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Abstract Background Beneficial effects from practising a Paleolithic diet as compared to a diabetes diet on weight, waist circumference, satiety, leptin, HbA1c and glucose control in randomised controlled trial participants with type 2 diabetes could be due to lower leptin resistance. Support for this hypothesis comes from an in vitro experiment that showed that digested wheat gluten, which is excluded from a Paleolithic diet, inhibits leptin from binding to its receptor, thus indicating a possible dietary cause of leptin resistance. However, the clinical relevance of the latter finding is unclear since removal of enzyme activity from the gluten digest by heat treatment also abolished leptin binding inhibition. Assessment of leptin binding inhibition in vivo is possible by comparison of total leptin levels with those of ‘biologically active’ leptin bound to its receptor (bioLep). Objectives To assess the effects of a Paleolithic diet compared to a diabetes diet on leptin binding inhibition and to replicate our in vitro study. Methods BioLep and total leptin levels were measured in secondary analysis of fasting plasma samples from our open label random order three plus three-month long cross-over trial performed in 2005–2007, that compared a Paleolithic diet with a diabetes diet in participants with type 2 diabetes without insulin treatment (per protocol). BioLep was also measured in vitro for known recombinant leptin concentrations incubated with a series of concentrations of 10 kDa spin-filtered digested wheat gluten, with or without prior heat treatment, at 100ºC for 30 min and centrifugation. Results There was no difference between diets when comparing differences between bioLep and total leptin levels and their ratio in the 13 participants, three women and 10 men, aged 52–74 years with a mean BMI of 30 kg/m2 and a mean diabetes duration of eight years. We found no carry-over or period effect for bioLep and total leptin. In vitro, wheat gluten digest inhibited leptin binding in a dose-dependent manner but not after heat treatment. Conclusions We found no leptin binding inhibition after the Paleolithic or diabetes diet, possibly due to its abolishment from cooking-related heat treatment of wheat gluten. Trial registration Registered on 14/02/2007 at ClinicalTrials.gov Identifier: NCT00435240.

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

Objective To examine cardiovascular risk factors in 40-year-old participants in the health screening program targeted health dialogues (THDs).Design Cross-sectional study.Setting 99 Swedish healthcare centers.Intervention Metabolic risk factors and health behaviors were assessed. THDs were provided.Subjects 1831 (62.3%) THD participants that consented to take part in the research project.Main outcome measures (1) Prevalence of metabolic risk factors (blood pressure, LDL cholesterol, fasting plasma glucose, BMI, waist-hip ratio) and unhealthy behaviors (tobacco, alcohol, diet, physical activity) by sex, education, and place of birth. (2) Associations between different health behaviors and between the number of unhealthy behaviors and prevalence of metabolic risk factors. (3) THD participation by sociodemographics compared to age-matched controls.Results Men had a higher prevalence of all metabolic risk factors, excessive alcohol use and tobacco use than women. Lower educated individuals had a higher prevalence of metabolic risk factors (except for LDL cholesterol) and tobacco use than highly educated. Participants born outside Sweden had a higher prevalence of obesity, high waist-hip ratio, and tobacco use. Participants with 3–4 unhealthy behaviors had significantly higher prevalence of each of the metabolic risk factors except BMI. Women, highly educated and Swedish-born participants were slightly over-represented in the THDs.Conclusion Considering the associations between unhealthy behaviors and metabolic risk factors, the THD method, covering lifestyle as well as objective health measures, may be an appropriate method for early identification of individuals at risk for future non-communicable diseases in the whole population with a specific focus on certain groups.ClinicalTrials.gov NCT04912739

