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Purpose: We aimed to analyze the risk of hereditary hemochromatosis (HH) among first-generation and second-generation immigrants in Sweden using Swedish-born individuals and Swedish-born individuals with Swedish-born parents as referents, respectively. Methods: All individuals aged 18 years of age and older, n = 6,180,500 in the first-generation study, and n = 4,589,930 in the second-generation study were included in the analyses. HH was defined as at least one registered diagnosis International Classification of Diseases 10th edition (E83.1) in the National Patient Register between January 1, 1998 and December 31, 2018. Cox regression was used to estimate the hazard ratios (HRs) with 99% confidence intervals (CI) owing to multiple testing, of incident HH with adjustments for age, cancer, other comorbidities, and socio-demographics. Results: In the first-generation study, there were 5,112 cases of HH, and in the second-generation study 4,626 cases of HH. The adjusted HRs for first-generation men and women overall were 0.72 (99% CI: 0.63–0.82) and 0.61 (99% CI: 0.52–0.72), respectively, and for the second-generation men and women 0.72 (99% CI: 0.62–0.83) and 0.97 (99% CI: 0.83–1.14), respectively, with a higher risk found only among first-generation men from Western Europe, HR 1.47 (99% CI: 1.05–2.06), compared to the control group. Conclusions: Our findings indicate that the overall risk of HH was lower among both first-generation and second-generation immigrants when compared to individuals born in Sweden or with Swedish-born parents. An elevated risk for HH was observed exclusively among first-generation men originating from Western Europe. These findings represent new knowledge and should be of global interest.

Abstract Background There is increasing evidence implicating hemoglobin/heme and their scavengers in oxidative stress-mediated pathologies, but information is limited in abdominal aortic aneurysm (AAA). Methods and results In this case-control study, we assessed heme/heme-related markers in 142 men with AAA and 279 men with a normal aortic diameter consecutively recruited from an ultrasound screening program in Sweden. Enzyme-linked immunosorbent assays (ELISAs) were used to measure heme oxygenase-1 (HO-1) and hemopexin (Hpx) plasma levels, colorimetric assays for cell-free heme and whole blood hemoglobin (Hb) levels, and droplet digital PCR (ddPCR) and real-time PCR to determine haptoglobin (Hp) (pheno)type and genotype, respectively. Hpx and heme plasma levels at baseline were elevated, while HO-1 levels were lower in men with AAA (p

Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with aging. A relationship between mtDNA-CN and degenerative disorders, e.g. osteoarthritis (OA) and osteoporosis (OP), has been suggested. We aimed to investigate the relationship of mtDNA-CN and incident OA and OP. Materials and methods: MtDNA-CN was studied in relationship to incident OA and OP in a population-based cohort study of 6916 middle-aged women (52–63 years). Totally 2521 women with sufficient quality of mtDNA were analyzed. After exclusions, 1978 women remained in the study population. Four different endpoints obtained from the National Patient register were studied: 1) OA, 2) OP 3) OA surgery, and 4) OP fracture. In the multivariate model adjustments were made for potential OA and OP risk factors. Results: Women with low mtDNA-CN were older and had more activity at work. 125 women (6.32%) were affected by incident OP and 254 women (12.84%) had an OP fracture. Incident OA affected 451 women (22.80%) and 175 women (8.85%) had OA surgery. There were no associations between mtDNA-CN and incident risk of OA (Hazard ratio ​= ​1.00, 95% confidence interval 0.83–1.20), OA surgery (0.79, 0.58–1.07), OP (0.89, 0.62–1.27), or OP fracture (1.00, 0.78–1.29). However, incident OP was significantly associated with T-score (bone density), smoking, diabetes mellitus, and chronic obstructive bronchitis (COPD). OA was associated with body mass index and COPD. Conclusions: The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, is not a major predictor for incident OA or OP. However, due to the limited study size minor associations cannot be excluded.

Abstract INTRODUCTION Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD. METHODS National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all‐cause dementia during 1998–2017 in Sweden, and 3,900,880 age‐ and sex‐matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018. RESULTS Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two‐fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11–2.32) or men with AD (2.68; 2.52–2.85), compared with controls. Similar results were found for all‐cause dementia. DISCUSSION Persons diagnosed with AD or related dementias need close follow‐up for timely detection and treatment of depression. Highlights In a large cohort, women and men with AD had >2‐fold subsequent risk of depression. Risks were highest in the first year (>3‐fold) but remained elevated ≥3 years later. Risk of depression was highest in persons aged ≥85 years at AD diagnosis. Persons with AD need close follow‐up for detection and treatment of depression.

Abstract Backround We wanted to characterize conditional survival in prostate cancer (PC) in Sweden around and after 2005 when the vast increase in incidence due to the opportunistic testing for prostate specific antigen (PSA) culminated. We hypothesize that analyzing survival data during that time period may help interpret survival trends. We focus on stage‐specific analysis using conditional survival in order to define the periods when deaths most commonly occurred. Methods Data on PC patients were obtained from the Swedish cancer registry for analysis of 1‐, 2.5‐ and 5‐year relative survival and conditional relative survival between years 2004 and 2018. Tumor‐node‐metastatic stage classification at diagnosis was used to specify survival. Results Small improvements were observed in stage‐ and age‐related relative survival duriring the study period. Applying conditional relative survival showed that survival in stage T3 up to 2.5 years was better than survival between years 2.5 and 5. Survival in stage T4 was approximately equal in the first and the subsequent 2.5‐year period. For M1, the first 2.5 year survival period was worse than the subsequent one. The proportion of high risk and M1 disease in old patients (80+ years) remained very high and their survival improved only modestly. Conclusions The data indicate that M1 metastases kill more patients in the first 2.5 years than between years 2.5 and 5 after diagnosis; T4 deaths are equal in the two periods, and in T3 mortality in the first 2.5‐year period is lower than between years 2.5 and 5 after diagnosis. Conditional survival could be applied to explore critical survival periods even past 5 years after diagnoses and to monitor success in novel diagnostic and treatment practices. Improvement of survival in elderly patients may require clinical input.

Abstract Background Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage. Methods To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR. Results We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10−12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer. Conclusions Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.

BackgroundAlcohol consumption contributes to excess morbidity and mortality in part through the development of alcohol-related medical conditions (AMCs, including alcoholic cardiomyopathy, hepatitis, cirrhosis, etc.). The current study aimed to clarify the extent to which risk for these outcomes differs as a function of socioeconomic position (SEP), as discrepancies could lead to exacerbated health disparities.Methods and findingsWe used longitudinal Swedish national registries to estimate the individual and joint associations between 2 SEP indicators, educational attainment and income level, and risk of AMC based on International Classification of Diseases codes, while controlling for other sociodemographic covariates and psychiatric illness. We conducted Cox proportional hazards models in sex-stratified analyses (N = 1,162,679 females and N = 1,196,659 males), beginning observation at age 40 with follow-up through December 2018, death, or emigration. By the end of follow-up, 4,253 (0.37%) females and 11,183 (0.93%) males had received an AMC registration, corresponding to overall AMC incidence rates among females and males of 2.01 and 5.20, respectively. In sex-stratified models adjusted for birth year, marital status, region of origin, internalizing and externalizing disorder registrations, and alcohol use disorder (AUD) registration, lower educational attainment was associated with higher risk of AMC in both females (hazard ratios [HRs] = 1.40 to 2.46 for low- and mid-level educational attainment across 0 to 15 years of observation) and males (HRs = 1.13 to 1.48). Likewise, risk of AMC was increased for those with lower income levels (females: HRs = 1.10 to 5.86; males: HRs = 1.07 to 6.41). In secondary analyses, we further adjusted for aggregate familial risk of AUD by including family genetic risk scores for AUD (FGRSAUD), estimated using medical, pharmacy, and criminal registries in extended families, as covariates. While FGRSAUD were associated with risk of AMC in adjusted models (HR = 1.17 for females and HR = 1.21 for males), estimates for education and income level remained largely unchanged. Furthermore, FGRSAUD interacted with income level, but not education level, such that those at higher familial liability to AUD were more susceptible to the adverse effect of low income. Limitations of these analyses include the possibility of false negatives for psychiatric illness registrations, changes in income after age 40 that were not accounted for due to modeling restrictions, restriction to residents of a high-income country, and the inability to account for individual-level alcohol consumption using registry data.ConclusionsUsing comprehensive national registry data, these analyses demonstrate that individuals with lower levels of education and/or income are at higher risk of developing AMC. These associations persist even when accounting for a range of sociodemographic, psychiatric, and familial risk factors. Differences in risk could contribute to further health disparities, potentially warranting increased screening and prevention efforts in clinical and public health settings.

