Performance of bowel preparation quality scales in patients with Crohn's disease.

BACKGROUND: The performance of bowel preparation (BP) in patients with Crohn's disease (CD) is unknown. AIMS: To evaluate the operating properties of instruments used to assess BP quality in patients with CD. METHODS: We used the Boston Bowel Preparation Scale, modified Boston Bowel Preparation Scale, Harefield Cleansing Scale, Food and Drug Administration Bowel Cleansing Assessment Scale (BCAS), and a 100-mm visual analogue scale of bowel cleanliness to assess BP quality in 50 videos from 40 patients with CD. We assessed endoscopic activity with the Simple Endoscopic Score for CD (SES-CD). Assessments were on endoscope insertion and withdrawal. Reliability was quantified using the intraclass correlation coefficient (ICC). We assessed validity by within-patient correlation between instruments and the visual analogue scale using mixed-effect models. The correlation between BP quality and SES-SD scores was assessed using Spearman's rho. RESULTS: Inter- and intra-rater reliability for all BP quality instruments was substantial (ICC ≥0.61) except for the Food and Drug Administration BCAS on insertion (inter-rater reliability ICC ≥0.41). The visual analogue scale had substantial inter- and almost perfect (ICC ≥0.81) intra-rater reliability. Correlation coefficients for the validity of the instruments exceeded 0.58. BP quality and endoscopic disease activity scores in the colon were negatively correlated. CONCLUSION: Most existing instruments reliably assess BP quality in patients with CD. These results support the use of these instruments in clinical practice, provide a framework for scoring BP quality in CD clinical trials, and support evaluation of novel BP agents in patients with CD.

Sample size planning for estimating the global win probability with precision and assurance.

Randomized controlled trials commonly employ multiple endpoints to collectively assess the intended effects of the new intervention on multiple aspects of the disease. Focusing on the estimation of the global win probability (WinP), defined as the (weighted) mean of the WinPs across the endpoints that a treated participant would have a better outcome than a control participant, we propose a closed-form sample size formula incorporating pre-specified precision and assurance, with precision denoted by the lower limit of confidence interval and assurance denoted by the probability of achieving that lower limit. We make use of the equivalence of the WinP and the area under the receiver operating characteristic curve (AUC) and adapt a formula originally developed for the difference between two AUCs to handle the global WinP. Unequal variances between treatment groups are allowed. Simulation results suggest that the method performs very well. We illustrate the proposed formula using a Parkinson's disease clinical trial design example.

Reliability of MR Enterography Features for Describing Fibrostenosing Crohn Disease.

Background Clinical decision making and drug development for fibrostenosing Crohn disease is constrained by a lack of imaging definitions, scoring conventions, and validated end points. Purpose To assess the reliability of MR enterography features to describe Crohn disease strictures and determine correlation with stricture severity. Materials and Methods A retrospective study of patients with symptomatic terminal ileal Crohn disease strictures who underwent MR enterography at tertiary care centers (Cleveland Clinic: September 2013 to November 2020; Mayo Clinic: February 2008 to March 2019) was conducted by using convenience sampling. In the development phase, blinded and trained radiologists independently evaluated 26 MR enterography features from baseline and follow-up examinations performed more than 6 months apart, with no bowel resection performed between examinations. Follow-up examinations closest to 12 months after baseline were selected. Reliability was assessed using the intraclass correlation coefficient (ICC). In the validation phase, after five features were redefined, reliability was re-estimated in an independent convenience sample using baseline examinations. Multivariable linear regression analysis identified features with at least moderate interrater reliability (ICC ≥0.41) that were independently associated with stricture severity. Results Ninety-nine (mean age, 40 years ± 14 [SD]; 50 male) patients were included in the development group and 51 (mean age, 45 years ± 16 [SD]; 35 female) patients were included in the validation group. In the development group, nine features had at least moderate interrater reliability. One additional feature demonstrated moderate reliability in the validation group. Stricture length (ICC = 0.85 [95% CI: 0.75, 0.91] and 0.91 [95% CI: 0.75, 0.96] in development and validation phase, respectively) and maximal associated small bowel dilation (ICC = 0.74 [95% CI: 0.63, 0.80] and 0.73 [95% CI: 0.58, 0.87] in development and validation group, respectively) had the highest interrater reliability. Stricture length, maximal stricture wall thickness, and maximal associated small bowel dilation were independently (regression coefficients, 0.09-3.97; P < .001) associated with stricture severity. Conclusion MR enterography definitions and scoring conventions for reliably assessing features of Crohn disease strictures were developed and validated, and feature correlation with stricture severity was determined. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder and Ma et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

Reliability of CT Enterography for Describing Fibrostenosing Crohn Disease.

