Faculty Bibliography

BACKGROUND:Infliximab (IFX) is commonly used in the management of acute severe ulcerative colitis (ASUC), yet up to 30% of individuals still require colectomy within 1 year. Clinical data characterizing these patients, however, are limited. AIMS/OBJECTIVE:We aimed to determine risk factors for colectomy among patients with ASUC who received in-hospital IFX treatment. METHODS:We performed a retrospective analysis of patients with ASUC who were treated with at least one dose of IFX while admitted between 2014 and 2022. Cox proportional hazards (PH) models were used to assess demographic, clinical, and laboratory risk factors for colectomy within 30 days and 1 year of IFX initiation. RESULTS:Overall, 36/170 (21.2%) patients underwent colectomy within 1 year of IFX initiation, with 22 (12.9%) individuals requiring colectomy within 30 days. On univariable analysis, concomitant Clostridioides difficile infection during admission, a ≤50% decrease in C-reactive protein (CRP) and experiencing 3 or more bowel movements per day within 48 hours after an initial IFX dose were significantly associated with 1-year colectomy. On multivariable Cox PH analysis, C. difficile infection during admission (aHR=2.92, 95% CI: 1.12-7.58) and a higher CRP/albumin ratio on admission (aHR=1.13, 95% CI: 1.01-1.27) were associated with increased colectomy risk within 1 year of IFX initiation. CONCLUSIONS:C. difficile infection and a higher CRP/albumin ratio on admission are associated with decreased time to colectomy within 1 year of IFX among patients presenting with ASUC. These factors may aid in early risk stratification to minimize delays in JAK-inhibitor initiation or surgical referral.

BACKGROUND:The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. METHODS:We investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242,283 cases, 1,569,734 controls), T1D (18,942 cases, 501,638 controls), and PDAC (10,244 cases and 360,535 controls) in individuals of European ancestry. RESULTS:Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. CONCLUSIONS:Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

BACKGROUND:Current CPR guidelines recommend 10 breaths/min in adult cardiac arrest patients with an advanced airway, though this is largely based on animal studies. We evaluated the association between ventilation rate and return of spontaneous circulation (ROSC) in in-hospital cardiac arrest (IHCA). METHODS:) monitoring. Patients were enrolled from 25 tertiary centers in the U.S. and U.K. A subset had intra-arrest arterial blood gases collected per routine care. RESULTS:did not differ significantly, suggesting a hemodynamic mechanism. CONCLUSIONS:monitors. Thus, more studies are needed to determine the need to re-evaluate current ventilation targets during CPR in intubated patients.

OBJECTIVE:People with migraine have a higher prevalence and severity of insomnia. We examined the relationship between insomnia severity and migraine-related disability (MIDAS) and migraine-specific quality of life (MSQv2.1). METHODS:We conducted a post-hoc analysis of a pilot randomized controlled study assessing the RELAXaHEAD application in those with insomnia and comorbid migraine. Descriptive statistics were used to summarize demographic and clinical characteristics. Linear mixed model analysis was conducted to evaluate Insomnia Severity Index (ISI) as a predictor of each MSQv2.1 domain and MIDAS. RESULTS:Forty-two participants completed baseline and at least one follow-up survey. Mean age was 43.8 years (SD 12.6) and the majority (85.7%) were female. Most participants (81.0%) had severe migraine-related disability (median baseline MIDAS, 32 (IQR 52)). Over half (54.8%) of participants had moderate clinical insomnia (mean baseline ISI, 18.5 (SD 4.6)). Baseline median MSQv2.1 scores were 44.3 (IQR 31.4) for Role Function-Restrictive (RFR), 65.0 (IQR 45.0) for Role Function-Preventive (RFP), and 46.7 (IQR 46.7) for Emotional Function (EF). The effect of ISI on MIDAS was statistically significant (rate ratio (RR)=1.10, p < 0.05, 95%CI [1.028, 1.171], meaning each one-point increase in ISI was associated with a 10% higher MIDAS score). Additionally, a 1-point increase in ISI was associated with a decrease of 1.2 points in MSQ-RFR (B=-1.205, p = 0.001),1.0 point in MSQ-RFP (B=-0.981, p = 0.020), and 1.4 points in MSQ-EF (B=-1.66, p = 0.001). CONCLUSIONS:Our study revealed significant associations between insomnia severity and migraine-related disability and quality of life, highlighting the importance of prevention and sleep intervention for patients with migraine.

