the O
HIV O
epidemic O
in O
sub B-LOC
- I-LOC
Saharan I-LOC
Africa I-LOC
matures O
, O
evidence O
about O
the O
age O
distribution O
of O
new O
HIV O
infections O
and O
how O
this O
distribution O
has O
changed O
over O
the O
epidemic O
is O
needed O
to O
guide O
HIV O
prevention O
. O

We O
aimed O
to O
assess O
trends O
in O
age O
- O
specific O
HIV O
incidence B-EPI
in O
six O
population O
- O
based O
cohort O
studies O
in O
eastern B-LOC
and I-LOC
southern I-LOC
Africa I-LOC
, O
reporting O
changes O
in O
mean O
age O
at O
infection O
, O
age O
distribution O
of O
new O
infections O
, O
and O
birth B-EPI
cohort I-EPI
cumulative B-EPI
incidence I-EPI
. O

We O
used O
a O
Bayesian O
model O
to O
reconstruct O
age O
- O
specific O
HIV O
incidence B-EPI
from O
repeated O
observations O
of O
individuals O
' O
HIV O
serostatus O
and O
survival O
collected O
among O
population O
HIV O
cohorts O
in O
rural O
Malawi B-LOC
, O
South B-LOC
Africa I-LOC
, O
Tanzania B-LOC
, O
Uganda B-LOC
, O
and O
Zimbabwe B-LOC
, O
in O
a O
collaborative O
analysis O
of O
the O
ALPHA O
network O
. O

We O
modelled O
HIV O
incidence B-EPI
rates I-EPI
by O
age O
, O
time O
, O
and O
sex O
using O
smoothing O
splines O
functions O
. O

We O
estimated B-EPI
incidence B-EPI
trends O
separately O
by O
sex O
and O
study O
. O

We O
used O
estimated B-EPI
incidence I-EPI
and O
prevalence B-EPI
results O
for O
2000 B-DATE
- I-DATE
17 I-DATE
, O
standardised O
to O
study O
population O
distribution O
, O
to O
estimate O
mean O
age O
at O
infection O
and O
proportion O
of O
new O
infections O
by O
age O
. O

We O
also O
estimated O
cumulative B-EPI
incidence I-EPI
( O
lifetime O
risk O
of O
infection O
) O
by O
birth O
cohort O
. O

Age B-EPI
- O
specific I-EPI
incidence B-EPI
declined O
at O
all O
ages O
, O
although O
the O
timing O
and O
pattern O
of O
decline O
varied O
by O
study O
. O

The O
mean O
age O
at O
infection O
was O
higher O
in O
men B-SEX
( O
cohort O
mean O
27·8 O
- O
34·6 O
years O
) O
than O
in O
women B-SEX
( O
24·8 O
- O
29·6 O
years O
) O
. O

Between B-DATE
2000 I-DATE
and I-DATE
2017 I-DATE
, O
the O
mean O
age O
at O
infection O
per O
cohort O
increased O
slightly O
: O
0·5 O
to O
2·8 O
years O
among O
men B-SEX
and O
-0·2 O
to O
2·5 O
years O
among O
women B-SEX
. O

Across O
studies O
, O
between O
38 O
% O
and O
63 O
% O
( O
cohort O
medians O
) O
of O
the O
infections O
in O
women B-SEX
were O
among O
those O
aged O
15 O
- O
24 O
years O
and O
between O
30 O
% O
and O
63 O
% O
of O
infections O
in O
men B-SEX
were O
in O
those O
aged O
20 O
- O
29 O
years O
. O

Lifetime O
risk O
of O
HIV O
declined O
for O
successive O
birth O
cohorts O
. O

HIV O
incidence B-EPI
declined O
in O
all O
age O
groups O
and O
shifted O
slightly O
to O
older O
ages O
. O

Disproportionate O
new O
HIV O
infections O
occur O
among O
women B-SEX
aged O
15 O
- O
24 O
years O
and O
men B-SEX
aged O
20 O
- O
29 O
years O
, O
supporting O
focused O
prevention O
in O
these O
groups O
. O

However O
, O
40 O
- O
60 O
% O
of O
infections O
were O
outside O
these O
ages O
, O
emphasising O
the O
importance O
of O
providing O
appropriate O
HIV O
prevention O
to O
adults O
of O
all O
ages O
. O

Bill O
& O
Melinda O
Gates O
Foundation O
. O

Over O
260,000 O
( O
2013 B-DATE
) O
new O
oral O
squamous O
cell O
carcinoma O
( O
OSCC O
) O
cases O
are O
reported O
annually O
worldwide B-LOC
. O

Despite O
development O
in O
OSCC O
management O
, O
the O
outcome O
is O
still O
unsatisfactory O
. O

Identification O
of O
new O
molecular O
markers O
may O
be O
of O
use O
in O
prevention O
, O
prognosis O
, O
and O
choice O
of O
an O
appropriate O
therapy O
. O

The O
intracellular O
molecular O
signalling O
pathway O
of O
phosphatidyl O
- O
inositol-3 O
- O
kinase O
is O
involved O
in O
the O
process O
of O
cell O
growth O
, O
differentiation O
, O
migration O
, O
and O
survival O
. O

The O
main O
components O
of O
this O
pathway O
: O
PIK3CA O
( O
phosphatidylinositol-4,5 O
- O
bisphosphate-3 O
- O
kinase O
catalytic O
subunit O
[alpha] O
) O
, O
PTEN O
( O
phosphatase O
and O
tensin O
homologue O
deleted O
on O
chromosome O
10 O
) O
, O
and O
AKT O
( O
serine O
- O
threonine O
kinase O
) O
are O
potential O
objects O
of O
research O
when O
introducing O
new O
therapeutic O
agents O
. O

The O
aim O
of O
this O
paper O
is O
to O
evaluate O
the O
PIK3CA O
, O
PTEN O
, O
and O
AKT O
gene O
mutations O
as O
prognostic O
factors O
in O
OSCC O
and O
to O
describe O
their O
role O
in O
aggressive O
disease O
progression O
. O

This O
is O
crucial O
for O
oral O
cancer O
biology O
understanding O
and O
for O
indicating O
which O
direction O
new O
clinical O
treatments O
should O
take O
. O

Gastrointestinal O
symptoms O
are O
among O
the O
most O
common O
complaints O
in O
patients O
with O
postural O
tachycardia O
syndrome O
( O
POTS O
) O
. O

In O
some O
cases O
, O
they O
dominate O
the O
clinical O
presentation O
and O
cause O
substantial O
disabilities O
, O
including O
significant O
weight O
loss O
and O
malnutrition O
, O
that O
require O
the O
use O
of O
invasive O
treatment O
to O
support O
caloric O
intake O
. O

Multiple O
cross O
- O
sectional O
studies O
have O
reported O
a O
high O
prevalence B-EPI
of O
gastrointestinal O
symptoms O
in O
POTS O
patients O
with O
connective O
tissue O
diseases O
, O
such O
as O
Ehlers O
- O
Danlos O
, O
hypermobile O
type O
, O
and O
in O
patients O
with O
evidence O
of O
autonomic O
neuropathy O
. O

Previous O
studies O
that O
evaluated O
gastric O
motility O
in O
these O
patients O
reported O
a O
wide O
range O
of O
abnormalities O
, O
particularly O
delayed O
gastric O
emptying O
. O

The O
pathophysiology O
of O
gastrointestinal O
symptoms O
in O
POTS O
is O
likely O
multifactorial O
and O
probably O
depends O
on O
the O
co O
- O
morbid O
conditions O
. O

In O
patients O
with O
POTS O
and O
Ehlers O
- O
Danlos O
syndromes O
, O
structural O
and O
functional O
abnormalities O
in O
the O
gastrointestinal O
connective O
tissue O
may O
play O
a O
significant O
role O
, O
whereas O
in O
neuropathic O
POTS O
, O
the O
gastrointestinal O
tract O
motility O
and O
gut O
hormonal O
secretion O
may O
be O
directly O
impaired O
due O
to O
localized O
autonomic O
denervation O
. O

In O
patients O
with O
normal O
gastrointestinal O
motility O
but O
persistent O
gastrointestinal O
symptoms O
, O
gastrointestinal O
functional O
disorders O
should O
be O
considered O
. O

We O
performed O
a O
systematic O
review O
of O
the O
literature O
related O
to O
POTS O
and O
gastrointestinal O
symptoms O
have O
proposed O
possible O
mechanisms O
and O
discussed O
diagnosis O
and O
treatment O
approaches O
for O
delayed O
gastric O
emptying O
, O
the O
most O
common O
gastrointestinal O
abnormality O
reported O
in O
patients O
with O
POTS O
. O

Background O
We O
evaluated O
the O
association O
between O
maternal O
antiretrovirals O
( O
ARVs O
) O
during O
pregnancy O
and O
infant O
congenital O
anomalies O
( O
CAs O
) O
, O
utilizing O
data O
from O
the O
National O
Institute O
of O
Child O
Health O
and O
Human O
Development O
International O
Site O
Development O
Initiative O
Perinatal O
Study O
. O

Methods O
The O
study O
population O
consisted O
of O
first O
singleton O
pregnancies O
on O
study O
, O
> O
or O
= O
20 O
weeks O
gestation O
, O
among O
women B-SEX
enrolled O
in O
NISDI B-LOC
from O
Argentina B-LOC
and O
Brazil B-LOC
who O
delivered O
between B-DATE
September I-DATE
2002 I-DATE
and I-DATE
October I-DATE
2007 I-DATE
. O

CAs O
were O
defined O
as O
any O
major O
structural O
or O
chromosomal O
abnormality O
, O
or O
a O
cluster O
of O
2 O
or O
more O
minor O
abnormalities O
, O
according O
to O
the O
conventions O
of O
the O
Antiretroviral O
Pregnancy O
Registry O
. O

CAs O
were O
identified O
from O
fetal O
ultrasound O
, O
study O
visit O
, O
and O
death O
reports O
. O

Prevalence B-EPI
rates I-EPI
[ O
number O
of O
CAs O
per I-STAT
100 I-STAT
live I-STAT
births I-STAT
( O
LBs I-STAT
) O
] O
were O
calculated O
for O
specific O
ARVs O
, O
classes O
of O
ARVs O
, O
and O
overall O
exposure O
to O
ARVs O
. O

Results O
Of O
1229 O
women B-SEX
enrolled O
, O
995 O
pregnancy O
outcomes O
( O
974 O
LBs O
) O
met O
the O
inclusion O
criteria O
. O

Of O
these O
, O
60 O
infants O
( O
59 O
LBs O
and O
1 O
stillbirth O
) O
had O
at O
least O
1 O
CA O
. O

