val.tsv

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	B-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	O
Nyimba	O
district	O
outbreak	O
,	O
in	O
the	O
Eastern	O
province	O
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	O
Nyimba	O
district	O
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	O
to	O
2015	O
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	B-LOC
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	O
were	O
calculated	O
for	O
each	O
disease	O
.	O

Incidence	B-EPI
rates	O
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	O
.	O

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

Birth	O
incidences	B-EPI
of	O
MPS	O
IV	O
,	O
VI	O
,	O
and	O
VII	O
were	O
0.14	O
,	O
0.04	B-LOC
and	O
0.027	B-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	O
in	O
the	O
US	B-LOC
.	O

Due	O
to	O
the	O
large	O
US	B-LOC
population	O
and	O
state	O
fragmentation	O
,	O
US	B-LOC
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	O
to	O
2008	O
.	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	B-STAT
(	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	B-STAT
,	O
33	O
%	O
)	O
followed	O
by	O
Gram	O
-	O
positive	O
cocci	O
(	O
40/142	B-STAT
,	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	O
citizens	O
receiving	O
a	O
diagnosis	O
of	O
CHD	O
between	O
1977	O
and	O
2007	O
.	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	O
January	O
1999	O
and	O
January	O
2019	O
,	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	B-STAT
and	I-STAT
2	I-STAT
(	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	O
,	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	O
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	O
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	O
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	O
biomes	O
:	O
Atlantic	B-LOC
Forest	I-LOC
,	O
Caatinga	B-LOC
,	O
Cerrado	O
,	O
and	O
Amazon	O
.	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	B-STAT
to	I-STAT
55.1	I-STAT
%	I-STAT
.	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	I-LOC
and	O
Caatinga	B-LOC
,	O
and	O
the	O
ST2	O
subtype	O
was	O
predominant	O
in	O
the	O
Amazon	O
biome	O
.	O

E.	O
histolytica	O
was	O
detected	O
only	O
in	O
the	O
Amazon	O
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	O
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	O
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	O
January	O
1	O
,	O
2003	O
and	O
December	O
31	O
,	O
2018	O
.	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	B-STAT
to	I-STAT
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
,	O
China	B-LOC
,	O
from	O
August	O
1	O
,	O
2018	O
to	O
April	O
30	O
,	O
2019	O
.	O

All	O
of	O
the	O
local	O
registered	O
pregnant	O
women	O
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	O
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	O
2005	O
and	O
2014	O
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	B-STAT
,	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	B-STAT
,	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	B-STAT
,	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	B-STAT
,	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	B-STAT
,	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	B-STAT
,	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	O
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
α3	O
,	O
α4	O
α5	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	B-STAT
to	O
85	O
%	O
of	O
cases	O
and	O
is	O
more	O
severe	O
in	O
boys	O
than	O
in	O
girls	O
.	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
β1	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	O
,	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	O
.	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	O
.	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	O
(	O
68.6	O
%	O
)	O
,	O
married	O
(	O
82.6	O
%	O
)	O
and	O
Muslim	O
(	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	B-EPI
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	O
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	O
.	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	O
Children	O
's	O
Tumour	O
Registry	O
from	O
1954	O
and	O
1985	O
are	O
presented	O
.	O

The	O
incidence	B-EPI
of	O
adrenal	O
cortical	O
carcinomas	O
was	O
0.3	B-STAT
%	I-STAT
,	O
mainly	O
in	O
girls	O
,	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
,	O
Brazil	B-LOC
.	O

We	O
recruited	O
women	O
participating	O
in	O
our	O
cohort	O
,	O
with	O
a	O
documented	O
pregnancy	O
from	O
January	O
2015	O
to	O
December	O
2016	O
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	O
with	O
ZIKV	O
seroconversion	O
during	O
pregnancy	O
)	O
or	O
unexposed	O
(	O
born	O
from	O
women	O
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	O
participating	O
in	O
the	O
cohort	O
,	O
66	B-STAT
(	O
10	O
%	O
)	O
were	O
pregnant	O
during	O
the	O
study	O
period	O
.	O

46	B-STAT
(	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	B-STAT
(	O
54	O
%	O
)	O
,	O
13	B-STAT
(	O
28	O
%	O
)	O
,	O
and	O
1	B-STAT
(	O
2	O
%	O
)	O
,	O
respectively	O
.	O

