Citations

Cardiovascular (CV) dysfunction is common in severe acute pancreatitis (AP) and contributes substantially to mortality. Although sex differences in CV diseases are well recognized, with males generally exhibiting higher risk and poorer outcomes, their influence on AP-associated CV responses remains poorly defined. Here, we examined sex-dependent alterations in vascular integrity and cardiac function using cerulein-induced mouse models of AP. Because obesity is associated with more severe forms of AP, cerulein was used to induce mild AP in lean wild-type C57BL/6J mice and a more severe phenotype in obese C57BL/6J mice. Across both models, pancreatic injury was comparable between sexes. A modest sex difference in vascular permeability was observed in the mild but not severe AP model. In mild AP, both males and females showed similar compensatory increases in cardiac systolic function; however, in severe AP, only female mice maintained this adaptive systolic augmentation. Circulating levels of free fatty acids, reflecting systemic tissue lipolysis, were lower in females. Impaired cardiac adaptation in males was accompanied by higher levels of seven different myocardial inflammatory cytokines, as well as elevated circulating levels of angiopoietin-2 (Angpt2). While Angpt2 levels correlated with the severity of cardiac dysfunction, Angpt2 neutralization did not improve, and indeed worsened cardiac function in males. Together, these findings delineate both sex-dependent and sex-independent CV responses in mild and severe AP and identify Angpt2 as a potential compensatory cardioprotective factor under obesity-associated severe AP.

BACKGROUND: Degenerative mitral regurgitation (DMR) due to valve prolapse predominates in men, but sex-specific differences are poorly understood due to a lack of quantitative and sex-stratified studies. METHODS: The international MIDA-Q (Mitral Regurgitation International Database-Quantitative) registry enrolled 3274 men and 2331 women with greater than or equal to mild DMR prospectively quantified, comprehensively characterized, and long-term follow-up. RESULTS: Women were more symptomatic despite lower effective regurgitant orifice (ERO, 27±18 versus 38±22 mm 2 , standardized mean difference 0.54; P <0.0001) and regurgitant volume (46±26 versus 61±31 mL/beat, standardized mean difference 0.52; P <0.0001), even for similar mitral lesions. With increasing ERO, women showed lower regurgitant volume, higher heart rate, lower blood pressure, but left ventricular size response in women was smaller in absolute measures while larger when body surface area normalized, with higher ejection fraction and cardiac index (all P <0.0001). Incidence of mitral valve surgery was similar in symptomatic women and men, but lower in asymptomatic women versus men (adjusted hazard ratio, 0.80 [0.69–0.94]; P =0.008) for similar ERO, linked to smaller left ventricular diastolic absolute diameter ( P <0.0001). Excess mortality under medical management (of severe versus mild ERO) was similar in women (adjusted hazard ratio, 1.67 [1.24–2.24]; P =0.0007) and men (adjusted hazard ratio, 1.63 [1.27–2.09]; P <0.0001) and versus expected survival (2.12 [1.51–2.98] in women and 2.27 [1.75–2.94] in men). However, moderate ERO (20–39 mm 2 ) was associated with significant excess mortality in women (1.47 [1.19–1.77] versus mild). In men, the corresponding hazard ratio did not reach statistical significance. Postoperative survival was similar in men and women. CONCLUSIONS: Women with DMR present with lower ERO and regurgitant volume than men and with considerable adaptive differences to increasing DMR severity versus men. Asymptomatic women are less referred to surgery than men of similar DMR severity, linked to smaller absolute left ventricular size. Severe DMR by similar quantitative thresholds causes similar excess mortality in men and women; moderate quantitative DMR shows a trend for higher excess mortality versus expected in women than men, requiring further confirmation. These data emphasize the importance of quantitative DMR and left ventricular remodeling assessment in men and women for appropriate clinical management.

Abstract Objective To evaluate whether systemic hormone replacement therapy (HRT) influences recurrence outcomes in postmenopausal patients with idiopathic subglottic stenosis (iSGS). Study Design Retrospective cohort study. Setting Tertiary academic medical center. Methods Postmenopausal women (≥50 years) with iSGS who underwent laser‐wedge excision between 2002 and 2024 were included. Patients were categorized by systemic HRT exposure (oral estrogen, progesterone, combined estrogen‐progesterone, or transdermal estrogen) at or before their first surgery. Overdispersion was assessed for all Poisson models; given significant overdispersion, negative binomial regression with a log‐offset for follow‐up time was used as the primary model. Surgery‐free intervals were analyzed using linear mixed models, and time to first recurrence using Cox regression. Models were adjusted for age, body mass index (BMI), parity, oophorectomy, follow‐up length, surgery type, and serial intralesional steroid injections (SILSI) use. Results Among 125 patients, 96 had never used HRT (Never HRT) and 29 used HRT, including 19 actively using HRT at presentation (Current HRT), 5 past users, and 5 subsequent users. The HRT versus Never‐HRT recurrence rate comparison was not significant (adjusted incidence rate ratio [IRR] = 0.81, 95% CI: 0.48‐1.37, P = .422). However, Current HRT use was associated with a 53% lower adjusted recurrence rate versus Never‐HRT use (adjusted IRR = 0.47, 95% CI: 0.25, 0.89, P = .0203). Surgery‐free intervals and time to first recurrence trended longer in Current HRT users but were not statistically significant. Conclusion Current HRT use at presentation was associated with significantly fewer recurrences in postmenopausal iSGS patients. These findings may inform individualized, shared decision‐making regarding HRT use in this population. Level of Evidence 3.

