Search

The purpose of this study was to clarify the clinical heterogeneity of alcohol use disorder (AUD) in a national Swedish sample of affected individuals using latent class analysis.Using a Swedish population-based sample of AUD cases ascertained from medical, criminal, and pharmacy registries (in/i= 217,071), we applied latent class analysis to sex, externalizing and internalizing syndromes before first registration, and age at first registration. The resulting types were evaluated against 15 diverse validators and degree of resemblance in relative pairs concordant for AUD.A three-class solution was preferred by fit indices. The three classes were as follows: type 1 (male preponderant, externalizing; 32%), type 2 (minimal prior psychopathology; 46%), and type 3 (mixed-sex internalizing; 23%). Repeated split-half analyses revealed the statistical stability of these solutions. Meaningful differences emerged between the classes on many validators. Type 1 had the greatest family disruption, lowest educational levels, most AUD registrations, highest rates of criminal registration, and highest genetic risk for externalizing disorders and AUD. Type 2 had the least social dysfunction. Type 3 had the highest educational attainment, genetic liability to internalizing disorders, and proportion of women. All types significantly aggregated in affected pairs of relatives.Meaningful and reproducible subtypes of AUD, consistent with prior typological results, can be obtained from national registry-based samples. Using a range of external validators and patterns of familial aggregation, our results suggest that our three-class solution captured a meaningful proportion of the clinical heterogeneity of AUD.

Substance use disorder (SUD) is related to widespread adverse consequences, including higher suicidality. Shared genetic liability has been demonstrated between SUD and suicidality. Here, we measured the factors that contribute to increased risk of non-fatal suicide attempt among individuals with SUD by focusing upon aggregate genetic risks and both childhood and past-year environmental factors.Longitudinal study. Family genetic risk scores and environmental factors (childhood, aged from 0 to 15 years, and the year preceding SUD registration) were used to predict the relative risk of non-fatal suicide attempt using Cox proportional hazards models. Additional analyses employed a co-relative design, accounting for genetic factors and shared familial environment, to test for potential causality.Based on longitudinal Swedish registry data, 228 617 individuals with SUD registrations from 1991 to 2015 were included.SUD and suicide attempts were identified using medical records (International Classification of Diseases codes). SUD was also identified using pharmacy and criminal registries.In multivariable analyses that jointly accounted for all the selected potential predictors, individuals with SUD were at higher risk for non-fatal suicide attempt if they had experienced a parental death [hazard ratio (HR) = 1.58; 95% confidence interval (CI) = 1.30, 1.93], were female (HR = 1.53, 95% CI = 1.49, 1.57), had low educational attainment (HR = 1.50, 95% CI = 1.46, 1.55), received social welfare (HR = 1.21, 95% CI = 1.17, 1.25) or had lived in a non-intact family (HR = 1.11, 95% CI = 1.08, 1.14). In co-relative analyses, low education was supported as a possible causal factor for suicide attempt. Aggregate genetic risks interacted with low education and being raised in a non-intact family, with increased prevalence of suicide attempt in people with high genetic risks and unfavorable environmental exposures.Aggregate genetic liability, childhood environmental experiences and specific socio-economic indicators are important risk factors for non-fatal suicide attempt among individuals with substance use disorder.

To study incident narcolepsy in first- and second-generation immigrant groups using Swedish-born individuals and native Swedes as referents.The study population included all individuals registered and alive in Sweden at baseline. Narcolepsy was defined as having at least one registered diagnosis of narcolepsy in the Swedish National Patient Register. The incidence of narcolepsy in different immigrant groups was assessed by Cox regression, with hazard ratios (HRs) and 95% 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 the first-generation study, 1225 narcolepsy cases were found; 465 males and 760 females, and in the second-generation study, 1710 cases, 702 males and 1008 females. Fully adjusted HRs (95% CI) in the first-generation study was for males 0.83 (0.61-1.13) and females 0.83 (0.64-1.07), and in the second-generation study for males 0.76 (0.60-0.95) and females 0.91 (95% CI 0.76-1.09). Statistically significant excess risks of narcolepsy were found in first-generation males from North America, and second-generation males with parents from North America, and second-generation females with parents from Latin America.There were only significant differences in incident narcolepsy between native Swedes and second-generation male immigrants. The observed differences can partly be explained by differences in Pandemrix® vaccinations and are probably not attributable to genetic differences between immigrants and natives.

Summary: Background: Peripheral arterial disease (PAD) is a common atherosclerotic disease with severity ranging from asymptomatic to chronic limb threatening ischemia. The aim of the present cross-sectional study was to identify novel biomarkers associated with PAD. Patients and methods: Levels of 91 cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III96x96 panel from a cohort consisting of 267 65-year-old men recruited from a screening program for abdominal aortic aneurysm (AAA) Levels of protein biomarkers were compared in men with and without PAD (defined as an ankle brachial index of

Background: The influence of familial factors on the prognosis of ischemic stroke (IS) is unknown. This nationwide follow-up study evaluated familial mortality risks of IS among Swedish sibling pairs hospitalized for IS. Methods: We linked Swedish nationwide registers for the identification of 1380 Swedish born sibling pairs (2760 cases), where both siblings were hospitalized for first-time IS between 1991 and 2010. Median age was 62 years (range, 26–78 years). Sibling pairs with cancer were excluded. Familial hazard ratios (FHRs) for mortality after first IS hospitalization were determined with Cox regression. The influence of proband survival after IS was categorized as short sibling survival ( Results: Short sibling survival (ie, Conclusions: Our results suggest that family history of short survival in siblings after IS is associated with mortality after IS for younger male subjects. Additional studies are needed to characterize possible genetic and nongenetic familial environmental causes of this association.

Purpose To analyse risk of vision impairment (VI) and blindness in adult foreign-born individuals and Swedish-born individuals. Methods A nationwide study of individuals 18 years of age and older (N = 6,042,891; 2,902,918 men and 3,139,973 women) in Sweden. VI (in general) and blindness was defined as at least one registered diagnosis in the National Patient Register between January 1, 1998 and December 31, 2015. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident VI in foreign-born compared to Swedish-born individuals. The Cox regression models were stratified by sex and adjusted for age, co-morbidities, and for sociodemographic status. Results A total of 14,597 cases (6433 men and 8164 women) of VI were registered, with an age-standardized incidence per 100,000 person-years of 10.37 in men and 11.03 in women. VI (in general) was more common in immigrants, fully adjusted HRs (95% CI) were for immigrant men 1.38 (95% CI, 1.29–1.48) and women 1.24 (95% CI, 1.16–1.32), with significantly higher HRs among men and women from Eastern Europe, Africa, Latin America and Asia. Higher risks of blindness were also seen for immigrant men, HR 1.75 (95% CI 1.36–2.25), as well as for the other degrees of VI among immigrant men, HR 1.36 (95% CI 1.26–1.47), and immigrant women, HR 1.26 (95% CI 1.18–1.35). Conclusions We observed a generally higher risk of VI among foreign-born men and women, especially from some regions.