Background Little is known about risks of hypertensive disorders of pregnancy in both first‐ and second‐generation immigrant women in Europe and other Western countries; such knowledge may help elucidate the influence of genetic versus social factors on such risks. We aimed to study both first‐ and second‐generation immigrant women for the presence of all types of hypertension (preexisting hypertension, gestational hypertension, preeclampsia, and eclampsia) during pregnancy. Methods and Results A cohort study was conducted using data derived from the Swedish National Birth Register, the National Patient Register, and the Total Population Register. We used Cox regression analysis to compute hazard ratios (HRs) and 99% CIs while adjusting for sociodemographic factors and comorbidities. The first‐generation study included a total of 1 084 212 deliveries and 68 311 hypertension cases, and the second‐generation study included 989 986 deliveries and 67 505 hypertension cases. The fully adjusted HR (with 99% CI) for hypertension in pregnancy among first‐generation immigrant women was 0.69 (0.66–0.72), and among second‐generation immigrant women, it was 0.88 (0.86–0.91), compared with Swedish‐born women with 2 Swedish‐born parents. Women born in Finland or with parent(s) from Finland had higher risks, with fully adjusted HRs (99% CIs) of 1.30 (1.18–1.43) and 1.12 (1.07–1.17), respectively. Conclusions Both first‐ and second‐generation immigrant women had overall lower risks of hypertension in pregnancy compared with other Swedish women. However, the risk reduction was less pronounced in second‐generation compared with first‐generation immigrant women, suggesting that environmental factors in Sweden may have an important influence on risk of hypertension during pregnancy.

Abstract To examine the risk of post-polio syndrome (PPS) in immigrant groups using native Swedish-born individuals as referents. This is a retrospective study. The study population included all individuals aged 18 years and older registered in Sweden. PPS was defined as having at least one registered diagnosis in the Swedish National Patient Register. The incidence of post-polio in different immigrant groups, using Swedish-born individuals as referents, was assessed by Cox regression, with hazard ratios (HRs) and 99% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, co-morbidities, and neighbourhood socioeconomic status. In total 5300 post-polio cases were registered, 2413 males and 2887 females. Fully adjusted HRs (99% CI) in immigrants versus Swedish-born were 1.77 in men (1.52–2.07) and 1.39 (1.19–1.62) in women. Statistically significant excess risks of post-polio were found in the following subgroups: men and women from Africa, HRs (with 99% CI) 7.40 (5.17–10.59) and 8.39 (5.44–12.95), respectively, and Asia, HRs 6.32 (5.11–7.81) and 4.36 (3.38–5.62) respectively, and in men from Latin America, HR 3.66 (2.17–6.18). It is of importance to be aware of risks of PPS in immigrants settled in Western countries, and that it is more common in immigrants from regions of the world where polio is still prevalent. Patients with PPS need treatment and proper follow-up until polio has been eradicated through global vaccination programs.

Summary: Background: Drug repurposing provides a cost-effective approach to address the need for breast cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR) and then validate the candidate drugs using population-based analyses. Methods: We identified genetic instruments for 1406 actionable targets of approved non-oncological drugs based on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL, respectively). Genome-wide association study (GWAS) summary statistics were obtained from the Breast Cancer Association Consortium (122,977 cases, 105,974 controls). We further conducted a nested case–control study using data retrieved from Swedish registers to validate the candidate drugs that were identified from MR analyses. Findings: We identified six significant MR associations with gene expression levels (TUBB, MDM2, CSK, ULK3, MC1R and KCNN4) and two significant associations with gene methylation levels across 21 CpG islands (RPS23 and MAPT). Results from the nested case–control study showed that the use of raloxifene (targeting MAPT) was associated with 35% reduced breast cancer risk (odds ratio, OR, 0.65; 95% confidence interval, CI, 0.51–0.83). However, usage of estradiol, tolterodine, and nitrofurantoin (also targeting MAPT) was associated with increased breast cancer risk, with adjusted ORs and 95% CI of 1.10 (1.07–1.13), 1.16 (1.09–1.24), and 1.09 (1.05–1.13), respectively. The effect of raloxifene and nitrofurantoin lost significance in further validation analyses using active-comparator and new-user design. Interpretation: This large-scale MR analysis, combined with population-based validation, identified eight druggable target genes for breast cancer and suggested that raloxifene is an effective chemoprevention against breast cancer. Funding: Swedish Research Council, Cancerfonden, Crafoordska Stiftelsen, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, 111 Project and MAS cancer.

ABSTRACTBackground: There are two primary phenotypic models of comorbidity between post-traumatic stress disorder (PTSD) and drug use disorder (DUD), i.e. self-medication (PTSD precedes and causes DUD) and susceptibility (DUD precedes and causes PTSD). We sought to clarify the longitudinal relationship between PTSD and DUD, while examining sex differences.Method: We used approximately 23 years of longitudinal data from Swedish population registries to conduct two complementary statistical models: Cox proportional hazard models (N ≈ 1.5 million) and a cross-lagged panel model (N ≈ 3.8 million).Results: Cox proportional hazards models, adjusting for cohort and socioeconomic status, found strong evidence for the self-medication hypothesis, as PTSD predicted increased risk for DUD among both women [hazard ratio (HR) = 5.34, 95% confidence interval (CI) 5.18, 5.51] and men (HR = 3.65, 95% CI 3.54, 3.77), and moreover, that the PTSD to DUD association was significantly higher among women (interaction term 0.68, 95% CI 0.65, 0.71). The results of the susceptibility model were significant, but not as strong as the self-medication model. DUD predicted risk for PTSD among both women (HR = 2.43, 95% CI 2.38, 2.50) and men (HR = 2.55, 95% CI 2.50, 2.60), and HR was significantly higher in men (interaction term 1.05, 95% CI 1.02, 1.08). Investigating the pathways simultaneously in the cross-lagged model yielded support for both pathways of risk. The cross-paths instantiating the susceptibility model (0.10–0.22 in females, 0.12–0.19 in males) were mostly larger than those capturing the self-medication model (0.01–0.16 in females, 0.04–0.22 in males).Conclusions: We demonstrate that the relationship between PTSD and DUD is bidirectional, with evidence that future research should prioritize examining specific pathways of risk that may differ between men and women.

Abstract Background Drug Use Disorder (DUD) is a major contributor to world-wide morbidity and mortality. The extensive national registers in Sweden provide the basis for a study of spatial and temporal patterns of DUD onset and recurrence in Sweden from 2001–2015. Methods To identify patterns of DUD over space, time and gender for Swedish individuals aged 15–35, space–time clustering using SaTScan was applied. We used yearly information on residential locations in Demographic Statistical Areas (DeSO) for all of Sweden. The clustering analysis used a Poisson probability model and a null hypothesis that the expected number of cases in each DeSO was proportional to the population size of DeSOs. As SaTScan results can be unstable, steps were taken to determine stable clusters and to refine and optimize cluster size. Results for each gender-register combination were compared to the results of spatial clustering using Gi* statistics. The space–time scanning model was also run with an adjustment for neighborhood socioeconomic status to determine DUD prevalence as it relates to education, income, unemployment and receipt of social welfare. Results DUD prevalence increased over time. Males yielded more significant clusters than females for both criminal and medical registers. Female DUD prevalence rates increased over time, especially after 2012. Higher correlations in DUD rates existed across the two registers than across gender. Male clusters were present from 2004 onwards while female–criminal clusters appeared after 2007, and female–medical clusters not until 2010. By 2013, clusters existed for all gender–register combinations. Male–criminal clusters were concentrated in Stockholm, Göteborg and Malmö as were male and female-medical clusters. Neighborhood SES was more highly related to the distribution of criminal than medical DUD clusters. A persistent gap in core clusters was identified in Stockholm in an area with notably high SES. Conclusions Persistent hotspots of DUD in Sweden were confirmed as well as new and emerging hotspots, especially in Stockholm, Göteborg and Malmö. Higher correlations existed in DUD rates across registers than across gender. The findings are useful for monitoring the current drug problem and for identifying drivers underlying patterns of spread and important causal pathways to DUD.

Abstract Background The ability of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to decrease certain microvascular events has called for the investigation of GLP-1 RAs against diabetic retinopathy (DR), but the evidence is limited. By combining data from observational and Mendelian randomization (MR) studies, we aimed to investigate whether GLP-1 RAs decrease the risk of DR. Methods We combined data from several Swedish Registers and identified patients with incident type 2 diabetes being treated with GLP-1 RAs between 2006 and 2015, and matched them to diabetic patients who did not use GLP-1 RAs as the comparisons. The Cox proportional hazards models were applied to assess the risk of DR. We further performed the summary-data-based MR (SMR) analyses based on the Genotype-Tissue Expression databases and the Genome-Wide Association Study of DR from the FinnGen consortium. Results A total of 2390 diabetic patients were treated with GLP-1 RAs and the incidence of DR was 5.97 per 1000 person-years. Compared with diabetic patients who did not use GLP-1 RAs having an incidence of 12.85 per 1000 person-years, the adjusted hazard ratio (HR) of DR was 0.42 [95% confidence interval (CI), 0.29–0.61]. Genetically-predicted GLP1R expression (the target of GLP-1 RAs) showed an inverse association with background [odds ratio (OR)=0.83, 95% CI, 0.71–0.97] and severe nonproliferative DR (OR=0.72, 95% CI, 0.53–0.98), and a non-significant association with overall (OR=0.97, 95% CI, 0.92–1.03) and proliferative DR (OR=0.98, 95% CI, 0.91–1.05). Conclusions Both observational and mendelian randomization analyses showed a significantly lower risk of DR for patients treated with GLP-1 RAs, which calls for further studies to validate these findings.

Abstract Aims This study aims to determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first‐degree, second‐degree, and third‐degree relatives of affected individuals. Methods and results In this population‐based multigenerational cohort study, full‐siblings, half‐siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included, and register‐based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6 334 979 subjects and consisted of 5 577 449 full‐siblings, 1 321 414 half‐siblings, and 3 952 137 cousins. Overall, 10 272 (0.16%) unique individuals were diagnosed with DCM and 3769 (0.06%) with HCM. Of these, 7716 (75.12%) and 2375 (63.01%) were males, respectively. Familial risk ORs for DCM were 5.35 [95% confidence intervals (CI): 4.85–5.90] for full‐siblings, 2.68 (95% CI:1.86–3.87) for half‐siblings, and 1.72 (95% CI:1.12–2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95% CI:37.66–47.82) for full‐siblings, 32.70 (95% CI:21.32–50.15) for half‐siblings, and 36.96 (95% CI:29.50–46.31) for cousins of affected individuals. In sex‐stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. Conclusions Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.

Objectives Vasospastic angina (VSA) is a complex coronary vasomotor disorder associated with an increased risk of myocardial infarction and sudden death. Despite considerable advances in understanding VSA pathophysiology, the interplay between genetic and environmental factors remains elusive. Accordingly, we aimed to determine the familial VSA risk among first-degree relatives of affected individuals.Methods A population-based multigenerational cohort study was conducted, including full-sibling pairs born to Swedish parents between 1932 and 2018. Register-based diagnoses were ascertained through linkage to the Swedish Multigeneration Register and National Patient Register. Incidence rate ratios (IRRs) and adjusted HRs were calculated for relatives of individuals with VSA compared with relatives of individuals without VSA.Results The total study population included 5 764 770 individuals. Overall, 3461 (0.06%) individuals (median age at disease onset 59 years, IQR: 63–76) were diagnosed with VSA. Of these, 2236 (64.61%) were women. The incidence rate of VSA for individuals with an affected sibling was 0.31 (95% CI: 0.24 to 0.42) per 1000 person-years compared with 0.04 (95% CI: 0.04 to 0.04) per 1000 person-years for those without an affected sibling, yielding an IRR of 7.58 (95% CI: 5.71 to 10.07). The risk of VSA for siblings with an affected sibling was significantly increased in the fully adjusted model (HR: 2.56; 95% CI: 1.73 to 3.79). No increased risk of VSA was observed in spouses of affected individuals (HR: 0.63; 95% CI: 0.19 to 2.09).Conclusions In this nationwide family study, we identified high familial risk for VSA independent of shared environmental risk factors. Our findings indicate that VSA tends to cluster in families, emphasising the need to explore genetic and non-genetic factors that may contribute.

Abstract Purpose We aimed to analyze the risk of cardiomyopathies (CMPs) among first-generation and second-generation immigrants. Methods All individuals aged 18 years of age and older, n = 6,123,661 in the first-generation study, and n = 4,587,764 in the second-generation study were analyzed. CMP was defined as at least one registered diagnosis in the National Patient Register between January 1, 1998 and December 31, 2018. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 99% confidence intervals (CI)) of incident CMP with adjustments made for age, cancer, other comorbidities, and sociodemographic factors. Results In the first-generation study, a total of 33,321 CMP cases were registered, 20,780 men and 12,541 women, where the fully adjusted models showed HRs (99% CI) for all foreign-born men of 0.92 (0.86–0.98) and for women of 0.90 (0.83–0.98). For dilated CMP, the risk was higher for men from Nordic countries, more specifically men from Finland, and lower for men and women from Asia. For hypertrophic CMP, the risk was higher for men from Africa and Asia. For other types of CMPs, the risk was lower in men and women from Asia. In the second-generation study, a total of 26,559 cases were registered (17,620 men and 8939 women), with no significant differences overall or among specific groups, when Swedish-born with foreign-born parents were compared to Swedish-born with Swedish-born parents. Conclusions We observed a generally lower risk of CMPs among foreign-born individuals, but with a higher risk especially for hypertrophic CMPs for men from Africa and Asia, and a higher risk of dilated CMP for men from Nordic countries.

Abstract Background Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking. Methods By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62–0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81). Conclusions This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.

Abstract The aim was to study the potential effect of neighborhood deprivation on incident and fatal coronary heart disease (CHD) in patients with bipolar disorder. This was a nationwide cohort study which included all adults aged 30 years or older with bipolar disorder (n = 61,114) in Sweden (1997–2017). The association between neighborhood deprivation and the outcomes was explored using Cox regression analysis, with hazard ratios (HRs) and 95% confidence intervals (CIs). Patients with bipolar disorder living in neighborhoods with high or moderate levels of deprivation were compared with those living in neighborhoods with low deprivation scores. There was an association between level of neighborhood deprivation and incident and fatal CHD among patients with bipolar disorder. The HRs were 1.24 (95% CI 1.07–1.44) for men and 1.31 (1.13–1.51) for women for incident CHD among patients with bipolar disorder living in high deprivation neighborhoods compared to those from low deprivation neighborhoods, after adjustments for potential confounders. The corresponding HR for fatal CHD were 1.35 (1.22–1.49) in men and 1.30 (1.19–1.41) in women living in high deprivation neighborhoods. Increased incident and fatal CHD among patients with bipolar disorder living in deprived neighborhoods raises important clinical and public health concerns.

