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ObjectivesObeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy.MethodsPatients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database.ResultsIn the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT.ConclusionsFunctional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

BackgroundObesity is an endemic problem with significant health and financial consequences. Text messaging has been shown to be a simple and effective method of facilitating weight reduction. In addition, waist-to-hip ratio (WHR) has emerged as a significant anthropometric measure. However, few studies have examined the effect of serial anthropometric self-measurement combined with text messaging. ObjectiveThe primary aim of this study was to assess whether an 8-week program, consisting of weekly serial self-measurements of waist and hip circumference, combined with motivational text messages, could reduce WHR among Australian workers. MethodsThis was a community-based, participant-blinded, staggered-entry, parallel group study. Adult workers with access to mobile phones were eligible and recruited through an open access Web-based survey. Participants were randomly allocated to receive intervention or control messages for 8 weeks. Outcome data were self-assessed through a Web-based survey. ResultsA total of 60 participants were randomized with 30 participants each allocated to a control and an intervention group. There was no significant change in WHR (P=.43), and all secondary outcome measures did not differ between the intervention group and the control group at the end of the 8-week intervention. Both groups, however, showed a significant decrease in burnout over time (mean [SE]: pre 4.80 [0.39] vs post 3.36 [0.46]; P=.004). The intervention uptake followed a downward trend. Peak participant replies to weekly self-measurements were received in week 3 (14/23, 61%) and the least in week 8 (8/23, 35%). No harm was found to result from this study. ConclusionsThis study is an innovative pilot trial using text messaging and serial anthropometric measurements in weight management. No change was detected in WHRs in Australian workers over 8 weeks; therefore, it could not be concluded whether the intervention affected the primary outcome. However, these results should be interpreted in the context of limited sample size and decreasing intervention uptake over the course of the study. This pilot trial is useful for informing and contributing to the design of future studies and the growing body of literature on serial self-measurements combined with text messaging. Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12616001496404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371696&isReview=true (Archived by WebCite at http://www.webcitation.org/73UkKFjSw)

ObjectiveRecent genome-wide association studies (GWASs) of alcohol-related phenotypes have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications.MethodsThe authors used longitudinal data from the cross-ancestry Million Veteran Program sample to identify 1) novel loci associated with AUD and alcohol consumption (measured by the score on the consumption subscale of the Alcohol Use Disorders Identification Test [AUDIT-C]), 2) the impact of phenotypic variation on genetic discovery, and 3) genetic variants with direct effects on AUD that are not mediated through alcohol consumption.ResultsThe authors identified 26 loci associated with AUD and 22 loci associated with AUDIT-C score, including ancestry-specific and novel loci. In secondary GWASs that excluded individuals who report abstinence, the authors identified seven additional loci for AUD and eight additional loci for AUDIT-C score. Although the heterogeneity of the abstinent group biases the GWAS findings, unique variance between alcohol consumption and disorder remained after the abstinent group was excluded. Finally, using mediation analysis, the authors identified a set of variants with effects on AUD that are not mediated through alcohol consumption.ConclusionsDifferences in genetic architecture between alcohol consumption and AUD are consistent with their having different biological contributions. Genetic variants with direct effects on AUD are potentially relevant to understanding the transition from heavy alcohol consumption to AUD and may be targets for translational prevention and treatment efforts.

The COVID-19 pandemic-related social distancing practices that colleges implemented in Spring 2020 disrupted the typical mechanisms of propinquity (physical proximity) and homophily (shared characteristics) that physical institutions rely on to help students build and maintain relationships critical to learning and wellbeing. To explore how social distancing shaped students' academic and social networks and associated educational outcomes, we conceptualized it as a "network shock" and collected unique ego network data in April 2020. For participating students, maintaining interactions with the same set of individuals before and after social distancing was related to more positive outcomes across a range of self-reported wellbeing and learning indicators. On average, students experienced a loss of frequent academic contacts, while they maintained or replaced social interactions in their interpersonal networks after social distancing. Our investigation of the ways students experienced changes in their social and academic networks after a loss of physical proximity points to the role of interpersonal interaction network continuity for fostering wellbeing and learning in times of disruption, as well as the potential need for support in maintaining or rebuilding academic networks.

