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Background A growing body of evidence supports the safety of the human papillomavirus (HPV) vaccines. However, concerns about autonomic dysfunction syndromes and non-specific symptoms continue to linger. These conditions are not easily captured by traditional diagnostic classification schemes and call for innovative approaches to the study of vaccine safety which take more general measures of all-cause morbidity into account. Methods Taking advantage of the unique Danish registers, including regional registration of absence from school, we conducted a cohort study of 14 068 adolescent Danish girls attending 5th through 9th grade in public schools in the municipality of Copenhagen during 1 August 2013–23 January 2018. We obtained time-varying HPV vaccination status and demographic information from nationwide registers. Using Poisson regression with random effects, we estimated rate ratios (RRs) of absence due to illness, comparing HPV-vaccinated girls with unvaccinated girls with adjustment for grade, season, calendar period, demographic factors and random effects at the individual, class and school levels. Results Our study included 6 206 188 school days with 213 221 days of absence from school due to illness (absence rate, 3.4%). Comparing absence rates due to illness in HPV-vaccinated and unvaccinated girls yielded an adjusted RR of 1.00 (95% confidence interval [CI], 0.98–1.03). Conclusions Our study provides an important and novel contribution to HPV vaccine safety. Using absence from school records, we were able to address important safety concerns without relying on medical diagnoses. We conclude that HPV vaccination does not increase the risk of morbidity in any manner that manifests as absence from school due to illness.

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35–3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49–2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78–2.54), n = 11). Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

Whether male circumcision in infancy or childhood provides protection against the acquisition of human immunodeficiency virus (HIV) or other sexually transmitted infections (STIs) in adulthood remains to be established. In the first national cohort study to address this issue, we identified 810,719 non-Muslim males born in Denmark between 1977 and 2003 and followed them over the age span 0–36 years between 1977 and 2013. We obtained information about cohort members’ non-therapeutic circumcisions, HIV diagnoses and other STI outcomes from national health registers and used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) associated with foreskin status (i.e., circumcised v. genitally intact). During a mean of 22 years of follow-up, amounting to a total observation period of 17.7 million person-years, 3375 cohort members (0.42%) underwent non-therapeutic circumcision, and 8531 (1.05%) received hospital care for HIV or other STIs. Compared with genitally intact males, rates among circumcised males were not statistically significantly reduced for any specific STI. Indeed, circumcised males had a 53% higher rate of STIs overall (HR = 1.53, 95% CI: 1.24–1.89), and rates were statistically significantly increased for anogenital warts (74 cases in circumcised males v. 7151 cases in intact males, HR = 1.51; 95% CI: 1.20–1.90) and syphilis (four cases in circumcised males v. 197 cases in intact males, HR = 3.32; 95% CI: 1.23–8.95). In this national cohort study spanning more than three decades of observation, non-therapeutic circumcision in infancy or childhood did not appear to provide protection against HIV or other STIs in males up to the age of 36 years. Rather, non-therapeutic circumcision was associated with higher STI rates overall, particularly for anogenital warts and syphilis.

ObjectiveOur objective was to estimate the relative risk of IBD among first-generation and second-generation immigrants in Denmark compared with native Danes.DesignUsing national registries, we established a cohort of Danish residents between 1977 and 2018. Cohort members with known country of birth were followed for Crohn’s disease (CD) and ulcerative colitis (UC) diagnoses. Incidence rate ratios (IRRs) served as measures of relative risk and were calculated by log-linear Poisson regression, using rates among native Danes as reference, stratified by IBD risk in parental country of birth, and among first-generation immigrants by age at immigration and duration of stay in Denmark.ResultsAmong 8.7 million Danes, 4156 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. Overall, comparing first-generation immigrants with native Danes, the IRR was 0.80 (95% CI 0.76 to 0.84) for CD and 0.74 (95% CI 0.71 to 0.77) for UC. The IRR of IBD increased with ≥20 years stay in Denmark. The IRR of CD increased with immigration at ≥40 years of age. Comparing second-generation immigrants with native Danes, the IRR of IBD was 0.97 (95% CI 0.91 to 1.04). There was significant interaction with sex, with higher IRR of IBD in male than in female immigrants.ConclusionRelative to native Danish men and women, IBD risk among first-generation immigrants was lower, reflected the risk in their parental country of birth and increased with ≥20 years stay in Denmark. For second-generation immigrants, relative risk of IBD was lower only among women. These complex patterns suggest the role of environmental IBD risk factors.

Background The possible etiologic link between tonsillectomy and inflammatory bowel diseases remains unclear. To investigate the hereditary component, we assessed the risk of inflammatory bowel disease after own tonsillectomy as well as after tonsillectomy among family members. Methods A nationwide Danish cohort of 7,045,288 individuals was established and linked to comprehensive national registers with data on kinship, tonsillectomy surgery, and diagnosis of inflammatory bowel disease from all health sectors. We used Poisson regression models to estimate hospital contact rate ratios (RR) for Crohn's disease and ulcerative colitis, with 95% confidence intervals (CI), between individuals with or without tonsillectomy, as well as between individuals with or without tonsillectomized relatives. Results During 189 million person-years of follow-up between 1977 and 2014, 276,673 individuals were tonsillectomized, 22,015 developed Crohn's disease, and 49,550 developed ulcerative colitis. Rates of inflammatory bowel disease were elevated up to 20 years after own tonsillectomy (Crohn's disease: RR 1.52 [95% CI = 1.43, 1.61]; ulcerative colitis: RR 1.24 [95% CI = 1.18, 1.29]). RRs for Crohn's disease was 1.22 (95% CI = 1.17, 1.27) after first-degree relatives' tonsillectomy, 1.14 (95% CI = 1.08, 1.19) after second-degree relatives' tonsillectomy, and 1.08 (95% CI = 1.01, 1.15) after third-degree relatives' tonsillectomy. Corresponding RRs for ulcerative colitis were 1.10 (95% CI = 1.07, 1.13), 1.05 (95% CI = 1.01, 1.08), and 1.03 (95% CI = 0.98, 1.09). Conclusions Even individuals with tonsillectomized family members were at increased risk of inflammatory bowel disease. These findings call into question a direct influence of tonsillectomy on gastrointestinal inflammation and point instead toward shared hereditary or environmental factors. See video abstract at, http://links.lww.com/EDE/B464.

Peptidylarginine deiminases (PADs) catalyze citrullination, a post-translational modification playing a pathogenic role in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). The interplay between single nucleotide polymorphisms (SNPs) in thePADIgenes and known risk factors for ACPA-positive RA, including smoking, HLA-DR4 and -1, and the PTPN22 R620W polymorphism, was investigated. We typed fourPADI2SNPs, fourPADI4SNPs, and the PTPN22 R620W SNP in 445 Danish RA patients and 533 age-matched healthy controls, as well as in 200 North American RA patients and 100 age- and sex-matched controls. TheHLA-DRB1locus was typed in the Danish cohort. Logistic regression analyses, adjusted for age, sex, smoking status, and PTPN22 R620W, revealed increased risk of anti-CCP-positive RA in carriers of rs11203367(T) (OR: 1.22, p=0.03) and reduced risk in carriers of rs2240335(A) inPADI4(OR: 0.82, p=0.04). rs74058715(T) inPADI4conferred reduced risk of anti-CCP-negative RA (OR: 0.38, p=0.003). InHLA-DRB1*04-positive individuals, specifically, the risk of anti-CCP-positive RA was increased by carriage ofPADI4rs1748033(T) (OR: 1.54, p=0.007) and decreased by carriage ofPADI4rs74058715(T) (OR: 0.44, p=0.01), and we observed an interaction between these SNPs andHLA-DRB1*04(p=0.004 and p=0.008, respectively) Thus,PADI4polymorphisms associate with ACPA-positive RA, particularly inHLA-DRB1*04-positive individuals, and with ACPA-negative RA independently ofHLA-DRB1*04.

Background: In recent years, human papillomavirus (HPV) vaccination of boys has been added to childhood vaccination programmes in several countries but, so far, no systematic population-based assessment with long-term follow-up has been undertaken of the relative incidence of adverse outcomes following HPV vaccination in this group. We investigated if quadrivalent HPV (qHPV) vaccination of 10-17-year-old boys is associated with any unusual risk of autoimmune diseases, neurological diseases or venous thromboembolism.Methods: We conducted a national cohort study of 568 410 boys born in Denmark 1988-2006 and followed for 4 million person-years during 2006-16, using nationwide registers to obtain individual-level information about received doses of the qHPV vaccine and hospital records for 39 autoimmune diseases, 12 neurological diseases and venous thromboembolism. For each outcome, we estimated incidence rate ratios (RRs) with 95% confidence intervals (CIs) according to qHPV vaccination status.Results: Altogether 7384 boys received at least one dose of the qHPV vaccine at age 10-17 years. Overall, RRs were close to unity for the combined groups of autoimmune diseases (RR = 0.96; 95% CI: 0.71-1.28, n = 46 cases in qHPV-vaccinated boys) and neurological diseases (RR = 0.67; 0.41-1.10, n = 16), as well as for venous thromboembolism (RR = 0.88; 0.33-2.35, n = 4). After taking multiple testing into account, none of the 52 individual outcomes studied appeared to occur in excess among qHPV-vaccinated boys.Conclusions: Although additional large-scale epidemiological studies are warranted, our findings provide population-based reassurance that qHPV vaccination of 10-17-year-old boys is unlikely to be associated with an elevated risk of autoimmune diseases, neurological diseases or venous thromboembolism.

Background: A breast cancer (BC) diagnosis can profoundly affect the sex life of patient and partner within a couple. The purpose of the present study is to examine whether individual and partner sexual functioning, affectionate behavior, emotional closeness and depressive symptoms are associated with change over time in satisfaction with sex life of sexually active heterosexual couples dealing with BC and to explore whether the associations differ between patients and partners after adjustment for basic sociodemographic characteristics, comorbidity and BC treatment.Material and methods: Women with BC and their male partners participated in a longitudinal study (Time 1, ≤4 months after surgery; Time 2, 5 months later). Participants completed items from the PROMIS® Sexual Function and Satisfaction measure (version 1.0), two items measuring affectionate behavior, a single item measuring emotional closeness and the Center for Epidemiologic Studies-Depression Scale. Registers provided sociodemographic and medical information. Multilevel models were used, which take the interdependency of couples’ scores into account.Results: A total of 287 sexually active couples were included in the analyses. Less vaginal discomfort and more vaginal lubrication were associated with increases in patients’ satisfaction with sex life. Patients’ and partners’ satisfaction increased with higher ratings of their own orgasm ability and of partners’ timing of ejaculation. Patients’ reports of affectionate behavior were positively associated with their partners’ satisfaction, and vice versa for partners. Patients’ satisfaction increased the more emotional closeness their partner experienced. Partners’ depressive symptoms were negatively associated with their satisfaction. Sociodemographic factors and BC treatment were not significantly associated with change in satisfaction.Conclusion: Satisfaction with sex life in sexually active couples dealing with BC needs to be seen as a couple issue. Health professionals should take the partner into account when addressing sexuality issues. Couples’ functioning and relationship-related factors may be promising targets for couple interventions.

Background The incidence of inflammatory bowel diseases (IBDs) among immigrants and in countries with historically low IBD risk is rising, implicating environmental risk factors in IBD pathogenesis. The purpose of our study was to determine the incidence rates of Crohn’s disease (CD) and ulcerative colitis (UC), among immigrants to Denmark, a high IBD incidence country, according to the country of birth and age at immigration, in comparison with the corresponding incidence rates in the Danish host population. Methods Using the Danish Civil Registration System, we identified all residents in Denmark with a known country of birth between January 1977 and December 2018. First-generation immigrants were persons who, along with parents, were born outside Denmark; second-generation immigrants were Danish-born persons whose parents were born outside Denmark. We recorded immigrants’ (or parents’) country of birth, age at immigration and duration of stay in Denmark. Study participants were followed for CD and UC diagnosis in the Danish National Patient Registry. Incidence rate ratios (IRRs) according to immigration status were estimated using log-linear Poisson regression analysis, and stratified by IBD prevalence in the country of birth (low, intermediate and high), and among first-generation immigrants, by age at immigration and duration of stay in Denmark. Results In this cohort of 9,038,025 subjects, among 1,295,518 first-generation and 208,826 second-generation immigrants eligible for inclusion, 4,805 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. The risk of IBD among first-generation immigrants reflected risk in the country of birth (low, intermediate or high, Table 1), and increased with >20 years stay in Denmark (Table 2). Among second-generation immigrants, the risk of CD and UC was comparable to that in Danish natives (Table 1). Younger age at immigration did not impact IBD risk. Conclusion In this population-based study, the risk of IBD among first-generation immigrants reflected that in their country of birth, and increased with >20 years stay in Denmark. Among second-generation immigrants, the risk was comparable to native Danes. These findings underscore the role of environmental risk factors in the aetiology of IBD. Further studies to determine risk factors for IBD among immigrants to Denmark are ongoing.

Background Suspected adverse events (AE) after human papillomavirus (HPV) vaccines include postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS), complex regional pain syndrome (CRPS) and symptoms including headache and orthostatic intolerance. Aim We aimed to identify phenotypes of AEs after HPV vaccination, defined as patterns of AE terms (signs, symptoms, diagnoses), and to evaluate if identified phenotypes reflected previously suspected symptomatology or heightened public concerns over HPV vaccine safety since 1 January 2015. Methods We conducted a retrospective observational study using latent class cluster analysis of all serious AE reports (n = 963) reported by females residing in Denmark between September 2009 and August 2017. Resulting clusters were characterised according to AE terms associated with POTS, CFS and CRPS before (September 2009–December 2014) and during (January 2015–August 2017) a time of heightened media activity regarding HPV vaccines. Results Four clusters of AE reports were distinguished. The most common symptoms were fatigue, dizziness and headache but their frequency varied among clusters. The majority of reports in one cluster were submitted during a period of heightened media activity, including an anomalous spike in submissions in December 2015; a high proportion of these reports included the symptoms cognitive disorder (78%), abdominal pain (77%), dysuria (60%) and sleep disorder (60%). Conclusions Non-specific symptoms including headache, fatigue and dizziness feature prominently in serious AE reports from females in Denmark. Our analysis identified a cluster of reports, likely media stimulated, with a focus on symptoms of CFS and POTS.

Objective To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome. Design Population-based self-controlled case series. Setting Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers. Participants 869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16. Main outcome measures Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses. Results During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38, 0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)). Conclusions When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.

Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis.

The 6%–9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%–55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.

Objective Based on converging observations in animal, clinical and ecological studies, we hypothesised a possible impact of ritual circumcision on the subsequent risk of autism spectrum disorder (ASD) in young boys. Design National, register-based cohort study. Setting Denmark. Participants A total of 342,877 boys born between 1994 and 2003 and followed in the age span 0–9 years between 1994 and 2013. Main outcome measures Information about cohort members’ ritual circumcisions, confounders and ASD outcomes, as well as two supplementary outcomes, hyperkinetic disorder and asthma, was obtained from national registers. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with foreskin status were obtained using Cox proportional hazards regression analyses. Results With a total of 4986 ASD cases, our study showed that regardless of cultural background circumcised boys were more likely than intact boys to develop ASD before age 10 years (HR = 1.46; 95% CI: 1.11–1.93). Risk was particularly high for infantile autism before age five years (HR = 2.06; 95% CI: 1.36–3.13). Circumcised boys in non-Muslim families were also more likely to develop hyperkinetic disorder (HR = 1.81; 95% CI: 1.11–2.96). Associations with asthma were consistently inconspicuous (HR = 0.96; 95% CI: 0.84–1.10). Conclusions We confirmed our hypothesis that boys who undergo ritual circumcision may run a greater risk of developing ASD. This finding, and the unexpected observation of an increased risk of hyperactivity disorder among circumcised boys in non-Muslim families, need attention, particularly because data limitations most likely rendered our HR estimates conservative. Considering the widespread practice of non-therapeutic circumcision in infancy and childhood around the world, confirmatory studies should be given priority.

Few studies have addressed the possible association between age at menarche and multiple sclerosis ( MS), and results are conflicting. We studied this issue in a large prospective cohort study. The study cohort comprised 77,330 women included in the Danish National Birth Cohort (1996-2002). Information on menarcheal age was ascertained at the first interview, which took place in the 16th week of pregnancy. Women were followed for MS from the first interview to December 31, 2011. Associations between age at menarche and risk of MS were evaluated with hazard ratios and 95% confidence intervals using Cox proportional hazards regression models. Overall, 226 women developed MS during an average follow-up period of 11.7 years. Age at menarche among women with MS was generally lower than that among women without MS (Wilcoxon rank-sum test; P = 0.002). We observed an inverse association between age at menarche and MS risk. For each 1-year increase in age at menarche, risk of MS was reduced by 13% ( hazard ratio = 0.87, 95% confidence interval: 0.79, 0.96). Early age at menarche appears to be associated with an increased risk of MS. The mechanisms behind this association remain to be established.

Background: Current knowledge concerning the association between exposure to stressful life-events (SFLEs) in childhood and later risk of multiple sclerosis (MS) is sparse. Objectives: We studied the associations between SFLEs in childhood and subsequent risk of MS in a nationwide cohort of 2.9 million Danes born from 1968 to 2011. Methods: A SFLE in childhood was defined as exposure before age 18 years to parental divorce, parental death, or death of a sibling, using information from the Danish Civil Registration System. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models. Results: Persons exposed to any SFLE in childhood were at 11% elevated risk of MS (RR = 1.11; 95% confidence interval: 1.03–1.20), compared to non-exposed persons. Stratification by subtype of SFLE showed that parental death and death of a sibling were not associated with MS risk. However, persons exposed to parental divorce were at 13% increased risk of developing MS compared to non-exposed (RR = 1.13; 1.04–1.23). Conclusions: Associations of SFLEs in childhood with risk of MS are weak. However, parental divorce is somehow associated with modestly increased risk of MS.

The hypothesized link between measles, mumps, rubella (MMR) vaccine and autism continues to cause concern and challenge vaccine uptake. This study finds no association of MMR vaccine and autism in ...

Background The hypothesized link between the measles, mumps, rubella (MMR) vaccine and autism continues to cause concern and challenge vaccine uptake. Objective To evaluate whether the MMR vaccine increases the risk for autism in children, subgroups of children, or time periods after vaccination. Design Nationwide cohort study. Setting Denmark. Participants 657 461 children born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013. Measurements Danish population registries were used to link information on MMR vaccination, autism diagnoses, other childhood vaccines, sibling history of autism, and autism risk factors to children in the cohort. Survival analysis of the time to autism diagnosis with Cox proportional hazards regression was used to estimate hazard ratios of autism according to MMR vaccination status, with adjustment for age, birth year, sex, other childhood vaccines, sibling history of autism, and autism risk factors (based on a disease risk score). Results During 5 025 754 person-years of follow-up, 6517 children were diagnosed with autism (incidence rate, 129.7 per 100 000 person-years). Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02). Similarly, no increased risk for autism after MMR vaccination was consistently observed in subgroups of children defined according to sibling history of autism, autism risk factors (based on a disease risk score) or other childhood vaccinations, or during specified time periods after vaccination. Limitation No individual medical charts were reviewed. Conclusion The study strongly supports that MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination. It adds to previous studies through significant additional statistical power and by addressing hypotheses of susceptible subgroups and clustering of cases. Primary funding source Novo Nordisk Foundation and Danish Ministry of Health.

