Citations

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety.

Background/Objectives: Antigen presenting cells (APCs) and immune cells have unique properties to drive or suppress immune responses. They are therefore key targets for the expression of vaccine antigens or transgene proteins. To better determine the utility of different molecular therapies to modify these cells, mRNA and DNA-based molecular therapy vectors were compared for their ability to genetically modify immune cells after intradermal injections in mice. DNA-based vectors included naked plasmid DNA, plasmid packaged in lipid nanoparticles (LNPs), and replication-defective adenovirus (Ad) vectors. mRNA delivery was mediated by packaging into LNPs like those used in COVID-19 vaccines. Methods: Each vector was used to deliver Cre recombinase into Cre reporter mice whose cells were activated to express green fluorescent protein (GFP) and firefly luciferase after Cre recombination. The mice were injected intradermally (ID) near the base of their tail at a site that drains into the inguinal lymph node. Luciferase activity was imaged in the living mice 1 or 4 days after vector injection. The animals were then euthanized, and luciferase activity was imaged in the draining inguinal lymph node. Cells were prepared from the intradermal injection site and from the draining lymph node to determine which immune cells were genetically modified by phenotyping CD45, CD3, and CD11b GFP-positive cells by flow cytometry. Given that the skin uniquely contains Langerhans dendritic cells, these CD207+ cells were also phenotyped in skin samples and in the draining lymph node. Results: In both the skin and in the draining lymph node, the rank order of luciferase and GFP activation by the vectors were: (1) Ad; (2) mRNA-LNP; (3) DNA-LNP; and (4) naked DNA. Only mRNA-LNP and Ad vectors mediated obvious luciferase activity in the living animals and in the draining lymph nodes by imaging. Notably, both vectors appeared to leak from the ID injection site and not only modify the draining lymph node but also strongly modify the livers of the mice. Naked DNA and DNA-LNP mediated detectable GFP activation in the skin and draining lymph node in some mice, but this activity was low and did not reach statistical significance when compared to PBS-treated animals. mRNA-LNPs and Ad both mediated significant Cre delivery in CD45+, CD3+, CD11b+, and CD207+ immune cells in the skin and in the lymph node, with adenovirus mediating consistently higher levels of expression in all of the tested cells. Conclusions: These data indicate that mRNA-LNP and Ad vectors mediate stronger modification of skin and lymph node immune cells after intradermal injections. Naked DNA and DNA-LNPs were markedly less potent at this activity than the other vectors. These data are consistent with the higher vaccine potency of mRNA-LNP and Ad vectors and suggest that approaches that increase targeting of immune cell subsets may have utility to increase efficacy while also reducing off-target modification of tissues like the liver.

Abstract Clinical interventions and neuroimaging in the subcortex require anatomical definitions that exceed the resolution and anatomical detail of currently available deformable brain atlases. Here, we introduce a high-resolution human brain atlas comprising 95 manually segmented grey and white matter structures as well as 82 white matter tracts compiled from a multitude of resources including ex-vivo MRI, histology, fibre dissections, and neuroanatomy textbooks. The atlas is defined at an isotropic resolution of 100 μm and can be precisely deformed to individual subject brain anatomy. By providing precise definitions of both grey and white matter structures within and around the basal ganglia, thalamus, subthalamus, midbrain and cerebellum, the atlas provides a foundational resource for stereotactic surgery and subcortical brain imaging research, as well as for development of next-generation neuromodulation strategies.