Objective: Targeted Health Dialogues (THD) is a public health intervention program that aims at preventing cardiovascular disease. THDs were implemented in the Swedish region Scania, in 2020, with the novelty of being conducted in a metropolitan area with a multiethnic population.This study investigated the prevalence of obesity among 40-year-old THD participants in Scania by region of birth, and its associations with self-efficacy and additional metabolic risk factors. Methods: Cross-sectional data were retrieved from measurements in the THDs. Study participants included 1831 40-year-olds. Differences in characteristics by region of birth were assessed using chi-squared and ANOVA tests. The associations between overweight, obesity, and high waist-hip ratio (WHR) and self-efficacy and metabolic risk factors (blood pressure, LDL cholesterol, plasma glucose) were assessed using binominal and ordinal logistic regression, adjusted for sex and education and tested for interactions by region of birth. Results: 35.1 % of the participants were overweight (BMI 25–29.9), and 18.7 % were obese (BMI ≥30) with the highest levels among participants born outside Sweden (p = 0.005). Abdominal obesity was also more prevalent among participants born outside Sweden (p = 0.002). Obesity was associated with increased odds of having low self-efficacy (OR per BMI-level: 1.48 (CI 1.24–1.76) and additional metabolic risk factors. No interactions with region of birth were detected. Conclusions: The prevalence of obesity differed between region of birth and obesity was associated with having low self-efficacy. These findings underline the need to customise lifestyle interventions in a multiethnic population to increase health equity.

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.

A diet with low content of fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) is established treatment for irritable bowel syndrome (IBS), with well-documented efficiency. A starch- and sucrose-reduced diet (SSRD) has shown similar promising effects. The primary aim of this randomized, non-inferiority study was to test SSRD against low FODMAP and compare the responder rates (RR = ∆Total IBS-SSS ≥ −50) to a 4-week dietary intervention of either diet. Secondary aims were to estimate responders of ≥100 score and 50% reduction; effects on extraintestinal symptoms; saturation; sugar craving; anthropometric parameters; and blood pressure. 155 IBS patients were randomized to SSRD (n = 77) or low FODMAP (n = 78) for 4 weeks, with a follow-up 5 months later without food restrictions. The questionnaires Rome IV, IBS-severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS) were completed at baseline and after 2 and 4 weeks and 6 months. Weight, height, waist circumference, and blood pressures were measured. Comparisons were made within the groups and between changes in the two groups. There were no differences between groups at baseline. The responder rate of SSRD was non-inferior compared with low FODMAPs at week 2 (79.2% vs. 73.1%; p = 0.661;95% confidence interval (CI) = −20–7.2) and week 4 (79.2% vs. 78.2%; p = 1.000;95%CI = −14–12). Responder rate was still high when defined stricter. All gastrointestinal and extraintestinal symptoms were equally improved (p < 0.001 in most variables). SSRD rendered greater reductions in weight (p = 0.006), body mass index (BMI) (p = 0.005), and sugar craving (p = 0.05), whereas waist circumference and blood pressure were equally decreased. Weight and BMI were regained at follow-up. In the SSRD group, responders at 6 months still had lowered weight (−0.7 (−2.5–0.1) vs. 0.2 (−0.7–2.2) kg; p = 0.005) and BMI (−0.25 (−0.85–0.03) vs. 0.07 (−0.35–0.77) kg/m2; p = 0.009) compared with baseline in contrast to non-responders. Those who had tested both diets preferred SSRD (p = 0.032). In conclusion, a 4-week SSRD intervention was non-inferior to low FODMAP regarding responder rates of gastrointestinal IBS symptoms. Furthermore, strong reductions of extraintestinal symptoms were found in both groups, whereas reductions in weight, BMI, and sugar craving were most pronounced following SSRD.

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.

