Citations

Abstract Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high seizure burden and mortality risk. Stiripentol, one of the first DS‐specific therapies, received FDA approval in 2018 but its real‐world use and impact post‐approval in the USA remain insufficiently characterized. The STIRUS study aimed to assess treatment patterns, clinical efficacy, and quality of life outcomes associated with stiripentol in a contemporary US cohort. Methods STIRUS was a retrospective, multicenter chart review of 98 DS patients who initiated stiripentol after FDA approval and were treated for at least 3 months. Data were collected from 10 USA epilepsy centers on seizure types and frequency, status epilepticus (SE), rescue medication use, emergency room visits, and quality of life, at baseline and during the first and final 3 months on stiripentol. Changes over time were assessed using generalized estimating equation models. Results Initiation of stiripentol was associated with a significant reduction in bilateral convulsive seizure frequency (OR = 2.16, p < 0.006) and a nearly 50% decrease in SE episodes (OR = 2.9, p < 0.003). Importantly, there was a marked decline in rescue medication use and seizure‐related hospital visits: the proportion of patients requiring no rescue medications increased from 23% to over 53%, and those needing frequent emergency interventions dropped from 39% at baseline to 14% during the final 3 months. Quality of life improved in more than half of patients and caregivers. Significance The STIRUS study supports the real‐world efficacy of stiripentol in reducing seizure burden and healthcare utilization in DS. Despite its demonstrated benefits and approval for use in infants, stiripentol remains underutilized and often introduced late in the treatment course. Early and broader adoption may help improve clinical outcomes and quality of life in this vulnerable population. Plain Language Summary The STIRUS study found that stiripentol, an anti‐seizure medication specifically approved for Dravet Syndrome, helped reduce seizures and hospital visits for children living with this severe form of epilepsy. Patients had fewer convulsive seizures, needed fewer rescue medicines, and reported better quality of life. Despite these benefits, stiripentol is still not widely used and often started too late in treatment, suggesting earlier use could further improve outcomes.

Objective To assess the impact of renal replacement therapy in people with lupus nephritis (LN)–associated end‐stage kidney disease (ESKD) and support the development of the 2024 American College of Rheumatology LN treatment guidelines. Methods We conducted a systematic literature review and meta‐analysis to address three Population, Intervention, Comparison, and Outcome (PICO) questions related to renal replacement therapy for ESKD due to LN, including comparisons of kidney transplant versus dialysis, hemodialysis versus peritoneal dialysis, and preemptive kidney transplant versus no preemptive kidney transplant. Outcomes of interest included mortality, cardiovascular (CV) events, infections, lupus flares, disease‐related damage, graft failure, and quality of life. We conducted a meta‐analysis and analyzed hazard ratios for time‐to‐event analyses and risk ratios for dichotomous outcomes, as well as absolute risk estimates. Results Sixteen comparative observational studies addressed at least one of the three PICO questions. Kidney transplant was found to reduce the risks of all‐cause mortality, CV mortality, infection‐related mortality, and CV events compared with dialysis (high certainty). Dialysis modality (peritoneal vs hemodialysis) was not associated with mortality (high certainty) or with other outcomes of infection, CV complications, and systemic lupus erythematosus flares (low certainty). Preemptive kidney transplant was associated with lower risks of graft failure and mortality (low certainty). Conclusion This systematic review identified improved outcomes with kidney transplant versus dialysis for people with LN‐associated ESKD and potential benefits of preemptive kidney transplant. This evidence supports the use of kidney transplant as a preferred renal replacement therapy for people with LN‐ESKD.

