Sex and Race Disparities in Diverticulosis Prevalence

Background & Aims: The prevalence of diverticulosis differs with demographic features of patients, but evidence is limited. Well-defined demographic studies are necessary to understand diverticulosis biology. We estimated the prevalence of diverticulosis among patients of different ages, sexes, and races and ethnicities and calculated odds ratios. Design: Using data from an endoscopic database, we identified 271,181 colonoscopy procedures performed from 2000 through 2012 at 107 sites in the United States. Our analysis included individuals 40 years and older who underwent colonoscopy examination for average-risk screening. The outcome was any reported diverticulosis on colonoscopy. Multivariate analyses were performed using logistic regression to estimate odds ratios (ORs) and 95% CI values, adjusting for confounding variables. Results: The prevalence of diverticulosis increased with age in men and women of all races and ethnicities. Women 40-49 years old had significantly lower odds of any diverticulosis (OR, 0.71; 95% CI, 0.63-0.80) compared with men 40-49 years old, after adjustment. The strength of this association decreased with age. Compared with non-Hispanic white individuals, non-Hispanic black individuals (OR, 0.80; 95% CI, 0.77-0.83) and Asian/Pacific Islanders (OR, 0.38; 95% CI, 0.35-0.41) had lower odds of any diverticulosis. However, non-Hispanic black individuals (OR, 1.53, 95% CI, 1.44-1.62) had increased odds of any proximal diverticulosis, whereas Asian/Pacific Islanders (OR, 3.12; 95% CI, 2.67-3.66) had increased odds of only proximal diverticulosis. Conclusions: In an analysis of data from 271,181 colonoscopy procedures, diverticulosis was less prevalent in women compared with men in the same age groups, indicating that sex hormones might affect pathogenesis. Differences in the odds of diverticulosis by race and ethnicity indicate a genetic contribution to risk

Medication use and microscopic colitis

Background: Microscopic colitis is an increasingly common cause of watery diarrhoea. Several classes of medications have been associated with microscopic colitis in prior studies. Aims: To determine the association between the use of previously implicated medications and microscopic colitis. Methods: This was a case-control study of patients referred for elective, outpatient colonoscopy for diarrhoea. Patients were excluded for inflammatory bowel disease, C difficile, or other infectious diarrhoea. Colon biopsies were reviewed by the study pathologist and patients were classified as microscopic colitis cases or non-microscopic colitis controls. Results: The study population included 110 microscopic colitis cases and 252 controls. The cases were older, better educated and more likely to be female. Cases reported a greater number of loose, watery, or liquid stools, nocturnal stools, more urgency and weight loss compared to controls. There was no association with proton pump inhibitors (PPIs), adjusted OR (aOR) 0.66, 95% CI 0.38-1.13 or nonsteroidal anti-inflammatory drugs, aOR 0.68, 95% CI 0.40-1.17. Cholecystectomy was less common in cases, aOR 0.33, 95% CI 0.17-0.64, but microscopic colitis cases had more frequent bowel movements following cholecystectomy. Conclusion: Compared to similar patients with diarrhoea, cases with microscopic colitis were not more likely to have taken previously implicated medications. They had more diarrhoea following cholecystectomy, suggesting that bile may play a role in symptoms or aetiology. We conclude that the appropriate choice of controls is crucial to understanding risk factors for microscopic colitis

Obesity is associated with decreased risk of microscopic colitis in women

BACKGROUND Microscopic colitis is a leading cause of diarrhea in the older adults. There is limited information about risk factors. We hypothesized that obesity would be associated with microscopic colitis. AIM To examine the association between obesity and microscopic colitis in men and women undergoing colonoscopy. METHODS We conducted a case-control study at the University of North Carolina Hospitals. We identified and enrolled men and women referred for elective, outpatient colonoscopy for chronic diarrhea. We excluded patients with a past diagnosis of Crohn's disease or ulcerative colitis. A research pathologist reviewed biopsies on every patient and classified them as microscopic colitis cases or non-microscopic colitis controls. Patients provided information on body weight, height and exposure to medications via structured interviews or Internet based forms. The analysis included 110 patients with microscopic colitis (cases) and 252 nonmicroscopic colitis controls. Multivariable analyses were performed using logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS Cases were older and more likely than controls to be white race. Study subjects were well educated, but cases were better educated than controls. Cases with microscopic colitis had lower body mass index than controls and reported more weight loss after the onset of diarrhea. Compared to patients who were normal or under-weight, obese (BMI > 30 kg/m2) patients were substantially less likely to have microscopic colitis after adjusting for age and education, adjusted OR (aOR) 0.35, 95% confidence interval (CI) 0.18-0.66). When stratified by sex, the association was limited to obese women, aOR 0.21, 95%CI: 0.10-0.45. Patients with microscopic colitis were more likely to report weight loss after the onset of diarrhea. After stratifying by weight loss, there remained a strong inverse association between obesity and microscopic colitis, aOR 0.33, 95%CI: 0.10 - 1.11 among the patients who did not lose weight. Ever use of birth control pills was associated with lower risk of microscopic colitis after adjusting for age, education and BMI, aOR 0.38, 95%CI: 0.17-0.84. CONCLUSION Compared to controls also seen for diarrhea, microscopic colitis cases were less likely to be obese. Mechanisms are unknown but could involve hormonal effects of obesity or the gut microbiome

Intraepithelial and Lamina Propria Lymphocytes Do Not Correlate with Symptoms or Exposures in Microscopic Colitis

