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Abstract BACKGROUND Craniopharyngiomas are a rare tumor along the pituitary-hypothalamic axis. Genetic analysis revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We previously reported that BRAF/MEK inhibition was associated with significant anti-tumor activity in newly-diagnosed PCP patients (Brastianos et al. NEJM 2023). We have now evaluated the efficacy of vemurafenib/cobimetinib in a separate cohort of patients with recurrent PCP whose tumors progressed after prior radiation. METHODS In this multicenter, NCI-sponsored cooperative group trial, patients with histologically confirmed BRAF-positive PCP who progressed after radiation were treated with vemurafenib/cobimetinib. The primary endpoint of response rate (RR) based on centrally determined imaging data was to be evaluated in 16 patients, where a partial response was defined as ≥20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR ≥ 30% (vs. null 5%; α=0.04). In this design, 3 or more observed responses in 16 evaluable patients would be considered evidence of promising activity. RESULTS Of the planned 16 patients, a total of 5 patients enrolled before the study was closed due to slow accrual. Median follow-up was 50 months (95% CI: 32 to not yet reached). Based on volumetric response criteria, all 5 patients had a response to treatment (100%; 95% CI: 47.8% to 100%). To date, 2 patients progressed, one of whom died 22 months after study entry. This cohort met the criteria for efficacy under the original design with >3 responders. No grade 4 or 5 toxicities were observed. CONCLUSIONS Vemurafenib/cobimetinib resulted in an objective response in all patients with previously treated PCP. The study met primary endpoint, similar to that reported for previously untreated PCP. Thus, BRAF/MEK inhibitors could be an effective tool for previously treated PCP and warrants further evaluation. SUPPORT U10CA180821; U10CA180882; Genentech, https://acknowledgments.alliancefound.org;ClinicalTrials.gov: NCT03224767

Background and Objectives Interscalene brachial plexus block is a useful technique to provide anesthesia and analgesia for the shoulder and proximal upper extremity. The initial needle direction at the interscalene groove has been described as being “perpendicular to the skin in every plane” (1). A cross-sectional (axial) approach may offer a more easily conceptualized directed needle placement. The purpose of this study is to define the cross-sectional anatomy and idealized needle angles important to interscalene brachial plexus block. Methods Following IRB approval, 50 patients were studied. Cross-sectional volume coil T1-weighted magnetic resonance images (MRI) were obtained from 50 patients undergoing cervical region imaging for other reasons. At the interscalene groove, a simulated needle path to contact the ventral rami or trunks of the brachial plexus was approximated at the level of C6 or C6-C7 interspace. The angle of this needle path intersecting the sagittal plane was recorded for each patient. Results The mean angle of the simulated needle path relative to sagittal plane was determined to be 61.1 ± 6.1° (range, 50-78°). In 13 of 50 (26%) MRI scans, the cervical nerve roots were not visualized at the level of C6 and were measured at the C6-C7 level. Conclusions These findings suggest initial needle placement at the interscalene groove should be angled less perpendicularly relative to the sagittal plane than is often observed. A cross-sectional approach enables more practical visualization of initial needle placement. A more accurate initial needle placement may minimize the number of needle passes necessary to contact the nerve roots, thereby more efficiently obtaining a successful block.

Background: The American opioid use disorder (OUD) and overdose epidemic require physicians and advanced care providers to be prepared to care for patients with this life-threatening condition. Learning to identify, engage, and treat patients with OUD with medications is an essential skill for providers, as is developing requisite confidence and therapeutic attitudes regarding the care of patients with OUD (CP-OUD). To address the need for improved OUD treatment education, our team built and implemented a 12-module asynchronous course entitled, “Care of Patients with Opioid Use Disorder”, in 3 Doctor of Medicine (MD) programs and a Graduate School of Nursing (GSN) program. Methods: Students self-reported their attitudes and confidence regarding the CP-OUD before and after each module. Twelve questions assessed confidence, and 12 questions assessed attitude. Students’ change in confidence and attitudes before and after training was calculated. Results: Responses were collected between January 2021 and November 2024. The number of students completing each module ranged from 552 to 967 MD students and 81 to 149 GSN students. Students reported improved confidence after completing each of the 12 modules (<0.0001). Students reported improved attitudes after completing 10 of the 12 modules (<0.0001). Differences ranging from small to medium size were observed between MD and GSN student’s baseline confidence for 4 modules, and baseline attitudes for 6 modules. Conclusions: Asynchronous learning modules can be effectively implemented in medical and nursing education to improve confidence and attitudes regarding the CP-OUD. The use of asynchronous training modules allows for flexible deployment, as evidenced by their use in 3 MD programs and a GSN program. Future research should investigate whether improved confidence and attitudes during medical and nursing education result in more graduates caring for patients with OUD post-training.

