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Abstract Purpose This study explores how new residents experienced the transition to residency, examines factors that made the transition process more or less difficult, and identifies potentially modifiable program features that enhanced or would have enhanced transition experiences. Method The authors conducted a qualitative interview study of postgraduate year (PGY) 1 residents in emergency medicine, family medicine, general surgery, internal medicine, obstetrics and gynecology, pediatric and adolescent medicine, and psychiatry at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin between December 2020 and March 2021. Open-ended questions explored residents’ transition experiences. Interviews were audio-recorded, transcribed, coded inductively, and analyzed iteratively using general thematic analysis from an epistemologically constructivist perspective. Results Forty-five residents (25 women, 20 men) from 12 programs, 7 specialties, and 4 states participated. PGY-1 residents experienced the transition to residency as a confluence of overlapping and interconnected transitions that unfolded over time, spanned multiple life domains, and generated numerous personal and professional demands. Residents appraised demands based on their effects on patient care, professional growth, and personal well-being and struggled when coincident demands forced tradeoffs among these concerns. Residents who experienced many difficulties during the transition to residency reported high demands (eg, due to transition-related discontinuities, depleted resources from prior transitions or a difficult match experience, structural and systemic barriers, coincident personal or situational stressors) and/or fewer resources (eg, insufficient residency or life skills, limited social support, financial strain). Preparedness and supportive relationships eased the transition process. Residency program features that enhanced or would have enhanced the transition experience included monitoring and limiting overall demands, minimizing unhelpful and harmful demands, calibrating constructive demands, and increasing holistic support. Conclusions Study findings illuminate transition experiences of PGY-1 residents, reveal person-centered considerations to inform ongoing improvement efforts, and identify potentially actionable steps programs can take to improve resident transition experiences.

Purpose To explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma. Methods Single-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria. Results Initial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity ( p = 0.034), hypertension ( p = 0.017), and diabetes mellitus ( p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus ( p = 0.01) and obesity ( p = 0.04) remained significantly associated with earlier T category on initial presentation. Conclusion Among patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Introduction: Plasma biomarkers of Alzheimer’s disease (AD), including amyloid-β (Aβ42/Aβ40), phosphorylated tau (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) have shown strong reliability in predicting dementia risk. White matter hyperintensities (WMH) represent a major vascular contributor to dementia. We investigated how plasma biomarkers of AD interact with WMH on MRI to influence incident dementia risk. Methods: We included dementia-free participants from the Atherosclerosis Risk in Communities (ARIC) Study who underwent MRI and plasma biomarker assessment at Visit 5 (2011–2013). WMH was quantified and considered continuously (log-transformed and standardized), and in tertiles. Plasma biomarkers were log-base-2-transformed. Cox proportional hazards models were used to estimate dementia risk over 10 years associated with plasma biomarkers and WMH, independently and multiplicatively. Models were adjusted for demographic variables (age, sex, race, and education), vascular risk factors (hypertension, diabetes, smoking status, body mass index, and estimated glomerular filtration rate), and APOE ε4 status. Results: Among 1,538 participants (aged 67- 90 years, 29% Black), 30% ( N = 462) developed dementia over the 10-year follow-up period. For every doubling of plasma Aβ42/Aβ40 , indicating lower amyloid burden, dementia risk decreased, while doubling of p-tau 181 , NfL, and GFAP were each associated with increased dementia risk, in separate models; each of these associations was independent of WMH (Table 1). Additionally, dementia risk increased per SD increase in WMH, independent of each plasma biomarker. Although no multiplicative interaction terms reached statistical significance (p<0.05), there was suggestive evidence that Aβ42/Aβ40 and GFAP have smaller effect sizes on dementia risk in subgroups at the highest WMH tertile (p-interactions<0.10; see Table 2). Discussion: Plasma biomarkers and WMH independently predict dementia risk over 10 years, though there remained limited evidence of multiplicative effects. Plasma biomarkers may be less important for dementia risk in individuals who also have extensive WMH. These findings emphasize the importance of incorporating both AD-specific plasma markers as well as indicators of cerebral small vessel disease, such as WMH, into dementia risk profiling.