The	O
rest	O
of	O
women	O
,	O
7	B-STAT
(	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	B-STAT
%	I-STAT
.	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	B-STAT
%	I-STAT
.	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	B-LOC
as	O
well	O
as	O
the	O
mean	O
deviation	O
(	O
MD	B-LOC
)	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
μm	O
.	O

The	O
mean	O
EZa	O
and	O
rEZ	O
were	O
22.2	O
±	O
23.6	O
μm	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	B-LOC
(	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	B-LOC
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.	B-LOC
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.	B-LOC
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	B-LOC
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	O
,	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.	B-LOC

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
11β	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	O
macaques	O
.	O

The	O
mean	O
concentrations	O
(	O
standard	O
error	O
;	O
sample	O
size	O
)	O
of	O
11β	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
μg	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
11β	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-LOC
macaques	O
in	O
Mt.	B-LOC

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.	B-LOC

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	O
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	O
population	O
of	O
1.7	O
million	O
,	O
mostly	O
Arabs	O
.	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	O
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	O
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	O
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	B-LOC
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	O
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	O
.	O

Some	O
consideration	O
has	O
been	O
given	O
by	O
the	O
nepalese	O
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	O
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	B-LOC
.	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

Grafting	O
watermelon	O
scions	O
to	O
interspecific	O
squash	O
hybrids	O
has	O
been	O
found	O
to	O
increase	O
fruit	O
firmness	O
.	O

Triploid	O
(	O
seedless	O
)	O
watermelon	O
are	O
prone	O
to	O
hollow	O
heart	O
(	O
HH	O
)	O
,	O
an	O
internal	O
fruit	O
disorder	O
characterized	O
by	O
a	O
crack	O
in	O
the	O
placental	O
tissue	O
expanding	O
to	O
a	O
cavity	O
.	O

Although	O
watermelon	O
with	O
lower	O
tissue	O
firmness	O
tend	O
to	O
have	O
a	O
higher	O
HH	O
incidence	B-EPI
,	O
associated	O
differences	O
in	O
cell	O
wall	O
polysaccharide	O
composition	O
are	O
unknown	O
.	O

Grafting	O
	O
Liberty	O
	O
watermelon	O
to	O
	O
Carnivor	O
	O
(	O
interspecific	O
hybrid	O
rootstock	O
,	O
C.	O
moschata	O
×	O
C.	O
maxima	O
)	O
reduced	O
HH	O
39	O
%	O
and	O
increased	O
tissue	O
firmness	O
by	O
3	O
N.	O
Fruit	O
with	O
and	O
without	O
severe	O
HH	O
from	O
both	O
grafted	O
and	O
non	O
-	O
grafted	O
plants	O
were	O
analyzed	O
to	O
determine	O
differences	O
in	O
cell	O
wall	O
polysaccharides	O
associated	O
with	O
grafting	O
and	O
HH	O
.	O

Alcohol	O
insoluble	O
residues	O
(	O
AIR	O
)	O
were	O
sequentially	O
extracted	O
from	O
placental	O
tissue	O
to	O
yield	O
water	O
soluble	O
(	O
WSF	O
)	O
,	O
carbonate	O
soluble	O
(	O
CSF	O
)	O
,	O
alkali	O
soluble	O
(	O
ASF	O
)	O
,	O
or	O
unextractable	O
(	O
UNX	O
)	O
pectic	O
fractions	O
.	O

The	O
CSF	O
was	O
lower	O
in	O
fruit	O
with	O
HH	O
(	O
24.5	O
%	O
)	O
compared	O
to	O
those	O
without	O
HH	O
(	O
27.1	O
%	O
)	O
.	O

AIRs	O
were	O
also	O
reduced	O
,	O
hydrolyzed	O
,	O
and	O
acetylated	O
for	O
GC	O
-	O
MS	O
analysis	O
of	O
monosaccharide	O
composition	O
,	O
and	O
a	O
portion	O
of	O
each	O
AIR	O
was	O
methylated	O
prior	O
to	O
hydrolysis	O
and	O
acetylation	O
to	O
produce	O
partially	O
methylated	O
alditol	O
acetates	O
for	O
polysaccharide	O
linkage	O
assembly	O
.	O

