Citations

Luxturna ® (voretigene neparvovec-rzyl) for RPE65 -associated retinal dystrophy was the first FDA-approved in vivo gene therapy and, 9 years later, remains the only approved retinal gene therapy. A search of clinicaltrials.gov identified 80 interventional phase 1–3 U.S. studies using AAV vectors, 45 using subretinal injection (SRI), and 33 using intravitreal injection (IVT). SRI efficiently transduces photoreceptors and RPE but transduces only the detached retinal area and carries procedure-related risks. IVT provides broader exposure and avoids retinal detachment but has shown limited efficacy for retinal targets and may produce dose-dependent inflammation. Overall, 11.6% of eyes in peer-reviewed publications receiving gene therapy via SRI experienced serious adverse events (SAEs); and in some studies, 100% experienced treatment-related adverse events (TRAEs). The gap between an active clinical pipeline and regulatory success raises the question: how does route of administration interact with therapeutic biology and clinical trial design? X-linked retinitis pigmentosa (XLRP) due to RPGR variants illustrates this challenge. Nine of 10 trials treating RPGR -related XLRP used SRI, with microperimetry and low light visual acuity as efficacy endpoints; 2 completed phase 2/3 studies failed to meet their primary endpoints. The XOLARIS XLRP natural history study suggests that other measures (e.g., visual field loss, central ellipsoid zone width) may better capture progression. Thus, retinal gene therapy clinical trial design must match the route of administration to the cellular target, therapeutic mechanism, and disease distribution. Emerging vectors and delivery strategies that expand retinal coverage while reducing procedural injury are critical to improve the likelihood of successful retinal gene therapy trials.

Obstructive sleep apnea (OSA) is a common, heterogeneous disorder managed through a multidisciplinary pathway that connects recognition, physiologic testing, treatment selection, specialty referral, insurance coverage, and longitudinal reassessment. This narrative review provides a clinically oriented, system-level overview of the adult OSA care ecosystem in the United States for an international clinical audience, with particular emphasis on the evolving role of otolaryngology. We describe the organization and complementary functions of sleep physicians, otolaryngologists, dentists, and allied health professionals. We also outline the roles of polysomnography and home sleep apnea testing, along with major therapeutic pathways including positive airway pressure, oral appliance therapy, weight management, upper-airway surgery, and neurostimulation. Otolaryngology provides an important interface between physiologic diagnosis and airway-specific treatment by integrating anatomic evaluation, sleep-state airway phenotyping, intervention selection, and post-treatment reassessment. Recent advances in neurostimulation, pharmacologic weight management, wearable and home-based monitoring, airflow analysis, and artificial intelligence are expanding opportunities for accessible and phenotype-informed care. Important challenges include underdiagnosis, treatment attrition, fragmented transitions, variable coverage, and reliance on the apnea–hypopnea index. Although health-care structures differ internationally, multidisciplinary coordination, individualized treatment selection, and longitudinal reassessment provide broadly applicable principles for developing patient-centered OSA programs.

Abstract The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8+ T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the subdominant antitumor response, particularly with regard to the naturally low affinity of tumor antigens to their cognate T-cell receptors. To investigate this experimentally, we first studied the interaction between the two responses in B16 and MC38 tumor models, both expressing ovalbumin (OVA). Contrary to the accepted paradigm, the inflammatory vesicular stomatitis virus (VSV) failed to expand OVA-specific T cells in vivo unless armed with tumor-associated antigen (TAA). In fact, treatment with the control VSV led to the ablation of antitumor T cells and a shift toward dysfunction as determined by the upregulation of markers, including LAG3 and CD39, correlating with lower rates of survival. Combination with anti–PD-1 immune checkpoint blockade therapy significantly improved survival only when VSV expressed TAA. VSV-expressing altered peptide ligand variants of tumor antigens, which evade mechanisms of central tolerance, expanded near self-antigen–specific T cells with the ability to cross-react with tolerized tumor antigens, thus providing an antitumor effector population capable of proliferating in the presence of a potent antiviral response. Taken together, these findings offer a rational approach to OV design which preserves acute antitumor therapy provided by antiviral innate and T-cell responses while promoting the induction of tumor-specific T cells. Significance: Oncolytic viruses can induce an antiviral T-cell response that occludes an antitumor response, challenging the paradigm in the field and elucidating strategies to optimize the efficacy of oncolytic viroimmunotherapy.