Background: Embolic stroke of undetermined source (ESUS) comprises infarct mechanisms presumed to be embolic and non-lacunar. One explanation for the lack of superiority of anticoagulation over aspirin is the inclusion of subcortical infarcts with white matter disease (WMD), reflecting small vessel pathology. We hypothesized that WMD is associated with recurrent ischemic stroke (RIS) in ESUS and this risk is not lessened by anticoagulation. Methods: We conducted a secondary analysis of the multicenter Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) registry, including ESUS patients from 27 U.S. centers (2015–2024). WMD severity was graded using the Fazekas scale from MRI and dichotomized as mild (0–1) vs. moderate-to-severe (2–3). The primary outcome was RIS. Secondary outcomes were major bleeding and all-cause mortality. Inverse probability of treatment weighting (IPTW) adjusted for baseline differences. Cox proportional hazards models assessed associations between WMD and outcomes. Subgroup analyses explored effect modification by age, risk factors, and treatment type. Results: Among 1,890 ESUS patients with MRI data, 684 (36.2%) had Fazekas 2–3. These patients were older with more vascular risk factors, but IPTW achieved covariate balance. In the weighted cohort, RIS occurred more frequently in Fazekas 2–3 vs. 0–1 (7.1% vs. 4.6%/year; HR 1.56, 95% CI 1.10–2.22, p = 0.01). Major bleeding and mortality were similar (bleeding: 1.7% vs. 1.8%/yr, HR 0.96, p = 0.92; death: 7.0% vs. 6.7%/yr, HR 1.04, p = 0.81). Subgroup analyses showed no interaction between WMD and age, vascular risk factors, or treatment type (antiplatelet vs. anticoagulation), suggesting consistent RIS risk in those with higher WMD. Discussion: Moderate-to-severe WMD identifies ESUS patients at higher risk of ischemic stroke recurrence, with no mitigation by anticoagulation. These findings suggest that WMD may indicate non-embolic mechanisms and support the use of imaging-based risk stratification in ESUS.

Introduction: Emerging evidence highlights the increased white matter hyperintensity (WMH) burden in APOE4 homozygotes, the greatest genetic risk factor for late-onset Alzheimer's disease (AD). The link between WMH and cerebral amyloid-beta (Aβ) accumulation remains unclear, especially in presymptomatic AD phases. We aimed to determine whether WMH burden (global or regional) mediates the association between APOE4 homozygosity and amyloid-PET Aβ deposition in a population of subjects with intact cognition. Methods: WMH were segmented using a deep learning model applied to T1 and T2-FLAIR MRI scans from 49 cognitively intact individuals older than 50. The global and regional (periventricular, lobar, basal ganglia, infratentorial) WMH volumes were adjusted for total intracranial volume and log-transformed to normalize distribution. Amyloid-PET cerebral Aβ burden was quantified in centiloid units; individuals with centiloid > 20 were classified as Aβ-positive. To examine our mediation hypothesis, we tested three pathways using logistic and linear regression models: 1) Path a, the association between APOE4 and global or regional WMH volumes (outcome); 2) Path b, the association between WMH volumes and Aβ positivity (outcome); 3) Path c (total) and c' (direct) effects of APOE4on Aβ positivity (outcome), before and after adjusting for WMH volumes. All models incorporated age and vascular risk factors (hypertension, diabetes, hypercholesterolemia, cigarette smoking). Results: We included 11 APOE4 homozygotes, of whom 7 were Aβ-positive and 38 non-carriers (35 3/3 and 3 3/2) (6 Aβ-positive). Compared to APOE4 non-carriers, APOE4 homozygotes had significantly greater WMH volumes in the posterior periventricular region only (p= 0.0453) (path a). Homozygotes were significantly more likely to be Aβ-positive compared to non-carriers (total effect, path c p=0.0019). This association remained significant after adjusting for WMH (direct effect, path c'= 0.0027). However, neither global (p=0.72) nor posterior periventricular (p=0.84) WMH volumes predicted Aβ positivity (path b) (Figure). Conclusions: In our cohort of cognitively normal individuals including preclinical AD, neither global nor regional WMH burden mediated the relationship between APOE4 homozygosity and Aβ positivity. Larger studies are needed to further evaluate the mechanistic relationship between WMH and neurodegeneration in APOE4 carriers.

