Citations

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. Tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .

Abstract Introduction Daily fluctuations in sleep disturbances have been shown to shape pain experiences among individuals with chronic pain. Additional biobehavioral factors, such as abuse history, depression, current and long-term anxiety, opioid use, physical functioning, and fatigue, may also affect daily pain outcomes. Yet the extent to which these factors collectively contribute to daily pain intensity and unpleasantness remains insufficiently understood. Methods Using baseline data from the SPINII randomized controlled trial (R01NR017168; McCrae, PI), women with insomnia and fibromyalgia (N = 294, x- age = 40) completed 14 days of sleep diaries assessing sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and pain intensity and unpleasantness (0–100). Additional predictors included abuse history, Beck Depression Inventory (BDI), State–Trait Anxiety Inventory (STAI), and PROMIS-57 physical functioning and social functioning. Linear mixed models examined the effects of sleep and related factors on daily pain. Results Significant predictors of pain intensity included higher between-person SOL (b = 0.08, p < .001) and WASO (b = 0.08, p < .001), lower between-person TST (b = -0.10, p < .001), lower within-person TST (b = −0.03, p < .001), opioid use (b = 2.84, p = .029), poorer physical functioning (b = −0.35, p = .008), and higher depression scores (b = 0.20, p = .046). Pain unpleasantness showed nearly identical patterns, with only physical functioning becoming non-significant. Random intercepts and residual variance values were significant in both models (p < .001), indicating within- and between-person variation in pain. ICCs of .80-.85 revealed that the majority of variance was between-person, while non-significant autocorrelations (p > .05) indicated minimal day-to-day carryover effects beyond stable individual differences. Conclusion Overall sleep quality and emotional health shape pain experience more strongly than daily fluctuations. Although TST offers some next-day relief, chronic contributors are more relevant to daily pain. Effects were largely consistent; between- and within-person TST showed strong effects, and depression had a slightly larger effect on pain unpleasantness than pain sensitivity, reinforcing a multidimensional biopsychosocial pain process. These findings highlight the need for integrated interventions that strengthen sleep, emotional well-being, and physical functioning. Support (if any) NIDA

Abstract Introduction Chronic and episodic headaches have a strong bidirectional relationship with insomnia and poor sleep outcomes. AM (morning) headaches are common among chronic pain populations, but additional research is needed to understand their pain experiences and potentially inform targeted interventions. Herein, we investigated whether presence of AM headaches is associated with differences in diary-based sleep parameters and pain ratings in women with pain and sleep complaints. We hypothesize individuals with AM headaches will have more sleep disturbances and fatigue as well as greater pain intensity and unpleasantness. Methods Women (N=293, Mage=39.59, SD 12.65, 65% with morning headaches) reporting insomnia and pain complaints (65% also reporting morning headaches) were recruited in mid-Missouri for an RCT (R01NR017168, ClinicalTrials.gov Identifier: NCT03744156). During baseline assessment, participants completed 2 weeks of daily electronic diaries and reported AM headache presence (Y/N). Independent samples t-tests (SPSS) evaluated differences in sleep parameters and pain ratings in those with and without AM headaches. Participants reporting diagnosed sleep apnea were excluded. Results Morning fatigue was higher among individuals with AM headaches (M=54.72+/-18.25) than those without (M=50.02+/-19.12), t(291)=-2.07, p=.04. Pain intensity was greater in the AM headache group in the morning (M=47.65+/-19.73 vs. M=42.52+/-21.91), t(291)=-2.04, p=.042, and evening, (M=49.62+/-19.10 vs. M=44.23+/-20.66), t(283)=-2.21, p=.028. Evening pain unpleasantness was also rated as higher among those with AM headaches (M=45.90+/-19.55) compared to those without (M=40.82+/-22.52), t(283)=-1.99, p=.048, but morning pain unpleasantness ratings only trended towards significance. Conclusion AM headaches can present as a chronic condition or as a symptom of other sleep disorders. Individuals with AM headaches had minimal sleep differences overall, but morning fatigue, pain intensity (AM and PM), and evening pain unpleasantness ratings were all significantly greater in those with AM headaches. Undiagnosed sleep disorders other than insomnia (i.e., obstructive sleep apnea) or other health concerns, like increased intracranial pressure, may have contributed to pain-related findings. Considering the high prevalence of COMISA in chronic pain populations, further investigation should examine its impact on sleep and headache severity. Support (if any) National Institute of Nursing Research (NR017168; Clinical trial: NCT03744156; PI: McCrae).

