Citations

Abstract Objective Epilepsy duration is a modifiable risk factor in the outcome of definitive epilepsy surgery; however, an analogous effect in palliative procedures has not been shown. We reviewed the Pediatric Epilepsy Surgery Database data for an association between epilepsy duration and seizure reduction in palliative procedures. Methods Patients enrolled between January 2018 and April 2025 who underwent their first epilepsy surgery with palliative intent with 6 months of follow‐up were included. Procedures included neuromodulation, corpus callosotomy, hemispherotomy, lesionectomy, and lobectomy where surgical intent was not seizure freedom. Outcomes of seizure freedom, 90% seizure reduction, and 50% seizure reduction were considered at 6–12 months and >12 months from surgery. Duration from epilepsy onset to surgery was compared for patients above and below each outcome threshold at each time point. Logistic regression analysis for the association between epilepsy duration and seizure reduction adjusted for potential confounders including procedure type, etiology, and other clinical factors. Logistic regression analysis was performed on the overall cohort and subgroups of patients with each procedure. Results A total of 588 patients were included. Initial univariate analysis suggested that epilepsy duration at time of surgery was significantly associated with seizure freedom and 90% seizure reduction at both 6–12 months and >12 months. After adjusting for confounders, only seizure freedom at >12 months was significantly associated with duration of epilepsy. When individual procedures were considered, only lobectomy was sensitive to duration of epilepsy in multivariate analysis, with significant impacts on >50% and >90% seizure reduction at >12 months. Lesional epilepsy predicted seizure freedom at >12 months. Neuromodulation and corpus callosotomy were less likely to achieve seizure reduction than other procedures. Significance We did not find an association between early epilepsy surgery and seizure reduction. This reflects the heterogeneity of our population, including different types of surgical procedures and lesional and nonlesional epilepsies.

Abstract Background Complications such as intermittent pouchitis (IP) and chronic inflammatory disorders of the pouch (CP) are common after ileal pouch-anal anastomosis (IPAA), particularly among patients with both ulcerative colitis and primary sclerosing cholangitis (PSC). There are no standardized approaches for prophylaxis against these complications for patients with PSC undergoing IPAA. We compared outcomes among patients with PSC and IPAA who received antibiotic or immunosuppressive therapies to those who did not. Methods We designed a retrospective cohort study that included patients with ulcerative colitis and PSC from 7 tertiary care centers that underwent IPAA between 1994 and 2023. Patients were categorized on whether they received medications following IPAA that may provide primary prophylactic benefit, such as antibiotics, probiotics, immunomodulators, or biologic medications; and the proportion of patients developing IP and CP was evaluated. Results A total of 172 patients were included in the cohort, and 13 (7.6%) patients received antibiotics or immunosuppressant medications. Antibiotics and probiotics were the most common therapy (5 patients, 2.9%), followed by biologics, small-molecule inhibitors, immunomodulators, or mesalamine (all 1 patient, 0.6%). Compared to patients not receiving antibiotics or immunosuppression, patients receiving antibiotics or immunosuppression were significantly less likely to develop IP (69.2% vs 91.2%; P = .03; odds ratio 0.22; 95% CI, 0.06-0.80) and CP (23.1% vs 56.0%, P = 0.04; OR 0.24, 95% CI, 0.06-0.89). Conclusions In this retrospective cohort of patients with ulcerative colitis and PSC undergoing IPAA, usage of concomitant antibiotics or immunosuppression was low. However, use of concomitant antibiotics or immunosuppression may decrease the burden of inflammatory conditions of the pouch in these high-risk patients.

Introduction Ultra-marathon races present a prolonged cardiopulmonary physiological stress but the magnitude, persistence, and impact of race environment on respiratory function are incompletely understood. The aim of this study is to observe the effect of ultra-marathon trail races on both lung function and airway impedance. Methods Fifty-seven individuals (49/8, M/F) participated in either the Courmayeur-Champex-Chamonix (CCC ® , 101.5km), Ultra Trail du Mont-Blanc (UMTB ® , 171.5 km), or the Hong Kong 100 (HK, 100 km) races. Participant demographics were measured pre-race and included: age (40.7±10.3 yrs); height (175.5±7.1 cm), body mass (69.7±8.3 kg). Spirometry, airway impedance (via forced oscillation technique, FOT), maximal inspiratory (MIP) and expiratory pressure (MEP), and exhaled nitric oxide (ExNO) were assessed before, immediately (18–4 hours after), and 188–24 hours post-race. Mixed effects analysis with Dunnett’s post-hoc correction were conducted to evaluate the effects of race and time. Results Results demonstrated significant effects of time for: forced vital capacity (FVC), forced expiratory flow over one second (FEV 1 ), peak expiratory flow (PEF), forced expiratory flow between 25-75% (FEF25-75), forced expiratory flow at 25% and at 50% (FEF 25 and FEF 50 , respectively), MIP, MEP, airway reactance (X) at all frequencies from FOT (X 5 , X 11 , X 19 ), respiratory rate, and ExNO (all p <0.05). A significant effect of race was also observed for ExNO ( p =0.002). Discussion Findings indicate declines in lung function and airway impedance immediately after ultra-marathon races, some of which, persisted up to 24 hours post-race. Further investigations are required to better understand the etiology of changes in lung function following ultra-endurance events.