ABSTRACT Background Evaluating fairness in artificial intelligence (AI) is essential before clinical implementation to prevent unintended harm across diverse patient populations. This study assesses performance differences of an image-based surgical site infection (SSI) detection model across age, gender, geography, race, and skin color. Methods Model development/validation study using retrospective, multicenter data across surgical subspecialties from adults who submitted an image of their incision via the electronic health record within 30 days of their procedure between 2019-2024. Area under receiver operating curve (AUROC) was compared by age (<55 vs. ≥55 years old), gender (male vs. female), geography (Rochester, Minnesota vs. Jacksonville, Florida vs. Scottsdale, Arizona vs. regional Minnesota/Wisconsin areas), race (White/Caucasian vs. non-White/Caucasian), and skin color (Fitpatrick I-III vs. IV-VI and Monk A-E vs. F-J). Results Training data contained 13,702 images from 4,274 patients between 2019-2022 (50.1% ≥55 years old; 63.2% female; 91.6% White/Caucasian; 58.5% Rochester, 17.3% Florida, 10.5% Arizona; 96.3% light skin tone), of which 1,348 images (9.8%) had an SSI. No differences in SSI detection existed for age, gender, race, or skin color (AUROC 0.83-0.87, p>0.09), however geographical differences were significant: lowest AUROC 0.83 (95% CI 0.77-0.88) vs. highest AUROC 0.87 (95% CI 0.84-0.89, p=0.01). Temporal validation using 4,242 images from 1,353 patients between 2022-2023 showed intact fairness across subgroups (ΔAUROC ≤0.06) except geography (ΔAUROC ≤0.16). Conclusions The model behaved fairly across age, gender, race, and skin color, however geographical differences persisted. These findings have practical implications underscoring the importance of evaluating bias in clinical AI before deployment.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.

Background & Aims: Multi-target stool DNA (mt-sDNA) is an established stool-based colorectal cancer screening test, yet long-term performance is not well-described. We evaluated follow-up colonoscopy rates & quality, neoplasia yield, and repeat-testing adherence over 10 years with an integrated screening program. Methods: We assembled a retrospective cohort of mt-sDNA tests (September 2014–July 2025) within a multi-site health system. A validated large-language-model pipeline extracted colonoscopy, pathology, and quality endpoints from free-text reports. Detection outcomes (adenoma detection rate, advanced neoplasia, modified advanced adenoma, sessile serrated lesion (SSL), and negative exams) were calculated among high-quality exams; adenocarcinoma, bowel preparation adequacy, and cecal intubation rate (CIR) used all screening exams. We assessed colonoscopy completion ≤1 year after positive mt-sDNA, follow-up colonoscopy findings, findings by time-to-colonoscopy, and adherence to repeat mt-sDNA after negative result. Results: Among 148,624 tests in 110,410 individuals, positivity was 13.6%. Of 19,506 positives, 65.1% completed colonoscopy within 12 months (median 82 days). Colonoscopy after a positive mt-sDNA had high yield: advanced adenoma diagnosis was 30.7%; adenocarcinoma was 1.3%. Of patients who had colonoscopy within 3 years of a negative mt-sDNA test, 45.2% had adenoma/serrated lesion, 9.3% had advanced adenoma and 0.5% had colon cancer. Adenoma detection rate after positive mt-sDNA (>50%) exceeded specialty society quality benchmarks and increased over time; Longer intervals (>6 months) to colonoscopy after a positive test were associated with higher advanced adenoma (trend P=0.001).After an initial negative mt-sDNA, only 35.3% were screened again by mt-sDNA testing within 3 years. Conclusions: Over a decade,mt-sDNA screening achieved high colonoscopy qualitybut revealed critical gaps in the care cascade. One-third of positive tests lacked timely follow-up and nearly two-thirds of negative tests were not repeated on schedule, suggesting opportunities for system-level interventions.

