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1.  Yoga’s effect on inflammatory biomarkers and metabolic risk factors in a high risk population – a controlled trial in primary care 
Yoga can reduce blood pressure and has also been suggested to reduce inflammatory biomarkers and metabolic risk factors for cardiovascular diseases (CVDs). We aimed to assess the benefit of two yoga interventions on inflammatory biomarkers and metabolic risk factors in a high risk population in primary care.
Adult patients from a health care center in Sweden, with diagnosed hypertension, were invited to undergo a baseline check at the health care center. Baseline check included standardized blood pressure measurement, BMI and weight circumference measurements, blood sampling (hs-CRP, IL-6, FP-glucose, HbA1c, cholesterol, TG, LDL and HDL) and a questionnaire on self-rated quality of life (WHOQOL-BREF). There were three groups: 1) yoga class with yoga instructor; 2) yoga at home; and 3) a control group. In total, 83 patients were included and matched at the group level for systolic blood pressure. A majority of the patients (92 %) were on antihypertensive medication, which they were requested not to change during the study. After 12 weeks of intervention, the assessments were performed again.
We recorded no evidence that yoga altered inflammatory biomarkers or metabolic risk factors in our study population. A total of 49 participants (59 %) met the criteria for metabolic syndrome.
The yoga interventions performed in our study did not affect inflammatory biomarkers or metabolic risk factors associated with CVD in the study population of primary care patients with hypertension. Further randomized trials are needed to elucidate the effects of yoga on CVD risk factors in this particular group.
Trail registration
NCT01302535, February 22, 2011.
PMCID: PMC4545550  PMID: 26286137
2.  Neighborhood linking social capital as a predictor of psychiatric medication prescription in the elderly: a Swedish national cohort study 
Little is known about the association between neighborhood linking social capital and psychiatric medication in the elderly. The present study analyzes whether there is an association between linking social capital (a theoretical concept describing the amount of trust between individuals and societal institutions) and prescription of antipsychotics, anxiolytics, hypnotics/sedatives, antidepressants, or anti-dementia drugs.
Design, Setting, Participants and Measurements
The entire Swedish population aged 65+, a total of 1,292,816 individuals, were followed from 1 July 2005 until first prescription of psychiatric medication, death, emigration, or the end of the study on 31 December 2010. Small geographic units were used to define neighborhoods. The definition of linking social capital was based on mean voting participation in each neighborhood unit, categorized in three groups. Multilevel logistic regression was used to estimate odds ratios (ORs) and between-neighborhood variance in three different models.
There was an inverse association between the level of linking social capital and prescription of psychiatric medications (except for anti-dementia drugs). The associations decreased, but remained significant, after accounting for age, sex, family income, marital status, country of birth, and education level (except for antidepressants). The OR for prescription of antipsychotics in the crude model was 1.65 (95% CI 1.53–1.78) and decreased, but remained significant (OR = 1.26; 95% CI 1.17–1.35), after adjustment for the individual-level sociodemographic variables.
Decision-makers should take into account the potentially negative effect of linking social capital on psychiatric disorders when planning sites of primary care centers and psychiatric clinics, as well as other kinds of community support for elderly patients with such disorders.
PMCID: PMC4085183  PMID: 24831853
Linking social capital; Neighborhood; Psychiatric medication; socioeconomic status
3.  The longitudinal age and birth cohort trends of regular exercise among adults aged 16–63 years in Sweden: a 24-year follow-up study 
The aim of this study is to analyze longitudinally, based on four measurements at intervals of eight years, the annual effect of age group and birth cohort on regular exercise in the Swedish population from 1980–1981 to 2004–2005.
We followed a randomly drawn subsample of individuals aged 16–63 years, interviewed by professional interviewers, from the Swedish Annual Level of Living Survey. We applied a mixed model with a random intercept and a random slope in order to analyze the annual effects.
The prevalence of regular exercise increased annually by 0.3 % among men and 0.7 % among women. For every one-unit increase in BMI, the odds of regular physical activity decreased by 6 % among men and 5 % among women. While the female birth cohorts all increased over time the male birth cohorts showed a different pattern, as only the three oldest birth cohorts (1926–1933, 1934–1941, 1942–1949) showed an increase in regular exercise. The three youngest birth cohorts (1958–1965, 1966–1973, 1974–1981) instead showed a decreased prevalence of regular exercise. There was an inverse relationship between regular exercise and age, although the differences between age groups tended to decrease over time. Differences related to educational level increased over time as the prevalence of exercise among those with higher educational attainment increased more than among those with lower educational attainment. The most dramatic relative increase in exercise over time (almost two-fold) was found among those who were obese or who reported a poor health status.