PURPOSE/OBJECTIVE:Many studies estimate that more than 50% of non-hospitalized patients with long-COVID develop moderate to severe autonomic dysfunction. However, the specific impact of autonomic dysfunction as it relates to quality of life in long-COVID is not fully understood. The aim of the current study is to assess autonomic symptoms and quality-of-life in patients with Post-Acute Sequelae of COVID-19 (PASC) recruited from a neurology department outpatient setting. METHODOLOGY/METHODS:In a two-year follow-up study of a baseline cohort of 93 non-hospitalized SARS-CoV-2 laboratory-positive patients evaluated for PASC between November 2020-August 2021, 44 participants completed follow-up telephone questionnaires examining quality-of-life as well as neurologic and autonomic symptoms. RESULTS:Among 93 participants, 44 (47 %) completed the two-year follow-up evaluation and 27 (61 %) were female with a median age of 55 years (IQR = 24-88). Most participants (95 %, 42/44) were vaccinated against COVID-19 and 43 % (19/44) had a pre-existing neurological disorder. Median time from index COVID-19 infection to follow-up was 26 months (IQR = 23-17), with a median of 15 months (IQR = 15-16) between visits. Fatigue, word finding difficulty, and changes in memory were the most commonly reported PASC symptoms. Sixty-six percent (29/44) of individuals met criteria for autonomic dysfunction as defined by the Composite Autonomic Symptom Score-31 (COMPASS-31) scale. Secretomotor and gastrointestinal subdomains demonstrated significant associations with Neuro-QoL metrics for Anxiety, Depression, and Fatigue. For every 1 additional PASC symptom reported at a follow-up study visit, there was an average increase of 1.5 points on the COMPASS-31 composite score. In addition, visual disturbances and sleep impairment were both associated with increased autonomic dysfunction. CONCLUSION/CONCLUSIONS:The strong association between autonomic dysfunction and reduced QoL in PASC and the relation to insomnia, visual dysfunction, and functional impairment are valuable findings, reinforcing the clinical impact of these symptoms longitudinally after index COVID-19 infection.

Standard genome-wide association studies (GWAS) and rare variant burden tests are essential tools for identifying trait-relevant genes¹. Although these methods are conceptually similar, by analysing association studies of 209 quantitative traits in the UK Biobank^2-4, we show that they systematically prioritize different genes. This raises the question of how genes should ideally be prioritized. We propose two prioritization criteria: (1) trait importance - how much a gene quantitatively affects a trait; and (2) trait specificity - the importance of a gene for the trait under study relative to its importance across all traits. We find that GWAS prioritize genes near trait-specific variants, whereas burden tests prioritize trait-specific genes. Because non-coding variants can be context specific, GWAS can prioritize highly pleiotropic genes, whereas burden tests generally cannot. Both study designs are also affected by distinct trait-irrelevant factors, complicating their interpretation. Our results illustrate that burden tests and GWAS reveal different aspects of trait biology and suggest ways to improve their interpretation and usage.