Abstract Background Aggregation of lung cancer (LCa) in family members is well-documented. However, little is known on the familial risk of LCa when first-degree relatives (FDRs, parents or siblings) are diagnosed with LCa as a second primary malignancy (LCa-2). We aimed to investigate whether and to what extent a family history of LCa-2 was associated with an increased LCa risk. Methods In this Swedish national cohort we identified 127,865 individuals who had one FDR affected by LCa as a first primary cancer (LCa-1) and 15,490 individuals who had one FDR affected by LCa-2, respectively. We then estimated relative risk (RR) of LCa using those without cancer family history as reference. Results The number of LCa-2 has been increasing annually and rather similarly in men and women in the last decade. Familial RR of LCa was 1.96 (95%, 1.85–2.07) for LCa-1 family history and 1.89 for LCa-2 (1.62–2.21). Risk was especially high when FDR was diagnosed with early-onset LCa-2 and when siblings were affected by LCa-2. The RR was 1.53 (1.10–2.12) when LCa-2 in FDR was diagnosed within 26 months after first primary cancer, and it increased to 2.16 (1.62–2.90) when LCa-2 was diagnosed between 74 to 154 months. Higher risk was observed for first primary cancer of the ovary (4.45, 1.85–10.7), nervous system (3.49, 1.45–8.38), upper aerodigestive tract (2.83, 1.78–4.49) and cervix (2.55, 1.41–4.61), and for non-Hodgkin lymphoma (3.13, 1.57–6.27). Conclusions LCa risk is associated with diagnosis of LCa-2 in FDR to a similar degree as LCa-1 in FDRs.

Abstract Background Adolescents are reporting increasing symptoms of anxiety, depression and somatization and an increase in perceived stress is a plausible explanation. The first aim of this study was to examine the occurrence of perceived stress and health outcomes in adolescents, and to evaluate if there are any sex differences. The second aim was to investigate if there is an association between perceived stress and the health outcomes and, if so, possible gender differences in this association. The third aim was to compare samples of adolescent girls and boys from two different European countries to enhance the generalizability of potential findings. Methods The sample included 636 students from Sweden and Bulgaria, aged 15–16, 164 (58% males, 41% females, 1% not specified) from Sweden and 472 (71% males, 28% females, 1% not specified) from Bulgaria. Perceived stress and health outcomes were measured by the 14-item “Perceived Stress Scale” (PSS-14), and a shorter version of the questionnaire "Children and Young People in Skåne" (Folkhälsoenkäten, FHE), respectively. T-test and Chi2 and/or Fisher’s exact test was used to compare results between boys and girls from the PSS-14 and health outcomes. The association between PSS and the health outcomes was assessed using Spearman’s rank correlation and comparisons between boys and girls were calculated using linear regression. Results There were significant associations between perceived stress and psychiatric symptoms in all groups. Adolescent girls in both Sweden and Bulgaria consistently reported higher levels of perceived stress and more psychiatric and somatic symptoms than the boys. Conclusions Evaluating methods for lessening the perception of stress, and their clinical presentation, should be considered in order to reduce the occurrence of psychiatric symptoms in adolescents.

Abstract Background Increasing number of individuals will have first-degree relatives (FDRs) diagnosed with colorectal cancer (CRC), as a second primary malignancy (CRCa-2) after a non-CRC cancer. We aimed to estimate whether and to what extent a family history of CRCa-2 is associated with an increased CRC risk. Methods In this Swedish nationwide cohort study, rate ratio (RR) and cumulative incidence of CRC were estimated among 172,531 individuals with a family history of CRC as a first primary malignancy (CRCa-1) and 17,830 with a family history of CRCa-2, respectively, using individuals without cancer family history as the reference group. Results A cumulative incidence of CRC by age 80 was 6.3 and 5.6% for individuals with a parental and a sibling family history of CRCa-2, respectively. RRs of CRC for one FDR diagnosed with CRCa-1 and CRCa-2 were respectively 1.72 (95% CI, 1.65–1.79) and 1.50 (1.32–1.70); the latter RR was lower than the former (P = 0.0356), but no difference was observed after adjusting age of diagnosis of CRC in FDR and family relationship (P = 0.6898). Increased RRs were found to be associated with a CRCa-2 diagnosis in FDR that occured after cancers in upper aerodigestive tract, breast, prostate, kidney and nervous system. Conclusions Individuals who have relatives with CRCa-2 have an increased risk of CRC, but the magnitude is lower than those having relatives with CRCa-1, which is related to different ages of diagnosis of CRC in FDR and family relationships.

Objectives Venous thromboembolism (VTE) is a common worldwide disease. The burden of multimorbidity, that is, two or more chronic diseases, has increased. Whether multimorbidity is associated with VTE risk remains to be studied. Our aim was to determine any association between multimorbidity and VTE and any possible shared familial susceptibility.Design A nationwide extended cross-sectional hypothesis - generating family study between 1997 and 2015.Setting The Swedish Multigeneration Register, the National Patient Register, the Total Population Register and the Swedish cause of death register were linked.Participants 2 694 442 unique individuals were analysed for VTE and multimorbidity.Main outcomes and measures Multimorbidity was determined by a counting method using 45 non-communicable diseases. Multimorbidity was defined by the occurrence of ≥2 diseases. A multimorbidity score was constructed defined by 0, 1, 2, 3, 4 or 5 or more diseases.Results Sixteen percent (n=440 742) of the study population was multimorbid. Of the multimorbid patients, 58% were females. There was an association between multimorbidity and VTE. The adjusted odds ratio (OR) for VTE in individuals with multimorbidity (2 ≥ diagnoses) was 3.16 (95% CI: 3.06 to 3.27) compared with individuals without multimorbidity. There was an association between number of diseases and VTE. The adjusted OR was 1.94 (95% CI: 1.86 to 2.02) for one disease, 2.93 (95% CI: 2.80 to 3.08) for two diseases, 4.07 (95% CI: 3.85 to 4.31) for three diseases, 5.46 (95% CI: 5.10 to 5.85) for four diseases and 9.08 (95% CI: 8.56 to 9.64) for 5 ≥ diseases. The association between multimorbidity and VTE was stronger in males OR 3.45 (3.29 to 3.62) than in females OR 2.91 (2.77 to 3.04). There were significant but mostly weak familial associations between multimorbidity in relatives and VTE.Conclusions Increasing multimorbidity exhibits a strong and increasing association with VTE. Familial associations suggest a weak shared familial susceptibility. The association between multimorbidity and VTE suggests that future cohort studies where multimorbidity is used to predict VTE might be worthwhile.

Background Abdominal aortic aneurysm (AAA) is a vascular disease with a mortality rate of >80% if ruptured. Mitochondrial dysfunction has been previously implicated in AAA pathogenesis. In this study, we aimed to characterize the mitochondrial genetic landscape in AAA. Methods and Results Whole mitochondrial genome sequencing and bioinformatics analysis were performed in comorbidity matched 48 cases without AAA and 48 cases with AAA, objectively diagnosed, and selected from a cohort of 65‐year‐old men recruited for a screening program. We identified differential mutational landscapes in men with and without AAA, with errors in mitochondrial DNA replication or repair as potential sources. Heteroplasmic insertions and overall heteroplasmy of structural rearrangements were significantly elevated in AAA cases. Three heteroplasmic variants were associated with risk factors of AAA: leukocyte concentration, plasma glucose, and cholesterol levels, respectively. Interestingly, mutations were more prevalent in regulatory part of the mitochondria, the displacement loop region, in AAA as compared with controls (P value

