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Polypharmacy is a major health issue for older adults. Entangled with several geriatric syndromes, including frailty, falls and cognitive decline, research focused on polypharmacy has been challenged by heterogeneity in its definition, confounding by comorbidities and limited prospective data. In this Review, we discuss varying definitions for polypharmacy and highlight the need for a uniform definition for future studies. We critically appraise strategies for reducing medication prescriptions and implementing deprescribing as a mechanism to reduce the potential harmful effects of polypharmacy. As we look to the future, we assess the role of novel analytics and high-throughput technology, including multiomics profiling, to advance research in polypharmacy and the development of new strategies for risk stratification in the age of precision medicine. Polypharmacy is a leading health concern entangled with many geriatric syndromes. This Review provides an overview of the current research landscape and a critical appraisal of existing and emerging approaches to address polypharmacy.

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.

Background & Aims Sulfur-metabolizing microbes, which convert dietary sources of sulfur into genotoxic hydrogen sulfide (H2S), have been associated with development of colorectal cancer (CRC). We identified a dietary pattern associated with sulfur-metabolizing bacteria in stool and then investigated its association with risk of incident CRC using data from a large prospective study of men. Methods We collected data from 51,529 men enrolled in the Health Professionals Follow-up Study since 1986 to determine the association between sulfur-metabolizing bacteria in stool and risk of CRC over 26 years of follow-up. First, in a subcohort of 307 healthy men, we profiled serial stool metagenomes and metatranscriptomes and assessed diet using semiquantitative food frequency questionnaires to identify food groups associated with 43 bacterial species involved in sulfur metabolism. We used these data to develop a sulfur microbial dietary score. We then used Cox proportional hazards modeling to evaluate adherence to this pattern among eligible individuals (n = 48,246) from 1986 through 2012 with risk for incident CRC. Results Foods associated with higher sulfur microbial diet scores included increased consumption of processed meats and low-calorie drinks and lower consumption of vegetables and legumes. Increased sulfur microbial diet scores were associated with risk of distal colon and rectal cancers, after adjusting for other risk factors (multivariable relative risk, highest vs lowest quartile, 1.43; 95% confidence interval 1.14–1.81; P-trend = .002). In contrast, sulfur microbial diet scores were not associated with risk of proximal colon cancer (multivariable relative risk 0.86; 95% CI 0.65–1.14; P-trend = .31). Conclusions In an analysis of participants in the Health Professionals Follow-up Study, we found that long-term adherence to a dietary pattern associated with sulfur-metabolizing bacteria in stool was associated with an increased risk of distal CRC. Further studies are needed to determine how sulfur-metabolizing bacteria might contribute to CRC pathogenesis.

Background COVID-19 is a deadly multisystemic disease, and bowel ischemia, the most consequential gastrointestinal manifestation, remains poorly described. Our goal is to describe our institution’s surgical experience with management of bowel ischemia due to COVID-19 infection over a one-year period. Methods All patients admitted to our institution between March 2020 and March 2021 for treatment of COVID-19 infection and who underwent exploratory laparotomy with intra-operative confirmation of bowel ischemia were included. Data from the medical records were analyzed. Results Twenty patients were included. Eighty percent had a new or increasing vasopressor requirement, 70% had abdominal distension, and 50% had increased gastric residuals. Intra-operatively, ischemia affected the large bowel in 80% of cases, the small bowel in 60%, and both in 40%. Sixty five percent had an initial damage control laparotomy. Most of the resected bowel specimens had a characteristic appearance at the time of surgery, with a yellow discoloration, small areas of antimesenteric necrosis, and very sharp borders. Histologically, the bowel specimens frequently have fibrin thrombi in the small submucosal and mucosal blood vessels in areas of mucosal necrosis. Overall mortality in this cohort was 33%. Forty percent of patients had a thromboembolic complication overall with 88% of these developing a thromboembolic phenomenon despite being on prophylactic pre-operative anticoagulation. Conclusion Bowel ischemia is a potentially lethal complication of COVID-19 infection with typical gross and histologic characteristics. Suspicious clinical features that should trigger surgical evaluation include a new or increasing vasopressor requirement, abdominal distension, and intolerance of gastric feeds.