ABSTRACT Background Pulsed field ablation (PFA) is an emerging non‐thermal ablation modality with proven safety in atrial arrhythmia ablation. However, data on its performance for ventricular arrhythmias (VA) remain limited. Objective To evaluate the feasibility, safety, and efficacy of PFA for complex VA in a multicenter real‐world US registry. Methods This retrospective study included consecutive patients undergoing PFA for ventricular tachycardia (VT) or premature ventricular contractions (PVCs) at three Mayo Clinic centers (April 2024 to July 2025). The primary feasibility outcome was the successful delivery of PFA lesions to the intended target substrate. Primary efficacy outcomes included acute procedural success; sustained VT recurrence requiring implantable cardioverter‐defibrillator (ICD) shocks or multiple antitachycardia pacing therapies; and ≥ 80% reduction in PVC burden. Safety outcomes included procedural complications, valvular function, thromboembolic events, renal function, and conduction disturbances. Results Twenty‐six patients were included (13 PVC, 13 VT). Acute success was achieved in all VT ablations (69.2% complete; 30.8% partial) and in 92.3% of PVC ablations. Complications occurred in 11.5% of patients (transient LBBB [ n = 1] and vascular complications [ n = 2]). No thromboembolic events, intracardiac thrombus, or acute kidney injury were observed. Lesions near the mitral valve apparatus did not worsen mitral regurgitation, including in patients with pre‐existing valve disease. After a median follow‐up of 365 days, one patient experienced VT recurrence requiring ICD shocks. Estimated recurrence‐free survival after VT ablation was 61.5% at 12 months; 58.3% of PVC patients achieved ≥ 80% burden reduction. Conclusion PFA for VA appears feasible and acutely effective, with a low rate of procedure‐related complications. While acute success was high, long‐term outcomes were acceptable for VT ablation and relatively modest for PVC ablation, highlighting the need for continued refinement of technology and energy‐delivery strategies. Larger prospective studies are warranted.

Abstract T-cell immune tolerance is established in part through the activity of the autoimmune regulator (AIRE) transcription factor in medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue–specific self-antigens for presentation to naïve T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of “selfness” at the RNA and protein levels which, when presented on major histocompatibility complexes (MHC), shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by resetting the immunologic selfness of cancer cells, this AIRE-mediated immunotherapy (i) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; (ii) conferred upon nonimmunogenic tumors de novo sensitivity to immune checkpoint blockade; (iii) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and (iv) lead to potent T cell–mediated rejection of aggressive, immunologically cold, nonimmunogenic tumors. Patient RNA sequencing data showed that the expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting that our studies have therapeutic translational value.

