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Søren Korsgaard, Frederikke Schønfeldt Troelsen, Katalin Veres, Cecilia Hvitfeldt Fuglsang, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, DenmarkCorrespondence: Søren Korsgaard, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43– 45, Aarhus N, 8200, Denmark, Tel +45 87167212, Email soren.korsgaard@clin.au.dkPurpose: In the Danish National Patient Registry (DNPR), covering all Danish hospitals and widely used in research, diseases have been recorded using International Classification of Diseases (ICD) codes, transitioning from the Eighth to the Tenth revision in 1994. Uncertainty exists regarding whether including ICD-8 codes alongside ICD-10 is needed for complete disease identification. We assessed the extent of left-truncation and left-censoring in the DNPR arising from omitting ICD-8 codes.Patients and Methods: We sampled 500,000 Danes ≥ 40 years of age in 1995, 2010, and 2018. From the DNPR, we identified cardiovascular, endocrine, gastrointestinal, neurological, pulmonary, rheumatic, and urogenital diseases as well as fractures. We obtained the number of people with a disease recorded with ICD-8 codes only (ie, the ICD-8 record would be left-truncated by not using ICD-8 codes), ICD-8 plus ICD-10 codes (ie, the ICD-8 record would be left-censored by not using ICD-8 codes), and ICD-10 codes only. For each ICD group, we calculated the proportion of people with the disease relative to the total sample (ie, 500,000 people) and the total number of people with the disease across all ICD groups.Results: Overall, the left-truncation issue decreased over the years. Relative to all people with a disease, the left-truncated proportion was for example 59% in 1995 and < 2% in 2018 for diabetes mellitus; 93% in 1995, and 54% in 2018 for appendicitis. The left-truncation issue increased with age group for most diseases. The proportion of disease records left-censored by not using ICD-8 codes was generally low but highest for chronic diseases.Conclusion: The left-truncation issue diminished over sample years, particularly for chronic diseases, yet remained rather high for selected surgical diseases. The left-truncation issue increased with age group for most diseases. Left-censoring was overall a minor issue that primarily concerned chronic diseases.Keywords: epidemiology, methodology, bias, left-truncation, left-censoring

Henrik Toft Sørensen,1 Tina Christensen,1 Hans Erik Bøtker,2 Christian Fynbo Christiansen,1 Cecilia H Fuglsang,1 Sigrid B Gribsholt,1 Frederik Pagh Bredahl Kristensen,1 Kristina Laugesen,1 Anne Sofie D Laursen,1 Mette Nørgaard,1 Morten Schmidt,1 Nils Skajaa,1 Frederikke S Troelsen,1 Lars Pedersen1 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, DenmarkCorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkPurpose: Humans are living longer and may develop multiple chronic diseases in later life. The Better Health in Late Life cohort study aims to improve our understanding of the risks and outcomes of multimorbidity in the Danish population.Methods: A randomly-selected sample of Danish residents who were 50– 65 years of age received a questionnaire and an invitation to participate in this study. Respondents completed an online survey between October 2021 and January 2022 which addressed topics that included self-assessed health, mental health, sleep, specific medical conditions, use of painkillers, diet, alcohol consumption, smoking, physical activity, and body composition. This information was linked to the Danish health and social registries (some established in 1943 and onwards) that maintain data on filled prescriptions, hospital records, socioeconomic status, and health care utilization.Results: Responses were received from 115,431 of the 301,244 residents invited to participate (38%). We excluded respondents who answered none of the questions as well as those who provided no information on sex or indicated an age other than 50– 65 years. Of the 114,283 eligible respondents, 54.8% were female, 30.3% were overweight, and 16.7% were obese. Most participants reported a weekly alcohol consumption of less than seven units and 13.3% were current smokers; 5.2% had a history of hospitalization for solid cancer, and 3.0%, 2.3%, 2.0%, and 0.9% reported chronic pulmonary disease, diabetes, stroke, and myocardial infarction, respectively. The most frequently filled prescriptions were for medications used to treat the nervous system and cardiovascular diseases (38.1% and 37.4%, respectively).Keywords: aging, epidemiology, health registries, life course epidemiology, multimorbidity, prospective cohort