Key Points Question Is there an association between a dietary pattern that correlates with sulfur-metabolizing bacteria in the gut and colorectal cancer risk? Findings In 3 large prospective cohort studies of US men and women, greater adherence to a sulfur microbial diet characterized by high intakes of low-calorie beverages and red meats and low intakes of fruits and vegetables was associated with increased risk of colorectal cancer, after controlling for various risk factors. Meaning This study suggests that sulfur-metabolizing bacteria may mediate the association between diet and colorectal cancer risk and could potentially be targeted for risk mitigation., Importance Sulfur-metabolizing bacteria that reduce dietary sulfur to hydrogen sulfide have been associated with colorectal cancer (CRC). However, there are limited studies investigating the association between diet and sulfur-metabolizing bacteria in the development of CRC. Objective To develop a dietary score that correlates with gut sulfur–metabolizing bacteria and to examine its association with CRC risk. Design, Setting, and Participants This prospective cohort study included data from the Health Professionals Follow-up Study (1986-2014), Nurses’ Health Study (1984-2016), and Nurses’ Health Study II (1991-2017). Participants were US male health professionals and female registered nurses who were free of inflammatory bowel disease and cancer at baseline, with a subsample of participants who provided stool samples from 2012 to 2014. Statistical analysis was conducted from September 1, 2020, to June 1, 2021. Exposure A dietary pattern, assessed by a food-frequency questionnaire, that most correlated with 43 sulfur-metabolizing bacteria identified through taxonomic and functional profiling of gut metagenome data. Main Outcomes and Measures Incident CRC. Results Among 214 797 participants comprising 46 550 men (mean [SD] age at baseline, 54.3 [9.7] years) and 168 247 women (mean [SD] age at baseline, 43.0 [9.2] years), 3217 incident cases of CRC (1.5%) were documented during 5 278 048 person-years of follow-up. The sulfur microbial diet, developed in a subsample of 307 men (mean [SD] age, 70.5 [4.3] years) and 212 women (mean [SD] age, 61.0 [3.8] years), was characterized by high intakes of low-calorie beverages, french fries, red meats, and processed meats and low intakes of fruits, yellow vegetables, whole grains, legumes, leafy vegetables, and cruciferous vegetables. After adjustment for other risk factors, greater adherence to the sulfur microbial diet was associated with an increased risk of CRC, with a hazard ratio (HR) of 1.27 (95% CI, 1.12-1.44) comparing the highest vs the lowest quintile of the diet score (linear trend of diet score quintiles; P, This cohort study uses data from the Health Professionals Follow-up Study, Nurses’ Health Study, and Nurses’ Health Study II to develop a dietary score that correlates with gut sulfur–metabolizing bacteria and to examine its association with colorectal cancer risk.

A 39-year-old man with untreated HIV presented with watery, non-bloody diarrhea and associated 25-lb weight loss. His workup was notable for a CT abdomen/pelvis which showed an entero-enteric intussusception of 3.4 cm without an underlying pathologic mass. The patient's intussusception resolved without intervention, as is typical of telescoping

Early reports raised concern that use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19). Users of the COVID Symptom Study smartphone application reported use of aspirin and other NSAIDs between March 24 and May 8, 2020. Users were queried daily about symptoms, COVID-19 testing, and healthcare seeking behavior. Cox proportional hazards regression was used to determine the risk of COVID-19 among according to aspirin or non-aspirin NSAID users. Among 2,736,091 individuals in the U.S., U.K., and Sweden, we documented 8,966 incident reports of a positive COVID-19 test over 60,817,043 person-days of follow-up. Compared to non-users and after stratifying by age, sex, country, day of study entry, and race/ethnicity, non-aspirin NSAID use was associated with a modest risk for testing COVID-19 positive (HR 1.23 [1.09, 1.32]), but no significant association was observed among aspirin users (HR 1.13 [0.92, 1.38]). After adjustment for lifestyle factors, comorbidities and baseline symptoms, any NSAID use was not associated with risk (HR 1.02 [0.94, 1.10]). Results were similar for those seeking healthcare for COVID-19 and were not substantially different according to lifestyle and sociodemographic factors or after accounting for propensity to receive testing. Our results do not support an association of NSAID use, including aspirin, with COVID-19 infection. Previous reports of a potential association may be due to higher rates of comorbidities or use of NSAIDs to treat symptoms associated with COVID-19.One Sentence SummaryNSAID use is not associated with COVID-19 risk.

Background There is limited prior investigation of the combined influence of personal and community-level socioeconomic factors on racial/ethnic disparities in individual risk of coronavirus disease 2019 (COVID-19). Methods We performed a cross-sectional analysis nested within a prospective cohort of 2,102,364 participants from March 29, 2020 in the United States (US) and March 24, 2020 in the United Kingdom (UK) through December 02, 2020 via the COVID Symptom Study smartphone application. We examined the contribution of community-level deprivation using the Neighborhood Deprivation Index (NDI) and the Index of Multiple Deprivation (IMD) to observe racial/ethnic disparities in COVID-19 incidence. ClinicalTrials.gov registration: NCT04331509. Findings Compared with non-Hispanic White participants, the risk for a positive COVID-19 test was increased in the US for non-Hispanic Black (multivariable-adjusted odds ratio [OR], 1.32; 95% confidence interval [CI], 1.18–1.47) and Hispanic participants (OR, 1.42; 95% CI, 1.33–1.52) and in the UK for Black (OR, 1.17; 95% CI, 1.02–1.34), South Asian (OR, 1.39; 95% CI, 1.30–1.49), and Middle Eastern participants (OR, 1.38; 95% CI, 1.18–1.61). This elevated risk was associated with living in more deprived communities according to the NDI/IMD. After accounting for downstream mediators of COVID-19 risk, community-level deprivation still mediated 16.6% and 7.7% of the excess risk in Black compared to White participants in the US and the UK, respectively. Interpretation Our results illustrate the critical role of social determinants of health in the disproportionate COVID-19 risk experienced by racial and ethnic minorities. Funding Please refer to the Funding section at the end of the article.

