Citations

Abstract Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.

Abstract Background Dementia with Lewy bodies (DLB) is a prevalent form of dementia associated with neuronal alpha‐synuclein aggregates (Lewy bodies). Symptoms include cognitive impairment, fluctuations, neuropsychiatric features including psychosis, sleep disorders, and dysautonomia. DLB is the most expensive form of dementia, and there are currently no treatments approved by the US FDA. Given the advent of sensitive and specific in vivo biomarkers for synuclein aggregation, drug developers are increasingly interested in DLB. FDA instituted Patient‐Focused Drug Development (PFDD) meetings in 2012 with the purpose of ensuring that patients’ experiences, perspectives, needs, and preferences are captured and meaningfully incorporated into drug development and evaluation. Method In October 2024, the Lewy Body Dementia Association (LBDA) and the Alzheimer’s Association (ALZ) co‐hosted an externally‐led PFDD (EL‐PFDD) meeting on DLB. Thirty days before the event, LBDA solicited public comment on the lived experience of DLB, the current state of treatment, and what people with DLB value in potential future therapies. During the live meeting, people with DLB, care partners and family members described their experiences and responded to live polling questions. Result The EL‐PFDD was attended by 347 people with DLB and care partners, drug developers (both industry and academic), FDA staff, and NIH staff. Preliminary analysis of the discussion content and survey responses shows several themes emerging from the meeting. The most bothersome and impactful symptoms varied over the course of the disease, but included cognitive impairment and fluctuations, neuropsychiatric symptoms, and sleepiness. Concerns for the future included progressive decline in cognition, changes in behavior/mood, and cost of care. Limitations to current treatments included lack of FDA‐approved medications, and side effects and lack of efficacy associated with “off label” medications. Priorities for future treatments included symptomatic treatments that do not worsen other DLB symptoms, slowing disease progression, accessibility/insurance coverage, and avoiding side effects. Conclusion The EL‐PFDD on DLB provided valuable information for drug developers and regulators to understand the lived experience of people with DLB and care partners. The results will be documented in a “Voice of the Patient” report that will be hosted at www.lbda.org/el‐pfdd .

Abstract Background: Chronic graft-versus-host disease (cGVHD) is a leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Further investigation is needed to understand cGVHD risk, diagnostic features, and outcomes. Patient-reported outcomes (PROs) are important for characterizing the direct and indirect impact of cGVHD on patients, caregivers, and the healthcare system. THRIVE (NCT05919511) is a prospective, longitudinal observational study of patients at risk for cGVHD to describe the clinical course, burden, and practice patterns for cGVHD. THRIVE uses a novel app-based platform designed for rigorous collection of PROs related to symptoms, quality of life, and indirect costs to the healthcare system. We report preliminary patient demographics and clinical characteristics at study enrollment. Methods: THRIVE includes adults aged ≥18 years in the United States who were enrolled 90–180 days after allo-HCT. Follow-up is for 36 months at intervals determined by clinician standard practice; a virtual site is available for patients who return to community sites for follow-up. Presence or absence of GVHD symptoms, cGVHD therapies when applicable, and adverse events are captured in medical records at clinical visits every ~3 months. In all, 13 PROs are assessed (Cutaneous GVHD Questionnaire [CuGQ], General Anxiety Disorder [GAD-7], Lee Total Symptom Scale [TSS; 7-day], modified Frenchay Activities Index [mFAI], modified Patient-Generated Subjective Global Assessment [mPG-SGA], Oral Health Impact Profile [OHIP-14], Ocular Surface Disease Index [OSDI-12], Patient Health Questionnaire [PHQ-9], Patient-Reported Baseline Data [PRBD], Patient-Reported Caregiver Assessment [PRCA], Patient-Reported Economic, Income, and Insurance Data [PREIID], Patient-Reported Outcomes Measurement Information System–Sexual Function [PROMIS-SF], and Pulmonary GVHD Questionnaire [PulmGQ]). Patients are randomized to sequence groups to complete rotating sets of 4–5 PRO measures via digital platform, monthly (Year 1) then every 2 months (Years 2–3). Recruitment is ongoing (target, 1500 patients). Results: This interim report includes the first 340 patients enrolled in THRIVE (data cutoff: June 17, 2025) at 22 sites across the United States since August 1, 2023. Median (range) age was 60.5 (19–83) years (>70 years, n=60 [18%]). Most patients were male (n=190, 56%), White (n=276, 81%), and had college/graduate education (n=219, 64%). Underlying disease was malignant in 328 (96%) patients; most common malignancies requiring allo-HCT were acute myeloid leukemia (n=129, 38%), myelodysplastic syndrome (n=50, 15%), and acute lymphocytic leukemia (n=37, 11%). Most patients (n=212, 62%) were in complete remission at time of allo-HCT, 282 (83%) enrolled after their first allo-HCT, and median (range) time from allo-HCT to enrollment was 111 (77–211) days. Transplant source was most commonly peripheral blood stem cells (n=272, 80%) from unrelated (n=229, 67%) donors, of whom 169 (50%) were male. Overall, 188 (55%) patients had human leukocyte antigen identical HCT, 72 (21%) had mismatched HCT, and 55 (16%) had haploidentical HCT. Conditioning regimens were myeloablative for 177 (34%) patients, reduced intensity for 164 (48%), and non-myeloablative for 16 (5%). At data cutoff, 296 (87%) patients were continuing in THRIVE; 18/44 (41%) patients who discontinued were alive at discontinuation. There were 107 patients (31%) who developed acute GVHD before enrollment (grade I, n=52; grade II, n=35; grade III, n=9; grade IV, n=0; missing/unknown, n=11); 85 (79%) received systemic treatment for acute GVHD. Overall, 28 (8%) patients had cGVHD at enrollment (mild, n=25; moderate/severe, n=3). Organs affected by cGVHD were skin (n=13), eyes (n=4), and gastrointestinal tract (n=3). Conclusions: THRIVE aims to report on clinical practice for managing risk and treatment of cGVHD after allo-HCT in a prospective cohort of ~1500 patients in the United States for ≤3 years. Although real-world assessment of PROs can be associated with challenges including willingness to participate in an observational study and the collection of data without routine clinical visits, the virtual hybrid design is intended to improve patient access and facilitate data collection. In the 22 months since initiation, 340 patients have been enrolled at 22 sites, and the discontinuation rate is low.