Abstract Objectives To investigate if the risk of prostate cancer (PC) differs based on the order of primary PC diagnosed in first‐degree relatives (FDRs) given possibly different risk factors for PC as first primary cancer (PCa‐1) and second primary cancer (PCa‐2). Subjects and Methods In this Swedish nationwide cohort, PC diagnosis was followed for among 149,985 men with one FDR affected by PCa‐1, 10,972 with one FDR affected by PCa‐2 and 2,896,561 without any FDRs affected by cancer in a maximum of 57 years. PC patients were further followed for death due to PC since diagnosis. Relative risk (RR) of PC was estimated with Poisson regression and hazard ratio (HR) with Cox proportional hazard model. Results Compared to men without any FDRs affected by cancer, the RRs of PC in men with one FDR affected by PCa‐1 and PCa‐2 were 2.12 (95% confidence interval [CI]: 2.07–2.17) and 1.69 (1.54–1.85), respectively. The risk in men with one FDR affected by PCa‐2 was significantly lower than those with one FDR affected by PCa‐1 after additionally adjusting for family relationship (father‐son and brothers) and age at diagnosis of PC in FDR (RR PCa‐2 vs PCa‐1, 0.85, 95% CI, 0.78–0.94). PC patients with a family history of PCa‐2 were more likely to be detected at late‐stage and less likely to be diagnosed by screening, compared to those with a family history of PCa‐1. Patients whose PC was diagnosed after the diagnosis of PCa‐1 in FDRs had a better survival than those without a family history of cancer (HR, 0.88, 95% CI, 0.80–0.97), but no such association was observed among patients with a family history of PCa‐2. Conclusion Our study indicates a discrepancy between PC risks associated with a family history of PCa‐1 and PC‐2 and the reason behind it may be multifactorial.

Summary: Background: Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences. Methods: Summary statistics from 18 common cancers (2107–491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000–31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers. Findings: We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49–0.83; P = 9.77 × 10−7), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03–1.07; P = 5.24 × 10−6) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03–1.09; P = 1.01 × 10−5), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk. Interpretations: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention. Funding: This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).

Summary: Background: The diagnosis of paediatric cancer is a crisis for the parents who are the primary caregivers of the affected child. A comprehensive assessment of the longitudinal impact of childhood cancer on parental mental health and the potential sex differences between the parents is lacking. Thus, we aimed to explore the subsequent short- and long-term mental health outcomes among the parents of children with cancer and examine whether the outcomes vary between the mother and father. Methods: By combining several Swedish registers, parents of a child (ages 0–14 years) with a cancer diagnosis between Jan 1, 2006, and Dec 31, 2016 were identified. For each parent of children with cancer, up to five mothers or fathers of cancer-free children were randomly selected and matched, respectively. Hospital contacts for any mental health disorders between 5 years before and 7 years after the diagnosis of childhood cancer were retrieved. An interrupted time series negative binomial regression was performed to assess the short- and long-term impact of a childhood cancer diagnosis on the parents’ subsequent mental health outcomes. Findings: 16,199 mothers (2852 with a child with cancer and 13,347 without) and 15,708 fathers (2769 with a child with cancer and 12,939 without) were included in this study. Compared with mothers of children without cancer, mothers of children with cancer had higher risks of mental health disorders in the first year after diagnosis (rate ratio [RR] and 95% Confidence Interval [CI], 1.17 (1.03–1.32)), and notably, the adverse impact became more severe over time (RR and 95% CI, 1.36 (1.07–1.74), in the seventh year). For fathers of children with cancer, the risk of mental health disorders was continuously higher compared to matched comparisons (RR and 95% CI, 1.31 (1.01-1.71)). Interpretation: Our findings suggested that parental mental health was affected continuously by a diagnosis of childhood cancer in their children. In particular, the mother's mental health was affected more severely. Customised psychological services or interventions are highly needed for the parents of children with cancer. Funding: Swedish Research Council, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, Swedish Heart-Lung Foundation, ALF funding from Region Skåne and China Scholarship Council.

Abstract Background Current evidence regarding the association of serum zonulin-related proteins (ZRP) levels with prevalent inflammatory bowel disease (IBD) is contradictory. Moreover, the association with the subsequent risk of incident IBD is still unexplored. This study aimed to investigate the association of serum ZRP levels with both prevalent and incident IBD. Method The study included a total of 130 women (51–61 years) from the Women’s Health in Lund Area (WHILA) study, which included 18 prevalent IBD (diagnosed before baseline) and 47 incident IBD diagnosed during the 17 years (median) follow-up and age- and sampling time-matched controls. Serum ZRP was tested in all participants by ELISA. Results The serum ZRP levels were significantly higher in prevalent IBD compared to their matched controls (63.2 ng/ml vs 57.0 ng/ml, p = 0.02), however, no evidence of a difference in ZRP levels was found between the women who developed IBD during the follow-up period and their matched controls (61.2 ng/ml vs 59.7 ng/ml, p = 0.34). Using linear mixed models, we found that the association between serum ZRP levels and prevalent IBD (β = 6.2, p = 0.01), remained after adjusting for potential confounders. Conditional logistic regression models showed no evidence of an association between ZRP level and incident IBD (OR 1.03, p = 0.34). Conclusion Higher serum ZRP levels were associated with prevalent IBD, but not with incident IBD in our study samples.

Abstract Background Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD. Methods In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women’s Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of developing MDD among individuals with different levels of miRNA expression. Results Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for developing MDD (OR = 0.33, p = 0.03, 95% CI = 0.12–0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis

Abstract Background With the increasing number of breast cancer (BC) diagnosed as a second primary malignancy after a first primary non-breast cancer (BCa-2), it is unclear about the familial risk of BC among women with a first-degree relative (FDR, parents or siblings) affected by a BCa-2. Methods In this Swedish nationwide cohort study, 5315 women with a FDR affected by BCa-2 and 115,048 women with a FDR affected by BC as the first primary cancer (BCa-1) were followed for the first primary invasive BC diagnosis. Relative risk (RR) of BC was estimated through Poisson regression by using 2,743,777 women without a family history of cancer as reference. The risk was stratified by the diagnostic age of BC in FDR, proband type, the time interval between the first primary cancer and BCa-2 in FDR as well as the site of first primary cancer diagnosed in FDR before BCa-2. We also calculated the cumulative incidence of BC from birth to a specific age for the three groups. Results The cumulative incidence from birth to age 70 was 10% among women with a family history of BCa-2. The RR of BC with a family history of BCa-2 (RR, 1.68, 95%CI, 1.49 to 1.88) was comparable to that with BCa-1 (1.68, 1.63 to 1.73). The risk was largely consistent irrespective of proband type. The age of onset of BCa-2 in FDR (RR early-onset, 1.72 vs. RR late-onset 1.67) had less influence on the risk compared to BCa-1 in FDR (1.89 vs. 1.63). In the analysis stratified by the time between the first primary cancer and BCa-2 in relatives, the risks were largely similar. For the site of first primary cancer diagnosed in FDR before BCa-2, the increased BC risk was found in women whose FDRs were diagnosed with first primary gastric, colorectal, endometrial, ovarian, nervous system and endocrine gland cancers, and non-Hodgkin lymphoma. Conclusions Women with a family history of BCa-2 have a similar overall BC risk as those with a family history of BCa-1. The risk varied according to the site of first primary cancer diagnosed in FDR before BCa-2.

Abstract Background Favorable survival in malignant cutaneous melanoma (melanoma) has increased the likelihood of second primary cancer (SPC). We assess the influence of patient characteristics at diagnosis of first melanoma and the type of SPC (second melanoma and other SPC) on overall survival. Methods We used the Swedish Cancer Registry data to assess overall survival in melanoma for the period 1990 to 2015. Kaplan-Meier curves were plotted and hazard ratios (HRs) were estimated with Cox regression models by considering SPC diagnosis as a time-dependent variable. Results A total of 46,726 patients were diagnosed with melanoma, and 15.3% of them developed SPC, among which, two thirds were other SPCs. Second melanomas were diagnosed early (31% during the first year) compared to non-melanoma SPCs (9.5%). Survival for women with second melanoma or other SPC (56 and 21% alive after 25 years of follow-up, respectively) exceeded the male rates (21 and 10%, respectively) but all these figures were lower than for females (60% alive) or males (48%) without SPC. Time dependent analysis showed vastly increased HRs for cancer types that are fatal also as first cancers, but SPC-specific HRs remained relatively uniform, irrespective of SPC diagnosed soon or late after first melanoma. In early-onset melanoma, SPC diagnosis after 10 years may not negatively influence overall survival. Conclusions As the overall survival of patients with many types of SPCs is unfavorable, advice about health lifestyle should benefit smoking patients and early detection methods may be recommended for SPCs of the breast, prostate and colorectum.

