In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is ...unknown.
Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use.
A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval CI 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94).
Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.
The short articles, by scholars who include many of the world’s leading Haydn specialists, are well-written, insightful, and full of useful information, giving readers a clear idea of the state of ...Haydn research in the second decade of the twenty-first century as seen from a North American perspective. Under such circumstances, contributors can hardly avoid referring, occasionally, to the same facts and anecdotes. ...Haydn’s recollections of his experiences with Nicola Porpora come up repeatedly throughout the book: “Chronology”: “Works as valet and keyboard accompanist for the Neapolitan opera composer and singing teacher Nicola Porpora, learning the Italian language and partimento counterpoint, which Haydn referred to as ‘the true fundamentals of composition’” (xxi). Many would have probably answered (like me) that they learned about Haydn through their parents, thus revealing the book as a document of upper-middle class tastes, passed as part our cultural capital from one generation to the next.
IMPORTANCE: Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that ...influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive. OBJECTIVE: To examine whether AD and MDD overlap genetically, using a polygenic score approach. DESIGN, SETTINGS, AND PARTICIPANTS: Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set. MAIN OUTCOMES AND MEASURES: Association between MDD PRS and AD. RESULTS: Participants analyzed included 788 cases (548 69.5% men; mean SD age, 38.2 10.8 years) and 522 controls (151 28.9.% men; age SD, 43.9 11.6 years) from COGA; 631 cases (333 52.8% men; age SD, 35.0 7.7 years) and 756 controls (260 34.4% male; age SD 36.1 7.7 years) from SAGE; 2135 cases (1375 64.4% men; age SD, 39.4 11.5 years) and 350 controls (126 36.0% men; age SD, 43.5 13.9 years) from Yale-Penn; and 317 cases (295 93.1% men; age SD, 59.1 13.1 years) and 1719 controls (1545 89.9% men; age SD, 64.5 13.3 years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10−6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10−9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10−6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007). CONCLUSIONS AND RELEVANCE: These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.
Ectopic heartbeats can trigger reentrant arrhythmias, leading to ventricular fibrillation and sudden cardiac death. Such events have been attributed to perturbed Ca2+ handling in cardiac myocytes ...leading to spontaneous Ca2+ release and delayed afterdepolarizations (DADs). However, the ways in which perturbation of specific molecular mechanisms alters the probability of ectopic beats is not understood. We present a multiscale model of cardiac tissue incorporating a biophysically detailed three-dimensional model of the ventricular myocyte. This model reproduces realistic Ca2+ waves and DADs driven by stochastic Ca2+ release channel (RyR) gating and is used to study mechanisms of DAD variability. In agreement with previous experimental and modeling studies, key factors influencing the distribution of DAD amplitude and timing include cytosolic and sarcoplasmic reticulum Ca2+ concentrations, inwardly rectifying potassium current (IK1) density, and gap junction conductance. The cardiac tissue model is used to investigate how random RyR gating gives rise to probabilistic triggered activity in a one-dimensional myocyte tissue model. A novel spatial-average filtering method for estimating the probability of extreme (i.e. rare, high-amplitude) stochastic events from a limited set of spontaneous Ca2+ release profiles is presented. These events occur when randomly organized clusters of cells exhibit synchronized, high amplitude Ca2+ release flux. It is shown how reduced IK1 density and gap junction coupling, as observed in heart failure, increase the probability of extreme DADs by multiple orders of magnitude. This method enables prediction of arrhythmia likelihood and its modulation by alterations of other cellular mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. Methods Here, we test ...the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: COGEND (ascertained for nicotine dependence n=918 cases, 988 controls), COGA (ascertained for alcohol dependence n=643 cases, 384 controls), and FSCD (ascertained for cocaine dependence n=210 cases, 317 controls). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to 1000 Genomes reference panel. Results In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo R2 range 0.8%-3.7%, minimum p=4x10-23 ). Conclusions These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.
Abstract This study examined the degree to which pain catastrophizing and pain-related fear explain pain, psychological disability, physical disability, and walking speed in patients with ...osteoarthritis (OA) of the knee. Participants in this study were 106 individuals diagnosed as having OA of at least one knee, who reported knee pain persisting for six months or longer. Results suggest that pain catastrophizing explained a significant proportion (all P s ≤ 0.05) of variance in measures of pain (partial r2 p r2 = 0.10), psychological disability (p r2 = 0.20), physical disability (p r2 = 0.11), and gait velocity at normal (p r2 = 0.04), fast (p r2 = 0.04), and intermediate speeds (p r2 = 0.04). Pain-related fear explained a significant proportion of the variance in measures of psychological disability (p r2 = 0.07) and walking at a fast speed (p r2 = 0.05). Pain cognitions, particularly pain catastrophizing, appear to be important variables in understanding pain, disability, and walking at normal, fast, and intermediate speeds in knee OA patients. Clinicians interested in understanding variations in pain and disability in this population may benefit by expanding the focus of their inquiries beyond traditional medical and demographic variables to include an assessment of pain catastrophizing and pain-related fear.
This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes ...affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.
The Australian Government has set an ambitious target that at least 20 per cent of Australia’s electricity needs will be met by Renewable Energy (RE) sources by 2020. Given the limited use of RE ...sources for electricity generation, this national Renewable Energy Target (RET) leaves state, territory and municipal governments in a challenging policy position. In this article, we examine the Australian state of Queensland where RE provides approximately 4 per cent of the region’s electricity supplies. The research utilizes stakeholder theory to examine the developmental barriers, targets, policies and actions identified by firms and stakeholder organizations in the RE industry sector. The results from our analysis show that RE developments face a range of socio-technical barriers that require timely actions in the areas of financial incentives, infrastructure enhancement, regulation reform, community-centred developments, technology and workforce investments, and information and education programs. Also, in the context of RE planning, while the national RET is the preferred setting, the differences between Queensland’s RE installed generation capacity and electricity supply targets require clarification and agreement.
► We examine RE barriers, targets, policies and actions in Queensland, Australia. ► Existing socio-technical barriers require timely actions to meet national RE targets. ► Regional RE targets may be applied for enhanced sustainable community development. ► RE targets for installed capacity and actual supply require clarification and agreement.
Patient specific models of ventricular mechanics require the optimization of their many parameters under the uncertainties associated with imaging of cardiac function. We present a strategy to reduce ...the complexity of parametric searches for 3-D FE models of left ventricular contraction. The study employs automatic image segmentation and analysis of an image database to gain geometric features for several classes of patients. Statistical distributions of geometric parameters are then used to design parametric studies investigating the effects of: (1) passive material properties during ventricular filling, and (2) infarct geometry on ventricular contraction in patients after a heart attack. Gaussian Process regression is used in both cases to build statistical models trained on the results of biophysical FEM simulations. The first statistical model estimates unloaded configurations based on either the intraventricular pressure or the end-diastolic fiber strain. The technique provides an alternative to the standard fixed-point iteration algorithm, which is more computationally expensive when used to unload more than 10 ventricles. The second statistical model captures the effects of varying infarct geometries on cardiac output. For training, we designed high resolution models of non-transmural infarcts including refinements of the border zone around the lesion. This study is a first effort in developing a platform combining HPC models and machine learning to investigate cardiac function in heart failure patients with the goal of assisting clinical diagnostics.
PDF