Purpose Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden. Methods We performed a follow-up study based on Swedish national register data for the period January 1997–December 2016. The study was based on 1,361,532 men aged 50–75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD. Results DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00–1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40–1.82, p Conclusions Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.

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.

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.

Background There is a lack of studies of amyotrophic lateral sclerosis (ALS) in immigrants. Objective The objective is to study the association between country of birth and incident ALS in first-generation immigrants versus Swedish-born individuals, and in second-generation immigrants versus native Swedes. Methods Study populations included all adults aged 18 years and older in Sweden, in the first-generation study 6,128,698 individuals (2,975,141 men, 3,153,557 women) with 5,344 ALS cases (3017 men, 2327 women), and in the second-generation study 4,588,845 individuals (2,346,855 men and 2,241,990 women) with 3,420 cases (2027 men and 1393 women). ALS was defined as having at least one registered diagnosis of ALS in the National Patient Register 1998–2017. The incidence of ALS in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) with 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighbourhood socioeconomic status. Results After adjusting for potential confounders, the HRs were lower in foreign-born men, 0.71 (95% CI 0.63–0.81), and women, 0.80 (95% CI 0.70–0.92). The ALS risk was lower among men and women from most Western countries (Europe outside Nordic countries, and North America), and from other regions of the world (Africa, Asia, and Latin America). Among men and women with foreign-born parents, the risk of ALS did not differ significantly from native Swedes. Significance In general, the risk of ALS was lower in first-generation men and women but did not differ in second-generation individuals.

Background and Purpose: Clinicians will increasingly encounter adult patients who were born preterm and will need to understand their long-term sequelae. Adult survivors of preterm birth have been reported to have increased risks of hypertension and other stroke risk factors. However, their stroke risks have seldom been examined and the findings are discrepant, possibly due to small sample sizes, insufficient follow-up, or survivor bias. We examined whether preterm birth is associated with stroke in a large population-based cohort. Methods: A national cohort study was conducted of all 2 140 866 singletons born in Sweden from 1973 to 1994 who survived to age 18 years, who were followed up for first-time stroke through 2015 (maximum age 43 years). Cox regression was used to examine stroke risks associated with gestational age at birth, adjusting for other perinatal and parental factors. Cosibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. Results: In 28.0 million person-years of follow-up, 4861 (0.2%) people were diagnosed with stroke. At ages 18 to 43 years, the adjusted hazard ratio for stroke associated with preterm birth (P P =0.005) for early preterm (22–33 weeks) and 1.22 (1.06–1.40; P =0.004) for late preterm (34–36 weeks), compared with full-term (39–41 weeks). Positive associations were found with both hemorrhagic stroke (early preterm: adjusted hazard ratio, 1.42 [95% CI, 1.04–1.94]; any preterm: 1.15 [0.97–1.35]) and ischemic stroke (early preterm: adjusted hazard ratio, 1.33 [95% CI, 0.87–2.03]; any preterm: 1.31 [1.07–1.60]). These findings were similar in men and women and only partially explained by shared determinants of preterm birth and stroke within families. Conclusions: In this large national cohort, preterm birth was associated with increased risks of both hemorrhagic and ischemic stroke in adulthood. Preterm birth survivors need early preventive evaluation and long-term clinical follow-up to reduce their lifetime risk of stroke.

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. The aim of this study was to analyse the risk of valvular heart diseases among foreign-born individuals in Sweden. Design. This was a nationwide study of individuals aged 18 years of age and older (N = 6,118,649; 2,970,055 men and 3,148,594 women). Valvular heart diseases were defined as at least one registered diagnosis in the National Patient Register between 1 January 1998 and 31 December 2012. Cox regression analysis was used to estimate hazard ratios (HR) with 99% confidence intervals (CI) of incident valvular heart diseases in foreign-born individuals compared to Swedish natives. The Cox regression models were adjusted for age, co-morbidities, and sociodemographic factors. Sub-categories were chronic rheumatic valvular heart diseases and non-rheumatic valvular heart diseases. Results. There were 64,979 male cases and 59,075 female cases. Fully adjusted HRs (99% CI) were among immigrant men 0.86 (0.82–0.89) and immigrant women 0.96 (0.92–1.00). For chronic rheumatic valvular disease among immigrant men and women, the HRs were 1.62 (1.37–1.92) and 1.75 (1.52–2.00), respectively, and, for non-rheumatic valvular disease among immigrant men 0.83 (0.80–0.87) and immigrant women 0.92 (0.88–0.96). Increased risks for chronic rheumatic valvular disease were found among men from Southern, Eastern and Central Europe, Africa and Asia and among women from Western, Eastern and Central Europe and Africa, Latin America and Asia. Conclusions. We observed lower risks in general of valvular heart disease, but higher risks of chronic rheumatic valvular heart disease in immigrants, which is important in the clinical situation.

Aim: We aimed to estimate the risk of hearing impairment in children and adolescents with foreign-born parents, compared to natives. Methods: A nationwide study of 1,923,590 (51.4% boys) individuals aged 0–17 years of age in Sweden. Hearing impairment was defined as at least one registered diagnosis in the National Patient Register between 1 January 1998 and 31 December 2015. We used Cox regression analysis to estimate relative risk (hazard ratios with 99% confidence intervals) of incident hearing impairment in children with foreign-born parents compared to Swedish-born natives. Cox regression models were stratified by sex and adjusted for age, co-morbidities and socioeconomic status. Results: A total of 20,514 cases (53.7% boys) with extended sensorineural hearing impairment were registered, also including noise-induced hearing impairment and that from other causes, and 6172 cases (50.0% boys) with conductive hearing impairment. The risk of extended sensorineural hearing impairment was higher in boys with parents from Asia, especially from Iraq, fully adjusted HR (99% CI) 1.30 (1.17–1.4), and lower in boys with parents from Nordic countries, South Europe, and North America. Conclusion: The risk of extended sensorineural hearing impairment was higher in boys with parents from Asia, in particular Iraq. (Less)

Aims Certain autoimmune diseases (ADs), such as Crohn’s disease and celiac diseases, have been linked to acute cardiovascular disorders. We examined whether there is an association between 43 different ADs and risk of subsequent hospitalization and mortality of cardiomyopathy in a nationwide follow-up study in Sweden. Methods and results All individuals in Sweden hospitalized with a main diagnosis of an AD (n = 955 410) without previous or coexisting cardiomyopathy, between 1 January 1987 and 31 December 2018, were followed for hospitalization or mortality of cardiomyopathy. The reference population was the total population of Sweden. Standardized incidence ratios (SIRs) for cardiomyopathy were calculated. Overall risk of cardiomyopathy during the first year after hospitalization for an AD was 3.63 [99% confidence interval (CI) 3.29–4.00]. A total of 21 of the 43 ADs studied were associated with an increased risk of cardiomyopathy during the first year after hospitalization. The overall risk of cardiomyopathy decreased over time, from 1.18 (99% CI 1.12–1.25) after 1+ year to 1.07 (99% CI 0.96–1.19) after 5+ years. Females generally had higher SIRs than males. The ADs for which the SIRs of cardiomyopathy were highest after 1 year of hospitalization included Crohn’s disease (1.92), rheumatoid arthritis (1.57), sarcoidosis (1.48), and psoriasis (1.31). Conclusion Most ADs are associated with an increased risk of cardiomyopathy, particularly in the first year after hospital admission. Our findings show that many hospitalized ADs are tightly linked to cardiomyopathy but the mechanisms need to be further evaluated.