To investigate whether polymorphisms in genes coding for mannose-binding lectin (MBL) and surfactant protein-D (SP-D) are associated directly or by interaction with smoking with rheumatoid arthritis (RA), anti-citrullinated peptide antibody (ACPA) positive RA, and erosive RA. MBL2 genotypes, SFTPD genotype at codon 11, and HLA-shared epitope were determined in 456 patients with rheumatoid arthritis and 533 sex- and age-matched controls. Patients were grouped according to the presence of ACPA antibodies and RA-associated bone erosions and sub-stratified according to smoking status as never or ever smokers. Odds ratios with 95 % confidence interval (OR, 95 % CI) were calculated using multiple logistic regression analyses controlling for shared epitope. The low-producing SFTPD genotype was not associated with risk of RA or ACPA positive RA, but with erosive disease in the RA patients (OR = 1.8; 95 % CI 1.1–3.0) particularly in RA ever smokers (OR = 2.4; 95 % CI 1.3–4.3). The high-producing MBL2 genotype YA/YA was associated with ACPA positive RA (OR = 1.4; 95 % CI 1.0–1.9) and erosive joint disease in RA ever smokers (OR = 1.8; 95 % CI 1.1–3.0). Genetic disposition for low SP-D was not associated with RA but with erosive RA by interaction with smoking. The genetic disposition for high MBL production was associated with ACPA positive RA irrespective of shared epitope. The findings need to be replicated but do as such offer further explanations for the clinical heterogeneity of RA.

Few population-based studies have investigated the relation between living arrangements and risk of invasive penile squamous cell carcinoma (iP-SCC). Using long-term national cancer registry data in Denmark we examined incidence trends of iP-SCC. Furthermore, we examined the relation between marital status, cohabitation status and risk of iP-SCC using hazard ratios (HRs) with 95% confidence intervals (CIs) obtained in Cox proportional hazards regression analyses as our measure of relative risk. Overall, 1,292 cases of iP-SCC were identified during 65.6 million person-years of observation between 1978 and 2010. During this period, the WHO world age-standardized incidence remained relatively stable (p-trend = 0.41) with an average incidence of 1.05 cases per 100,000 person-years. When compared to married men, those who were unmarried (HR 1.37; 95% CI: 1.13–1.66), divorced (HR 1.49; 95% CI: 1.24–1.79) or widowed (HR 1.36; 95% CI: 1.13–1.63) were at increased risk of iP-SCC. Regarding cohabitation status, single-living men were at increased risk of iP-SCC compared to men in opposite-sex cohabitation (HR 1.43; 95% CI: 1.26–1.62). Risk increased with increasing numbers of prior opposite-sex (p-trend = 0.02) and same-sex (p-trend

Background: Apart from a recent study reporting a 2- to 3-fold increased risk of multiple sclerosis (MS) among women and men who were delivered by Cesarean section (C-section), little attention has been given to the possible association between mode of delivery and the risk of MS. Objectives: We studied the association between C-section and risk of MS, in a cohort of 1.7 million Danes born from 1973 to 2005. Methods: Information on C-section and MS was obtained from the Danish Medical Birth Register and the Danish MS Register, respectively. The association between C-section and MS was evaluated by means of MS incidence rate ratios (RR) with 95% confidence intervals (CI) obtained in log-linear Poisson regression analyses. Results: There were 930 cases of MS in the study cohort, of whom 80 (9%) were delivered by C-section. Overall, we found there was no significant association between C-section and risk of MS (RR = 1.17; 0.92–1.46). Analyses stratified by sex revealed no unusual risk of MS for women (RR = 1.08: 0.80–1.42) nor men (RR = 1.37: 0.91–1.98). A supplementary sibling-matched Cox regression analysis likewise suggested there was no excess risk of MS in persons delivered by C-section (HR = 1.03; 0.63–1.69). Conclusions: Mode of delivery appears to be unimportant in relation to MS development in the offspring.

Background & Aims Treatments for inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) have changed over time, with unclear effects on prognosis. We assessed overall and cause-specific mortality in a Danish cohort of patients with IBD during a 30-year time period. Methods We compared data from 36,080 patients with UC and 15,361 with CD, who were diagnosed in Denmark from 1982 to 2010, and compared them with data from 2,858,096 matched individuals from the general population (controls). Overall and cause-specific mortality were estimated by Cox regression analysis, adjusted for age, sex, disease duration, and known comorbidities before IBD diagnosis. Results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Results Mortality greatly increased in the first year after individuals were diagnosed with IBD; intermediate-term and long-term mortalities increased by approximately 10% among individuals with UC and 50% among those with CD, compared with the general population. Compared with the time period of 1982–1989, overall mortalities decreased among patients diagnosed with UC from 1990 to 1999 (HR, 0.96; 95% CI, 0.90–1.02) and from 2000 to 2010 (HR, 0.88; 95% CI, 0.82–0.95). These reductions were mainly due to decreased mortality from colorectal cancer, gastrointestinal disorders, and suicide. For individuals with CD, mortality did not change among these time periods because of long-term increases in mortality from infections, cancer, respiratory diseases, and gastrointestinal diseases. Conclusions In a Danish cohort, mortality from UC decreased from 1982 to 2010, largely because of reduced mortalities from gastrointestinal disorders and colorectal cancer. People with CD had 50% greater mortality than the general population, and this value did not change during this time period.

Background: It has been suggested that onset of multiple sclerosis (MS) is preceded by a clinically silent period of up to 10 years. Objectives: Examine whether such a period should be associated with poor self-rated health (SRH). Methods: Information on SRH before pregnancy was ascertained among 80,848 women participating in the Danish National Birth Cohort (DNBC) 1996–2002. Women were followed for MS from enrolment in DNBC in the 16th week of pregnancy until 31 December 2011. Associations between SRH and MS were evaluated by means of hazard ratios (HR) with 95% confidence intervals (CIs) using Cox proportional hazard models. Results: During on average 11.7 years of follow-up, 239 women were diagnosed with MS. Overall, neither women with fair (HR = 1.09 (95% CI = 0.83–1.41), n = 113) nor poor pre-pregnancy SRH (HR = 0.94 (95% CI = 0.47–1.87), n = 9) were at an increased risk of MS compared with women reporting very good pre-pregnancy SRH. Supplementary analyses showed no significant differences in MS risk in consecutive periods of follow-up. Conclusion: In this first prospective cohort study assessing MS risk as a function of SRH, we found no indication of a long period of poor SRH prior to MS. Our findings based on pregnant women may not necessarily apply to all women.