Søren Hauge Okholm,1 Dávid Nagy,1 Dóra Körmendiné Farkas,1 Cecilia Hvitfeldt Fuglsang,1 Frederikke Schønfeldt Troelsen,1 Victor W Henderson,1,2 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USACorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus N, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkIntroduction: Cancer may increase the risk of bleeding. However, whether subdural hematoma is a marker of occult cancer remains unknown. We examined the association between non-traumatic subdural hematoma and cancer risk in a cohort study.Materials and Methods: Using Danish nationwide health registries, we identified 2713 patients with non-traumatic subdural hematoma and no previous cancer diagnosis, who were hospitalized between April 1, 1996 and December 31, 2019. We computed age-, sex-, and calendar year-standardized incidence ratios (SIRs) as the ratio of the observed to expected number of patients with cancer by using national incidence rates as reference as a measure of relative risk.Results: We identified 77 cancer cases within the first year of follow-up and 272 cancer cases thereafter. The one-year risk of cancer was 2.8% (95% confidence interval: 2.2– 3.5), and the one-year SIR was 1.7 (95% confidence interval: 1.3– 2.1). During the subsequent years, the SIR was 1.0 (95% confidence interval: 0.9– 1.1). The relative risk was elevated for some hematological and liver cancers.Conclusion: The risk of a new cancer diagnosis was clearly increased in patients with non-traumatic subdural hematoma compared with the general population during the first year of follow-up. However, the absolute risk was low, thus limiting the clinical relevance of pursuing early cancer detection in these patients.Keywords: cancer, cohort study, epidemiology, non-traumatic subdural hematoma, population-based

Kristina Laugesen,1 Jonas Mengel-From,2,3 Kaare Christensen,2– 4 Jørn Olsen,1 David M Hougaard,5,6 Lasse Boding,7 Anja Olsen,8,9 Christian Erikstrup,10 Merete Lund Hetland,11,12 Estrid Høgdall,12,13 Alisa D Kjaergaard,14 Erik Sørensen,15 Anja Brügmann,16 Eva Rabing Brix Petersen,17 Ivan Brandslund,17,18 Børge G Nordestgaard,19 Gorm B Jensen,20 Nils Skajaa,1 Frederikke Schønfeldt Troelsen,1 Cecilia Hvitfeldt Fuglsang,1 Lise Skovgaard Svingel,1 Henrik T Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Epidemiology, Biostatistics and Biodemography, the Danish Twin Registry, and the Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Genetics, Odense University Hospital, Odense, Denmark; 4Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; 5iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; 6Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark; 7The Danish National Biobank, Statens Serum Institut, Copenhagen, Denmark; 8Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark; 9Department of Public Health, Aarhus University, Aarhus, Denmark; 10Department of Clinical Immunology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 11The DANBIO Registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark; 12Department of Clinical Medicine, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; 13Bio- and GenomeBank Denmark (RBGB), Molecular Unit, Department of Pathology, Herlev Hospital, Herlev, Denmark; 14Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 15Department of Clinical Immunology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark; 16Department of Pathology, Aalborg University Hospital, Aalborg, Denmark; 17Department of Clinical Biochemistry and Immunology, Lillebaelt Hospital, Vejle, Denmark; 18Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; 19The Copenhagen General Population Study, Department of Clinical Biochemistry, Copenhagen University Hospital – Herlev Gentofte, University of Copenhagen, Herlev, Denmark; 20The Copenhagen City Heart Study, Frederiksberg and Bispebjerg Hospital, Frederiksberg, DenmarkCorrespondence: Kristina Laugesen, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 871 68063, Email Kristina.laugesen@clin.au.dkAbstract: Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.Keywords: biobank, research, healthcare system, registries, epidemiology, precision medicine