The O
overall B-EPI
prevalence I-EPI
of O
CAs O
( O
per I-STAT
100 I-STAT
LBs I-STAT
) O
was O
6.2 B-STAT
[ O
95 O
% O
confidence O
interval O
( O
CI O
) O
4.6 O
to O
7.7 O
] O
. O

The O
prevalence B-EPI
of O
CAs O
after O
first O
trimester O
ARVs O
( O
6.2 O
; O
95 O
% O
CI O
3.1 O
to O
9.3 O
) O
was O
similar O
to O
that O
after O
second O
( O
6.8 O
; O
95 O
% O
CI O
4.5 O
to O
9.0 O
) O
or O
third O
trimester O
( O
4.3 O
; O
95 O
% O
CI O
1.5 O
to O
7.2 O
) O
exposure O
. O

The O
rate O
of O
CAs O
identified O
within O
7 O
days O
of O
delivery O
was O
2.36 O
( O
95 O
% O
CI O
1.4 O
to O
3.3 O
) O
. O

Conclusions O
The O
prevalence B-EPI
of O
CAs O
after O
first O
trimester O
exposure O
to O
ARVs O
was O
similar O
to O
that O
after O
second O
or O
third O
trimester O
exposure O
. O

Continued O
surveillance O
for O
CAs O
among O
children O
exposed O
to O
ARVs O
during O
gestation O
is O
needed O
. O

The O
zoonosis O
Q O
fever O
is O
caused O
by O
the O
obligate O
intracellular O
bacterium O
Coxiella O
burnetii O
. O

Besides O
the O
main O
transmission O
route O
via O
inhalation O
of O
contaminated O
aerosols O
, O
ticks O
are O
discussed O
as O
vectors O
since O
the O
first O
isolation O
of O
the O
pathogen O
from O
a O
Dermacentor O
andersonii O
tick O
. O

The O
rare O
detection O
of O
C. O
burnetii O
in O
ticks O
and O
the O
difficult O
differentiation O
of O
C. O
burnetii O
from O
Coxiella O
-like O
endosymbionts O
( O
CLEs O
) O
are O
questioning O
the O
relevance O
of O
ticks O
in O
the O
epidemiology O
of O
Q O
fever O
. O

In O
this O
review O
, O
literature O
databases O
were O
systematically O
searched O
for O
recent O
prevalence B-EPI
studies O
concerning O
C. O
burnetii O
in O
ticks O
in O
Europe B-LOC
and O
experimental O
studies O
evaluating O
the O
vector O
competence O
of O
tick O
species O
. O

A O
total O
of O
72 O
prevalence B-EPI
studies O
were O
included O
and O
evaluated O
regarding O
DNA O
detection O
methods O
and O
collection O
methods O
, O
country O
, O
and O
tested O
tick O
species O
. O

Specimens O
of O
more O
than O
25 O
different O
tick O
species O
were O
collected O
in O
23 O
European O
countries O
. O

Overall O
, O
an O
average B-EPI
prevalence I-EPI
of O
4.8 B-STAT
% I-STAT
was O
determined O
. O

However O
, O
in O
half O
of O
the O
studies O
, O
no O
Coxiella O
-DNA O
was O
detected O
. O

In O
Southern B-LOC
European I-LOC
countries I-LOC
, O
a O
significantly O
higher O
prevalence B-EPI
was O
observed O
, O
possibly O
related O
to O
the O
abundance O
of O
different O
tick O
species O
here O
, O
namely O
Hyalomma O
spp O
. O

and O
Rhipicephalus O
spp O
. O

In O
comparison O
, O
a O
similar O
proportion O
of O
studies O
used O
ticks O
sampled O
by O
flagging O
and O
dragging O
or O
tick O
collection O
from O
animals O
, O
under O
30 O
% O
of O
the O
total O
tick O
samples O
derived O
from O
the O
latter O
. O

There O
was O
no O
significant O
difference O
in O
the O
various O
target O
genes O
used O
for O
the O
molecular O
test O
. O

In O
most O
of O
the O
studies O
, O
no O
distinction O
was O
made O
between O
C. O
burnetii O
and O
CLEs O
. O

The O
application O
of O
specific O
detection O
methods O
and O
the O
confirmation O
of O
positive O
results O
are O
crucial O
to O
determine O
the O
role O
of O
ticks O
in O
Q O
fever O
transmission O
. O

Only O
two O
studies O
were O
available O
, O
which O
assessed O
the O
vector O
competence O
of O
ticks O
for O
C. O
burnetii O
in O
the O
last O
20 O
years O
, O
demonstrating O
the O
need O
for O
further O
research O
. O

Background O
Wilson O
disease O
( O
WD O
) O
is O
an O
autosomal O
recessive O
disorder O
caused O
by O
mutations O
in O
the O
ATP7B O
gene O
. O

In O
1984 B-DATE
, O
Scheinberg B-LOC
and O
Sternlieb B-LOC
estimated O
the O
prevalence B-EPI
of O
WD O
to O
be O
1:30,000 B-STAT
. O

However O
, O
recent O
epidemiological O
studies O
have O
reported O
increasing O
prevalence B-EPI
rates I-EPI
in O
different O
populations O
. O

The O
carrier O
frequency O
of O
ATP7B O
variants O
and O
the O
prevalence B-EPI
of O
WD O
in O
the O
Japanese B-ETHN
population O
have O
not O
been O
reported O
using O
multiple O
databases O
. O

Methods O
Multiple O
public O
databases O
were O
used O
. O

First O
, O
we O
included O
mutations O
in O
the O
ATP7B O
gene O
that O
were O
registered O
in O
the O
Human O
Gene O
Mutation O
Database O
( O
HGMD O
) O
Professional O
, O
where O
885 O
ATP7B O
variants O
were O
identified O
as O
pathogenic O
. O

Next O
, O
we O
investigated O
the O
allele O
frequencies O
of O
these O
885 O
variants O
in O
Japanese B-ETHN
individuals O
using O
the O
Human O
Genetic O
Variation O
Database O
( O
HGVD O
) O
and O
the O
Japanese B-ETHN
Multi O
Omics O
Reference O
Panel O
( O
jMorp O
) O
. O

Results O
Of O
the O
885 O
variants O
of O
ATP7B O
, O
7 O
and O
12 O
missense O
and O
nonsense O
variants O
, O
0 O
and O
3 O
splicing O
variants O
, O
and O
0 O
and O
2 O
small O
deletions O
were O
found O
in O
the O
HGVD O
and O
in O
jMorp O
, O
respectively O
. O

The O
total O
allele O
frequencies O
of O
the O
ATP7B O
mutations O
were O
0.011 O
in O
the O
HGVD O
and O
0.014 O
in O
the O
jMorp O
. O

According O
to O
these O
data O
, O
the O
carrier O
frequencies O
were O
0.022 O
( O
2.2 O
% O
) O
and O
0.028 O
( O
2.8 O
% O
) O
, O
respectively O
, O
and O
patient O
frequencies O
were O
0.000121 B-STAT
( O
1.21/10,000 B-STAT
individuals I-STAT
) O
and O
0.000196 B-STAT
( O
1.96/10,000 B-STAT
individuals I-STAT
) O
, O
respectively O
. O

Conclusion O
This O
is O
the O
first O
study O
to O
report O
the O
carrier O
frequency O
of O
ATP7B O
variants O
and O
the O
prevalence B-EPI
of O
WD O
in O
Japan B-LOC
using O
multiple O
databases O
. O

The O
calculated B-EPI
prevalence I-EPI
of O
WD O
was O
comparatively O
higher O
than O
that O
of O
previous O
reports O
, O
indicating O
previous O
underdiagnosis O
or O
the O
existence O
of O
less O
severe O
phenotypes O
. O

Purpose O
of O
review O
In O
this O
review O
, O
we O
report O
on O
the O
state O
of O
knowledge O
about O
human O
Q O
fever O
in O
Brazil B-LOC
and O
on O
the O
Guiana B-LOC
Shield I-LOC
, O
an O
Amazonian B-LOC
region O
located O
in O
northeastern B-LOC
South I-LOC
America I-LOC
. O

There O
is O
a O
contrast O
between O
French B-LOC
Guiana I-LOC
, O
where O
the O
incidence B-EPI
of O
this O
disease O
is O
the O
highest O
in O
the O
world O
, O
and O
other O
countries O
where O
this O
disease O
is O
practically O
non O
- O
existent O
. O

Recent O
findings O
Recent O
findings O
are O
essentially O
in O
French B-LOC
Guiana I-LOC
where O
a O
unique O
strain O
MST17 O
has O
been O
identified O
; O
it O
is O
probably O
more O
virulent O
than O
those O
usually O
found O
with O
a O
particularly O
marked O
pulmonary O
tropism O
, O
a O
mysterious O
animal O
reservoir O
, O
a O
geographical O
distribution O
that O
raises O
questions O
. O

Summary O
Q O
fever O
is O
a O
bacterial O
zoonosis O
due O
to O
Coxiella O
burnetii O
that O
has O
been O
reported O
worldwide B-LOC
. O

On O
the O
Guiana B-LOC
Shield I-LOC
, O
a O
region O
mostly O
covered O
by O
Amazonian O
forest O
, O
which O
encompasses O
the O
Venezuelan B-ETHN
State I-LOC
of O
Bolivar B-LOC
, O
Guyana B-LOC
, O
Suriname B-LOC
, O
French B-LOC
Guiana I-LOC
, O
and O
the O
Brazilian B-ETHN
State I-LOC
of O
Amapá B-LOC
, O
the O
situation O
is O
very O
heterogeneous O
. O

While O
French B-LOC
Guiana I-LOC
is O
the O
region O
reporting O
the O
highest O
incidence B-EPI
of O
this O
disease O
in O
the O
world O
, O
with O
a O
single O
infecting O
clone O
( O
MST O
117 O
) O
and O
a O
unique O
epidemiological O
cycle O
, O
it O
has O
hardly O
ever O
been O
reported O
in O
other O
countries O
in O
the O
region O
. O

This O
absence O
of O
cases O
raises O
many O
questions O
and O
is O
probably O
due O
to O
massive O
under O
- O
diagnosis O
. O

Studies O
should O
estimate O
comprehensively O
the O
true O
burden O
of O
this O
disease O
in O
the O
region O
. O

Background O
& O
methods O
Blastocystis O
sp O
. O

is O
one O
of O
the O
most O
prevalent B-EPI
unicellular O
eukaryote O
of O
the O
human O
large O
intestine O
in O
Chile B-LOC
and O
worldwide B-LOC
. O

It O
is O
classified O
in O
subtypes O
( O
STs O
) O
, O
where O
using O
the O
polymorphic O
sequences O
of O
its O
18S O
rRNA O
genes O
currently O
recognizes O
22 O
. O