Abstract The use of natural killer (NK) cells for the treatment of solid tumors such as cholangiocarcinoma has been hindered by challenges related to cell production, persistence and trafficking, as well as by reduced efficacy within an immunosuppressive tumor microenvironment. Antitumor immunity can be reduced by the interaction of NK cell expressed programmed cell death protein 1 (PD1) with ligands on tumor and other cells within the tumor microenvironment. The antitumor effect of NK cells is enhanced in cells engineered to express a truncated PD1 without an intracellular domain. The cytolytic potential and therapeutic efficacy of extracellular vesicles (EVs) derived from human NK cells expressing truncated PD1 was evaluated as a cell-free therapeutic to overcome some limitations faced by cell therapies. We demonstrate the feasibility of efficient expansion, production and isolation of therapeutic vesicles from human NK cell lines and from engineered NK92 cells expressing truncated PD1. The cytotoxic efficacy of these therapeutic vesicles was validated in both monolayer tumor cell cultures and in multicellular tumor spheroids. Concomitant administration of gemcitabine upregulated NKG2D ligands on tumor cells and increased susceptibility to NK cell and to NK cell derived EV mediated killing. These findings position engineered NK cell derived-EVs as a scalable and promising cell-free immunotherapeutic for cholangiocarcinoma.

Introduction Out‐of‐hospital community births account for 1.6% to 2% of births in the United States and are associated with fewer obstetric interventions but increased neonatal risk. Little is known about how maternity care providers’ characteristics, values, and prior exposure to community birth influence attitudes toward community birth. Methods We conducted an observational cross‐sectional survey using a 40 to 43 item Research Electronic Data Capture questionnaire distributed October 2 to 30, 2024. Eligible participants (“providers”) included in‐hospital physicians, midwives, community birth providers, and registered nurses. The survey assessed demographics, practice characteristics, provider values, prior community birth experience, and attitudes toward community birth. Descriptive statistics were used to summarize characteristics. Group comparisons between in‐hospital and community birth providers were conducted using analysis of variance and χ 2 or Fisher exact tests. Associations between attitudes and provider values were evaluated using linear models with Bonferroni correction. Results Sixty‐seven providers completed the survey (51 in hospital, 16 community based). Most respondents were female (89.6%) and White (77.6%), with a median of 7 years in practice (IQR, 3‐14.5). Attitudes significantly differed by role ( P = .007) and credentials ( P = .002). In‐hospital providers reported safety concerns about community birth and perceived antenatal counseling to be inadequate. Perceived patient distrust during transfer was common among both in‐hospital and community‐based providers (69% and 81%, respectively). After adjustment for provider role and multiple comparisons, no significant differences in personal values were noted by attitude group; however, providers with positive attitudes toward community birth were more likely to believe that patients value compassion (β = 2.3, P = .004). Discussion Provider attitudes toward community birth appear to be shaped more by professional role and clinical experience than by differences in underlying value systems. High levels of perceived patient distrust during transfer highlight the need for interventions that strengthen compassion across maternity care settings.

Abstract Background Peritumoral brain edema (PTBE) is a frequent complication of CNS tumors and radiation therapy (RT). PTBE is primarily treated with corticosteroids, but prolonged use is associated with severe toxicities including myopathy and immunosuppression. Bevacizumab, an alternative treatment, is not recommended in patients with thromboembolic events and intracerebral hemorrhage. Plasma kallikrein is a key driver of tumor-related edema. By targeting this pathogenic enzyme, the orally delivered inhibitor, RZ402, may provide therapeutic value by controlling edema and decreasing corticosteroid use. Methods In this single-patient investigational new drug protocol, we report results from use of RZ402 for treatment of cerebral edema related to metastatic melanoma and RT. Results A 74-year-old man with BRAF-wildtype melanoma had a right frontal and basal ganglia hemorrhagic metastasis not amenable to resection, treated with stereotactic RT (30 Gy, 5 fractions), followed by ipilimumab and nivolumab. MRI obtained 5 months after RT showed increased edema associated with midline shift. After 12 weeks of treatment with high-dose dexamethasone (16 mg daily), edema remained persistent and patient was unable to tolerate dose reduction below 4 mg daily. Course was complicated by a pulmonary embolus prompting initiation of anticoagulation, leading to deferral of bevacizumab. Patient was treated with RZ402, which was tolerated well with no reported toxicities. Dexamethasone was discontinued over 4 weeks. Follow up imaging 6 weeks after RZ402 initiation and off dexamethasone demonstrated stability without rebound edema. Patient did experience adrenal insufficiency characterized by severe fatigue, managed with low-dose prednisone. RZ402 was discontinued after 8 weeks of treatment with patient remaining clinically stable. Conclusion Despite persistent edema after prolonged use of corticosteroids, the selective plasma kallikrein inhibitor RZ402 was associated with radiographic stabilization and discontinuation of dexamethasone for this patient. These findings support prospective evaluation of RZ402 in treatment of symptomatic cerebral edema related to CNS tumors.