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Abstract Background Immunosuppression (IS) is required in AAV-mediated gene therapy to maximize safety and efficacy, in part to mitigate potential hepatotoxicity and prevent immune-mediated loss of transgene expression. However, prolonged IS increases the risk of complications, including infections. MYBPC3-associated HCM patients have limited treatment options. MyPEAK-1 is a first-in-human trial to assess the safety and efficacy of TN-201, a gene replacement therapy, which was designed to address the underlying genetic cause of MYBPC3-associated HCM in symptomatic adults. Objective To describe the safety and refinement of the IS regimen and monitoring used during the dosing of Cohorts 1 and 2 in the MyPEAK-1 trial. Methods The dose-escalation study utilized two cohorts (n=3 each) receiving 3E13 vg/kg (Cohort 1) or 6E13 vg/kg (Cohort 2) of TN-201 as a single IV infusion. All patients received prophylactic prednisone (starting at 1 mg/kg, maximum 80 or 60 mg/day) and sirolimus (target trough level of 4–8 ng/mL). Prednisone was tapered over several weeks, with variable timing depending on safety laboratory results. The dose of prednisone and timing of sirolimus were adjusted to reduce IS burden in Cohort 2. Specifically, sirolimus was initiated earlier (Day -7 vs Day -3) and the maximum starting dose of prednisone was reduced (from 80 to 60 mg/day). Monitoring frequency was increased to weekly throughout the course of IS. An independent data safety monitoring board provided safety oversight. Results All six patients successfully completed the IS regimen. TN-201 was generally well-tolerated at both dose levels (follow-up >52 weeks and >12 weeks in Cohort 1 and 2, respectively). Adjustments to the IS regimen and monitoring during Cohort 1 facilitated a significantly shorter course of IS in Cohort 2, with a mean duration of prednisone use of 256 vs 81 days. Despite receiving a higher dose of TN-201, peak transaminase levels, reflecting liver inflammation, were lower in Cohort 2 than Cohort 1. There was no clinical TMA in either cohort. Mean sirolimus trough levels remained consistent between groups (7.2 vs 7.4 ng/mL). Increases in MyBP-C protein, decreases in circulating cardiac biomarkers, and a reduction in LV hypertrophy were observed during follow up. Conclusion Standardized adjustments to the prophylactic immunosuppressive regimen in the MyPEAK-1 trial successfully managed the immunogenicity of AAV9-based gene therapy. Cohort 2 patients required lower cumulative corticosteroid doses without compromising safety or cardiac transduction. These refinements enabled lower cumulative steroid exposure and shorter IS durations in the higher-dose cohort. These results suggest that individualized, protocol-driven IS is effective in controlling the immune response to TN-201 while supporting transgene expression, paving the way for continued investigation of this gene therapy clinical investigation in MYBPC3-associated HCM population.Corticosteroid duration and daily doseFor image description, please refer to the figure legend and surrounding text.

Abstract Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263 ), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

Objectives: To summarize the current evidence for radiation therapy (RT) in the prevention and treatment of heterotopic ossification (HO), including patient selection, optimal RT technique, and associated risks. Methods: This multispecialty-led committee includes radiation oncologists, rheumatologists, orthopedic surgeons, and physical medicine/rehabilitation physicians. Using the population, intervention, comparator, outcome, timing and study design (PICOTS) framework, evidence regarding treatment outcomes was assessed using Cochrane and PRISMA methodology. Eligible studies included prospective and retrospective studies published between January 1, 1980, and November 1, 2025, from Embase, Medline, and PubMed databases. Of the 197 articles identified using the search strategy, 83 were selected for inclusion as evidence, including 27 well-designed studies (phase II randomized and phase III), 16 moderately well-designed studies that account for most common biases (matched cohort and phase II studies), 31 studies with design limitations (retrospective reviews), 2 supplemental studies (not useful as primary evidence), and 7 meta-analyses. Additional studies were included to provide context and were not used to guide recommendations. Well-established RAND-UCLA consensus methodology (modified Delphi) was used to rate the appropriateness of the treatment options. Results: The results of this analysis demonstrate that in appropriately selected patients, RT is an effective and safe therapy for prophylaxis of HO formation. Conclusions: This systematic review provides consensus guidelines for the use of RT as prophylaxis of HO based on current peer-reviewed evidence in the literature.