The association between neighbourhood crime and major depression (MD) has been described before but previous studies may be limited by biases in self-reported data and the use of homogenous study populations. Our study aimed to examine the association between neighbourhood crime and clinically diagnosed MD among the immigrant and non-immigrant populations in Sweden.A retrospective cohort study was performed, which included non-immigrants and first- and second-generation immigrants residing in Sweden, who were born between 1960 and 1996. We used linked Swedish national registers, geospatial analysis and multilevel logistic regression models to examine the potential effect of neighbourhood crime on the odds of major depression between January 1, 2012, and December 31, 2015.Overall, individuals living in neighbourhoods with high levels of neighbourhood crime had higher odds of MD than those who did not. There was a significant interaction by immigrant status; the odds of MD among those with non-immigrant backgrounds were more strongly associated with increases in neighbourhood crime, after adjusting for potential confounders. Male and female immigrants born outside Sweden did not seem to be affected by increases in neighbourhood crime.The apparent effect of increases in neighbourhood crime on the odds of MD seemed to differ between those of different immigrant statuses. Future research should aim to explore the possible mechanisms behind the differences in the rates of MD among the non-immigrant and immigrant populations in neighbourhoods with high crime.

Background There is a lack of evidence-based recommendations for the age at which women with a family history of cancers other than breast cancer should start breast cancer screening. Methods Using Swedish family cancer data sets, the authors conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931 (follow-up, 1958-2015). Accounting for calendar time, they calculated the relative risk of breast cancer for women with a family history of a discordant cancer in 1 first-degree relative. Furthermore, the authors used 10-year cumulative risk to determine the ages at which women with a family history of discordant cancer reached risk thresholds at which women in the general population were recommended to start breast cancer screening. Results A family history of cancer at 15 sites was associated with an increased risk of breast cancer. Among women younger than 50 years, the highest risk of breast cancer was observed for those with a family history of ovarian cancer (standardized incidence ratio, 1.44; 95% confidence interval, 1.26-1.64). In these women, the risk of breast cancer associated with a family history at other cancer sites ranged from 1.08-fold for prostate cancer to 1.18-fold for liver cancer. When breast cancer screening was recommended to be started at the age of 50 years for the general population, women with 1 first-degree relative with ovarian cancer attained the threshold risk for screening at the age of 46 years. Women with a family history of other discordant cancers did not reach the risk thresholds for screening at younger ages. Conclusions Many cancers showed familial associations with breast cancer, but women with a family history of these cancers (except for ovarian cancer) did not reach risk thresholds for screening at younger ages.

Background There is a lack of studies of Huntington’s disease (HD) in immigrants. Objective To study the association between country of birth and incident HD in first-generation immigrants versus Swedish-born individuals and in second-generation immigrants versus Swedish-born individuals with Swedish-born parents. Methods Study populations included all adults aged 18 years and older in Sweden, i.e., in the first-generation study 6,042,891 individuals with 1034 HD cases and in the second-generation study 4,860,469 individuals with 1001 cases. HD was defined as having at least one registered diagnosis of HD in the National Patient Register. The incidence of HD in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighborhood socioeconomic status. Results Mean age-standardized incidence rates per 100,000 person-years were for all Swedish-born 0.82 and for all foreign born 0.53 and for all men 0.73 and for all women 0.81, with the highest incidence rates for the group 80–84 years of age. After adjusting for potential confounders, the HRs were lower in women in the first- and second-generation, i.e., 0.49 (95% CI 0.36–0.67) and 0.63 (95% 0.45–0.87), respectively, and also among women from Finland or with parents from Finland. Significance In general, the risk of HD was lower in first-generation and second-generation immigrant women but not among male immigrants.

Summary In this national study of osteoporotic fractures in second-generation immigrants in Sweden, we found a similar risk of osteoporotic fractures in general compared to Swedish natives, which suggests that environmental factors are important for the high risk of osteoporotic fractures in Nordic countries. Introduction Second generation immigrants may have a similar environment as individuals with two native-born parents. These individuals may be of interest to study concerning whether environmental or hereditary factors could be mostly associated to the risk of osteoporotic fractures. The aim of this study was to analyse the risk of osteoporotic fractures in second-generation immigrants compared to Swedish natives. Methods This was a nationwide study of individuals aged 50 years of age and older (N = 1,377,035; 691,750 men and 685,285 women). Osteoporotic fractures were defined as at least one registered diagnosis of fractures in the hip, humerus, forearm or vertebrae, in the National Patient Register between January 1, 1998, and December 31, 2012. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident osteoporotic fractures in second generation immigrants compared to Swedish natives. The Cox regression models were adjusted for age, comorbidities and for sociodemographic status. Results A total of 114,505 osteoporotic fractures were registered, 109,622 (8.4%) were among individuals with Swedish-born parents and 4883 (7.5%) among those with foreign-born parents, with distal forearm fractures dominating in general (44.9%). Fully adjusted HRs (95% CI) were for all immigrants 0.95 (95% CI, 0.91–0.99), for men 0.96 (95% CI, 0.89–1.04) and for women 0.95 (95% CI, 0.90–1.00). Conclusions We observed a similar risk of osteoporotic fractures among second-generation immigrants as in Swedish natives, which suggests that environmental factors are important for osteoporotic fractures. Supplementary Information The online version contains supplementary material available at 10.1007/s00198-020-05776-4.

Abdominal aortic aneurysm (AAA) is a life-threatening condition with a mortality rate of over 80%. Persistent smoking, which is a risk factor for AAA, has lasting effects on DNA methylation. Moreover, a plasma-amino acid, homocysteine, previously implicated in vascular diseases, including aneurysms, has well-established biological association with methylation. In the present study, we aimed to determine the global DNA methylation, homocysteine levels and their association with AAA and its growth. Enzyme-linked immunosorbent assay (ELISA) was used to quantify global DNA methylation in whole blood-DNA samples and diagnostic enzymatic assay quantified plasma homocysteine, from 65-year old men with (n = 116) and without AAA (n = 230) diagnosed at ultrasound screening. We found significantly higher global DNA methylation (p .001) and homocysteine levels (p .001) in men with AAA compared to those without AAA, and direct linear associations with baseline aortic diameter. On multivariable regression analysis, global DNA methylation (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.1-2.9) and homocysteine levels (OR: 1.1; 95% CI:1.0-1.1) were positively associated with AAA, independent of smoking, medication use, and major co-morbidities. However, we did not find any significant association between DNA methylation or homocysteine levels with AAA growth during follow-up. We found that global DNA methylation and homocysteine levels are higher in men with AAA but are not associated with AAA growth. This indicates that different pathways and mechanisms may be involved in initiation and progression of AAA. More studies are needed to understand the precise role of DNA methylation, homocysteine and their interplay in AAA pathophysiology.