Louise Thomsen,* Frederikke Schønfeldt Troelsen,* David Nagy, Nils Skajaa, Dóra Körmendiné Farkas, Rune Erichsen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, 8200, Denmark*These authors contributed equally to this workCorrespondence: Louise ThomsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N, 8200, DenmarkTel +45 20477642Email louisethomsen3@gmail.comPurpose: Venous thromboembolism may be a harbinger of cancer. Patients with diverticular disease are suggested to have an increased risk of developing venous thromboembolism compared with the general population, but it remains unclear whether venous thromboembolism is also a marker of occult cancer in these patients. We investigated the risk of cancer after venous thromboembolism among patients with diverticular disease.Patients and Methods: We used Danish health registries to conduct a nationwide, population-based cohort study during 1996– 2017. We identified all venous thromboembolism patients with a diagnosis of diverticular disease and calculated absolute risks of cancer and standardized incidence ratios (SIRs) by comparing observed and expected cancer incidence based on national cancer incidence in the Danish population.Results: We followed 3406 patients with venous thromboembolism and diverticular disease for a median of 3.0 years (interquartile range: 1.0– 6.0). During the first year of follow-up, we observed 212 cancer cases. The corresponding one-year risk of cancer was 6.2% (95% confidence interval [CI]: 5.5– 7.1) with a SIR of 2.9 (95% CI: 2.5– 3.3). The SIRs were particularly elevated for cancers of the stomach, pancreas, ovary, and kidney. During the second and subsequent years of follow-up, 337 cancers were diagnosed with a SIR of 1.1 (95% CI: 1.0– 1.3).Conclusion: Venous thromboembolism is a harbinger of occult cancer in patients with diverticular disease.Keywords: epidemiology, pulmonary embolism, deep venous thrombosis, diverticulitis, perforated diverticulitis, cancer

Background & Aims: Several studies have investigated the association between diverticular disease (DD) and colorectal cancer. However, whether there is an association between DD and malignancies other than those in the colorectum remains uncertain., Methods: For the 1978-2019 period, we conducted a nationwide, population-based cohort study using national Danish health care data. We followed patients with DD for up to 20 years, beginning 1 year after the date of DD diagnosis until the first occurrence of incident cancer, emigration, death, 20 years of follow-up, or December 31, 2019. We calculated cumulative incidence proportions of cancer and standardized incidence ratios (SIRs) comparing cancer incidence among patients with DD with that in the general population., Results: We identified 200,639 patients with DD, of whom 20,498 were diagnosed with cancer during the 1-20 years after their DD diagnosis. The SIRs were increased for most cancer sites except for those in the colorectum (SIR, 0.75; 95% confidence interval, 0.72-0.78). The highest SIRs were observed for cancers of the lung, bronchi, and trachea (SIR, 1.20; 95% confidence interval, 1.15-1.24) and kidney (SIR, 1.27; 95% confidence interval, 1.16-1.39)., Conclusions: Our findings show an increased long-term relative risk of cancer following a diagnosis of DD. These findings are likely caused by prevalence of numerous risk factors in patients with DD that confer an increased risk of cancer. The decreased relative risk of colorectal cancer might be explained by an increased likelihood of patients with DD undergoing colonoscopy with polypectomy., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Studies suggest that patients with type two diabetes mellitus (T2D) may be at increased risk of post-colonoscopy colorectal cancer (PCCRC). We investigated clinical and molecular characteristics and survival of T2D patients with PCCRC to elucidate how T2D-related PCCRC may arise., Methods: We identified T2D patients with colorectal cancer (CRC) from 1995 to 2015 and computed prevalence ratios (PRs) comparing clinical and molecular characteristics of CRC in T2D patients with PCCRC vs. in T2D patients with colonoscopy-detected CRC (dCRC). We also followed T2D patients from the diagnosis of PCCRC/dCRC until death, emigration, or study end and compared mortality using Cox-proportional hazards regression models adjusted for sex, age, year of CRC diagnosis, and CRC stage., Results: Compared with dCRC, PCCRC was associated with a higher prevalence of proximal CRCs (54% vs. 40%; PR: 1.43, 95% confidence interval [CI] 1.27-1.62) in T2D patients. We found no difference between PCCRC vs. dCRC for CRC stage, histology, and mismatch repair status. The proportion of CRCs that could be categorized as PCCRC decreased over time. Within one year after CRC, 63% of PCCRC vs. 78% of dCRC patients were alive (hazard ratio [HR] 1.85 [95% CI 1.47-2.31]). Within five years after CRC, 44% of PCCRC vs. 54% of dCRC patients were still alive (HR 1.44 [95% CI 1.11-1.87])., Conclusion: The increased prevalence of proximally located PCCRCs and the poorer survival may suggest overlooked colorectal lesions as a predominant explanation for T2D-related PCCRC, although altered tumor progression cannot be ruled out., (© 2024. The Author(s).)