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 Background Associations between different cancer types are known. The affirmation of the risk for non-ovarian cancer after ovarian borderline tumors (BOT) is, however, sparse. Aim To analyze the risk of subsequent or simultaneous cancers in women with BOTs compared with the general female Swedish population. Methods An open cohort study (1995–2018) was conducted where a diagnosis of BOTs as well as subsequent or simultaneous cancer diagnoses were obtained from the Swedish Cancer Register and matched to the Total Population Register. Each woman with BOT was followed until non-ovarian cancer, death or emigration and could only be included once for the outcome. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for specific non-ovarian cancers were analyzed. Results The 4998 women with serous and mucinous BOTs were diagnosed during 1995–2018 with a mean age of 55.7 years (SD 16.0) at diagnosis. Compared with the general female population, women with BOTs had increased risks for non-ovarian cancer in colon (SIR = 2.5; 95% CI 2.0–3.1), rectum (SIR = 1.7; 95% CI 1.1–2.5), small intestine (SIR = 5.0; 95% CI 2.3–9.5), cervix (SIR = 2.5; 95% CI 1.4–4.2), endometrium (SIR = 2.4; 95% CI 1.9–3.1), pancreas (SIR = 2.3; 95% CI 1.4–3.5), upper aerodigestive tract (SIR = 2.2; 95% CI 1.2–3.8), lung (SIR = 1.8; 95% CI 1.4–2.3), kidney (SIR = 2.3; 95% CI 1.4–3.7) and bladder (SIR = 1.8; 95% CI 1.1–2.8). Among women with serous BOTs, the risk of thyroid gland cancer (SIR = 3.1; 95% CI 1.2–6.4) was also increased. Lung and pancreas cancer showed increased risks more than 1 year after a diagnosis of BOT. Conclusions This Swedish population-based study demonstrated an increased risk of multiple malignancies including lung and pancreatic cancers beyond the first year of diagnosis in patients with borderline ovarian tumors (BOTs), suggesting a potential shared etiology.

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.

Objective: Individuals with psychiatric illness suffer from poorer physical health compared with the general population and have a higher risk of developing cardiovascular and metabolic diseases. This cross-sectional study aims to describe the prevalence of lifestyle and cardiovascular risk factors and the association with self-reported psychiatric symptoms in a population of 40-year-old individuals screened with targeted Health Dialogues in southern Sweden. Methods: All 40-year-old individuals registered at 99 primary healthcare centers in southern Sweden were invited to participate. Self-reported lifestyle habits on a web questionnaire, anthropometric measurements, blood pressure, and blood tests were collected. The Health Dialogue resulted in a risk level assessment for different lifestyle habits and a meeting with a trained coach. Results: A total of 1831 individuals completed a Health Dialogue between 1st January 2021 and 30th June 2022. There were more individuals with high-risk levels for several lifestyle habits in the group with self-reported psychiatric illness compared with the rest of the study population. The analysis showed that physical inactivity, unhealthy diet, high-risk alcohol intake, tobacco use, psychosocial strain, higher BMI, and waist-hip ratio were associated with increased levels of psychiatric symptoms after adjustment for sex and socioeconomic factors. Conclusion: Unhealthy lifestyle habits were associated with self-reported psychiatric symptoms in 40-year-old individuals assessed with targeted Health Dialogues in a primary care context. Organized screening might contribute to early detection of modifiable risk factors for cardiovascular disease. Individuals with psychiatric symptoms should be prioritized for screening of unhealthy lifestyle behaviors.

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.

Abstract Background The experiences of art and music are an essential part of human life and this study aimed to examine the longitudinal association between cultural participation and coronary heart disease. Methods This was a longitudinal study on a randomly selected representative adult cohort (n = 3296) of the Swedish population. The study period was over 36 years (1982–2017) with three separate eight-year interval measurements of cultural exposure (for example, visiting theatres and museums) starting in 1982/83. The outcome was coronary heart disease during the study period. Marginal structural Cox models with inverse probability weighting were used to account for time-varying weights of the exposure and potential confounders during the follow-up. The associations were also examined through a time-varying Cox proportional hazard regression model. Results Cultural participation shows a graded association, the higher the exposure the lower the risk of coronary heart disease; the hazard ratio was 0.66 (95% confidence interval, 0.50 to 0.86) for coronary heart disease in participants with the highest level of cultural exposure compared with the lowest level. Conclusion Although causality cannot be determined due to the remaining risk of residual confounding and bias, the use of marginal structural Cox models with inverse probability weighting strengthens the evidence for a potentially causal association with cardiovascular health, which warrants further studies.

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.

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.

