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Objectives To analyse the prevalence of respiratory tract infection (RTI) episodes with and without antibiotic prescriptions in adult patients in Norwegian general practice during the period 2012–2019. Methods Observational study linking data from the Norwegian Control and Payment for Health Reimbursements Database and the Norwegian Prescription Database. Episodes of acute RTIs in patients aged 18 years or older were identified and linked to antibiotic prescriptions dispensed within 7 days after diagnosis. We analysed annual infection rates and antibiotic prescription rates and antibiotics prescribed for the different RTI conditions. Results RTI episode rate per 1000 inhabitants was 312 in 2012 and 277 in 2019, but showed no linear trend of change during the study period (P = 0.205). Antibiotic prescription rate decreased from 37% of RTI episodes in 2012 to 23% in 2019 (P Conclusions This study demonstrates stable RTI episode rates and reduced antibiotic prescription rates for RTIs for adults in Norwegian general practice 2012–2019. We also observed a shift towards relatively more use of phenoxymethylpenicillin and less broad-spectrum antibiotics. These changes are in line with the aims of the Norwegian strategy against antibiotic resistance.

BackgroundThe Nordic countries are an ideal case study of the COVID-19 pandemic due to their comparability, high data quality, and variable responses. Excess mortality is a key metric but it is sensitive to data quality, model assumptions, and population structure, with diverse estimates published so far.MethodsWe investigated the age- and sex-specific mortality patterns during 2020−2021 for the five Nordic countries using annualized age- and sex specific death rates and populations. We compared the total age- and sex-adjusted excess deaths, ratios of actual vs. expected death rates, and age-standardized excess death estimates. We estimated excess deaths with several time periods and sensitivity tests, using 42 sex and age groups. Our models are less sensitive to outlier years than models based on 5 years of data.ResultsAge-specific death rates have declining trends that reflect real improving health demographics. Our total excess mortality is close to WHO’s estimates, except higher for Norway and lower for Sweden, partly due to data used. Total excess deaths were dominated by the age group 70−89 years, was not identified in children, and more pronounced in men than women. Sweden had more excess deaths in 2020 than 2021 whereas Finland, Norway, and Denmark had the opposite. Denmark has the highest death rates before and during the pandemic, whereas Sweden in 2020 had the largest mortality increase. The age-standardized mortality of Denmark, Iceland and Norway was lowest in 2020, and 2021 was one of the lowest mortality years for all Nordic countries. We show that neutral baseline methods underestimate excess deaths and we document the importance of outlier mortality years.ConclusionsWe provide excess mortality estimates mortality of the Nordic countries in relation to sex and age, with several metrics important in combination for a full understanding and comparison of the countries. We additionally identify important effects such as mortality displacement and sensitivities that affect our estimates and those of other excess mortality models.

Background: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. Methods: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio to either receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. Results: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). Conclusions: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

BackgroundExcess mortality during the COVID-19 pandemic is of major scientific and political interest.MethodsWe critically reviewed different estimates of all-cause excess mortality for the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), which have been much studied during the COVID-19 pandemic, using the latest register data to discuss uncertainties and implications.ResultsWe show using back-calculation of expected deaths from Nordic all-cause deaths that the Institute for Health Metrics and Evaluation model is a clear outlier in the compared estimates and likely substantially overestimates excess mortality of Finland and Denmark, and probably Sweden. Our review suggests a range of total Nordic excess deaths of perhaps 15 000–20 000, but results are sensitive to assumptions in the models as shown.ConclusionsWe document substantial heterogeneity and uncertainty in estimates of excess mortality. All estimates should be taken with caution in their interpretation as they miss detailed account of demographics, such as changes in the age group populations over the study period.

Excess deaths during the covid-19 pandemic are of major scientific and political interest. Here we review excess all-cause death estimates from different methods for the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden), which have been much studied during the covid-19 pandemic. In the comparison of the methods, we use simple sensitivity estimates and linear interpolations of the death data to discuss uncertainties and implications for reporting ratios and infection fatality rates. We show using back-calculation of expected deaths from Nordic all-cause deaths that a recent study in Lancet, which is a clear outlier in the overviewed estimates, most likely substantially overestimates excess deaths of Finland and Denmark, and probably Sweden. The other estimates are more consistent and suggest a range of total Nordic excess deaths of approximately half of that in the Lancet study, a more uniform ability to identify covid-19-related deaths, and more similar infection fatality rates for the Nordic countries.

Background and Aims Microscopic colitis (MC) is an inflammatory bowel disease and a common cause of chronic diarrhea. Appendectomy has been suggested to have immunomodulating effects in the colon, influencing the risk of gastrointestinal disease. The relationship between appendectomy and MC has only been sparsely studied. Methods This was a case-control study based on the nationwide ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) cohort, consisting of histopathological examinations in Sweden, linked to national registers. Patients with MC were matched to population controls by age, sex, calendar year of biopsy, and county of residence. Data on antecedent appendectomy and comorbidities were retrieved from the Patient Register. Unconditional logistic regression models were conducted presenting odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for country of birth and matching factors. Further subanalyses were made based on MC subtypes (lymphocytic colitis and collagenous colitis), follow-up time postappendectomy and severity of appendicitis. Results The study included 14,520 cases of MC and 69,491 controls, among these 7.6% (n = 1103) and 5.1% (n = 3510), respectively, had a previous appendectomy ≥1 year prior to MC or matching date. Patients with a previous appendectomy had an increased risk of MC in total (OR, 1.50; 95% CI, 1.40–1.61) and per the collagenous colitis subtype (OR, 1.67; 95% CI, 1.48–1.88) or lymphocytic colitis subtype (OR, 1.42; 95% CI, 1.30–1.55). The risk remained elevated throughout follow-up, and the highest risk was observed in noncomplicated appendicitis. Conclusions This nationwide case-control study found a modestly increased risk of developing MC following appendectomy.