Individuals with cancer may be at high risk for coronavirus disease 2019 (COVID-19) and adverse outcomes. However, evidence from large population-based studies examining whether cancer and cancer-related therapy exacerbates the risk of COVID-19 infection is still limited. Data were collected from the COVID Symptom Study smartphone application since March 29 through May 8, 2020. Among 23,266 participants with cancer and 1,784,293 without cancer, we documented 10,404 reports of a positive COVID-19 test. Compared with participants without cancer, those living with cancer had a 60% increased risk of a positive COVID-19 test. Among patients with cancer, current treatment with chemotherapy or immunotherapy was associated with a 2.2-fold increased risk of a positive test. The association between cancer and COVID-19 infection was stronger among participants >65 years and males. Future studies are needed to identify subgroups by tumor types and treatment regimens who are particularly at risk for COVID-19 infection and adverse outcomes.

Objectives Proton pump inhibitor (PPI) therapy is a potentially modifiable risk factor for recurrent Clostridioides difficile infection (CDI). Citing an absence of clinical trials, many guidelines do not provide recommendations for addressing PPI management. Our aim was to perform an updated systematic review and meta-analysis evaluating the association between PPI use and recurrent CDI addressing prior methodological limitations. Methods Data sources were MEDLINE and EMBASE. Eligible studies were cohort and case–control studies; there were no restrictions on study setting or duration of follow-up. Participants were adults with prior CDI who did or did not receive PPI therapy and were assessed for recurrent CDI. Summary (unadjusted) odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Prespecified subgroup analyses were performed to explore heterogeneity including study design, study quality, duration of follow-up, adjustment for confounders, and outcome definition. Results Sixteen studies were included in the meta-analysis, comprising 57 477 patients with CDI, of whom 6870 (12%) received PPIs. The rate of recurrent CDI was 24% in patients treated with PPIs versus 18% in those who were not. A meta-analysis that pooled unadjusted odds ratios demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.69, 95%CI 1.46–1.96) versus those who did not. There was moderate heterogeneity between studies (I2 56%); however, a sensitivity analysis restricted to studies with 56 days of follow-up substantially reduced the heterogeneity (OR 1.59, 95%CI 1.36–1.85; I2 12%). An analysis restricted to multivariate studies that combined adjusted ORs also demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.49, 95%CI 1.12–2.00). No publication bias was identified. Conclusions We found significantly higher odds of recurrent CDI among users of PPIs that persisted across multiple sensitivity analyses. These results support stronger recommendations for PPI stewardship at CDI diagnosis.

BackgroundRacial and ethnic minorities have disproportionately high hospitalization rates and mortality related to the novel coronavirus disease 2019 (Covid-19). There are comparatively scant data on race and ethnicity as determinants of infection risk.MethodsWe used a smartphone application (beginning March 24, 2020 in the United Kingdom [U.K.] and March 29, 2020 in the United States [U.S.]) to recruit 2,414,601 participants who reported their race/ethnicity through May 25, 2020 and employed logistic regression to determine the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for a positive Covid-19 test among racial and ethnic groups.ResultsWe documented 8,858 self-reported cases of Covid-19 among 2,259,841 non-Hispanic white; 79 among 9,615 Hispanic; 186 among 18,176 Black; 598 among 63,316 Asian; and 347 among 63,653 other racial minority participants. Compared with non-Hispanic white participants, the risk for a positive Covid-19 test was increased across racial minorities (aORs ranging from 1.24 to 3.51). After adjustment for socioeconomic indices and Covid-19 exposure risk factors, the associations (aOR [95% CI]) were attenuated but remained significant for Hispanic (1.58 [1.24-2.02]) and Black participants (2.56 [1.93-3.39]) in the U.S. and South Asian (1.52 [1.38-1.67]) and Middle Eastern participants (1.56 [1.25-1.95]) in the U.K. A higher risk of Covid-19 and seeking or receiving treatment was also observed for several racial/ethnic minority subgroups.ConclusionsOur results demonstrate an increase in Covid-19 risk among racial and ethnic minorities not completely explained by other risk factors for Covid-19, comorbidities, and sociodemographic characteristics. Further research investigating these disparities are needed to inform public health measures.