Background: Post-colonoscopy colorectal cancers (PCCRCs) may account for up to 30% of all colorectal cancers (CRCs) diagnosed in patients with diverticular disease; however, absolute and relative risks of PCCRC among these patients undergoing colonoscopy remain unknown., Methods: We performed a cohort study (1995-2015) including patients with and without diverticular disease who underwent colonoscopy. We calculated 7-36-month cumulative incidence proportions (CIPs) of PCCRC. We used Cox proportional hazards regression models to compute hazard ratios (HRs) of PCCRC, comparing patients with and without diverticular disease, as a measure of relative risk. We calculated 3-year PCCRC rates, as per World Endoscopy Organization recommendations, to estimate the proportion of CRC patients with and without diverticular disease who were considered to have PCCRC. We stratified all analyses by PCCRC location., Results: We observed 373 PCCRCs among 56 642 patients with diverticular disease and 1536 PCCRCs among 306 800 patients without diverticular disease. The PCCRC CIP after first-time colonoscopy was 0.45% (95%CI 0.40%-0.51%) for patients with and 0.36% (95%CI 0.34%-0.38%) for patients without diverticular disease. Comparing patients with and without diverticular disease undergoing first-time colonoscopy, the adjusted HR was 0.84 (95%CI 0.73-0.97) for PCCRC and 1.23 (95%CI 1.01-1.50) for proximal PCCRCs. The 3-year PCCRC rate was 19.0% (22.3% for proximal PCCRCs) for patients with and 6.5% for patients without diverticular disease., Conclusions: Although the absolute risk was low, the relative risk of proximal PCCRCs may be elevated in patients with diverticular disease undergoing colonoscopy compared with patients without the disease., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background  Bleeding and venous thromboembolism (VTE) are adverse outcomes after colorectal cancer (CRC) surgery. Type 2 diabetes (T2D) clusters with bleeding and VTE risk factors. We examined the bleeding and VTE risk in patients with T2D undergoing CRC surgery and the prognosis after these adverse outcomes. Methods  We conducted a prognostic population-based cohort study of 48,295 patients with and without T2D undergoing surgery for incident CRC during 2005 to 2019. Patients with T2D were diagnosed in a hospital setting or had redeemed a glucose-lowering drug prescription; the remaining cohort was patients without diabetes. We estimated the 30-day and 1-year risks of bleeding and VTE and used a Fine-Gray model to compute age-, sex-, and calendar year-adjusted subdistribution hazard ratios (SHRs). The Kaplan-Meier method was used to calculate 1-year mortality after bleeding or VTE. Results  Within 30 days after CRC surgery, the risk of bleeding was 2.7% in patients with T2D and 2.0% in patients without diabetes (SHR: 1.30 [95% confidence interval [CI]: 1.10-1.53]). For VTE, the 30-day risks were 0.6% for patients with T2D and 0.6% for patients without diabetes (SHR: 1.01 [95% CI: 0.71-1.42]). The SHRs for bleeding and VTE within 1 year after CRC surgery were similar. The 1-year mortality was 26.0% versus 24.9% in the bleeding cohort and 25.8% versus 27.5% in the VTE cohort for patients with T2D versus without diabetes, respectively. Conclusion  Although absolute risks were low, patients with T2D have an increased risk of bleeding but not VTE after CRC surgery., Competing Interests: Conflict of Interest The authors declare no competing interests related to the work under study. Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of these studies have any relation to the current study., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background:  Venous thromboembolism (VTE) may be a harbinger of cancer in the general population. Patients with kidney disease have an a priori increased VTE risk. However, it remains unknown how a VTE affects subsequent cancer risk in these patients., Objectives:  To examine the cancer risk in patients with kidney disease following a VTE., Methods:  We conducted a nationwide population-based cohort study in Denmark (1996-2017), including all VTE patients with a diagnosis of kidney disease. We calculated absolute risks of cancer (accounting for competing risk of death) and age-, sex-, and calendar-period standardized incidence ratios (SIRs) comparing the observed cancer incidence with national cancer incidence rates and cancer incidence rates of VTE patients without kidney disease., Results:  We followed 3,362 VTE patients with kidney disease (45.9% females) for a median follow-up time of 2.4 years (interquartile range: 0.6-5.4). During follow-up, 464 patients were diagnosed with cancer, of whom 169 (36.4%) were diagnosed within the first year. The 1-year absolute risk of any cancer was 5.0% (95% confidence interval [CI]: 4.3-5.8), with a SIR of 2.9 (95% CI: 2.5-3.4) when compared with the general population, and 2.0 (95% CI: 1.8-2.4) when compared with VTE patients without kidney disease. During subsequent years of follow-up, the SIRs declined to 1.5 (95% CI: 1.3-1.6) when compared with the general population, and 1.1 (95% CI: 0.9-1.2) compared with VTE patients without kidney disease., Conclusion:  Patients with hospital-diagnosed kidney disease have increased cancer risk after VTE, especially within the first year following the VTE diagnosis., Competing Interests: None declared., (Thieme. All rights reserved.)

