Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic forma...Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.展开更多
Objective:Pulmonary hypertension secondary to left heart failure is associated with an abnormal response to exercise and poor prognosis.The objective of this study is to develop an algorithm by using data from cardiop...Objective:Pulmonary hypertension secondary to left heart failure is associated with an abnormal response to exercise and poor prognosis.The objective of this study is to develop an algorithm by using data from cardiopulmonary exercise testing(CPET)to assess the severity of pulmonary hemodynamics and predict clinical worsening and mortality in patients with heart failure.Methods:From April 2017 to December 2018,a total of 102 patients with heart failure who underwent CPET and invasive right heart catheterization participated in this prospective study.All enrolled patients had their clinical characteristics,hemodynamic parameters,and CPET results.Based on the CPET data namely peak oxygen uptake,the minute ventilation/carbon dioxide production slope,resting end-tidal carbon dioxide,oxygen uptake/work rate flattening,exercise oscillatory ventilation,and oxygen uptake efficiency slope,a Heart Failure Cardiopulmonary Exercise(HFCE)score was developed.The total score was then calculated to categorize patients into 3 groups:low score(0-3)(n=31),intermediate score(4-7)(n=45),and high score(8-14)(n=26).Clinical events were defined as all-cause death and rehospitalization for heart failure,which were recorded and tracked for at least 12 months.Pearson’s correlation coefficients were calculated to assess the relationship between the HFCE score and hemodynamic parameters,6-minute walk distance,and N-terminal-pro hormone brain natriuretic peptide.Cox proportional hazards regression analysis was used to identify independent predictors of clinical events.Survival curves for clinical events were generated using the Kaplan-Meier method and compared among the 3 groups with different HFCE scores with a log-rank test.Results:The high HFCE score group had a higher prevalence of New York Heart Association classⅢ-Ⅳ(high score vs.intermediate score vs.low score:85%(22/26)vs.56%(25/45)vs.45%(14/31),P=0.008),higher N-terminal-pro hormone brain natriuretic peptide levels(high score vs.intermediate score vs.low score:(3,039±2,171)ng/L vs.(2,039±2,353)ng/L vs.(1,438±947)ng/L,P=0.035),lower 6-minute walk distance(high score vs.intermediate score vs.low score:(312±79)m vs.(362±84)m vs.(363±76)m,P=0.042)compared to intermediate score or low score.The high HFCE score correlated well with high levels of pulmonary vascular resistance(r=0.539,P<0.01),pulmonary artery wedge pressure(r=0.292,P<0.01),and mean pulmonary artery pressure(r=0.474,P<0.01),as well as low levels of cardiac output(r=-0.357,P<0.01).Moreover,46 patients developed composed clinical events at 12 months.In the multivariate model,the HFCE score was an independent predictor of composed clinical events(hazard ratio=1.142,95%confidence interval:1.041-1.253,P=0.005).Kaplan-Meier analysis showed a significantly higher probability of composed clinical events in patients with a higher HFCE score(P_(log-rank)=0.004).Conclusion:The HFCE score-obtained through CPET-provides valuable prognostic information by indicating the severity of hemodynamics in patients with pulmonary hypertension secondary to left heart failure.It can likely serve as a reliable predictor for clinical worsening and mortality.展开更多
基金This work was supported by the National Natural Science Foundation of China(31625013,81941015,32000726,and 61973086)the Shanghai Brain-Intelligence Project from STCSM(16JC1420501)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDBS01060200)the Program of Shanghai Academic Research LeaderThe Open Large Infrastructure Research of the Chinese Academy of Sciences,and the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01).
文摘Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.
基金supported by research funds from the Nanjing Health Committee(QRX17016)the Nanjing Medical University(NMUC2018009A).
文摘Objective:Pulmonary hypertension secondary to left heart failure is associated with an abnormal response to exercise and poor prognosis.The objective of this study is to develop an algorithm by using data from cardiopulmonary exercise testing(CPET)to assess the severity of pulmonary hemodynamics and predict clinical worsening and mortality in patients with heart failure.Methods:From April 2017 to December 2018,a total of 102 patients with heart failure who underwent CPET and invasive right heart catheterization participated in this prospective study.All enrolled patients had their clinical characteristics,hemodynamic parameters,and CPET results.Based on the CPET data namely peak oxygen uptake,the minute ventilation/carbon dioxide production slope,resting end-tidal carbon dioxide,oxygen uptake/work rate flattening,exercise oscillatory ventilation,and oxygen uptake efficiency slope,a Heart Failure Cardiopulmonary Exercise(HFCE)score was developed.The total score was then calculated to categorize patients into 3 groups:low score(0-3)(n=31),intermediate score(4-7)(n=45),and high score(8-14)(n=26).Clinical events were defined as all-cause death and rehospitalization for heart failure,which were recorded and tracked for at least 12 months.Pearson’s correlation coefficients were calculated to assess the relationship between the HFCE score and hemodynamic parameters,6-minute walk distance,and N-terminal-pro hormone brain natriuretic peptide.Cox proportional hazards regression analysis was used to identify independent predictors of clinical events.Survival curves for clinical events were generated using the Kaplan-Meier method and compared among the 3 groups with different HFCE scores with a log-rank test.Results:The high HFCE score group had a higher prevalence of New York Heart Association classⅢ-Ⅳ(high score vs.intermediate score vs.low score:85%(22/26)vs.56%(25/45)vs.45%(14/31),P=0.008),higher N-terminal-pro hormone brain natriuretic peptide levels(high score vs.intermediate score vs.low score:(3,039±2,171)ng/L vs.(2,039±2,353)ng/L vs.(1,438±947)ng/L,P=0.035),lower 6-minute walk distance(high score vs.intermediate score vs.low score:(312±79)m vs.(362±84)m vs.(363±76)m,P=0.042)compared to intermediate score or low score.The high HFCE score correlated well with high levels of pulmonary vascular resistance(r=0.539,P<0.01),pulmonary artery wedge pressure(r=0.292,P<0.01),and mean pulmonary artery pressure(r=0.474,P<0.01),as well as low levels of cardiac output(r=-0.357,P<0.01).Moreover,46 patients developed composed clinical events at 12 months.In the multivariate model,the HFCE score was an independent predictor of composed clinical events(hazard ratio=1.142,95%confidence interval:1.041-1.253,P=0.005).Kaplan-Meier analysis showed a significantly higher probability of composed clinical events in patients with a higher HFCE score(P_(log-rank)=0.004).Conclusion:The HFCE score-obtained through CPET-provides valuable prognostic information by indicating the severity of hemodynamics in patients with pulmonary hypertension secondary to left heart failure.It can likely serve as a reliable predictor for clinical worsening and mortality.