Objective.: To provide population-based estimates of relative risk of SLE and other autoimmune diseases (ADs) in relatives of SLE patients.Methods.: A cohort of 5 237 319 Danish residents identified through the Civil Registration System was coupled to their relatives through the parental link and followed for SLE and other ADs between 1977 and 2013 through linkage to the National Patient Register. Twin zygosity was established through the Danish Twin Registry. Hazard ratios (HRs) with 95% CIs were calculated using Cox proportional hazards regression analyses.Results.: During 117.5 million person-years of follow-up, 3612 persons were hospitalized with SLE. HRs of SLE were high among first-degree (HR = 10.3; 95% CI: 8.25, 12.9; n = 80) and second- or third-degree relatives of SLE patients (HR = 3.60; 95% CI: 2.20, 5.90; n = 16). HRs for any AD were elevated in first-degree (HR = 1.51; 95% CI: 1.41, 1.62; n = 785) and second- or third-degree relatives of SLE patients (HR = 1.28; 95% CI: 1.18, 1.39; n = 582). Among individuals with SLE-affected first-degree relatives, the risk was significantly increased for RA (HR = 1.64; 95% CI: 1.35, 1.99; n = 103), IBD (HR = 1.21; 95% CI: 1.02, 1.43; n = 130) and type 1 diabetes mellitus (HR = 1.23; 95% CI: 1.01, 1.48; n = 106). Risk of other ADs was significantly increased both among SLE-affected first-degree (HR = 2.08; 95% CI: 1.88, 2.31; n = 371) and second- or third-degree relatives (HR = 1.38; 95% CI: 1.23, 1.54; n = 313).Conclusion.: Family history of SLE is associated with a clearly elevated risk of SLE and, to a much lesser degree, of RA and other ADs.

Background: Meatal stenosis is markedly more common in circumcised than genitally intact males, affecting 5–20 per cent of circumcised boys. However, no population-based study has estimated the relative risk of meatal stenosis and other urethral stricture diseases (USDs) or the population attributable fraction (AF p) associated with non-therapeutic circumcision. Methods: In two nationwide cohort studies (comprising 4.0 million males of all ages and 810 719 non-Muslim males aged 0–36 years, respectively), we compared hospital contact rates for USD during 1977–2013 between circumcised and intact Danish males. Hazard ratios (HRs) were obtained using Cox proportional hazards regression, and the AF p estimated the proportion of USD cases in

In December of 2014, an anonymous working group under the United States' Centers for Disease Control and Prevention (CDC) issued a draft of the first-ever federal recommendations regarding male circumcision. In accordance with the American Academy of Pediatrics' circumcision policy from 2012 - but in contrast to the more recent 2015 policy from the Canadian Paediatric Society as well as prior policies (still in force) from medical associations in Europe and Australasia - the CDC suggested that the benefits of the surgery outweigh the risks. In this article, we provide a brief scientific and conceptual analysis of the CDC's assessment of benefit versus risk, and argue that it deserves a closer look. Although we set aside the burgeoning bioethical debate surrounding the moral permissibility of performing non-therapeutic circumcisions on healthy minors, we argue that, from a scientific and medical perspective, current evidence suggests that such circumcision is not an appropriate public health measure for developed countries such as the United States.

I read with great interest the recent paper by Crosby et al., in which the authors failed to find any significant difference in the prevalence of HIV (or other sexually transmitted infections) between circumcised and intact young black men who have sex with men (MSM) in the United States [1]. Their findings are in line with those of a 2011 Cochrane review showing no significant association overall between circumcision/foreskin status and HIV infection in MSM, although a subanalysis suggested a possible reduction in HIV risk among circumcised MSM who predominantly take the insertive role during anal sex [2]. However, a subsequent British study found no evidence that circumcision is protective against HIV among MSM who predominantly engage in anal sex as the insertive partner [3]. Crosby et al. highlight an additional, potentially noteworthy finding in their article’s abstract [1]. They report that ‘‘The mean frequency of unprotected insertive anal sex for circumcised men was about twice as high compared to those intact (P = .04).’’ This finding is consistent with evidence from another recent study by Feldblum et al. [4], which pointed to reduced condom use following adult circumcision among a large sample of Kenyan men. Unfortunately, Crosby et al. make no mention anywhere in the main text about this statistically significant finding. Perhaps the authors considered it to be a chance finding because, apparently, it was the only statistically significant result in their study. However, there are reasons why this finding may actually deserve some attention. First, such a result is plausible on anatomical and behavioral grounds. Since circumcision removes the adult equivalent of approximately 50 cm of touch-sensitive tissue (see below), one might expect an overall reduction in penile sensitivity as a function of the surgery. Since condoms tend to decrease penile sensitivity [5], circumcised men may have conscious or unconscious motivations to avoid any further desensitization during sex, which could explain their reduced condom use. Laboratory investigations have sought to determine whether the foreskin is a particularly sensitive penile structure, and have produced conflicting results. Some researchers have provided evidence that the foreskin is the most sensitive part of the penis [6], while others fail to confirm such findings [7]. However, regardless of whether sensitivity per square centimeter is actually higher in the foreskin compared to other parts of the penis, or the foreskin is merely as sensitive as other parts of the sexual organ, the overall sensory input from a circumcised penis during sex will be reduced in a manner that plausibly depends—at least to some extent—on the amount of foreskin removed. The obvious reason for this is that any sensation that would be experienced in the foreskin itself is necessarily eliminated by circumcision [8]. The adult foreskin—with its rich supply of nerve endings and specialized sensory structures [9]—may comprise up to 100 cm, with reported average values between 30 and 50 cm [10, 11]. The contribution of this motile sleeve of erogenous tissue to overall penile sensitivity is not known with certainty. However, any specific qualitative sensation elicited by the mechanical rolling and gliding movements of the foreskin during sexual activity will in fact be absent or reduced in circumcised men [8]. & Morten Frisch mfr@ssi.dk

Objective The possible aetiological link between appendicitis and UC remains unclear. In order to investigate the hereditary component of the association, we studied the risk of UC in family members of individuals with appendicitis. Design A cohort of 7.1 million individuals was established by linkage of national registers in Denmark with data on kinship and diagnoses of appendicitis and UC. Poisson regression models were used to calculate first hospital contact rate ratios (RR) for UC with 95% CIs between individuals with or without relatives with a history of appendicitis. Results During 174 million person-years of follow-up between 1977 and 2011, a total of 190 004 cohort members developed appendicitis and 45 202 developed UC. Individuals having a first-degree relative with appendicitis before age 20 years had significantly reduced risk of UC (RR 0.90; 95% CI 0.86 to 0.95); this association was stronger in individuals with a family predisposition to UC (RR 0.66; 95% CI 0.51 to 0.83). Conclusions Individuals with a first-degree relative diagnosed with appendicitis before age 20 years are at reduced risk of UC, particularly when there is a family predisposition to UC. Our findings question a previously hypothesised direct protective influence of appendicitis on inflammation of the large bowel. Rather, genetic or environmental factors linked to an increased risk of appendicitis while being protective against UC may explain the repeatedly reported reduced relative risk of UC in individuals with a history of appendicitis.

Summary Objective Studies addressing possible socio-demographic and reproductive factors in the aetiology of osteoarthritis (OA) are few. We studied possible influences of educational level, household income, marital status and parenting patterns on OA risk overall and at anatomical sites. Method We linked national register data about socio-demographic variables, reproductive histories and OA hospital contacts to a cohort of 4.6 million Danes. Ratios of first OA hospitalisation rates (RRs) were calculated using Poisson regression. Results Overall, 100,437 women and 92,020 men had a first OA hospital contact during 91.5 million person-years between 1982 and 2008. Short education, low income and married status were significantly associated with increased OA risk, and persons with children were at higher risk of OA overall (RR=1.10 in women; RR=1.22 in men), OA knee (RRs 1.14; 1.28), OA back (RRs 1.18; 1.33), and OA hand (RRs 1.21; 1.43), but not of OA hip (RRs 0.96; 1.00) than persons without children. The RR of OA overall increased by a factor of 1.05 in women and 1.04 in men per additional child, most notably for OA knee in women (1.10 per child). Conclusion Risk of OA hospitalisation was highest among married persons and persons with short education or low income. The similar or even stronger associations with reproductive factors in men than women suggest that unmeasured lifestyle factors rather than biological factors associated with pregnancy might explain the higher OA risk in persons with children. However, the particularly strong association between parity and risk of OA knee in women is compatible with a role of pregnancy-associated factors.

Background It has been suggested that reproductive factors may be involved in the etiology of multiple sclerosis (MS). We studied associations of reproductive history with MS risk in a population-based setting. Methods Using national databases, we established a cohort comprising 4.4 million Danish men and women born between 1935 and 1989 and alive in 1968 or later. We obtained information about their live-born children, pregnancy losses, pregnancy complications, and infertility diagnoses. MS cases in the cohort were identified through 2004 in the Danish Register of Multiple Sclerosis. Associations between reproductive factors and MS risk were evaluated using rate ratios (RRs) obtained in log-linear Poisson regression analysis. Results MS was diagnosed in 6332 women and 3426 men. In both sexes, parents had a lower risk of MS compared with childless persons (in women, RR = 0.76 [95% confidence interval = 0.71-0.82]; in men, 0.89 [0.80-0.98]). RRs were inversely associated with number of children, age at first childbirth, and proximity in time since most recent birth. Among women, MS risk was unrelated to histories of pregnancy loss, pregnancy complications, or infertility. A supplementary analysis in which the date of MS diagnosis was backdated by 5 years to address the possibility of reverse causality did not confirm a protective effect of parenthood (in women, 0.95 [0.88-1.03]; in men, 1.08 [0.98-1.20]). Conclusions Similar findings in women and men argue against a biologic role of pregnancy in the etiology of MS. Moreover, the observed differences in childbearing patterns were restricted to the 5 years before MS diagnosis, suggesting that reverse causality (ie, reduced reproductive activity in persons with yet-undiagnosed MS) might explain the observed associations.

Enteric pathogens have been implicated in the aetiology of inflammatory bowel disease (IBD), but increased rates of stool testing of patients with unclear gastrointestinal symptoms might cause detection bias. Hence, the objective of this study was to analyse incidence rates of Crohn's disease and ulcerative colitis among patients with Salmonella- or Campylobacter-positive and negative stool tests and to study the incidence of positive and negative stool tests among patients already diagnosed with IBD.The Danish population was followed for 94.3 million person-years during 1992-2008 using national registers to identify persons with positive and negative stool tests and patients with IBD. Using Poisson regression, incidence rate ratios (IRRs) for IBD after positive or negative stool tests and, conversely, IRRs for positive and negative stool tests following IBD, were calculated.IRRs for IBD were significantly high in the first year after Salmonella- or Campylobacter-positive stool tests (IRRs 5.4-9.8), and they remained moderately increased 1-10 years later (IRRs 1.6-2.2), and less so10 years later (IRRs 0.8-1.8). However, IRRs for IBD1 year after a negative stool test were several-fold higher (IRRs 53.2-57.5), and a decreasing incidence pattern over time was parallel to that following positive test results. Among patients with IBD, IRRs for subsequent positive and-most notably-negative stool test results were also significantly high.Similarities in temporal risk patterns for IBD following positive or negative stool tests indicate that the increased occurrence of Salmonella- or Campylobacter-positive results around the time of first IBD hospitalisation results from detection bias.

Background The composition of the intestinal microflora has been proposed as an important factor in the development of inflammatory bowel diseases (IBD). Antibiotics have the potential to alter the composition of the intestinal microflora. A study was undertaken to evaluate the potential association between use of antibiotics and IBD in childhood. Methods A nationwide cohort study was conducted of all Danish singleton children born from 1995 to 2003 (N=577 627) with individual-level information on filled antibiotic prescriptions, IBD and potential confounding variables. Using Poisson regression, rate ratios (RRs) of IBD were calculated according to antibiotic use. Antibiotic use was classified according to time since use, type, number of courses used and age at use. Results IBD was diagnosed in 117 children during 3 173 117 person-years of follow-up. The RR of IBD was 1.84 (95% CI 1.08 to 3.15) for antibiotic users compared with non-users. This association appeared to be an effect on Crohn9s disease (CD) alone (RR 3.41) and was strongest in the first 3 months following use (RR 4.43) and among children with ≥7 courses of antibiotics (RR 7.32). Conclusions Antibiotic use is common in childhood and its potential as an environmental risk factor for IBD warrants scrutiny. This is the first prospective study to show a strong association between antibiotic use and CD in childhood. However, as with any observational study, causality cannot be inferred from our results and confounding by indication—in particular, prescribing of antibiotics to children with intestinal symptoms of as yet undiagnosed CD—should also be considered as a possible explanation.

Objectives Elevated levels of serological markers of EBV infection in patients with SLE and observations that infectious mononucleosis (IM) may precede some cases of SLE suggest a possible role of EBV in the aetiology of SLE. We evaluated the relationship between EBV-associated IM and subsequent risk of SLE in a population-based cohort study. Methods We followed cohorts of Danes tested serologically for IM using the Paul-Bunnell (PB) heterophile antibody test between 1939 and 1989, and patients hospitalized with IM between 1977 and 2007 for subsequent first hospitalizations with SLE in the period 1977-2008. Standardized incidence ratios (SIRs) with 95% CI served as measures of relative risk. Results Risk of SLE was not increased either in individuals with a positive PB test (SIR = 1.1; 95% CI 0.8, 1.6; n = 27) or in individuals hospitalized with IM (SIR = 1.3; 95% CI 0.7, 2.2; n = 12). However, SLE risk in PB-negative individuals was significantly increased (SIR = 2.6; 95% CI 2.1, 3.2; n = 82), a risk that was particularly high 1-4 years after the PB test (SIR = 6.6; 95% CI 3.3, 13.2) and remained significantly elevated for >25 years. Conclusions EBV-associated IM does not seem to be a risk factor for SLE. The temporal pattern of increased SLE risk in individuals with a negative PB test suggests that some patients who go on to develop SLE may present with unspecific symptoms, for which they may be tested for IM, long in advance of their SLE diagnosis.

