Citations

Individuals with congenital heart disease are living well into adulthood, resulting in a growing population at risk for neurocognitive and psychosocial challenges. Numerous studies have described these risks in childhood, but significant gaps remain in our understanding of how those challenges evolve across stages of adulthood and how to optimally integrate neurocognitive and psychosocial care for adults with congenital heart disease. A multidisciplinary group of experts and patient partners assembled in April 2024 in Atlanta, GA, forming 3 working groups: (1) Genetics and Brain Health, (2) Characterizing Neuropsychological and Psychological Outcomes, and (3) Neuropsychological and Psychosocial Interventions. Current knowledge was reviewed, knowledge gaps were identified, and recommendations to address these gaps were formulated. Five critical questions regarding the characterization of neuropsychological and psychological outcomes of adults with congenital heart disease were prioritized for discussion: which neurocognitive and psychosocial domains should be prioritized in research and clinical care, what are the trajectories of neurocognitive and psychosocial functioning over the lifespan, how should neurocognitive and psychosocial screening be deployed, what should neurocognitive and psychosocial assessments include, and how do we make comprehensive neurocognitive and psychosocial care a reality. Although many gaps in knowledge were identified, particularly around characterizing neurocognitive trajectories throughout adulthood, there is substantial evidence of increased risk for poor psychosocial outcomes among adults with with congenital heart disease. Clinical and research advances must progress in tandem to address these risks. Specific recommendations for advancing this field over the next decade are offered.

Pediatric obesity is an increasingly prevalent, chronic, and multifactorial disease. Achieving successful and sustained weight reduction with current interventions remains challenging due to significant heterogeneity in treatment response. This review summarizes current evidence describing variability in outcomes across lifestyle, pharmacologic, and metabolic/bariatric surgery interventions in children and adolescents, and examines key biological, metabolic, behavioral, environmental, and psychosocial factors that influence response. In adults, recent findings on energy balance obesity phenotypes (characterized by abnormal satiation, abnormal postprandial satiety, abnormal hedonic eating, and reduced energy expenditure) have demonstrated promise in predicting weight loss outcomes and guiding tailored interventions. However, data on obesity phenotyping within children and adolescents remain limited. Addressing this gap is essential for advancing precision medicine approaches in pediatric obesity, with the potential to improve treatment selection, enhance effectiveness, and optimize long-term clinical outcomes.

ABSTRACT Approximately 10% of patients with Ewing sarcoma (EwS) have pathogenic germline variants. Here, we report two cases: first, a novel germline pathogenic variant in partner and localizer of BRCA2 ( PALB2) in a patient with a late EwS relapse. Its impact on homologous recombination is demonstrated, and breast cancer risk is discussed. Second, we report a pathogenic germline variant in RAD50 in a patient with a rare prostate primary EwS and later concurrent relapsed EwS and therapy‐related acute myeloid leukemia (tAML) with two rare KMT2A translocations. Understanding rare pathogenic germline variants and the impact on cancer behavior, response to treatment and treatment‐associated toxicities is important for patients.

ABSTRACT Background Despite histologic remission (HR) being important in management of ulcerative colitis, the impact of endoscopic sampling on newer scoring systems remains uncertain. This study examines the outcome of applying PICaSSO Histologic Remission Index (PHRI) scoring on biopsies collected during routine clinical care and investigates the impact of endoscopic sampling variation on PHRI scoring and HR status. Methods A retrospective survey of UC endoscopic biopsies ( N = 128, 559 bites, 1–13 bites/biopsy) was evaluated using standard H&E stain and myeloperoxidase (MPO) immunohistochemistry to aid neutrophil identification. Convolutional neural networks (CNN), trained on colonic tissue architecture and cytomorphology features, were deployed alongside pathologist interpretations. In silico modeling of bite‐derived virtual biopsies ( N = 19,760) was investigated to determine the impact of sampling variation on PHRI scores and compared with ground truth clinical samples. Results PHRI MPO scoring displayed improved sensitivity and specificity for identifying neutrophils, compared with PHRI H&E . CNN‐derived PHRI scoring was most accurate for chronic active and chronic active with ulceration categories, with greatest variability observed in chronic inactive biopsies. Virtual patient biopsies comprised of < 5 endoscopic bites were impacted most by sampling permutations. Limited variability in PHRI scores was observed in samples consisting of ≥ 5 bites. Conclusions HR status (PHRI = 0) determination was slightly impacted by sampling. Biopsies consisting of < 5 endoscopic bites exhibited the most variability. Conservative sampling of 5–7 endoscopic bites may produce more accurate assessments of microscopic heterogeneity in clinical studies employing quantitative histologic measurements to assess disease activity and remission. Additionally, incorporating MPO increased the sensitivity and specificity of detecting active inflammation for PHRI scoring.