INTRODUCTION:Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and lamina propria on microscopy. We sought to determine whether T-cell percentage was associated with exposures or symptoms.METHODS:We conducted a case-control study that enrolled patients referred for colonoscopy for diarrhea. Patients were classified as microscopic colitis cases or controls by an experienced pathologist. Participants provided information on symptoms and exposures during a telephone or internet survey. Research biopsies from the ascending colon and descending colon were examined using immunofluorescence stains for CD3, CD8, and FOXP3 to determine percent T cells per total epithelial or lamina propria cells. Digital images were analyzed by regions of interest using Tissue Studio.RESULTS:There were 97 microscopic colitis cases and 165 diarrhea controls. There was no association between demographic factors and percentage of intraepithelial or lamina propria T cells. In cases, the mean percent T cells were similar in the right colon and left colon. There was no association between mean percent T cells and stool frequency or consistency. There was no association with irritable bowel syndrome, abdominal pain, or medications purported to cause microscopic colitis.DISCUSSION:The lack of association between the density of T cells and medications raises further doubts about their role in disease etiology. Loose and frequent stools in patients with microscopic colitis are not correlated with T-cell density

Colonic Diverticula Are Not Associated With Mucosal Inflammation or Chronic Gastrointestinal Symptoms

Background & Aims: Colonic diverticulosis has been reported to be associated with low-grade mucosal inflammation, possibly leading to chronic gastrointestinal symptoms. However, there is poor evidence for this association. We aimed to determine mucosal inflammation and whether diverticula are associated with chronic gastrointestinal symptoms. We explored whether inflammation was present among symptomatic participants with and without diverticula. Methods: We analyzed data from a prospective study of 619 patients undergoing a screening colonoscopy from 2013 through 2015 at the University of North Carolina Hospital in Chapel Hill, North Carolina. Among our participants, 255 (41%) had colonic diverticula. Colonic mucosal biopsy specimens were analyzed for levels of interleukin 6 (IL6), IL10, and tumor necrosis factor messenger RNAs by quantitative reverse-transcriptase polymerase chain reaction, and numbers of immune cells (CD4+, CD8+, CD57+, and mast cell tryptase) by immunohistochemistry. Gastrointestinal symptoms were assessed using Rome III criteria. Proportional odds models were used to estimate odds ratios (ORs) and 95% confidence interval (CIs). Results: After adjustment for potential confounders, there was no association between diverticulosis and tumor necrosis factor (OR, 0.85; 95% CI, 0.63–1.16), and no association with CD4+ cells (OR, 1.18; 95% CI, 0.87–1.60), CD8+ cells (OR, 0.97; 95% CI, 0.71–1.32), or CD57+ cells (OR, 0.80; 95% CI, 0.59–1.09). Compared with controls without diverticulosis, biopsy specimens from individuals with diverticulosis were less likely to express the inflammatory cytokine IL6 (OR, 0.59; 95% CI, 0.36–0.96). There was no association between diverticulosis and irritable bowel syndrome (OR, 0.53; 95% CI, 0.26–1.05) or chronic abdominal pain (OR, 0.68; 95% CI, 0.38–1.23). There was no evidence for inflammation in patients with symptoms when patients with vs without diverticulosis were compared. Conclusions: We found no evidence that colonic diverticulosis is associated with mucosal inflammation or gastrointestinal symptoms. Among patients with symptoms and diverticula, we found no mucosal inflammation

Maternal Morbidity after Previable Prelabor Rupture of Membranes

OBJECTIVE: To identify risk factors for maternal morbidity after previable prelabor rupture of membranes (PROM). METHODS: We conducted a case-control study of singleton and twin pregnancies complicated by previable PROM (14.0-22.9 weeks of gestation) at a single tertiary care referral institution, 2000-2015. Pregnancies complicated by fetal anomalies, previable PROM within 2 weeks of chorionic villus sampling or amniocentesis, and those with contraindications to expectant management (eg, chorioamnionitis) were excluded. Cases were women with the primary outcome of composite maternal morbidity (defined as having at one or more of the following: sepsis, intensive care unit admission, acute renal insufficiency, uterine curettage, hysterectomy, deep vein thrombosis, pulmonary embolus, blood transfusion, readmission, or maternal death). Controls were women without the primary composite morbidity. Bivariate analysis compared demographic, clinical, and management characteristics of women in the case group and those in the control group. Multivariable logistic regression models were developed to quantify the association between maternal characteristics and composite severe maternal morbidity. RESULTS: During the study period, 174 women presented with by previable PROM and were candidates for expectant management. Sixty-five (37%) women opted for immediate delivery; 109 (63%) elected expectant management. Twenty-five of 174 (14%) experienced one or more components of the composite maternal morbidity (cases) and were compared with 149 (86%) women in the control group. Women in the case group were more not more likely to elect expectant management (68% compared with 59%, P=.40), but were more likely to be aged 35 years or older (40% compared with 14%, P=.002) or to be carrying twins (52% compared with 16%, P<.01). In the regression model, twin gestation and age 35 years or older were both significantly associated with increased odds of composite maternal morbidity (odds ratio [OR] 5.62, 95% confidence interval [CI] 2.21-14.3 and OR 4.00, 95% CI 1.48-10.8, respectively). CONCLUSION: Antenatal counseling of women with previable PROM should include that one in seven women experience significant morbidity. Although expectant management was not associated with increased risk in this cohort, women with twins or those aged 35 years or older were at substantially increased risk

Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth

ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of fulllength ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2mRNAabundance and associated with APC tumorsuppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a KrasG12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study

Background The association of fitness with cancer risk is not clear. Methods We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. Results After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. Discussion Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention

Discovery of common and rare genetic risk variants for colorectal cancer

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P &amp;lt; 5 × 10 −8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply