Citations

Importance Friedreich ataxia (FA), a fatal, autosomal recessive disorder caused by pathogenic variants in the frataxin ( FXN ) gene, is characterized by progressive neurologic and cardiac disease, with cardiac disease being the major cause of death. Preclinical studies have demonstrated that systemic administration of AAVrh.10hFXN, an rh.10 serotype cardiotropic adenoassociated virus (AAV) vector expressing the normal human FXN coding sequence, reverses the cardiomyopathy in FXN-deficient mice. Objective To assess the safety and preliminary efficacy of administration of AAVrh.10hFXN to adults with FA cardiomyopathy. Design, Setting, and Participants This nonrandomized clinical trial evaluates the pooled data of 2 independent, open-label, dose-escalation trials that used the same gene therapy vector and similar clinical protocols among patients with FA cardiomyopathy at academic medical centers. Data were collected from February 22, 2022, to October 4, 2025, for trial 1 and from February 14, 2023, to September 10, 2025, for trial 2 and analyzed together from November 5, 2025, to March 12, 2026. Intervention AAVrh.10hFXN, administered intravenously in 3 dose cohorts (1.8 × 10 11 , 5.6 × 10 11 , and 1.2 × 10 12 vector genomes per kilogram of body weight). Main Outcomes and Measures In addition to safety as the primary outcome, multiple parameters of exploratory end points were assessed, including cardiac biopsy levels of FXN protein, cardiac magnetic resonance imaging–derived left ventricular mass index (LVMI), and serum high-sensitivity (hs) troponin I. Results Seventeen patients with FA cardiomyopathy (mean [SD] age, 25 [6] years; 11 [65%] female) were followed up for a mean (SD) of 20 (8) months. There were 4 serious adverse events, 3 possibly related to prednisone immunosuppression and 1 possibly vector-related myocarditis 12 months after therapy, all of which resolved. Other adverse events were transient, nonserious, or not treatment related. In all 8 patients with cardiac biopsy 3 months after therapy, there were higher levels of cardiac FXN (dose cohort 1, 20%; cohort 2, 81%; cohort 3, 123%). After therapy, LVMI was lower by at least 10% in 9 patients and stabilized in 8 patients. Excluding the patient with myocarditis, posttherapy values of serum hs troponin I were lower by at least 10% in 15 patients and higher by at least 10% in 2 patients. Conclusions and Relevance Findings of this nonrandomized clinical trial suggest that intravenous administration of AAVrh.10hFXN was well tolerated and may be a potential treatment for FA cardiomyopathy, as evidenced by preliminary improvement in exploratory efficacy end points. Trial Registration ClinicalTrials.gov Identifiers: NCT05302271 and NCT05445323

Abstract Objective To evaluate otolaryngology (ENT) residency match trends before and after the USMLE Step 1 transition to pass/fail. Study Design Observational longitudinal analysis of annual, publicly available specialty‐level data (2010‐2025). Setting National Resident Matching Program (NRMP). Methods Data from 2010 to 2025 were used to calculate applicants per PGY‐1 position, fill rate, and nonmatch‐in‐specialty rate. ENT was compared with plastic surgery, orthopedic surgery, neurological surgery, and general surgery. We used ordinary least squares (OLS), segmented regression with a 2023 breakpoint, and difference‐in‐differences (DID) models. Results From 2010 to 2025, ENT programs increased from 105 to 139 and positions from 280 to 394. Applicants per position ranged from 1.06 to 1.60 (mean 1.38). OLS showed no significant long‐term trend in applicants per position (+0.002/year, P = .86), fill rate (+0.03 percentage points/year, P = .68), or nonmatch‐in‐specialty rate (+0.04 percentage points/year, P = .94). Segmented regression showed no significant post‐2023 changes in applicants per position (slope change +0.03/year, P = .78), and no significant changes in applicant counts ( P = .7). ENT had the largest 2022 to 2023 decline in this cohort, in both applicants (−14.1%) and applicants per position (−16.9%). However, in two‐way fixed‐effects DID models, there was no ENT‐specific post‐transition change in applicants per position ( P > .05 in primary and sensitivity analyses). Conclusion ENT remained highly competitive but trend‐stable from 2010 to 2025. Although 2023 showed a notable drop in applicants, we found no consistent evidence of a sustained ENT‐specific competitiveness shift after the Step 1 pass/fail transition. Level of Evidence 4.

A 70-year-old woman with a past medical history of breast cancer is undergoing surveillance. She also had a history of repeated blood transfusions for refractory anemia caused by treated marrow metastatic disease. Laboratory tests showed elevated AST (50 U/L) and ALT (115 U/L). 99m Tc MDP bone scintigraphy revealed intense diffuse splenic uptake. No splenic calcifications or infarcts were found on contrast-enhanced CT. MRI demonstrated signal dropout on in-phase sequences and marked T2 hypointensity of the spleen and liver, without focal splenic lesions, suggesting transfusion-related secondary hemosiderosis. Iron overload should be considered when diffuse splenic uptake is observed on bone scintigraphy.

PIK3CA-related overgrowth spectrum (PROS) encompasses rare disorders characterized by vascular malformations and predisposition to thrombotic complications. COVID-19 has been associated with diverse cutaneous manifestations through endothelial dysfunction and microvascular thrombosis. We present a 33-year-old female with PROS and extensive capillary malformations who developed multiple cutaneous ulcerations on her affected right leg exclusively during COVID-19 infection in 2020, with complete resolution following recovery. Preexisting endothelial abnormalities and thrombotic predisposition in PROS may create heightened vulnerability to COVID-19-induced vascular injury, explaining why cutaneous manifestations occurred exclusively in zones of capillary malformation. This susceptibility may be mediated by the Phosphoinositide 3-kinase/ Protein kinase B/ mechanistic target of Rapamycin (PI3K/AKT/mTOR) pathway, which regulates cell growth and vascular homeostasis, is constitutively activated in PROS, and is exploited by SARS-CoV-2 during infection. Clinicians managing patients with vascular malformations should be aware of this potential interaction.

Introduction Guillain-Barré syndrome (GBS) is an autoimmune polyradiculopathy linked to various triggers. Recently, several case reports described GBS development following intracranial hemorrhage (ICH), posing diagnostic and therapeutic challenges. Methods PubMed and EMBASE were searched from inception till February 2023 for case reports. Two reviewers independently screened the articles and extracted data using a standardized form. The extracted data were then analyzed narratively. Quality was assessed with the JBI Checklist for Case Reports. Results Twenty-three cases from 11 countries were identified (14 males, mean age of 60.1 years). Onset of GBS occurred after a median of 9 days (range 2–24) post-ICH, with intracerebral hemorrhage being the most common antecedent (39.1%), followed by subarachnoid (26.1%) and subdural hemorrhage (21.7%). Electrophysiology showed predominantly axonal variants, while CSF consistently demonstrated albuminocytologic dissociation with positive antiganglioside antibodies in five cases. The clinical course was severe, marked by rapid progression to nadir (median 2.5 days), profound functional impairment (average Hughes Functional Grading Scale: 4.57 ± 0.66), and a high rate of respiratory failure requiring mechanical ventilation (78.3%). Axonal variants were associated with higher rates of mechanical ventilation and poorer outcomes than demyelinating forms. Among the 21 patients who received immunomodulatory treatment, 3 (14.3%) showed complete recovery, 13 (61.9%) had partial recovery, 3 (14.3%) had a poor recovery, and 2(9.5%) died at last follow up. Conclusion GBS may complicate recovery after ICH and appears to present with an aggressive course, particularly in axonal variants. Clinicians should consider GBS when patients with ICH develop progressive, symmetrical weakness unexplained by the initial brain injury, as prompt initiation of immunotherapy may improve outcomes.

Gephyrin is a postsynaptic scaffold protein essential for inhibitory neurotransmission. Gephyrin‐immunoglobulin G (IgG) was reported, decades ago, in a single case of paraneoplastic stiff‐person‐like syndrome, but its broader clinical relevance remains unknown. While investigating unclassified synaptic IgGs mimicking amphiphysin‐IgG, we identified gephyrin‐IgG in 3 patients using human protein microarray. Gephyrin specificity was confirmed using confocal tissue‐based immunofluorescence assay, cell‐based assay, and Western blot. The 3 patients, all female, had: encephalitis (2) and myeloneuropathy and breast cancer (1). All had inflammatory cerebrospinal fluid and abnormal magnetic resonance imaging, and improved following immunotherapy. Gephyrin‐IgG is associated with a treatable autoimmune neurological disease, sometimes paraneoplastic. ANN NEUROL 2026

Abstract Introduction: There is growing focus on community-engaged research (CEnR) in the clinical and translational sciences, supportive policies, environments, and processes within academic medical centers. The purpose of this evaluation was to gather academic and community member perspectives on key actionable strategies for supporting CEnR in an academic medical center. Materials and Methods: We used a sequential mixed method design by first conducting qualitative in-depth interviews with academic leaders, investigators, and staff (total, n = 54) and focus group discussions with community members ( n = 33). Themes from these qualitative data informed the adaptation of an institutional survey that gathered perspectives from a broader group of academic and community members affiliated with the institution ( n = 85). Both qualitative and quantitative data were integrated to inform actionable strategies. Results: Survey findings revealed that the institution was perceived as committed to health equity and CEnR, but institutional respondents expressed more concerns than community members about instrumental support of the work. Interviews and focus groups highlighted the opportunity to better align research efforts with community needs through more robust CEnR infrastructure and through interface with the clinical practice to promote patient access. Academic and community members emphasized the need for authentic, sustained engagement beyond federal mandates, including financial investment, capacity-building, and fostering trust. Leaders acknowledged structural challenges, siloed efforts, and the necessity for stronger coordination to increase integration of community engagement into the institutional mission. Conclusion: Findings suggest that aligning academic leaders, researchers, staff perspectives, and community members is essential to support and promote CEnR at an institutional level.

Objective: To evaluate the institutional learning curve of robotic liver resection (RLR), its association with surgical complexity and outcomes in an international multicenter cohort. Summary of Background Data: RLR is increasingly adopted worldwide, but the dynamics of the learning process and its impact on surgical outcomes remain poorly defined. Methods: This international, multicenter, retrospective cohort study included consecutive patients who underwent RLR between 06/2013 and 12/2024 across 22 expert centers. Based on the first 150 cases at each center, three phases were used to define the learning curve: operative time for competency, major complications for proficiency, and textbook outcome for mastery. Risk-adjusted generalized additive models were used to assess the learning process. Benchmark performance was compared to international reference values. Results: Among 2,331 patients, the most common indications were hepatocellular carcinoma (36%), benign lesions (23%) and colorectal liver metastases (21%). Operative time decreased after achieving competency (case #62), from 240 to 220 minutes ( P <0.001). Major morbidity reached a plateau during the proficiency phase (cases #63–138; 9% vs. 11%, P =0.144), while progression to mastery (cases #139–150) was associated with a higher rate of textbook outcome (76% vs. 87%, P =0.021). In contrast, conversion (5.1% vs. 4.9% vs. 2%), bile leak (4.0% vs. 5.3% vs. 3.8%), and 90-day mortality (0.7% vs. 0.9% vs. 0.9%) remained low and stable across all learning phases. Importantly, benchmark criteria for operative time, hospital stay, and textbook outcome were met across all complexity groups, including during the early learning phase. Conclusions: Robotic liver surgery shows progressive outcome improvement with early achievement of benchmark-level results and stable performance across increasing complexity. These findings indicate that, in experienced centers, RLR can be safely implemented and integrated into clinical practice, supporting its key role in modern hepatobiliary surgery.