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., Children whose mother or father was ever diagnosed with central nervous system tumor below age of 20 didn't have a higher risk to experience mental diseases, however, they were at an increased risk of mild intellectual disability.

Circulating cell‐free nuclear DNA (nDNA) has been implicated in individual cancer types with a diagnostic value; however, the role of cell‐free mitochondrial DNA (mtDNA) in cancers is controversial. We aimed to investigate and compare the diagnostic potential of both nDNA and mtDNA for multiple cancers and to investigate their ability to distinguish multiple cancers from healthy controls and from nonmalignant diseases. We also investigated the prognostic value of both nDNA and mtDNA. The absolute copy number of circulating DNAs in suspected cancer patients (n = 286) referred to a cancer diagnostic center and healthy controls (n = 109) was quantified by droplet digital polymerase chain reaction. Among the suspected cancer patients, 66 (23%) were diagnosed with various cancers, 193 (67%) with nonmalignant diseases, and 27 (10%) with no active disease. Levels of nDNA were significantly higher in cancers (copies/μl; mean ± SD, 21.0 ± 14.2) as compared with nonmalignant diseases (15.2 ± 10.0) and controls (9.3 ± 4.1). In contrast, levels of mtDNA were significantly lower in cancers (copies/μl; mean ± SD, 68,557 ± 66,663) and nonmalignant diseases (60,174 ± 55,831) as compared with controls (98,714 ± 77,789). Receiver operating curve analysis showed that nDNA not only could distinguish multiple cancers from controls (area under curve [AUC] = 0.78; 95% confidence interval [CI] = 0.70–0.86) but also from nonmalignant diseases (AUC = 0.68; 95% CI = 0.59–0.76). However, mtDNA could only differentiate cancers from controls (AUC = 0.65; 95% CI = 0.56–0.73). Higher levels of nDNA were also associated with increased mortality in the cancer patients (hazard ratio = 2.3; 95% CI = 1.1–4.7). Circulating cell‐free nDNA, but not the mtDNA, could distinguish multiple cancers from nonmalignant diseases and was associated with poor survival of cancer patients.

Objectives To analyze the risk of hearing impairment in adult first-generation immigrants, i.e., foreign-born individuals as compared to Swedish-born individuals. Study design A register-based study follow-up study. Methods A 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. Results A 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. Conclusions We 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.

INTRODUCTION: Alcohol use disorder (AUD) has been identified as a strong risk factor for suicide attempt. However, few studies have considered protective factors that may moderate this association, such as resilience. METHODS: We used longitudinal nationwide Swedish data of 903,333 males born 1960–1980 and 48,285 males born 1949–1951. We performed Cox proportional hazards models to test the role of AUD, resilience, and their interaction on risk for suicide attempt. We used co-relative models to account for familial factors. RESULTS: Alcohol use disorder was strongly associated with increased risk of suicide attempt [hazard ratio (HR) = 12.22], while resilience was associated with reduced risk (HR = 0.73). Multiplicative interaction (HR = 1.21) showed that, in the context of AUD, the protective role of resilience on risk of suicide attempt was somewhat attenuated. Co-relative analyses supported both familial liability and a possible causal pathway between AUD, resilience, and suicide attempt. In the cohort born 1949–1951, resilience subcomponents—social maturity, interests, psychological energy, home conditions, and emotional control—were all associated with reduced suicide attempt risk (HRs between 0.63 and 0.74). CONCLUSION: While resilience is associated with reduced risk of suicide attempt, this effect is less pronounced in the context of AUD. These associations are potentially causal.

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).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.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 (RROur 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.

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., Relative risks for a single second primary cancer after any first primary cancer (top), and RRs for any second primary cancer after a single first primary cancer (bottom). Male data are blue and female data in yellow symbols. The vertical bars show 95%CIs. NHL, non‐Hodgkin lymphoma, CLL, chronic lymphocytic leukemia.

Introduction Academic achievement (AA) is associated with smoking rates. Can we determine the degree to which this relationship is likely a causal one? Methods We predict smoking in male conscripts (mean age 18.2) assessed from 1984 to 1991 (N = 233 248) and pregnant females (mean age 27.7) receiving prenatal care 1972–1990 (N = 494 995) from AA assessed in all students at 16. Instrumental variable (IV) analyses used the instrument month-of-birth as in each school year, older children have high AA. Co-relative analyses used AA-smoking associations in the population, cousins and siblings to predict the AA-smoking relationship in MZ twins, thereby controlling for familial confounding. Results In males, higher AA was associated with a substantial decrease in risk for smoking (odds ratio [OR] [95% confidence intervals [CIs]] per standard deviation [SD] = 0.41 [0.40–0.41]) while the parallel figures obtain from our IV and co-relative analyses were 0.47 (0.39–0.57) and 0.51 (0.43–0.60), respectively. In females, these figures for pre-pregnancy smoking were, respectively, 0.39 (0.39–0.39), 0.50 (0.46–0.54) and 0.54 (0.51–0.58). Results for heavy versus light smoking suggested a causal effect but were inconsistent across methods. However, among females smoking prior to pregnancy, AA predicted a reduced risk for continued smoking with ORs for uncontrolled, IV, and co-relative analyses equaling, respectively, were 0.54 (0.53–0.55) 0.68 (0.56–0.82) and 0.78 (0.66–0.91), respectively. Conclusions Two different methods produced consistent evidence that higher AA has a causal effect on reducing smoking rates and increasing cessation rates in smoking pregnant females. Improving AA may result in meaningful gains in population health through reduced smoking. Implications This study provides consistent evidence across two different methods that high AA is causally related to reduced rates of smoking and increasing rates of smoking cessation among pregnant women. Our results suggest that interventions that improve educational achievement in adolescence would reduce tobacco consumption, thereby improving public health.

Summary In this national study of osteoporotic fractures in foreign-born individuals, we found a lower risk of osteoporotic fractures in general among foreign-born individuals compared with Swedish-born, especially in immigrants from southern Europe. A higher risk was found among some groups, i.e. men and women from Bosnia and Iraq and men from Lebanon. Introduction The aim of this study was to analyse risk of osteoporotic fractures in foreign-born individuals compared with Swedish-born individuals. Methods This was a nationwide study of individuals 50 years of age and older (N = 2,775,736). Osteoporotic fractures were defined as at least one registered diagnosis of fractures in the hip, humerus, forearm or vertebrae, in the National Patient Register between January 1, 1998, and December 31, 2012. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 99% confidence intervals (CI)) of incident osteoporotic fractures in foreign-born compared with Swedish-born individuals. The Cox regression models were stratified by sex and adjusted for age, comorbidities and sociodemographic status. Results A total of 362,899 osteoporotic fractures were registered (96,847 among men and 266,052 among women), with hip fractures dominating (54.0% among men, 42.6% among women). Fully adjusted HRs (99% CI) were for all immigrant men 0.75 (99% CI, 0.73–0.78) and women 0.83 (99% CI, 0.81–0.84), with significantly lower HRs among most groups but with higher HRs in certain countries. For the specific fractures, higher HRs were found for lower forearm fractures for men from Asia and for vertebral fractures among women from Asia. Conclusions We observed a generally lower risk of osteoporotic fractures among first-generation immigrants, with few exceptions. Electronic supplementary material The online version of this article (10.1007/s00198-020-05597-5) contains supplementary material, which is available to authorized users.

