Citations

This study presents a refined murine MetALD model designed to distinguish ethanol-modified features from FFC-driven metabolic steatohepatitis. Chronic ethanol did not uniformly worsen liver injury. Instead, it selectively modified disease trajectory through greater early collagen-positive fibrotic remodeling, altering lipid-droplet architecture, and context-dependent inflammatory chemokine signaling. By 24 wk, FFC and FFC/ethanol injury programs converged, supporting MetALD as a timing- and pathway-dependent modification of metabolic steatohepatitis.

Abstract Health and biomedical science-related academic societies have played significant roles in the development and evolution of science and medicine, as well as the evolution of disciplines, including the diversification of medicine into specialties and subspecialties. They have also had formative roles in the development of clinical practice, professionalism, and training standards. The communities they establish promote knowledge creation and dissemination, provide career and professional development opportunities, articulate professional matters, offer networking opportunities, provide recognition, support members, and perform public engagement and advocacy work. They also play increasingly important roles in educating the public and disseminating objective, evidence-based medical and scientific information. Academic societies face challenges related to membership (recruiting new members and engaging and retaining current members), technology, hosting meetings and conferences, generational shifts (e.g., in demographics and attitudes toward working conditions, career paths, work-life integration), costs and logistics related to operations, and morale within institutions and professions. The Council of Faculty and Academic Societies of the Association of American Medical Colleges plays a unique role in supporting academic medical and related societies by providing an interprofessional forum for their interaction and dialogue, and is a vehicle for asserting their collective voice. To the extent that past is prologue, future advances in health care and science will depend, in part, on the resilience of academic societies and on the health professional workforces that they nourish.

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

Abstract Objective Surgery is an effective, yet underutilized treatment for children with drug‐resistant epilepsy. Although predictors of surgical outcomes are well described, the decision to recommend surgery varies by institution. We aim to evaluate the rates of not recommending surgery, identify associated patient characteristics, and quantify variability across centers. Methods We queried the Pediatric Epilepsy Research Consortium Surgery database, a prospective multicenter cohort of children (0–18 years) undergoing initial evaluation for epilepsy surgery. Patients with documented surgical decisions were included. Demographic, clinical, and presurgical evaluation variables were compared by surgical recommendation status. Logistic regression identified factors associated with not recommending surgery. Mixed‐effects models quantified between‐center variability. Results Among 2480 patients across 29 centers, 532 (21%) were not recommended epilepsy surgery (median center rate 17%, interquartile range [IQR] 10%–28%). After accounting for patient characteristics associated with surgical candidacy, substantial variation in decision‐making remained across centers, with a median twofold difference in the odds of not recommending surgery between otherwise similar patients evaluated at different institutions (Median Odds Ratio = 2.25; Intraclass Correlation Coefficient = .18). The clinical characteristics most strongly associated with not recommending surgery included monthly or less frequent seizures (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.75–2.69), non‐structural etiology (OR 2.02, 95% CI 1.56–2.61), and taking ≤2 anti‐seizure medications (ASMs) (OR 1.67, 95% CI 1.34–2.08, all p 's < .01). These characteristics showed minimal clustering across centers (ICCs < .05). Significance One in five children evaluated for epilepsy surgery are not recommended to pursue surgical treatment. Although clinical factors influence decision‐making, they do not explain the substantial variation in recommendations across pediatric epilepsy centers. Similar children evaluated at different institutions had significant differences in the odds of not being recommended surgery, suggesting that institutional decision‐making contributes importantly to surgical candidacy.