INTRODUCTION: A Model for End-Stage Liver Disease-lactate (MELD-LA) score is an independent predictor of inpatient mortality and organ failure validated in more than 8,600 patients across diverse settings. However, its utility in sepsis, particularly when combined with lactate clearance (LA clearance), has not been fully evaluated. In this study, we examined the dynamic role of MELD-LA with 24-hour LA clearance as a predictor of 30-day mortality in critically ill patients with cirrhosis and sepsis. METHODS: We analyzed cirrhosis patients with sepsis admitted to the intensive care unit (ICU) in a large US healthcare system (20 hospitals) from 2014 to 2022, examining MELD-LA and LA clearance within 24 hours as predictors of 30-day mortality. We externally validated our findings in the Asian Pacific Association for the Study of the Liver-acute-on-chronic liver failure Research Consortium, a multinational Asian cohort (31 centers) from 2009 to 2019. RESULTS: A total of 3,879 cirrhosis patients with sepsis were admitted to the ICU (43.2% female, 20.5% Hispanic, 12.4% on dialysis; mean initial LA 4.5 mmol/L, MELD 20.8, MELD-LA 17.6). Survivors showed a median lactate change of −1.04 (35% clearance) compared with −0.4 (12%) for nonsurvivors. LA clearance within 24 hours was influenced by the presenting MELD-LA. In the North American cohort, ≥35% LA clearance was associated with improved 30-day survival (odds ratio 0.41, 95% CI 0.31–0.53; P < 0.001). Similarly, in the Asian Pacific Association for the Study of the Liver cohort (n = 1,259), ≥35% clearance was linked to a 60% reduction in mortality (odds ratio 0.42, 95% CI 0.28–0.62; P < 0.001). When stratified by LA clearance, patients with LA clearance of ≥35% had a higher percentage of early administration of resuscitative measures than those with LA clearance of < 10% especially regarding early antibiotic administration (82.5% vs 67.6%; P value <0.001). DISCUSSION: Early reduction in initial LA by one-third predicts 30-day mortality and may indicate treatment response in cirrhosis patients with sepsis in the ICU. Combining MELD-LA and LA clearance early enables better risk stratification and informs management.

Background: Venous air embolism (VAE) is a potentially catastrophic complication during neurosurgical procedures, particularly in the sitting position. As practices vary widely, we conducted a survey to describe the global practice patterns for intraoperative detection and management of VAE. Methods: Following institutional review board (IRB) approval, we conducted a cross-sectional study using a 48-question online survey that was distributed via a snowball sampling approach, initially to the Society of Neuroscience in Anesthesiology and Critical Care (SNACC) community and subsequently to international collaborators. Descriptive statistics summarized responses, and proportional comparisons between high-income and low- and middle-income country respondents were assessed using a χ 2 or the Fisher exact tests, as appropriate. Results: Of 307 responses, 297 were analyzed, representing 40 countries. Survey response rate was 25% among SNACC members. End-tidal carbon dioxide (EtCO 2 ) monitoring was the most frequently reported VAE monitoring modality, particularly for sitting craniotomies. Common barriers to implementing advanced monitoring included limited equipment availability and a lack of a transesophageal echocardiography (TEE) specialist. Decision-making for cases at VAE risk relied on team consensus (62%), review articles and primary literature (48%), and institutional protocols (42%). Among respondents, 89% expressed interest in consensus guidelines for VAE management. Conclusions: There is substantial global variability in both the preparation for and management of VAE during neurosurgical procedures. EtCO 2 is the preferred monitoring approach in routine practice, as resource limitations prevent the broader adoption of more sensitive techniques, such as TEE. The high interest in consensus guidelines underscores an opportunity for professional societies to standardize approaches and improve patient safety.