Background & Aims: The term post-colonoscopy colorectal cancer (PCCRC) refers to colorectal cancer (CRC) diagnosed after a negative colonoscopy. Using the root-cause algorithm proposed by the World Endoscopy Organization, we aimed to investigate plausible explanations for PCCRCs and potential changes in plausible explanations for PCCRCs over time in a Danish Region., Methods: During 1995 to 2021, we used national health registries and electronic medical records in the Central Denmark Region to identify PCCRC cases, defined as CRCs recorded within 6 to 48 months after a colonoscopy. We then applied the World Endoscopy Organization algorithm to categorize explanations for PCCRC as follows: (A) possible missed lesion, prior examination adequate; (B) possible missed lesion, prior examination inadequate; (C) detected lesion, not resected; or (D) likely incomplete resection of previously identified lesion. PCCRCs were identified before (1995-2013) and after (2014-2021) implementation of nationwide fecal immunochemical test-based CRC screening and quality indicators for colonoscopy., Results: We identified 762 PCCRCs, 53.5% among males and 57% among individuals ≥70 years. Forty-five percent were located in the proximal colon. We identified 616 (80.8%; 95% confidence interval [CI], 74.6%-87.5%) category A PCCRCs; 36 (4.7%; 95% CI, 3.3%-6.5%) category B PCCRCs; 26 (3.4%; 95% CI, 2.2%-4.9%) category C PCCRCs; and 84 (11%; 95% CI, 8.8%-13.6%) category D PCCRCs. Similar patterns were observed during the early (1995-2013) and late (2014-2021) study periods., Conclusions: Most PCCRCs originate from possible missed lesions and incompletely resected lesions during the complete study period. These findings indicate the importance of quality assurance of colonoscopy procedures and polypectomy techniques., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: A laparoscopic approach to total colectomy (TC) for inflammatory bowel disease (IBD) is being increasingly used, but data on its comparative benefits over open TC are conflicting. The aim of this study was to examine 90-day outcomes following laparoscopic and open TC for IBD in a nationwide cohort after the introduction of laparoscopy., Method: IBD patients undergoing TC in Denmark from 2005 to 2017 were identified from the Danish National Patient Registry. We used Kaplan-Meier methodology to estimate mortality and Cox regression analysis to estimate adjusted mortality rate ratios (aMRRs) and adjusted hazard ratios (aHRs) of reoperation, readmission and intensive care unit (ICU) transfer, comparing patients undergoing laparoscopic versus open TC., Results: We identified 1095 patients undergoing laparoscopic TC and 1523 patients undergoing open TC. Following emergency TC, 90-day mortality was 2.8% (1.6%-4.9%) after laparoscopic TC and 9.1% (7.0%-11.8%) after open TC. Ninety-day mortality was 0.9% (0.3%-2.5%) after laparoscopic TC and 2.6% (1.5%-4.3%) after open elective TC. The aMRRs associated with laparoscopic TC were 0.45 (95% CI 0.25-0.80) in emergency cases and 0.29 (95% CI 0.10-0.86) in elective cases. Risks of readmission were comparable following laparoscopic versus open TC, both in emergency [aHR = 0.93 (95% CI 0.76-1.15)] and elective [aHR = 0.83 (95% CI 0.68-1.02)] cases, while risks of ICU transfer and reoperation were lower following laparoscopic TC, both in emergency cases [aHR = 0.53 (95% CI 0.35-0.82) and aHR = 0.26 (95% CI 0.15-0.47)] and elective [aHR = 0.58 (95% CI 0.35-0.95) and aHR = 0.37 (95% CI 0.21-0.66)] cases., Conclusion: The introduction of laparoscopic TC for IBD in Denmark was not associated with increased mortality or morbidity. In fact, laparoscopic TC for IBD may be associated with lower short-term mortality and morbidity compared with open TC., (© 2023 Association of Coloproctology of Great Britain and Ireland.)

Health registries provide opportunities for conducting large-scale, population-based studies, but attention must be devoted to their specific limitations. Herein, we describe potential limitations that may affect the validity of registry-based research. Our review includes descriptions of 1) populations, 2) variables, 3) medical coding systems for medical information and 4) selected key methodological challenges. Knowledge of such factors and epidemiological study designs in general is likely to increase the quality of registry-based research and reduce potential biases., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background: Existing evidence on the link between smoking and appendicitis is scarce and ambiguous. We therefore conducted a population-based cohort study in Denmark to investigate whether smoking during pregnancy is associated with an increased risk of appendicitis in offspring., Methods: We used the Danish Birth Registry to include all singletons born during 1991-2017 and to identify maternal smoking status during pregnancy. We followed the children from birth until date of appendicitis, emigration, death, or administrative end of study (31 December 2018), whichever came first. We calculated crude and adjusted hazard ratios (HRs) of appendicitis with 95% confidence intervals (CIs) comparing children of mothers who smoked during pregnancy to children of nonsmokers. Further, we conducted a bias analysis and sibling analysis., Results: We included 1,659,526 singletons of whom 19% were born to mothers who smoked during pregnancy. After maximum 28 years of follow-up, hazard rates for children of smokers were slightly higher than for children of nonsmokers [adjusted HR: 1.07 (95% CI = 1.04, 1.10)]. Stratification by sex revealed no association for males [adjusted HR: 1.02 (95% CI = 0.99, 1.06)], but a higher HR for females [adjusted HR: 1.13 (95% CI = 1.09, 1.18)]. This association increased with increasing length of follow-up, indicating that the association may be mediated by later-life exposures. The bias analysis indicated that misclassification of maternal smoking could attenuate a true association, while the sibling analysis showed no association., Conclusions: Maternal smoking during pregnancy and appendicitis in the offspring may be associated., Competing Interests: Disclosure: Dr. Fuglsang owns stock in Novo Nordisk. The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background  Aspirin may reduce the risk of cancer, particularly gastrointestinal cancer, and venous thromboembolism (VTE). VTE can be the first symptom of occult cancer, but whether it is also a marker of occult cancer in aspirin users remains unknown. Therefore, we investigated the risk of cancer subsequent to VTE among users of low-dose aspirin. Methods  We conducted a population-based cohort study using data from Danish health registries for the years 2001 to 2018. We identified all patients with a first-time diagnosis of VTE who also redeemed a prescription for low-dose aspirin (75-150mg) within 90 days prior to the first-time VTE. We categorized aspirin users by the number of prescriptions filled as new users (<5 prescriptions), short-term users (5-19 prescriptions), and long-term users (>19 prescriptions). We computed the absolute cancer risks and standardized incidence ratios (SIRs) for cancer using national cancer incidence rates. Results  We followed-up 11,759 users of low-dose aspirin with VTE. Long-term users comprised 50% of aspirin users. The 1-year absolute risk of cancer was 6.0% for new users and 6.7% for short-term and long-term users, with corresponding SIRs of 3.3 (95% confidence interval [CI]: 2.8-4.0), 3.2 (95% CI: 2.9-3.7), and 2.8 (95% CI: 2.6-3.2), respectively. After the first year of follow-up, the SIR decreased to 1.2 (95% CI: 1.1-1.4) for new users, 1.1 (95% CI: 1.1-1.3) for short-term users, and 1.1 (95% CI: 1.0-1.2) for long-term users. Conclusion  VTE may be a harbinger of cancer, even in users of low-dose aspirin, regardless of duration of use., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Inflammatory bowel disease (IBD) may be associated with increased dementia risk, but the literature is conflicting., Aim: To investigate dementia risk in patients with IBD., Methods: We conducted a nationwide population-based cohort study in Denmark (1977-2018) including all patients with incident IBD matched with up to 10 general population comparators without IBD by sex, year of birth and region of residence. We calculated cumulative incidence proportions (CIPs) of dementia treating death as a competing risk, and adjusted hazard ratios (HRs) comparing IBD patients with matched comparisons. In a nested case-control analysis, we investigated the impact of IBD severity, steroid use, colorectal and small bowel surgery, and healthcare system contacts on dementia risk., Results: Of 88,985 patients with IBD (69.6% with ulcerative colitis [UC], 30.4% with Crohn's disease [CD]) and 884,108 comparisons, 2076 patients (78.1% with UC) and 23,011 comparisons (76.6% UC comparisons) developed dementia. The 40-year CIP of all-cause dementia was 7.2% for UC patients and 5.8% for CD patients. UC patients had a slightly increased HR of all-cause dementia (HR = 1.07 [95% confidence interval (CI): 1.01;1.12]) and Alzheimer's disease (HR = 1.10 [95% CI: 1.01-1.19]). CD patients had an increased HR of all-cause dementia (HR = 1.15 [95% CI: 1.05-1.27]) and frontotemporal dementia (HR = 2.70 [95% CI: 1.44-5.05]). Dementia in IBD patients was associated with frequent healthcare system contacts., Conclusions: UC and CD are associated with slightly increased all-cause dementia risk, particularly frontotemporal dementia in CD patients. Frequent healthcare system contacts by patients with IBD and detection bias may play a role in the association., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Postcolonoscopy colorectal cancers (PCCRCs) account for up to 50% of colorectal cancers (CRCs) in patients with inflammatory bowel disease (IBD). We investigated characteristics of IBD patients with PCCRC and their survival., Methods: We identified IBD patients (ulcerative colitis [UC] and Crohn's disease) diagnosed with CRC from 1995 to 2015. We defined PCCRC as diagnosed between 6 and 36 months, and detected CRC (dCRC) as diagnosed within 6 months after colonoscopy. We computed prevalence ratios comparing PCCRC vs dCRC and followed up patients from the diagnosis of PCCRC/dCRC until death, emigration, or study end. Mortality was compared using Cox proportional hazards regression models adjusted for sex, age, year of CRC diagnosis, and stage. The main analyses focused on patients with UC., Results: Among 23,738 UC patients undergoing colonoscopy, we identified 352 patients with CRC, of whom 103 (29%) had PCCRC. Compared with dCRC, PCCRC was associated with a higher prevalence of metastatic cancer (33% vs 20%; prevalence ratio, 1.64; 95% CI, 1.13-2.38), cancers showing mismatch repair deficiency (79% vs 56%; prevalence ratio, 1.40; 95% CI, 1.13-1.72), and proximally located cancers (54% vs 40%; prevalence ratio, 1.34; 95% CI, 1.06-1.69). The 1- and 5-year adjusted hazard ratios of death for PCCRC vs dCRC among UC patients were 1.29 (95% CI, 0.77-2.18) and 1.24 (95% CI, 0.86-1.79), respectively., Conclusions: The characteristics of UC-related PCCRC suggest tumor biology as an important factor in the progression to cancer. However, the prognosis of PCCRC appears similar to that of dCRC., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Prevalent type 2 diabetes (T2D) is associated with an increased risk of colorectal cancer and could impair the quality of bowel preparation for colonoscopy. This may in turn increase the risk of overlooked precancerous polyps and subsequent risk of post-colonoscopy colorectal cancer (PCCRC). We investigated whether patients with T2D are at increased risk of PCCRC compared with patients without T2D., Design: We conducted a population-based cohort study of patients with T2D and without T2D undergoing colonoscopy in Denmark (1995-2015). We investigated the risk of PCCRC by calculating >6 to 36 months cumulative incidence proportions (CIPs) treating death and colectomy as competing risks. Using Cox proportional-hazards regression analyses, we also computed HRs of PCCRC, comparing patients with T2D and non-T2D. According to the World Endoscopy Organization guidelines, we calculated PCCRC 3-year rates to estimate the proportions of T2D and non-T2D CRC patients experiencing PCCRC., Results: We identified 29 031 patients with T2D and 333 232 patients without T2D undergoing colonoscopy. We observed 250 PCCRCs among patients with T2D and 1658 PCCRCs among patients without T2D. The >6 to 36 months CIP after a first-time colonoscopy was 0.64% (95% CI 0.55% to 0.74%) for T2D and 0.36% (95% CI 0.34% to 0.38%) for patients without T2D. The HRs of PCCRC were 1.43 (95% CI 1.21 to 1.72) after a first-time colonoscopy and 1.18 (95% CI 0.75 to 1.85) after a second-time colonoscopy. The PCCRC 3-year rate was 7.9% for patients with T2D and 7.4% for patients without T2D., Conclusion: T2D may be associated with an increased HR of PCCRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Venous thromboembolism (VTE) may be the first symptom of cancer. Statins are suggested to prevent VTE, but the risk of cancer in VTE patients using statins remains poorly understood., Objectives: To examine if VTE is a marker of cancer in users of statins., Methods: We identified all Danish patients during 1996-2017 with a first-time diagnosis of VTE and a filled prescription for a statin within 90 days prior to the VTE diagnosis. We classified patients as prevalent users if the first filling of a statin occurred more than one year preceding the VTE diagnosis, and as new users if the first filling occurred within the preceding year. We computed cumulative incidences of cancer, with death as a competing risk, and age-, sex-, and calendar-period standardized incidence ratios (SIRs), comparing the observed cancer incidence with the expected based on national cancer statistics., Results: Among 9280 (85%) prevalent users of statin and 1580 (15%) new users, the one-year cumulative incidence of any cancer was 6.6 (95% CI: 6.1-7.2) for prevalent users and 6.4 (95% CI: 5.2-7.6) for new users; the corresponding SIRs were 3.1 (95% CI: 2.9-3.3) and 3.5 (95% CI: 2.9-4.3). In the second and subsequent years, the SIRs diminished and approached unity for both prevalent (1.1 [95% CI: 1.1-1.2]) and new users (1.1 [95% CI: 0.9-1.3])., Conclusions: VTE patients using statins had a 3-fold increased rate of cancer in the first year after diagnosis. A first VTE serves as an important marker of cancer, regardless of statin use., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Aspirin inhibits platelet function and may therefore accelerate early lower gastrointestinal bleeding (LGIB) from colorectal cancer (CRC) precursor polyps. The bleeding may increase endoscopic polyp detection., Study Question: To estimate the prevalence of polyps and CRC comparing new users of low-dose aspirin with nonusers who all received a diagnosis of LGIB and to investigate the mortality among these patients., Study Design: Using Danish nationwide health registries, we conducted a cohort study (2006-2013) of all new aspirin users who also received a diagnosis of LGIB (n = 40,578). Each new user was matched with 5 nonusers with LGIB by gender and age at the LGIB diagnosis date., Measures and Outcomes: We computed the prevalence and prevalence ratios (PRs) of colorectal polyps and CRCs, and the mortality ratios within 6 months after the LGIB, comparing new users with nonusers., Results: We identified 1038 new aspirin users and 5190 nonusers with LGIB. We observed 220 new users and 950 nonusers recorded with endoscopically detected polyps. New aspirin users had a higher prevalence of conventional {PR = 1.28 [95% confidence interval (CI): 1.06-1.55]} and serrated [PR = 1.31 (95% CI: 0.95-1.80)] polyps. New users and nonusers had a similar prevalence of CRC [PR = 1.04 (95% CI: 