Abstract Among 1141 inpatients from Arizona with community-acquired pneumonia, 865 (75.8%) were tested for Coccidioides infection and 85 (9.8%) had positive results. Patients more commonly underwent testing if they had concerning radiographs, fever, dyspnea, or fatigue. Patients with night sweats, rash, headache, or eosinophilia more commonly had positive results.

Abstract Introduction Mucosal immunization and respiratory IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of respiratory IgA responses following mucosal vaccination remain poorly understood. Methods In this project, we established SARS-CoV-2 breakthrough infection and mucosal adenovirus-based booster vaccination models. Using genetic mouse models and various in vivo and in vitro blockade or depletion approaches, we further investigated the mechanisms regulating respiratory IgA responses. Results Here we found that a mucosal adenovirus-based booster vaccination in mouse models revealed that respiratory booster immunization elicited markedly stronger and more durable respiratory IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we identified that local CD4+ T cells support respiratory IgA production by promoting IgA+ B cell class switching, proliferation, and survival in situ. This T cell help depended on interactions between local Blimp-1+ T-bet+ Th1 cells and B cells, mediated through ICOS/CD40L/MHC-II engagement and IL-21 signaling. Furthermore, lung macrophages contributed to the mucosal IgA response via TGF-β production. Consequently, mucosal administration of SARS-CoV-2 Spike-encoding mRNA encapsulated in pulmonary surfactant (PS)- incorporated lipid nanoparticles designed to target lung macrophages elicited a stronger mucosal IgA response. Conclusion Our results uncover a local cellular network supporting enhanced mucosal IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens such as H5N1 influenza. Funding Source AI147394, AG069264, AI112844, HL170961, AI154598, AI176171 to J.S., AI67986, AI177467 to Hui.H; U54CA260582 to S.L.L; R01AI168684 to G. Z.; S.L.L was also supported by a fund provided by an anonymous private donor to The Ohio State University. Topic Categories Mucosal and Regional Immunology (MUC)

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) &lt;0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend&lt;0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend&lt;0.001 and &lt;0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend&lt;0.001 and &lt;0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Background Cardiac rehabilitation (CR) leads to increased exercise capacity (VO 2 peak) and risk reduction of major adverse cardiovascular events (MACEs). Women exhibit blunted VO 2 peak improvements following CR. The purpose was to examine sex differences in the clinical predictors of VO 2 peak improvement and odds of MACEs following CR. Methods From 1999 to 2017, all consecutive patients undergoing cardiopulmonary exercise testing before and after CR were included. Sex differences in peak exercise metrics in response to CR were compared. Multiple logistic regression models were fit to assess clinical predictors of VO 2 peak improvement (defined as >0% from pre‐CR) and MACEs following CR for men and women. Results A total of 513 men and 158 women were included. Men had greater increases in VO 2 peak than women following CR ( P =0.001). For men, independent predictors of VO 2 peak improvement following CR included higher CR session attendance (odds ratio [OR], 1.04 [95% CI, 1.02–1.06]), peripheral artery disease (OR, 0.47 [95% CI, 0.25–0.86]), and pre‐CR VO 2 peak (OR, 0.98 [95% CI, 0.97–0.99]) (all, P <0.02). Independent predictors of lower odds of MACEs following CR in men included higher number of CR sessions (OR, 0.97 [95% CI, 0.95–0.99]), pre‐CR VO 2 peak (OR, 0.98 [95% CI, 0.97–0.99]), surgical CR indication (OR, 0.34 [95% CI, 0.18–0.68]), and no history of peripheral artery disease (OR, 2.94 [95% CI, 1.60–5.38]) (all, P <0.02). For women, the selected clinical characteristics were not statistically significant independent predictors of VO 2 peak improvement or odds of MACEs (except for diabetes) following CR. Conclusions These findings suggest that clinical predictors of VO 2 peak improvement and odds of MACEs following CR are sex specific.