Background: During the first wave of the Covid-19 epidemic, a national lockdown was established in Norway, and inhabitants were asked to contact healthcare only if absolutely necessary. We investigated hospital admissions and mortality due to non-Covid-19 disease during the lockdown compared to previous years. Methods: We compared the number of emergency admissions and in-hospital fatality for diagnoses probably unaffected (acute myocardial infarction, acute abdominal conditions, cerebrovascular diseases) and affected by the lockdown (infections, injuries) in the South-Eastern Health Region of Norway during weeks 12–22, 2020, compared to the mean of the same period in the years 2017–2019. We also compared population mortality March–May 2020, to the mean of the same period in years 2017–2019. Results: A total of 280,043 emergency admissions were observed; 20,911 admissions probably unaffected, and 30,905 admissions probably affected by the lockdown. Admissions due to diagnoses probably unaffected was reduced by 12% (95% confidence interval (CI) 9–15%), compared to 2017–2019. Admissions for diagnoses probably affected was reduced by 30% (95% CI 28–32%). There was a 34% reduction in in-hospital fatality due to acute myocardial infarction (95% CI 4–56%), 19% due to infections (95% CI 1–33%), and no change for the other diagnoses, compared to 2017–2019. The risk of in-hospital mortality to total mortality was lower for acute myocardial infarction (relative risk 0.85, 95% CI 0.73–0.99) and injuries (relative risk 0.83, 95% CI 0.70–0.98). Conclusions: Even though fewer patients were admitted to hospital, there was no increase in in-hospital fatality or population mortality, indicating that those who were most in need still received adequate care.

BackgroundLittle is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports.MethodsThrough the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015–2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review.ResultsSPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89–98%). By year of diagnosis, the PPV was 89% (95%CI = 69–97%), 96% (95%CI = 81–99%) and 97% (95%CI = 89–99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93–100%), and 93% (95%CI = 86–97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84–98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84–98%). In total, 57% had ≥2 polyps (1:n = 44, 2–3:n = 33 and ≥ 4:n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were ≥ 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%).ConclusionColorectal histopathology reports are a reliable data source to identify individuals with SPs.

Background IgA nephropathy (IgAN) is the most common primary glomerulonephritis affecting all ages and both sexes, but there is a lack of studies on its association with cancer and whether it is a paramalignant condition. Methods In a Swedish population-based cohort study we compared the risk of cancer among 3882 biopsy-verified IgAN patients diagnosed during 1974–2011 with 19 341 reference individuals and followed them until 2015. Cox regression was used to estimate hazard ratios (HRs) for cancer in IgAN patients versus controls and conditional logistic regression assessed the risk of cancer before the IgAN was confirmed. Results During a median follow-up of 12.6 years, 488 (12.6%) patients with IgAN and 1783 (9.2%) matched reference individuals were diagnosed with cancer {HR 1.70 [95% confidence interval (CI), 1.52–1.89]}. The increased risk was only seen in IgAN patients developing end-stage renal disease (ESRD), with an HR of 4.01 (95% CI 3.33–4.82) for any cancer and HR of 2.22 (95% CI 1.79–2.75) when excluding non-melanoma skin cancer (NMSC). Non-ESRD IgAN patients did not have an increased overall cancer risk [HR 1.13 (95% CI 0.99–1.30)]. There was no increased risk of cancer preceding an IgAN diagnosis [odds ratio 1.10 (95% CI 0.92–1.32)]. Conclusions We found no support for IgAN being a paramalignant condition. There was an increased risk of cancer in IgAN patients, but only for those with ESRD. Our results indicate ∼6 extra cancer cases per 100 IgAN patients with ESRD per 10 years, or >17 extra cases if including NMSC as well.

Introduction Because individuals with serrated polyps and adenomas are at increased risk of developing new polyps and colorectal cancer (CRC), surveillance after resection is justified. After adenoma resection, most international guidelines are consistent, but recommendations for surveillance after serrated polyp resection vary. The United States Multi-Society Taskforce on CRC (US-MSTF) base surveillance intervals on serrated polyp subtype (traditional serrated adenoma, sessile serrated polyp, hyperplastic polyps), while the European Society of Gastrointestinal Endoscopy (ESGE) guidelines do not take serrated polyp subtype into account. We evaluated the implications of this difference in a primary colonoscopy screening cohort. Methods We included participants from a large colonoscopy screening trial. In a post-hoc simulation, assuming full protocol adherence, we determined the surveillance interval for each subject based on their polyp burden, using the most recent US-MSTF and ESGE guidelines. Results We included 5323 participants, of whom 1228 had one or more serrated polyps. In 5201 of all participants (98 %; Cohen’s kappa 0.90) and in 1106 of those with serrated polyps (90 %; Cohen’s kappa 0.80), both guidelines recommended identical surveillance intervals. Recommendations for a 3-year surveillance interval were identical between the two guidelines. All 122 subjects with discordant recommendations would receive a follow-up colonoscopy after 10 years using ESGE guidance and after 5 years using US-MSTF guidance. Conclusion Despite the different criteria used to determine surveillance after serrated polyp resection, most individuals are recommended identical colonoscopy surveillance intervals whether following the ESGE or US-MSTF guidelines. This suggests that surveillance recommendations do not need to consider the serrated polyp subtype.

Background & Aims Celiac disease (CD) is associated with increased mortality, in part due to cancer. Most studies investigating this cancer risk involved patients diagnosed before widespread increases in CD diagnosis rates and access to gluten-free food. We performed a population-based study of the risk of cancer in CD. Methods We identified all patients in Sweden with CD as defined as duodenal/jejunal villus atrophy, using the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. Each patient was matched to ≤5 controls by age, sex, and county. We used stratified Cox proportional hazards model, following patients from diagnosis until first cancer, or by December 31, 2016. Results Among 47,241 patients with CD, 30,080 (64%) were diagnosed since 2000. After a median follow-up of 11.5 years, the incidence of cancer was 6.5 and 5.7 per 1000 person-years in CD patients and controls, respectively. The overall risk of cancer was increased (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.07–1.15), but it was only significantly elevated in the first year after CD diagnosis (HR, 2.47; 95% CI, 2.22–2.74) and not subsequently (HR, 1.01; 95% CI, 0.97–1.05), although the risks of hematologic, lymphoproliferative, hepatobiliary, and pancreatic cancers persisted. The overall risk was highest in those diagnosed with CD after age 60 years (HR, 1.22; 95% CI, 1.16–1.29) and was not increased in those diagnosed before age 40. The cancer risk was similar among those diagnosed with CD before or after the year 2000. Conclusions There is an increased risk of cancer in CD even in recent years, but this risk increase is confined to those diagnosed with CD after age 40 and is primarily present within the first year of diagnosis.