STs O
1 O
- O
9 O
and O
ST12 O
have O
been O
reported O
in O
humans O
. O

It O
has O
been O
hypothesized O
that O
different O
STs O
of O
Blastocystis O
sp O
. O

differentially O
affect O
the O
clinical O
severity O
of O
the O
digestive O
disease O
in O
Irritable O
Bowel O
Syndrome O
( O
IBS O
) O
patients O
, O
but O
more O
studies O
ar4e O
needed O
to O
establish O
this O
statement O
. O

To O
contribute O
in O
the O
elucidation O
of O
the O
potential O
relationship O
between O
Blastocystis O
sp O
. O

subtypes O
and O
IBS O
severity O
, O
37 O
IBS O
patient O
fecal O
samples O
were O
collected O
at O
hospitals O
in O
Santiago B-LOC
( O
Chile B-LOC
) O
and O
were O
screened O
for O
the O
presence O
of O
vacuolated O
forms O
of O
Blastocystis O
sp O
. O

by O
using O
conventional O
microscopy O
. O

Positive O
samples O
were O
submitted O
to O
PCR O
and O
sequencing O
for O
determining O
STs O
. O

The O
same O
procedure O
was O
performed O
in O
fecal O
samples O
from O
five O
non O
- O
IBS O
Blastocystis O
sp O
. O

carriers O
for O
preliminary O
comparative O
purpose O
. O

Results O
and O
discussion O
Four O
out O
of O
the O
37 O
samples O
from O
the O
IBS O
patients O
were O
found O
positive O
for O
Blastocystis O
sp O
. O

( O
10.81 O
% O
) O
by O
using O
microscopy O
. O

The O
presence O
of O
this O
microorganism O
in O
these O
four O
samples O
were O
confirmed O
by O
PCR O
and O
sequencing O
. O

Subtypes O
and O
their O
respective O
closest O
match O
alleles O
were O
searched O
and O
the O
ST1 O
, O
ST2 O
and O
ST4 O
subtypes O
were O
found O
in O
these O
patients O
. O

ST4 O
subtype O
is O
scarcely O
detected O
in O
South B-LOC
America I-LOC
countries O
, O
being O
reported O
previously O
only O
in O
Colombia B-LOC
and O
Brazil B-LOC
. O

In O
this O
ST4 O
subtype O
we O
determined O
the O
allele O
42 O
which O
is O
the O
most O
frequent O
allele O
observed O
in O
human O
Blastocystis O
isolates O
. O

In O
the O
non O
- O
IBS O
individuals O
' O
carriers O
, O
three O
subtypes O
were O
found O
: O
ST1 O
, O
ST2 O
and O
ST3 O
, O
even O
belonging O
to O
the O
same O
family O
group O
. O

Closest O
match O
alleles O
: O
2 O
, O
12 O
and O
34 O
here O
detected O
were O
also O
commonly O
reported O
globally O
. O

Instead O
of O
the O
small O
number O
of O
IBS O
patients O
studied O
here O
, O
the O
frequency O
of O
blastocystosis O
detected O
( O
10.81 O
% O
) O
was O
lower O
than O
the O
prevalence B-EPI
of O
Blastocystis O
sp O
. O
infections O
described O
for O
the O
Chilean B-ETHN
general O
population O
( O
30.4 O
% O
) O
. O

In O
Chile B-LOC
, O
clear O
correlation O
of O
Blastocystis O
sp O
. O
subtypes O
and O
IBS O
severity O
is O
still O
lacking O
with O
this O
study O
but O
it O
may O
lead O
and O
contribute O
to O
a O
better O
understanding O
of O
its O
pathogenicity O
and O
worldwide O
epidemiology O
. O

Introduction O
: O
Charcot O
- O
Marie O
- O
Tooth O
disease O
( O
CMT O
) O
and O
related O
neuropathies O
represent O
the O
most O
prevalent B-EPI
inherited O
neuromuscular O
disorders O
. O

Nonetheless O
, O
there O
is O
still O
no O
pharmacological O
treatment O
available O
for O
any O
CMT O
type O
. O

However O
, O
the O
landscape O
is O
rapidly O
evolving O
and O
several O
novel O
approaches O
are O
providing O
encouraging O
results O
in O
preclinical O
studies O
and O
leading O
to O
clinical O
trials O
. O

Areas O
covered O
: O
The O
authors O
review O
the O
most O
promising O
therapies O
under O
study O
and O
the O
ongoing O
/ O
planned O
clinical O
trials O
. O

Several O
approaches O
to O
address O
PMP22 O
overexpression O
underlying O
CMT1A O
, O
the O
most O
frequent O
subtype O
, O
are O
being O
tested O
. O

Gene O
silencing O
, O
targeting O
PMP22 O
, O
and O
gene O
therapy O
, O
to O
introduce O
specific O
genes O
or O
to O
substitute O
or O
modulate O
defective O
ones O
, O
are O
being O
experimented O
in O
animal O
models O
. O

Compounds O
acting O
on O
ER O
stress O
, O
unfolded O
protein O
response O
, O
neuregulin O
pathways O
, O
phosphoinositides O
metabolism O
, O
axonal O
transport O
and O
degeneration O
, O
inflammation O
, O
polyol O
pathway O
, O
deoxysphingolipid O
metabolism O
, O
purine O
nucleotide O
pool O
are O
potential O
therapeutic O
candidates O
for O
different O
forms O
of O
CMT O
and O
related O
neuropathies O
. O

Expert O
opinion O
: O
We O
are O
getting O
closer O
to O
find O
effective O
therapies O
for O
CMT O
, O
but O
are O
far O
behind O
the O
exciting O
examples O
of O
other O
genetic O
neuromuscular O
disorders O
. O

The O
authors O
analyze O
the O
possible O
reasons O
for O
this O
gap O
and O
the O
way O
to O
fill O
it O
. O

Preclinical O
and O
clinical O
research O
is O
ongoing O
with O
coordinated O
efforts O
and O
they O
are O
confident O
that O
in O
the O
next O
few O
years O
we O
will O
see O
the O
first O
effective O
treatments O
. O

Over O
90 O
years O
ago O
, O
Otto O
Warburg O
's O
seminal O
discovery O
of O
aerobic O
glycolysis O
established O
metabolic O
reprogramming O
as O
one O
of O
the O
first O
distinguishing O
characteristics O
of O
cancer O
1 O
. O

The O
field O
of O
cancer O
metabolism O
subsequently O
revealed O
additional O
metabolic O
alterations O
in O
cancer O
by O
focusing O
on O
central O
carbon O
metabolism O
, O
including O
the O
citric O
acid O
cycle O
and O
pentose O
phosphate O
pathway O
. O

Recent O
reports O
have O
, O
however O
, O
uncovered O
substantial O
non O
- O
carbon O
metabolism O
contributions O
to O
cancer O
cell O
viability O
and O
growth O
. O

Amino O
acids O
, O
nutrients O
vital O
to O
the O
survival O
of O
all O
cell O
types O
, O
experience O
reprogrammed O
metabolism O
in O
cancer O
. O

This O
review O
outlines O
the O
diverse O
roles O
of O
amino O
acids O
within O
the O
tumor O
and O
in O
the O
tumor O
microenvironment O
. O

Beyond O
their O
role O
in O
biosynthesis O
, O
they O
serve O
as O
energy O
sources O
and O
help O
maintain O
redox O
balance O
. O

In O
addition O
, O
amino O
acid O
derivatives O
contribute O
to O
epigenetic O
regulation O
and O
immune O
responses O
linked O
to O
tumorigenesis O
and O
metastasis O
. O

Furthermore O
, O
in O
discussing O
the O
transporters O
and O
transaminases O
that O
mediate O
amino O
acid O
uptake O
and O
synthesis O
, O
we O
identify O
potential O
metabolic O
liabilities O
as O
targets O
for O
therapeutic O
intervention O
. O

Objective O
Non O
- O
operative O
management O
of O
blunt O
splenic O
injury O
in O
adults O
has O
been O
applied O
increasingly O
at O
the O
end O
of O
the O
last O
century O
. O

Therefore O
, O
the O
lifelong O
risk O
of O
overwhelming O
post O
- O
splenectomy O
infection O
has O
been O
the O
major O
impetus O
for O
preservation O
of O
the O
spleen O
. O

However O
, O
the O
prevalence B-EPI
of O
posttraumatic O
infection O
after O
splenectomy O
in O
contrast O
to O
a O
conservative O
management O
is O
still O
unknown B-STAT
. O

Objective O
was O
to O
determine O
if O
splenectomy O
is O
an O
independent O
risk O
factor O
for O
the O
development O
of O
posttraumatic O
sepsis O
and O
multi O
- O
organ O
failure O
. O

Methods O
13,433 O
patients O
from O
113 O
hospitals O
were O
prospective O
collected O
from O
1993 B-DATE
to I-DATE
2005 I-DATE
. O

Patients O
with O
an O
injury O
severity O
score O
> O
16 O
, O
no O
isolated O
head O
injury O
, O
primary O
admission O
to O
a O
trauma O
center O
and O
splenic O
injury O
were O
included O
. O

Data O
were O
allocated O
according O
to O
the O
operative O
management O
into O
2 O
groups O
( O
splenectomy O
( O
I O
) O
and O
conservative O
managed O
patients O
( O
II O
) O
) O
. O

Results O
From O
1,630 O
patients O
with O
splenic O
injury O
758 O
patients O
undergoing O
splenectomy O
compared O
with O
872 O
non O
- O
splenectomized O
patients O
. O

96 O
( O
18.3 O
% O
) O
of O
the O
patients O
with O
splenectomy O
and O
102 O
( O
18.5 O
% O
) O
without O
splenectomy O
had O
apparent O
infection O
after O
operation O
. O

Additionally O
, O
there O
was O
no O
difference O
in O
mortality O
( O
24.8 O
% O
versus O
22.2 O
% O
) O
in O
both O
groups O
. O

After O
massive O
transfusion O
of O
red O
blood O
cells O
( O
> O
10 O
) O
non O
- O
splenectomy O
patients O
showed O
a O
significant O
increase O
of O
multi O
- O
organ O
failure O
( O
46 O
% O
vs. O
40 O
% O
) O
and O
sepsis O
( O
38 O
% O
vs. O
25 O
% O
) O
. O

Conclusions O
Non O
- O
operative O
management O
leads O
to O
lower O
systemic O
infection O
rates O
and O
mortality O
in O
adult O
patients O
with O
moderate O
blunt O
splenic O
injury O
( O
grade O
1 O
- O
3 O
) O
and O
should O
therefore O
be O
advocated O
. O

Patients O
with O
grade O
4 O
and O
5 O
injury O
, O
patients O
with O
massive O
transfusion O
of O
red O
blood O
cells O
and O
unstable O
patients O
should O
be O
managed O
operatively O
. O