Abstract Arthroscopic posterior labral repair is an effective surgical technique for managing patients with posterior labral tears and symptomatic unidirectional posterior shoulder instability. It is well documented that a curved liberator from the mid‐glenoid (anterior‐inferior) portal passed from anterior to posterior provides an effective trajectory for liberation and mobilization of the posterior and posterior‐inferior labral tear. However, biologic preparation of the posterior and inferior glenoid rim with a shaver can be challenging because the anterior mid‐glenoid portal and the posterior portal do not provide an adequate trajectory for instruments to be parallel to the posterior glenoid rim. The purpose of this technical note is to describe a simple efficient procedure for biologic preparation of the posterior and inferior glenoid rim in the setting of arthroscopic posterior labral repair. Technique Video video See video under supplementary data.

AbstractThe goal of national interoperability is to improve care quality and decrease administrative burden and costs. Patients, providers, and other stakeholders are increasingly concerned that indiscriminate sharing of data may have deleterious, permanent consequences, as well as fail to provide granular control over the sharing of individual health data. Data segmentation and consent standards to date have been limited in scope and implementation, which has hindered efforts to scale data sharing preferences. Shift, an independent expert stakeholder task force, has been convened to mature standards, terminologies, and consensus-driven implementation guidance, which are prerequisites for more robust policy drivers needed to support nationwide sensitive data segmentation and consent capabilities. This paper describes Shift's framework and processes as means to advance equitable interoperability.

Background Dementia with Lewy bodies (DLB) is a common degenerative dementia, but no studies investigate bereaved caregiver experiences. Objective To investigate the experiences of caregivers three months after the death of persons with DLB using a mixed-methods approach. Methods Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were followed prospectively every 6 months until the person with DLB died. Caregivers completed a study visit with questionnaires and a semi-structured interview ∼3 months later. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of post-death measures with pre-death patient and caregiver variables. Thematic analysis was used to analyze the interviews. Results Seventy-three caregivers completed visits (mean 3.5 months post-death). Most of the caregivers were women (82.2%) and spouses (76.7%) or adult children (17.8%). Over 40% had scores indicating risk for clinical depression. Post-death caregiver experiences (depression, quality of life, grief, resilience) correlated with pre-death caregiver experiences. Post-death experiences did not associate with patient characteristics, disease-related symptoms, or healthcare services used in the last 6 months of life. Trajectories for caregiver measures from pre- to post-death visits varied widely. Interview themes included grief and sadness, anger, guilt and regret, relief, appreciation/gratitude, and adjusting to a new normal. Conclusions The finding that pre-death caregiving experiences have the strongest association with post-death experiences emphasizes the critical importance of accessible and evidence-based caregiver support before and after the death of a person with DLB. Research is needed to develop interventions for current and bereaved caregivers of individuals with DLB. Trial registration information NCT04829656 (submitted 2021-03-22).

Abstract Background Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term—5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)—with the option to provide additional comments. Median score ≥4 and interquartile range ≤1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.

Abstract Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease‐modifying agents. Consequently, definitions of Alzheimer's disease and Parkinson's disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging‐Alzheimer's Association) and alpha‐synucleinopathy and dopaminergic degeneration (Neuronal α‐synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha‐synuclein (α‐synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. Highlights DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer's and Parkinson's definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson's under one pathobiology.