Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

An Activity Recognition Model Using Inertial Sensor Nodes in a Wireless Sensor Network for Frozen Shoulder Rehabilitation Exercises

This paper proposes a model for recognizing motions performed during rehabilitation exercises for frozen shoulder conditions. The model consists of wearable wireless sensor network (WSN) inertial sensor nodes, which were developed for this study, and enables the ubiquitous measurement of bodily motions. The model employs the back propagation neural network (BPNN) algorithm to compute motion data that are formed in the WSN packets; herein, six types of rehabilitation exercises were recognized. The packets sent by each node are converted into six components of acceleration and angular velocity according to three axes. Motor features such as basic acceleration, angular velocity, and derivative tilt angle were input into the training procedure of the BPNN algorithm. In measurements of thirteen volunteers, the accelerations and included angles of nodes were adopted from possible features to demonstrate the procedure. Five exercises involving simple swinging and stretching movements were recognized with an accuracy of 85%–95%; however, the accuracy with which exercises entailing spiral rotations were recognized approximately 60%. Thus, a characteristic space and enveloped spectrum improving derivative features were suggested to enable identifying customized parameters. Finally, a real-time monitoring interface was developed for practical implementation. The proposed model can be applied in ubiquitous healthcare self-management to recognize rehabilitation exercises

Residual Right Coronary Artery Stenosis after Left Main Coronary Artery Intervention Increased the 30-Day Cardiovascular Death and 3-Year Right Coronary Artery Revascularization Rate

Background. The outcomes of patients with concomitant left main coronary artery (LMCA) and right coronary artery (RCA) diseases are reportedly worse than those with only LMCA disease. To date, only few studies have investigated the clinical impact of percutaneous coronary intervention (PCI) on RCA stenosis during the same hospitalization, in which LMCA disease was treated. This study was aimed at comparing the outcomes between patients with and without right coronary artery intervention during the same hospital course for LMCA intervention. Methods and Results. From a total of 776 patients who were undergoing PCI to treat LMCA disease, 235 patients with concomitant RCA significant stenosis (more than 70% stenosis) were enrolled. The patients were divided into two groups: 174 patients received concomitant PCI for RCA stenosis during the same hospitalization, in which LMCA disease was treated, and 61 patients did not receive PCI for RCA stenosis. Patients without intervention to the right coronary artery had higher 30-day cardiovascular mortality rates and 3-year RCA revascularization rates compared to those with right coronary artery intervention. Patients without RCA intervention at the same hospitalization did not increase the 30-day total death, 3-year myocardial infarction rate, 3-year cardiovascular death, and 3-year total death. Conclusions. In patients with LM disease and concomitant above or equal to 70% RCA stenosis, PCI for RCA lesion during the same hospitalization is recommended to reduce the 30-day cardiovascular death and 3-year RCA revascularization rate

Association of School Environment and After-School Physical Activity with Health-Related Physical Fitness among Junior High School Students in Taiwan

The relationship between students’ school environment and exercise habits is complex, and is affected by numerous factors. However, the few studies that have been conducted on this relationship have reported inconsistent results, especially regarding Taiwanese students. We conducted this cross-sectional study to investigate the association of school environment and after-school physical activity with health-related physical fitness in Taiwanese adolescents. Data were drawn from a national survey conducted by the Ministry of Education in Taiwan in 2008 of health-related physical fitness measurements among junior high school students (649,442 total) in grades seven to nine.School environment (level of urbanization, school size, presence of sports field or gymnasium) and after-school physical activity were assessed for their association with adolescents’ physical fitness measurements (body mass index (BMI), bent-leg sit-ups, 800-/1600-m run, sit-and-reach, standing long jump). Urban boys and girls perform significantly better in muscle strength and endurance, cardiorespiratory endurance, flexibility, and explosive power; girls from rural areas exhibited significantly worse scores in body composition. Boys from large-size schools performed the worst in cardiorespiratory endurance, flexibility, and explosive power; whereas girls from large-size schools performed the worst in muscle strength, muscle endurance, and explosive power, but had the best score for body composition. However, the differences in body composition of boys from large-, medium-, and small- size schools did not reach a statistically significant level. Adolescents of both genders in schools with a sports field or gymnasium exhibited significantly better in muscle strength and endurance, cardiorespiratory endurance, and explosive power. Boys in schools with a sports field or gymnasium had significantly better body composition; girls in schools with sports field or gymnasium differed significantly in flexibility. Adolescents of both genders who participated in physical activity after school had significantly better body composition, cardiorespiratory endurance, and flexibility. Boys who participated in physical activity after school significantly differed in explosive power, whereas girls who participated in physical activity after school exhibited significantly better flexibility. Thus, the current study demonstrated that some factors, including urbanization (school location in rural or urban areas), school size, school facility provision (school with or without sports fields or gymnasiums), and after-school physical activity participation are more important than others in shaping adolescents’ physical fitness in Taiwan; meanwhile, these association patterns differed by gender