diff --git "a/val.tsv" "b/val.tsv"
new file mode 100644--- /dev/null
+++ "b/val.tsv"
@@ -0,0 +1,32489 @@
+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
+