In spring 2020, many U.S. colleges and universities rapidly shifted to online instruction and implemented social distancing policies to respond to the COVID-19 pandemic. Students experienced unprecedented disruption of their interpersonal academic and social networks due to the loss of physical proximity. We used egocentric network analysis and latent profile analysis with survey data from April 2020 and conducted follow-up interviews in September 2020 to examine some of the pandemic's immediate effects on student interpersonal network change. We found the disappearance of interpersonal network patterns featuring coworkers and academic ties, as well as reductions in students' overall number of connections and the role diversity of their networks. Results suggest potential ongoing reduction of peer academic relationships, implying that institutional personnel may need to pay particular attention to academic connections in online spaces and to regenerating students' academic networks when on-campus physical spaces may again be used to support learning.

To date, the Intentions to Seek Counseling Inventory (ISCI) is the most widely used instrument to measure psychological help-seeking intentions. However, the ISCI is yet to be validated with international students. In this study, we examine the dimensionality and reliability of the ISCI by performing exploratory factor analysis, Cronbach alpha reliability analysis, and split-half reliability analysis in a sample of international students (N = 183). We find a two-factor, 15-item assessment that explains 49.92% of the common variance. Our findings provide support for the use of ISCI with international students, albeit with different dimensionality. Implications of the findings for both research and practice are discussed.

Faculty development (FD) programs are critical for providing the knowledge and skills necessary to drive positive change in health professions education, but they take many forms to attain the program goals. The Macy Faculty Scholars Program (MFSP), created by the Josiah Macy Jr. Foundation (JMJF) in 2010, intends to develop participants as leaders, scholars, teachers, and mentors. After a decade of implementation, an external review committee conducted a program evaluation to determine how well the program met its intended goals and defined options for ongoing improvement.The committee selected Stufflebeam's CIPP (context, input, process, products) framework to guide the program evaluation. Context and input components were derived from the MFSP description and demographic data, respectively. Process and product components were obtained through a mixed-methods approach, utilizing both quantitative and qualitative data obtained from participant survey responses, and curriculum vitae (CV).The evaluation found participants responded favorably to the program and demonstrated an overall increase in academic productivity, most pronounced during the two years of the program. Mentorship, community of practice, and protected time were cited as major strengths. Areas for improvement included: enhancing the diversity of program participants, program leaders and mentors across multiple sociodemographic domains; leveraging technology to strengthen the MFSP community of practice; and improving flexibility of the program.The program evaluation results provide evidence supporting ongoing investment in faculty educators and summarizes key strengths and areas for improvement to inform future FD efforts for both the MFSP and other FD programs.

Synthesis research in ecology and environmental science improves understanding, advances theory, identifies research priorities, and supports management strategies by linking data, ideas, and tools. Accelerating environmental challenges increases the need to focus synthesis science on the most pressing questions. To leverage input from the broader research community, we convened a virtual workshop with participants from many countries and disciplines to examine how and where synthesis can address key questions and themes in ecology and environmental science in the coming decade. Seven priority research topics emerged: (1) diversity, equity, inclusion, and justice (DEIJ), (2) human and natural systems, (3) actionable and use-inspired science, (4) scale, (5) generality, (6) complexity and resilience, and (7) predictability. Additionally, two issues regarding the general practice of synthesis emerged: the need for increased participant diversity and inclusive research practices; and increased and improved data flow, access, and skill-building. These topics and practices provide a strategic vision for future synthesis in ecology and environmental science.

Despite an estimated heritability of ~50%, genome-wide association studies of opioid use disorder (OUD) have revealed few genome-wide significant loci. We conducted a cross-ancestry meta-analysis of OUD in the Million Veteran Program (N = 425,944). In addition to known exonic variants in OPRM1 and FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1 and KCNN1. A meta-analysis including other datasets identified a locus in TSNARE1. In total, we identified 14 loci for OUD, 12 of which are novel. Significant genetic correlations were identified for 127 traits, including psychiatric disorders and other substance use-related traits. The only significantly enriched cell-type group was CNS, with gene expression enrichment in brain regions previously associated with substance use disorders. These findings increase our understanding of the biological basis of OUD and provide further evidence that it is a brain disease, which may help to reduce stigma and inform efforts to address the opioid epidemic.