Background: Norway and Sweden are similar countries in terms of socioeconomics and health care. Norway implemented extensive COVID-19 measures, such as school closures and lockdowns, whereas Sweden did not. Aims: To compare mortality in Norway and Sweden, two similar countries with very different mitigation measures against COVID-19. Methods: Using real-world data from national registries, we compared all-cause and COVID-19-related mortality rates with 95% confidence intervals (CI) per 100,000 person-weeks and mortality rate ratios (MRR) comparing the five preceding years (2015–2019) with the pandemic year (2020) in Norway and Sweden. Results: In Norway, all-cause mortality was stable from 2015 to 2019 (mortality rate 14.6–15.1 per 100,000 person-weeks; mean mortality rate 14.9) and was lower in 2020 than from 2015 to 2019 (mortality rate 14.4; MRR 0.97; 95% CI 0.96–0.98). In Sweden, all-cause mortality was stable from 2015 to 2018 (mortality rate 17.0–17.8; mean mortality rate 17.1) and similar to that in 2020 (mortality rate 17.6), but lower in 2019 (mortality rate 16.2). Compared with the years 2015–2019, all-cause mortality in the pandemic year was 3% higher due to the lower rate in 2019 (MRR 1.03; 95% CI 1.02–1.04). Excess mortality was confined to people aged ⩾70 years in Sweden compared with previous years. The COVID-19-associated mortality rates per 100,000 person-weeks during the first wave of the pandemic were 0.3 in Norway and 2.9 in Sweden. Conclusions: All-cause mortality in 2020 decreased in Norway and increased in Sweden compared with previous years. The observed excess deaths in Sweden during the pandemic may, in part, be explained by mortality displacement due to the low all-cause mortality in the previous year.

Objective To assess the risk of colorectal cancer (CRC) in first degree relatives (parents and full siblings) of patients with precursor lesions (polyps) for CRC. Design Case-control study. Setting Linkage to the multi-generation register and gastrointestinal ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) histopathology cohort in Sweden. Participants 68 060 patients with CRC and 333 753 matched controls. Main outcome measures Multivariable adjusted odds ratios of CRC according to the number of first degree relatives with a colorectal polyp and the histology of polyps and age at diagnosis in first degree relatives. Subgroup analysis was also performed according to age at CRC diagnosis and evaluated the joint association of family history of colorectal polyps and family history of CRC. Results After adjusting for family history of CRC and other covariates, having a first degree relative with a colorectal polyp (8.4% (5742/68 060) in cases and 5.7% (18 860/333 753) in controls) was associated with a higher risk of CRC (odds ratio 1.40, 95% confidence interval 1.35 to 1.45). The odds ratios ranged from 1.23 for those with hyperplastic polyps to 1.44 for those with tubulovillous adenomas. To better put this risk in perspective, the age specific absolute risk of colon and rectal cancers was estimated according to family history of polyps based on the 2018 national CRC incidence in Sweden. For example, the absolute risk of colon cancer in individuals aged 60-64 years with and without a family history of colorectal polyp was, respectively, 94.3 and 67.9 per 100 000 for men and 89.1 and 64.1 per 100 000 for women. The association between family history of polyps and CRC risk was strengthened by the increasing number of first degree relatives with polyps (≥2 first degree relatives: 1.70, 1.52 to 1.90, P Conclusions After adjusting for family history of CRC, the siblings and children of patients with colorectal polyps are still at higher risk of CRC, particularly early onset CRC. Early screening for CRC might be considered for first degree relatives of patients with polyps.

Importance The COVID-19 pandemic is the greatest global test of health leadership of our generation. There is an urgent need to provide guidance for leaders at all levels during the unprecedented preresolution recovery stage. Objective To create an evidence- and expertise-informed framework of leadership imperatives to serve as a resource to guide health and public health leaders during the postemergency stage of the pandemic. Evidence Review A literature search in PubMed, MEDLINE, and Embase revealed 10 910 articles published between 2000 and 2021 that included the terms leadership and variations of emergency, crisis, disaster, pandemic, COVID-19, or public health. Using the Standards for Quality Improvement Reporting Excellence reporting guideline for consensus statement development, this assessment adopted a 6-round modified Delphi approach involving 32 expert coauthors from 17 countries who participated in creating and validating a framework outlining essential leadership imperatives. Findings The 10 imperatives in the framework are: (1) acknowledge staff and celebrate successes; (2) provide support for staff well-being; (3) develop a clear understanding of the current local and global context, along with informed projections; (4) prepare for future emergencies (personnel, resources, protocols, contingency plans, coalitions, and training); (5) reassess priorities explicitly and regularly and provide purpose, meaning, and direction; (6) maximize team, organizational, and system performance and discuss enhancements; (7) manage the backlog of paused services and consider improvements while avoiding burnout and moral distress; (8) sustain learning, innovations, and collaborations, and imagine future possibilities; (9) provide regular communication and engender trust; and (10) in consultation with public health and fellow leaders, provide safety information and recommendations to government, other organizations, staff, and the community to improve equitable and integrated care and emergency preparedness systemwide. Conclusions and Relevance Leaders who most effectively implement these imperatives are ideally positioned to address urgent needs and inequalities in health systems and to cocreate with their organizations a future that best serves stakeholders and communities.