No	O
differences	O
in	O
degree	O
of	O
methylation	O
or	O
galacturonic	O
and	O
glucuronic	O
acid	O
concentrations	O
were	O
found	O
.	O

Glucose	O
and	O
galactose	O
were	O
in	O
highest	O
abundance	O
at	O
75.9	O
and	O
82.4	O
μg⋅mg	O
-1	O
AIR	O
,	O
respectively	O
,	O
followed	O
by	O
xylose	O
and	O
arabinose	O
(	O
29.3	O
and	O
22.0	O
μg⋅mg	O
-1	O
)	O
.	O

Mannose	O
was	O
higher	O
in	O
fruit	O
with	O
HH	O
(	O
p	O
<	O
0.05	O
)	O
and	O
xylose	O
was	O
highest	O
in	O
fruit	O
from	O
grafted	O
plants	O
(	O
p	O
<	O
0.05	O
)	O
.	O

Mannose	O
is	O
primarily	O
found	O
in	O
heteromannan	O
and	O
rhamnogalacturonan	O
I	O
side	O
chains	O
,	O
while	O
xylose	O
is	O
found	O
in	O
xylogalacturonan	O
or	O
heteroxylan	O
.	O

In	O
watermelon	O
,	O
34	O
carbohydrate	O
linkages	O
were	O
identified	O
with	O
galactose	O
,	O
glucose	O
,	O
and	O
arabinose	O
linkages	O
in	O
highest	O
abundance	O
.	O

This	O
represents	O
the	O
most	O
comprehensive	O
polysaccharide	O
linkage	O
analysis	O
to	O
date	O
for	O
watermelon	O
,	O
including	O
the	O
identification	O
of	O
several	O
new	O
linkages	O
.	O

However	O
,	O
total	O
pectin	O
and	O
cell	O
wall	O
composition	O
data	O
could	O
not	O
explain	O
the	O
increased	O
tissue	O
firmness	O
observed	O
in	O
fruit	O
from	O
grafted	O
plants	O
.	O

Nonetheless	O
,	O
grafting	O
onto	O
the	O
interspecific	O
hybrid	O
rootstock	O
decreased	O
the	O
incidence	B-EPI
of	O
HH	O
and	O
can	O
be	O
a	O
useful	O
method	O
for	O
growers	O
using	O
HH	O
susceptible	O
cultivars	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	O
.	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	O
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	O
women	O
.	O

We	O
performed	O
a	O
genome	O
-	O
wide	O
association	O
study	O
(	O
GWAS	O
)	O
of	O
women	O
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	O
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	O
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	O
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	O
prevalence	B-EPI
is	O
unknown	O
,	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	O
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	O
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	B-STAT
%	I-STAT
of	O
patients	O
undergoing	O
surgery	O
,	O
with	O
a	O
mortality	O
of	O
up	O
to	O
46	B-STAT
%	I-STAT
.	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	O
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	O
to	O
2017	O
.	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	O
(	I-STAT
0.76	I-STAT
%	I-STAT
for	O
MMA	O
;	O
0.13	B-STAT
%	I-STAT
for	O
PA	O
)	O
to	O
2017	O
(	O
1.61	O
%	O
for	O
MMA	O
;	O
0.32	B-STAT
%	I-STAT
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	O
county	O
.	O

Methods	O
Using	O
the	O
Norwegian	O
patient	O
registry	O
,	O
we	O
identified	O
patients	O
in	O
Møre	O
and	O
Romsdal	B-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	O
2010	O
to	O
January	O
2020	O
.	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	O
prevalence	B-EPI
of	O
PNES	O
on	O
January	O
1	O
,	O
2020	O
and	O
incidence	B-EPI
rates	O
for	O
the	O
period	O
2010	O
-	O
2019	O
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
23.8/100	B-STAT
000	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
10.6/100	B-STAT
000	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
59.5/100	B-STAT
000	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	O
between	O
2010	O
and	O
2019	O
was	I-STAT
3.1/100	I-STAT
000	I-STAT
/	O
year	O
(	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	O
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	O
57.5	O
%	I-STAT
.	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	B-STAT
%	I-STAT
.	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	O
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	B-STAT
(	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	B-STAT
(	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	O
,	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	O
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	O
1	O
,	O
1990	O
,	O
to	O
July	O
1	O
,	O
2018	O
.	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	O
)	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	O
or	O
transgender	O
women	O
who	O
have	O
sex	O
with	O
men	O
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	B-LOC
.	O