Abstract Background Distinguishing physiological cardiac adaptation from pathological remodeling in endurance athletes is challenging. While the athletic heart typically demonstrates balanced biventricular enlargement, extreme exercise may rarely trigger disproportionate right ventricular (RV) changes that challenge diagnostic classification. Case Summary A 47-year-old male ultra-endurance athlete presented with exertional symptoms three months after recovery from a pulmonary embolism (PE). Initial post-PE echocardiography was normal. After resuming extreme training, he developed severe RV dilation (basal diameter 5.7 cm on echocardiography; RV volume index 92 cc/m² on cardiac magnetic resonance imaging) disproportionate to the left ventricle, with preserved systolic function and no late gadolinium enhancement. Cardiopulmonary exercise testing revealed significant chronotropic incompetence with below-expected peak oxygen uptake for his elite training status. Symptoms and ventricular ectopy improved with detraining, but severe RV dilation persisted. Evaluation excluded arrhythmogenic cardiomyopathy and significant pulmonary vascular sequelae. Discussion This case illustrates disproportionate RV remodeling precipitated by the resumption of extreme exercise in a susceptible athlete post-PE. The temporal dissociation from the PE and absence of residual clot burden implicate exercise-related hemodynamic stress as the primary driver, challenging the boundary between physiological adaptation and maladaptation. These findings highlight a potential maladaptive response to extreme exercise, possibly potentiated by a prior vascular insult, and underscore the value of integrated functional assessment and monitored detraining in athletes with borderline findings.

Background: Emerging neuromodulation approaches, including epidural electrical stimulation (EES), offer hope for restoration of function following chronic spinal cord injury (SCI). However, integrating neuromodulation therapies into clinical procedures is challenging due to the unique needs of the SCI population. Objectives: The purpose of this study was to understand the experiences of participants during a first-in-human trial of perilesional EES aimed at restoring sensorimotor function. Methods: We report participants’ experiences by describing their clinical care, experiences during experimental neuromodulation sessions, and perspectives on the utility of a perilesional EES system. Three participants with chronic thoracic SCI participated in semistructured interviews after completing a 14-day inpatient experimental protocol, which included stimulation mapping, lower extremity motor control experiments, and treadmill stepping. Interview data were analyzed using an applied thematic analysis approach. Nine key themes addressed 4 major topic areas: clinical experiences, experiences during laboratory experiments, experiences as a research participant, and perceived value of perilesional EES. Results: All participants noted the potential for EES to enhance functional recovery, though their postoperative experiences related to clinical care, postoperative pain, and disruptions to routine care differed. Insights gained from qualitative analyses highlighted challenges and opportunities for improving postsurgical care and refining application of EES technology. Further, these results inform recommendations for neuromodulation trials in the SCI community to help mitigate postoperative complications and improve study participant experiences. Conclusion: Key recommendations include being proactive regarding potential postsurgical complications, educating clinical staff regarding common SCI comorbidities, and customizing experimental protocols to align with the priorities and clinical needs of each participant.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug‐resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. Methods The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A + DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID‐III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI‐IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3), Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF‐P), and Pediatric Evaluation of Disability Inventory (PEDI). Results Fifty‐eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age‐appropriate milestones. Mean BSID‐III Cognitive raw scores increased minimally, with age‐equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: –11.0, 95% confidence interval [CI]: −15.3 to −6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF‐P Global Executive Composite T‐scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS‐3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: –9.0, 95% CI: −11.9 to −6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. Significance Infants and young children with SCN1A + DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Abstract DDX3X dysfunction causes an X-linked multisystem disorder with high penetrance and variable expressivity. The phenotypic spectrum spans from learning disability without somatic involvement to profound intellectual disability with severe impairments in the central nervous system and other organs. A few multicenter studies and single case reports have previously highlighted some common phenotypic patterns but were unable to delineate correlations between underlying DDX3X variants and phenotypic findings.From the second largest patient cohort published to date, we analysed clinical, psychometric and diagnostic findings of 52 female and 7 male individuals, harbouring de novo and inherited DDX3X variants. These female patients revealed previously unknown quantitative correlations between variant type and localization and specific phenotypic findings (growth features, epilepsy, brain anomalies, dysmorphisms, motor-focused neurological findings). Moreover, by analysing the in silico folding and RNA binding capability of mutant DDX3X monomers, we were able to delineate novel correlations between DDX3X monomer misfolding grade and phenotypic severity.

Polycystic kidney disease (PKD) is a genetic disorder characterized by progressive kidney cyst formation and eventual kidney failure. Emerging evidence suggests that plant-based diets may confer therapeutic benefits in patients with PKD by modulating mTOR and AMPK signaling, reducing oxidative stress and inflammation, while improving metabolic and cardiovascular profiles. These diets, which are low in animal protein and rich in antioxidants, may help lower uric acid levels and support blood pressure control, thereby potentially reducing fibrosis. However, careful planning is required to avoid nutritional deficiencies. Well-designed clinical trials are warranted to validate their role in ADPKD management.