ObjectivesNorway and Sweden are similar countries regarding ethnicity, socioeconomics and health care. To combat Covid-19, Norway implemented extensive measures such as school closures and lock-downs, while Sweden has been criticised for relaxed measures against Covid-19. We compared the effect of the different national strategies on all-cause and Covid-19 associated mortality.DesignRetrospective cohort.SettingThe countries Norway and Sweden.ParticipantsAll inhabitants.Main outcome measuresWe calculated weekly mortality rates (MR) with 95% confidence intervals (CI) per 100,000 individuals as well as mortality rate ratios (MRR) comparing the epidemic year (29th July, 2019 to 26th July, 2020) to the four preceding years (July 2015 to July 2019). We also compared Covid-19 associated deaths and mortality rates for the weeks of the epidemic in Norway and Sweden (16th March to 26th July, 2020).ResultsIn Norway, mortality rates were stable during the first three 12-month periods of 2015/16; 2016/17 and 2017/18 (MR 14.8 to 15.1 per 100,000), and slightly lower in the two most recent periods including during epidemic period (2018/19 and 2019/20; 14.5 per 100,000). In Sweden, all-cause mortality was stable during the first three 12-month periods of 2015/16; 2016/17 and 2017/18 (MR 17.2 to 17.5 per 100,000), but lower in the year 2018/19 immediately preceding the epidemic (16.2 per 100,000). Covid-19 associated mortality rates were 0.2 per 100,000 (95%CI 0.1 to 0.4) in Norway and 2.9 (95%CI 1.9 to 3.9) in Sweden. The increase in mortality was confined to individuals in 70 years or older.ConclusionsAll-cause mortality remained unaltered in Norway. In Sweden, the observed increase in all-cause mortality during Covid-19 was partly due to a lower than expected mortality preceding the epidemic and the observed excess mortality, was followed by a lower than expected mortality after the first Covid-19 wave. This may suggest mortality displacement.Strengths and limitations of this studyCompares two similar contries in all aspects but the handling of the Covid-19 epidemicEvaluates the mortality for several years before and during the epidemicProvides a possible explanation of the observed mortality changesDiscusses the socioeconomic effects of the different strategies in the two countriesDoes not evaluate cause-specific mortality

INTRODUCTION Endoscopic screening reduces colorectal cancer (CRC) incidence and mortality. Individuals with a negative result are recommended to undergo rescreening within a 10-year interval, but evidence supporting this advice is limited. METHODS We performed a matched cohort study using prospectively collected data from 88,798 individuals in Sweden with normal mucosa at the first colorectal biopsy (aged ≥50 years) in the nationwide gastrointestinal epidemiology strengthened by histopathology reports (ESPRESSO) (1965-2016) and 424,150 matched reference individuals from the general population. Cox proportional hazards regression estimated multivariable hazard ratios and 95% confidence intervals (CIs) of CRC incidence and mortality of incident CRCs up to 44 years of follow-up. RESULTS In the normal biopsy and reference groups, respectively, the 20-year incidences of CRC were 3.03% and 4.53% and the 20-year mortalities of incident CRC were 0.89% and 1.54%. The multivariable hazard ratio comparing the normal biopsy and reference groups was 0.62 for CRC incidence (95% CI = 0.58-0.66, P < 0.001) and 0.56 for mortality of incident CRC (95% CI = 0.49-0.64, P < 0.001). When assessed by time interval after biopsy, lower CRC incidence and mortality were observed throughout the follow-up. The association seemed weaker for proximal colon cancer than for rectal and distal colon cancer. DISCUSSION A normal colorectal biopsy was associated with lower CRC incidence and mortality for at least 20 years after the examination. Our findings confirm previous data and suggest that the screening intervals after a normal colonoscopy could be longer than the commonly recommended 10 years. It may be time to open the discussion for a revision of the international guidelines.

BACKGROUND & AIMS: Use of antibiotics affects the composition of the microbiome and might affect development of colorectal polyps, which are precursors to colorectal cancer. METHODS: We performed a nested case–control study in Sweden of 45,744 patients with a colorectal polyp (cases) in the nationwide gastrointestinal ESPRESSO histopathology cohort, using unaffected full siblings as controls (n=93,307). Polyps were classified by morphology SnoMed codes into conventional adenomas and serrated polyps. Through linkage to the Prescribed Drug Register, we assessed use and cumulative dispensations of antibiotic until one year prior to polyp diagnosis for cases and their sibling controls. RESULTS: During a median study period of 6.9 years, compared with non-users, users of antibiotics (28,884 cases [63.1%] and 53,222 sibling controls [57.0%]) had a higher risk of colorectal polyps. Risk increased with higher number of dispensations (odds ratio [OR] for ≥ 6 dispensations, 1.33; 95% CI, 1.25–1.43) (P(trend)0.10). We found stronger associations for younger (

Long-term colorectal cancer incidence and mortality after colorectal polyp removal remains unclear. We aimed to assess colorectal cancer incidence and mortality in individuals with removal of different histological subtypes of polyps relative to the general population.We did a matched cohort study through prospective record linkage in Sweden in patients aged at least 18 years with a first diagnosis of colorectal polyps in the nationwide gastrointestinal ESPRESSO histopathology cohort (1993-2016). For each polyp case, we identified up to five matched reference individuals from the Total Population Register on the basis of birth year, age, sex, calendar year of biopsy, and county of residence. We excluded patients and reference individuals with a diagnosis of colorectal cancer either before or within the first 6 months after diagnosis of the index polyp. Polyps were classified by morphology codes into hyperplastic polyps, sessile serrated polyps, tubular adenomas, tubulovillous adenomas, and villous adenomas. Colorectal cancer cases were identified from the Swedish Cancer Registry, and cause-of-death data were retrieved from the Cause of Death Register. We collected information about the use of endoscopic examination before and after the index biopsy from the Swedish National Patient Registry, and counted the number of endoscopies done before and after the index biopsies. We calculated cumulative risk of colorectal cancer incidence and mortality at 3, 5, 10, and 15 years, and computed hazard ratios (HRs) and 95% CIs for colorectal cancer incidence and mortality using a stratified Cox proportional hazards model within each of the matched pairs.178 377 patients with colorectal polyps and 864 831 matched reference individuals from the general population were included in our study. The mean age of patients at polyp diagnosis was 58·6 (SD 13·9) years for hyperplastic polyps, 59·7 (14·2) years for sessile serrated polyps, 63·9 (12·9) years for tubular adenomas, 67·1 (12·1) years for tubulovillous adenomas, and 68·9 (11·8) years for villous adenomas. During a median of 6·6 years (IQR 3·0-11·6) of follow-up, we documented 4278 incident colorectal cancers and 1269 colorectal cancer-related deaths in patients with a polyp, and 14 350 incident colorectal cancers and 5242 colorectal cancer deaths in general reference individuals. The 10-year cumulative incidence of colorectal cancer was 1·6% (95% CI 1·5-1·7) for hyperplastic polyps, 2·5% (1·9-3·3) for sessile serrated polyps, 2·7% (2·5-2·9) for tubular adenomas, 5·1% (4·8-5·4) for tubulovillous adenomas, and 8·6% (7·4-10·1) for villous adenomas compared with 2·1% (2·0-2·1) in reference individuals. Compared with reference individuals, patients with any polyps had an increased risk of colorectal cancer, with multivariable HR of 1·11 (95% CI 1·02-1·22) for hyperplastic polyps, 1·77 (1·34-2·34) for sessile serrated polyps, 1·41 (1·30-1·52) for tubular adenomas, 2·56 (2·36-2·78) for tubulovillous adenomas, and 3·82 (3·07-4·76) for villous adenomas (p0·05 for all polyp subtypes). There was a higher proportion of incident proximal colon cancer in patients with serrated (hyperplastic and sessile) polyps (52-57%) than in those with conventional (tubular, tubulovillous, and villous) adenomas (30-46%). For colorectal cancer mortality, a positive association was found for sessile serrated polyps (HR 1·74, 95% CI 1·08-2·79), tubulovillous adenomas (1·95, 1·69-2·24), and villous adenomas (3·45, 2·40-4·95), but not for hyperplastic polyps (0·90, 0·76-1·06) or tubular adenomas (0·97, 0·84-1·12).In a largely screening-naive population, compared with individuals from the general population, patients with any polyps had a higher colorectal cancer incidence, and those with sessile serrated polyps, tubulovillous adenomas, and villous adenomas had a higher colorectal cancer mortality.US National Institutes of Health, American Cancer Society, American Gastroenterological Association, Union for International Cancer Control.