Background Standardized methods to measure and describe Crohn disease strictures at CT enterography are needed to guide clinical decision making and for use in therapeutic studies. Purpose To assess the reliability of CT enterography features to describe Crohn disease strictures and their correlation with stricture severity. Materials and Methods A retrospective study was conducted in 43 adult patients with symptomatic terminal ileal Crohn disease strictures who underwent standard-of-care CT enterography at a tertiary care center at the Cleveland Clinic between January 2008 and August 2016. After training on standardized definitions, four abdominal radiologists blinded to all patient information assessed imaging features (seven continuous measurements and nine observations) of the most distal ileal stricture in two separate sessions (separated by ≥2 weeks) in random order. Features with an interrater intraclass correlation coefficient (ICC) of 0.41 or greater (ie, moderate reliability or better) were considered reliable. Univariable and multivariable linear regression analysis identified reliable features associated with a visual analog scale of overall stricture severity. Significant reliable features were assessed as components of a CT enterography-based model to quantitate stricture severity. Results Examinations in 43 patients (mean age, 52 years ± 16 [SD]; 23 female) were evaluated. Five continuous measurements and six observations demonstrated at least moderate interrater reliability (interrater ICC range, 0.42 [95% CI: 0.25, 0.57] to 0.80 [95% CI: 0.67, 0.88]). Of these, 10 were univariably associated with stricture severity, and three continuous measurements-stricture length (interrater ICC, 0.64 [95% CI: 0.42, 0.81]), maximal associated small bowel dilation (interrater ICC, 0.80 [95% CI: 0.67, 0.88]), and maximal stricture wall thickness (interrater ICC, 0.50 [95% CI: 0.34, 0.62])-were independently associated (P value range, <.001 to .003) with stricture severity in a multivariable model. These three measurements were used to derive a well-calibrated (optimism-adjusted calibration slope = 1.00) quantitative model of stricture severity. Conclusion Standardized CT enterography measurements and observations can reliably describe terminal ileal Crohn disease strictures. Stricture length, maximal associated small bowel dilation, and maximal stricture wall thickness are correlated with stricture severity. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

Extending the DeLong algorithm for comparing areas under correlated receiver operating characteristic curves with missing data.

A nonparametric method proposed by DeLong et al in 1988 for comparing areas under correlated receiver operating characteristic curves is used widely in practice. However, the DeLong method as implemented in popular software quietly deletes individuals with any missing values, yielding potentially invalid and/or inefficient results. We simplify the DeLong algorithm using ranks and extend it to accommodate missing data by using a mixed model approach for multivariate data. Simulation results demonstrate the validity and efficiency of our procedure for data missing at random. We illustrate our proposed procedure in SAS, Stata, and R using the original DeLong data.

Re-evaluating Methods for Assessing Differences in Response in Ileal vs. Colonic Crohn's Disease: A Post-hoc Analysis of the FITZROY Trial.