BackgroundData for frontline healthcare workers (HCWs) and risk of SARS-CoV-2 infection are limited and whether personal protective equipment (PPE) mitigates this risk is unknown. We evaluated risk for COVID-19 among frontline HCWs compared to the general community and the influence of PPE.MethodsWe performed a prospective cohort study of the general community, including frontline HCWs, who reported information through the COVID Symptom Study smartphone application beginning on March 24 (United Kingdom, U.K.) and March 29 (United States, U.S.) through April 23, 2020. We used Cox proportional hazards modeling to estimate multivariate-adjusted hazard ratios (aHRs) of a positive COVID-19 test.FindingsAmong 2,035,395 community individuals and 99,795 frontline HCWs, we documented 5,545 incident reports of a positive COVID-19 test over 34,435,272 person-days. Compared with the general community, frontline HCWs had an aHR of 11·6 (95% CI: 10·9 to 12·3) for reporting a positive test. The corresponding aHR was 3·40 (95% CI: 3·37 to 3·43) using an inverse probability weighted Cox model adjusting for the likelihood of receiving a test. A symptom-based classifier of predicted COVID-19 yielded similar risk estimates. Compared with HCWs reporting adequate PPE, the aHRs for reporting a positive test were 1·46 (95% CI: 1·21 to 1·76) for those reporting PPE reuse and 1·31 (95% CI: 1·10 to 1·56) for reporting inadequate PPE. Compared with HCWs reporting adequate PPE who did not care for COVID-19 patients, HCWs caring for patients with documented COVID-19 had aHRs for a positive test of 4·83 (95% CI: 3·99 to 5·85) if they had adequate PPE, 5·06 (95% CI: 3·90 to 6·57) for reused PPE, and 5·91 (95% CI: 4·53 to 7·71) for inadequate PPE.InterpretationFrontline HCWs had a significantly increased risk of COVID-19 infection, highest among HCWs who reused PPE or had inadequate access to PPE. However, adequate supplies of PPE did not completely mitigate high-risk exposures.FundingZoe Global Ltd., Wellcome Trust, EPSRC, NIHR, UK Research and Innovation, Alzheimer’s Society, NIH, NIOSH, Massachusetts Consortium on Pathogen ReadinessRESEARCH IN CONTEXTEvidence before this studyThe prolonged course of the coronavirus disease 2019 (COVID-19) pandemic, coupled with sustained challenges supplying adequate personal protective equipment (PPE) for frontline healthcare workers (HCW), have strained global healthcare systems in an unprecedented fashion. Despite growing awareness of this problem, there are few data to inform policy makers on the risk of COVID-19 among HCWs and the impact of PPE on their disease burden. Prior reports of HCW infections are based on cross sectional data with limited individual-level information on risk factors for infection. A PubMed search for articles published between January 1, 2020 and May 5, 2020 using the terms “covid-19”, “healthcare workers”, and “personal protective equipment,” yielded no population-scale investigations exploring this topic.Added value of this studyIn a prospective study of 2,135,190 individuals, frontline HCWs may have up to a 12-fold increased risk of reporting a positive COVID-19 test. Compared with those who reported adequate availability of PPE, frontline HCWs with inadequate PPE had a 31% increase in risk. However, adequate availability of PPE did not completely reduce risk among HCWs caring for COVID-19 patients.Implications of all the available evidenceBeyond ensuring adequate availability of PPE, additional efforts to protect HCWs from COVID-19 are needed, particularly as lockdown is lifted in many regions of the world.

BACKGROUND & AIMS: Diet may contribute to the increasing incidence of colorectal cancer (CRC) before age 50 (early-onset CRC). Microbial metabolism of dietary sulfur produces hydrogen sulfide (H(2)S), a gastrointestinal carcinogen that cannot be easily measured at scale. As a result, evidence supporting its role in early neoplasia is lacking. METHODS: We evaluated long-term adherence to the sulfur microbial diet, a dietary index defined a priori based on increased abundance of 43 bacterial species involved with sulfur metabolism, with risk of CRC precursors among 59,013 individuals who underwent lower endoscopy in the Nurses’ Health Study II (NHSII, 1991–2015), a prospective cohort study with dietary assessment every four years through validated food frequency questionnaires and an assessment of dietary intake during adolescence in 1998. The sulfur microbial diet was characterized by intake high in processed meats and low in mixed vegetables and legumes, foods previously linked to CRC development. Multivariable logistic regression for clustered data was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We documented 2,911 cases of early-onset adenoma. After adjusting for established risk factors, higher sulfur microbial diet scores were associated with increased risk for early-onset adenomas (OR(Q4vs.Q1)=1.31, 95% CI: 1.10 to 1.56, P(trend)=0.02), but not serrated lesions. Compared to the lowest, women in the highest quartile of sulfur microbial diet scores had significantly increased risk of early-onset adenomas with greater malignant potential (OR(Q4vs.Q1)=1.65 for villous/tubulovillous histology, 95% CI: 1.12 to 2.43; P(trend)=0.04). Similar trends for early onset-adenoma were observed based on diet consumed during adolescence. In contrast, there was no clear association for adenomas identified after age 50. CONCLUSION: Our findings in a cohort of young women support a role for dietary interactions with gut sulfur-metabolizing bacteria in early-onset colorectal carcinogenesis, possibly beginning in adolescence.

This cohort study evaluated the joint association of dietary and lifestyle factors with risk of gastroesophageal reflux disease symptoms among women participating in the Nurses’ Health Study II.

Evidence remains inconclusive about the association of systemic inflammatory markers with colorectal neoplasia. We investigated whether circulating inflammatory markers were associated with risk of advanced colorectal adenoma. We measured plasma macrophage inhibitory cytokine-1 (MIC-1), C-reactive protein (CRP), interleukin-6 (IL6), and soluble TNF receptor 2 (sTNFR-2) in blood samples drawn from 32,826 women in 1989 to 1990 in the Nurses' Health Study. Through 2008, we documented 757 cases of advanced colorectal adenomas (≥1 cm or any size with advanced histology); each case was matched by age and time of blood draw with one control randomly selected from participants who underwent lower endoscopy and did not have neoplasia. Plasma MIC-1 was associated with higher risk of advanced adenoma (Ptrend = 0.04), with an OR of 1.55 (95% confidence interval, 1.03–2.32) comparing extreme quintiles of MIC-1 after adjusting for colorectal cancer–risk factors and other inflammatory markers. Among cases, MIC-1 level was positively associated with the number of adenomas (P < 0.001) and gradually increased from adenomas located in the rectum, distal colon, and up to the proximal colon. There was a strong positive association between MIC-1 and risk of adenomas with multiplicity, ≥1 cm size and location in the proximal colon (all Ptrend < 0.05). CRP, IL6, or sTNFR-2 was not associated with adenoma risk. In conclusion, plasma MIC-1 was associated with higher risk of colorectal adenoma, especially multiple, large, and proximal adenomas. Our results provide further support for a role for MIC-1 in carcinogenesis and the potential for MIC-1 as an adjunctive biomarker for detection of advanced colorectal adenoma. Cancer Prev Res; 9(1); 27–34. ©2015 AACR.