Background O
Adrenocortical O
carcinoma O
( O
ACC O
) O
is O
a O
rare O
endocrine O
carcinoma O
with O
poor O
5 O
- O
year O
survival O
rates O
of O
< O
40 O
% O
. O

According O
to O
the O
literature O
, O
ACC O
is O
rarely O
an O
incidental O
imaging O
finding O
. O

However O
, O
presentation O
, O
treatment O
and O
outcome O
may O
differ O
in O
modern O
series O
. O

Design O
and O
methods O
We O
studied O
all O
patients O
( O
n O
= O
47 O
, O
four O
children O
) O
from O
a O
single O
centre O
during O
years O
2002 B-DATE
- I-DATE
2018 I-DATE
. O

We O
re O
- O
evaluated O
radiologic O
and O
histopathological O
findings O
and O
assessed O
treatments O
and O
outcome O
. O

We O
searched O
for O
possible O
TP53 O
gene O
defects O
and O
assessed O
nationwide O
incidence B-EPI
of O
ACC O
. O

Results O
In O
adults O
, O
incidental O
radiologic O
finding O
led O
to O
diagnosis O
in O
79 O
% O
at O
median O
age O
of O
61 O
years O
. O

ENSAT O
stage O
I O
, O
II O
, O
III O
and O
IV O
was O
19 O
% O
, O
40 O
% O
, O
19 O
% O
and O
21 O
% O
, O
respectively O
. O

Nonenhanced O
CT O
demonstrated O
> O
20 O
Hounsfield O
Units O
( O
HU O
) O
for O
all O
tumours O
( O
median O
34 O
( O
21 O
- O
45 O
) O
) O
, O
median O
size O
92 O
mm O
( O
20 O
- O
196 O
) O
, O
Ki67 O
17 O
% O
( O
1 O
- O
40 O
% O
) O
, O
Weiss O
score O
7 O
( O
4 O
- O
9 O
) O
and O
Helsinki O
score O
24 O
( O
4 O
- O
48 O
) O
. O

ACC O
was O
more O
often O
found O
in O
the O
left O
than O
the O
right O
adrenal O
( O
p O
< O
0.05 O
) O
. O

One O
child O
had O
Beckwith O
- O
Wiedemann O
and O
one O
a O
TP53 O
mutation O
. O

In O
adults O
, O
the O
primary O
tumour O
was O
resected O
in O
88 O
and O
79 O
% O
received O
adjuvant O
mitotane O
therapy O
. O

Median O
hospital O
stay O
was O
significantly O
shorter O
in O
the O
laparoscopic O
vs. O
open O
surgery O
group O
( O
4 O
( O
3 O
- O
7 O
) O
vs. O
8 O
( O
5 O
- O
38 O
) O
days O
, O
respectively O
; O
p O
< O
0.001 O
) O
. O

In O
3/4 O
patients O
, O
prolonged O
remission O
of O
> O
5 O
to O
> O
10 O
years O
was O
achieved O
after O
repeated O
surgery O
of O
metastases O
. O

Overall O
5 O
- O
year O
survival O
was O
67 O
% O
, O
and O
96 O
% O
vs. O
26 O
% O
for O
ENSAT O
stage O
I O
- O
II O
vs. O
III O
- O
IV O
( O
p O
< O
0.0001 O
) O
. O

ENSAT O
stage O
and O
Ki67 O
predicted O
survival O
, O
type O
of O
surgery O
did O
not O
. O

Mitotane O
associated O
with O
better O
survival O
. O

Conclusions O
Contemporary O
ACC O
predominantly O
presents O
as O
an O
incidental O
imaging O
finding O
, O
characterised O
by O
HU O
> O
20 O
on O
nonenhanced O
CT O
but O
variable O
tumour O
size O
( O
20 O
- O
196 O
mm O
) O
. O

Malignancy O
can O
not O
be O
ruled O
out O
by O
small O
tumour O
size O
only O
. O

The O
5 O
- O
year O
survival O
of O
96 O
% O
in O
ENSAT O
stage O
I O
- O
III O
compares O
favourably O
to O
previous O
studies O
. O

Study O
objectives O
The O
primary O
objective O
was O
to O
describe O
trends O
in O
the O
2 O
- O
year O
limited O
duration O
prevalence B-EPI
of O
narcolepsy O
from O
2013 B-DATE
- I-DATE
2016 I-DATE
in O
a O
large O
insured O
population O
with O
claims O
activity O
. O

Secondary O
objectives O
were O
to O
assess O
the O
prevalence B-EPI
of O
other O
sleep O
disorders O
and O
the O
frequency O
of O
diagnostic O
sleep O
testing O
. O

Methods O
Nationwide O
medical O
/ O
prescription O
claims O
( O
Symphony O
Health O
) O
were O
analyzed O
to O
estimate O
the O
annual B-EPI
prevalence I-EPI
per I-STAT
100,000 I-STAT
persons I-STAT
of O
narcolepsy O
and O
other O
sleep O
disorders O
( O
obstructive O
sleep O
apnea O
, O
idiopathic O
hypersomnia O
, O
rapid O
eye O
movement O
sleep O
behavior O
disorder O
, O
periodic O
limb O
movement O
disorder O
) O
and O
the O
frequency O
of O
diagnostic O
sleep O
testing O
. O

Prevalence B-EPI
was O
adjusted O
to O
the O
age O
/ O
sex O
distribution O
of O
the O
2016 B-DATE
US B-LOC
census O
estimates O
. O

Results O
The O
prevalence B-EPI
of O
narcolepsy O
per I-STAT
100,000 I-STAT
persons I-STAT
increased O
14 O
% O
from O
38.9 B-STAT
in O
2013 B-DATE
to I-DATE
44.3 I-STAT
in O
2016 I-DATE
. O

Obstructive O
sleep O
apnea O
prevalence B-EPI
increased O
41 O
% O
over O
the O
study O
period O
from O
2,429 B-STAT
to I-STAT
3,420 I-STAT
per I-STAT
100,000 I-STAT
. O

Large O
increases O
in O
prevalence B-EPI
were O
also O
seen O
for O
idiopathic O
hypersomnia O
( O
32 O
% O
) O
, O
periodic O
limb O
movement O
disorder O
( O
30 O
% O
) O
, O
and O
rapid O
eye O
movement O
sleep O
behavior O
disorder O
( O
64 O
% O
) O
. O

For O
each O
sleep O
disorder O
, O
prevalence B-EPI
was O
higher O
for O
those O
with O
commercial O
insurance O
versus O
Medicare O
/ O
Medicaid O
, O
and O
markedly O
lower O
prevalence B-EPI
was O
observed O
for O
the O
Northeast B-LOC
compared O
with O
the O
Midwest B-LOC
, O
South B-LOC
, O
and O
Western B-LOC
US I-LOC
regions O
. O

The O
frequency O
of O
multiple O
sleep O
latency O
/ O
maintenance O
of O
wakefulness O
testing O
declined O
by O
20 O
% O
, O
and O
polysomnography O
declined O
by O
15 O
% O
. O

Conversely O
, O
home O
sleep O
apnea O
testing O
increased O
by O
117 O
% O
. O

Conclusions O
The O
prevalence B-EPI
of O
narcolepsy O
, O
obstructive O
sleep O
apnea O
, O
and O
the O
other O
sleep O
disorders O
increased O
appreciably O
over O
the O
2013 B-DATE
- I-DATE
2016 I-DATE
period O
. O

It O
remains O
to O
be O
determined O
whether O
the O
trends O
seen O
in O
our O
analyses O
are O
due O
to O
increased O
incidence B-EPI
or O
increased O
awareness O
of O
these O
conditions O
. O

Most O
of O
the O
studies O
examining O
the O
impact O
of O
cannabis O
use O
in O
first O
episode O
psychosis O
( O
FEP O
) O
have O
been O
carried O
out O
in O
samples O
with O
adult O
- O
onset O
FEP O
. O

Data O
in O
persons O
with O
early O
onset O
psychosis O
( O
EOP O
) O
is O
scarce O
. O

The O
aims O
of O
the O
study O
were O
: O
To O
describe O
the O
prevalence B-EPI
of O
lifetime O
cannabis O
use O
, O
current O
use O
, O
and O
daily O
use O
in O
patients O
with O
EOP O
compared O
to O
healthy O
controls O
. O

To O
study O
the O
differences O
in O
clinical O
presentation O
between O
cannabis O
users O
and O
non O
- O
users O
. O

To O
examine O
the O
risk O
of O
presenting O
an O
EOP O
associated O
with O
cannabis O
use O
and O
the O
effect O
of O
doses O
and O
age O
of O
onset O
of O
use O
. O

An O
observational O
cross O
- O
sectional O
study O
was O
performed O
in O
90 O
EOP O
cases O
and O
62 O
healthy O
controls O
, O
aged O
between O
7 O
and O
17 O
years O
. O

Our O
results O
show O
a O
higher O
prevalence B-EPI
of O
lifetime O
use O
( O
p O
= O
0002 O
) O
, O
current O
use O
( O
p O
< O
0.001 O
) O
, O
and O
daily O
use O
( O
p O
< O
0.001 O
) O
in O
EOP O
cases O
in O
comparison O
with O
healthy O
controls O
. O

Regarding O
clinical O
presentation O
, O
we O
did O
not O
find O
significant O
differences O
in O
any O
subscale O
of O
the O
Positive O
and O
Negative O
Syndrome O
Scale O
( O
PANSS O
) O
. O

Non O
- O
user O
patients O
presented O
more O
severe O
depressive O
symptoms O
( O
p O
= O
0002 O
) O
and O
worse O
social O
functioning O
than O
cannabis O
users O
( O
p O
= O
0026 O
) O
. O

Compared O
with O
subjects O
who O
never O
used O
cannabis O
, O
the O
risk O
of O
an O
EOP O
was O
significantly O
higher O
for O
those O
with O
a O
lifetime O
use O
( O
OR O
= O
2.88 O
, O
p O
= O
0.002)current O
use O
( O
O.R O
= O
6.09 O
, O
p O
< O
0001 O
) O
, O
and O
especially O
in O
those O
with O
daily O
use O
( O
O.R O
= O
42.77 O
, O
p O
= O
< O
0001 O
) O
. O

We O
found O
a O
higher O
risk O
of O
EOP O
in O
patients O
that O
have O
used O
cannabis O
before O
15 O
years O
of O
age O
. O

In O
conclusion O
, O
it O
is O
necessary O
to O
develop O
early- O
detection O
and O
specific O
treatment O
programs O
for O
adolescents O
with O
cannabis O
use O
. O