Sepsis is a severe condition, representing a significant public health concern, especially in the elderly. There is, however, little insight into the potential effects of sociodemographic factors and comorbidities on sepsis incidence and how these factors interact. This was a nationwide open cohort study including individuals (N = 6 746 010) in Sweden ≥ 18 years of age spanning from 1997 to 2018, with 116 175 995 person years of follow-up. The outcome was time to first occurrence of sepsis. The following variables were included in the analysis: sociodemographic factors (age, sex, income, education, marital status, region of residency, and country of origin), severe mental disorders (schizophrenia and bipolar disorders), and Charlson Comorbidity Index. Interaction tests were conducted. A total of 161 558 individuals were diagnosed with sepsis during the study period, corresponding to an incidence rate of 13.9 per 10 000 person years (95% CI: 13.8 – 14.0). The main findings were that male sex, high age, low education, and comorbid conditions were positively associated with sepsis, after adjustments for the other covariates. Being aged 80 years and above yielded a HR of 18.19 (95% CI: 17.84 – 18.55) and the effect of high age was more than twice as high in men than in women. In conclusion, this large nationwide cohort found that several sociodemographic factors and comorbid conditions were independently associated with sepsis and men were more affected by higher age than women. These findings can help improve sepsis awareness and preventive work in risk groups.

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.

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.

Objectives: We aimed to explore the association between various physiological factors and pyelonephritis in parous women. Methods: Swedish nationwide registers were used to identify 1,073,467 parous women aged 15-50 years. The study period began in 1997 and ended in 2018, or at the first incidence of pyelonephritis, death, or emigration. Cox proportional hazards methods were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) of pyelonephritis in relation to body mass index (BMI) and body height adjusted for age, parity, and individual-level sociodemographic variables. Results: A total of 21,625 women (2.0%) were diagnosed with pyelonephritis during follow-up. In the fully adjusted model, low BMI (

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.

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.

Objectives To examine whether multimorbidity aggregates in families in Sweden.Design National explorative family study.Setting Swedish Multigeneration Register linked to the National Patient Register, 1997-2015. Multimorbidity was assessed with a modified counting method of 45 chronic non-communicable diseases according to ICD-10 (international classification of diseases, 10th revision) diagnoses.Participants 2 694 442 Swedish born individuals (48.73% women) who could be linked to their Swedish born first, second, and third degree relatives. Twins were defined as full siblings born on the same date.Main outcome measures Multimorbidity was defined as two or more non-communicable diseases. Familial associations for one, two, three, four, and five or more non-communicable diseases were assessed to examine risks depending on the number of non-communicable diseases. Familial adjusted odds ratios for multimorbidity were calculated for individuals with a diagnosis of multimorbidity compared with relatives of individuals unaffected by multimorbidity (reference). An initial principal component decomposition followed by a factor analysis with a principal factor method and an oblique promax rotation was used on the correlation matrix of tetrachoric correlations between 45 diagnoses in patients to identify disease clusters.Results The odds ratios for multimorbidity were 2.89 in twins (95% confidence interval 2.56 to 3.25), 1.81 in full siblings (1.78 to 1.84), 1.26 in half siblings (1.24 to 1.28), and 1.13 in cousins (1.12 to 1.14) of relatives with a diagnosis of multimorbidity. The odds ratios for multimorbidity increased with the number of diseases in relatives. For example, among twins, the odds ratios for multimorbidity were 1.73, 2.84, 4.09, 4.63, and 6.66 for an increasing number of diseases in relatives, from one to five or more, respectively. Odds ratios were highest at younger ages: in twins, the odds ratio was 3.22 for those aged ≤20 years, 3.14 for those aged 21-30 years, and 2.29 for those aged >30 years at the end of follow-up. Nine disease clusters (factor clusters 1-9) were identified, of which seven aggregated in families. The first three disease clusters in the principal component decomposition were cardiometabolic disease (factor 1), mental health disorders (factor 2), and disorders of the digestive system (factor 3). Odds ratios for multimorbidity in twins, siblings, half siblings, and cousins for the factor 1 cluster were 2.79 (95% confidence interval 0.97 to 8.06), 2.62 (2.39 to 2.88), 1.52 (1.34 to 1.73), and 1.31 (1.23 to 1.39), and for the factor 2 cluster, 5.79 (4.48 to 7.48) 3.24 (3.13 to 3.36), 1.51 (1.45 to 1.57), and 1.37 (1.341.40).Conclusions The results of this explorative family study indicated that multimorbidity aggregated in Swedish families. The findings suggest that map clusters of diseases should be used for the genetic study of common diseases to show new genetic patterns of non-communicable diseases.