Congestive heart failure (CHF) is the most important cause of death in patients with atrial fibrillation (AF). We aimed to study the association between cardiovascular drugs in AF patients and incident CHF. The study population included all adults (n = 120 756) aged ≥45 years diagnosed with AF in Sweden diagnosed for the period 1998‐2006. Outcome was incident congestive heart failure (follow‐up 2007‐2015) in AF patients. Associations between treatment with cardiovascular pharmacotherapies and CHF were evaluated using Cox regression to estimate hazard ratios (HRs) with 95% CIs, after adjustment for age, sociodemographic variables, and comorbidities. During a mean 5.3 years (SD 3.0) of follow‐up, there were 28 257 (23.4%) incident cases of CHF. Treatment with beta‐1‐selective and non‐selective beta‐blockers and statins was associated with lower risks of incident CHF in men, HR, (95% CI); 0.90, (0.87‐0.94); 0.90, (0.84‐0.97), and 0.94, (0.90‐0.99), respectively. Only beta‐1‐selective beta‐blockers were protective in women 0.94 (0.91‐0.98). Treatment with loop diuretics, potassium‐saving agents, ACE inhibitors, and angiotensin receptor blockers was associated with a higher risk of CHF. For men, treatment with heart‐active calcium channel blockers also led to a higher risk of CHF. In conclusion, we found that beta‐blockers, in particular, but also statins were associated with lower risk of incident CHF in patients with AF.

OBJECTIVE: We evaluated the claim that interventions to improve academic achievement can reduce the risk for alcohol use disorder (AUD). METHOD: Using nationwide data for individuals born in Sweden from 1972 to 1981 (n = 930,182), we conducted instrumental variable and co-relative analyses of the association between academic achievement and AUD with a mean 21.4-year follow-up. Our instrument, used in the instrumental variable analyses, was month of birth. Co-relative analyses were conducted in cousins, full siblings, and monozygotic twins discordant for AUD, with observed results fitted to a genetic model. The academic achievement–AUD association was modeled in Cox regression. AUD was assessed using national medical, criminal, or pharmacy registries. RESULTS: Later month of birth was significantly associated with poorer academic achievement. Lower standardized academic achievement had a strong relationship with the risk for subsequent AUD registration: hazard ratio (HR) [per SD] = 2.14 [2.11, 2.17]. Instrumental variable analysis produced a substantial but moderately attenuated association: HR = 1.52 [1.28, 1.80]. Controlling for modest associations between month of birth and parental education and AUD risk reduced the association to HR = 1.43 [1.20, 1.69]. Our genetic co-relative model fitted the observed data relatively well and estimated the academic achievement–AUD association in monozygotic twins discordant for academic achievement to equal an HR of 1.44 [1.35, 1.52]. Results were broadly similar when analyzed separately in males and females. CONCLUSIONS: Two distinct methods with different assumptions produced results suggesting that the association observed between academic achievement at age 16 and the risk for AUD into middle adulthood is partly causal, thereby providing support for interventions to improve academic achievement as a means to prevent later AUD risk.

The authors examined the association between alcohol use disorder (AUD) and risk of suicide, before and after accounting for psychiatric comorbidity, and assessed the extent to which the observed association is due to a potentially causal mechanism or genetic and familial environmental confounding factors that increase risk for both.Longitudinal population-wide Swedish medical, criminal, and pharmacy registries were used to evaluate the risk of death by suicide as a function of AUD history. Analyses employed prospective cohort and co-relative designs, including data on 2,229,880 native Swedes born between 1950 and 1970 and observed from age 15 until 2012.The lifetime rate of suicide during the observation period was 3.54% for women and 3.94% for men with AUD, compared with 0.29% and 0.76% of women and men, respectively, without AUD. In adjusted analyses, AUD remained robustly associated with suicide: hazard ratios across observation periods ranged from 2.61 to 128.0 among women and from 2.44 to 28.0 among men. Co-relative analyses indicated that familial confounding accounted for some, but not all, of the observed association. A substantial and potentially causal relationship remained after accounting for a history of other psychiatric diagnoses.AUD is a potent risk factor for suicide, with a substantial association persisting after accounting for confounding factors. These findings underscore the impact of AUD on suicide risk, even in the context of other mental illness, and implicate the time frame shortly after a medical or criminal AUD registration as critical for efforts to reduce alcohol-related suicide.

Women who deliver pre-term have been reported to have increased future risks of cardiometabolic disorders. However, their long-term risks of ischemic heart disease (IHD) and whether such risks are due to shared familial factors are unclear. A better understanding of these risks may help improve long-term clinical follow-up and interventions to prevent IHD in women.The purpose of this study was to determine the long-term risks of IHD in women by pregnancy duration.A national cohort study was conducted of all 2,189,190 women with a singleton delivery in Sweden from 1973 to 2015, who were followed up for IHD through the end of 2015. Cox regression was used to compute adjusted hazard ratios (aHRs) for IHD associated with pregnancy duration, and cosibling analyses assessed the influence of shared familial (genetic and/or environmental) factors.In 47.5 million person-years of follow-up, 49,955 (2.3%) women were diagnosed with IHD. In the 10 years following delivery, the aHR for IHD associated with pre-term delivery (37 weeks) was 2.47 (95% confidence interval [CI]: 2.16 to 2.82), and further stratified was 4.04 (95% CI: 2.69 to 6.08) for extremely pre-term (22 to 27 weeks), 2.62 (95% CI: 2.09 to 3.29) for very pre-term (28 to 33 weeks), 2.30 (95% CI: 1.97 to 2.70) for late pre-term (34 to 36 weeks), and 1.47 (95% CI: 1.30 to 1.65) for early-term (37 to 38 weeks), compared with full-term (39 to 41 weeks). These risks declined but remained significantly elevated after additional follow-up (pre-term vs. full-term, 10 to 19 years: aHR: 1.86; 95% CI: 1.73 to 1.99; 20 to 29 years: aHR: 1.52; 95% CI: 1.45 to 1.59; 30 to 43 years: aHR: 1.38; 95% CI: 1.32 to 1.45). These findings did not appear attributable to shared genetic or environmental factors within families. Additional pre-term deliveries were associated with further increases in risk.In this large national cohort, pre-term delivery was a strong independent risk factor for IHD. This association waned over time but remained substantially elevated up to 40 years later. Pre-term delivery should be recognized as a risk factor for IHD in women across the life course.