BACKGROUND AND AIMS: The ileum is the most commonly affected segment of the gastrointestinal tract in Crohn's disease (CD). We aimed to determine whether disease location affects response to filgotinib, a Janus kinase (JAK) inhibitor, in patients with moderate-to-severely active Crohn's disease (CD) and applying appropriate methods to account for differences in measuring disease activity in the ileum compared to the colon. METHODS: This post-hoc analysis of data from the FITZROY phase 2 trial (NCT02048618) compared changes in the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) amongst patients with ileal-dominant and isolated colonic CD treated with 10 weeks of filgotinib 200 mg daily or placebo. A mixed effects model for repeated measures was used to test whether ileal disease responded differently than colonic disease, by evaluating for effect modification using the interaction term of treatment assignment-by-disease location. RESULTS: Numerically greater proportions of patients with isolated colonic disease compared to ileal-dominant CD achieved clinical remission (CDAI <150, 75.9% vs. 41.6%) and endoscopic response (SES-CD reduction by 50%, 52.5% vs. 15.5%) at Week 10. However, after adjusting for baseline disease activity by disease location and within-patient clustering effects, there was no significant difference in treatment response by disease location (mean difference in ΔCDAI between ileal-dominant vs. isolated colonic disease +9.24 [95% CI: -87.19, +105.67], p=0.85; mean difference in ΔSES-CD -1.93 [95% CI: -7.03, +3.44], p=0.48). CONCLUSIONS: Filgotinib demonstrated similar efficacy in ileal-dominant and isolated colonic CD when controlling for baseline disease activity and clustering effects.

A simple Cox approach to estimating risk ratios without sharing individual-level data in multi-site studies.

Epidemiologic studies frequently use risk ratios to quantify associations between exposures and binary outcomes. When the data are physically stored at multiple data partners, it can be challenging to perform individual-level analysis if data cannot be pooled centrally due to privacy constraints. Existing methods either require multiple file transfers between each data partner and an analysis center (e.g., distributed regression) or only provide approximate estimation of the risk ratio (e.g., meta-analysis). Here we develop a practical method that requires a single transfer of eight summary-level quantities from each data partner. Our approach leverages an existing risk-set method and software originally developed for Cox regression. Sharing only summary-level information, the proposed method provides risk ratio estimates and confidence intervals identical to those that would be provided - if individual-level data were pooled - by the modified Poisson regression. We justify the method theoretically, confirm its performance using simulated data, and implement it in a distributed analysis of COVID-19 data from the U.S. Food and Drug Administration's Sentinel System.

Nanoscale flow cytometry-based quantification of blood-based extracellular vesicle biomarkers distinguishes MCI and Alzheimer's disease.

INTRODUCTION: Accurate testing for Alzheimer's disease (AD) represents a crucial step for therapeutic advancement. Currently, tests are expensive and require invasive sampling or radiation exposure. METHODS: We developed a nanoscale flow cytometry (nFC)-based assay of extracellular vesicles (EVs) to screen biomarkers in plasma from mild cognitive impairment (MCI), AD, or controls. RESULTS: Circulating amyloid beta (Aß), tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, p-tauS235, ubiquitin, and lysosomal-associated membrane protein 1-positive EVs distinguished AD samples. p-tau181, p-tau217, p-tauS235, and ubiquitin-positive EVs distinguished MCI samples. The most sensitive marker for AD distinction was p-tau231, with an area under the receiver operating characteristic curve (AUC) of 0.96 (sensitivity 0.95/specificity 1.0) improving to an AUC of 0.989 when combined with p-tauS235. DISCUSSION: This nFC-based assay accurately distinguishes MCI and AD plasma without EV isolation, offering a rapid approach requiring minute sample volumes. Incorporating nFC-based measurements in larger populations and comparison to "gold standard" biomarkers is an exciting next step for developing AD diagnostic tools. HIGHLIGHTS: Extracellular vesicles represent promising biomarkers of Alzheimer's disease (AD) that can be measured in the peripheral circulation. This study demonstrates the utility of nanoscale flow cytometry for the measurement of circulating extracellular vesicles (EVs) in AD blood samples. Multiple markers including amyloid beta, tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, and p-tauS235 accurately distinguished AD samples from healthy controls. Future studies should expand blood and cerebrospinal fluid-based EV biomarker development using nanoflow cytometry approaches.

Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials.