Summary In adults with classic Hodgkin lymphoma (cHL), metabolic tumour volume (MTV) is valuable for risk stratification. This systematic review explored the role of volumetric parameters in children, adolescents and young adults (CAYA) with cHL. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) method. Five databases were searched on 16 October 2024. Eligible studies were peer‐reviewed manuscripts, written in English, published since database inception that included patients ≤21 years of age with a diagnosis of cHL treated with chemotherapy ± radiotherapy with a baseline 18 F‐Fluorodeoxyglucose (F‐FDG) PET/CT scan for MTV quantification. The search strategy identified 3669 studies, of which 35 were eligible for inclusion. Fifteen studies (43%) evaluated a cohort exclusively ≤21 years of age. All eight studies that explored the association of baseline PET parameters with known risk factors identified a significant correlation. Nine of 12 papers (75%) demonstrated a statistically significant correlation with disease response to therapy on PET/CT. Fifteen of 20 papers (75%) demonstrated an independent statistically significant correlation with clinical outcomes. In the CAYAHL population, volumetric PET parameters are valuable for risk stratification despite heterogeneity in results. Future harmonization of the segmentation approach will facilitate incorporation of MTV into clinical practice.

Abstract INTRODUCTION The genetic basis of sporadic early‐onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late‐onset Alzheimer's disease (LOAD) polygenic risk in EOAD. METHODS A LOAD polygenic score (PGS) was calculated in the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. RESULTS Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset ( p = 0.106) or with cognitive performance ( p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal‐associated protein 25 (SNAP‐25) ( p = 2.3 × 10 −5 ). DISCUSSION While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. Highlights LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal‐associated protein 25 (SNAP‐25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD.

Sharing research code in an open access version-controlled repository offers significant benefits for both science as a whole and for individual researchers. In this article, we focus on this practice, which is fully aligned with the NIH’s Gold Standard Science (GSS) program as well as FAIR (findable, accessible, interoperable, reusable) and TRUST (transparency, responsibility, user focus, sustainability, technology) principles. Gold Standard Science supports open science by emphasizing transparency, reproducibility, and the use of best practices that enable others to verify and extend research. Pairing a research article’s cited data snapshot with a versioned, environment-specific code release, deposited in a companion code repository, ensures that, upon submission to a medical journal, readers and reviewers can directly verify results. An executable and updatable companion code repository complements, rather than replaces, established research data repositories. When code underlying medical research results is made openly available, then other scientists can inspect, run, and validate analyses. These activities enhance reproducibility, which is a core aim of GSS. Shared code also facilitates collaborative innovation by allowing researchers to extend the utility of the code to new datasets and applications. For researchers, code sharing can increase visibility, credibility, and citation impact. Demonstrating transparency through shared executable and updatable code builds trust with journal readers, peer reviewers, funders, and peers. Shared code in an open access repository signals adherence to high standards of scientific integrity and attracts opportunities for collaboration. A researcher who shares code receives recognition as a leader in reproducible, trustworthy research consistent with NIH’s GSS principles.