Objective In terms of number of X chromosomes, women with Turner's syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turner's syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with Turner's syndrome is characterized by diseases with a female or male predominance. Methods Using the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798 Danish women with Turner's syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. Results The overall risk of autoimmune disease among women with Turner's syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6–2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turner's syndrome was 1.7 (95% CI 1.2–2.4), whereas the SIR for autoimmune diseases with a male predominance among these women was 3.9 (95% CI 2.5–5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7–27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5–6.3]). Conclusion Women with Turner's syndrome are at excess risk of autoimmune diseases, notably autoimmune diseases characterized by male predominance.

Objectives:While reproductive factors might plausibly be involved in the aetiology of rheumatoid arthritis (RA), the female predominance remains unexplained. A study was undertaken to address the possible impact of live births, pregnancy losses and pregnancy complications on the subsequent risk of RA in a nationwide cohort study.Methods:National register data were used to link reproductive histories and later RA hospitalisations in a cohort of 4.4 million Danes. As a measure of relative risk associated with different reproductive histories, ratios of first inpatient RA hospitalisation rates (RRs) were used with 95% confidence intervals (CIs) obtained by Poisson regression analysis.Results:Overall, 7017 women and 3041 men were admitted to hospital with RA in 1977–2004 (88.8 million person-years). The risk of RA was inversely associated with age at birth of first child in both women and men (p for trend Conclusions:One-child mothers and young parents are at increased risk of RA later in life, possibly due to socioeconomic factors. The novel finding of a significantly increased risk of RA in women whose pregnancies were complicated by hyperemesis, gestational hypertension or pre-eclampsia might reflect reduced immune adaptability to pregnancy in women disposed to RA or a role of fetal microchimerism in the aetiology of RA.

Few etiologic studies of squamous cell carcinoma (SCC) of the penis have been carried out in populations where childhood circumcision is rare. A total of 71 patients with invasive (n = 53) or in situ (n = 18) penile SCC, 86 prostate cancer controls, and 103 population controls were interviewed in a population-based case-control study in Denmark. For 37 penile SCC patients, tissue samples were PCR examined for human papillomavirus (HPV) DNA. Overall, 65% of PCR-examined penile SCCs were high-risk HPV-positive, most of which (22 of 24; 92%) were due to HPV16. Penile SCC risk was positively associated with measures of early and high sexual activity, including lifetime number of female sex partners, number of female sex partners before age 20, age at first intercourse, penile-oral sex, a history of anogenital warts, and never having used condoms. Histories of phimosis and priapism at least 5 years before diagnosis were also significant risk factors, whereas alcohol abstinence was associated with reduced risk. Our study confirms sexually transmitted HPV16 infection and phimosis as major risk factors for penile SCC and suggests that penile-oral sex may be an important means of viral transmission. The association with priapism was unexpected and needs replication. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2683–91)

An unexplained excess of overweight has been reported among lesbians. In contrast, reports suggest that gay men may be, on average, slightly lighter and shorter than heterosexual men. We studied associations between weight, length, and body mass index (BMI) at birth and same-sex marriage in young adulthood among 818,671 Danes. We used linear regression to calculate differences in mean body measures at birth and Poisson regression analysis to calculate confounder-adjusted incidence rate ratios (IRR) of same-sex marriage according to body measures at birth. Overall, 739 persons entered same-sex marriage at age 18–32 years during 5.6 million person-years of follow-up. Birth year-adjusted mean body measures at birth were similar for same-sex married and other women. However, same-sex marriage rates were 65% higher among women of heavy birth weight (IRR = 1.65; 95% CI = 1.18–2.31, for ≥4000 vs. 3000–3499 g, p = .02), and rates were inversely associated with birth length (p trend = .04). For same-sex married men, birth year-adjusted mean weight (−72 g, p = .03), length (−0.3 cm, p = .04), and BMI (−0.1 kg/m2, p = .09) at birth were lower than for other Danish men. Same-sex marriage rates were increased in men of short birth length (IRR = 1.45; 95% CI = 1.01–2.08, for ≤50 vs. 51–52 cm), although not uniformly so (p trend = .16). Our population-based findings suggest that overweight in lesbians may be partly rooted in constitutional factors. Novel findings of smaller average body measures at birth in same-sex marrying men need replication. Factors affecting intrauterine growth may somehow influence sexual and partner-related choices in adulthood.

Background: Bacterial gastrointestinal infections cause considerable morbidity in industrialized countries, but little is known about socioeconomic factors affecting the risk of infection. Methods: By linkage among 3 national registers, we followed the entire population of Denmark (5.3 million people) from 1993 to 2004 for the occurrence of laboratory-confirmed bacterial gastrointestinal infections. Using Poisson regression analyses, incidence rate ratios (IRRs) were estimated for the major groups of bacteria in different socioeconomic strata, focusing on income group, level of education, marital status, number of children in the household, and country of birth. Results: Associations with socioeconomic variables varied by type of bacterium. High-income groups had increased risks of infection with Campylobacter, Shigella, and Salmonella Enteritidis, and education was positively associated with increased risk of infection with Campylobacter and Shigella. Married persons were generally at higher risk than single persons, but adults with children had lower risks compared with adults without children. Foreign-born persons generally had lower risks, whereas Danish-born persons with foreign-born parents were at reduced risk of infection with the pork-associated bacterium Yersinia (IRR = 0.33; 95% confidence interval 0.25–0.42), but increased risk with Shigella (5.7; 4.8–6.1), Salmonella, and Shiga toxin-producing Escherichia coli. Conclusions: The findings suggest that risk of infection is not primarily associated with poverty, but rather with increasing socioeconomic status. Risk of infection also varies with cultural background. Observed differences may be explained by differences in diet and travel activity, although they may also in part reflect differential probabilities of diagnostic reporting.

Objective: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA). Methods: Case–control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein–Barr virus and parvovirus B19. Results: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-α and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein–Barr virus and parvovirus B19 did not differ significantly between case and control sera. Conclusions: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.

