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Importance The incidence of human papillomavirus type 16 (HPV16–positive) recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rising. Approved therapies offer a durable response to a minority of patients. Objective To determine the efficacy and safety of a therapeutic HPV16-targeted immunotherapy, PDS0101, in combination with pembrolizumab in participants with HPV16-positive R/M HNSCC, with separate evaluation of immune checkpoint inhibitor (ICI)–naive and ICI-resistant cohorts. Design, Setting, and Participants VERSATILE-002 was a phase 2, open-label, multicenter nonrandomized clinical trial conducted at 26 oncology centers from March 29, 2021, to May 15, 2025, across the US, UK, and Ireland using the Simon 2-stage optimal design. Efficacy analyses were performed on modified intent-to-treat (mITT) population; safety analyses included all participants who received 1 or more doses. Eighty-eight participants with histologically confirmed R/M HPV16-positive HNSCC were enrolled, of whom 87 (98.9%) received treatment and composed the safety population. Seventy five (85.2%) were in the mITT population used for efficacy analyses, of whom 53 (70.7%) were ICI-naive with a programmed cell death ligand 1 combined positive score of 1 or greater and 22 (29.3%) were ICI-resistant. Exposures Pembrolizumab (200 mg, intravenously, every 3 weeks for up to 35 cycles) plus subcutaneous PDS0101 (5 scheduled doses per protocol). Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors , version 1.1, by a masked independent central reviewer. Secondary end points included progression-free survival (PFS), median overall survival (mOS), and safety, with exploratory end points of duration of response, disease control rate, and response rates by programmed cell death ligand 1 status. Results Of the 75 patients in the mITT population, the mean (SD) age was 64.0 (8.3) years; 4 individuals (5%) were female and 71 (95%) were male; and 2 individuals (3%) were Asian, 1 (1%) was Black, 5 (7%) were Hispanic, and 71 (95%) were White. Among 53 ICI-naive participants in the mITT cohort, ORR by the central reviewer was 34.0%, median PFS was 5.3 months (95% CI, 2.10-9.00), and mOS was 39.3 months (95% CI, 23.90 to not evaluable). Among 22 ICI-resistant patients in the mITT cohort, no objective responses were observed and the primary end point (ORR by central reviewer) was not met, but mOS was 14.8 months (95% CI, 8.50-26.00). The treatment was well tolerated, with 13.8% experiencing grade 3 or higher treatment-related adverse events. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that PDS0101 plus pembrolizumab showed antitumor activity in ICI-naive HPV16-positive R/M HNSCC, with favorable safety, response rates, and survival outcomes. The findings support further evaluation in a first-line setting. Trial Registration ClinicalTrials.gov Identifier: NCT04260126

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Background N‐methyl‐D‐aspartate receptor antibody encephalitis (NMDAR‐Ab‐E) is an autoantibody‐mediated disorder, characterized by acute development of neuropsychiatric symptoms, seizures, movement disorders, and autonomic instability. Objectives To describe acute seizure semiology and electroencephalogram (EEG) findings in patients with a first episode of NMDAR‐Ab‐E. Methods Medical records and EEG results were retrospectively evaluated from 14 adult patients with definite NMDAR‐Ab‐E, recruited between April 2009 and September 2017, and followed up until October 2024. Results A total of 92.8% (13/14) were women with a mean age of 29.6 years. 85.7% (12/14) patients experienced seizures. Focal and/or generalized seizures were described at presentation or in the first days of the illness in 57% (8/14). EEGs showed diffuse slowing in 13/14 and this coexisted with epileptiform activity in 10/13; fast frequencies in 7/13 (potentially owing to a benzodiazepine effect); and asymmetric focal slowing in 6/13. Six patients had periods of rhythmic slow activity (focal or diffuse), without evolution to electrographic seizures. An extreme delta brush (EDB) pattern was recorded in 2/13 patients, and this was associated with non‐convulsive status epilepticus in one of these individuals. Significance Most patients in this case series of NMDAR‐Ab‐E were young adult females with early focal and/or generalized seizures. Diffuse slowing in theta/delta range was the most common EEG finding, with or without epileptiform discharges, focal slowing, superimposed fast activities, and focal or diffuse rhythmic slowing. An EDB pattern was rare. Even with non‐specific findings, EEG seems to be a sensitive tool to aid diagnosis and decision‐making in NMDAR‐Ab‐E.

Background Early-life dysbiosis associated with Cesarean section (C-section) delivery is increasingly recognized as a modifiable risk factor influencing short- and long-term health outcomes. This multidisciplinary expert consensus summarizes the clinical implications of C-section on infant gut microbiota. It proposes evidence-based strategies to mitigate these effects, with a focus on the critical window of the first 1,000 days of life. Methods A multidisciplinary panel of 16 pediatricians, neonatologists, pediatric gastroenterologists, and nutrition experts conducted a targeted narrative review of the literature to inform a structured expert consensus process and participated in an online structured consensus process. Seventeen consensus statements were developed and validated through discussion, expert voting, and commentary, supported by a targeted review of current scientific evidence. Results The expert panel reached consensus on the impact of C-section delivery on early microbiota composition and its clinical relevance, emphasizing that the rising prevalence of C-sections worldwide demands urgent attention. Experts unanimously emphasized the importance of exclusive breastfeeding as the primary strategy to support healthy microbiota development in infants born by cesarean section. When exclusive breastfeeding is not possible, evidence-based nutritional approaches, including selected prebiotics and probiotic strains with documented clinical efficacy, are recognized as promising alternatives for supporting microbial balance. Notably, the panel underscored that not all probiotics are equally effective and recommended shifting toward evidence-based strains shown to help restore gut dysbiosis in this population. Also, experts advocated for continuing microbiota-targeted support throughout the first 1,000 days of life, viewing this developmental window as a critical continuum rather than a limited early-life phase, while acknowledging the need for more long-term data. Additionally, education for healthcare professionals and parents about the long-term implications of C-section delivery was emphasized as a key enabler of the broader adoption of eubiosis-targeted strategies. Conclusions Optimizing microbial colonization in infants born by cesarean section requires a multifaceted approach that prioritizes breastfeeding, supports judicious use of evidence-based nutritional interventions when needed, and emphasizes education and continuity of care across early life. By aligning clinical practice with emerging microbiome science, early-life interventions may reduce dysbiosis-associated risks and improve long-term health outcomes.

Background: Access to high-quality airway equipment is critical for effective otolaryngological and emergency care. In sub-Saharan Africa (SSA), challenges in the procurement infrastructure may hinder equipment availability, impacting patient outcomes. Given the paucity of literature investigating equipment procurement in SSA, this study aims to map out the multilevel barriers to procurement of airway equipment in SSA to inform opportunities for improvement. Methods: A qualitative study design was employed using semi-structured interviews and open-ended survey responses. Participants included otolaryngologists in SSA, manufacturing company representatives and international policymakers, selected through purposive sampling to ensure representation of various roles in the procurement process. Six interviews, one focus group and six survey responses with regional healthcare providers (n = 13), manufacturing representatives (n = 3) and international policymakers (n = 2) explored supply chain dynamics, regulatory challenges, manufacturing capabilities, financial constraints and policy frameworks. Data were analysed using thematic analysis to identify recurrent themes and interrelationships. Results: Systemic barriers exist in the procurement process, including fragmented supply chains, inconsistent regulatory enforcement, limited local manufacturing capacity and insufficient funding mechanisms. Otolaryngologists emphasised frequent delays in equipment availability, while manufacturers reported logistical challenges and regulatory hurdles. Policymakers noted gaps in infrastructure and regional coordination. Emerging themes suggest opportunities for streamlining procurement processes, fostering local production and enhancing collaboration to improve supply chain efficiency. Conclusion: This study underscores the multifaceted challenges in airway equipment procurement in SSA and highlights the need for integrated approaches involving stakeholders across the supply chain. Contribution: Findings provide actionable insights to inform policy development and capacity-building initiatives with the goal of enhancing access to life-saving airway equipment and improving healthcare outcomes.