ABSTRACT Endoluminal flow diverters are increasingly used to treat cerebral aneurysms. Despite good aneurysm occlusion efficacy, delayed ischemic complications due to side branch or perforator occlusion remain a serious concern. However, the mechanisms leading to side branch occlusion are poorly understood. To investigate these mechanisms, a combination of animal and computational models was utilized. Flow diverters were deployed in four rabbit superior mesenteric artery (SMA) and studied with computational fluid dynamics (CFD) and a previously developed fibrin dynamics model. Subject‐specific vascular models were reconstructed from 3D rotational angiography images and flow conditions were derived from Doppler ultrasound velocity measurements. Flow diverting devices were virtually deployed within the vascular models under guidance from angiography images. Coupled flow and fibrin production, transport, and adhesion simulations were carried out and the effects of fibrin accumulation at the origin of jailed side branches after flow diverter implantation were analyzed. The results of the computational models suggest significant fibrin accumulation across the struts of all flow diverting devices jailing side branches. Larger accumulation was observed at the more distal branches. However, minor flow alterations were produced which were not detectable in angiography sequences. These results were in agreement with experimental observations. On the other hand, fibrin accumulation alone did not explain complete side branch occlusions, which are likely the result of the interaction between initial fibrin accumulation and subsequent cell migration from the peripheral parent artery.

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received &lt;7/8 MMUD grafts; 82.4% of the &lt;7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the &lt;7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the &lt;7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

Background: Perinatal and early-life factors may influence non-Hodgkin lymphoma (NHL) risk, but study results have been mixed and exposure data for childhood ages are limited. Herein, we investigated associations of these exposures with risk of NHL and common subtypes. Methods: This case–control study included 2280 NHL cases and 2253 controls, enrolled from 2002 to 2014 at the Mayo Clinic Rochester. Self-reported perinatal and early-life exposures included maternal age at birth, birth order, birthweight, time breastfed, height and weight at ages 7, 12, and 18 years relative to peers, and age and weight when growth ceased. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for design variables and potential confounders. Linear trend tests were performed for ordinal variables, and heterogeneity tests were performed to evaluate whether associations varied across four NHL subtypes. Results: After multivariable adjustment, greater birth weight (OR = 1.15 for quartile 4 vs. 1; p-trend = 0.04), weight at age 7 relative to peers (compared to average, OR = 1.05 for heavy and OR = 0.87 for thin; p-trend = 0.002), and weight when growth ceased (OR = 1.30 for quartile 4 vs. 1; p-trend < 0.001) were associated with increased NHL risk. An inverse association was observed for breastfeeding duration with NHL risk (OR = 0.77 for >6 months vs. never; 95% CI 0.61–0.97). Associations did not significantly vary by major NHL subtype (p-heterogeneity > 0.05). Other perinatal and early-life exposures were not associated with NHL risk. Conclusions: Greater body weight at birth and through childhood may be associated with increased NHL risk, potentially extending the life-course perspective on adiposity and lymphomagenesis, with implications for prevention.

This study examines the patient- and hospital-level variation in time to initiation of inpatient management among patients admitted to general medical services.

Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health–supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.

ABSTRACT Background Post‐pancreatectomy exocrine insufficiency is common after resection for pancreatic cancer and requires pancreatic enzyme replacement therapy (PERT). We sought to determine the out‐of‐pocket cost of PERT and the association between PERT and survival. Methods The SEER‐linked Medicare database was queried for patients with pancreatic cancer who underwent pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) from 2010 to 2019. Cumulative out‐of‐pocket costs were calculated and stratified by procedure and radiation. Results 11,854 Medicare beneficiaries with resected pancreatic cancer were identified, 4,653 (39%) required PERT and 7,201 (61%) did not. Median age was 73.0, 50.6% were female and 83.6% White. 25.9% underwent DP and 74.1% underwent PD; 7% received neoadjuvant radiation while 23.5% received adjuvant radiation. Logistic regression demonstrated that female sex (OR 1.25, 95% CI 1.16‐1.35, p < 0.001), neoadjuvant radiation (OR 1.93, 95% CI 1.67‐2.24, p < 0.001), and PD (OR 2.45, 95% CI 2.23‐2.7, p < 0.001) were risk factors for requiring PERT. Patients without subsidies who underwent DP paid a cumulative $4,736 out‐of‐pocket for PERT after 5 years, those who underwent PD paid $5,601 out‐of‐pocket. Conclusions Nearly 40% of Medicare beneficiaries took PERT after resection for pancreatic cancer and paid thousands in out‐of‐pocket costs. While a conservative estimate, these findings highlight the importance of addressing this financial burden to patients.