Patients are frequently advised to eliminate coffee, tea, and/or soda to reduce symptoms of gastroesophageal reflux (GER), such as heartburn or regurgitation. However, there are no data from prospective studies to support these recommendations.We collected data from the prospective Nurses' Health Study II from 48,308 women, 42-62 years old, who were free of regular GER symptoms, without cancer, and not taking proton pump inhibitors or H2 receptor agonists. Multivariate Cox proportional hazards models were used to assess associations between beverage intake and risk for GER symptoms.During 262,641 person-years of follow up, we identified 7961 women who reported symptoms of GER once or more per week. After multivariable adjustment, hazard ratios (HRs) for women with the highest intake of each beverage (more than 6 servings/day) compared to women with the lowest intake (0 servings/day) were 1.34 for coffee (95% CI, 1.13-1.59; Ptrend .0001), 1.26 for tea (95% CI, 1.03-1.55; Ptrend.001), and 1.29 for soda (95% CI, 1.05-1.58; Ptrend.0001). We obtained similar results when we stratified patients according to caffeine status. No association was observed between milk, water, or juice consumption and risk for GER symptoms. In a substitution analysis, replacement of 2 servings/day of coffee, tea, or soda with 2 servings of water was associated with reduced risk of GERD symptoms: coffee HR, 0.96 (95% CI, 0.92-1.00); tea HR, 0.96 (95% CI, 0.92-1.00); and soda HR, 0.92 (95% CI, 0.89- 0.96).In an analysis of data from the prospective Nurses' Health Study II, intake of coffee, tea, or soda was associated with an increased risk of GER symptoms. In contrast, consumption of water, juice, or milk was not associated with GER symptoms. Drinking water instead of coffee, tea, or soda reduced the risk of GER symptoms.

OBJECTIVE: Recent evidence suggests that antibiotic use, which alters the gut microbiome, is associated with an increased risk of colorectal cancer. However, the association between antibiotic use and risk of colorectal adenoma, the precursor for the majority of colorectal cancers, has not been investigated. DESIGN: We prospectively evaluated the association between antibiotic use at age 20–39 and 40–59 (assessed in 2004) and recent antibiotic use (assessed in 2008) with risk of subsequent colorectal adenoma among 16,642 women aged ≥60 enrolled in the Nurses’ Health Study who underwent at least one colonoscopy through 2010. We used multivariate logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We documented 1,195 cases of adenoma. Increasing duration of antibiotic use at age 20–39 (P(trend)=0.002) and 40–59 (P(trend)=0.001) was significantly associated with an increased risk of colorectal adenoma. Compared to non-users, women who used antibiotics for ≥2 months between age 20–39 had a multivariable OR of 1.36 (95% CI: 1.03–1.79). Women who used ≥2 months of antibiotics between age 40–59 had a multivariable OR of 1.69 (95% CI: 1.24–2.31). The associations were similar for low-risk vs. high-risk adenomas (size ≥1 cm, or with tubulovillous/villous histology, or ≥3 detected lesions), but appeared modestly stronger for proximal compared with distal adenomas. In contrast, recent antibiotic use within the past 4 years was not associated with risk of adenoma (P(trend)=0.44). CONCLUSIONS: Long-term antibiotic use in early to middle adulthood was associated with increased risk of colorectal adenoma.