Abstract Background The amygdala is closely connected to the olfactory bulb and involved in olfactory processing as well. It is a particularly susceptible region that accumulates a‐synuclein pathology in Parkinson's disease (PD). Our previous work revealed olfactory bulb gene alterations related to neuroinflammation, and neurotransmitter dysfunction to be associated with olfactory function. We aimed to extend this work and assess gene expression changes, affected pathways and co‐expression networks by transcriptomic profiling of the amygdala in subjects with and without clinicopathologically defined PD. Method Bulk RNA sequencing was performed on frozen human amygdala of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative Disorders. Result Differential expression analysis, corrected for age, sex and post‐mortem interval revealed 40 significantly differentially expressed genes (DEGs) in PD. Downregulated genes were mainly related to altered hemoglobin expression while upregulated genes included inflammatory markers and glutamine transporter. Significantly enriched pathways were involved in oxygen and carbon dioxide transport, cellular oxidant detoxification and regulation of glutamine secretion. Cell enrichment revealed these genes to be mainly expressed in neurons. Co‐expression network analysis using Weighted correlation network analysis (WGCNA ) subsequently identified four significant modules correlated with both PD and premortem olfactory dysfunction which were involved in pathways related to neuroinflammatory processes, mitochondrial, endoplasmic reticulum and lysosomal dysfunction. Conclusion These preliminary results suggest cellular alterations in the amygdala related to mitochondrial dysfunction, altered oxygen homeostasis, oxidative stress, inflammation as well as glutamatergic neurotransmitter dysfunction that may contribute to neurodegeneration in PD.

A practical patterned approach to neonatal bowel obstructions helps radiologists localize the obstruction and perform the appropriate imaging examination to accurately make the diagnosis and help guide proper management.

6037 Background: The incidence of HPV-associated head and neck squamous cell carcinoma (HNSCC) continues to rise with over 90% of cases being driven by HPV16. Median overall survival (OS) with pembrolizumab in first-line recurrent/metastatic (R/M) HNSCC is 12.3 months in subjects with CPS ≥1, 10.8 months for CPS ≥1-19, and 14.9 months for CPS ≥20. There is an urgent need to improve survival rates in the growing population of HPV16-positive R/M HNSCC. PDS0101 (Versamune HPV) is an investigational T cell stimulating immunotherapy that unleashes a potent, durable attack against HPV16-positive cancers and is being studied in combination with pembrolizumab. Preliminary results were presented at ASCO 2023. (Price KAR, et al. ASCO 2023. Abstract 6012). Methods: VERSATILE-002 is a single-arm phase 2 study evaluating PDS0101 and pembrolizumab for first-line HPV16-positive R/M HNSCC with CPS ≥1. Subjects received pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 and pembrolizumab alone for all other Cycles up to Cycle 35 (approx. 2 years). The primary study endpoint is confirmed objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free survival (PFS), OS, and safety. Results: The median follow-up is 18.4 months (range 0.2-42.7 months). The efficacy population consists of 53 subjects: 32 (60%) with CPS ≥1-19 and 21 (40%) with CPS ≥20. The median OS for subjects with CPS ≥1 is 30 months (95% CI 23.9, NE). For the CPS ≥1-19 subgroup, the median OS is 29.5 months (95% CI 15.3, NE). For the CPS ≥20 subgroup, the median OS is 39.3 months (95% CI 18.4, NE). Confirmed response rates by investigator assessment are shown in the Table. Twenty-three subjects are still on study: 3 on treatment and 20 in long-term follow-up. No new safety signals have emerged. The most common TRAEs are injection site reactions, fatigue, headache, and pruritus. Only 19% of subjects experienced Grade ≥3 TRAEs. No subject had a Grade 5 TRAE. Conclusions: These data represent one of the most extended follow-up periods to date of subjects receiving an HPV16-targeted therapy for HPV16-positive R/M HNSCC. The PDS0101 and pembrolizumab combination is well tolerated and has demonstrated deep and durable clinical responses. Median OS is promising in light of historic expectations, both overall and relative to PD-L1 subgroup, and remains durable with continued follow up. The results support further evaluation in a randomized phase 3 study with OS as the primary endpoint. Clinical trial information: NCT04260126 . Summary of results. CPS ≥1-19 (N=32) CPS ≥20 (N=21) CPS ≥1 (N=53) ORR, % 28.1 47.6 35.8 DCR, % 75.0 81.0 77.4 Median DOR, months (95 % CI) 21.8 (4.2, NE) NE (5.6, NE) 21.8 (11.5, NE) Median PFS, months (95% CI) 5.1 (2.4, 8.1) 14.1 (2.1, NE) 6.3 (3.5, 9.0) Median OS, months (95% CI) 29.5 (15.3, NE) 39.3 (18.4, NE) 30.0 (23.9, NE)