Heart failure (HF) is a leading cause of death in both men and women. However, risk factors seem to differ for men and women and significant gaps in sex-specific knowledge exist. Mitochondria are critical for cardiomyocytes and in this study, we investigated the role of baseline mitochondrial DNA copy number (mtDNA-CN) in HF incidence in middle-aged women and its possible role in the association between myocardial infarction (MI) and HF. Finally, we also investigated whether baseline mtDNA-CN was associated with overall and HF mortality. Baseline levels of mtDNA-CN were quantified by droplet digital PCR in a population-based follow-up study of middle-aged (50–59 years) Swedish women (n = 2,508). The median follow-up period was 17 years. Levels of mtDNA-CN were associated with age, BMI, alcohol, smoking, education, physical activity and lipid biomarkers. Multivariable Cox regression analysis adjusted for potential confounders showed that each standard deviation decrease of baseline mtDNA-CN was associated with higher incidence of HF (HR = 1.34; 95% CI=1.11–1.63). Similar results were obtained when mtDNA-CN levels were categorized into quartiles with lowest vs. highest quartile showing the highest risk of HF incidence (HR = 2.04 95% CI=1.14; 3.63). We could not detect any role of mtDNA-CN in the association between MI and HF incidence. Lower baseline mtDNA-CN levels were associated with both overall (HR = 1.27; 95% CI=1.10–1.46) and HF mortality (HR = 1.93; 95% CI=1.04–3.60); however, in multivariable analysis adjusted for potential confounders, the higher risks of HF mortality were no longer significant (HR=1.57; 95% CI=0.85–2.90). In conclusion, low baseline mtDNA-CN is an easily quantifiable molecular risk factor for HF incidence and may be a risk factor for overall and HF-related mortality.

Abstract Background Opioid overdose (OD) and opioid OD death are major health threats to people with opioid use disorder (OUD). Socioeconomic factors are underexplored potential determinants of opioid OD. In this study, we assessed socioeconomic and other factors and their associations with incident and fatal opioid OD, in a cohort consisting of 22,079 individuals with OUD. Methods We performed a retrospective, longitudinal study based on Swedish national register data for the period January 2005–December 2017. We used Cox proportional hazard models to investigate the risk of incident and fatal opioid OD as a function of several individual, parental and neighborhood covariates. Results Univariate analysis showed that several covariates were associated with incident and fatal opioid OD. In the multivariate analysis, incident opioid OD was associated with educational attainment (Hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.94–0.97), having received social welfare (HR 1.31; 95% CI 1.22–1.39), and criminal conviction (HR 1.53; 95% CI 1.42–1.65). Fatal opioid OD was also associated with criminal conviction (HR 1.93; 95% CI 1.61–2.32). Conclusion Individuals with low education and receipt of social welfare had higher risks of incident opioid OD and individuals with criminal conviction were identified as a risk group for both incident and fatal opioid OD. Our findings should raise attention among health prevention policy makers in general, and among decision-makers within the criminal justice system and social services in particular.

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia, while the other types, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) are much rarer. While data on familial risks for childhood ALL have been emerging, such data for the other childhood leukemias are hardly available. We aim to fill in the gap of knowledge by assessing familial clustering of each childhood leukemia with childhood and adult leukemia and with any cancer. We identified 4461 childhood leukemias from the Swedish Cancer Registry and obtained their family members from the Multigeneration Register. Standardized incidence ratios (SIRs) were 3.34 for singleton siblings both diagnosed with ALL before age 20 years and 1.64 for those who had a family member diagnosed with ALL in adult age. Other childhood leukemias showed no familial risk, but childhood ALL risk was increased to 1.40 when adult family members were diagnosed with CLL. Childhood ALL was associated with endometrial cancer, and female ALL patients showed increased risk when family members were diagnosed with testicular cancer, melanoma, and skin squamous cell carcinoma. Childhood CLL was associated with rectal cancer, and childhood AML was associated with pancreatic and bladder cancers. As most of these associations are reported for the first time, there is a need to replicate the findings from independent sources.

Background: We aim to estimate population-attributable fractions (PAF) for 13 comorbidities potentially predisposing to hepatobiliary cancer of hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cancers of the intrahepatic and extrahepatic bile ducts (ICC and ECC), and ampullary cancer. Methods: Patients were identified from the Swedish Inpatient Register from 1987 to 2018 and cancers from the Swedish Cancer Registry from 1997 through 2018. PAFs were calculated for each comorbidity-associated cancer using a cohort study design. Results: For male HCC, the major individual comorbidities (PAF > 10) were diabetes, alcohol-related liver disease, and hepatitis C virus infection. For female HCC, diabetes and autoimmune diseases were important contributors. For female GBC, gallstone disease was an overwhelming contributor, with a PAF of 30.57%, which was also important for men. The overall PAF for male ICC was almost two times higher than the female one. For ECC and ampullary cancer, infection of bile ducts was associated with the highest PAF. Conclusions: The 13 comorbidities accounted for 50% or more of the potential etiological pathways of each hepatobiliary cancer except female ICC. The underlying convergent mechanism for these cancers may be chronic inflammation lasting for decades and thus offering possibilities for intervention and disease monitoring.

Abstract The association between type 2 diabetes (T2D) and ischemic heart disease (IHD) is well established but the potential causal association needs further studying. In an attempt to elucidate the causal effect of T2D on IHD, we used three different analytical approaches in two different datasets. A well-defined cohort of 6047 women aged 50–59 years were included at baseline (1995 to 2000) and followed until 2015 for IHD. The median follow-up was 16.3 years. We used a Marginal Structural Cox model (MSM Cox) to account for time-varying exposure (time at onset of T2D) and for ten confounders (using inverse probability weighting, IPW). We also compared the MSM-Cox models with traditional Cox regression modelling in the cohort. Finally, we analyzed information on individuals from Swedish population-based registers with national coverage in a comprehensive co-relative design and extrapolated the results to MZ twins. The Hazard Ratio (HR) for IHD in relation to T2D at baseline and T2D occurring during the follow-up in the MSM Cox model weighted by IPW (based on the ten included confounders) was 1.43 (95% confidence interval [CI] 1.07–1.92). The corresponding HR from the traditional Cox regression model was of similar effect size. The average extrapolated MZ twin estimate from our co-relative model was 1.61 (95% CI 1.48–1.86). Our findings, based on a triangular approach, support the existence of a causal association between T2D and IHD and that preventive long-term measures in order to avoid or postpone IHD should include monitoring and treatment of both the T2D itself as well as other cardiovascular risk factors.

Abstract Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions.

Abstract To clarify the structure of genetic risks for 11 major psychiatric disorders, we calculated, from morbidity risks for disorders in 1st–5th degree relatives controlling for cohabitation effects, in the Swedish population born between 1932 and 1995 (n = 5,830,014), the family genetic risk scores (FGRS) for major depression (MD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), bulimia (BUL), anorexia nervosa (AN), alcohol use disorder (AUD), drug use disorder (DUD), ADHD, and autism-spectrum disorder (ASD). For all affected individuals, we calculated their mean standardized FGRS for each disorder. The patterns of FGRS were quite similar for MD and AD, and for AUD and DUD, but substantially less similar for BUL and AN, BD and SZ, and ADHD and ASD. While OCD had high levels of FGRS for MD and AD, the overall FGRS profile differed considerably from MD and AD. ADHD FGRS scores were substantially elevated in AUD and DUD. FGRS scores for BD, OCD, AN, ASD, ADHD, and especially SZ were relatively disorder-specific while genetic risk for MD and AD had more generalized effects. The levels of FGRS for BMI, coronary artery disease, and educational attainment across our disorders replicated prior associations found using molecular genetic methods. All diagnostic categories examined had elevated FGRS for many disorders producing, for each condition, an informative FGRS profile. Using a novel method which approximates, from pedigree data, aggregate genetic risk, we have replicated and extended prior insights into the structure of genetic risk factors for key psychiatric illnesses.