Background O
The O
combination O
of O
esophageal O
atresia O
, O
congenital O
duodenal O
obstruction O
, O
and O
anorectal O
malformation O
has O
seldom O
been O
reported O
. O

We O
describe O
the O
largest O
series O
of O
patients O
with O
such O
association O
, O
which O
we O
summed O
up O
with O
the O
mnemonic O
acronym O
DATE O
[ O
D O
- O
duodenal O
obstruction O
, O
A O
- O
anorectal O
malformation O
( O
ARM O
) O
, O
and O
TE O
- O
tracheoesophageal O
fistula O
with O
esophageal O
atresia O
] O
. O

Methods O
This O
was O
a O
multicenter O
retrospective O
review O
of O
13 O
patients O
recruited O
from O
8 O
institutions O
over O
a O
nearly O
5 O
- O
decade O
period O
( O
1968 B-DATE
- I-DATE
2017 I-DATE
) O
. O

Information O
gathered O
included O
type O
of O
DATE O
malformations O
, O
other O
associated O
anomalies O
, O
type O
and O
timing O
of O
surgery O
, O
and O
clinical O
outcomes O
. O

Results O
The O
DATE O
association O
consisted O
of O
type O
C O
esophageal O
atresia O
( O
13 O
) O
, O
complete O
( O
9 O
) O
or O
incomplete O
( O
4 O
) O
congenital O
duodenal O
obstruction O
( O
CDO O
) O
, O
and O
high O
or O
intermediate O
( O
8) O
or O
low O
( O
5 O
) O
ARM O
. O

Eight O
patients O
had O
at O
least O
one O
additional O
component O
feature O
of O
VACTERL O
association O
. O

A O
total O
of O
6 O
patients O
died O
. O

Overall O
, O
9 O
patients O
achieved O
complete O
restoration O
of O
gastrointestinal O
continuity O
, O
7 O
of O
whom O
are O
alive O
at O
a O
median O
follow O
- O
up O
of O
4 O
Y O
( O
range O
, O
1 O
to O
9 O
) O
. O

Survivors O
received O
a O
median O
of O
6 O
major O
operations O
( O
range O
, O
4 O
to O
14 O
) O
to O
overcome O
their O
anomalies O
and O
surgical O
complications O
. O

Two O
incomplete O
duodenal O
obstructions O
were O
initially O
overlooked O
. O

All O
survivors O
with O
high O
or O
intermediate O
ARM O
defects O
required O
some O
form O
of O
bowel O
management O
to O
keep O
them O
clean O
. O

Conclusions O
The O
DATE O
association O
is O
a O
low O
- O
frequency O
entity O
, O
often O
occurring O
among O
the O
wider O
spectrum O
of O
VACTERL O
association O
. O

Functional O
outcomes O
largely O
depend O
on O
the O
severity O
of O
ARM O
or O
other O
major O
associated O
malformations O
. O

Awareness O
of O
the O
DATE O
association O
may O
avoid O
untoward O
diagnostic O
delays O
of O
subtler O
component O
features O
of O
the O
spectrum O
, O
such O
as O
an O
incomplete O
CDO O
. O

Background O
A O
preliminary O
safety O
signal O
for O
neural O
- O
tube O
defects O
was O
previously O
reported O
in O
association O
with O
dolutegravir O
exposure O
from O
the O
time O
of O
conception O
, O
which O
has O
affected O
choices O
of O
antiretroviral O
treatment O
( O
ART O
) O
for O
human O
immunodeficiency O
virus O
( O
HIV O
) O
- O
infected O
women B-SEX
of O
reproductive O
potential O
. O

The O
signal O
can O
now O
be O
evaluated O
with O
data O
from O
follow O
- O
up O
of O
additional O
pregnancies O
. O

Methods O
We O
conducted O
birth O
- O
outcomes O
surveillance O
at O
hospitals O
throughout O
Botswana B-LOC
, O
expanding O
from O
8 O
to O
18 O
sites O
in O
2018 B-DATE
. O

Trained O
midwives O
performed O
surface O
examinations O
of O
all O
live O
- O
born O
and O
stillborn O
infants O
. O

Research O
assistants O
photographed O
abnormalities O
after O
maternal O
consent O
was O
obtained O
. O

The O
prevalence B-EPI
of O
neural O
- O
tube O
defects O
and O
major O
external O
structural O
defects O
according O
to O
maternal O
HIV O
infection O
and O
ART O
exposure O
status O
was O
determined O
. O

In O
the O
primary O
analyses O
, O
we O
used O
the O
Newcombe O
method O
to O
evaluate O
differences O
in O
prevalence B-EPI
with O
95 O
% O
confidence O
intervals O
. O

Results O
From O
August B-DATE
2014 I-DATE
through I-DATE
March I-DATE
2019 I-DATE
, O
surveillance O
captured O
119,477 O
deliveries O
; O
119,033 O
( O
99.6 O
% O
) O
had O
an O
infant O
surface O
examination O
that O
could O
be O
evaluated O
, O
and O
98 O
neural O
- O
tube O
defects O
were O
identified O
( O
0.08 O
% O
of O
deliveries O
) O
. O

Among O
1683 O
deliveries O
in O
which O
the O
mother O
was O
taking O
dolutegravir O
at O
conception O
, O
5 O
neural O
- O
tube O
defects O
were O
found O
( O
0.30 O
% O
of O
deliveries O
) O
; O
the O
defects O
included O
two O
instances O
of O
myelomeningocele O
, O
one O
of O
anencephaly O
, O
one O
of O
encephalocele O
, O
and O
one O
of O
iniencephaly O
. O

In O
comparison O
, O
15 O
neural O
- O
tube O
defects O
were O
found O
among O
14,792 O
deliveries O
( O
0.10 O
% O
) O
in O
which O
the O
mother O
was O
taking O
any O
non O
- O
dolutegravir O
ART O
at O
conception O
, O
3 O
among O
7959 O
( O
0.04 O
% O
) O
in O
which O
the O
mother O
was O
taking O
efavirenz O
at O
conception O
, O
1 O
among O
3840 O
( O
0.03 O
% O
) O
in O
which O
the O
mother O
started O
dolutegravir O
treatment O
during O
pregnancy O
, O
and O
70 O
among O
89,372 O
( O
0.08 O
% O
) O
in O
HIV O
- O
uninfected O
mothers O
. O

The O
prevalence B-EPI
of O
neural O
- O
tube O
defects O
was O
higher O
in O
association O
with O
dolutegravir O
treatment O
at O
conception O
than O
with O
non O
- O
dolutegravir O
ART O
at O
conception O
( O
difference O
, O
0.20 O
percentage O
points O
; O
95 O
% O
confidence O
interval O
[ O
CI O
] O
, O
0.01 O
to O
0.59 O
) O
or O
with O
other O
types O
of O
ART O
exposure O
. O

Major O
external O
structural O
defects O
were O
found O
in O
0.95 O
% O
of O
deliveries O
among O
women B-SEX
exposed O
to O
dolutegravir O
at O
conception O
and O
0.68 O
% O
of O
those O
among O
women B-SEX
exposed O
to O
non O
- O
dolutegravir O
ART O
at O
conception O
( O
difference O
, O
0.27 O
percentage O
points O
; O
95 O
% O
CI O
, O
-0.13 O
to O
0.87 O
) O
. O

Conclusions O
The O
prevalence B-EPI
of O
neural O
- O
tube O
defects O
was O
slightly O
higher O
in O
association O
with O
dolutegravir O
exposure O
at O
conception O
than O
with O
other O
types O
of O
ART O
exposure O
at O
conception O
( O
3 B-STAT
per I-STAT
1000 I-STAT
deliveries I-STAT
vs. O
1 B-STAT
per I-STAT
1000 I-STAT
deliveries I-STAT
) O
. O

( O
Funded O
by O
the O
National O
Institutes O
of O
Health O
. O

) O
. O

Ataxia O
- O
telangiectasia O
is O
the O
second O
most O
common O
autosomal O
recessive O
hereditary O
ataxia O
, O
with O
an O
estimated B-EPI
incidence I-EPI
of O
1 B-STAT
in I-STAT
100,000 I-STAT
births I-STAT
. O

Besides O
ataxia O
and O
ocular O
telangiectasias O
, O
eye O
movement O
abnormalities O
have O
long O
been O
associated O
with O
this O
disorder O
and O
is O
frequently O
present O
in O
almost O
all O
patients O
. O

A O
handful O
of O
studies O
have O
described O
the O
phenomenology O
of O
ocular O
motor O
deficits O
in O
ataxia O
- O
telangiectasia O
. O

Contemporary O
literature O
linked O
their O
physiology O
to O
cerebellar O
dysfunction O
and O
secondary O
abnormalities O
at O
the O
level O
of O
brainstem O
. O

These O
studies O
, O
while O
providing O
a O
proof O
of O
concept O
of O
ocular O
motor O
physiology O
in O
disease O
, O
i.e. O
, O
ataxia O
- O
telangiectasia O
, O
also O
advanced O
our O
understanding O
of O
how O
the O
cerebellum O
works O
. O

Here O
, O
we O
will O
summarize O
the O
clinical O
abnormalities O
seen O
with O
ataxia O
- O
telangiectasia O
in O
each O
subtype O
of O
eye O
movements O
and O
subsequently O
describe O
the O
underlying O
pathophysiology O
. O

Finally O
, O
we O
will O
review O
how O
these O
deficits O
are O
linked O
to O
abnormal O
cerebellar O
function O
and O
how O
it O
allows O
better O
understanding O
of O
the O
cerebellar O
physiology O
. O

: O
The O
Bernard O
- O
Soulier O
syndrome O
( O
BSS O
) O
is O
a O
rare O
disease O
with O
a O
prevalence B-EPI
of O
1/1000000 B-STAT
; O
it O
is O
characterized O
by O
macrothrombocytopenia O
. O

BSS O
develops O
as O
a O
result O
of O
a O
defect O
in O
the O
glycoprotein O
GPIb O
- O
IX O
- O
V O
complex O
on O
the O
platelet O
surface O
. O

In O
this O
article O
, O
we O
present O
a O
pediatric O
patient O
with O
the O
novel O
mutation O
that O
has O
been O
identified O
for O
the O
first O
time O
in O
BSS O
. O

A O
13 O
- O
month O
- O
old O
male B-SEX
patient O
was O
admitted O
with O
severe O
thrombocytopenia O
unresponsive O
to O
intravenous O
immunoglobulin O
in O
the O
neonatal O
period O
and O
recurrent O
mucocutaneous O
bleeding O
which O
initiated O
at O
5 O
months O
of O
age O
. O

glycoprotein O
( O
GP O
) O
IX O
( O
CD42a O
) O
expression O
was O
normal O
as O
per O
flow O
cytometry O
results O
. O

