Background Antibiotics use may increase colorectal cancer (CRC) risk by altering the gut microbiota, with suggestive evidence reported. Our study aims to investigate antibiotics use in relation to subsequent CRC risk. Methods This is a nationwide, population-based study with a matched case-control design (first primary CRC cases and 5 matched, cancer-free controls). Complete-population data, extracted from Swedish national registers for the period 2005-2016, were used to calculate odds ratios and 95% confidence intervals. Results We included 40 545 CRC cases and 202 720 controls. Using the full dataset, we found a positive association between more frequent antibiotics use and CRC, excluding antibiotics prescribed within 2 years of diagnosis attenuated results toward the null. In site-specific analyses, excluding the 2-year washout, the positive association was confined to the proximal colon (adjusted odds ratio for very high use vs no use = 1.17, 95% confidence interval = 1.05 to 1.31). For rectal cancer, an inverse association, which appears to be driven by women, was observed. Quinolones and sulfonamides and/or trimethoprims were positively associated with proximal colon cancer, whereas a more general inverse association, across antibiotics classes, was observed for rectal cancer. We found no association between methenamine hippurate, a urinary tract antiseptic not affecting the gut microbiota, and CRC risk. Conclusions This register-based study covering the entire population of Sweden found a robust association between antibiotics use and higher risk of proximal colon cancer and an inverse association with rectal cancer in women. This study strengthens the evidence from previous investigations and adds important insight into site-specific colorectal carcinogenesis.

Background: Despite global achievements in reducing early childhood mortality, disparities remain. There have been empirical studies of inequalities conducted in low-and middleincome countries. However, there have been no epidemiological studies on socioeconomic inequalities and early childhood survival in Myanmar. Objective: To estimate associations between two measures of parental socioeconomic statushousehold wealth and educationand age-specific early childhood mortality in Myanmar. Methods: Using cross-sectional data obtained from the Myanmar Demographic Health Survey (2015-2016), univariate and multiple logistic regressions were performed to investigate associations between household wealth and highest attained parental education, and under-5, neonatal, post-neonatal and child mortality. Data for 10,081 children born to 5,932 married women (aged 15-49 years) 10 years prior to the survey, were analysed. Results: Mortality during the first five years was associated with household wealth. In multiple logistic models, wealth was protective for post-neonatal mortality. After adjusting for individual proximate determinants, the odds of post-neonatal mortality in the richest households were 85% lower (95% CI: 50-96%) than in the poorest households. However, significant association was not found between wealth and neonatal mortality. Parental education was important for early childhood mortality; the highest benefit from parental education was for child mortality in the one-to five-year age bracket. After adjusting for proximate determinants, children with a higher educated parent had 95% (95% CI 77-99%) lower odds of death in this age group compared with children whose parents' highest educational attainment was at primary level. The association between parental education and neonatal mortality was not significant. Conclusions: In Myanmar, household wealth and parental education are important for childhood survival before five years of age. This study identified nuanced age-related differences in associations. Health policy must take socioeconomic determinants into account in order to address unfair inequalities in early childhood mortality. ARTICLE HISTORY

Background Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients. Methods Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease. Results In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02–1.10). The HR for CMD was 1.25 (95% CI: 0.97–1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00–1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01–2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa. Conclusions Our results suggest that cumulative exposure to higher BMI during early to mid-adulthood was associated with poorer survival in patients with breast and colorectal cancer, independent of CMD prior to cancer diagnosis. The association between a CMD diagnosis prior to cancer and survival in patients with breast and colorectal cancer was independent of BMI.

<p>Supplementary Figure S6: Sensitivity analyses for antibiotics use in relation to overall and cancer-specific survival in stage I-III and stage IVcolorectal cancer.(A) Multilevel mix-effect analyses, assuming Weibull distribution and including operating hospitals as a second-levelvariable (n =36 061). (B) Analyses limited to colon cancer patients who underwent elective surgery (n= 21 096). (C) Analyseslimited to colon cancer patients who underwent emergency surgery (n= 2 897). (D) Analyses excluding cases who diedwithin 90 days after surgery, i.e., fatal perioperative complications (n=35 200). (E) Multilevel mix-effect analyses, assumingWeibull distribution and including treating hospitals as a second-level variable (n =11 242). (F) Analyses limited to caseswith complete covariate information (n= 4 729).</p>