Objectives Important gaps in previous research include a lack of studies on the association between socioeconomic characteristics of the workplace and coronary heart disease (CHD).We aimed to examine two contextual factors in association with individuals’ risk of CHD: the mean educational level of all employees at each individual’s workplace (educationwork) and the neighbourhood socioeconomic characteristics of each individual’s workplace (neighbourhood SESwork).Design Nationwide follow-up/cohort study.Setting Nationwide data from Sweden.Participants All individuals born in Sweden from 1943 to 1957 were included (n=1 547 818). We excluded individuals with a CHD diagnosis prior to 2008 (n=67 619), individuals without workplace information (n=576 663), individuals lacking residential address (n=4139) and individuals who had unknown parents (n=7076). A total of 892 321 individuals were thus included in the study (426 440 men and 465 881 women).Primary and secondary outcome measures The outcome variable was incident CHD during follow-up between 2008 and 2012. The association between educationwork and neighbourhood SESwork and the outcome was explored using multilevel and cross-classified logistic regression models to determine ORs and 95% CIs, with individuals nested within workplaces and neighbourhoods. All models were conducted in both men and women and were adjusted for age, income, marital status, educational attainment and neighbourhood SESresidence.Results Low (vs high) educationwork was significantly associated with increased CHD incidence for both men (OR 1.29, 95% CI 1.23 to 1.34) and women (OR 1.38, 95% CI 1.29 to 1.47) and remained significant after adjusting for potential confounders. These findings were not replicable for the variable neighbourhood SESwork.Conclusions Workplace socioeconomic characteristics, that is, the educational attainment of an individual’s colleagues, may influence CHD risk, which represents new knowledge relevant to occupational health management at workplaces.

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.

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.

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.

Objective: This study aimed to estimate the association between potential risk factors and common vaginal infections using nationwide primary health care and other national registers. Methods: An open cohort study consisting of 2,357,711 women aged 15 years to 50 years (2001 to 2018) was conducted in Sweden. The outcomes were first event of vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV) in relation to sociodemographic factors. Cox regression models were used. Sensitivity analyses including diabetes mellitus, contraceptive use, and cervical cancer were conducted. Results: The incidence rates per 1,000 person-years for VVC and BV were 3.3 (95% confidence interval [CI] 3.2-3.3) and 3.4 (95% CI 3.4-3.4), respectively. In the fully adjusted model, sociodemographic factors were significantly associated with both outcomes. Compared with Swedish-born women, women from Middle East/North Africa had the highest risk of VVC (hazard ratio [HR] 2.77, 95% CI, 2.72-2.83), followed by Africa (excluding North Africa) (HR 2.53, 95% CI, 2.45-2.61), and Latin America and the Caribbean (HR 2.18, 95% CI, 2.09-2.27). For BV, women from Latin America and the Caribbean had the highest risk (HR 1.83, 95% CI, 1.75-1.92). Conclusion: This study presents novel risk factors associated with medically attended vaginal infections. Women from non-Western countries seem to develop these conditions disproportionately.

Abstract In this nationwide cohort of one million fertile women, BMI, height, and parity only had minor but statistically significant effects on the risk of uncomplicated cystitis. The results indicate that underweight women and certain sociodemographic groups might have higher risks, which could have underlying explanations that need further studying.

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.