To determine whether alcohol use disorder (AUD) is transmitted within families as predicted by contagion, we examined parent-offspring, siblings, and cousin pairs ascertained from Swedish registries with a primary case with AUD. Our outcome variable was AUD registration in at-risk secondary cases. In offspring, risks for AUD registration in the 3 years after a parental index registration residing in the same household, neighborhood, or municipality increased by 1.6%, -0.5%, and 0.3%, respectively. For siblings of sibling index cases, parallel results were 3.2%, 1.2%, and 0.3%. For cousins of cousin index cases, no excess risk was seen for those residing in the same neighborhood or municipality. In siblings, AUD transmission was stronger in same versus opposite sex pairs and from older to younger versus younger to older siblings. These results support the hypothesis that AUD is transmitted among close family relationships and over limited geographical distances by a temporally dynamic contagion model.

BackgroundAlthough alcohol use disorder (AUD) runs strongly within families, studies examining the impact of rearing environment, unconfounded by genetic effects, are rare and, to date, contradictory. We here seek to conduct such a study using an adoptive co-sib control design.MethodsDefining high-risk as having ⩾1 biological parent with an externalizing syndrome (AUD, drug abuse or crime), we identified 1316 high-risk full-sibships and 4623 high-risk half-sibships containing at least one member who was home-reared and one who was adopted-away. Adoptive families are carefully screened in Sweden to provide high-quality rearing environment for adoptees. AUD was assessed from national medical, criminal and pharmacy registries.ResultsControlling for sex, parental age at birth, and, for half-siblings, affection status of the non-shared parent, hazard ratios (±95% CI) for AUD in the matched adopted v. home-reared full- and half-siblings were, respectively, 0.76 (0.65–0.89) and 0.77 (0.70–0.84). The protective effect of adoption on AUD risk was stronger in the full- and half-sibling pairs with very high familial liability (two high-risk parents) and significantly weaker when the adoptive family was broken by death or divorce or contained a high-risk adoptive parent.ConclusionsIn both full- and half-sibling pairs, we found evidence that the rearing environment substantially impacts on the risk for AUD. High-quality rearing environments can meaningfully reduce the risk for AUD, especially in those at high familial risk.

Aim: To compare incidence of urolithiasis in second-generation immigrant children aged 0-17 years to children of Swedish-born parents. Methods: A nationwide study of individuals residing in Sweden. Urolithiasis was defined as having at least one registered diagnosis of urolithiasis in the Swedish National Patient Register between January 1, 1998 and December 31, 2015. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident urolithiasis compared to individuals with Swedish-born parents. The models were stratified by sex and adjusted for age, co-morbidities and sociodemographic status of parents. Results: Totally, 1653 incident cases of urolithiasis were registered, 658 boys and 995 girls, with a mean annual incidence per 100 000 person-years for children with Swedish-born parents of 4.0 (95% CI 3.7-4.3) in boys and 6.7 (95% CI 6.2-7.2) in girls, and for children with foreign-born parents of 5.3 (95% CI 5.1-5.4) in boys and 7.2 (95% CI 6.9-7.4) in girls. The fully adjusted HRs of urolithiasis in second-generation immigrants were non-significant, in boys (1.20, 95% CI 0.99-1.46) and girls (0.95, 95% CI 0.80-1.12). Conclusion: The risk of urolithiasis in second-generation immigrants was not significantly different from that of children with Swedish-born parents. (Less)

Background Our aim was to study the potential effect of neighborhood deprivation on incident heart failure (HF) in patients with diabetes mellitus (DM). Methods The study population included adults (n = 434,542) aged 30 years or older with DM followed from 2005 to 2015 in Sweden for incident HF. The association between neighborhood deprivation and the outcome was explored using Cox regression analysis, with hazard ratios (HRs) and 95% confidence intervals (95% CIs). All models were conducted in both men and women and adjusted for age, educational level, family income, employment status, region of residence, immigrant status, marital status, mobility, and comorbidities. DM patients living in neighborhoods with high or moderate levels of deprivation were compared with those living in neighborhoods with low deprivation scores (reference group). Results There was an association between level of neighborhood deprivation and HF in DM patients. The HRs were 1.27, 95% CI 1.21–1.33, for men and 1.30, 95% CI 1.23–1.37, for women) among DM patients living in high deprivation neighborhoods compared with those from low deprivation neighborhoods. After adjustments for potential confounders, the higher HRs of HF remained significant: 1.11, 95% CI 1.06–1.16, in men and 1.15, 95% CI 1.09–1.21, in women living in high deprivation neighborhoods. Conclusions Increased incidence rates of HF among DM patients living in deprived neighborhoods raise important clinical and public health concerns. These findings could serve as an aid to policy-makers when allocating resources in primary health-care settings as well as to clinicians who encounter patients in deprived neighborhoods.

Purpose A growing number of young patients with central nervous system (CNS) tumour survived for more than five years. However, these long-term survivors might be at risk of multiple late effects thus leading to a higher risk of late mortality. We aimed to explore the risk of late mortality and the pattern of mortality among long-term survivors of childhood or adolescent CNS tumour. Methods We identified 5-year survivors with childhood or adolescent CNS tumour before age 20 years through the Swedish Cancer Registry. Five controls were randomly matched for each patient to generate the reference group. We retrieved information about death via Cause of Death Register. We calculated the absolute excess risk (AER) of death and the hazard ratio (HR) of death using Cox proportional hazard model. Results Long-term survivors with CNS tumour suffered a significant higher risk of overall mortality (HR 6.56, 95% CI 5.71–7.53; AER 5.89, 95% CI 5.03–6.87). The mortality rate declined with the increasing survival time, but it was still higher even after 30 years of follow-up. Malignant neoplasms contributed mostly to late mortality with an AER of 3.75 (95% CI 2.95–4.75). Female survivors, survivors diagnosed at a younger age and survivors with medulloblastoma were particularly strongly associated with a higher risk of death. Conclusions Long-term survivors of childhood and adolescent CNS tumours are at a higher risk of late mortality, and the risk of death is affected by gender, age at diagnosis and types of CNS tumour.