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, and despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teff) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Treg), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular adenosine 5-triphosphate receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell–specific P2RX7-knockout (P2RX7-KO) mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared with P2RX7-KO Tregs, which failed to inhibit type 1 and follicular helper T–like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared with P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

Abstract Background & Aims Central reading of endoscopy and histopathology is the current standard for disease activity assessment in inflammatory bowel disease (IBD) clinical trials but is limited by interreader and intrareader variability, operational delays, and cost. Artificial intelligence (AI) and machine learning (ML) offer the potential to improve accuracy, efficiency, and reproducibility. The International Organization for the Study of IBD (IOIBD) developed consensus statements on AI/ML use for endoscopic and histologic endpoint assessment in IBD trials. Methods As part of the IOIBD endpoints cluster initiative, a narrative, evidence-informed review with literature searches of Medline and Embase (January 2018-February 2025) identified studies applying AI/ML to endoscopy or histology in IBD. Relevant evidence informed 36 survey statements formulated by a steering committee. Seventy-two IOIBD members were invited to vote online; consensus required ≥80% agreement (score: 7-10 on a 10-point scale). Results Forty-five members completed the survey. Consensus was reached for 28 statements related to endoscopy, pathology, and trial design. Experts agreed that AI-based central reading could improve diagnostic accuracy, expedite processes, reduce costs, and enhance reproducibility. Combining human and AI assessments was favored over AI replacement. The key limitations identified included insufficient validation, generalizability concerns, and dependence on human-annotated training datasets. Conclusions This IOIBD consensus supports the integration of AI/ML into central reading for IBD clinical trials to improve objectivity, efficiency, and consistency, while maintaining human oversight. Further research should address validation, regulatory frameworks, and multimodal integration to enable broader adoption in both trials and clinical practice.

83 Background: Colon cancer is among the leading causes of cancer-related morbidity and mortality globally, with an increasing incidence observed in younger populations. Lifestyle and metabolic risk factors seem to play an important role in this rising incidence. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Emerging evidence suggests that these agents may have potential anti-tumor activity as GLP-1 signaling may influence pathways involved in cell proliferation and inflammation. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with colon cancer with comorbid obesity, exploring potential interactions between metabolic modulation and disease behavior. Methods: A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Adult patients aged 18 and above with colon cancer and comorbid obesity were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and common comorbidities. We followed these patients for 5 years to assess outcomes, including overall mortality, myocardial infarction, sepsis, acute pancreatitis, need for mechanical ventilation and hemodialysis. Results: We identified 1986 patients with colon cancer and obesity who received GLP-1 receptor agonists, and 16384 patients with colon cancer and obesity who did not receive GLP-1 therapy. The average age was 68.8 years in the first cohort and 74.3 years in the second cohort. After propensity matching, each cohort consisted of 1983 patients with similar baseline characteristics and ethnicity distribution. Our analysis found that over 5 years, patients with colon cancer and obesity who received GLP-1 receptor agonists had a significantly lower risk of overall mortality (Hazard Ratio (HR): 0.461, 95% CI: 0.401 to 0.532, p-value < 0.001), myocardial infarction (HR: 0.827, 95% CI: 0.668 to 0.993, p-value =0.005), sepsis (Risk Difference: -3.48%, 95% CI: -4.774 to -2.185, p-value < 0.001), and need for mechanical ventilation (HR: 0.486, 95% CI: 0.321 to 0.739, p-value = 0.037). There was no statistically significant difference in the risk of acute pancreatitis and need for hemodialysis between the two subgroups. Conclusions: Our study revealed that patients with colon cancer and obesity who received GLP-1 receptor agonists had a significantly lower risk of mortality, myocardial infarction, sepsis, and need for mechanical ventilation. Further longitudinal cohort studies are imperative to better understand these associations and guide evidence-based clinical practice in this population.