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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.

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

ObjectivesHuntington's disease (HD) is a neurodegenerative disease in which cognitive and behavioural symptoms impair the performance of instrumental activities of daily living, including the handling of finances. We sought to determine the prevalence of financial dysfunction in HD, and the demographic and clinical predictors of such impairments.MethodsWe analysed longitudinal data for pre-manifest gene carriers and HD patients from the Enroll-HD dataset. Financial dysfunction was determined by finance-related items in the Total Functional Capacity (TFC) and Functional Assessment (FA) scales. A binary logistical regression model was used to investigate the predictive value of demographic and clinical factors for the development of financial dysfunction.ResultsFinancial impairment was found to be common in HD gene carriers, and over half required financial assistance within 5 years from diagnosis. Cognitive impairment, apathy, unemployment and disease severity predicted financial dysfunction in manifest patients. For pre-manifest patients, the predictors were proximity to disease onset and depression.ConclusionsLoss of financial autonomy is common in HD, and cognitive and psychiatric factors are important in its development. Clinicians must be vigilant to identify patients that may be vulnerable to financial exploitation.

BackgroundCLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition.MethodsAn expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria.ResultsTwenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality).ConclusionThis program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.

Preparing tomorrow's faculty members to respond to emerging challenges presented by the ever-changing realities of international higher education requires faculty professional development that mirrors high-impact practices advocated for tomorrow's students. Auburn University, through its Global Teaching Academy and International Perspectives on University Teaching and Learning Symposium, continues to provide opportunities to respond to these challenges to enhance learning for the world-wide context.

The Caledonian pinewoods of northern Scotland represent the remnants of once extensive forests found at the western edge of the natural range of Scots pine (Pinus sylvestris L.). The surviving pinewoods are of international significance and are of high conservation and cultural value. However, for many decades, there has been concern about their long-term future because of a lack of regenerating seedlings and young trees. This problem is thought to be driven by high deer populations resulting in intensive browsing and severe damage to young trees, as well as a lack of favourable micro-sites for seedling germination. An experiment was established on the Mar Lodge estate in 2007–08 adjacent to native pinewood stands to test the effects of protection and site cultivation upon seedling numbers and growth. The experiment was located within a regeneration zone where intensive deer control had reduced numbers to <5 animals km−2. Ten years after initiation, occurrence and numbers of both Scots pine and birch seedlings were substantially increased in cultivated treatments compared with uncultivated controls. There were no effects of protection upon seedling numbers. Protection improved height growth of Scots pine, but not of birch. Cultivation had no effect upon the growth of pine seedlings but did influence the height of birch seedlings due to the rapid growth of some pre-existing seedlings in the uncultivated control. Vegetation cover had increased from ~60%to at least 80% cover 6 years after cultivation. The results suggest that site cultivation may be desirable to boost seedling germination within a Caledonian pinewood, but sustained measures to control browsing pressure are a prerequisite for satisfactory establishment of these seedlings. [ABSTRACT FROM AUTHOR]

Evidence of vicarious exposure to racism has primarily been garnered from in-group racial-ethnic samples to convey its harmful psychological impacts on individuals who share identities with those who are directly experiencing the racist act being observed. The extent to which this evidence applies to out-group members exposed to vicarious racism is underexamined. The present study investigated the extent to which vicarious exposure to racialized violence in policing leading to the death of George Floyd predicted negative affect among a sample of undergraduate students when accounting for other factors that may contribute to negative affect. A sample (N = 683) of nonhomogeneous racial-ethnic (67% People of Color; 33% White) undergraduate students aged 18 to 41 completed an online survey assessing demographic characteristics, vicarious racism exposure, everyday discrimination exposure, and affect during the summer and fall of 2020. Bivariate analyses indicated racial-ethnic disparities in negative affect among the sample. After controlling for race-ethnicity, gender identity, sexual identity, and everyday discrimination, a hierarchical linear regression analysis indicated that exposure to vicarious racialized violence in policing significantly predicted increased levels of negative affect. These findings provide vital insight into the harmful psychological impacts of vicarious exposure to racialized violence on individuals in the U.S. which has individual, population, and public health implications. [ABSTRACT FROM AUTHOR]