Abstract Background A distorted blood lipid profile is an important risk factor for ischemic heart disease (IHD) but the predictive ability of the different lipid measures has rarely been studied. Our aim was to examine and compare, in a large sample of women, the predictive ability of total cholesterol/HDL cholesterol ratio (TC/HDL-C) and non-HDL-C in relation to IHD, adjusted for age, exercise, smoking, waist-hip ratio, blood pressure, and diabetes mellitus. Methods Between 1995 and 2000, a total of 6537 women aged 50–59 years from the Women’s Health in Lund area (WHILA) study in southern Sweden were included and underwent a baseline examination. The women were followed through national registers for incidence of IHD during a mean follow-up of 17 years. The prediction accuracy was estimated through Harrell’s C and Akaike Information Criterion (AIC). Results Increasing TC/HDL-C as well as non-HDL-C showed strong associations with IHD, with the highest risk in the 5th quintile, where the HR was 2.30 (95% CI: 1.70–3.11) for TC/HDL-C and 1.67 (95% CI: 1.25–2.24) for non-HDL-C, after adjustments. Comparisons using Harrell’s C and AIC indicated that TC/HDL-C has a slightly higher predictive ability than that of non-HDL-C (Harrell’s C 0.62 and 0.59 respectively, p = 0.003 for difference, age-adjusted model; AIC for TC/HDL-C

Objective To evaluate compliance to workflow and accuracy of tests in Sweden’s first fast-track referral pathway for patients with nonspecific symptoms and suspected cancer (SCAN). Design Prospective cohort study with consecutive inclusion of patients referred to the diagnostic center (DC). Setting Patients with nonspecific symptoms were examined in primary care according to a protocol including two test packages and diagnostic imaging. If symptoms were not explained, patients were referred to the DC and a DC-test package was taken. At the DC, further investigations resulted in diagnosis/no diagnosis. Subjects A total of 290 patients, median age 69 years (interquartile range [IQR] 59–76), 48% men, participated. A total of 64 (22%) were diagnosed with cancer, 186 (64%) with non-malignant disease and 40 (14%) had no new disease. Main outcome measure Compliance was estimated by percentage of compulsory tests taken. Test accuracy was assessed by likelihood ratios (LRs) regarding cancer. Results A total of 23 (8%) patients had taken both primary care packages, whereas 150 (52%) patients went through entire diagnostic imaging. Abnormal pulmonary X-ray, peak expiratory flow (PEF) and calcium had the highest LRs in primary care (3.5; 3.2; 2.7). A total of 105 (36%) took the complete DC-package, of which bilirubin and cytomegalovirus had the highest LRs (11.5; 10.9). The median number (IQR) of abnormal primary care tests was 5 (3–6) for cancer, 3 (2–6) for other diagnoses and 1 (0–3) for no diagnosis. Conclusions Compliance to test packages in primary care was low, which warrants review of the workflow. Few single tests had high accuracy regarding cancer, but the number of abnormal tests can provide guidance in complicated investigations of suspected malignancies.KEY POINTS Fast-track referral pathways for patients with nonspecific serious symptoms have been implemented in several countries and are part of the national cancer strategy in all of Scandinavia. Compliance with compulsory tests in primary care was modest in this study; 8% of the patients had taken the entire compulsory test packages. Few single compulsory tests had high accuracy regarding subsequent cancer, which warrants a review of tests and examinations. However, patients diagnosed with cancer had a higher number of abnormal test results compared to the other groups.

Sweden has witnessed an increase in the rates of sexual crimes including rape. Knowledge of who the offenders of these crimes are is therefore of importance for prevention. We aimed to study characteristics of individuals convicted of rape, aggravated rape, attempted rape or attempted aggravated rape (abbreviated rape+), against a woman ≥18 years of age, in Sweden. By using information from the Swedish Crime Register, offenders between 15 and 60 years old convicted of rape+ between 2000 and 2015 were included. Information on substance use disorders, previous criminality and psychiatric disorders were retrieved from Swedish population-based registers, and Latent Class Analysis (LCA) was used to identify classes of rape+ offenders. A total of 3 039 offenders were included in the analysis. A majority of them were immigrants (n = 1 800; 59.2%) of which a majority (n = 1 451; 47.7%) were born outside of Sweden. The LCA identified two classes: Class A — low offending class (LOC), and Class B — high offending class (HOC). While offenders in the LOC had low rates of previous criminality, psychiatric disorders and substance use disorders, those included in the HOC had high rates of previous criminality, psychiatric disorders and substance use disorders. While HOC may be composed by more “traditional” criminals probably known by the police, the LOC may represent individuals not previously known by the police. These two separated classes, as well as our finding in regard to a majority of the offenders being immigrants, warrants further studies that take into account the contextual characteristics among these offenders. Key points Rape, aggravated rape, attempted rape or attempted aggravated rape (rape+) are increasing in Sweden. The majority of those convicted of rape+ are immigrants. LCA identifies two classes of rape+ offenders: LOC and HOC.

Abstract Increased physical activity can have health benefits among inactive individuals. In Sweden, the healthcare system uses physical activity on prescription (PAP) to motivate patients to increase their physical activity level. Mindfulness may further heighten the internal motivation to engage in physical activity. However, previous research has not demonstrated clear evidence of such an association. Aim Examine the feasibility of the study design as a preparation for a full-scale study, and examine the differences, between three interventions, in change over time in physical activity levels and in related variables. Method Comparison between three different interventions in an ordinary primary health care setting: PAP, mindfulness, and a combination of PAP and mindfulness. Physical activity was measured with self-report and ACTi Graph GT1X activity monitor. Statistical analysis was performed with a mixed-effect model to account for repeated observations and estimate differences both within groups and between groups at 3- and 6-months follow-up. Results Between September 2016 and December 2018, a total of 88 participants were randomised into three groups. The total dropout rate was 20.4%, the attendance rate to the mindfulness courses (52% > 6 times) and the web-based mindfulness training (8% > 800 min) was low according to the stated feasibility criteria. Eleven participants were excluded from analysis due to low activity monitor wear time. Neither the activity monitor data nor self-reported physical activity showed any significant differences between the groups. Conclusion The study design needs adjustment for the mindfulness intervention design before a fully scaled study can be conducted. A combination of PAP and mindfulness may increase physical activity and self-rated health more than PAP or mindfulness alone. Trial registration ClinicalTrials.gov, registration number NCT02869854 . Regional Ethical Review Board in Lund registration number 2016/404.

Abstract Background This study aimed to explore associations between various elements of primary care, patient satisfaction, and loyalty. Methods This cross-sectional study used a modified version of the Primary Care Assessment Tool (PCAT), which was adapted for Japan. We distributed the PCAT questionnaire to patients aged 20 years or older at five rural primary care centres in Japan. We confirmed the validity and reliability of the measure for our study. Next, we examined which elements of primary care were related to patient satisfaction and loyalty using Spearman’s correlation and structural equation modelling. Results Of 220 eligible patients, 206 participated in this study. We developed nine component scales: first contact (regular access), first contact (urgent access), longitudinality, coordination, comprehensiveness (variety of care), comprehensiveness (risk prevention), comprehensiveness (health promotion), family-centeredness, and community orientation. Longitudinality and first contact (urgent access) were related with patient satisfaction. Longitudinality, first contact (regular access), and family-centeredness were related to patient loyalty. In the structural equation modelling analysis, two variables were significantly related to loyalty, namely a combined variable including longitudinality and first contact (regular access), along with family-centeredness. Conclusions While a patient satisfaction model could not be distilled from the data, longitudinality, first contact (urgent access), and family-centeredness were identified as important elements for the cultivation of patient loyalty. This implies that primary care providers need to develop a deep understanding of patients’ contexts and concerns and pay attention to their level of access to cultivate greater patient loyalty.