Abstract Background Hidradenitis suppurativa (HS) is a chronic, relapsing, debilitating skin disease characterized by deep‐seated nodules, abscesses and tunnels. Objectives To investigate the efficacy of bimekizumab using International Hidradenitis Suppurativa Severity Score System (IHS4) outcomes in patients with moderate to severe HS in the pooled BE HEARD I and II Phase 3 studies. Methods Patients received (initial/maintenance) bimekizumab 320 mg every 2 weeks (Q2W)/Q2W, bimekizumab Q2W/every 4 weeks (Q4W), bimekizumab Q4W/Q4W or placebo/bimekizumab Q2W. Change from baseline (CfB) in IHS4, IHS4 severity stages and the dichotomous IHS4‐55/75/90/100 (an improvement of at least 55%/75%/90%/100% in IHS4 from baseline) are reported to Week 48. Lesion count data by lesion type are reported to Week48. Results In total, 1014 patients were enrolled across BE HEARD I and II. At baseline, mean (standard deviation [SD]) IHS4 for bimekizumab‐treated patients ranged from 33.4 (25.4) for bimekizumab Q2W/Q2W to 36.0 (34.0) for bimekizumab Q2W/Q4W versus 30.6 (21.8) for placebo. At Week16, patients receiving bimekizumab demonstrated greater reductions in mean (SD) IHS4 from baseline, ranging from −17.2 (24.8) for bimekizumab Q4W/Q4W to −17.8 (21.1) for bimekizumab Q2W/Q2W versus −6.1 (16.3) for placebo. Proportions of patients with severe HS at baseline ranged from 83.7% (bimekizumab Q2W/Q2W) to 88.4% (bimekizumab Q2W/Q4W) and decreased by ~50% to Week48 across all treatment arms, ranging from 28.6% (placebo/bimekizumab Q2W) to 34.3% (bimekizumab Q2W/Q2W). Proportions of patients with IHS4 = 0 at Week48 ranged from 23.7% (bimekizumab Q2W/Q4W) to 26.7% (placebo/bimekizumab Q2W). At Week16, IHS4‐55, IHS4‐75, IHS4‐90 and IHS4‐100 thresholds were achieved by greater proportions of patients treated with bimekizumab versus placebo, while comparable improvements were seen across treatment arms from Week16 to Week48. At Week16, lesion counts were lower for patients treated with bimekizumab versus placebo, decreasing to comparable numbers across all groups at Week48. Conclusions Bimekizumab‐treated patients showed improvements across IHS4 outcome measures.

Radiated chronic scalp wounds with exposed bone present a significant reconstructive challenge, particularly when prior attempts have failed or when further surgery is contraindicated due to patient comorbidities or preference. We retrospectively reviewed 10 patients (2014–2024) with radiated chronic scalp wounds with exposed bone who have either failed prior reconstruction, could not medically tolerate anesthesia, or declined surgery. Patients performed daily cleansing with soap and water followed by application of Aquaphor and Silvadene. Treatment duration ranged from 1 to 73 months (mean: 29.4 mo). The area of exposed bone decreased in 6 patients (60%), remained stable in 1 (10%), and increased in 3 (30%). Three of 7 patients with wound improvement (30%) achieved complete healing. Two of 3 patients with wound progression deceased of unrelated causes. To our knowledge, no major complications occurred. These findings support wound care as a safe, and often effective, treatment when larger reconstruction is not feasible.

Abstract Recent advances in long-read transcriptome sequencing enable high-throughput profiling of full-length RNA isoforms in bulk, single-cell, and single-nucleus samples. However, long-read datasets typically contain a mixture of complete and partial transcripts, leading to pervasive ambiguity in read-to-isoform assignment and complicating accurate isoform identification and quantification, particularly in the absence of reliable reference annotations. These challenges are further amplified in single-cell and single-nucleus samples, where coverage is sparse and transcriptional heterogeneity is high. Here, we present the Long Read Alignment Assembler (LRAA), a unified and versatile computational framework for isoform identification and quantification from long-read RNA sequencing data across bulk, single-cell, and single-nucleus transcriptomic samples. LRAA combines splice-graph based structural modeling with expectation maximization based optimization to probabilistically resolve ambiguous read assignments and improve isoform abundance estimation. The framework supports quantification-only, reference-guided, and fully reference-free (de novo) modes of analysis within a single methodological paradigm. We benchmarked LRAA using both simulated and genuine long-read datasets spanning sequencing standards and whole transcriptomes. Central to this evaluation is a novel benchmarking strategy based on Multiplexed Overexpression of Regulatory Factors (MORFs), which provides biologically expressed, barcoded isoforms with unambiguous read-level ground truth. Across all benchmarks, including MORFs, synthetic spike-ins, and whole-transcriptome datasets, LRAA consistently outperformed state-of-the-art methods in isoform identification accuracy, sensitivity, and expression quantification. Finally, we demonstrate the biological utility of LRAA by resolving cell-type-specific isoform usage across peripheral blood immune cell populations and by detecting a pathogenic cryptic isoform of STMN2 with associated transcriptional changes in single-nucleus RNA-seq data from frontal cortex tissue of an individual with frontotemporal dementia (FTD). Together, these results establish LRAA as a robust and general solution for resolving transcript diversity in complex biological systems, from development to disease.