The prevalence of regular exercise increased in all studied sub-groups. However, the increased difference related to education level is worrying. To reduce the risk for ill health in these groups, there is a need for targeted interventions.
PMCID: PMC4518872
Exercise; Physical activity; Lifestyle; Longitudinal studies; Cohort effect; Mixed models; Public health
4.  Circulating microRNA-144-5p is associated with depressive disorders 
Clinical Epigenetics  2015;7(1):69.
Depressive/anxiety disorders are the most common types of mental illnesses in the world. The present study was the first to explore the association between plasma microRNAs (miRNAs) and depression/anxiety in primary care patients.
In total, 169 patients (aged 20–64 years) from 16 primary health centers were enrolled in the present study. The healthy controls were consisted of 52 individuals. We first performed miRNA screening of plasma samples from 11 patients using a Serum/Plasma Focus microRNA Panel comprising 179 miRNA primer sets. Six miRNAs were differentially expressed and were then validated by quantitative real-time (qRT)-PCR in the entire study cohort. The mean plasma miR-144-5p level in the depression/anxiety patients increased significantly compared to baseline (p < 0.0001) after the 8-week follow-up. No significant associations were found between the differentially expressed miRNAs and a change in the Montgomery-Åsberg Depression Rating Scale (MADRS-S) score after the follow-up. In linear regression analysis, the plasma miR-144-5p expression level was inversely related to the depression score (MADRS-S) (β = −0.02, p < 0.01), after adjustment for sex and age, at baseline. In addition, plasma miR-144-5p levels at baseline in the depression/anxiety patients were significantly lower compared with the healthy controls (p < 0.001).
Our findings show that plasma miR-144-5p levels are associated with depressive symptoms. Although confirmatory analyses are required, plasma miRNA-144-5p is a potential peripheral biomarker for pathologic processes related to depression.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0099-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4509564  PMID: 26199675
miR-144-5p; Depression; Severity
5.  Unexpected adverse childhood experiences and subsequent drug use disorder: a Swedish population study (1995–2011) 
Addiction (Abingdon, England)  2014;109(7):1119-1127.
Exposure to extraordinary traumatic experience is one acknowledged risk factor for drug use. We aim to analyse the influence of potentially life-changing childhood stressors, experienced second-hand, on later drug use disorder in a national population of Swedish adolescent and young adults (aged 15–26 years).
We performed Cox Proportional Hazard regression analyses, complemented with co-relative pair comparisons.
All individuals in the Swedish population born 1984 to 1995, who were registered in Sweden at the end of the calendar year they turned 14 years of age. Our follow-up time (Mean: 6.2 years; Range 11 years) started at the year they turned 15 and continued to December 2011 (N=1,409,218).
Our outcome variable was drug use disorder, identified from medical, legal and pharmacy registry records. Childhood stressors, as per DSM-IV stressor criteria, include death of an immediate family member and second-hand experience of diagnoses of malignant cancer, serious accidental injury, and victim of assault. Other covariates include parental divorce, familial psychological well-being, and familial drug and alcohol use disorders.
After adjustment for all considered confounders, individuals exposed to childhood stressors ‘parental death’ or ‘parental assault’ had over twice the risk of drug use disorder than those who were not (HR = 2.63 (2.23–3.09) and 2.39 (2.06–2.79), respectively).
Children under 15 who experience second-hand an extraordinary traumatic event (such as a parent or sibling being assaulted, diagnosed with cancer, or dying) appear to have approximately twice the risk of developing a drug use disorder than those who do not.