Objectives To examine the association between cultural attendance and all-cause mortality.Design A longitudinal cohort study over 36 years (1982–2017) with three 8-year interval measurements of exposure (1982/1983, 1990/1991 and 1998/1999) to cultural attendance and a follow-up period to 31 December 2017.Setting Sweden.Participants The study included 3311 randomly selected individuals from the Swedish population with complete data for all three measurements.Primary outcome measurements All-cause mortality during the study period in relation to level of cultural attendance. Cox regression models with time-varying covariates were used to estimate HRs adjusted for potential confounders.Results The HRs of cultural attendance in the lowest and middle levels compared with the highest level (reference; HR=1) were 1.63 (95% CI 1.34 to 2.00) and 1.25 (95% CI 1.03 to 1.51), respectively.Conclusion Attending cultural events has a suggested gradient, the lesser cultural exposure the higher all-cause mortality during the follow-up.

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 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.

Objective: To study the relationship between sociodemographic factors and pyelonephritis.Methods: A nationwide open cohort study consisting of 2,052,873 women (76.2% Swedish-born) aged 15-50 years was conducted (1997-2018). The outcome was the first event of acute uncomplicated pyelonephritis diagnosed in primary healthcare settings in relation to the sociodemographic factors. Cox regression models were used in the analyses.Results: The study identified 40,724 cases. In the fully adjusted model, women from non-Western countries had a higher risk of pyelonephritis compared to Swedish-born women. Women from Latin America/the Caribbean had the highest risk (Hazard ratio = 1.60; 95% CI 1.49-1.72), followed by Eastern Europe (HR = 1.26; 95% CI 1.21-1.32) and the Middle East/North Africa (HR = 1.25; 95% CI 1.19-1.30). Low education, low income, urban living, and young age were also associated with higher risks of pyelonephritis.Conclusion: This study presents novel risk factors associated with pyelonephritis. Women from non-Western countries and with low socioeconomic status might disproportionately suffer from this serious infection. This might be due to biological predispositions and the fact that immigrant women do not acquire the same level of health or might receive less healthcare compared to native women, even in the presence of universal healthcare.

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.

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.

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 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.

Summary: Background: Paleolithic Diet Fraction (PDF), calculated as the fraction of intake from Paleolithic food groups divided by the intake from all food groups, was developed as a measure of compliance hitherto lacking in interventional studies on Paleolithic diet. Mean PDFs in our previously published study comparing Paleolithic diet with a Mediterranean-like diet were around 80% and 40% for the two diets, respectively, and higher PDF was associated with healthier levels in several glucometabolic outcome measures. We now present PDF comparing a Paleolithic diet with a diabetes diet. Methods: 13 adult patients (3 women and 10 men, mean age 64) with type 2 diabetes followed in 2005–07 a Paleolithic diet and a diabetes diet during two consecutive 3-month periods in a randomized order cross-over design study. Mean daily PDF was calculated using four-day weighed food records. Linear mixed models were used to assess associations between PDF and relative change in the outcome measures used in this study and in aggregated data from this study combined with data from the study comparing Paleolithic diet with a Mediterranean-like diet. Results: Mean PDF for energy was 77% for the Paleolithic diet and 38% for the diabetes diet. The corresponding percentages for PDF for weight were 81% and 54%. A 10% higher PDF for energy was associated with 0.8% lower weight, 0.7% smaller waist circumference, 2.1% lower total cholesterol, 7.6% lower triglyceride, 2.0% lower HbA1C, 9.9% lower leptin and, in the aggregated data, also with 1.6% lower area under the curve (AUC) for glucose during an oral glucose tolerance test (OGTT). Similar results were found for PDF for weight. Conclusions: A mean PDF of around 80% for a Paleolithic diet in both this study and our previous study comparing the Paleolithic diet with a Mediterranean-like diet indicate a high reproducibility of the PDF. The mean PDF of around 40% for both the diabetes diet and the Mediterranean-like diet indicates their similarity and how far removed both diets are from a Paleolithic diet in terms of food group content. The associations between higher PDF and healthier glucometabolic outcome measures indicate that this removal is unhealthy. The results from this post hoc data analysis should be corroborated in future studies. Trial registration: ClinicalTrials.gov. NCT00435240. Registered 14 February 2007. Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT00435240?term=tommy+jönsson&cond=paleolithic&draw=2&rank=2.

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.