Background: Disease extent in Ulcerative Colitis (UC) has prognostic implications for disease course. It is unclear whether the efficacy of medical therapies for moderate to severely active UC vary according to disease extent at enrollment. Methods: We analyzed patient level data from 11 Phase 2 and 3 clinical trials of advanced therapies in patients with moderate-to-severe UC to assess modifications of advanced therapy effects by disease extent. Primary outcome was clinical response and secondary outcomes were clinical remission, endoscopic response/remission and endoscopic improvement, and Mayo clinic subscore for both induction and maintenance studies. Binary and continuous outcomes were analyzed using the modified Poisson regression model and the mixed-effects model, respectively, adjusting for age, sex, disease duration, concomitant steroid use and prior anti-TNF use. Effect modifications with binary outcomes were quantified by ratios of risk ratio for left-sided to that for extensive colitis while effect modifications with the Mayo subscores were quantified by differences of the differences between mean scores of the left-sided and extensive colitis. Results were presented with point estimates and 95% confidence intervals as well as p-values. Findings: Eleven clinical trials enrolling 5450 UC patients (infliximab = 2, adalimumab = 2, golimumab = 2, vedolizumab = 2, tofacitinib = 3) were included. In induction trials, there was evidence to suggest effect modification by disease extent for clinical response with tofacitinib (the ratio of RRs 0.67, 95% CI [0.45, 0.99], p = 0.049) and clinical remission with infliximab (ratio of RRs 0.33, 95% CI [0.13, 0.85], p = 0.020) favoring patients with extensive colitis. There was no evidence to suggest effect modification for endoscopic improvement and clinical outcomes. There was evidence to suggest effect modification by disease extent for clinical remission with tofacitinib (ratio of RRs 0.44, 95% CI [0.22, 0.89], p = 0.020) favoring patients with extensive colitis. For symptom subscores from the Mayo Clinic score, tofacitinib was associated with a greater reduction in both stool frequency (difference of differences 0.37, 95% CI [0.08, 0.65], p = 0.012) and rectal bleeding scores (difference of differences 0.25, 95% CI [0.03, 0.47], p = 0.026) in patients with extensive colitis compared to left sided. Interpretation: These findings underscore the possibility of differential efficacy of medical therapies according to disease distribution. These results warrant further exploration in forthcoming trials to better inform treatment strategies and consideration of disease distribution as a baseline stratification factor in clinical trials. Funding: This study did not receive any financial support.

Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

BACKGROUND: Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. METHODS: Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. RESULTS: Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). CONCLUSION: Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

This study largely supports current regulatory guidance for Crohn's disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

Identification of immune cell markers associated with ulcerative colitis histological disease activity in colonic biopsies.

AIMS: Accurate determination of histological activity in ulcerative colitis (UC) is essential given its diagnostic and prognostic importance. Data on the relationship between histology and immune cell markers are limited. We aimed to evaluate the association between histological disease activity and immune cell marker concentration in colonic biopsies from patients with UC. METHODS: Sigmoid colon biopsies from 20 patients with UC were retrospectively assessed using the Robarts Histopathology Index (RHI). Targeted mass spectrometry determined the concentration of 18 immune cell markers (cluster of differentiation (CD) 4, CD8, CD19, CD20, CD40, CD56, CD68, CD103, forkhead box p3 (FOXP3), human leucocyte antigen, DR alpha chain (HLA-DRA), interleukin 10 (IL-10), IL-23 subunit alpha (IL-23A), IL-23 receptor (IL-23R), IL-2 receptor alpha chain (IL-2RA), Ki67, lymphocyte-activation gene 3 (LAG-3), programmed cell death protein 1 (PD-1) and PD ligand 1 (PD-L1)). The association between RHI score and immune cell marker concentration was quantified using Spearman's rank correlation coefficient (ρ) and related 95% CIs. RESULTS: Fourteen of the 18 immune cell marker proteins were detected, with tissue concentration ranging from 0.003 to 11.53 fmol/µg. The overall RHI score was positively correlated with CD19, CD20, CD40, FOXP3, LAG-3, PD-1 and PD-L1 concentration (ρ=0.596-0.799) and negatively correlated with CD56 concentration (ρ=-0.460). There was no significant association between RHI score and CD4, CD8, CD68, CD103, HLA-DRA or Ki67 concentration. CONCLUSIONS: This study provides insight into the correlation between immune cell marker expression and histological disease activity and the possible molecular and immunological determinants underlying microscopic disease activity in UC.