ABSTRACT Background Most genomic studies of adult-type diffuse gliomas have focused on predominantly European ancestry populations, limiting the generalizability of molecular classifications and precision medicine approaches. We assembled a multi-institutional glioma cohort of diverse patients to investigate how germline ancestry, molecular subtypes, and mutational processes shape tumor biology and clinical outcomes. Methods We analyzed 1,102 adults with WHO 2021–classified diffuse gliomas (IDH-mutant, 1p/19q-codeleted oligodendroglioma; IDH-mutant astrocytoma; IDH-wildtype glioma) from seven U.S. institutions. Whole-exome sequencing (WES) of FFPE tumors identified somatic alterations and COSMIC SBS v3.2 mutational signatures. Genetic ancestry was estimated from WES using 1000 Genomes reference populations. Overall survival was assessed using Kaplan–Meier and multivariable models. Results The cohort included 66.9% European (EUR), 21.1% Admixed American/Hispanic (AMR), 10.3% Admixed African (AFR), and 1.6% Asian (AS) ancestry. Survival followed expected molecular hierarchy (median overall survival: oligodendroglioma 15.7 years, astrocytoma 10.6 years, IDH-wildtype glioma 1.9 years). Within oligodendroglioma, AMR patients showed improved survival versus EUR (HR 0.67, 95% CI 0.48–0.94; p=0.011), with similar trends across subtypes. Somatic profiling confirmed canonical subtype-defining alterations and revealed higher ATRX alterations in AFR and AMR IDH-wildtype tumors compared with EUR. ATRX alterations were associated with improved survival only in AFR (p=0.003). Mutational signature analysis identified subtype-specific signatures, including therapy-associated signatures. Chemotherapy-related signatures were more frequent in EUR and AMR than in AFR. Conclusions This ancestrally diverse glioma cohort confirms established molecular classifications and identifies ancestry-associated differences in survival, somatic alterations, and mutational processes, indicating the critical need for broad representation to inform precision neuro-oncology. Key Points A multi-institutional glioma cohort validates subtype and survival patterns across ancestries. Therapy-associated mutational signatures differ by ancestry, suggesting distinct treatment-related mutational processes. Admixed American patients show improved survival, particularly in oligodendroglioma. Importance of the Study Most genomic studies of adult-type diffuse glioma have focused on populations of predominantly European ancestry which limits the ability to examine variation in tumor biology and clinical outcomes across populations. In this study, we assembled one of the largest ancestrally diverse cohorts of molecularly characterized adult diffuse gliomas, integrating germline ancestry inference with tumor whole-exome sequencing and mutational signature analysis. We confirm that established molecular classifications and survival hierarchies remain robust across ancestry groups. However, we also identified ancestry-associated differences in survival within specific tumor subtypes, higher ATRX alteration frequencies in African American and admixed American patients with IDH-wildtype tumors, and variation in therapy-associated mutational signatures across ancestry groups. These findings highlight the importance of incorporating population differences into genomic studies of glioma and provide a resource for future multi-ancestry investigations of glioma risk, tumor evolution, and treatment response, ultimately supporting more inclusive precision neuro-oncology.

Abstract Background Arrhythmogenic mitral valve prolapse (AMVP) is increasingly recognized as a cause of sustained ventricular arrhythmias (VA) and sudden cardiac death. Although prior studies have identified clinical and imaging risk markers in AMVP, it remains unclear whether the arrhythmogenic phenotype differs between women and men. Purpose To investigate sex-specific differences in clinical profiles, structural substrates, and arrhythmia presentations in patients with AMVP who experienced sustained VA. Methods We conducted a sex-based sub-analysis of a multicenter cohort (35 centers from 15 countries) of patients with AMVP and sustained VA. Participants were grouped by sex and by initial arrhythmia type (sustained monomorphic ventricular tachycardia [SMVT] vs ventricular fibrillation [VF]). Data collected included clinical history, ECG findings, echocardiographic measurements, and cardiac MRI (CMR) markers, such as late gadolinium enhancement (LGE) patterns and mitral annular disjunction (MAD). These factors were compared across groups. Results The study comprised 129 women (57%) and 96 men (43%). Women were diagnosed at younger ages (39±16 years vs. 49±16 years, p<0.03) and had more frequently a family history of MVP (22% vs 10%, p=0.027). MAD was significantly more common in women (66% vs 48%, p=0.015) while LGE was more frequently observed in men than women (N=39 (72%) vs N=41 (53%), p=0.028), with no significant regional patterns (myocardial and/or papillary muscle). ECG T-wave inversion (p=0.627), PVC burden (p>0.03) and arrhythmia types were similar in men and women. However, stress was a more often commonly recognized as the initiating trigger for VA in men than in women (38% [N=24] vs. 18% [N=18], p<0.05). The overwhelming majority of VA were initiated by PVCs in both sexes with no differences in the initiating mechanisms. Conclusion In patients with AMVP presenting with sustained VA, the arrhythmic phenotype and initiating mechanisms are similar between sexes, although stress was a significantly stronger trigger for VA in men. Women more often exhibited MAD, whereas LGE was more frequent in men. These findings suggest that structural and tissue-based markers, rather than sex alone, contribute to the development of malignant arrhythmias in AMVP.