Background: Antibiotic use has been hypothesized to modify colorectal cancer (CRC) risk by altering the composition of gut microbiota, with some suggestive evidence reported. The aim of the current study was to investigate the possible association between antibiotic use and CRC risk, taking into consideration daily dose, antibiotic type, and tumor location. Methods: This is a nation-wide, registry-based study with a matched case-control design. All primary CRC cases diagnosed during 2010 to 2016 were selected from the Swedish Colorectal Cancer Register to ensure availability of antibiotic prescription data and a minimum of 5 years of follow-up. Five cancer-free controls were matched to each case for age, sex, and county using the Register of the Total Population. Defined daily doses of antibiotics were extracted from the Swedish Prescribed Drug Register (with complete data from 2005), antibiotic prophylaxis use was estimated using surgical procedural codes from the Swedish National Patient Register, and potential confounders related to socioeconomic status (level of education, country of birth and marital status) were obtained from the LISA database. Multivariable conditional logistic regression was performed to investigate associations between antibiotic use (divided into 5 categories ranging from non-use to very high use (&gt;6months)) and CRC risk. Results: Our study included 40,545 cases and 202,720 matched controls. We identified a positive, linear association between antibiotic use and CRC risk (adjusted OR for very high users vs non-users = 1.11 (95% CI: 1.03-1.19), p-trend=0.014), which was pronounced for proximal colon cancer (OR = 1.42 (95% CI: 1.28-1.58), p-trend = 1.20 × 10−15), less robust for distal colon and null for rectal cancer. The association was strongest for broad-spectrum beta lactams (adjusted OR =1.50 (95% CI, 1.01-2.23), p-trend=3.12 × 10−6). In contrast, Hiprex, an antibiotic used for treatment and prevention of urinary tract infections, with no known effect on gut microbiota, was not associated with CRC risk (OR = 0.92 (95% CI, 0.81-1.05), p-trend=0.217). Conclusion: In this registry-based study covering the entire population of Sweden, we identified a robust association between antibiotic use, particularly broad-spectrum beta-lactams, and an increased risk of colon cancer, particularly proximal colon cancer, and a null relationship for rectal cancer. The null findings for Hiprex, which does not affect gut microbiota, lend support to the microbiota hypothesis for the putative influence of antibiotic use in colonic carcinogenesis. Citation Format: Sai San Moon Lu, Zahraa Mohammed, Christel Häggström, Robin Myte, Elisabeth Lindquist, Åsa Gylfe, Bethany Van Guelpen, Sophia Harlid. Antibiotic use and risk of colorectal cancer: A Swedish population-based registry study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1055.

<p>Supplementary Figure S2: Model fitness test using Cox-snell residuals for the multivariable model for stage IV colorectalcancer.The Cox proportional hazards model was stratified by tumour site (proximal colon, distal colon, rectum,unspecified), sex (male/female), age at diagnosis (</≥ 50 years), prediagnostic Charlson comorbidityindex (no/any comorbidity), income status (quartiles), and adjusted for age at diagnosis andprediagnostic Charlson comorbidity index as continuous variables, place of birth, county of residence,marital status, level of education, family history of colorectal cancer, calendar year at diagnosis, palliativechemotherapy and surgical therapy as categorical variables, defined as presented in SupplementaryTable S4.</p></p>

<p>Supplementary Figure S2: Model fitness test using Cox-snell residuals for the multivariable model for stage IV colorectalcancer.The Cox proportional hazards model was stratified by tumour site (proximal colon, distal colon, rectum,unspecified), sex (male/female), age at diagnosis (</≥ 50 years), prediagnostic Charlson comorbidityindex (no/any comorbidity), income status (quartiles), and adjusted for age at diagnosis andprediagnostic Charlson comorbidity index as continuous variables, place of birth, county of residence,marital status, level of education, family history of colorectal cancer, calendar year at diagnosis, palliativechemotherapy and surgical therapy as categorical variables, defined as presented in SupplementaryTable S4.</p></p>

<p>Supplementary Figure S4: Antibiotics use in relation to survival outcomes in stage I-III colorectal cancer (crude and completecasemultivariable analyses).(A) Antibiotics use in relation to overall survival. (B) Antibiotics use in relation to cancer-specific survival.Prediagnostic antibiotics use was categorized as no use, any use, low use (1-10 days), moderate use (11-60days), high use (61-180 days) and very high use (>180 days), based on defined daily doses. Antibiotics useduring one year before colorectal cancer diagnosis was excluded to account for potential use due toundiagnosed but clinically manifest colorectal cancer. CI = confidence interval; HR = Hazard Ratio. Model 0 iscrude or univariable Cox analysis. Model 1 is a Cox proportional hazard model including main demographic andsocioeconomic factors (age and calendar year of diagnosis and prediagnostic Charlson comorbidity index ascontinuous variables, and sex, place of birth, county of residence, marital status, level of education, incomestatus and family history of colorectal cancer as categorical variables). Model 2 includes tumour sites andtumour stage in addition to the covariates in model 1. Model 3 includes therapy-related variables such asoperation type, preoperative chemotherapy (yes/no) and preoperative radiotherapy (yes/no) in addition tocovariates in model 2. Variable definitions and categorization for the covariates in models 1-3 are as presentedin Table 1. For each multivariable model, variables violating the proportional hazard assumption werecontrolled for by stratification in the respective models. They were age at diagnosis (</≥ 50 years), sex(men/women), prediagnostic Charlson comorbidity index (CCI) (no/any comorbidity), income status (quartilecategories) and family history of colorectal cancer (0/1/≥2 first degree relatives) for model 1; age at diagnosis,prediagnostic CCI, family history of colorectal cancer, tumour sites (proximal colon, distal colon, rectum,unspecified) and tumour stage (stage I-III) for model 2, age at diagnosis, prediagnostic CCI, type of surgery2(elective/emergency), tumour sites and tumour stage for model 3. For age at diagnosis and prediagnostic CCI (continuous variables), binary variable types (age at diagnosis: </≥ 50 years, prediagnostic CCI: no/any CCI) were used and continuous variable types were also adjusted to account for residual confounding in each stratum.</p></p>