Abstract Introduction: Recruitment for rare disease studies is challenging due to small eligible populations. Traditional clinical research management systems often lack tools to track recruitment contacts prior to enrollment. The NET-PRO study, focused on neuroendocrine tumors (NETs), implemented a participation monitoring system to enhance recruitment efficiency and representativeness. Methods: NET-PRO is a multicenter cohort study of 2538 adults diagnosed with gastroenteropancreatic (GEP) or lung NETs between January 2018 and September 2024. Recruitment occurred from January 2022 to February 2025 across 14 U.S. medical centers. Sites used flexible recruitment methods (email, mail, phone, in-clinic) and tracked contacts using REDCap-based tools. Participant characteristics were analyzed by enrollment mode (online or mail) and recruitment difficulty (number of contacts required prior to enrollment) using standardized mean differences, chi-square tests, and ANOVA. Results: Of 9279 contacted patients, 2675 consented (28.8%) and 2538 enrolled (27.4%). Most enrolled online (83.2%), while 16.8% enrolled by mail. Mail respondents were older, had lower education and income, and more comorbidities. Among those enrolled, recruitment difficulty was associated with older age, lower education and income, but not comorbidity. Over half of the most difficult-to-recruit participants enrolled online. Contact methods varied by attempt, with email dominating early contacts and phone/mail used more in later attempts. Conclusions: A participation monitoring tool supported flexible, multimodal recruitment and improved sample representativeness in a rare cancer study. Tracking recruitment contacts enabled adaptive strategies and may reduce bias in observational research by enabling better outreach to harder-to-reach populations.

Abstract This publication represents the first part of an update to the clinical practice guideline on the diagnosis and management of group A streptococcal (GAS) pharyngitis, developed by the Infectious Diseases Society of America (IDSA). Diagnosis of GAS pharyngitis by clinician judgment alone is unreliable, and universal testing incurs cost and inconvenience for individuals at low risk of having GAS infection. Clinical scoring systems have been used to quantify the probability of a positive GAS throat culture based on standardized criteria such as the presence of fever, tonsillar enlargement or exudate, tender and enlarged anterior cervical lymph nodes, and the absence of cough. The goal of this manuscript is to review the evidence and provide a recommendation as to whether a scoring system should be used to decide which patients should have a GAS diagnostic test (ie, rapid antigen test [RADT], molecular method, and/or throat culture) performed. We performed a systematic review of randomized and nonrandomized studies that compared the use of a clinical scoring system to clinician judgment alone in predicting the result of a throat culture. Evidence from studies in children and adults suggests the diagnostic accuracy is comparable or slightly higher using a scoring system compared to clinician judgment alone. Although the studies are limited due to small size, lack of uniformity in outcome measures, and incomplete data, the consensus of the panel is that the balance of benefits and harms favors incorporation of a clinical scoring system as part of the evaluation of patients with sore throat and suspected GAS pharyngitis.

Purpose: The ASPiration to Improve Renal Calculi Removal Effectiveness study showed steerable ureteroscopic renal evacuation (SURE) with CVAC that significantly reduced residual stone volume at 30 days vs standard ureteroscopy (URS). This report presents 2-year health care consumption and stone events (SE) and their link to residual stone volume and other variables ( n = 101 at primary end point; n = 93 at 2 years). Materials and Methods: Logistic regression identified predictors of health care consumption events (HCEs), that is, emergency department visits, hospitalization, surgical retreatment, and SE across the study population. Incidence was compared between the treatment groups with Kaplan–Meier survival analysis. Results: At 2 years, residual stone volume was significantly associated with both HCEs and SE. For every 100 mm 3 increase in residual stone volume, the HCE risk increased by 50% to 54%, and the SE risk increased by 70%. Stone-free rate, the number of residual fragments (RFs), and RF total stone burden (based on diameter) were not predictors. Significantly fewer HCEs occurred in the SURE group (3 vs 20 events, p = 0.0004). Survival analysis confirmed this (4.3% vs 20%, log-rank p = 0.02), with a 73% risk reduction (hazard ratio 0.27, 95% Cl 0.09–0.80, p = 0.02). Fewer SE occurred in the SURE group, although not statistically significant. These subjects also had longer event-free survival. Conclusion: High-quality volumetric analysis supports evaluation of stone removal therapies, as residual stone volume predicts HCEs and SE. SURE significantly reduces the downstream incidence and risk of HCEs compared with standard URS.