Importance Fusobacterium nucleatum appears to play a role in colorectal carcinogenesis through suppression of the hosts’ immune response to tumor. Evidence also suggests that diet influences intestinal F nucleatum. However, the role of F nucleatum in mediating the relationship between diet and the risk of colorectal cancer is unknown. Objective To test the hypothesis that the associations of prudent diets (rich in whole grains and dietary fiber) and Western diets (rich in red and processed meat, refined grains, and desserts) with colorectal cancer risk may differ according to the presence of F nucleatum in tumor tissue. Design, Setting, and Participants A prospective cohort study was conducted using data from the Nurses’ Health Study (June 1, 1980, to June 1, 2012) and the Health Professionals Follow-up Study (June 1, 1986, to June 1, 2012) on a total of 121 700 US female nurses and 51 529 US male health professionals aged 30 to 55 years and 40 to 75 years, respectively (both predominantly white individuals), at enrollment. Data analysis was performed from March 15, 2015, to August 10, 2016. Exposures Prudent and Western diets. Main Outcomes and Measures Incidence of colorectal carcinoma subclassified by F nucleatum status in tumor tissue, determined by quantitative polymerase chain reaction. Results Of the 173 229 individuals considered for the study, 137 217 were included in the analysis, 47 449 were male (34.6%), and mean (SD) baseline age for men was 54.0 (9.8) years and for women, 46.3 (7.2) years. A total of 1019 incident colon and rectal cancer cases with available F nucleatum data were documented over 26 to 32 years of follow-up, encompassing 3 643 562 person-years. The association of prudent diet with colorectal cancer significantly differed by tissue F nucleatum status ( P = .01 for heterogeneity); prudent diet score was associated with a lower risk of F nucleatum– positive cancers ( P = .003 for trend; multivariable hazard ratio of 0.43; 95% CI, 0.25-0.72, for the highest vs the lowest prudent score quartile) but not with F nucleatum– negative cancers ( P = .47 for trend, the corresponding multivariable hazard ratio of 0.95; 95% CI, 0.77-1.17). There was no significant heterogeneity between the subgroups in relation to Western dietary pattern scores. Conclusions and Relevance Prudent diets rich in whole grains and dietary fiber are associated with a lower risk for F nucleatum –positive colorectal cancer but not F nucleatum –negative cancer, supporting a potential role for intestinal microbiota in mediating the association between diet and colorectal neoplasms.

The symptom burden of menopause extends well beyond hot flashes, vaginal dryness, and fluctuations in mood. We frequently field questions from patients with chronic gastrointestinal complaints about how their symptoms may change during the menopausal transition (MT). Those with preexisting irritable

Background & Aims Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and tumor necrosis factor–receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on an empiric dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota. Colonization by Fusobacterium nucleatum has been associated with the presence and features of colorectal adenocarcinoma. We investigated the association between diets that promote inflammation (based on EDIP score) and colorectal cancer subtypes classified by level of F nucleatum in the tumor microenvironment. Methods We calculated EDIP scores based on answers to food frequency questionnaires collected from participants in the Nurses' Health Study (through June 1, 2012) and the Health Professionals Follow-up Study (through January 31, 2012). Participants in both cohorts reported diagnoses of rectal or colon cancer in biennial questionnaires; deaths from unreported colorectal cancer cases were identified through the National Death Index and next of kin. Colorectal tumor tissues were collected from hospitals where the patients underwent tumor resection and F nucleatum DNA was quantified by a polymerase chain reaction assay. We used multivariable duplication-method Cox proportional hazard regression to assess the associations of EDIP scores with risks of colorectal cancer subclassified by F nucleatum status. Results During 28 years of follow-up evaluation of 124,433 participants, we documented 951 incident cases of colorectal carcinoma with tissue F nucleatum data. Higher EDIP scores were associated with increased risk of F nucleatum–positive colorectal tumors (Ptrend = .03); for subjects in the highest vs lowest EDIP score tertiles, the hazard ratio for F nucleatum–positive colorectal tumors was 1.63 (95% CI, 1.03–2.58). EDIP scores did not associate with F nucleatum–negative tumors (Ptrend = .44). High EDIP scores associated with proximal F nucleatum–positive colorectal tumors but not with proximal F nucleatum–negative colorectal tumors (Pheterogeneity = .003). Conclusions Diets that may promote intestinal inflammation, based on EDIP score, are associated with increased risk of F nucleatum–positive colorectal carcinomas, but not carcinomas that do not contain these bacteria. These findings indicate that diet-induced intestinal inflammation alters the gut microbiome to contribute to colorectal carcinogenesis; nutritional interventions might be used in precision medicine and cancer prevention.

Circulating adiponectin is inversely related to the risk of colorectal cancer. However, its influence on colorectal cancer survival is unclear. We conducted a prospective study to evaluate the association between prediagnostic plasma levels of adiponectin and mortality in patients with colorectal cancer. We identified 621 incident colorectal cancer cases who provided blood specimens prior to diagnosis within the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI). After a median follow-up of 9 years, there were 269 (43%) total deaths, of which 181 (67%) were due to colorectal cancer. Compared with participants in the lowest quartile of adiponectin, those in the highest quartile had multivariate HRs of 1.89 (95% CI, 1.21–2.97; Ptrend = 0.01) for colorectal cancer–specific mortality and 1.66 (95% CI, 1.15–2.39; Ptrend = 0.009) for overall mortality. The apparent increased risk in colorectal cancer–specific mortality was more pronounced in patients with metastatic disease (HR, 3.02: 95% CI, 1.50–6.08). Among patients with colorectal cancer, prediagnostic plasma adiponectin is associated with an increased risk of colorectal cancer–specific and overall mortality and is more apparent in patients with metastatic disease. Adiponectin may be a marker for cancers which develop through specific pathways that may be associated with worsened prognosis. Further studies are needed to validate these findings. Cancer Prev Res; 8(12); 1138–45. ©2015 AACR.

Background & Aims Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or growth differentiation factor 15), a marker of inflammation that might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality. Methods We collected data on survival of 618 participants diagnosed with CRC who provided prediagnosis blood specimens in 1990 (Nurses' Health Study) and 1994 (Health Professionals' Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by enzyme-linked immunosorbent assay and then were categorized into quartiles based on the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or cyclooxygenase-2), measured in 245 tumor samples by immunohistochemistry. Results Compared with participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval: 1.33−4.34; P for linear trend = .009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples ( P interaction = .04). For individuals with PTGS2-positive tumors, the hazard ratio for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% confidence interval: 0.99−4.58) compared with participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate hazard ratio = 0.61; 95% confidence interval: 0.13−2.93). Conclusions Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (growth differentiation factor 15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors.