Objective: Endotracheal intubation can cause laryngeal injury, with clinical presentation ranging from transient hoarseness to persistent vocal cord immobility. This study examines the incidence, clinical features, and outcomes of post-intubation laryngeal injuries following procedures traditionally considered low risk for such complications. Methods: We conducted a retrospective review of adult patients who underwent tracheal intubation for surgical procedures between May 1, 2018, and December 31, 2024, and subsequently presented with postoperative laryngeal injury–related symptoms. Patients who underwent cardiothoracic, thyroid, parathyroid, or anterior cervical spine procedures were excluded. We reviewed patient demographics, airway and intubation characteristics, treatments, and clinical outcomes. Results: Among 267 824 patients undergoing 454 924 general anesthetics, 30 developed postoperative laryngeal injury (6.6/100 000; 95% CI 4.5–9.4) which did not resolve spontaneously and required laryngology evaluation. Of these 22 (67%) had well defined movement abnormalities : unilateral (n = 15) and bilateral vocal cord immobility (n = 1), unilateral hypomobility (n = 4), bilateral hypomobility (n = 1), combined unilateral vocal cord immobility with contralateral hypomobility (n = 1), and 11 (33%) had no movement abnormality . Twenty-one (64%) were intubated via video laryngoscopy. Follow-up was available for 21 patients (70%) with a median [IQR] duration of 12 [9-35] months; 15 (72%) showed partial improvement without complete resolution, while 6 showed no improvement. Conclusion: Laryngeal injury following general anesthesia with tracheal intubation is a uncommon complication. In our series, approximately two-thirds of patients had identifiable injuries, while one-third exhibited no structural abnormality. While 75% of patients demonstrated partial symptomatic improvement, however, complete resolution was not observed in any of the patients who received follow-up in our institution, underscoring the severity of this complication.

ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth, inflammation, fibrosis, and renal failure. Klotho is a renoprotective protein with antiproliferative, anti-inflammatory, and antioxidant properties, but its mechanistic role in ADPKD remains poorly defined. Methods Klotho expression was analyzed in human ADPKD kidneys, public bulk and single-cell RNA sequencing datasets, Pkd1 mutant renal epithelial cells, and Pkd1 mouse models. The therapeutic effects of recombinant Klotho were evaluated in late-onset Pkd1fl/fl:tamoxifen-Cre mice. Molecular mechanisms were investigated using cell viability assays, western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, ferroptosis assays, DNA methylation analysis, and chromatin immunoprecipitation assay. Results Klotho expression was markedly reduced in human ADPKD kidneys and Pkd1-deficient cells and mice, particularly in distal nephron segments. Recombinant Klotho treatment significantly reduced cyst burden, kidney enlargement, and blood urea nitrogen levels, while decreasing epithelial proliferation and increasing apoptosis in cyst-lining cells. Mechanistically, Klotho suppressed PKD-associated signaling pathways, including protein kinase B (AKT), signal transducer and activator of transcription 3 (STAT3), and retinoblastoma protein (Rb), reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammation via downregulation of Smyd2, and attenuated transforming growth factor-beta (TGF-β)-Smad-dependent renal fibrosis. Klotho also inhibited ferroptosis by upregulating GPX-4 and reducing lipid peroxidation. Epigenetic analyses revealed DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of the Klotho promoter and gene body in ADPKD kidneys, contributing to Klotho silencing. Inhibition of DNMT1 restored Klotho expression, and recombinant Klotho reduced DNMT1 levels, suggesting a negative feedback loop. Conclusions Klotho is epigenetically repressed in ADPKD and functions as a central regulator of cyst growth, inflammation, fibrosis, and ferroptosis. Restoration of Klotho signaling markedly attenuates disease progression in Pkd1 mutant mice, identifying the Klotho–DNMT1 axis as a promising therapeutic target for ADPKD.