Genetic O
analysis O
revealed O
a O
homozygous O
c.243C O
> O
A O
( O
p. O
Cys81 O
) O
( O
p. O
C81 O
) O
mutation O
. O

This O
novel O
mutation O
identified O
by O
us O
presents O
with O
severe O
thrombocytopenia O
and O
normal O
GPIX O
( O
CD42a O
) O
expression O
and O
is O
mistaken O
for O
immune O
thrombocytopenia O
in O
the O
neonatal O
period O
. O

This O
mutation O
creates O
an O
early O
stop O
codon O
and O
possibly O
leads O
to O
loss O
of O
function O
of O
the O
receptor O
. O

Scurvy O
is O
a O
disease O
caused O
by O
chronic O
vitamin O
C O
deficiency O
. O

The O
greater O
prevalence B-EPI
was O
found O
in O
the O
paediatric O
population O
with O
neurodevelopmental O
disorders O
such O
as O
autism O
spectrum O
disorders O
due O
to O
their O
restricted O
dietary O
intake O
. O

Our O
case O
reported O
a O
child O
with O
autism O
who O
presented O
with O
arthralgia O
and O
anaemia O
. O

Systemic O
lupus O
erythematosus O
was O
the O
first O
diagnostic O
impression O
, O
resulting O
in O
over O
investigation O
and O
delayed O
diagnosis O
of O
vitamin O
C O
deficiency O
. O

After O
the O
child O
was O
treated O
with O
ascorbic O
acid O
, O
the O
child O
's O
symptoms O
resolved O
. O

This O
case O
highlighted O
the O
importance O
of O
developmental O
and O
nutritional O
history O
taking O
in O
the O
paediatric O
population O
. O

Furthermore O
, O
parents O
and O
physicians O
should O
be O
concerned O
about O
nutritional O
status O
, O
especially O
in O
children O
with O
restrictive O
dietary O
intake O
. O

The O
hierarchical O
information O
flow O
through O
DNA O
- O
RNA O
- O
protein O
- O
metabolite O
collectively O
referred O
to O
as O
' O
molecular O
fingerprint O
' O
defines O
both O
health O
and O
disease O
. O

Environment O
and O
food O
( O
quality O
and O
quantity O
) O
are O
the O
key O
factors O
known O
to O
affect O
the O
health O
of O
an O
individual O
. O

The O
fundamental O
concepts O
are O
that O
the O
transition O
from O
a O
healthy O
condition O
to O
a O
disease O
phenotype O
must O
occur O
by O
concurrent O
alterations O
in O
the O
genome O
expression O
or O
by O
differences O
in O
protein O
synthesis O
, O
function O
and O
metabolites O
. O

In O
other O
words O
, O
the O
dietary O
components O
directly O
or O
indirectly O
modulate O
the O
molecular O
fingerprint O
and O
understanding O
of O
which O
is O
dealt O
with O
nutrigenomics O
. O

Although O
the O
fundamental O
principles O
of O
nutrigenomics O
remain O
similar O
to O
that O
of O
traditional O
research O
, O
a O
collection O
of O
comprehensive O
targeted O
/ O
untargeted O
data O
sets O
in O
the O
context O
of O
nutrition O
offers O
the O
unique O
advantage O
of O
understanding O
complex O
metabolic O
networks O
to O
provide O
a O
mechanistic O
understanding O
of O
data O
from O
epidemiological O
and O
intervention O
studies O
. O

In O
this O
review O
the O
challenges O
and O
opportunities O
of O
nutrigenomic O
tools O
in O
addressing O
the O
nutritional O
problems O
of O
public O
health O
importance O
are O
discussed O
. O

The O
application O
of O
nutrigenomic O
tools O
provided O
numerous O
leads O
on O
biomarkers O
of O
nutrient O
intake O
, O
undernutrition O
, O
metabolic O
syndrome O
and O
its O
complications O
. O

Importantly O
, O
nutrigenomic O
studies O
also O
led O
to O
the O
discovery O
of O
the O
association O
of O
multiple O
genetic O
polymorphisms O
in O
relation O
to O
the O
variability O
of O
micronutrient O
absorption O
and O
metabolism O
, O
providing O
a O
potential O
opportunity O
for O
further O
research O
toward O
setting O
personalized O
dietary O
recommendations O
for O
individuals O
and O
population O
subgroups O
. O

Background O
Neuromyelitis O
optica O
spectrum O
disorders O
( O
NMOSD O
) O
is O
an O
increasing O
diagnostic O
and O
therapeutic O
challenge O
in O
Latin B-LOC
America I-ETHN
( O
LATAM B-LOC
) O
. O

Despite O
the O
heterogeneity O
of O
this O
population O
, O
ethnic O
and O
socioeconomic O
commonalities O
exist O
, O
and O
epidemiologic O
studies O
from O
the O
region O
have O
had O
a O
limited O
geographic O
and O
population O
outreach O
. O

Identification O
of O
some O
aspects O
from O
the O
entire O
region O
are O
lacking O
. O

Objectives O
To O
determine O
ethnic O
, O
clinical O
characteristics O
, O
and O
utilization O
of O
diagnostic O
tools O
and O
types O
of O
therapy O
for O
patients O
with O
NMOSD O
in O
the O
entire O
Latin B-ETHN
American I-ETHN
region I-LOC
. O

Methods O
The O
Latin B-ETHN
American I-ETHN
Committee O
for O
Treatment O
and O
Research O
in O
MS O
( O
LACTRIMS O
) O
created O
an O
exploratory O
investigational O
survey O
addressed O
by O
Invitation O
to O
NMOSD O
Latin B-ETHN
American I-ETHN
experts O
identified O
through O
diverse O
sources O
. O

Data O
input O
closed O
after O
30 O
days O
from O
the O
initial O
invitation O
. O

The O
questionnaire O
allowed O
use O
of O
absolute O
numbers O
or O
percentages O
. O

Multiple O
option O
responses O
covering O
25 O
themes O
included O
definition O
of O
type O
of O
practice O
; O
number O
of O
NMOSD O
cases O
; O
ethnicity O
; O
utilization O
of O
the O
2015 B-DATE
International O
Panel O
criteria O
for O
the O
diagnosis O
of O
Neuromyelitis O
optica O
( O
IPDN O
) O
; O
clinical O
phenotypes O
; O
methodology O
utilized O
for O
determination O
of O
anti O
- O
Aquaporin-4 O
( O
anti- O
AQP4 O
) O
antibodies O
serological O
testing O
, O
and O
if O
this O
was O
performed O
locally O
or O
processed O
abroad O
; O
treatment O
of O
relapses O
, O
and O
long O
- O
term O
management O
were O
surveyed O
. O

Results O
We O
identified O
62 O
investigators O
from O
21 O
countries O
reporting O
information O
from O
2154 O
patients O
( O
utilizing O
the O
IPDN O
criteria O
in O
93.9 O
% O
of O
cases O
) O
, O
which O
were O
categorized O
in O
two O
geographical O
regions O
: O
North B-LOC
- I-LOC
Central I-LOC
, O
including O
the O
Caribbean B-LOC
( O
NCC O
) O
, O
and O
South B-LOC
America I-LOC
( O
SA B-LOC
) O
. O

Ethnic O
identification O
disclosed O
Mestizos B-ETHN
61.4 O
% O
as O
the O
main O
group O
. O

The O
most O
common O
presenting O
symptoms O
were O
concomitant O
presence O
of O
optic O
neuritis O
and O
transverse O
myelitis O
in O
31.8 O
% O
( O
p=0.95 O
) O
; O
only O
optic O
neuritis O
in O
31.4 O
% O
( O
more O
common O
in O
SA O
) O
, O
p<0.001 O
) O
; O
involvement O
of O
the O
area O
postrema O
occurred O
in O
21.5 O
% O
and O
brain O
stem O
in O
8.3 O
% O
, O
both O
were O
more O
frequent O
in O
the O
South B-ETHN
American I-ETHN
cases O
( O
p<0.001 O
) O
. O

Anti O
- O
AQP4 O
antibodies O
were O
positive O
in O
63.9 O
% O
and O
anti O
- O
Myelin O
Oligodendrocyte O
Glycoprotein O
( O
MOG O
) O
antibodies O
in O
4.8 O
% O
of O
total O
cases O
. O

The O
specific O
laboratorial O
method O
employed O
was O
not O
known O
by O
23.8 O
% O
of O
the O
investigators O
. O

Acute O
relapses O
were O
identified O
in O
81.6 O
% O
of O
cases O
, O
and O
were O
treated O
in O
93.9 O
% O
of O
them O
with O
intravenous O
steroids O
( O
IVS O
) O
; O
62.1 O
% O
with O
plasma O
exchange O
( O
PE O
) O
, O
and O
40.9 O
% O
with O
intravenous O
immunoglobulin O
- O
G O
( O
IVIG O
) O
. O

Therapy O
was O
escalated O
in O
some O
cases O
due O
to O
suboptimal O
initial O
response O
. O

Respondents O
favored O
Rituximab O
as O
long O
- O
term O
therapy O
( O
86.3 O
% O
) O
, O
whereas O
azathioprine O
was O
also O
utilized O
on O
81.8 O
% O
of O
the O
cases O
, O
either O
agent O
used O
indistinctly O
by O
the O
investigators O
according O
to O
treatment O
accessibility O
or O
clinical O
judgement O
. O

There O
were O
no O
differences O
among O
the O
geographic O
regions O
. O

Conclusions O
This O
is O
the O
first O
study O
including O
all O
countries O
of O
LATAM B-LOC
and O
the O
largest O
cohort O
reported O
from O
a O
multinational O
specific O
world O
area O
. O

Ethnic O
distributions O
and O
phenotypic O
features O
of O
the O
disease O
in O
the O
region O
, O
challenges O
in O
access O
to O
diagnostic O
tools O
and O
therapy O
were O
identified O
. O

The O
Latin B-ETHN
American I-ETHN
neurological O
community O
should O
play O
a O
determinant O
role O
encouraging O
and O
advising O
local O
institutions O
and O
health O
officials O
in O
the O
availability O
of O
more O
sensitive O
and O
modern O
diagnostic O
methodology O
, O
in O
facilitating O
the O
the O
access O
to O
licensed O
medications O
for O
NMOSD O
, O
and O
addressing O
concerns O
on O
education O
, O
diagnosis O
and O
management O
of O
the O
disease O
in O
the O
community O
. O

Skeletal O
dysplasia O
( O
SD O
) O
, O
a O
heterogeneous O
disease O
group O
with O
rare O
incidence B-EPI
and O
various O
clinical O
manifestations O
, O
is O
associated O
with O
multiple O
causative O
genes O
. O

