Citations

Abstract Paruresis (shy bladder syndrome) is difficulty voiding in public or shared restrooms because of the actual or anticipated presence of others, affecting 2.8% to 6.6% of the general population. Although 59% of transgender persons avoid public restrooms, often for reasons distinct from paruresis, to our knowledge its assessment and treatment in this population remain undocumented. A 53-year-old transgender woman with Klinefelter syndrome (47,XXY) and paruresis since age 5 was referred for treatment. Over the first 14 visits (about 9 months), she received a cognitive-behavioral, schema-informed, and minority-stress-informed protocol integrating psychoeducation, imagery rescripting, cognitive restructuring, breath-holding, and graduated in vivo exposure with paradoxical intention, then supportive psychotherapy. On the Shy Bladder Scale (SBS), she achieved reliable and clinically significant change by Visit 8 (43 to 31, meeting a clinician-defined goal of ≤ 33; RCI = 3.60, p < .05) and her SBS decreased to 8 by Visit 24 in a supportive phase; the reliable-change statistic being defensible only over short intervals, later changes are described by clinical-range and goal status. At 10-year follow-up, the SBS was 18, still below the treatment goal, with minimal depressive and mild anxiety symptoms and improved well-being (PHQ-9 = 4; GAD-7 = 6; WHO-5 = 80%).

ABSTRACT Colony stimulating factor‐1 receptor–related disorder (CSF1R‐RD) is a rare, autosomal dominant neurodegenerative disease caused by loss‐of‐function variants in the CSF1R gene, leading to microglial dysfunction and progressive white matter degeneration. Therapeutic strategies targeting microglial pathways, including activation of triggering receptor expressed on myeloid cells 2 (TREM2), have been proposed to compensate for impaired CSF1R signaling. Iluzanebart (VGL101), a monoclonal antibody TREM2 agonist, has shown promise in preclinical models. We report a longitudinal clinical course, neuroimaging findings, genetic analysis, and postmortem neuropathological examination of a 52‐year‐old patient with genetically confirmed CSF1R‐RD (c.2507G>A, p.Ser836Asn). The patient received iluzanebart as part of a Phase 2 clinical trial. Clinical progression, MRI changes, and histopathological features at autopsy were systematically analyzed. Despite treatment, the patient experienced progressive cognitive decline, neuropsychiatric symptoms, motor impairment, and seizures, culminating in death. Serial neuroimaging demonstrated worsening white matter degeneration and brain atrophy without evidence of therapeutic response. Neuropathological examination revealed characteristic features of CSF1R‐RD, including severe myelin loss, axonal spheroids, infiltration of Iba1‐positive cells with macrophage‐like morphology, and cortical neuronal abnormalities. There was no histological evidence of treatment‐related benefit or harm. This case represents the first clinicopathological assessment of iluzanebart in CSF1R‐RD and demonstrates no observable clinical, radiological, or neuropathological improvement. These findings highlight the challenges of targeting microglial dysfunction in advanced disease and suggest that TREM2 activation alone may be insufficient to alter disease progression.

Abstract The trabecular meshwork (TM) and ciliary body (CB) regulate aqueous humor dynamics and intraocular pressure (IOP), and TM/Schlemm’s canal (SC) dysfunction underlies glaucoma. Here, we present a spatially resolved multi-omics atlas of human TM and CB, integrating snRNA-seq, scRNA-seq, and snATAC-seq from over one million cells and nuclei across 112 donors with Xenium spatial transcriptomics. We identified 9 major cell classes and 21 cell types, revealing heterogeneity, including undercharacterized fibroblast and epithelial subpopulations. Spatial mapping supported TM fibroblast zonation and CB epithelial organization. Regulatory analyses identified cell type–specific programs, including OTX/PAX networks in CB epithelium and SMAD3/TGF-β signaling in fibroblasts. Integration with glaucoma loci showed enrichment of non-coding variants in regulatory elements associated with POAG and PACG. Age- and ancestry-associated remodeling revealed divergent fibroblast aging with increased PIEZO1 , suggesting impaired outflow and elevated IOP. Together, this high-resolution atlas links cellular, regulatory, and genetic variation to anterior segment function and glaucoma susceptibility.

Summary Long-read nanopore sequencing enables simultaneous detection of germline variation and native DNA base modifications on individual DNA molecules, providing a unique opportunity to investigate allele-specific epigenetic regulation. Here, we performed whole-genome nanopore sequencing on normal and tumor prostate tissues to characterize differential methylation, methylation entropy, and allele-specific methylation (ASM) associated with noncoding genetic variants. Genome-wide analysis identified extensive cancer-associated differentially methylated regions (DMRs), with hypermethylated DMRs significantly enriched near transcription start sites and transcriptional regulatory regions. Integration with transcriptomic datasets revealed strong inverse relationships between promoter methylation and gene expression, while 5-hydroxymethylcytosine (5hmC) levels positively correlated with transcriptional activity across gene bodies. Using fragment-level methylation patterns enabled by long-read sequencing, we further quantified methylation entropy incorporating both 5mCG and 5hmCG states. Cancer-hypermethylated DMRs exhibited markedly reduced entropy, consistent with clonal fixation of methylation states during tumor progression. Entropy profiling across chromatin annotations demonstrated maximal epigenetic heterogeneity at partially modified enhancer-associated regions. To investigate cis-regulatory genetic effects, we developed a simple ASM framework (nanoASM) that can partition sequencing reads by allelic state and identifies allele-specific DMRs directly from long-read data. Compared with conventional population-level mQTL analysis, ASM demonstrated substantially improved statistical efficiency by leveraging within-individual contrasts and reducing sample-level heterogeneity. Although germline single nucleotide polymorphisms (SNPs) were largely shared between normal and tumor tissues, ASM patterns differed substantially, with tumor-associated ASM regions displaying significantly larger genomic span and stronger allelic methylation differences. Comparative analysis with TCGA prostate mQTL and GTEx prostate eQTL datasets demonstrated substantial concordance between ASM directionality and downstream transcriptional effects, particularly for variants located within DMRs and near transcription start sites. At the IRX4 prostate cancer risk locus, ASM identified an androgen-responsive regulatory domain overlapping AR ChIP-seq and H3K27ac peaks, nominating rs6885084 as a candidate functional variant. At the PSCA locus, ASM anchored by rs4736369 was associated with allele-specific methylation, chromatin activation, transcript abundance, and isoform usage. Together, these findings establish nanopore-based ASM analysis as a powerful approach for resolving functional noncoding variants and their regulatory domains they control in prostate cancer.