Background & Aims The incidence of small bowel cancers is increasing. Associations have been made between celiac disease (CD) and small bowel cancers, but there have been no detailed studies of large cohorts. Methods Through the nationwide Epidemiology Strengthened by Histopathology Reports in Sweden cohort study, we retrieved data from Sweden’s 28 pathology departments on all individuals who received a diagnosis of CD from 1965 through 2017. Individuals with CD, defined as duodenal or jejunal villous atrophy (stage 3 Marsh score), were matched with as many as 5 randomly selected reference individuals from the general population. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids. Results During a median follow-up of 11 years, we identified 48,119 individuals with CD (patients) and 239,249 reference individuals. Beginning at 1 year after a diagnosis of CD, 29 patients (0.06%) received a diagnosis of small bowel adenocarcinoma vs 45 reference individuals (0.02%), 7 patients received a diagnosis of carcinoids vs 31 reference individuals, and 48 patients received a diagnosis of adenomas vs 50 reference individuals. Corresponding HRs were small bowel adenocarcinoma 3.05 (95% confidence interval [CI], 1.86–4.99), carcinoids 0.59 (95% CI, 0.16–2.10), and adenomas 5.73 (95% CI, 3.70–8.88). HRs were independent of sex and age. Overall, there was 1 extra case of small bowel adenocarcinoma in every 2944 patients with CD followed for 10 years. There was an inverse association between mucosal healing risk of future small bowel adenocarcinoma (HR, 0.18; 95% CI, 0.02–1.61), although the HR failed to attain statistical significance. Conclusions In an analysis of a nationwide pathology database in Sweden, we found the absolute risk of small bowel adenocarcinoma is low in individuals with CD. However, risks of small bowel adenocarcinoma and adenomas (but not carcinoids) are significantly increased in people with CD compared to people without this disease.

Background and aims: Small bowel cancer is a rare but rising malignancy. The etiology is poorly understood and there is a need for large-scale studies. Gallbladder disease (GBD), inducing localized inflammation, has been suggested to increase small bowel cancer risk. Methods: We retrieved nationwide data from Sweden’s 28 pathology departments on all adults (age 20–79) with pathology-confirmed GBD diagnosed in 1965–2017. In total 156,390 GBD patients were matched with up to 5 matched comparators from the general population and follow-up started one year after GBD diagnosis. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids. Results: During a median follow-up of 12 years, we identified 92 small bowel adenocarcinomas, 132 adenomas, and 81 carcinoid tumors in the GBD cohort. Corresponding incidence rates were 4.8, 6.9, and 4.2 per 100,000 person-years (PY), compared to 3.2, 3.2, and 1.8 in matched comparators. The adjusted HR was 1.42 (95% CI = 1.08–1.87) for small bowel adenocarcinoma, 1.79 (95% CI = 1.41–2.27) for adenoma, and 2.07 (95% CI = 1.52–2.81) for carcinoid. The excess cancer risk was most pronounced during the first year of follow-up for adenocarcinomas and during the first six years for adenomas while for carcinoids the HR peaked 10–15 years after start of follow-up. Conclusions: In this nationwide cohort study, GBD was associated with an increased risk of small bowel cancer. The excess risk of small bowel adenocarcinoma was mainly seen during the first years of follow-up while small bowel carcinoid risk peaked 11–16 years after GBD diagnosis.