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

Abstract Roux‐en‐Y gastric bypass (RYGB) surgery is a highly effective technique for treating obesity. However, it may result in nutritional deficiencies. Here we report the case of a 55‐year‐old woman presenting with chronic diarrhea lasting 2 years, accompanied by lower limb paresthesia, macrocytic anemia, leukopenia, and thrombocytopenia. Her medical history included hypothyroidism treated with levothyroxine, and RYGB surgery performed in 2014, with intermittent micronutrient supplementation. The patient developed copper and zinc deficiencies. To our knowledge, this is the first report of a patient presenting with both deficiencies simultaneously with pancytopenia 10 years after RYGB. This case underscores the need to verify adherence to existing preoperative screening recommendations involving preoperative micronutrient measurements to assess micronutrient deficiency risks and multidisciplinary postoperative follow‐up, the importance of monitoring micronutrient levels, close follow‐up of both symptomatic and asymptomatic patients and evaluating adherence to supplementation regimens.

ABSTRACT Objective Little is known about shifting from pediatric to adult‐focused multiple sclerosis (MS) care. This study aims to explore transition of care and follow‐up in the US pediatric‐onset MS (POMS) population. Methods Surveys were distributed to 10 sites in the US Network of Pediatric MS Centers (US NPMSC) about transition‐of‐care practices. A cohort of POMS/clinically isolated syndrome (CIS) at 12 US NPMSC sites was analyzed. The primary comparison was between < 18 and ≥ 18‐years of age. The primary outcome was 1‐ and 2‐year lapse in last follow‐up visit, measured from last recorded database visit to data lock date or, if ≥ 18 years of age, up to 1 year after a patient reached their site's typical transition age, if earlier. Secondary outcomes were baseline factors associated with follow‐up lapse. The model was adjusted for preidentified confounders. Results Compared with < 18 years, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse. In POMS/CIS, the estimated hazard was 1.61 for 1‐year lapse (95% confidence interval [CI] 1.32–1.97, p < 0.001) and 1.40 for 2‐year lapse (95% CI 1.11–1.76, p = 0.004). In POMS‐only, the estimated hazard was 1.70 for 1‐year lapse (95% CI 1.33–2.18, p < 0.001) and 1.49 for 2‐year lapse (95% CI 1.11–1.99, p = 0.007). Platform injectable disease‐modifying therapy was associated with greater and intravenous with lesser hazard of lapse in follow‐up, while MS was associated with lower hazard than CIS. Conclusion Variable transition‐of‐care practices and barriers were reported by major US POMS centers. Before typical transition age, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse than < 18. Developing standardized, targeted transition‐of‐care practices in POMS may be important.

Abstract Aims Transcatheter mitral valve replacement (TMVR) with the Tendyne Mitral Valve System is a treatment option for patients with severe symptomatic mitral regurgitation (MR) unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). This study sought to evaluate the safety and effectiveness of TMVR through 5-year follow-up. Methods and Results The Tendyne Expanded Clinical Study is a prospective, single-arm, multicentre study that enrolled patients between November 2014 and June 2020. The study enrolled 191 patients (mean age 74.1 ± 8.0 years, 62.8% male, 70.2% New York Heart Association Class (NYHA) class III/IV, 88.5% secondary MR), of whom 186 (97.4%) underwent TMVR with Tendyne. MR grade decreased from ≥3+ in 99.5% patients at baseline to grade ≤1+ in 95.3% at 5 years. In those patients surviving to 5 years (n = 49), durable symptomatic improvement was evidenced by 73.5% patients being in NYHA class I/II at 5 years. The Kansas City Cardiomyopathy Questionnaire overall summary score increased from 48.5 ± 22.5 points at baseline to 67.6 ± 21.5 points at 5 years. Serious adverse events that occurred through 5 years included life-threatening bleeding (11.5%), fatal bleeding (2.6%), renal insufficiency/failure (28.8%), endocarditis (7.3%), device thrombosis (5.8%), and new onset atrial fibrillation (13.1%). No structural device degeneration or device embolism occurred through 5 years. Conclusions The Tendyne TMVR was effective at achieving immediate and sustainable elimination of MR, which was associated with symptomatic improvement and absence of structural valve degeneration in a high-risk cohort over 5 years. These findings support TMVR with the Tendyne System as an alternative for patients with appropriate mitral valve anatomy and symptomatic secondary MR unsuitable for mitral surgery or TEER.