Background & Aims Western and prudent dietary patterns have been associated with higher and lower risks of colorectal cancer (CRC), respectively. However, little is known about the associations between dietary patterns and specific anatomic subsites or molecular subtypes of CRC. Methods We used multivariable Cox proportional hazards models to examine the associations between Western and prudent dietary patterns and CRC risk in the Health Professionals Follow-up Study and Nurses' Health Study. Results After up to 32 years of follow-up of 137,217 men and women, we documented 3260 cases of CRC. Among individuals from whom subsite data were available, we observed 1264 proximal colon, 866 distal colon, and 670 rectal tumors. Western diet was associated with an increased incidence of CRC (P trend trend = .0004) and rectum (RR, 1.35; 95% CI, 1.03–1.77; P trend = .01) but not proximal colon (RR, 1.11; 95% CI, 0.91–1.35; P trend = .51) when we comparing extreme quartiles. In contrast, for the prudent pattern, we observed a RR of 0.86 for overall CRC (95% CI, 0.77–0.95; P trend = .01), with similar trends at anatomic subsites. However, the trend appeared stronger among men than women. Among 1285 cases (39%) with tissue available for molecular profiling, Western diet appeared to be more strongly associated with some CRC molecular subtypes (no mutations in KRAS [KRAS wildtype] or BRAF [BRAF wildtype], no or a low CpG island methylator phenotype, and microsatellite stability), although formal tests for heterogeneity did not produce statistically significant results. Conclusions Western dietary patterns are associated with an increased risk of CRC, particularly distal colon and rectal tumors. Western dietary patterns also appear more strongly associated with tumors that are KRAS wildtype, BRAF wildtype, have no or a low CpG island methylator phenotype, and microsatellite stability. In contrast, prudent dietary patterns are associated with a lower risk of CRC that does not vary according to anatomic subsite or molecular subtype.

Background & Aims Low estrogen levels can contribute to development of fecal incontinence (FI) in women after menopause by altering neuromuscular continence mechanisms. However, studies have produced conflicting results on the association between menopausal hormone therapy (MHT) and risk of FI. Methods We studied the association between MHT and risk of FI among 55,828 postmenopausal women (mean age, 73 years) who participated in the Nurses' Health Study, were enrolled since 2008, and with no report of FI. We defined incident FI as a report of at least 1 liquid or solid FI episode per month during 4 years of follow-up from self-administered, biennial questionnaires administered in 2010 and 2012. We used Cox proportional hazard models to calculate multivariate-adjusted hazard ratios and 95% confidence intervals (CIs) for FI risk in women receiving MHT, adjusting for potential confounding factors. Results During more than 185,000 person-years of follow-up, there were 6834 cases of incident FI. Compared with women who never used MHT, the multivariate hazard ratio for FI was 1.26 (95% CI, 1.18−1.34) for past users of MHT and 1.32 (95% CI, 1.20−1.45) for current users. The risk of FI increased with longer duration of MHT use ( P trend ≤ .0001) and decreased with time since discontinuation. There was an increased risk of FI among women receiving MHT that contained a combination of estrogen and progestin (hazard ratio, 1.37; 95% CI, 1.10–1.70) compared with estrogen monotherapy. Conclusions Current or past use of MHT was associated with a modestly increased risk of FI among postmenopausal women in the Nurses' Health Study. These results support a potential role for exogenous estrogens in the impairment of the fecal continence mechanism.