Background: Gender-based reimbursement disparities in orthopedic surgery remain poorly understood, particularly when accounting for practice composition and setting. The purpose of this study was to compare and evaluate gender-based differences in Medicare reimbursement and practice patterns among female and male orthopedic surgeons. Methods: A cross sectional analysis of public Medicare data from 2013 to 2021 was performed. Outcomes included annual Medicare payments, submitted charges, total services, service categories, and beneficiaries treated by orthopedic surgeons who bill Medicare. Univariate and multivariable analyses quantified differences in payment, practice volume and composition, geographic adjustment, and Current Procedural Terminology (CPT)-matched reimbursements. Results: A total of 29,357 orthopedic surgeons (27,442 men and 1,919 women) billed Medicare fee-for-service during the study period. Female surgeons, on average, submitted 48.3% fewer total charges and received 44.1% lower annual Medicare payments per surgeon compared with male surgeons. These differences persisted after multivariable regression adjusted for practice metrics and excluded top and bottom earners. Female surgeons also billed fewer services, treated fewer beneficiaries, and submitted fewer unique CPT codes. However, payment disparities persisted even after matching surgeons by volume of services, beneficiaries, and years in practice. Male surgeons performed higher volumes of all 10 highest-paying orthopedic CPT codes. In CPT matched analyses, female surgeons received lower reimbursement per service than male surgeons performing identical procedures. Conclusion: These findings suggest that the observed gender-based disparities in orthopedic surgery Medicare reimbursement cannot be explained by differences in volume, procedural mix, or geographic practice cost. Instead, they likely reflect a combination of structural and behavioral mechanisms described in prior literature that may influence how access to clinical opportunities, referrals, and reimbursement practices unfold in surgical practices. Variations in coding practices may represent an important focus for future investigation and targeted educational initiatives. Level of Evidence: Level III , Retrospective Cohort Study. See Instructions for Authors for a complete description of levels of evidence.

The 2025 American College of Cardiology/American Heart Association/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome guideline focuses on strategies to reduce bleeding risk with antiplatelet therapy yet lacks any recommendation related to CYP2C19 genotyping. The impact of CYP2C19 loss‐of‐function alleles on the effectiveness of clopidogrel is well documented, and although prasugrel and ticagrelor more effectively reduce the risk for atherothrombotic events compared with clopidogrel in patients with a CYP2C19 loss‐of‐function allele, clopidogrel reduces bleeding risk without an increase in atherothrombotic events compared with prasugrel or ticagrelor in those without a loss‐of‐function allele. Accordingly, an American Heart Association Scientific Statement supports CYP2C19 genetic testing before oral P2Y 12 inhibitors are prescribed. This commentary summarizes the evidence in support of CYP2C19 ‐guided P2Y 12 inhibitor selection in the context of other 2025 acute coronary syndrome guideline recommendations and urges future guidelines to incorporate recommendations for CYP2C19 genotyping, especially for those at high bleeding risk.

Introduction: Adolescent obesity is linked to significantly increased risk of cardiovascular and metabolic comorbidities. Exercise outcomes are often impaired in adolescents with obesity (AO), but it remains unclear whether this reflects compromised cardiovascular reserve or non-cardiovascular factors. This study aimed to characterize mechanisms of reduced exercise performance in AO using cardiopulmonary exercise testing (CPET). The secondary aim was to assess the contribution of excess weight burden by correcting for extra fat mass in AO through estimated standard body mass (eSBM). Methods: We retrospectively analyzed CPET data from asymptomatic AO, defined as BMI ≥ 30 (n = 94), and age-matched, normal-weight controls without obesity (n = 139). In a subset of AO (n = 47), % body fat was measured by bioelectric impedance analysis, and eSBM was calculated as if they have comparable % body fat to controls using median values by sex and age in US adolescents. CPET was performed with a cycle ergometer following a ramp protocol. Results: Both male and female AO exhibited higher resting HR (p < 0.001) while peak HR remained comparable to controls. Absolute peak oxygen consumption (VO2) was higher in female AO (p < 0.001), while males showed no difference. Absolute ventilatory anaerobic threshold (VAT) was elevated in AO in both sexes (p < 0.001). When indexed by total body weight, peak VO2, peak work rate (WR), and VAT were lower in both male and female AO (p < 0.001). Peak respiratory exchange ratio (RER), peak VO2/VAT, and peak WR/peak VO2 were also significantly reduced in AO (p < 0.001). When indexed by eSBM, peak VO2 normalized only in female AO; peak WR remained lower, but VAT normalized in AO of both sexes with overcorrection in females, suggesting comparable submaximal exercise performance to controls. Conclusion: Reduced exercise performance in AO appears characterized by elevated resting HR, early exhaustion near peak exercise (lower peak RER and peak VO2/VAT), and decreased work efficiency (lower peak WR/peak VO2). Indexing CPET parameters by eSBM revealed relatively normal cardiopulmonary performance in AO during submaximal exercise, suggesting that reduced performance primarily reflects premature, fatigue-driven termination of exercise due to excess weight burden rather than true cardiopulmonary compromise. Further study is needed to clarify factors contributing to the observed sex-specific differences in AO exercise performance.