BACKGROUND:Data on patient-centered outcomes of mobile health cardiac rehabilitation (mHealth-CR) for older adults with ischemic heart disease are limited. The RESILIENT (Rehabilitation at Home Using Mobile Health in Older Adults After Hospitalization for Ischemic Heart Disease) trial, the largest randomized study of mHealth-CR in this population, found no significant improvements in functional capacity, health status, angina, or disability compared with usual care. OBJECTIVES/OBJECTIVE:The purpose of this study was to evaluate whether mHealth-CR affects personalized goal attainment-a prespecified secondary endpoint of RESILIENT-using goal attainment scaling (GAS). METHODS:A total of 400 patients (≥65 years) with ischemic heart disease were randomized to mHealth-CR or usual care. Participants specified goals for CR at baseline using the five-category goal attainment scale: much-less-than-expected (-2), less-than-expected (-1), expected (0), better-than-expected (+1), and much-better-than-expected (+2). Goal attainment was assessed at 3 months. RESULTS:Of 400 patients (median age, 71.0 years [range 65.0-91.0]; 72.8% male; 65.2% prefrail/frail) randomized to mHealth-CR (n = 298) or usual care (n = 102), 353 (88.3%) completed GAS. Most goals addressed physical activity (54.0% mHealth-CR vs 59.0% usual care), health care behaviors (14.4% vs 11.9%), or symptom management (13.1% vs 9.0%). Rates of attaining or exceeding goals (GAS ≥0) were similar between groups (80.5% vs 77.6%; P = 0.492). However, in the intervention arm, there was a higher rate of exceeding expected level of goal attainment (GAS +1, +2) compared with usual care (52.6% vs 34.2%; P = 0.006). CONCLUSIONS:In a trial that did not demonstrate differences on traditional endpoints, those receiving mHealth-CR were more likely to exceed personalized CR goals. These findings suggest the intervention facilitated greater progress toward individualized goals and underscore the importance of patient-centered outcomes in CR.

OBJECTIVE:This study examines how social determinants of health (SDOH) influence mild cognitive impairment (MCI) and its progression to dementia across racial/ethnic groups, identifying disparities and key predictors using machine learning approaches. METHODS:We analyzed data from 83,180 participants aged 50+ in the All of Us Research Program (65,582 White, 6,207 Black, 4,170 Hispanic, 7,221 Other). The sample had mean ages ranging from 62.4 (Hispanic) to 68.1 (White) years, with significant gender disparities (70.9% Black females vs. 46.0% Other females). We developed machine learning classification models to predict MCI and its progression to dementia across the four racial/ethnic groups using 18 SDOH, along with key sociodemographic variables. We then applied SHapley Additive exPlanations (SHAP) to quantify each factor's contribution and interpret its risk and protective effects on individual predictions. RESULTS:MCI prevalence was comparable across groups (7.5%-8.0%), but progression to dementia varied (9.4% Black vs. 11.4% Other). Perceived stress was the strongest predictor of MCI across all groups, with SHAP values of 15.1% (White), 13.5% (Black), 17.4% (Other), and 19.3% (Hispanic). Predictors of progression to dementia varied by groups: perceived stress (7.0%) for Whites, instrumental social support (14.2%) for Hispanics, daily spiritual experience (34.0%) for Blacks, and everyday discrimination (11.2%) for other groups. DISCUSSION/CONCLUSIONS:The findings underscore the need for group-specific interventions addressing stress mitigation for MCI prevention and culturally-tailored support systems to delay dementia progression. This machine learning approach reveals complex SDOH interactions that traditional methods might overlook, particularly for racial/ethnic underrepresented populations.

BACKGROUND:Prior prediction equations for heart failure (HF) omitted cardiac biomarkers and used select populations. We assessed the added value of NT-proBNP (NT-terminal pro-brain natriuretic peptide) and hsTnT (high-sensitivity troponin T) as predictors of HF, across a broad population, including participants with chronic kidney disease or atherosclerotic cardiovascular disease. METHODS:Among 41 427 individuals free of HF from 9 prospective cohort studies, we performed an individual-participant data meta-analysis, quantifying the associations of NT-proBNP and hsTnT with incident HF when added to a clinical model. Changes in Harrel's C-statistic with and without NT-proBNP or hsTnT were estimated within each cohort and then pooled using random effects meta-analysis. RESULTS:<0.001). CONCLUSIONS:NT-proBNP improved risk discrimination of incident HF when added to traditional HF risk factors, even in individuals with chronic kidney disease and atherosclerotic cardiovascular disease. The contribution of hsTnT was modest. Measurement of NT-proBNP may help identify individuals at risk of HF.