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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.

Research focusing on the experiences of special education students in online K-12 schools is scant despite growing numbers of enrollments. This study utilized an emailed survey to understand the motivations and experiences of a group of special education students (n = 30) and their parents (n = 29) while enrolled in an online K-12 school in the U.S. Responses indicated that the three most compelling reasons for choosing the school were flexibility, previous poor fit, and teacher availability. Qualitative analysis of open-ended responses produced two major themes--prior experiences and affordances of the learning environment--with sub-themes related to bullying, personnel, academics, disabilities and accommodations, health considerations, lack of support, self-determination, and the where, when, and how of online learning. These findings may help policy makers enact policies and online educators adapt their approach to better meet the needs of K-12 students with special needs.

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.

In the United States, K-12 special education students are increasingly enrolling in online schools in hopes of improved opportunities and outcomes. In this study, researchers interviewed five special education students enrolled in a targeted online school along with their parents to better understand their motivations for enrolling and their experiences of what worked for them in the unique setting. Students and parents explained how their prior schools had not worked for them and how the online school better met their needs for self-determination, mattering, differentiation, and positive socialization. Results are intended to inform policymakers and stakeholders in online schools to provide the best learning opportunities for special education students.

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.

The purpose of this qualitative study was to understand whether certain theoretical benefits that open educational resources (OER) might have on teacher practice were being realized by a group of secondary teachers using open science textbooks. In surveys and interviews, teachers were asked to describe their classroom practice before and after adopting an open textbook, including practices relating to openness. Teachers were also asked to rate the quality of open textbooks they were using in contrast to textbooks used previously. Most participants reported changes to practice, and the most commonly cited changes could be attributed to a combination of openness and online format. For example, participants described linking textbook content to other online resources. In comparisons of current to previous practice, however, teachers did not report increases in the open practices of collaboration, revising, or adapting.

Background & aimsGut-homing lymphocytes that express the integrin α4β7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4β7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD.MethodsWe collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes.ResultsIn the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation.ConclusionsIn an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.

Over the past few years an increasing number of schools and community organizations have developed transformative learning spaces referred to as "MakerSpaces" for research and training purposes. MakerSpaces are organizations in which members sharing similar interests in science, technology, engineering, and math (STEM) gather to work on self-selected projects. Proponents of MakerSpaces highlight the implicit benefits arising from participants' increased engagement with complex technical content in a voluntary, authentic context. We extend the MakerSpace concept to applications of training special education teachers to address the needs of students with Autism Spectrum Disorder (ASD). Applied behavior analysis (ABA) has vast empirical support for treating ASD. We believe the MakerSpace model provides a platform for developing a new generation of special education teachers. However, rather than making novel products, the focus is on shaping the behavior-analytic repertoires of special education teachers. In the field of ABA, the term "shaping" describes the differential reinforcement of successive approximations to a target behavior. Accordingly, we propose the name ShaperSpace to describe a novel clinical training approach to developing special education teachers who employ research-validated interventions for individuals with ASD. The supervision model described in this article is provided, not as a recommendation, but as an exemplar that has developed over four years' contingency shaping and continues to be refined. We appeal to the reader to consider the ShaperSpace as a starting point from which skills developed through free-operant field experiences will ultimately be shaped and selected by the naturally occurring contingencies of the environment.

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Zika virus is a flavivirus that was first isolated in 1947 from a rhesus macaque in the Zika Forest in Uganda. Zika virus is primarily transmitted to humans by infected [...]

Supervision is vital for personal and professional development of counselors. Practicing school counselors (n = 1557) across the nation were surveyed to explore current supervision practices. Results indicated that 41.1% of school counselors provide supervision. Although 89% receive some type of supervision, only 10.3% of school counselors receive weekly supervision from another school counselor. Most school counselors receive supervision from principals (62.8%). Approximately 32% engage in supervision with other mental health professionals. Only 5.1% of school counselors engage in technology-mediated supervision. Implications, limitations, and future directions for research are provided. (Contains 1 table.)

Consultation, an indirect school counselor service, is provided by 79% (n = 998) school counselor currently. Most frequently consultation occurs with teachers, parents, and principals. MANOVA and post hoc analysis indicate differences in consultation practices across academic levels. Choosing a consultation model based on the type of service recipient (i.e., administration, faculty, parents, other mental health professionals) may improve the benefits of this common school counselor service. Future directions for research and limitations of the study are provided. (Contains 2 tables.)

Effect sizes for single-subject research were examined to determine to what extent they measure similar aspects of the effects of the treatment. Seventy-five articles on the reduction of problem behavior in children with autism were recharted on standard celeration charts. Pearson product-moment correlations were then conducted between two previously unexamined effect sizes, celeration and celeration change, as well as three more common statistics, the mean baseline reduction, the percentage of non-overlapping data, and the percentage of zero data. Significant correlations were found for both celeration and celeration change, suggesting that these and other effect sizes measure somewhat similar aspects of the effect of the treatment. These findings and limitations are discussed within the broader context of evidence-based practices in education. (Contains 1 table and 4 figures.)