Background Long-acting injectable buprenorphine (LAI-BUP) is safe and effective, however is underutilized. Little is known regarding how buprenorphine prescribers view LAI-BUP, and which medication attributes they prioritize when selecting opioid use disorder (OUD) treatment. Methods Secondary analysis of a national, cross-sectional survey of U.S. physicians prescribing buprenorphine for OUD. Respondents reported OUD caseload, LAI-BUP use, and importance of medication attributes (eg, efficacy, safety, ease of prescribing, administrative requirements). Providers were categorized as no LAI-BUP use or, among LAI-BUP prescribers, Low vs High use by a median split. Group comparisons used chi-square (or Fisher’s exact) tests for categorical variables and Jonckheere–Terpstra tests for ordinal responses. Results Among 125 respondents, 39 (31.2%) reported no LAI-BUP use. The remaining 86 (68.8%) were split evenly into Low and High use groups (n’s = 43). LAI-BUP use did not differ meaningfully by specialty, region, or practice setting. Greater LAI-BUP use was reported by providers with larger OUD panels. Ratings of medication attributes were uniformly high. Conclusions LAI-BUP remains underused, with uptake highest among clinicians managing larger OUD caseloads. Measured attitudes toward medication attributes did not explain these differences. Future work should assess clinic workflow, staffing, reimbursement, and REMS burden, testing targeted implementation strategies using mixed-methods trials.

Abstract Purpose: VV1 is designed to induce selective oncolysis of tumor cells and amplify cellular antitumor immune responses. This open-label, phase I, multicenter clinical trial assessed the safety and tolerability of VV1 monotherapy administered intratumorally or intravenously or administered intravenously in combination with avelumab. Patients and Methods: Patients with advanced solid tumors received intratumoral (n = 27) or intravenous VV1 monotherapy (n = 33) or intravenous VV1 plus avelumab (n = 16). Infusion durations (15–180 minutes) and viral dose (1.7 × 1010 or 1 × 1011 TCID50) were also evaluated. Study objectives included VV1 safety and tolerability, pharmacokinetics, pharmacodynamics, preliminary efficacy, and immune responses. Results: Intratumoral and intravenous VV1 were well tolerated, and injection reactions were infrequent. The most common adverse events of any grade related to VV1 were cytokine release syndrome (58%), fatigue (33%), and decreased lymphocyte count (32%). Virus infection of tumors was confirmed by NIS imaging and increases in serum levels of virally encoded interferon-β (IFNβ). Histologic tumor analysis at 28 days after intratumoral VV1 administration indicated increases in tumor-infiltrating immune cells. Two durable partial responses were recorded: a patient with pheochromocytoma after one intravenous dose of VV1 and a patient with thymic cancer in the combination arm. Stable disease was observed in 17 of 49 patients (34.7%) who received intravenous VV1. Conclusions: This first-in-human study demonstrates that intratumoral or intravenous VV1 administration had an acceptable safety profile as monotherapy and intravenously in combination with avelumab. There is preliminary antitumor activity. Intratumoral VV1 plus cemiplimab is now showing promise in the neoadjuvant setting. Significance: VV1 is a tumor-selective oncolytic vesicular stomatitis virus engineered to express IFNβ and the thyroidal NIS reporter gene. In this phase I study, we have demonstrated that a single administration of VV1, as a monotherapy or with an immune checkpoint inhibitor is safe, infects tumor lesions resulting in intratumoral infiltration of immune cells, and exhibits early signs of antitumor activity in patients with advanced unresectable and metastatic solid tumors.

Hill‐Sachs lesions are defects in the posterior humeral head from anterior glenoid impaction during dislocation. Left untreated, they can contribute to failure after arthroscopic Bankart repair. Arthroscopic remplissage, involving capsulotenodesis of the posterior capsule and infraspinatus tendon, is the most frequently performed approach to address this lesion. In this technical note, we describe a bone graft remplissage that augments the remplissage with the arthroscopic insertion of a flexible bone graft between the capsule and the sutures to fill the Hill‐Sachs defect. Once secured, the graft is compressed into the defect to create a biological scaffold. This technique combines the simplicity of the knotless remplissage technique with the addition of structural bone graft to Hill‐Sachs lesions.