Background There is concern but no solid evidence that morcellation during laparoscopic or vaginal hysterectomy may cause abdominal spread and thereby impaired prognosis of incidental uterine sarcomas. Objective Our purpose was to compare survival among patients with uterine sarcomas who underwent hysterectomy with or without morcellation to test the hypothesis that morcellation impairs prognosis. Study design We identified all women in Norway diagnosed with uterine sarcoma between 1953 and 2012 through national registries and retrieved data on surgical technique and morcellation by evaluation of patient files. Patients were categorised into abdominal, laparoscopic or vaginal hysterectomy with or without morcellation. Vaginal and laparoscopic hysterectomies were introduced in 1991; our main comparison is from 1991 to 2012. We compared age-adjusted disease-specific survival of sarcoma patients treated with or without morcellation and calculated age-adjusted hazard ratios (HRs) and subdistribution HR (accounting for competing risk) with 95% confidence intervals (CIs). Results Among 1367 patients with uterine sarcoma between 1953 and 2012 in Norway, 653 were diagnosed after 1991, and 23 of these patients (3.5%) underwent morcellation. Uterine sarcoma prevalence was 3.6 per 1000 laparoscopic hysterectomies. Mean follow-up was 6.0 years in the morcellated group and 6.9 years in the non-morcellated group. The risk of dying from uterine sarcoma after morcellation was 1.5 per 1000 procedures. Sarcoma mortality was higher in the morcellated group than in the non-morcellated group (age-adjusted HR 1.90, CI 1.05–3.44; multivariate HR, 2.50, 95% CI 0.57–10.9). Age-adjusted 10-year uterine sarcoma survival was 32.2% for women treated with morcellation compared with 57.2% for non-morcellated group (difference 25.5%; CI −55.7 to 18.1). All-cause 10-year survival was 32.2% in the morcellated group and 44.1% in the non-morcellated group (difference 11.9%; CI −40.9 to 32.7). Conclusion Our results strengthen the evidence that morcellation during hysterectomy in patients with incidental uterine sarcoma may cause impaired survival. These results can guide shared decision-making in clinical practice.

A recent study found a 10-fold increased risk of celiac disease (CD) in individuals with Henoch-Schonlein purpura (HSP), but the confidence interval (CI) was wide. The retrospective cohort study of all patients with CD in Sweden, diagnosed through small intestinal biopsy from 1969 to 2008 (n=29,077). Each individual with CD was matched to up to 5 controls (n=144,433). Data on study participants were linked to diagnostic codes for HSP in the National Patient Registry. Through Cox regression we estimated hazard ratios for CD and later HSP. Through logistic regression we calculated odds ratios for HSP preceding CD. During follow-up 19 individuals with CD and 99 controls developed HSP. This corresponded to a hazard ratio of 0.96 (95% CI, 0.59-1.56). Looking backward, we found no increased risk of earlier HSP in patients with CD (odds ratio=1.02; 95% CI, 0.60-1.72). In this study of more than 29,000 patients with CD, we found no increased risk of HSP before or after CD.

Improved understanding of the subsequent risk death from colorectal cancer (CRC) among individuals who had adenomas removed is needed. We aimed to quantify this risk using prospectively collected data from population-based cohorts.Using Norwegian and Swedish registries, a cohort of 90,864 individuals with colorectal adenomas removed between 1980 and 2013 was identified. Surveillance was only recommended for high-risk adenomas. The validity of the registry data did not allow classification into low- and high-risk adenomas. Virtually complete follow-up was achieved through linkage to nationwide registers. We calculated incidence-based standardised mortality ratios (SMRs) with 95% confidence intervals (CI).The median follow-up was 7.2 years; 48,058 individuals were followed for more than 10 years. We observed 819 deaths (0.9%) from CRC and expected 731 CRC deaths (0.8%), corresponding to an absolute excess risk of 88 cases (0.1%) and a relative risk of 12% (SMR 1.12; 95%CI 1.05-1.20). The relative risk of CRC death following adenoma removal was slightly higher in Sweden (SMR 1.22; 95%CI 1.11-1.34) than in Norway (SMR 1.03; 95%CI 0.93-1.14), and higher in women (SMR 1.24; 95%CI 1.12-1.36) than in men (SMR 1.02; 95%CI 0.93-1.13). Among individuals with more than 10 years of follow-up, the estimates were similar to the overall cohort, absolute excess risk 0.1% (SMR 1.15; 95%CI 1.06-1.24).The excess risk of CRC death following adenoma removal is small. Optimal surveillance recommendations should be tested in randomised trials.

Background Patients with celiac disease (CD) are at increased risk of certain infections, but it is unknown if mucosal healing influences this risk. Methods We collected data on 29,096 individuals with CD (equal to villous atrophy) through Sweden’s 28 pathology departments undergoing biopsy 1969–2008. Through the Swedish Patient Register we obtained information on any infection and specifically sepsis, streptococcal infection, influenza, Clostridium difficile, herpes zoster and pneumococcal infection up until December 2009. We used Cox regression to calculate hazard ratios (HRs) for the risk of future diagnosis of infection according to mucosal healing on follow-up biopsy (persistent villous atrophy vs mucosal healing). Results Of 5598 CD individuals with no record of any infections before follow-up biopsy, 45% had persistent villous atrophy, 619 (24%) of them had a later infection, compared to 579 (19%) in those with mucosal healing ( p Conclusions In CD, mucosal healing does not influence the risk of serious infection requiring hospital-based medical attention.

Background & aims Partner burden is common in celiac disease (CD), but it is unclear if parents of children with CD have increased burden, and if this may translate into depression and anxiety meriting healthcare. Methods Nationwide population-based study of 41,753 parents and spouses (“caregivers”) to 29,096 celiac patients and 215,752 caregivers to 144,522 matched controls. Caregivers were identified from the Swedish Total Population Register, and linked to data on psychiatric disease in the National Patient Registry. Hazard ratios (HRs) for depression, anxiety, and (as a reference outcome measure) bipolar disorder were examined in a lifetime fashion but also in temporal relationship to date of CD diagnosis using Cox regression. A priori, we focused on parents of individuals diagnosed ≤19 years of age (children at the age of disease onset) and spouses of individuals diagnosed in adulthood, as such parents and spouses (“high-risk caregivers”) were most likely to live together with the patient at time of disease onset. Results On Cox analysis, depression was 11% more common in high-risk caregivers (HR = 1.11: 95%CI = 1.03–1.19) than in control caregivers while anxiety was 7% more common (HR = 1.07: 95%CI = 0.98–1.16). Combining anxiety and depression into a composite outcome measure, there was an 8% statistically significant risk increase (95%CI = 1.02–1.14). The highest excess risks for both depression and anxiety were seen just before and 4–8 years after the CD diagnosis. In contrast, bipolar disorder was not more common in caregivers to CD patients. Conclusion Caregivers to patients with CD may be at increased risk of severe burden.