)	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	O
2019	O
to	O
April	O
2020	O
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	B-STAT
-	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	O
-	O
2015	O
,	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	B-STAT
;	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	O
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	O
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	O
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
,	O
Pakistan	B-LOC
from	O
December	O
2018	O
to	O
September	O
2019	O
.	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	B-STAT
%	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	O
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	O
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	B-STAT
(	O
11.9	O
%	O
)	O
and	O
21	B-STAT
(	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	O
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	O
,	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
	O
pregnancy	O
complication	O
	O
AND	O
	O
adolescent	O
	O
OR	O
	O
pregnancy	O
in	O
adolescence	O
	O
.	O

Only	O
full	O
original	O
articles	O
in	O
English	O
or	O
Portuguese	O
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	O
studies	O
,	O
the	O
adolescent	O
pregnancy	O
rate	O
was	O
26	B-STAT
%	I-STAT
.	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	O
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	O
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	B-STAT
)	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	B-STAT
%	I-STAT
.	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	O
January	O
2001	O
and	O
January	O
2020	O
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	O
-	O
2020	O
.	O

We	O
searched	O
PubMed	O
for	O
case	O
series	O
through	O
April	O
2020	O
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	O
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	O
to	O
2016	O
referred	O
to	O
CR	O
from	O
The	O
Alberta	O
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	B-STAT
(	I-STAT
0.3	I-STAT
%	I-STAT
)	O
from	O
CKD	O
and	O
106	B-STAT
(	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	O
to	O
2018	O
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	B-STAT
(	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	B-STAT
(	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	O
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	O
.	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
,	O
China	B-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	B-STAT
(	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	B-LOC
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	B-LOC
)	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	B-LOC
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	B-LOC
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	B-LOC
and	O
Photophobia	B-LOC
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	B-LOC
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	O
,	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	O
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	O
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	O
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	O
in	O
one	O
million	O
population	O
.	O

There	O
is	O
a	O
slight	O
female	O
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	O
out	O
of	O
every	O
three	O
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
	O
classical	O
	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	O
in	O
1,000,000	O
live	O
births	O
.	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	O
.	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	B-EPI
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	B-STAT
(	O
47.2	O
%	O
)	O
cows	O
and	O
in	O
69	O
out	O
of	O
271	B-STAT
(	O
25.5	O
%	O
)	O
small	O
ruminants	O
,	O
among	O
them	O
in	O
47	O
out	O
of	O
200	B-STAT
(	O
23.5	O
%	O
)	O
sheep	O
and	O
in	O
22	O
out	O
of	O
71	B-STAT
(	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	B-STAT
(	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	B-STAT
(	O
56.3	O
%	O
)	O
sheep	O
flocks	O
and	O
2	O
out	O
of	O
4	B-STAT
(	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	O
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	B-STAT
%	I-STAT
.	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	B-LOC
,	O
VPS13B	O
,	O
ACTG1	O
,	O
EP300	B-LOC
,	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	O
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	O
Union	O
Medical	O
College	O
Hospital	O
from	O
January	O
2016	O
to	O
January	O
2018	O
.	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	O
(	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	O
and	O
26.6	O
%	O
(	O
41/154	O
)	O
in	O
female	O
patients	O
,	O
respectively	O
.	O

