Treatment of severe Coronavirus Disease 2019(COVID-19)is challenging.We performed a phase 2 trial to assess the efficacy andsafety of human umbilical cord-mesenchymal stem cells(UC-MScs)to treat severe coViD-19 patien...Treatment of severe Coronavirus Disease 2019(COVID-19)is challenging.We performed a phase 2 trial to assess the efficacy andsafety of human umbilical cord-mesenchymal stem cells(UC-MScs)to treat severe coViD-19 patients with lung damage,based onour phase 1 data.In this randomized,double-blind,and placebo-controlled trial,we recruited 101 severe coVID-19 patients withlung damage.They were randomly assigned at a 2:1 ratio to receive either UC-MSCs(4×10^(7)cells per infusion)or placebo on day 0,3,and 6.The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28.Other imagingoutcomes,6-minute walk test(6-MWT),maximum vital capacity,diffusing capacity,and adverse events were recorded and analyzed.In all,100 COVID-19 patients were finally received either UC-MSCs in=65)or placebo(n=35).UC-MSCs administrationexerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo(the mediandifference was-13.31%,95%Cl-29.14%,2.13%,P=0.08).UC-MSCs significanty reduced the proportions of solid componentlesion volume compared with the placebo(median difference:-15.45%;95%CI-30.82%,-0.39%;P=0.043).The 6-MWT showedan increased distance in patients treated with UC-MSCs(difference:27.00 m;95%CI 0.00,57.00;P=0.057).The incidence of adverseevents was similar in the two groups.These results suggest that UC-MSCs treatment is a safe and potentially effective therapeuticapproach for COVID-19 patients with lung damage.A phase 3 trial is required to evaluate effects on reducing mortality andpreventing long-term pulmonary disability.展开更多
Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clin...Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.展开更多
To the Editor:The SRY-related high-mobility-group-box protein-2(SOX2)is most notably expressed in the eye,placodes,forebrain,and hypothalamus-pituitary and is involved in early embryonic development.[1]Loss-of-functio...To the Editor:The SRY-related high-mobility-group-box protein-2(SOX2)is most notably expressed in the eye,placodes,forebrain,and hypothalamus-pituitary and is involved in early embryonic development.[1]Loss-of-function mutations or deletions in SOX2 could lead to uni-or bi-lateral anophthalmia/microphthalmia(A/M)as well as other related disorders,such as anophthalmia/esophageal-genital syndrome.An increasing number of studies have found that SOX2 mutations can cause variable extraocular symptoms,including growth retardation,sensorineural hearing loss,mental retardation,no pubertal signs,and male genitourinary tract malformations(micropenis,cryptorchidism,and hypospadias).Indeed,cases with SOX2 pathogenic mutations but no or minor ocular symptoms have been reported less frequently.Several studies found that SOX2 heterozygous mutations cause typical signs of complete hypogonadism without major ocular malformations in men or women,such as isolated hypogonadotropic hypogonadism(HH),but no other HH pathogenic gene was identified.[2,3]Therefore,our study is the first to report the cases of three Chinese patients with SOX2 mutations referred due to micropenis and/or cryptorchidism combined with craniofacial deformities or intellectual disability.展开更多
Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pe...Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD.Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children’s Hospital to assess for the study.Prediction software tools were used to predict variant pathogenicity in these subjects.results:Among the 113 DSD patients,22 cases had CHD7 variants.Twenty-four different CHD7 variants were identified in the 22 DSD patients.Prediction software combined with ClinVar database information and their clinical manifestations revealed that,of the 18 patients with 46,XY DSD,two had CHARGE syndrome and two had Kallmann syndrome.Seven of the variants were highly categorized as“likely to be pathogenic”and seven as“suspected to be pathogenic”.Of the four patients with 46,XX DSD,three had ovotesticular DSD(c.305A>G,c.2788G>A,and c.3098G>A)and one had testicular DSD(c.2831G>A).Interpretation:A high frequency of CHD7 variants was found in the DSD patients,especially those with 46,XY DSD.Thus,the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46,XY DSD patients,but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis.This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients.Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46,XX DSD,and the accumulation of these data is essential and necessary for DSD research.展开更多
基金Funded by The National Key R&D Program of China and others.ClinicalTrials.gov number,NCT04288102supported by The National Key R&D Program of China(2020YFC0841900,2020YFC0844000,2020YFC08860900)+1 种基金The Innovation Groups of the National Natural Science Foundation of China(81721002)The National Science and Technology Major Project(2017YFA0105703).