Comparative Efficacy of Advanced Therapies for Achieving Endoscopic Outcomes in Crohn's Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: We conducted a network meta-analysis to compare the efficacy of advanced therapies for achieving endoscopic outcomes in patients with moderate-to-severely active Crohn's disease. METHODS: MEDLINE, Embase, and Cochrane CENTRAL databases were searched from inception to August 2, 2023 to identify phase II and III randomized controlled trials (RCTs) in adults (≥18 years) with moderate-to-severe Crohn's disease treated with tumor necrosis factor (TNF) antagonists, etrolizumab, vedolizumab, anti-interleukin (IL)12/23p40, anti-IL23p19, or Janus kinase-1 (JAK1) inhibitors, compared with placebo/active comparator, for induction and/or maintenance of remission and reported endoscopic outcomes. Primary outcome was endoscopic response after induction therapy, and endoscopic remission after maintenance therapy. We performed a random-effects network meta-analysis using a frequentist approach, and estimated relative risk (RRs), 95% confidence interval (CI) values, and P score for ranking agents. We used GRADE to ascertain certainty of evidence. RESULTS: A total of 20 RCTs (19 placebo-controlled and 1 head-to-head trial; 5592 patients) were included out of which 12 RCTs reported endoscopic outcomes for the induction phase, 5 reported for the maintenance phase, and 3 reported for both induction and maintenance phases. JAK1 inhibitors (RR, 3·49 [95% CI, 1·48-8·26]) and anti-IL23p19 (RR, 2·30 [95% CI, 1·02-5·18]) agents were more efficacious than etrolizumab (moderate certainty of evidence), and JAK1 inhibitors (RR, 2·34 [95% CI, 1·14-4·80]) were more efficacious than anti-IL12/23p40 agents for inducing endoscopic response (moderate certainty of evidence). JAK1 inhibitors and anti-IL23p19 ranked highest for induction of endoscopic response. There was paucity of RCTs of TNF antagonists reporting endoscopic outcomes with induction therapy. On network meta-analysis of 6 RCTs, all agents except vedolizumab (RR, 1.89 [95% CI, 0.61-5.92]) were effective in maintaining endoscopic remission compared with placebo. TNF antagonists, IL12/23p40, and JAK1 inhibitors were ranked highest. CONCLUSIONS: On network meta-analysis, JAK1 inhibitors and anti-IL23p19 agents may be the most effective among non-TNF-targeting advanced therapies for inducing endoscopic response. Future head-to-head trials will further inform positioning of different therapies for the management of Crohn's disease.

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials.

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.

Who sleeps well in Canada? The social determinants of sleep health among middle-aged and older adults in the Canadian Longitudinal Study on Aging.

OBJECTIVES: Sleep health inequities likely contribute to disparities in health outcomes. Our objective was to identify social determinants of sleep health among middle-aged/older adults in Canada, where prior evidence is limited. METHODS: We analyzed cross-sectional data from the Canadian Longitudinal Study on Aging, a survey of over 30,000 community-dwelling adults aged 45-85years. Self-reported measures included sleep duration, sleep satisfaction, and sleep efficiency. We explored associations between sleep measures and social determinants of health. We used modified Poisson regression to estimate prevalence ratios for sleep satisfaction and sleep efficiency, and linear regression for sleep duration. Estimates were adjusted for all social, lifestyle, and clinical covariates. We explored effect modification by sex. RESULTS: Of the 11 social determinants explored, all were significantly associated with at least one domain of sleep health. These associations were reduced to 9 variables with adjustment for all social variables, and 7 with further adjustment for lifestyle and clinical covariates, including differences by sex, age, education, marital status, employment, race/ethnicity, and sexual orientation. Better sleep health in >1 domain was observed among males, older age groups (65 and older), higher income groups, the retired group, and homeowners with adjustment for social variables, and only in males and older age groups with additional adjustment for lifestyle and clinical variables. Only sleep duration associations were modified by sex. CONCLUSIONS: Sleep health disparities among Canadian adults exist across socioeconomic gradients and racial/ethnic minority groups. Poor sleep health among disadvantaged groups warrants increased attention as a public health problem in Canada.

Does prescribing apixaban or rivaroxaban versus warfarin for patients diagnosed with atrial fibrillation save health system costs? A multivalued treatment effects analysis.