The	O
M	O
(	O
Q	O
1	B-STAT
,	I-STAT
Q	I-STAT
3	I-STAT
)	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	O
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	B-STAT
,	I-STAT
Q	I-STAT
3	I-STAT
)	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	O
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	O
'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	O
.	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
62	O
000	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	B-LOC
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	O
2003	O
and	O
2014	O
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	O
and	O
106,965	O
(	O
50.92	O
%	O
)	O
were	O
female	O
.	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	O
,	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	O
,	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	O
.	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
∼1	O
%	O
of	O
women	O
.	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
∼10	O
%	O
of	O
women	O
.	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	O
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	O
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	O
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	B-EPI
in	O
female	O
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	O
produced	O
significantly	O
fewer	O
pups	O
than	O
Setx+/+	O
females	O
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	O
August	O
,	O
2020	O
,	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	O
-	O
Ottawa	O
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	B-LOC
)	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	O
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	O
(	O
64.2	O
%	O
)	O
and	O
2	O
of	O
38	O
females	O
(	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	O
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	O
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	O
-	O
2015	O
.	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	B-STAT
-	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	B-STAT
%	I-STAT
.	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	O
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
	O
neutrality	O
of	O
the	O
examiners	O
.	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	B-LOC
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
	O
on	O
	O
and	O
	O
off	O
	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	B-LOC
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
.	O

Our	O
aim	O
was	O
to	O
establish	O
the	O
effectiveness	O
of	O
LipoDDx	O
®	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	B-STAT
biochemist	I-STAT
and	I-STAT
1	I-STAT
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
.	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
®	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
®	O
the	O
success	O
rate	O
was	O
17	O
±	O
20	O
%	O
,	O
while	O
with	O
LipoDDx	O
®	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
®	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	O
with	O
Pierson	O
syndrome	O
with	O
a	O
novel	O
mutation	O
in	O
LAMB2	B-LOC
.	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	O
who	O
presented	O
with	O
diabetes	O
mellitus	O
which	O
remitted	O
after	O
thiamine	O
replacement	O
.	O

The	O
girl	O
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	B-STAT
%	I-STAT
.	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	B-STAT
-	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	O
1:1,500,000	O
.	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	O
-	O
Saharan	B-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	O
and	O
southern	O
Africa	B-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	O
cohort	O
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	O
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	I-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	O
-	O
17	O
,	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	O
-	O
specific	O
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	O
(	O
cohort	O
mean	O
27·8	O
-	O
34·6	O
years	O
)	O
than	O
in	O
women	O
(	O
24·8	O
-	O
29·6	O
years	O
)	O
.	O

Between	O
2000	O
and	O
2017	O
,	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	O
and	O
-0·2	O
to	O
2·5	O
years	O
among	O
women	O
.	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	O
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	O
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	O
aged	O
15	O
-	O
24	O
years	O
and	O
men	O
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	B-STAT
-	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	O
)	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
α	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	B-LOC
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	B-LOC
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	B-LOC
.	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	O
enrolled	O
in	O
NISDI	O
from	O
Argentina	B-LOC
and	O
Brazil	B-LOC
who	O
delivered	O
between	O
September	O
2002	O
and	O
October	O
2007	O
.	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	O
[	O
number	O
of	O
CAs	B-STAT
per	I-STAT
100	I-STAT
live	I-STAT
births	I-STAT
(	I-STAT
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	O
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	B-STAT
(	I-STAT
per	I-STAT
100	I-STAT
LBs	I-STAT
)	O
was	O
6.2	O
[	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	O
%	O
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	O
European	O
countries	O
,	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	O
,	O
Scheinberg	B-LOC
and	O
Sternlieb	O
estimated	O
the	O
prevalence	B-EPI
of	O
WD	O
to	O
be	O
1:30,000	O
.	O

However	O
,	O
recent	O
epidemiological	O
studies	O
have	O
reported	O
increasing	O
prevalence	B-EPI
rates	O
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	O
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	O
individuals	O
using	O
the	O
Human	O
Genetic	O
Variation	O
Database	O
(	O
HGVD	O
)	O
and	O
the	O
Japanese	O
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	B-LOC
,	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	O
(	O
1.21/10,000	B-STAT
individuals	O
)	O
and	O
0.000196	O
(	O
1.96/10,000	B-STAT
individuals	O
)	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	O
prevalence	B-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	O
Shield	O
,	O
an	O
Amazonian	O
region	O
located	O
in	O
northeastern	O
South	B-LOC
America	I-LOC
.	O