ImportanceUnderstanding the global barriers to otolaryngology–head and neck surgery (OHNS) care is crucial in addressing disparities in access to care, particularly in low-income and middle-income countries (LMICs).ObjectiveTo characterize barriers to comprehensive otolaryngology care across World Bank income groups.Design, Setting, and ParticipantsUsing an online cross-sectional survey that was administered by the Global OHNS Initiative via international and national professional societies, personal contacts, and social media, this study captured the perceptions of otolaryngologists regarding barriers to OHNS care at the levels of the country, health sector, clinician, and patient. Participants included otolaryngologists from the 194 World Health Organization member states and Taiwan. Eligibility criteria included a medical degree and specialized training in managing conditions of the ear, nose, and throat. The nonresponse rate was not recorded. The data collection period spanned from October 2022 to June 2023.ExposuresExposures included World Bank income group classification.Main Outcomes and MeasuresThe primary outcomes were Likert scale responses regarding frequency of barriers to OHNS care. The a priori hypothesis was that LMICs would report more frequent barriers to OHNS care.ResultsThe study involved 146 otolaryngologists (47 female individuals [32%]), with 69 (47%) from high-income countries and 77 (53%) from LMICs. Male individuals represented 45 high-income country respondents (65%) and 54 LMIC respondents (70%). Barriers were reported across income groups at all levels of the health system, with a higher frequency in LMICs. Several barriers were reported to be more substantial in LMICs, such as the national volume and distribution of otolaryngologists, financial compensation for clinicians, and patient stigma, and others were common across income settings, such as the availability of operating rooms and inflexible working hours. Common concerns included national and health sector barriers: OHNS workforce, referral networks, government support; clinician barriers: excessive clinician workloads, understaffing, poor administration support; patient barriers: distance to health care facilities, financial burdens such as medical costs and foregone wages, stigma, and health literacy.Conclusions and RelevanceThe results of this cross-sectional study suggest that there are barriers to otolaryngology care globally that affected all levels of the health care system. This work may inform prioritization of otolaryngology within research and policy, and it emphasizes the need for effective strategies to expand access to otolaryngology care, particularly in lower-income settings.

ABSTRACTImportanceHighlighting the global disparities in otolaryngology training and, ultimately, service delivery, emphasizing the need for equitable access to training resources and programs.ObjectiveTo describe the relationship between the quality, content, and location of otolaryngology–head and neck surgery training and education and the resulting impact on the delivery of otolaryngology care globally.DesignAn online cross‐sectional survey to otolaryngologists, gathering information on their training and education experiences, and factors influencing their choice of training location and practice.SettingThe online survey was available in multiple languages, distributed via national and international professional otolaryngology societies, snowballing and social media.ParticipantsThe respondents were practicing otolaryngologists representing all seven World Health Organization regions.ExposuresWorld Bank income groups classification.Main Outcomes and MeasuresOur expected outcome was that subspecialty training and access to educational resources were significantly readily available to respondents from high‐income countries, leading to more confidence in performing complex procedures post training.ResultsA total of 91 participants were included in the analysis, with 47 (52%) practicing in high‐income countries and 44 (48%) in low‐ and middle‐income countries. Sixty‐one participants (67%) were male. Subspecialty training and access to educational resources were significantly less available in low‐ and middle‐income countries, leading to lower confidence among low‐ and middle‐income countries physicians in performing complex procedures. High‐income country respondents reported better access to diverse training resources and felt more prepared for a broader range of procedures.Conclusion and RelevanceSignificant disparities exist in OHNS training resources and subspecialty training opportunities between high‐ and low‐middle‐income countries. There is a critical need to integrate complementary training and educational modalities into local systems. Addressing the shortage of educational resources and promoting open‐access initiatives in low‐middle‐income countries are essential steps toward enhancing surgical education and improving global otolaryngology healthcare outcomes.