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Background Although inflammatory bowel disease (IBD) is heritable, the heritability is still largely unexplained despite substantial progress through GWAS and WGS. However, recent advances in epigenetics (gene environmental interactions), including DNA methylation (DNAm) analysis, has identified new disease-specific mechanisms controlling gene expression. We recently showed that IBD-associated blood DNAm patterns strongly correlated with inflammation (CRP as surrogate marker) and reverted to patterns seen in healthy controls following treatment, regardless of whether or not the underlying IBD was in remission, suggesting blood DNAm is more representative of the systemic inflammatory status rather than disease status (Gastroenterology, 2019, 156 (8): 2254–2265). Thus, we aimed to study DNAm patterns in rectal biopsies hypothesizing that DNAm in rectal biopsies will reflect disease status rather than systemic inflammatory status alone. Method Genome-wide DNA methylation was measured using the Illumina MethylationEPIC array on rectal biopsy DNA samples of 85 non-inflammatory, non-IBD controls and 215 newly diagnosed ulcerative colitis (UC) patients prior to therapy, along with 49 one-year follow-up UC cases (PROTECT cohort) to identify disease specific methylation patterns. Epigenome wide association studies (EWAS) were performed with UC and CRP as the outcomes in linear models adjusted for age, gender, race and five genotype-based principal components. Results At diagnosis, 2446 disease-specific CpG sites in rectal tissue (FDR Conclusion When studied longitudinally, the UC-specific DNA methylation patterns in rectal tissue are distinct from blood samples. In contrast to blood DNAm which normalizes after therapy during follow-up, rectal tissue DNAm changes persist after treatment in UC. This suggests the currently available therapies control the systemic inflammation effectively, but have less direct effect on the disease itself. Future therapies targeting disease-specific DNAm may be more effective in disease management and long-term remission.

Not all patients with acute pulmonary embolism (PE) have a high risk of an adverse short-term outcome.This prospective cohort study aimed to develop a multimarker prognostic model that accurately classifies normotensive patients with PE into low and high categories of risk of adverse medical outcomes.The study enrolled 848 outpatients from the PROTECT (PROgnosTic valuE of Computed Tomography) study (derivation cohort) and 529 patients from the Prognostic Factors for Pulmonary Embolism (PREP) study (validation cohort). Investigators assessed study participants for a 30-day complicated course, defined as death from any cause, hemodynamic collapse, and/or adjudicated recurrent PE.A complicated course occurred in 63 (7.4%) of the 848 normotensive patients with acute symptomatic PE in the derivation cohort and in 24 patients (4.5%) in the validation cohort. The final model included the simplified Pulmonary Embolism Severity Index, cardiac troponin I, brain natriuretic peptide, and lower limb ultrasound testing. The model performed similarly in the derivation (c-index of 0.75) and validation (c-index of 0.85) cohorts. The combination of the simplified Pulmonary Embolism Severity Index and brain natriuretic peptide testing showed a negative predictive value for a complicated course of 99.1 and 100% in the derivation and validation cohorts, respectively. The combination of all modalities had a positive predictive value for the prediction of a complicated course of 25.8% in the derivation cohort and 21.2% in the validation cohort.For normotensive patients who have acute PE, we derived and validated a multimarker model that predicts all-cause mortality, hemodynamic collapse, and/or recurrent PE within the following 30 days.

To analyze the frequency, rationale and determinants of attending physicians requesting that their eligible patients not be approached for participation in a thromboprophylaxis trial. Research personnel in 67 centers prospectively documented eligible non-randomized patients due to physicians declining to allow their patients to be approached. In 67 centers, 3,764 patients were enrolled, but 1,460 eligible patients had no consent encounter. For 218 (14.9 %) of these, attending physicians requested that their patients not be approached. The most common reasons included a high risk of bleeding (31.2 %) related to fear of heparin bioaccumulation in renal failure, the presence of an epidural catheter, peri-operative status or other factors; specific preferences for thromboprophylaxis (12.4 %); morbid obesity (9.6 %); uncertain prognosis (6.4 %); general discomfort with research (3.7 %) and unclear reasons (17.0 %). Physicians were more likely to decline when approached by less experienced research personnel; considering those with >10 years of experience as the reference category, the odds ratios (OR) for physician refusals to personnel without trial experience was 10.47 [95 % confidence interval (CI) 2.19–50.02] and those with less than 10 years experience was 1.72 (95 % CI 0.61–4.84). Physicians in open rather than closed units were more likely to decline (OR 4.26; 95 % CI 1.27–14.34). Refusals decreased each year of enrollment compared to the pilot phase. Tracking, analyzing, interpreting and reporting the rates and reasons for physicians declining to allow their patients to be approached for enrollment provides insights into clinicians’ concerns and attitudes to trials. This information can encourage physician communication and education, and potentially enhance efficient recruitment.