For O
clinicians O
, O
accurate O
diagnosis O
of O
SD O
is O
clinically O
and O
genetically O
difficult O
. O

The O
development O
of O
next O
- O
generation O
sequencing O
( O
NGS O
) O
has O
substantially O
aided O
in O
the O
genetic O
diagnosis O
of O
SD O
. O

In O
this O
study O
, O
we O
conducted O
a O
targeted O
NGS O
of O
437 O
genes O
- O
included O
in O
the O
nosology O
of O
SD O
published O
in O
2019 B-DATE
- O
in O
31 O
patients O
with O
a O
suspected O
SD O
. O

The O
clinical O
and O
genetic O
diagnoses O
were O
confirmed O
in O
16 O
out O
of O
the O
31 O
patients O
, O
and O
the O
diagnostic O
yield O
was O
51.9 O
% O
. O

In O
these O
patients O
, O
18 O
pathogenic O
variants O
were O
found O
in O
13 O
genes O
( O
COL2A1 O
, O
MYH3 O
, O
COMP O
, O
MATN3 O
, O
CTSK O
, O
EBP O
, O
CLCN7 O
, O
COL1A2 O
, O
EXT1 O
, O
TGFBR1 O
, O
SMAD3 O
, O
FIG4 O
, O
and O
ARID1B O
) O
, O
of O
which O
, O
four O
were O
novel O
variants O
. O

The O
diagnosis O
rate O
was O
very O
high O
in O
patients O
with O
a O
suspected O
familial O
SD O
and O
with O
radiological O
evidence O
indicating O
clinical O
SD O
( O
11 O
out O
of O
15 O
, O
73.3 O
% O
) O
. O

In O
patients O
with O
skeletal O
involvement O
and O
other O
clinical O
manifestations O
including O
dysmorphism O
or O
multiple O
congenital O
anomalies O
, O
and O
various O
degrees O
of O
developmental O
delay O
/ O
intellectual O
disability O
, O
the O
diagnosis O
rate O
was O
low O
( O
5 O
out O
of O
16 O
, O
31.2 O
% O
) O
but O
rare O
syndromic O
SD O
could O
be O
diagnosed O
. O

In O
conclusion O
, O
NGS O
- O
based O
gene O
panel O
sequencing O
can O
be O
helpful O
in O
diagnosing O
SD O
which O
has O
clinical O
and O
genetic O
heterogeneity O
. O

To O
increase O
the O
diagnostic O
yield O
of O
suspected O
SD O
patients O
, O
it O
is O
important O
to O
categorize O
patients O
based O
on O
the O
clinical O
features O
, O
family O
history O
, O
and O
radiographic O
evidence O
. O

Background O
The O
prevalence B-EPI
of O
perinatal O
infection O
from O
maternal O
exposure O
is O
increasing O
. O

The O
prevalence B-EPI
of O
acute O
maternal O
infections O
identifies O
cytomegalovirus O
, O
parvovirus O
B19 O
, O
toxoplasmosis O
, O
and O
varicella O
as O
the O
most O
common O
organisms O
and O
in O
the O
order O
of O
frequency O
. O

Maternal O
informed O
consent O
and O
understanding O
is O
required O
before O
intrauterine O
testing O
for O
fetal O
infectious O
and O
possible O
genetic O
risk O
assessment O
. O

Methods O
This O
structured O
review O
of O
the O
reproductive O
published O
literature O
focuses O
on O
the O
risks O
of O
amniocentesis O
and O
cordocentesis O
diagnostic O
procedure O
- O
related O
fetal O
loss O
rates O
and O
fetal O
vertical O
transmission O
( O
VT O
) O
rates O
from O
published O
infected O
pregnant O
cohorts O
. O

Results O
The O
total O
postprocedure O
fetal O
loss O
rate O
for O
diagnostic O
amniocentesis O
procedures O
, O
in O
limited O
infectious O
cohorts O
, O
is O
1.5 O
% O
and O
does O
not O
appear O
to O
be O
increased O
compared O
to O
noninfected O
amniocentesis O
cohorts O
using O
an O
estimated O
background O
spontaneous O
fetal O
loss O
rate O
( O
no O
procedure O
) O
of O
0.65 O
% O
. O

The O
pooled O
unintended O
fetal O
loss O
rate O
is O
from O
small O
infected O
population O
cohorts O
, O
but O
can O
be O
used O
for O
counseling O
purposes O
. O

Postcordocentesis O
fetal O
loss O
risk O
, O
in O
an O
infected O
cohort O
, O
is O
not O
possible O
to O
estimate O
due O
to O
limited O
data O
. O

The O
biological O
spontaneous O
fetal O
loss O
rate O
risk O
with O
a O
perinatal O
infection O
( O
positive O
or O
negative O
fetal O
anomalies O
) O
and O
no O
diagnostic O
procedure O
before O
20 O
weeks O
of O
gestation O
is O
reviewed O
. O

The O
risk O
of O
VT O
in O
acute O
infection O
cohorts O
as O
a O
result O
of O
the O
intra O
- O
amniotic O
diagnostic O
procedure O
is O
not O
found O
to O
be O
increased O
. O

Conclusion O
The O
unintended O
fetal O
loss O
rate O
after O
amniocentesis O
for O
perinatal O
infected O
cohorts O
is O
similar O
to O
that O
of O
noninfected O
cohorts O
, O
but O
the O
estimate O
is O
based O
on O
limited O
infected O
cohorts O
. O

There O
was O
no O
procedure O
- O
based O
risk O
of O
fetal O
VT O
in O
the O
infected O
cohorts O
, O
but O
identification O
of O
postprocedure O
maternal O
bleeding O
into O
the O
amniotic O
cavity O
increases O
the O
potential O
risk O
. O

Maternal O
knowledge O
translation O
and O
an O
informed O
consent O
process O
with O
risk O
- O
benefit O
maternal O
/ O
fetal O
risk O
counseling O
are O
required O
prior O
to O
any O
diagnostic O
amniocentesis O
procedure O
. O

Background O
Skin O
adnexal O
tumors O
( O
SAT O
) O
encompass O
wide O
spectrum O
of O
benign O
and O
malignant O
tumors O
that O
differentiate O
toward O
one O
or O
more O
adnexal O
structures O
found O
in O
normal O
skin O
. O

Overall B-EPI
incidence I-EPI
of O
SATs O
is O
low O
yet O
they O
can O
be O
challenging O
to O
diagnose O
. O

Aims O
The O
aim O
of O
this O
study O
is O
to O
study O
the O
spectrum O
and O
microscopic O
features O
of O
SATs O
. O

Materials O
and O
methods O
It O
was O
a O
retrospective O
cross O
- O
sectional O
, O
descriptive O
study O
conducted O
over O
a O
period O
of O
3 O
years O
. O

Formalin O
fixed O
, O
paraffin O
- O
embedded O
sections O
were O
stained O
with O
hematoxylin O
and O
eosin O
for O
histopathological O
analysis O
. O

Results O
Out O
of O
the O
total O
34,400 O
biopsies O
, O
110 O
cases O
were O
diagnosed O
as O
SATs O
comprising O
39.09 O
% O
of O
tumors O
with O
follicular O
differentiation O
followed O
by O
tumors O
showing O
sweat O
gland O
differentiation O
( O
37.27 O
% O
) O
, O
and O
sebaceous O
differentiation O
( O
23.63 O
% O
) O
. O

The O
age O
ranged O
from O
5 O
years O
to O
85 O
years O
and O
male B-SEX
: O
female B-SEX
ratio O
was O
1.03:1 O
. O

Most O
of O
the O
tumors O
were O
benign O
( O
82.73 O
% O
) O
while O
only O
17.27 O
% O
were O
malignant O
. O

Pilomatricoma O
( O
28.2 O
% O
) O
was O
the O
most O
common O
benign O
tumor O
while O
sebaceous O
carcinoma O
( O
11.8 O
% O
) O
was O
the O
most O
common O
malignant O
tumor O
. O

Conclusion O
Architectural O
features O
are O
of O
great O
importance O
in O
differentiating O
benign O
tumors O
from O
malignant O
. O

Objective O
To O
verify O
the O
prevalence B-EPI
of O
novel O
definitions O
of O
familial O
short O
stature O
on O
a O
cross O
- O
sectional O
cohort O
of O
children O
referred O
for O
short O
stature O
when O
their O
height O
and O
that O
of O
both O
parents O
were O
measured O
. O

Methods O
We O
consecutively O
enrolled O
65 O
individuals O
referred O
for O
short O
stature O
when O
both O
parents O
were O
present O
. O

We O
defined O
target O
height O
- O
related O
short O
stature O
( O
TH O
- O
SS O
) O
when O
child O
's O
height O
is O
≤ O
- O
2 O
SDS O
and O
included O
in O
the O
range O
of O
target O
height O
; O
suspected O
autosomal O
dominant O
short O
stature O
( O
AD O
- O
SS O
) O
when O
child O
height O
and O
at O
least O
one O
parent O
height O
are O
≤ O
- O
2 O
SDS O
; O
constitutional O
familial O
short O
stature O
( O
C O
- O
FSS O
) O
when O
a O
child O
with O
TH O
- O
SS O
does O
not O
have O
any O
parents O
with O
height O
≤ O
- O
2 O
SDS O
. O

Results O
Of O
65 O
children O
referred O
for O
SS O
, O
48 O
individuals O
had O
a O
height O
≤ O
- O
2 O
SDS O
. O

Based O
on O
the O
parents O
' O
measured O
heights O
, O
24 O
children O
had O
TH O
- O
SS O
, O
16 O
subjects O
AD O
- O
SS O
, O
and O
12 O
individuals O
C O
- O
FSS O
. O

If O
we O
had O
considered O
only O
the O
parents O
' O
reported O
height O
, O
3 O
of O
24 O
children O
with O
TH O
- O
SS O
, O
9 O
of O
16 O
with O
AD O
- O
SS O
, O
and O
10 O
of O
12 O
with O
C O
- O
FSS O
would O
have O
been O
lost O
. O

Conclusion O
We O
suggest O
novel O
definitions O
to O
adequately O
detect O
and O
approach O
the O
cases O
of O
FSS O
since O
C O
- O
FSS O
( O
25 O
% O
) O
might O
not O
need O
any O
specific O
investigation O
, O
while O
on O
the O
contrary O
, O
AD O
- O
SS O
( O
33 O
% O
) O
should O
undergo O
genetic O
evaluation O
. O

Moreover O
, O
this O
study O
underlines O
that O
adequate O
measurement O
and O
consideration O
of O
children O
's O
and O
parents O
' O
heights O
( O
individually O
and O
together O
) O
are O
crucial O
in O
the O
clinical O
evaluation O
of O
every O
child O
with O
short O
stature O
. O