Background Patients with atrial fibrillation (AF) have an increased dementia risk dementia. We aimed to study the effect of antihypertensive drugs on dementia in AF patients. Methods Included patients were ≥45 years diagnosed with AF in Swedish National Patient Register (n = 160,251; 89,723 men and 70,528 women) and alive on January 1, 2007. We excluded patients with dementia before onset of AF. Cox regression was used (hazard ratios, HRs, and 99% confidence interval, CI) with adjustments for sex, age, socioeconomic factors and co-morbidities, using incident dementia diagnosis until December 31, 2015 as outcome. Cardiovascular pharmacotherapies were obtained from the Swedish Prescribed Drug Register. Results Incident dementia occurred in 9532 patients (5.9%), 4669 men (5.2%) and 4863 women (6.9%). ARBs were associated with lower risk for all patients (HR 0.87, 99% CI 0.78–0.98), especially in the ages 65–84 years of age (HR 0.87, 99% CI 0.76–0.99). Loop-diuretics were associated with higher risk for all dementia among patients 65–84 years of age (HR 1.16, 99% CI 1.00–1.35), and in the sub-group of other causes of dementia than Alzheimer Disease (AD) and vascular dementia (VaD) (HR 1.14, 99% CI 1.00–1.30), but with a lower risk in the sub-group of AD and VaD (HR 0.81, 99% CI 0.68–0.95). Conclusion ARBs were associated with a decreased incidence of dementia, and loop diuretics with a higher risk in general but lower risk in the AD and VaD sub-group. ARBs could have specific advantages in prevention of dementia, but the results need confirmation in further studies.

Literature on familial risk of carcinomas in situ (CISs) is limited because many cancer registries do not collect information on CIS. In Sweden CISs are collected, and we used these data to analyze familial relative risks (RRs) for concordant (CIS-CIS) types of anogenital (cervical, other female and male genital and anal) and skin squamous cell CIS; additionally RRs were assessed between CIS types and between CIS and invasive forms. RRs were calculated for the offspring generations when family members were diagnosed CIS. Case numbers for CIS ranged from 330 in anal to 177,285 in cervical CIS. Significant concordant CIS-CIS RRs were 2.74 for female genital, 1.77 for cervical and 2.29 for SCC skin CISs. The CIS forms associated also with each other, except for cervical and skin CIS types. RRs for concordant CIS-invasive cancer associations were lower than CIS-CIS associations. Cervical CIS associated with non-Hodgkin CIS which may suggest immune dysfunction as a contributing factors. The results for anogenital CIS types suggest that life style related human papilloma virus infections contributed to the observed familial associations. Lower risks for CIS-invasive cancer than CIS-CIS suggest that CIS and invasive cancers share only partially risk factors that underlie familial clustering.

An increasing number of patients with central nervous system (CNS) tumor could survive to reproductive age. However, it is largely unknown whether the history of CNS tumor might affect pregnancy outcome. We aimed to explore the risk of being born preterm among children of CNS tumor survivors. By linking several nationwide registers in Sweden, we identified 1,369 children whose parents were childhood or adolescent CNS tumor survivors. Children whose parents did not have CNS tumor were matched randomly with a 5:1 ratio to generate the reference group. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI). The prevalence of preterm birth (PTB) was 6.9% among children of survivors with CNS tumor and 5.2% among the matched controls. Children of survivors had an increased risk of PTB (adjusted OR = 1.29, 95%CI 1.01-1.65) compared to the matched controls. This risk was increased specifically among offspring of those diagnosed in childhood (adjusted OR = 1.53, 95%CI 1.14-2.06) but not adolescence (adjusted OR = 0.89, 95%CI 0.56-1.41). For families with more than one child, the risk was slightly lower among the second child as compared to the first child. The risk was negatively associated with time interval between parental diagnosis and childbirth. Parental medulloblastoma and ependymoma were most strongly associated with a higher risk of PTB. Children of survivors with CNS tumor experienced an elevated risk of PTB. However, the risk diminishes gradually after parental diagnosis of CNS tumor. Offspring of childhood CNS tumor survivors and medulloblastoma or ependymoma survivors may have the highest risk of PTB.

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

BACKGROUND: The aim of this study was to clarify the possible causal associations between education phenotypes and non-fatal suicide attempts. In particular, we evaluated the roles of academic achievement (school grades), cognitive performance (IQ), and educational attainment (education level). METHODS: Based on longitudinal Swedish registry data, we included 2,335,763 individuals (48.7% female) with available school grades, 1,448,438 men with IQ measures, and 4,352,989 individuals (48.4% female) with available data on education level. We combined two different approaches to aid in causal inference: 1) instrumental variables analysis, using month of birth as an instrument related to education but not suicide attempt, to control for measured and unmeasured confounders, and 2) co-relative analysis, comparing pairs of different genetic relatedness (cousins, half, and full siblings) to control for genetic and environmental influences. RESULTS: High education was associated with reduced risk of suicide attempt. Instrumental variable analysis indicated evidence of a likely causal association between higher school grades and lower risk of suicide attempts (HR=0.71). Co-relative analyses supported the causality between the three predictors and suicide attempt risk (school grades, HR=0.80, IQ, HR=0.83, education level, HR=0.76). Finally, we examined the specificity of education phenotypes and found that both cognitive (IQ) and non-cognitive (school grades, education level) processes were involved in suicide attempt risk. LIMITATIONS: IQ was only available in men, limiting the generalizability of this analysis in women. CONCLUSIONS: Efforts to support causal associations in psychiatric research are needed to offer better intervention. Programs improving education during adolescence would decrease suicide attempt risk.

BACKGROUND: Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions, and the extent to which genetic and environmental factors shared with, versus distinct from, AUD contribute to this progression has not yet been determined. METHODS: Using data from Swedish national registries for a cohort born 1932-1970 (N=1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. RESULTS: We identified AUD registrations in 3.2% of women and 9.2% of men. Among those with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A=0.32) and men (A=0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. CONCLUSIONS: A moderate to substantial proportion of genetic and environmental variance contributing to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of potential prevention targets. We did not observe significant sex differences in the etiology of AMC, though follow-up is warranted in other well-powered studies.

ObjectiveObesity is a well-known risk factor for coronary heart disease (CHD), but there is little evidence on the effect of long-term trajectories of body mass index (BMI) over the life course. By using repeated assessments, the aim was to study the risk of CHD in adults during 38 years in different trajectories of BMI.MethodsA sample of 2129 men and women, aged 20-59 years at baseline, took part in four repeated interviews between 1980 and 2005. Data on BMI, medical history, lifestyle and socioeconomy were collected. Based on the World Health Organization categories of BMI, life course trajectories of stable normal weight, stable overweight, stable obesity, increasing BMI and fluctuating BMI were created. The individuals were followed through national registers for first hospitalization of CHD (389 events) until the end of 2017, and Hazard Ratios (HRs) were calculated, adjusted for age, sex, socioeconomic factors, lifestyle factors and metabolic comorbidities.ResultsStable normal weight in all assessments was the reference group. Those who had an increase in BMI from normal weight in the first assessment to overweight or obesity in later assessments had no increased risk of CHD, HR 1.04 (95% CI: 0.70-1.53). The HR for individuals with fluctuating BMI was 1.25 (0.97-1.61), for stable overweight 1.43 (1.03-1.98), for stable obesity 1.50 (0.92-2.55), and for stable overweight or obesity 1.45 (1.07-1.97), after full adjustments.ConclusionHaving a stable overweight or obesity throughout adult life was associated with increased CHD risk but changing from normal weight at baseline to overweight or obesity was not associated with increased CHD risk. Prevention of obesity early in life may be particularly important to reduce CHD risk.