The relationship between appendectomy and Crohn's disease is controversial. A Swedish-Danish cohort study was conducted to assess the risk of developing Crohn's disease after an appendectomy.709 353 appendectomy patients in Sweden (since 1964) and Denmark (since 1977) were followed for first hospitalisations for Crohn's disease to 2004. Standardised incidence ratios (SIR) served as relative risks.Overall, 1655 Crohn's disease cases were observed during 11.1 million person-years of follow-up. Whereas appendectomy before the age of 10 years was not associated with the risk of Crohn's disease (SIR 1.00; 95% CI 0.80-1.25), the overall SIR of developing Crohn's disease was 1.52 (95% CI 1.45-1.59), being highest in the first 6 months (SIR 8.69; 95% CI 7.68-9.84). SIR diminished rapidly thereafter, with the risk of Crohn's disease reaching background levels after 5-10 years for Crohn's disease overall, as well as for Crohn's ileitis, ileocolonic Crohn's disease, Crohn's colitis and other/unspecified Crohn's disease. A long-term increased risk of Crohn's disease up to 20 years after the appendectomy was seen only in appendectomy patients without appendicitis or mesenteric lymphadenitis.The transient increased risk of Crohn's disease after an appendectomy is probably explained by diagnostic bias.

Reproductive patterns have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL) in women, and fathering patterns in relation to NHL risk have not been studied. The authors conducted a register-based cohort study of 4.1 million Danes to investigate associations of livebirths with subsequent NHL incidence (85 million person-years, 3819 NHL cases). The impact of induced abortions, ectopic pregnancies, spontaneous abortions, missed abortions, stillbirths, and hydatidiform moles on subsequent NHL incidence was studied in a subcohort of 1.2 million women. Ratios of NHL incidence rates, accompanying trend tests and two-sided p-values were calculated by log-linear Poisson regression analyses. Pregnancies, whether ending in livebirths or not, were unrelated to NHL incidence in women. The only statistically significant finding in women was that, among parous women, age at first child-birth was inversely associated with NHL incidence (p-trend = 0.001). In men, there was no overall difference in NHL incidence between fathers and non-fathers. However, in men with children, NHL risk declined with increasing number of children (p-trend = 0.02) and increased with time since birth of the most recent child (p-trend < 0.001). Pregnancies have limited impact, if any, on subsequent NHL risk in women. Our findings in men need replication, but, if verified, they may reflect lymphomagenesis-associated male subfertility prior to NHL diagnosis.

Multiple sclerosis has been hypothesized to be the result from an aberrant immune response possibly triggered by delayed exposure to a common childhood infection. Because the vast majority of previous studies testing this hypothesis have been based on a history of childhood infections recalled years to decades later in adulthood, we investigated whether age at six common childhood infections was associated with risk of multiple sclerosis, using information recalled in the childhood of a historical cohort of school children in Denmark. Cases included all individuals with multiple sclerosis in the country born between 1940 and 1975, who had attended school in the capital, Copenhagen. Controls were age- and sex-matched peers. School health records were obtained for all subjects. The records contained information on measles, pertussis, scarlet fever, birth order, sibship size, social class of the father, school years, and name of school and attended school classes for children born since 1940 (n(cases) = 455, n(controls) = 1801). For children born since 1950, the records also contained information on rubella, varicella and mumps (n(cases) = 182, n(controls) = 690). Neither age at infection with measles, rubella, varicella, mumps, pertussis and scarlet fever (upper age limit, 14 years) nor the cumulative number of these infections between the ages of 10 and 14 years was associated with the risk of multiple sclerosis. In addition, the risk of multiple sclerosis was not associated with birth order or social class. No clustering of multiple sclerosis in school classes was observed. Our findings suggest that measles, rubella, mumps, varicella, pertussis and scarlet fever, even if acquired late in childhood, are not associated with increased risk of multiple sclerosis later in life.

Cancer patterns among broad populations of homosexual men and women have not been studied systematically. The authors followed 1,614 women and 3,391 men in Denmark for cancer from their first registration for marriage-like homosexual partnership between 1989 and 1997. Ratios of observed to expected cancers measured relative risk. Women in homosexual partnerships had cancer risks similar to those of Danish women in general (overall relative risk (RR) = 0.9, 95% confidence interval (CI): 0.6, 1.4), but only one woman developed cervical carcinoma in situ versus 5.8 women expected (RR = 0.2, 95% CI: 0.0, 0.97). Overall, men in homosexual partnerships were at elevated cancer risk (RR = 2.1, 95% CI: 1.8, 2.5), due mainly to human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (RR = 136, 95% CI: 96, 186) and non-Hodgkin's lymphoma (RR = 15.1, 95% CI: 10.4, 21.4). Anal squamous carcinoma also occurred in excess (RR = 31.2, 95% CI: 8.4, 79.8). After exclusion of Kaposi's sarcoma, non-Hodgkin's lymphoma, and anal squamous carcinoma, no unusual cancer risk remained (RR = 1.0, 95% CI: 0.8, 1.3). With anal squamous carcinoma and HIV/AIDS-associated cancers as notable exceptions in men, cancer incidence rates among homosexual persons in marriage-like partnerships are similar to those prevailing in society at large.

Background. High parity is associated with reduced risk of ovarian cancer. One hypothesis is that pregnancy is associated with clearance of a fraction of the genetically modified (pre-malignant) cells from the ovaries. Methods. We evaluated this hypothesis using a model that estimates the cell clearance fraction at first and second pregnancy according to age at pregnancy. The model was fitted using reproductive history data from a cohort of 1.5 million Danish women born between 1935 and 1978 and followed for 28.7 million person-years. During this follow-up period, 2,035 developed invasive ovarian cancer. Results. We found the model to have a satisfactory fit despite the very few parameters involved. The model estimated similar cell clearance fractions for the first and second pregnancy and decreasing clearance with later age at pregnancy. Conclusion. The relation of pregnancy history to risk of ovarian cancer can be well described by a cell clearance model that allows the cell clearance fraction to decrease with age at pregnancy.

Hepatitis C virus (HCV) infection is highly prevalent in some subpopulations with AIDS. HCV is linked to hepatocellular carcinoma (HCC) and possibly non-Hodgkin lymphoma (NHL), but the impact of AIDS on these associations is uncertain. We used U.S. registry data to study HCC and NHL risk in 304,411 adults with AIDS, comparing cohort subgroups with high prevalence (hemophiliacs and injection drug users) or low prevalence (homosexual men, heterosexuals, and others) of HCV infection. The ratio of observed to expected cancer cases (standardized incidence ratio [SIR]) measured risk relative to the general population. Sixty-one HCC cases were observed (SIR, 7.5; 95% confidence interval, 5.7-9.6). Risk for HCC was higher in subgroups with high prevalence of HCV infection than in subgroups with low prevalence of HCV infection (SIR: 11.4 versus 5.5, respectively; p =.004). Subjects developed the following NHL grades: low, 35 cases; intermediate, 1035 cases; high, 784 cases; and unspecified, 1395 cases. For each NHL grade, SIRs were highest in subgroups with low prevalence of HCV infection. These data suggest an effect of HCV infection on HCC risk among adults with AIDS. On the other hand, NHL risk was not higher for groups in whom HCV infection was prevalent.