Background: Antibiotics shift the gut microbiota to temporally quasi-stable or alternative stable states, marked by a loss of diversity, alternations in the abundance of specific taxa, shifts in metabolic capacity, and by reduced resistance to colonization against invading pathogens. Recent evidence suggests that antibiotic use may be associated with an increased risk of colorectal cancer. However, these prior studies may be confounded by symptoms associated with colorectal cancer or differential exposure to medical care. To address these potential concerns, we examined the association of chronic antibiotic exposure and recent antibiotic use with risk of colorectal adenomas, which are largely asymptomatic and the precursor of majority of colorectal cancers. Methods: We prospectively evaluated the association between chronic lifetime antibiotic use at age 20-39 and age 40-59 (assessed in 2004), and recent antibiotic use (assessed in 2008) and risk of subsequent colorectal adenoma among women aged ≥60 in the Nurses' Health Study who underwent at least one lower endoscopy through 2010. Antibiotic use was categorized according to the total time using antibiotics (excluding skin creams, mouthwash or Isoniazid) during a specific time period (age 20-39, or age 40-59, or past 4 years). We also investigated the association between antibiotic exposure during each time period and risk of high-risk (adenoma ≥1cm, or with villous histology, or ≥3 adenomas) vs. low-risk adenoma, as well as risk of adenoma according to anatomic location. We used multivariate logistic regression adjusting for known and putative risk factors for adenoma to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Among 17,002 women aged ≥60 who reported their antibiotic exposure and then subsequently underwent at least one lower endoscopy, we documented 1,213 cases of adenoma over 6 years of follow-up. An increasing duration of antibiotic use at age 20-39 (Ptrend=0.002) and 40-59 (Ptrend=0.001) was significantly associated with an increased risk of colorectal adenoma. Compared to non-users, women who used antibiotics for ≥2 months between age 20-39 had a multivariable OR for adenoma of 1.37 (95% CI: 1.04-1.81). Women who used ≥2 months of antibiotics between age 40-59 had a multivariable OR of 1.71 (95% CI: 1.25-2.33). The associations were similar for high-risk compared to low-risk adenomas, but appeared somewhat stronger for adenomas of the proximal compared with distal colon. In contrast, recent antibiotic use within the past 4 years was not associated with risk of adenoma (Ptrend=0.44). Conclusion: In this prospective study, exposure to antibiotics earlier in life (age 20-39 and 40-59) was significantly associated with an increased risk for colorectal adenoma. This increased risk was evident even after adjustment for known colorectal cancer risk factors. In contrast, more recent antibiotic use (within 4 years) was not associated with risk. To the best of our knowledge, this study is the first to link midlife antibiotic use, in a dose-dependent fashion, to colorectal adenoma. These data provide additional support for the association of the gut microbiome with colorectal neoplasia. Citation Format: Yin Cao, Kana Wu, Raaj Mehta, David Drew, Mingyang Song, Paul Lochhead, Jacques Izard, Charles Fuchs, Wendy Garrett, Curtis Huttenhower, Shuji Ogino, Edward Giovannucci, Andrew Chan. Lifetime use of antibiotics and risk of colorectal adenoma. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A24.

Considerable evidence suggests that chronic inflammation plays an important role in the development of colorectal cancer (CRC). Individuals with long-standing colonic inflammation due to inflammatory bowel disease have an increased susceptibility to CRC (1). Furthermore, nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, are associated with a lower risk of CRC and improved clinical outcomes after diagnosis (2,3,4). One proposed pathway through which inflammation promotes carcinogenesis is the overexpression of PTGS2 (prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 [COX-2]) (5,6). PTGS2-positive colorectal tumors appear to respond more favorably to aspirin and NSAIDs than PTGS2-negative tumors (2). The circulating inflammatory cytokine growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine-1 (MIC-1), may be an important mediator in the systemic inflammatory response (7). MIC-1 levels rise in the circulation in response to injury or inflammation (8). Elevated levels of MIC-1 have been previously associated with an increased risk of diseases hypothesized to result from chronic inflammation, such as atherosclerosis and inflammatory arthritis (8,9). MIC-1 has also been linked to the development of cancers, including those of the prostate, thyroid, pancreas, and colon (7,10,11). Recently, within the Polyp Prevention Trial, MIC-1 levels were associated with an increased risk of recurrent adenoma among patients with a history of prior adenoma (12). Experimental evidence also suggests that MIC-1, as a member of the human transforming growth factor-β (TGFβ1) superfamily (8), may play a specific role in carcinogenesis (7,13–15). Although we and others have examined the relationship between other inflammatory markers—including C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor receptor 2 (also known as TNFRSF1B), and adiponectin—and the risk of CRC, prospective data relating MIC-1 levels and incident CRC are limited (16,17). Therefore, we examined the association between prediagnostic levels of MIC-1 risk of CRC in a prospective, nested, case–control study of men and women enrolled in the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). We also explored the association between MIC-1 levels and CRC according to the expression status of intratumoral PTGS2.

Background Children of mothers infected with soil-transmitted helminths (STH) may have an increased susceptibility to STH infection. Methods and Findings We did a case-control study nested in a birth cohort in Ecuador. Data from 1,004 children aged 7 months to 3 years were analyzed. Cases were defined as children with Ascaris lumbricoides and/or Trichuris trichiura, controls without. Exposure was defined as maternal infection with A. lumbricoides and/or T. trichiura, detected during the third trimester of pregnancy. The analysis was restricted to households with a documented infection to control for infection risk. Children of mothers with STH infections had a greater risk of infection compared to children of uninfected mothers (adjusted OR 2.61, 95% CI: 1.88–3.63, p, Author Summary Soil-transmitted helminths (intestinal worms) are among the most common childhood infections worldwide and are a significant cause of morbidity particularly among poor populations living in developing countries. The potent immune modulatory effects of these parasites have been suggested to be a determinant of the epidemiological distributions of other infectious diseases (e.g., HIV and tuberculosis) and allergy. There is strong epidemiological evidence that some individuals have an increased susceptibility to re-infection after treatment and the mechanisms underlying this are not well understood. A possible explanation is that in utero exposure to maternal STH infections may increase the risk of infection during childhood, but, as far as we are aware, no published study has addressed this hypothesis for STH infections in humans. In this study, we evaluated whether children of mothers infected with STH infections have a greater risk of infection when compared to children of uninfected mothers. We also examined whether this increased susceptibility to infection might occur through the tolerogenic effects of increased levels in the systemic circulation of the immune regulatory cytokine IL-10, in early life. Our data provide evidence that maternal STH infections predispose children to infections with STH parasites, and this effect was associated with elevated levels of IL-10 in newborn blood.