The O
short O
telomere O
syndromes O
encompass O
a O
spectrum O
of O
clinical O
manifestations O
that O
present O
from O
infancy O
to O
late O
adulthood O
. O

They O
are O
caused O
by O
mutations O
in O
telomerase O
and O
other O
telomere O
maintenance O
genes O
and O
have O
a O
predominantly O
degenerative O
phenotype O
characterized O
by O
organ O
failure O
across O
multiple O
systems O
. O

They O
are O
collectively O
one O
of O
the O
most O
common O
inherited O
bone O
marrow O
failure O
syndromes O
; O
however O
, O
their O
most O
prevalent B-EPI
presentations O
are O
extrahematopoietic O
. O

This O
review O
focuses O
on O
these O
common O
nonhematologic O
complications O
, O
including O
pulmonary O
fibrosis O
, O
liver O
pathology O
, O
and O
immunodeficiency O
. O

The O
short O
telomere O
syndrome O
diagnosis O
informs O
clinical O
care O
, O
especially O
in O
guiding O
diagnostic O
evaluations O
as O
well O
as O
in O
the O
solid O
organ O
transplant O
setting O
. O

Early O
recognition O
allows O
an O
individualized O
approach O
to O
screening O
and O
management O
. O

This O
review O
illustrates O
a O
myriad O
of O
extrahematopoietic O
presentations O
of O
short O
telomere O
syndromes O
and O
how O
they O
impact O
clinical O
decisions O
. O

Second O
malignant O
neoplasms O
pose O
a O
concern O
for O
survivors O
of O
childhood O
cancer O
. O

We O
evaluated O
incidence B-EPI
, O
type O
and O
risk O
factors O
for O
second O
malignant O
neoplasms O
in O
patients O
included O
in O
Berlin O
- O
Frankfurt O
- O
Muenster O
protocols O
for O
childhood O
non O
- O
Hodgkin O
lymphoma O
. O

3590 O
patients O
< O
15 O
years O
of O
age O
at O
diagnosis O
registered O
between B-DATE
01/1981 I-DATE
and I-DATE
06/2010 I-DATE
were O
analyzed O
. O

Second O
malignant O
neoplasms O
were O
reported O
by O
the O
treating O
institutions O
and O
the O
German B-ETHN
Childhood O
Cancer O
Registry O
. O

After O
median O
follow O
- O
up O
of O
9.4 O
years O
( O
Quartile O
, O
Q1 O
6.7 O
and O
Q3 O
12.1 O
) O
95 O
second O
malignant O
neoplasms O
were O
registered O
( O
26 O
carcinomas O
including O
9 O
basal O
cell O
carcinomas O
, O
21 O
acute O
myeloid O
leukemias O
/ O
myelodysplastic O
syndromes O
, O
20 O
lymphoid O
malignancies O
, O
12 O
CNS O
- O
tumors O
, O
and O
16 O
other O
) O
. O

Cumulative B-EPI
incidence I-EPI
at O
20 O
years O
was O
5.7±0.7 O
% O
, O
standard O
incidence I-EPI
ratio O
excluding O
basal O
cell O
carcinomas O
was O
19.8 O
( O
95 O
% O
CI O
14.5 O
- O
26.5 O
) O
. O

Median O
time O
from O
initial O
diagnosis O
to O
second O
malignancy O
was O
8.7 O
years O
( O
range O
: O
0.2 O
- O
30.3 O
) O
. O

Acute O
- O
lymphoblastic O
- O
leukemia O
- O
type O
therapy O
, O
cumulative O
anthracycline O
dose O
, O
and O
cranial O
radiotherapy O
for O
brain O
tumor O
- O
development O
were O
significant O
risk O
factors O
in O
univariate O
analysis O
only O
. O

In O
multivariate O
analysis O
including O
risk O
factors O
significant O
in O
univariate O
analysis O
, O
female B-SEX
sex O
( O
HR O
1.87 O
, O
95 O
% O
CI O
1.23 O
- O
2.86 O
, O
p=0.004 O
) O
, O
CNS O
- O
involvement O
( O
HR O
2.24 O
, O
95 O
% O
CI O
1.03 O
- O
4.88 O
, O
p=0.042 O
) O
, O
lymphoblastic O
lymphoma O
( O
HR O
2.60 O
, O
95 O
% O
CI O
1.69 O
- O
3.97 O
, O
p<0.001 O
) O
, O
and O
cancer O
- O
predisposing O
condition O
( O
HR O
11.2 O
, O
95 O
% O
CI O
5.52 O
- O
22.75 O
, O

p<0.001 O
) O
retained O
an O
independent O
risk O
. O

Carcinomas O
were O
the O
most O
frequent O
second O
malignant O
neoplasms O
after O
non O
- O
Hodgkin O
lymphoma O
in O
childhood O
followed O
by O
acute O
myeloid O
leukemia O
and O
lymphoid O
malignancies O
. O

Female B-SEX
sex O
, O
lymphoblastic O
lymphoma O
, O
CNS O
- O
involvement O
, O
or O
/ O
and O
known O
cancer O
- O
predisposing O
condition O
were O
risk O
factors O
for O
second O
malignant O
neoplasm O
- O
development O
. O

Our O
findings O
set O
the O
basis O
for O
individualized O
long O
- O
term O
follow O
- O
up O
and O
risk O
assessment O
of O
new O
therapies O
. O

Background O
: O
Urticaria O
is O
a O
disorder O
affecting O
skin O
and O
mucosal O
tissues O
characterized O
by O
the O
occurrence B-EPI
of O
wheals O
, O
angioedema O
or O
both O
, O
the O
latter O
defining O
the O
urticaria O
- O
angioedema O
syndrome O
. O

It O
is O
estimated O
that O
12 O
- O
22 O
% O
of O
the O
general O
population O
has O
suffered O
at O
least O
one O
subtype O
of O
urticaria O
during O
life O
, O
but O
only O
a O
small O
percentage O
( O
estimated O
at O
7.6 O
- O
16 O
% O
) O
has O
acute O
urticaria O
, O
because O
it O
is O
usually O
self O
- O
limited O
and O
resolves O
spontaneously O
without O
requiring O
medical O
attention O
. O

This O
makes O
likely O
that O
its O
incidence B-EPI
is O
underestimated O
. O

The O
epidemiological O
data O
currently O
available O
on O
chronic O
urticaria O
in O
many O
cases O
are O
deeply O
discordant O
and O
not O
univocal O
, O
but O
a O
recent O
Italian B-ETHN
study O
, O
based O
on O
the O
consultation O
of O
a O
national O
registry O
, O
reports O
a O
prevalence B-EPI
of O
chronic O
spontaneous O
urticaria O
of O
0.02 B-STAT
% I-STAT
to I-STAT
0.4 I-STAT
% I-STAT
and O
an O
incidence B-EPI
of O
0.1 B-STAT
- I-STAT
1.5 I-STAT
cases/1000 I-STAT
inhabitants I-STAT
/ I-STAT
year I-STAT
. O

Methods O
: O
We O
reviewed O
the O
recent O
international O
guidelines O
about O
urticaria O
and O
we O
described O
a O
methodologic O
approach O
based O
on O
classification O
, O
pathophysiology O
, O
impact O
on O
quality O
of O
life O
, O
diagnosis O
and O
prognosis O
, O
differential O
diagnosis O
and O
management O
of O
all O
the O
types O
of O
urticaria O
. O

Conclusions O
: O
The O
aim O
of O
the O
present O
document O
from O
the O
Italian O
Society O
of O
Allergology O
, O
Asthma O
and O
Clinical O
Immunology O
( O
SIAAIC O
) O
and O
the O
Italian O
Society O
of O
Allergological O
, O
Occupational O
and O
Environmental O
Dermatology O
( O
SIDAPA O
) O
is O
to O
provide O
updated O
information O
to O
all O
physicians O
involved O
in O
diagnosis O
and O
management O
of O
urticaria O
and O
angioedema O
. O

Bullous O
pemphigoid O
( O
BP O
) O
is O
the O
most O
prevalent B-EPI
autoimmune O
blistering O
skin O
disease O
in O
the O
Western I-LOC
world I-LOC
affecting O
mainly O
the O
elderly O
population O
. O

The O
diagnosis O
is O
based O
on O
clinical O
assessment O
along O
with O
specific O
immunopathologic O
findings O
on O
skin O
biopsy O
. O

Risk O
factors O
include O
genetic O
factors O
, O
environmental O
exposures O
, O
and O
several O
infections O
including O
hepatitis O
B O
, O
hepatitis O
C O
, O
Helicobacter O
pylori O
, O
Toxoplasma O
gondi O
, O
and O
cytomegalovirus O
. O

A O
variety O
of O
drugs O
have O
been O
associated O
with O
BP O
including O
but O
not O
limited O
to O
dipeptidyl O
peptidase-4 O
inhibitors O
, O
loop O
diuretics O
, O
spironolactone O
, O
and O
neuroleptics O
. O

Associated O
neurologic O
disorders O
( O
dementia O
, O
Parkinson O
's O
disease O
, O
bipolar O
disorder O
, O
previous O
stroke O
history O
, O
and O
multiple O
sclerosis O
) O
have O
also O
been O
described O
. O

Common O
clinical O
presentation O
consists O
of O
extremely O
pruritic O
inflammatory O
plaques O
that O
resemble O
eczematous O
dermatitis O
or O
urticaria O
, O
followed O
by O
formation O
of O
tense O
bullae O
with O
subsequent O
erosions O
. O

Typical O
distribution O
involves O
the O
trunk O
and O
extremities O
. O

Mucosa O
is O
typically O
spared O
affecting O
only O
10 O
% O
to O
30 O
% O
of O
patients O
. O

Several O
unusual O
clinical O
presentations O
of O
BP O
have O
been O
described O
such O
as O
nonbullous O
forms O
with O
erythematous O
excoriated O
papules O
, O
plaques O
, O
and O
nodules O
. O

Other O
reported O
findings O
include O
urticarial O
lesions O
, O
prurigo O
- O
like O
nodules O
, O
multiple O
small O
vesicles O
resembling O
dermatitis O
herpetiformis O
or O
pompholyx O
, O
vegetating O
and O
purulent O
lesions O
localized O
in O
intertriginous O
areas O
, O
and O
even O
exfoliative O
erythroderma O
. O

Recognition O
and O
management O
of O
such O
cases O
can O
present O
a O
diagnostic O
challenge O
to O
clinicians O
. O

In O
this O
article O
, O
we O
describe O
another O
variant O
which O
to O
our O
knowledge O
is O
the O
first O
case O
to O
present O
with O
a O
cellulitis O
- O
like O
presentation O
in O
a O
patient O
with O
a O
known O
history O
of O
BP O
. O