The view, that rapidly growing tumours are more likely than slow-growing tumours to metastasize and become lethal, has remained almost axiomatic for decades. Unaware of any solid evidence supporting this view, we undertook an exhaustive system-level analysis of intra- and intercellular signalling networks. This analysis indicated that rapid growth and metastasis are often different outcomes of complex integrated molecular events. Evidence from humans can be derived chiefly from screening interventions because interval cancers that surface clinically shortly after a negative screening test are, on average, more rapidly growing than cancers not detected by screening. We reviewed all available data limited to cancers of the breast, cervix and large bowel. The evidence from humans provides no support for the theory that rapidly growing cancers are more prone to metastasize. These findings indicate that the prevailing view should be reconsidered, as should the impact of length-biased sampling in cancer screening, and the findings provide no support for treating interval cancers more aggressively than non-interval cancers.

SummaryBackground Both aspirin use and screening with flexible sigmoidoscopy or guaiac faecal occult blood testing (FOBT) may reduce mortality from colorectal cancer, but comparative effectiveness of these interventions is unknown. Aim To compare aspirin to guaiac FOBT screening with regard to incidence and mortality of colorectal cancer in a network meta-analysis. Methods We searched Medline, EMBASE and the COCHRANE central register (CENTRAL) for relevant randomised trials identified until 31 October 2015. Randomised trials in average-risk populations that reported colorectal cancer mortality, colorectal cancer incidence, or both, with a minimum follow-up of 2 years, and more than 100 randomised individuals were included. Three investigators independently extracted data. We calculated relative risks [RR with 95% predictive intervals (PrIs)] for the comparison of the interventions by frequentist network meta-analyses. Results The effect of aspirin on colorectal cancer mortality was similar to FOBT (RR 1.03; 95% PrI 0.76–1.39) and flexible sigmoidoscopy (RR 1.16; 95% PrI 0.84–1.60). Aspirin was more effective than FOBT (RR 0.36; 95% PrI 0.22–0.59) and flexible sigmoidoscopy (RR 0.37; 95% PrI 0.22–0.62) in preventing death from or cancer in the proximal colon. Aspirin was equally effective as screening in reducing colorectal cancer incidence, while flexible sigmoidoscopy was superior to FOBT (RR 0.84; 95% PrI 0.72–0.97). Conclusions Low-dose aspirin seems to be equally effective as flexible sigmoidoscopy or guaiac FOBT screening to reduce colorectal cancer incidence and mortality, and more effective for cancers in the proximal colon. A randomised comparative effectiveness trial of aspirin vs. screening is warranted.

Several studies have shown an excess mortality in individuals with celiac disease (CD). However, it is unknown if also first-degree relatives (FDRs) to celiac patients are at increased risk of death.We aimed to assess mortality in FDRs to celiac patients.Individuals with CD were identified through biopsy reports (equal to Marsh grade III). Each celiac individual was matched on sex, age, county and calendar year with up to five control individuals. Through Swedish healthcare registries we identified all FDRs (father, mother, sibling, offspring) of CD individuals and controls. Through Cox regression we calculated hazard ratios (HRs) for mortality (all-cause death, circulatory, cancer and other).We identified 109,309 FDRs of celiac individuals and 549,098 FDRs of controls. Overall mortality was increased in FDRs to celiac individuals (HR=1.02, 95%CI=1.00-1.04, p=0.03). This corresponded to an excess risk of 5.9 deaths per 100,000 person-years of follow-up. When limiting follow-up to time since celiac diagnosis in the index individual, we found no increased risk of death (HR=1.01; 95%CI=0.98-1.03).FDRs to individuals with CD are at increased risk of death. This excess risk is however minimal and unlikely to be of any clinical importance to the individual.

An increased risk of colorectal cancer (CRC) among individuals with IBD was suggested in the 1920s and later supported by epidemiologic studies.1 The association between IBD and CRC is not thought to arise from shared risk factors,2 but rather from a causal effect of IBD on CRC through chronic inflammation and other mechanisms that promote malignant transformation of the colonic mucosa.3 As a result, patients with IBD are considered at high risk of CRC and therefore receive anti-inflammatory treatment, colonoscopic surveillance with biopsies and prophylactic colectomy. Multiple reviews and meta-analyses have tried to estimate CRC risk in patients with IBD (see table 1 for a summary from six such analyses4–9) and several additional studies were published during the last year.10–13 Few of these studies are large, prospective, population-based studies, which reflect the substantial methodological challenges. Here, we first outline the criteria for valid studies on IBD and cancer and then use those criteria to critically review the existing studies. View this table: Table 1 Summary of meta-analyses of the association between IBD, UC and Crohn's disease (CD) and risk of colorectal cancer (CRC) ### Defining disease onset Failure to accurately ascertain the onset of IBD may bias the effect estimates of IBD on cancer if increasing duration of disease increases the probability of somatic mutations that lead to malignant transformation. However, IBD may only be detected years after onset during colonoscopy screening14 or after early symptoms of CRC. As a result, the relative risk of CRC may be overestimated. Unfortunately, the identification of IBD onset in existing population-based registers is challenging. Its replacement by first hospitalisation due to IBD may misclassify disease onset because outpatient management may suffice until exacerbations, surgical treatment or complications require inpatient care. A better choice for an operational definition of disease onset would be the date of first …

Background: Current guidelines recommend surveillance colonoscopies after polyp removal depending on the number and characteristics of polyps, but there is a lack of evidence supporting the recommendations. This report outlines the rationale and design of two randomized trials and one observational study investigating evidence-based surveillance strategies following polyp removal. Study design and endpoints: The EPoS studies started to recruit patients in April 2015. EPoS study I randomizes 13 746 patients with low-risk adenomas (1-2 tubular adenomas size = 10mm in diameter, or adenoma with high-grade dysplasia, or >25% villous features) to surveillance after 3, 5, and 10 years, or 5 and 10 years only. EPoS study III offers surveillance after 5 and 10 years to patients with serrated polyps >= 10mm in diameter at any location, or serrated polyps >= 5mm in diameter proximal to the splenic flexure. All polyps are removed before patients enter the trials. The primary end point is colorectal cancer incidence after 10 years. We assume a colorectal cancer risk of 1% for patients in EPoS I, and 2% for patients in EPoS II. Using a noninferiority hypothesis with an equivalence interval of 0.5% for EPoS I and 0.7% for EPoS II, the trials are 90% powered to uncover differences larger than the equivalence intervals. For EPoS III, no power analyses have been performed. Conclusions: The present trials aim to develop evidence-based strategies for polyp surveillance, thereby maximizing effectiveness and minimizing resources.