0.77-1.39)]. However, after stratifying by location of CRC, the prevalence of proximal tumors was lower [PR = 0.71 (95% CI: 0.35-1.43)] in new users than in nonusers. No difference in mortality was observed., Conclusions: These findings indicate that new use of low-dose aspirin is associated with an increased detection of colorectal polyps compared with nonuse., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) may be the first manifestation of occult cancer. Dementia has been linked to reduced cancer risk., Objective: We examined the risk of cancer following VTE in people with dementia in comparison to the risk in the general population., Methods: We conducted a population-based Danish registry-based cohort study following patients with a first-time VTE and a previous or concurrent diagnosis of dementia during the period 1 April 1996 -31 December 2017. We followed the study participants from date of VTE until diagnosis of cancer, death, emigration, or end of study period, whichever came first. The absolute risk of cancer within one year after VTE was computed, treating death as a competing risk. We calculated gender, age, and calendar-period standardized incidence ratios (SIRs) of cancer based on national cancer rates., Results: We followed 3,552 people with dementia and VTE for a median of 1.3 years. Within the first year after VTE, they had a 90% increased risk of cancer in comparison with the general population [SIR: 1.9 (95% confidence interval: 1.6-2.4)]. During subsequent follow-up years, the SIR fell to 0.7 (95% confidence interval: 0.5-0.8). Findings for Alzheimer's disease and VTE were similar., Conclusion: People with dementia have an increased risk of a cancer diagnosis during the first year following VTE, perhaps related to increased surveillance, and a lower risk thereafter. Overall risk is similar to that of the general population.

Objective: Aspirin may increase the risk of lower gastrointestinal bleeding (LGIB) from precursors of colorectal cancer (CRC). We investigated whether use of low-dose aspirin, through initiation of LGIB, may lead patients to undergo colonoscopy and polypectomy before manifest CRC., Design: We conducted a historical cohort study (2005-2013) of all Danish residents who initiated low-dose aspirin treatment (n=412 202) in a setting without screening for CRC. Each new aspirin user was matched with three non-users (n=1 236 560) by age, sex and region of residence on the date of their matched new user's first-time aspirin prescription (index date). We computed absolute risks (ARs), risk differences and relative risks (RRs) of LGIB, lower gastrointestinal endoscopy, colorectal polyps and CRC, comparing aspirin users with non-users., Results: The ARs were higher for new users than non-users for LGIB, lower gastrointestinal endoscopy, colorectal polyps and CRC within 3 months after index. Comparing new users with non-users, the RRs were 2.79 (95% CI 2.40 to 3.24) for LGIB, 1.73 (95% CI 1.63 to 1.84) for lower gastrointestinal endoscopy, 1.56 (95% CI 1.42 to 1.72) for colorectal polyps and 1.73 (95% CI 1.51 to 1.98) for CRC. The RRs remained elevated for more than 12 months after the index date, with the exception of CRC where the RRs were slightly decreased during the 3-5 years (RR 0.90, 95% CI 0.83 to 0.98) and more than 5 years (RR 0.91, 95% CI 0.82 to 1.00) following the index date., Conclusion: These findings indicate that aspirin may contribute to reduce CRC risk by causing premalignant polyps to bleed, thereby expediting colonoscopy and polypectomy before CRC development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inflammatory bowel disease (IBD) causes serious morbidity and disability, and the incidence is increasing. The disease etiology is not well understood, though inflammatory reactions after antibiotic exposure may be associated with development of IBD. We investigated the association between IBD and prior antibiotic use., Methods: We conducted this case-control study among individuals in the United Kingdom Clinical Practice Research Datalink GOLD (CPRD GOLD). Each case of IBD was matched to 4 controls on age, sex, general practice, and registration year in the CPRD GOLD. Antibiotic exposure was classified by ever or never use, number of prescriptions, and class of antibiotic before the index date. Odds ratios were calculated using conditional logistic regression., Results: We identified 461 cases of ulcerative colitis (UC) and 683 cases of Crohn's disease (CD). There was no association between ever use of any antibiotic and UC (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.72-1.44) or CD (OR, 1.01; 95% CI, 0.73-1.39) compared with never use. A slightly increased CD risk was observed among ever users of quinolones (OR, 1.76; 95% CI, 1.00-3.11) and metronidazole (OR, 1.43; 95% CI, 0.87-2.34) compared with never users. CD was associated with antibiotic exposure before age 5 (OR, 2.20; 95% CI, 0.75-6.43) in an analysis restricted to individuals followed from birth., Conclusions: There was no association between UC or CD and overall prior use of antibiotics, though prior use of metronidazole and quinolones was associated with a slightly increased risk of CD. Antibiotic use in early childhood may increase the risk of CD., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)