Background: The use of validated risk stratification tools for the workup of suspected pulmonary embolism (PE) is a recommendation of the American Society of Hematology and the American College of Emergency Physicians. Methods: We designed and implemented electronic clinical pretest probability (PTP) tools for use in emergency departments (ED). Overall, 38 EDs (tertiary and regional EDs) in the United States were involved across three health systems. PTP use was analyzed between September 12, 2022 and January 11, 2023 in 270,247 ED visits. PTP use was examined in terms of the percentage of visits for which patients underwent computed tomography pulmonary angiography (CTPA). Each site chose the 3-tier Wells’ score for implementation and Site 2 designed a combined Wells’, pulmonary embolism rule-out criteria (PERC), and YEARS score. Results: At Site 3, forced use resulted in documented PTP scores in 49–53% of ordered CTPAs. At Sites 1 and 2, where PTP scores were optional, documented PTP scores occurred in 2–3% and 1–3% of CTPA orders, respectively. At Site 1, the use of PTP increased slightly over the study period, with signs that PE yield on imaging was also increasing (3.4–5.9%). At Site 2, PE yield on imaging was 9–10%, and it remained similar, with similar use of PTP tools over the study period. PE yield (6–8%) on imaging also remained similar throughout the study at Site 3. Conclusions: Guideline-endorsed PTP scores for PE at three independent health systems in the United States did not increase PE yield on imaging. Novel implementation strategies involving interdisciplinary teams are urgently needed.

ABSTRACT Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic β-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role β-cell senescence in diabetes progression. In contrast, β-cell senescence also promotes immune surveillance, promoting β-cell survival and function. Thus, a better understanding of senescent cells’ phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent β-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21 Cip1 ) and Cdkn2a (encoding p16 Ink4a ) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent β-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a -expressing β-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a + cells was sufficient to induce secondary senescence and β-cell dysfunction in vitro . JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored β-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT

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.

ABSTRACT Objective Availability of surgical equipment and access to essential clinical services remains an important barrier to surgical care delivery, particularly in low‐ and middle‐income countries (LMICs). This study aims to characterize the relative availability of essential equipment for otolaryngology‐head and neck surgery (OHNS) care across World Bank income groups. Methods We conducted a cross‐sectional survey on otolaryngologists' perceptions on the availability of surgical equipment and ancillary services in their respective practice settings per a 5‐point Likert scale ranging from never to always available. The study was disseminated online via professional societies, personal contacts, and social media. Eligible participants included otolaryngologists from 194 WHO‐recognized countries, which were grouped by World Bank income group classification and WHO region. Results The study involved 146 otolaryngologists, 69 (47%) from high‐income countries (HICs), and 77 (53%) from LMICs. LMIC respondents were predominantly from the African and South‐East Asian regions, which comprised 48% and 7.8% of all LMIC respondents, respectively. Results revealed significant differences in the availability of otologic, rhinologic, and endoscopic airway equipment between HICs and LMICs. Differences existed among commonly used equipment such as tympanomastoidectomy equipment and rigid bronchoscopy, to subspecialized equipment such as functional endoscopic sinus surgery equipment and cochlear implants ( p < 0.05 each). Conclusions The study highlighted key disparities in the availability of essential equipment for baseline OHNS care, especially for pediatric airway and otologic conditions. These results can be used to guide investment and advocacy efforts to improve specialty‐specific surgical infrastructure relative to the global burden of OHNS diseases in low‐resource settings. Level of Evidence 3

Guidelines for diagnosing pulmonary embolism (PE) start with a risk assessment using a pretest probability (PTP) tool, followed by D-dimer testing or computed tomography pulmonary angiography (CTPA) depending on risk. The project aimed to develop an electronic clinical quality measure (eCQM) to encourage broader use of a validated PTP scoring tool in emergency departments (EDs) to more accurately diagnose PE and to reduce unnecessary CTPAs. To identify a value set to accurately identify CTPA and abnormal D-dimer tests using standard classification systems and clinical vocabularies (ie, Current Procedural Terminology [CPT], Logical Observation Identifiers Names and Codes [LOINC], systematized nomenclature of medicine clinical terms [SNOMED CT]) across 3 academic United States health care systems. A comprehensive value set to identify CTPAs was selected, which contained 31 codes. Additionally, each health care system had unique, site-specific codes to more granularly identify CTPAs. Three health care systems representing 38 EDs from across the country submitted data from all ED encounters between September 12, 2022, and January 11, 2023. Imaging types were reviewed from each of the CPT codes and LOINC. The project evaluated whether a D-dimer was obtained using CPT and LOINC and whether the D-dimer result was elevated using SNOMED CT. The number of ED encounters, PTP use, and diagnosis of PE using different codes were determined. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for selected codes were calculated. Over a 4-month study period, 270,214 encounters were included from 38 EDs. 11,794 ED encounters with CTPAs during the study period, using the site-specific codes were identified. The comprehensive value set had a PPV of 63.4%. Restricting the CTPA value set to CPT code 71275 or LOINC 88322-3 improved the PPV to 82% with 100% sensitivity and 99% specificity. The restricted value set captured the highest proportion of relevant site-specific codes. D-dimer values were identified using LOINC codes 48065-7 and 91556-1 at Site 1 and 48067-3 at Site 2. SNOMED CT codes were not used at any site to identify elevated D-dimer results. Different D-dimer tests with different normal ranges were used at each site, and only one site provided an abnormal flag for D-dimer results. Heterogeneity in the use of nationally standardized codes for labs and imaging tests limits the ability to measure and compare quality across health care organizations for CTPA and D-dimer results. Restricting the identification of CTPA to CPT Code 71275 or LOINC 88322-3 resulted in high sensitivity and specificity, but false positives remain. Additionally, coding for an abnormal D-dimer test result is not standardized across institutions. Therefore, the currently available value sets cannot be used to develop eCQMs whose aim is to evaluate whether CTPA is ordered appropriately based on the PTP risk level and laboratory testing.