Introduction. Conduct disorder is a psychiatric diagnosis characterized by repetitive and persistent norm-breaking behavior. This study aimed to compare the risk of conduct disorder between first- and second-generation immigrant children and adolescents and their native controls. Methods. In this nationwide, open-cohort study from Sweden, participants were born 1987–2010, aged 4–16 years at baseline, and were living in the country for at least one year during the follow-up period between 2001 and 2015. The sample included 1,902,526 and 805,450 children-adolescents with native and immigrant backgrounds, respectively. Data on the conduct disorder diagnoses were retrieved through the National Patient Register. We estimated the incidence of conduct disorder and calculated adjusted Hazard Ratios. Results. Overall, the adjusted risk of conduct disorder was lower among first-generation immigrants and most second-generation immigrant groups compared with natives (both males and females). However, second-generation immigrants with a Swedish-born mother and a foreign-born father had a higher risk of conduct disorder than natives. Similar results were found for sub-diagnoses of conduct disorder. Conclusions. The higher risk of conduct disorder among second-generation immigrants with a Swedish-born mother and the lower risk among most of the other immigrant groups warrants special attention and an investigation of potential underlying mechanisms.

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.

The authors examined the extent to which the genetic and environmental etiology of suicide attempt and suicide death is shared or unique.The authors used Swedish national registry data for a large cohort of twins, full siblings, and half siblings (N=1,314,990) born between 1960 and 1990 and followed through 2015. They conducted twin-family modeling of suicide attempt and suicide death to estimate heritability for each outcome, along with genetic and environmental correlations between them. They further assessed the relationship between suicide attempt by young people compared with adults.In bivariate models, suicide attempt and death were moderately heritable among both women (attempt: additive genetic variance component [A]=0.52, 95% CI=0.44, 0.56; death: A=0.45, 95% CI=0.39, 0.59) and men (attempt: A=0.41, 95% CI=0.38, 0.49; death: A=0.44, 95% CI=0.43, 0.44). The outcomes were substantially, but incompletely, genetically correlated (women: rA=0.67, 95% CI=0.55, 0.67; men: rA=0.74, 95% CI=0.63, 0.87). Environmental correlations were weaker (women: rE=0.36, 95% CI=0.29, 0.45; men: rE=0.21, 95% CI=0.19, 0.27). Heritability of suicide attempt was stronger among people ages 10-24 (A=0.55-0.62) than among those age 25 and older (A=0.36-0.38), and the genetic correlation between attempt during youth and during adulthood was stronger for women (rA=0.79, 95% CI=0.72, 0.79) than for men (rA=0.39, 95% CI=0.26, 0.47).The genetic and environmental etiologies of suicide attempt and death are partially overlapping, exhibit modest sex differences, and shift across the life course. These differences must be considered when developing prevention efforts and risk prediction algorithms. Where feasible, suicide attempt and death should be considered separately rather than collapsed, including in the context of gene identification efforts.

Past research on the social determinants of colorectal cancer (CRC) has shown that lower socioeconomic status (SES) is associated with a higher risk of CRC. Similar to SES at the individual level, the neighbourhood social environment may partly affect the development of CRC. Although one important aspect of the neighbourhood social environment is social capital, no large-scale follow-up study has examined its potential effect on CRC. We examined whether neighbourhood "linking social capital," which is established through social relationships and may enable individuals to gain health-promotional resources, is associated with the incidence of and mortality related to CRC, after adjusting for individual- and familial-level factors. This longitudinal study, conducted in Sweden, comprised over 2 million men and over 2 million women aged 25 years or older. The follow-up period started on January 1, 2002 and continued until first incidence of CRC, death due to CRC, death from any other cause, emigration, or the end of the study period on December 31, 2015. We identified over 20,000 CRC cases during the follow-up period. We used multilevel logistic regression models to calculate odds ratios (ORs) with 95% confidence intervals. After adjustment for potential confounding factors, higher ORs of CRC were observed in individuals who lived in neighbourhoods with low, relative to high social capital. Our results suggest that neighbourhood linking social capital has independent effects on CRC. Future studies could explore how simple interventions that can build linking social capital can enhance people's health.

OBJECTIVE: The purpose of this study was to clarify the mediational pathways from genetic risk for alcohol use disorder (AUD) to AUD itself. METHOD: Using information on AUD status from first- through fourth-degree relatives obtained from national registries, we created a genetic risk score for AUD for the Swedish population. We first tested a simple mediational path model in males and females separately, with early onset externalizing psychopathology (EPP), internalizing psychopathology (IPP), and poor educational attainment (EA). We then tested a more complex model in a smaller, older sample of males that contained additional self-report measures from late adolescence. RESULTS: In our basic model, the largest mediational pathway from AUD genetic risk to AUD in both sexes was via high EPP followed by low EA and high IPP. The EPP pathway was considerably stronger in males, the low EA pathway was modestly stronger in females, and the IPP pathway was identical in both sexes. Our more complex model replicated the strong externalizing pathway to AUD, showing that it connected to key downstream risk factors such as early drug and alcohol use and low resilience. CONCLUSIONS: Our models concurred in showing that the strongest mediational pathway for genetic risk to AUD includes externalizing symptoms and disorders, which in turn predict further key downstream risk factors. Pathways through lower EA and IPP had smaller effects. IPP had mixed effects (partly predisposing and partly protective) on downstream risk factors. The largest sex difference was a stronger externalizing pathway to genetic risk to AUD in males than in females.

Background Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. Methods and findings In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. Conclusions Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa., Xing Xu and co-workers assess prostate cancer risk in relatives of men with prostate cancer., Author summary Why was this study done? Family history is the strongest known risk factor for prostate cancer (PCa), and current guidelines concur that an earlier screening for men with a family history of PCa is necessary. However, limited evidence-based guidance is available on at what age actually this early screening should start. This study was conducted to provide precise recommendations about at what age should relatives of PCa patients start screening based on the number of affected relatives and the age at onset of PCa in the family. What did the researchers do and find? In this nationwide study on 6,343,727 men, the risk of stage III/IV or fatal PCa in close family members of patients with PCa was estimated. It was observed that men with family history of PCa reach the screening risk threshold up to 12 years earlier than the general population. This study found that age, age at diagnosis of PCa in relative/s, and number of affected first-degree relatives (FDRs) are important elements in increased risk of stage III/IV or fatal PCa, and these factors accordingly resulted in different risk-adapted starting ages of PCa screening. Comparison between our evidence-based risk-adapted starting age of screening and recommended age of PCa screening by different guidelines showed a difference ranging from −2 to 11 years. What do these findings mean? This study made use of the largest dataset available, to our knowledge, to identify the optimal age for starting PCa screening in relatives of patients with PCa. This study took into account not only the number of relatives but also age at onset of PCa in the family members, which is an additional important piece of information for the guidelines. The results may contribute to a more evidence-based personalized PCa screening guidance in real-world settings, and clinicians could inform patients with PCa about this possibility and encourage individualized counseling for their relatives.