Background Coeliac disease has been linked to anxiety and depression. However, their association with mucosal healing is unknown. Aim To examine the relationship between anxiety, depression and mucosal healing in coeliac disease. Methods Between 1969 and 2008, we collected data on all small intestinal biopsies with villous atrophy from Sweden's 28 pathology departments. We restricted our cohort to individuals with data on follow-up biopsy (either persistent villous atrophy [n = 3317] or mucosal healing [n = 4331]). Through Cox regression, we estimated hazard ratios (HRs) for anxiety or depression. Results During follow-up, 123 (2.8/1000 person-years) individuals with mucosal healing had developed anxiety, compared to 94 (2.1/1000 person-years) with persistent villous atrophy. Mucosal healing was hence associated with a higher risk of future anxiety (HR = 1.49; 95% CI = 1.12-1.96). Similarly, 167 (3.8/1000 person-years) individuals with mucosal healing developed depression, compared to 148 (3.3/1000 person-years) with persistent villous atrophy, corresponding to a HR of 1.25 (95% CI = 0.99-1.59). Mucosal healing was more common in individuals with prior diagnoses of anxiety or depression before follow-up biopsy. Anxiety diagnosed between diagnostic and follow-up biopsy for coeliac disease was associated with an almost nine-fold increased chance of mucosal healing (odds ratio = 8.94; 95%CI = 2.03-39.27). Conclusion Anxiety and depression are more common in coeliac disease patients with mucosal healing, both before and after follow-up biopsy, an association potentially mediated through more vigilant compliance with a gluten-free diet. This finding raises concern that achieving the goal of mucosal healing may come at a cost of an increased risk of mood disorders.

Background High experienced continuity is known to be associated with lower needs for supportive care and most likely higher quality of life. On this background, the aim of this study was to investigate if patient-experienced continuity of care was associated with health-related quality of life (HRQoL) in breast cancer patients treated at two different-sized breast cancer units. Methods In 2016, two questionnaires, “Statements on experienced continuity of care” and “The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)”, were sent out to patients diagnosed between 2011 and 2014 at two different-sized breast cancer units in Sweden. Lead times and other data reflecting medical quality were collected from the patients’ medical records and from the National Swedish Breast Cancer Quality Register. Results Of 356 eligible patients, 231 (65%) answered the questionnaires, of whom 218 patients were included in the analyses. A statistically significant association was found between high experienced continuity and high global HRQoL (p = 0.03). Continuity was higher at the smaller unit, while no major differences between the units were found regarding medical quality or lead times. Conclusion The study found that high experienced continuity and HRQoL was strongly associated. A statistically significant higher continuity of care was found at the smaller unit, in line with what was expected. The absence of clinically relevant differences in lead times and medical quality may indicate that continuity could be achieved without loss of quality.

Letter : you can stare at a vicious circle, but you can also try to break it-psychological health and coeliac disease. Authors' reply

Background Coeliac disease has been associated with an increased risk of cardiovascular disease in some studies, whereas other studies have shown no association. We performed a systematic review and meta-analysis of cardiovascular disease in celiac disease. Methods Pubmed, Cinahl, EMBASE and Medline via Ovid were searched for relevant articles published until January 5, 2015. English-language articles on studies with more than 20 patients were included, and were quality rated using the GRADE risk of bias tool. We used random-effects models and assessed heterogeneity using the I 2 statistic. Results Ten studies were relevant, reporting the risk of myocardial infarction, cardiovascular death and stroke in 33,128/32,903/32,466 coeliac disease patients respectively. Only one study examined celiac disease and a composite measure of cardiovascular disease and this study found a hazard ratio of 1.10 (95%CI 1.03–1.28). In a meta-analysis, we observed an increased risk of stroke (OR 1.11; 95%CI 1.02–1.20). The risks of myocardial infarction (OR 1.12; 95%CI 0.83–1.40) and cardiovascular death (OR 1.12; 95%CI 0.96–1.29) were similar but were estimated with less certainty. Heterogeneity was low for all outcomes except for myocardial infarction where it was moderate. Conclusion Coeliac disease was associated with a modestly increased risk of cardiovascular disease, but the evidence base is limited.

Background & Aims There have been inconsistent reports of prenatal and perinatal factors that affect risk for development of celiac disease. We assessed the association of fetal growth, birth weight, and mode of delivery with development of celiac disease within the Norwegian Mother and Child (MoBa) Cohort Study. Methods The MoBa cohort contains pregnancy information on 95,200 women and data on their 114,500 children, which were collected in Norway from 1999 through 2008; it is linked to the Medical Birth Registry. Women and children with celiac disease were identified from the National Patient Registry and from women's responses to MoBa questionnaires. We calculated odds ratios (ORs) for celiac disease by using a multivariable logistic regression model, adjusting for maternal celiac disease, sex of children, and children's age (model 1); in a second model, we adjusted for age of gluten introduction and duration of breastfeeding (model 2). Results We identified 650 children with celiac disease and 107,828 controls in the MoBa database. We found no association between birth weight or height with celiac disease (born small for gestational age was not associated). Celiac disease was not associated with mode of delivery (cesarean section, model 1: OR, 0.84; 95% confidence interval [CI], 0.65–1.09, and model 2: OR, 0.83; 95% CI, 0.63–1.09). Maternal celiac disease, adjusted for age and sex of the children (OR, 12.45; 95% CI, 8.29–18.71) and type 1 diabetes (model 1: OR, 2.58; 95% CI, 1.19–5.53, and model 2: OR, 2.61; 95% CI, 1.14–5.98) were associated with development of celiac disease in children, whereas maternal type 2 diabetes and gestational diabetes were not. Conclusions On the basis of analysis of the Norwegian MoBa cohort, development of celiac disease in children is significantly associated with sex of the child, maternal celiac disease, and type 1 diabetes but not with intrauterine growth.