BACKGROUND: Non-valvular atrial fibrillation (AF) is a common heart arrhythmia in the elderly population. AF patients are at high-risk of ischemic strokes, but oral anticoagulant (OAC) therapy reduces such risks. Warfarin had been the standard OAC for AF patients, however its effectiveness is highly variable and dependent on close monitoring of the anticoagulant response. Newer OACs such as rivaroxaban and apixaban address these drawbacks but are more costly. It is uncertain which OAC therapy for AF is cost-saving from the healthcare system perspective. METHODS: We followed a cohort of patients in Ontario, Canada, aged ≥ 66 who were newly diagnosed with AF and prescribed OACs between 2012 and 2017. We used a two-stage estimation procedure. First, we account for the patient selection into OACs using a multinomial logit regression model and estimated propensity scores. Second, we used an inverse probability weighted regression adjustment approach to determine cost-saving OAC options. We also examined component-specific costs (i.e., drug, hospitalization, emergency department and physician) to understand the drivers of cost-saving OACs. RESULTS: We found that compared to warfarin, rivaroxaban and apixaban treatments were cost-saving options, with per-patient 1-year healthcare cost savings at $2436 and $1764, respectively. These savings were driven by cost-savings in hospitalization, emergency department visits, and physician visits, outweighing higher drug costs. These results were robust to alternative model specifications and estimation procedures. CONCLUSIONS: Treating AF patients with rivaroxaban and apixaban than warfarin reduces healthcare costs. OAC reimbursement policies for AF patients should consider rivaroxaban or apixaban over warfarin as the first-line treatment.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Severe (level 3) hypoglycaemia occurrence in a real-world cohort of adults with type 1 or 2 diabetes mellitus (iNPHORM, United States).

AIMS: Among adults with insulin- and/or secretagogue-treated diabetes in the United States, very little is known about the real-world descriptive epidemiology of iatrogenic severe (level 3) hypoglycaemia. Addressing this gap, we collected primary, longitudinal data to quantify the absolute frequency of events as well as incidence rates and proportions. MATERIALS AND METHODS: iNPHORM is a US-wide, 12-month ambidirectional panel survey (2020-2021). Adults with type 1 diabetes mellitus (T1DM) or insulin- and/or secretagogue-treated type 2 diabetes mellitus (T2DM) were recruited from a probability-based internet panel. Participants completing ≥1 follow-up questionnaire(s) were analysed. RESULTS: Among 978 respondents [T1DM 17%; mean age 51 (SD 14.3) years; male: 49.6%], 63% of level 3 events were treated outside the health care system (e.g. by family/friend/colleague), and <5% required hospitalization. Following the 12-month prospective period, one-third of individuals reported ≥1 event(s) [T1DM 44.2% (95% CI 36.8%-51.8%); T2DM 30.8% (95% CI 28.7%-35.1%), p = .0404, α = 0.0007]; and the incidence rate was 5.01 (95% CI 4.15-6.05) events per person-year (EPPY) [T1DM 3.57 (95% CI 2.49-5.11) EPPY; T2DM 5.29 (95% CI 4.26-6.57) EPPY, p = .1352, α = 0.0007]. Level 3 hypoglycaemia requiring non-transport emergency medical services was more common in T2DM than T1DM (p < .0001, α = 0.0016). In total, >90% of events were experienced by <15% of participants. CONCLUSIONS: iNPHORM is one of the first long-term, prospective US-based investigations on level 3 hypoglycaemia epidemiology. Our results underscore the importance of participant-reported data to ascertain its burden. Events were alarmingly frequent, irrespective of diabetes type, and concentrated in a small subsample.