Abstract Background Fecal microbiota, live-jslm (RBL) is FDA-approved for prevention of recurrent Clostridioides difficile infection (rCDI) in adults following completion of antibiotic treatment. The safety and efficacy of RBL have been demonstrated in trials, but few studies have evaluated outcomes in real-world populations. The primary objective of ROAR (NCT05835219) is to assess RBL effectiveness in reducing rCDI through 8 weeks in clinical practice. Table 1. Treatment success rates by subgroup Methods ROAR is an ongoing, prospective, multicenter, open-label, non-interventional registry of patients receiving RBL for rCDI prevention in the United States. Adults who completed antibiotics for rCDI and are not in an interventional trial are eligible. The primary endpoint assesses the proportion of patients who experience treatment success (no CDI recurrence through 8 weeks). Other objectives describe rCDI management in real-world clinical practice and adverse events (AEs) after RBL administration. This analysis includes patients who received RBL within 30 days of completing antibiotics for rCDI. Results As of September 18, 2024, 76 patients received RBL within 30 days of completing antibiotics and completed 8 weeks of follow-up. Patients were mostly White (93.4%) and female (76.3%), with a median age of 69 years (range, 19-96 years) and a median body mass index of 24.4 (range, 16.5-49.4). Through 8 weeks, 82.9% of patients (63/76; 95% CI, 72.5%-90.6%) experienced treatment success. Similarly, the rate of treatment success was 87.8% (36/41) in the subgroup of patients who received RBL after an antibiotic washout period &gt; 72 hours. Treatment success rates ranged from 77-100% across patient subgroups, including those stratified by age and number of previous CDI episodes within the past 3 years (Table). Overall, 18 (23.7%) patients experienced an AE, 6 (7.9%) experienced a serious AE, and 1 (1.3%) experienced an AE of special interest (large bowel obstruction). AEs assessed as related to RBL occurred in 3 patients (3.9%). There was 1 fatal AE during the study, considered unrelated to RBL. Conclusion Initial results from ROAR are consistent with previous RBL trial results, indicating that RBL is effective and safe for preventing rCDI through 8 weeks after administration in real-world practice. Disclosures Nicholas W. Van Hise, PharmD, Ferring: Advisor/Consultant|Ferring: Grant/Research Support|Innoviva: Advisor/Consultant Teena Chopra, MD, MPH, Cepheid: Advisor/Consultant|Ferring Pharmaceuticals, Inc: Advisor/Consultant|Melinta: Speaker|Pfizer: Advisor/Consultant|Pfizer: Speaker|Shinogi: Speaker Kelly R. Reveles, PharmD, PhD, AstraZeneca: Advisor/Consultant|Ferring Pharmaceuticals: Advisor/Consultant Sahil Khanna, MBBS, MS, Ferring Pharmaceuticals, Inc: Grant/Research Support|ProbioTech Inc: Advisor/Consultant|Rise: Advisor/Consultant|Takeda: Advisor/Consultant|Vedanta: Grant/Research Support Lasse Nielsen, MS, Ferring: Employee Lorien E. Urban, PhD, Ferring Pharmaceuticals Inc: Employee

Background Motor speech disorders are early, common, and functionally limiting features of atypical parkinsonian disorders (APDs) such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA). These impairments are underrecognized and undertreated in neurology clinics. Objectives This review aims to characterize speech impairment in APDs, offer practical guidance for clinical evaluation, highlight the role of Speech‐Language pathologists (SLPs) in diagnosis and management, and outline current and emerging management strategies. Methods A narrative review was conducted by the Diagnosis and Treatment Working Group of CurePSP's Centers of Care, integrating literature and clinical experience to summarize evaluation, diagnosis, and treatment of motor speech disorders in APDs. Results Speech changes in APDs are often mixed dysarthrias with hypokinetic, spastic, and/or ataxic components, and may include apraxia of speech; these are frequently more severe and progress quicker than in Parkinson's disease. These features can assist in differential diagnosis and should prompt early referral to SLPs. Despite the high prevalence of speech and voice changes, comprehensive assessment of motor speech disorders is uncommon in neurology clinics. Current evidence regarding the efficacy of interventions is mixed. Digital acoustic analysis and neuromodulation offer promising directions for diagnosis and treatment. Conclusions Early, collaborative management of motor speech impairment elevates care in APDs. Neurologists and SLPs must work together to improve recognition, diagnosis, and care. Future research should focus on objective biomarkers and personalized therapies to support communication, autonomy, and quality of life for individuals living with APDs.

We present a subset analysis on the adolescent cohort of the S1826 randomized phase three trial, comparing nivolumab, doxorubicin, vinblastine, dacarbazine (N-AVD) to brentuximab vedotin-AVD (BV-AVD) in newly diagnosed advanced-stage (AS, stages III and IV) classic Hodgkin lymphoma (cHL). Among 994 patients enrolled, 24% (n = 240) were age 12-17 years. The 3-year progression-free survival (PFS) was significantly higher in the N-AVD group (93% [95% CI, 87 to 96]) compared with the BV-AVD group (82% [95% CI, 73 to 88]; hazard ratio, 0.37 [95% CI, 0.17 to 0.80]). One N-AVD and two BV-AVD patients received protocol-specified residual site radiotherapy (RT). Rates of febrile neutropenia and sepsis were low in both groups. Severe immune-related adverse events were infrequent, although thyroid dysfunction was seen in 7% with N-AVD. Sensory neuropathy (grade ≥2) was more frequent with BV-AVD (14% v 7%) by clinician report. Although premature discontinuation of therapy was reported in 12 N-AVD patients and four BV-AVD patients, no PFS events were noted in the N-AVD group. Patient-reported outcomes indicated less toxicity with N-AVD. N-AVD demonstrated high 3-year PFS in adolescents with AS cHL, with minimal RT use. S1826 exemplifies the benefits of harmonized clinical trial protocols, resulting in timely access to novel agents for adolescents.