Inferring causal molecular networks: empirical assessment through a community-based effort

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense

Inferring causal molecular networks: empirical assessment through a community-based effort

Inferring molecular networks is a central challenge in computational biology. However, it has remained unclear whether causal, rather than merely correlational, relationships can be effectively inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge that focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results constitute the most comprehensive assessment of causal network inference in a mammalian setting carried out to date and suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess the causal validity of inferred molecular networks

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Neurogenic Bowel and Management after Spinal Cord Injury: A Narrative Review

People with spinal cord injury (SCI) suffer from the sequela of neurogenic bowel and its disabling complications primarily constipation, fecal incontinence, and gastrointestinal (GI) symptoms. Neurogenic bowel is a functional bowel disorder with a spectrum of defecatory disorders as well as colonic and gastrointestinal motility dysfunction. This manuscript will review the anatomy and physiology of gastrointestinal innervation, as well as the pathophysiology associated with SCI. It will provide essential information on the recent guidelines for neurogenic bowel assessment and medical management. This will allow medical providers to partner with their patients to develop an individualized bowel plan utilizing a combination of various pharmacological, mechanical and surgical interventions that prevent complications and ensure successful management and compliance. For people with SCI and neurogenic bowel dysfunction, the fundamental goal is to maintain health and well-being, promote a good quality of life and support active, fulfilled lives in their homes and communities

Relationship of Spasticity to Soft Tissue Body Composition and the Metabolic Profile in Persons With Chronic Motor Complete Spinal Cord Injury

Background/Objective: To determine the effects of spasticity on anthropometrics, body composition (fat mass [FM] and fat-free mass [FFM]), and metabolic profile (energy expenditure, plasma glucose, insulin concentration, and lipid panel) in individuals with motor complete spinal cord injury (SCI). Methods: Ten individuals with chronic motor complete SCI (age, 33 ± 7 years; BMI, 24 ± 4 kg/m 2 ; level of injury, C6-T11; American Spinal Injury Association A and B) underwent waist and abdominal circumferences to measure trunk adiposity. After the first visit, the participants were admitted to the general clinical research center for body composition (FFM and FM) assessment using dual energy x-ray absorptiometry. After overnight fasting, resting metabolic rate (RMR) and metabolic profile (plasma glucose, insulin, and lipid profile) were measured. Spasticity of the hip, knee, and ankle flexors and extensors was measured at 6 time points over 24 hours using the Modified Ashworth Scale. Results: Knee extensor spasticity was negatively correlated to abdominal circumferences (r = -0.66, P = 0.038). After accounting for leg or total FFM, spasticity was negatively related to abdominal circumference (r = -0.67, P = 0.03). Knee extensor spasticity was associated with greater total %FFM (r = 0.64; P = 0.048), lower %FM (r = -0.66; P = 0.03), and lower FM to FFM ratio. Increased FFM (kg) was associated with higher RMR (r = 0.89; P = 0.0001). Finally, spasticity may indirectly influence glucose homeostasis and lipid profile by maintaining FFM (r = -0.5 to -0.8, P < 0.001). Conclusion: Significant relationships were noted between spasticity and variables of body composition and metabolic profile in persons with chronic motor complete SCI, suggesting that spasticity may play a role in the defense against deterioration in these variables years after injury. The exact mechanism is yet to be determined

Cutaneous nodules in Irrawaddy dolphins: an emerging disease in vulnerable populations

The presence of cutaneous nodules is reported in vulnerable populations of Irrawaddy dolphins Orcaella brevirostris from Malaysia (Kuching, Bintulu-Similajau, Kinabatangan Segama and Penang Island), India (Chilika Lagoon) and Bangladesh (Sundarbans). Approximately 5700 images taken for photo-identification studies in 2004 to 2013 were examined for skin disorders. Nodules were detected in 6 populations. They appeared as circumscribed elevations of the skin and varied in size from 2 to >30 mm, were sparse or numerous and occurred on all visible body areas. In 8 photo-identified (PI) dolphins from India and Malaysia, the lesions remained stable (N = 2) or progressed (N = 6) over months but did not regress. The 2 most severely affected individuals were seen in Kuching and the Chilika Lagoon. Their fate is unknown. Cutaneous nodules were sampled in a female that died in a gillnet in Kuching in 2012. Histologically, the lesions consisted of thick collagen bundles covered by a moderately hyperplasic epithelium and were diagnosed as fibropapillomas. Whether the nodules observed in the other O. brevirostris were also fibropapillomas remains to be investigated. Disease prevalence ranged from 2.2% (N = 46; Bintulu-Similajau) to 13.9% (N = 72; Chilika) in 4 populations from Malaysia and India. It was not significantly different in 3 study areas in eastern Malaysia. In Chilika, prevalence was significantly higher (p = 0.00078) in 2009 to 2011 (13.9%) than in 2004 to 2006 (2.8%) in 72 PI dolphins. The emergence of a novel disease in vulnerable O. brevirostris populations is of concern

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done. We conducted a subanalysis of 3 single-center, randomized, and blinded clinical trials: (1) TAC-HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1-year cardiac structure and function and quality-of-life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within-group, =0.002) compared to ICM (1.5%; within-group, =0.14; between-group, =0.003). Similarly, stroke volume increased in DCM by 10.59 mL ( =0.046) versus ICM (-0.2 mL; =0.73; between-group, =0.02). End-diastolic volume improved only in ICM (10.6 mL; =0.04) and end-systolic volume improved only in DCM (17.8 mL; =0.049). The sphericity index decreased only in ICM (-0.04; =0.0002). End-diastolic mass increased in ICM (23.1 g; <0.0001) versus DCM (-4.1 g; =0.34; between-group, =0.007). The 6-minute walk test improved in DCM (31.1 m; =0.009) and ICM (36.3 m; =0.006) with no between-group difference ( =0.79). The New York Heart Association class improved in DCM ( =0.005) and ICM ( =0.02; between-group =0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (-19.5; =0.002) and ICM (-6.4; =0.03; δ between-group difference =0.042) patients. Mesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies. URL: http://www.clinicaltrials.gov. Unique identifiers: TAC-HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON-DCM: NCT01392625