Background: Second primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce. Objective: In this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks. Design, setting, and participants: Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register. Outcome measurements and statistical analysis: We employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC. Results and limitations: We identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC. Conclusions: The bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits. Patient summary: Close to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer.

Abstract Mitochondrial dysfunction is an important factor of the aging process and may play a key role in various diseases. Mitochondrial DNA copy number (mtDNA-CN) is an indirect measure of mitochondrial dysfunction and is associated with type 2 diabetes mellitus (T2DM); however, whether mtDNA-CN can predict the risk of developing T2DM is not well-known. We quantified absolute mtDNA-CN in both prevalent and incident T2DM by well-optimized droplet digital PCR (ddPCR) method in a population-based follow-up study of middle aged (50–59 years) Swedish women (n = 2387). The median follow-up period was 17 years. Compared to those who were free of T2DM, mtDNA-CN was significantly lower in both prevalent T2DM and in women who developed T2DM during the follow-up period. Mitochondrial DNA-copy number was also associated with glucose intolerance, systolic blood pressure, smoking status and education. In multivariable Cox regression analysis, lower baseline mtDNA-CN was prospectively associated with a higher risk of T2DM, independent of age, BMI, education, smoking status and physical activity. Moreover, interaction term analysis showed that smoking increased the effect of low mtDNA-CN at baseline on the risk of incident T2DM. Mitochondrial DNA-copy number may be a risk factor of T2DM in women. The clinical usefulness of mtDNA-CN to predict the future risk of T2DM warrants further investigation.

Abstract Background Children experience a higher risk of psychiatric problems when their parents are diagnosed with cancer. However, the psychological effect among offspring who are born after parental cancer diagnosed in childhood or adolescence is unknown. We aimed to investigate the risk of psychiatric disorders in children of survivors with childhood or adolescent central nervous system (CNS) tumors. Methods By combining several nationwide Swedish registers, we identified all children who had at least one parent previously diagnosed with CNS tumor below the age of 20. Five children without parental CNS tumor were randomly selected for the matching. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence interval (CI). Results The incidence rate of psychiatric disorders was 8.46 per 1000 person‐years in children of CNS tumor survivors, whereas the rate was 7.47 in the matched comparisons, yielding an adjusted HR of 1.10 (95% CI = 0.94, 1.28). Boys of survivors had a higher risk of psychiatric disorders (adjusted HR = 1.29, 95% CI = 1.04, 1.59). The risk of the specific types of psychiatric disorders in children of tumor survivors was comparable with that in the matched comparisons, except for mental retardation. Children of survivors experienced 2.36 times higher risk of mental retardation (95% CI = 1.21, 4.58), mainly of mild mental retardation (adjusted HR = 2.99, 95% CI = 1.40, 6.38). Conclusion Children of survivors with CNS tumor in early life did not experience a significantly increased risk of overall psychiatric disorders, with the exception of an elevated risk of mental retardation that was mainly mild.

Design: Addison’s disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, present as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce, and we aimed to carry out an unbiased study on AD and related AIDs. Methods: We collected data on patients diagnosed with AIDs in Swedish hospitals and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks. Results: The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was assoc iated with 11 other AIDs, including thyroid AIDs and type 1 diabetes and some rarer AIDs such as Guillain–Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren’s syndrome. Conclusions: The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.

Abstract Background Wide implementation of mammography screening has resulted in increased numbers of women diagnosed with breast carcinoma in situ. We aimed to determine the risk of invasive breast cancer in relatives of patients with breast carcinoma in situ in comparison to the risk in relatives of patients with invasive breast cancer. Methods We analyzed the occurrence of cancer in a nationwide cohort including all 5,099,172 Swedish women born after 1931 with at least one known first-degree relative. This was a record linkage study of Swedish family cancer datasets, including cancer registry data collected from January 1, 1958, to December 31, 2015. We calculated standardized incidence ratios (SIRs) and 10-year cumulative risk of breast cancer diagnosis for women with a family history of in situ and invasive breast cancer. Results Having one first-degree relative with breast carcinoma in situ was associated with 50% increased risk of invasive breast cancer (SIR = 1.5, 95% CI 1.4–1.7) when compared to those who had no family history of invasive breast cancer or breast carcinoma in situ in either first- or second-degree relatives. Similarly, having one first-degree relative with invasive breast cancer was associated with 70% (1.7, 1.7–1.8) increased risk. The 10-year cumulative risk for women at age 50 with a relative with breast carcinoma in situ was 3.5% (2.9–3.9%) and was not significantly different from 3.7% (3.6–3.8%) risk for 50-year-old women with a relative with invasive breast cancer (95% confidence intervals overlapped). Conclusions The risk of invasive breast cancer for women with a family history of breast carcinoma in situ was comparable to that for women with a family history of invasive breast cancer. Therefore, family history of breast carcinoma in situ should not be overlooked in recommendations for breast cancer prevention for women with a family history of breast cancer.

Abstract Background Many cancers are increased in immunosuppressed patients and evidence is accumulating that immune dysfunction may be a contributing risk factor for second primary cancers (SPCs). The aim of this study was to explore the potential influence of immune mechanisms in SPC. Methods We used the Swedish Cancer Registry (1990‐2015) to select 13 male and 14 female first primary cancers (FPCs) that are known to be related to immune suppression. We assessed relative risks (RRs) for any of these as concordant (same first and second cancer) and discordant FPC‐SPC pairs. Hierarchical clustering of significant RRs was performed for cancers as FPC and SPC. Results Concordant risks for SPCs were excessive in men and women for nasal (RRs 59.3 for men and 150.6 for women), tongue/mouth (51.7 and 100.8), and lip (32.4 and 61.2) cancers. Heatmaps showed that some cancers, such as skin cancer, tongue/mouth cancers, and non‐Hodgkin lymphoma had multiple bidirectional associations as FPC and SPC. Nasal cancer and chronic lymphocytic leukemia had associations mainly as FPC while liver and kidney cancers showed most associations as SPC. Conclusions Immune dysfunction may be a plausible contributing factor for most of the associations, which calls for experimental verification.

ObjectivesTo analyze the risk of hearing impairment in adult first-generation immigrants, i.e., foreign-born individuals as compared to Swedish-born individuals.Study designA register-based study follow-up study.MethodsA nationwide study of individuals 25 years of age and older (N = 5 464 245; 2 627 364 men and 2 836 881 women) in Sweden. Hearing impairment was defined as at least one registered diagnosis in the National Patient Register between January 1st, 1998 and December 31st, 2015. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident hearing impairment in foreign-born compared to Swedish-born individuals. Cox regression models were stratified by sex and adjusted for age, comorbidities, and socioeconomic status.ResultsA total of 244 171 cases (124 349 men and 119 822 women) of hearing impairment were registered. Hearing impairment risk expressed as fully adjusted HRs (99% CI) was somewhat lower among immigrant men 0.95 (0.92-97) but not among immigrant women 0.97 (0.95-1.00), with significantly higher fully adjusted HRs among men and women from Asia, and Eastern Europe, and women from Africa.ConclusionsWe observed a somewhat lower risk of hearing impairment among foreign-born men, but there was a higher risk among men and women from some regions.

Phosphodiesterase-5 (PDE5) inhibitors have been suggested to have an anti-tumor effect and block surgery-induced immunosuppression. Here, the authors show that postdiagnostic use of PDE5 inhibitors is associated with a decreased risk of colorectal cancerspecific mortality as well as a decreased risk of metastasis.