Effects of Exercise Alone or Combined With Cognitive Training and Vitamin D Supplementation to Improve Cognition in Adults With Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Exercise, cognitive training, and vitamin D may enhance cognition in older adults with mild cognitive impairment (MCI). Objective: To determine whether aerobic-resistance exercises would improve cognition relative to an active control and if a multidomain intervention including exercises, computerized cognitive training, and vitamin D supplementation would show greater improvements than exercise alone. Design, Setting, and Participants: This randomized clinical trial (the SYNERGIC Study) was a multisite, double-masked, fractional factorial trial that evaluated the effects of aerobic-resistance exercise, computerized cognitive training, and vitamin D on cognition. Eligible participants were between ages 65 and 84 years with MCI enrolled from September 19, 2016, to April 7, 2020. Data were analyzed from February 2021 to December 2022. Interventions: Participants were randomized to 5 study arms and treated for 20 weeks: arm 1 (multidomain intervention with exercise, cognitive training, and vitamin D), arm 2 (exercise, cognitive training, and placebo vitamin D), arm 3 (exercise, sham cognitive training, and vitamin D), arm 4 (exercise, sham cognitive training, and placebo vitamin D), and arm 5 (control group with balance-toning exercise, sham cognitive training, and placebo vitamin D). The vitamin D regimen was a 10 000 IU dose 3 times weekly. Main Outcomes and Measures: Primary outcomes were changes in ADAS-Cog-13 and Plus variant at 6 months. Results: Among 175 randomized participants (mean [SD] age, 73.1 [6.6] years; 86 [49.1%] women), 144 (82%) completed the intervention and 133 (76%) completed the follow-up (month 12). At 6 months, all active arms (ie, arms 1 through 4) with aerobic-resistance exercise regardless of the addition of cognitive training or vitamin D, improved ADAS-Cog-13 when compared with control (mean difference, -1.79 points; 95% CI, -3.27 to -0.31 points; P = .02; d = 0.64). Compared with exercise alone (arms 3 and 4), exercise and cognitive training (arms 1 and 2) improved the ADAS-Cog-13 (mean difference, -1.45 points; 95% CI, -2.70 to -0.21 points; P = .02; d = 0.39). No significant improvement was found with vitamin D. Finally, the multidomain intervention (arm 1) improved the ADAS-Cog-13 score significantly compared with control (mean difference, -2.64 points; 95% CI, -4.42 to -0.80 points; P = .005; d = 0.71). Changes in ADAS-Cog-Plus were not significant. Conclusions and Relevance: In this clinical trial, older adults with MCI receiving aerobic-resistance exercises with sequential computerized cognitive training significantly improved cognition, although some results were inconsistent. Vitamin D supplementation had no effect. Our findings suggest that this multidomain intervention may improve cognition and potentially delay dementia onset in MCI. Trial Registration: ClinicalTrials.gov Identifier: NCT02808676.

Development and validation of a real-world model to predict 1-year Level 3 (severe) hypoglycaemia risk in adults with diabetes (the iNPHORM study, United States).

AIMS: We aimed to develop and internally validate a real-world prognostic model for Level 3 hypoglycaemia risk compatible with outpatient care in the United States. MATERIALS AND METHODS: iNPHORM is a 12-month, US-based panel survey. Adults (18-90 years old) with type 1 diabetes mellitus or insulin- and/or secretagogue-treated type 2 diabetes mellitus were recruited from a nationwide, probability-based internet panel. Among participants completing ≥ 1 follow-up questionnaire(s), we modelled 1-year Level 3 hypoglycaemia risk using Andersen and Gill's Cox survival and penalized regression with multiple imputation. Candidate variables were selected for their clinical relevance and ease of capture at point-of-care. RESULTS: In total, 986 participants [type 1 diabetes mellitus: 17%; men: 49.6%; mean age: 51 (SD: 14.3) years] were analysed. Across follow-up, 035.1 (95% CI: 32.2-38.1)% reported ≥1 Level 3 event(s), and the rate was 5.0 (95% CI: 4.1-6.0) events per person-year. Our final model showed strong discriminative validity and parsimony (optimism corrected c-statistic: 0.77). Numerous variables were selected: age; sex; body mass index; marital status; level of education; insurance coverage; race; ethnicity; food insecurity; diabetes type; glycated haemoglobin value; glycated haemoglobin variability; number, type and dose of various medications; number of SH events requiring hospital care (past year and over follow-up); type and number of comorbidities and complications; number of diabetes-related health care visits (past year); use of continuous/flash glucose monitoring; and general health status. CONCLUSIONS: iNPHORM is the first US-based primary prognostic study on Level 3 hypoglycaemia. Future model implementation could potentiate risk-tailored strategies that reduce real-world event occurrence and overall diabetes burden.