ABSTRACT Three novel HLA‐B alleles, HLA‐B*27:297, ‐B*41:97 and ‐B*44:436 , were identified by next‐generation sequencing.

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Abstract Context Patients with mild autonomous cortisol secretion (MACS) have higher rates of vertebral fractures compared to patients with non-functioning adrenal nodules, yet bone density is not always reduced. Objective To characterize the effect of MACS on bone density, metabolism, and microstructure as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Design Cross-sectional study, 2019-2022 Setting Tertiary referral center Participants Seventy-five patients with MACS and 75 age-, sex-, and gonadal status–matched referent subjects. Measurements Bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan, and HR-pQCT. Outcomes Areal and volumetric bone mineral density (aBMD, vBMD), trabecular bone score (TBS), microstructural parameters including trabecular bone volume to total volume (BV/TV) ratio. Results While no differences in aBMD were observed at any skeletal site, patients with MACS had decreased TBS (1.389 vs 1.475, P &lt; .001) and lower osteocalcin concentration (17.1 vs 19.5 ng/mL, P = .030) than referent subjects. On HR-pQCT at the tibia, patients with MACS had reduced trabecular BV/TV (0.220 vs 0.233, P = .015) compared to referent subjects. On multivariable analysis, MACS was associated with lower TBS (odds ratio [OR] per SD decrease 2.87 [1.65-5.00]), lower trabecular BV/TV at the radius (OR per SD decrease 2.58 [1.33-5.00]), and lower trabecular BV/TV at the tibia (OR per SD decrease 4.06 [2.10-7.86]). Conclusion Patients with MACS have microstructural deterioration that may not be evident on routine DXA aBMD testing.

Background Children's media both reflects and shapes societal attitudes toward physical disability. Despite its potential impact on self-concept and stigma, longitudinal, data-driven analysis of these portrayals remains scarce. This study aimed to quantify longitudinal trends in the tone and framing of physical disability representation in children's media and to explore implications for pediatric rehabilitation. Methods A quantitative content analysis was conducted on 68 children's media productions (1933–2025) sourced from the Vanderbilt Peabody database. Content was filtered to age-appropriate ratings (G, PG, PG-13, TV-14). Three trained reviewers classified depictions of physical disability by clinical category (e.g., spinal cord injury, limb difference) and tone (Positive, Neutral, Negative) and coded for the presence of rehabilitation themes. Inter-rater reliability (κ = 0.83) was achieved. Statistical testing included Mann-Kendall trend analysis and Fisher's exact tests to compare pre-2000 vs post-2000 portrayals. Results Positive portrayals increased significantly from pre-2000 (63%) to post-2000 (90%) (p = 0.01). A consistent upward trend across decades was confirmed (Z = 3.47, p < 0.01). Spinal cord injury was the most frequently depicted disability (40%); rehabilitation themes appeared in 24% of productions, more commonly post-2000. Productions with rehabilitation content were more likely to feature positive portrayals (94% vs 89%). Conclusions Over nine decades, children's media has shifted toward more affirming representations of physical disability, particularly after 2000. Findings suggest that pediatric rehabilitation providers can use positive media examples to reinforce therapeutic engagement, normalize assistive devices, and address stigma in age-appropriate ways.