文摘Treatment of severe Coronavirus Disease 2019(COVID-19)is challenging.We performed a phase 2 trial to assess the efficacy andsafety of human umbilical cord-mesenchymal stem cells(UC-MScs)to treat severe coViD-19 patients with lung damage,based onour phase 1 data.In this randomized,double-blind,and placebo-controlled trial,we recruited 101 severe coVID-19 patients withlung damage.They were randomly assigned at a 2:1 ratio to receive either UC-MSCs(4×10^(7)cells per infusion)or placebo on day 0,3,and 6.The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28.Other imagingoutcomes,6-minute walk test(6-MWT),maximum vital capacity,diffusing capacity,and adverse events were recorded and analyzed.In all,100 COVID-19 patients were finally received either UC-MSCs in=65)or placebo(n=35).UC-MSCs administrationexerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo(the mediandifference was-13.31%,95%Cl-29.14%,2.13%,P=0.08).UC-MSCs significanty reduced the proportions of solid componentlesion volume compared with the placebo(median difference:-15.45%;95%CI-30.82%,-0.39%;P=0.043).The 6-MWT showedan increased distance in patients treated with UC-MSCs(difference:27.00 m;95%CI 0.00,57.00;P=0.057).The incidence of adverseevents was similar in the two groups.These results suggest that UC-MSCs treatment is a safe and potentially effective therapeuticapproach for COVID-19 patients with lung damage.A phase 3 trial is required to evaluate effects on reducing mortality andpreventing long-term pulmonary disability.
基金funded in part by the Beijing Natural Science Foundation(JQ20032 to N.W.and to 7191007 to Z.W.)National Natural Science Foundation of China(81822030 and 82072391 to N.W.,81772299and 81930068 to Z.W.,81772301 and 81972132 to G.Q.,81672123and 81972037 to J.Z.)+7 种基金Capital's Funds for Health Improvement and Research(2020-4-40114 to N.W.)Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research ProgramNational Key Research and Development Program of China(2018YFC0910500 to N.W.and Z.W.,2016YFC0901501 to S.Z.)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(3332019052 to Y.M.)the CAMS Initiative Fund for Medical Sciences(2016-I2M-3-003 to G.Q.and N.W.,2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT320025 to N.W.)sponsored by GeneScience Pharmaceuticals Co.,Ltd.(Changchun,China)funded by the United States National Institutes of Health(UM1HG006542 and K08 HG008986)。
文摘Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
基金This study was supported by The Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority(No.XTYB201808)the Public Health Project for Residents in Beijing(No.Z151100003915103)the National Key Research and Development Program of China(No.2016YFC0901505)。
文摘To the Editor:The SRY-related high-mobility-group-box protein-2(SOX2)is most notably expressed in the eye,placodes,forebrain,and hypothalamus-pituitary and is involved in early embryonic development.[1]Loss-of-function mutations or deletions in SOX2 could lead to uni-or bi-lateral anophthalmia/microphthalmia(A/M)as well as other related disorders,such as anophthalmia/esophageal-genital syndrome.An increasing number of studies have found that SOX2 mutations can cause variable extraocular symptoms,including growth retardation,sensorineural hearing loss,mental retardation,no pubertal signs,and male genitourinary tract malformations(micropenis,cryptorchidism,and hypospadias).Indeed,cases with SOX2 pathogenic mutations but no or minor ocular symptoms have been reported less frequently.Several studies found that SOX2 heterozygous mutations cause typical signs of complete hypogonadism without major ocular malformations in men or women,such as isolated hypogonadotropic hypogonadism(HH),but no other HH pathogenic gene was identified.[2,3]Therefore,our study is the first to report the cases of three Chinese patients with SOX2 mutations referred due to micropenis and/or cryptorchidism combined with craniofacial deformities or intellectual disability.
文摘Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD.Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children’s Hospital to assess for the study.Prediction software tools were used to predict variant pathogenicity in these subjects.results:Among the 113 DSD patients,22 cases had CHD7 variants.Twenty-four different CHD7 variants were identified in the 22 DSD patients.Prediction software combined with ClinVar database information and their clinical manifestations revealed that,of the 18 patients with 46,XY DSD,two had CHARGE syndrome and two had Kallmann syndrome.Seven of the variants were highly categorized as“likely to be pathogenic”and seven as“suspected to be pathogenic”.Of the four patients with 46,XX DSD,three had ovotesticular DSD(c.305A>G,c.2788G>A,and c.3098G>A)and one had testicular DSD(c.2831G>A).Interpretation:A high frequency of CHD7 variants was found in the DSD patients,especially those with 46,XY DSD.Thus,the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46,XY DSD patients,but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis.This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients.Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46,XX DSD,and the accumulation of these data is essential and necessary for DSD research.