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

Summary Background Body composition is recognized as a major determinant of health outcomes, but its multidimensional nature makes clinical adoption challenging. We sought to develop and validate a body composition index (BCI) for all-cause mortality risk assessment, integrating variables of six body composition tissues. Methods We analyzed 28509 consecutive patients undergoing myocardial perfusion imaging with routine low-dose chest CT attenuation correction (CTAC) scans acquired during myocardial perfusion imaging (MPI) at 12 centers across four countries. An artificial intelligence-based BCI was developed in a cohort of 15037 patients’ CTACs by integrating the CT-derived metrics of bone, skeletal muscle, and four adipose tissue compartments, coronary artery calcium score, and basic demographic variables (age, sex, BMI). The performance of BCI for mortality prediction was validated in an internal cohort of 6444 patients and an external cohort of 7028 patients by prognosis, calibration, net benefit, and explainability. Model-based simulation of tissue metrics modification was performed to evaluate estimated mortality risk reduction. Findings During a median of 3.5 (IQR [1.9, 5.1]) years, 4697 (16%) patients died. In the external testing cohort, the BCI demonstrated excellent discrimination for mortality (area under receiver operating characteristic curve 0.78 (95% CI [0.76, 0.79]) and Harrell’s concordance index 0.75 [0.73, 0.76]), calibration, and net benefit overall and across pre-specified subgroups stratified by patient characteristics and imaging protocols. Visceral adipose tissue attenuation was the most influential body composition measure, followed by skeletal muscle volume. Simulated improvement in body composition was associated with significant mortality risk reduction. Interpretation An index combining six body composition measures obtained opportunistically from routine chest CT provides robust mortality risk stratification. By converting complex body composition information into a single interpretable score, the BCI can facilitate clinical implementation of opportunistic CT biomarkers and guide individualized preventive strategies. Funding National Institute of Health Research in context Evidence before this study We searched PubMed and Google Scholar on July 7, 2026 for English language studies using the terms (“mortality prediction” OR “death prediction”) AND (“integrated body composition analysis” OR “body composition metrics integration”) AND (“predictive model” OR “model development”), and identified 41 publications describing predictive models incorporating body composition metrics. Recent advances in artificial intelligence (AI) have enabled increasingly granular quantification of body composition from CT, with multiple tissues and tissue-specific metrics showing independent prognostic value for all-cause mortality (ACM) prediction. However, reported associations of body composition metrics with mortality risk were highly inconsistent or even contradictory across studies. This heterogeneity likely reflected the differences in study design or the inherent complexity of body composition analysis, such as the interaction among variables derived from multiple tissues. Thus, it is difficult to interpret body composition results reliably in clinical practice. We hypothesized that integrating multiple body composition metrics could achieve comprehensive and reliable prediction of mortality across patient populations. Added value of this study In this large international, multicenter longitudinal cohort study of 28509 consecutive patients with suspected or known coronary artery disease (CAD) undergoing myocardial perfusion imaging across 12 sites in four countries, we developed and externally validated an artificial intelligence-based body composition index (BCI) for all-cause mortality prediction. The BCI integrated chest CT-derived metrics of six body composition tissue compartments – bone, skeletal muscle (SM), subcutaneous adipose tissue (SAT), intramuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and epicardial adipose tissue (EAT), together with demographics (age, sex, BMI) and CT-derived coronary artery calcium (CAC) score, all derived automatically from routine low-dose attenuation correction CT scans without additional imaging or laboratory tests. In an external validation cohort of 7028 patients, the BCI achieved robust discrimination for mortality prediction, substantially outperforming a baseline model using demographics and calcium score alone, and exceeded the discriminative performance of prior body composition models. Performance was consistent across subgroups defined by sex, age, body mass index, cardiometabolic risk factors, imaging modality, and acquisition protocol, supporting generalizability across clinical settings. The BCI demonstrated excellent calibration and net clinical benefit. Explainability analysis identified visceral adipose tissue attenuation and skeletal muscle volume as the dominant contributors to mortality risk, offering tissue-specific therapeutic targets that complement generic weight-based metrics. Model-based simulations suggested that improvements in these specific compartments could reduce estimated mortality risk more effectively than equivalent changes in BMI alone, pointing toward precision therapeutic targets beyond weight reduction. Our study improved over previous literatures on body composition-based predictive models in one or more of the following ways: (1) we considered six types of body composition tissues while existing studies considered only three or less tissues, thus significantly higher granularity and improved ability to capture refined tissue interactions; (2) our model was rigorously validated in external sites, showing cross-site generalizability while most previous work lacked external validation; (3) our model achieved significant prediction performance improvement over previous body composition predictive models, offering better clinical outcomes prediction and facilitating the suitability for widespread clinical adoption; (4) our study was conducted with a large multi-center cohort across multiple countries, achieving statistical power and demonstrating reliability towards patients characteristics and imaging acquisition protocols while previous studies involved small single-center cohorts; (5) our model required only CT scans and basic demographics which were widely available in clinical routine while the existing models required dedicated laboratory tests or specialized imaging modalities, enhancing the applicability in routine clinical practice. Implications of all the available evidence BCI offers an explainable and clinically deployable tool for improved prediction of mortality risk from existing chest CT scans. Its use could inform updates to existing risk models, guide precision preventive strategies, and support development of therapeutics targeting specific body composition phenotypes.

Abstract Background Vagally mediated syncope and functional bradyarrhythmias can cause recurrent symptoms, injury and a need for permanent pacing, yet standard therapies do not address the underlying autonomic reflex. Cardioneuroablation (CNA) targets this mechanism, but adoption has been limited by uncertainty about patient selection, procedural endpoints and durable outcomes. Methods We studied 95 consecutive patients with vagally mediated syncope (n=78) or functional bradyarrhythmia (n=17) who underwent CNA at a single center by a single lead operator under a uniform, prospectively maintained protocol. Extracardiac vagal stimulation (ECVS) was performed before and after ablation to confirm vagally mediated sinus or atrioventricular (AV) nodal responses and to verify their attenuation. Outcomes through 1 year included clinical recurrence, quality of life, pacing burden and pacemaker extraction. Results Before ablation, ECVS provoked sinus pauses in 95.8% of patients and AV block in 91.6%; after ablation, sinus pauses were abolished in every patient and residual AV block was present in 4.2%. One-year freedom from recurrent syncope and from bradyarrhythmia-related events was 93.8% and 94.1%. Syncope burden fell from a median of 2.7 episodes per year to none, and disease-specific quality of life improved substantially (P<0.001). Among patients with pre-existing devices, atrial pacing burden fell from a median of 22% to 0%. There were no strokes, deaths or myocardial infarctions. Conclusions In this single-center cohort, physiology-guided CNA was associated with durable symptom control, improved quality of life and reduced pacing across vagally mediated bradyarrhythmia syndromes. Multicenter controlled studies are needed to confirm these findings.