There	O
is	O
a	O
contrast	O
between	O
French	O
Guiana	B-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	O
Guiana	B-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	O
Shield	O
,	O
a	O
region	O
mostly	O
covered	O
by	O
Amazonian	O
forest	O
,	O
which	O
encompasses	O
the	O
Venezuelan	O
State	O
of	O
Bolivar	O
,	O
Guyana	B-LOC
,	O
Suriname	B-LOC
,	O
French	O
Guiana	B-LOC
,	O
and	O
the	O
Brazilian	O
State	O
of	O
Amapá	B-LOC
,	O
the	O
situation	O
is	O
very	O
heterogeneous	O
.	O

While	O
French	O
Guiana	B-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	B-STAT
-	I-STAT
9	I-STAT
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	O
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	B-LOC
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	O
.	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	O
to	O
2005	O
.	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	B-STAT
(	O
18.3	O
%	O
)	O
of	O
the	O
patients	O
with	O
splenectomy	O
and	O
102	B-STAT
(	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	B-STAT
-	I-STAT
3	I-STAT
)	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
<	B-STAT
40	I-STAT
%	I-STAT
.	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	O
-	O
2018	O
.	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	B-EPI
incidence	I-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	B-LOC
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	B-STAT
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	B-STAT
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	O
-	O
2016	O
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-STAT
prevalence	I-STAT
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	O
US	B-LOC
census	O
estimates	O
.	O

Results	O
The	O
prevalence	B-EPI
of	O
narcolepsy	B-STAT
per	I-STAT
100,000	I-STAT
persons	I-STAT
increased	O
14	O
%	O
from	O
38.9	O
in	O
2013	O
to	O
44.3	O
in	O
2016	O
.	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	B-STAT
%	I-STAT
.	O

Conversely	O
,	O
home	O
sleep	O
apnea	O
testing	O
increased	O
by	O
117	B-STAT
%	I-STAT
.	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	O
-	O
2016	O
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	O
-	O
2017	O
)	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	B-STAT
to	I-STAT
9	I-STAT
)	I-STAT
.	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)-infected	O
women	O
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	O
.	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	O
2014	O
through	O
March	O
2019	O
,	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	B-STAT
%	I-STAT
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	B-STAT
%	I-STAT
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	B-STAT
%	I-STAT
)	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	B-STAT
(	I-STAT
0.04	I-STAT
%	I-STAT
)	O
in	O
which	O
the	O
mother	O
was	O
taking	O
efavirenz	O
at	O
conception	O
,	O
1	B-STAT
among	I-STAT
3840	B-STAT
(	I-STAT
0.03	I-STAT
%	I-STAT
)	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	B-STAT
%	I-STAT
)	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	B-STAT
%	I-STAT
of	O
deliveries	O
among	O
women	O
exposed	O
to	O
dolutegravir	O
at	O
conception	O
and	O
0.68	B-STAT
%	I-STAT
of	O
those	O
among	O
women	O
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	O
deliveries	I-STAT
vs.	I-STAT
1	I-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	O
in	O
100,000	O
births	O
.	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
1/1000	B-STAT
000	O
;	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	O
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-LOC
(	O
LATAM	O
)	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	O
American	O
region	O
.	O

Methods	O
The	O
Latin	O
American	O
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	O
American	O
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	O
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	O
)	O
.	O

Ethnic	O
identification	O
disclosed	O
Mestizos	O
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	B-LOC
)	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	O
American	O
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	O
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	O
American	O
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	O
-	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	B-STAT
%	I-STAT
.	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	B-LOC
,	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	B-STAT
,	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	B-STAT
,	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	B-LOC
)	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
	O
noninfected	O
	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	B-STAT
%	I-STAT
.	O

The	O
	O
pooled	O
	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
	O
biological	O
spontaneous	O
fetal	O
loss	O
rate	O
	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	B-LOC
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
	O
fetal	O
loss	O
	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	B-LOC
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	O
:	O
female	O
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
	O
target	O
height	O
-	O
related	O
short	O
stature	O
	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
	O
autosomal	O
dominant	O
short	O
stature	O
	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
	O
constitutional	O
familial	O
short	O
stature	O
	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	B-LOC
-	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	O
01/1981	B-STAT
and	O
06/2010	B-STAT
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	O
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	B-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	O
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	O
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	B-STAT
-	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	B-STAT
-	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	O
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	O
-	O
1.5	O
cases/1000	O
inhabitants	O
/	O
year	O
.	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	O
world	O
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