PMCID: PMC4048632  PMID: 24612271
6.  Accessible Transportation, Geographic Elevation, and Masticatory Ability Among Elderly Residents of a Rural Area 
Given that public transportation networks are often worse in rural areas than in urban areas, rural residents who do not drive can find it difficult to access health-promoting goods, services, and resources related to masticatory ability. Moreover, geographical location, assessed by elevation, could modify this association. The aim of this study was to test whether the association between access to transportation and masticatory ability varied by elevation. Data were collected from a cross-sectional study conducted in Mizuho and Iwami counties, Japan. Objective masticatory ability was evaluated using a test gummy jelly and elevation was estimated by the geographic information systems according to the participant’s address. After excluding subjects with missing data, 672 subjects (Mizuho = 401 and Iwami = 271) were analyzed. After adjustment for potential confounders, being a driver was not significantly associated with masticatory ability among elderly people living at low elevation (≤313 m) in Mizuho county. However, after the same adjustment, being a driver remained significantly associated with increased masticatory ability among elderly at high elevations. Similar findings were observed in Iwami county. Accessible transportation was significantly associated with increased mastication ability in elderly people living at high elevations, but not in those living at low elevations.
PMCID: PMC4515650  PMID: 26132474
masticatory ability; accessible transportation; elevation; mountainous area
7.  Perinatal Risk Factors for Wilms Tumor in a Swedish National Cohort 
European journal of epidemiology  2014;29(3):191-197.
Perinatal risk factors including high birth weight have been associated with Wilms tumor in case-control studies. However, these findings have seldom been examined in large cohort studies, and the specific contributions of gestational age at birth and fetal growth remain unknown.
We conducted the largest population-based cohort study to date consisting of 3,571,574 persons born in Sweden in 1973-2008, followed up for Wilms tumor incidence through 2009 to examine perinatal risk factors.
There were 443 Wilms tumor cases identified in 66.3 million person-years of follow-up. After adjusting for gestational age and other perinatal factors, high fetal growth was associated with increased risk of Wilms tumor among girls (hazard ratio per 1 standard deviation [SD], 1.36; 95% CI, 1.20-1.54; P<0.001), but not boys (1.10; 95% CI, 0.97-1.25; P=0.14) (Pinteraction=0.02). Among girls, high fetal growth was associated with disease onset before age 5 years (odds ratio per 1 SD, 1.47; 95% CI, 1.28-1.69; P<0.001), but not beyond (1.00; 95% CI, 0.76-1.31; P=0.99). No clear associations were found for gestational age at birth or other perinatal factors.
In this large cohort study, high fetal growth was associated with Wilms tumor before age 5 years among girls. These findings suggest that early-life growth factor pathways for Wilms tumor may be more common among girls than boys. Further elucidation of these mechanisms may reveal better targets for prevention or treatment of specific subtypes of Wilms tumor.
PMCID: PMC4461217  PMID: 24510487
fetal development; gestational age; risk factors; Wilms tumor
8.  Perinatal risk factors for premature ischaemic heart disease in a Swedish national cohort 
BMJ Open  2015;5(6):e007308.
Several studies have reported associations between restricted fetal development, as shown by birth weight or birth length, and later ischaemic heart disease (IHD). However, few studies have examined the importance of these perinatal factors when taking into account gestational age at birth, hereditary factors, sociodemographic factors and comorbidities. This study investigated the importance of perinatal risk factors for premature IHD and myocardial infarction (MI) in a large Swedish cohort.
Setting and participants
National cohort study of 1 970 869 individuals who were live-born in Sweden in 1973 through 1992, and followed up to 2010 (ages 18–38 years).
Primary and secondary outcome measures
The main outcome was IHD, and the secondary outcome was MI.
A total of 668 individuals were diagnosed with IHD in 18.8 million person-years of follow-up. After adjusting for gestational age at birth, sociodemographic factors, comorbidities and family history of IHD, low fetal growth was associated with increased risk of IHD (HR for <−2 vs −1 to <1 SD, 1.54; 95% CI 1.15 to 2.07; p=0.004) and increased risk of MI (HR for <−2 vs −1 to <1 SD, 2.48; 95% CI 1.66 to 3.71; p<0.001) in young adulthood. In contrast, gestational age at birth was not associated with the risk of IHD or MI.
In this large national cohort, low fetal growth was strongly associated with IHD and MI in young adulthood, independently of gestational age at birth, sociodemographic factors, comorbidities and family history of IHD.
PMCID: PMC4458615  PMID: 26038357
9.  Season of birth and other perinatal risk factors for melanoma 
Background: Ultraviolet radiation (UVR) exposure is the main risk factor for cutaneous malignant melanoma (CMM), but its specific effect in infancy is unknown. We examined whether season of birth, a proxy for solar UVR exposure in the first few months of life, is associated with CMM in childhood through young adulthood.
Methods: National cohort study of 3 571 574 persons born in Sweden in 1973–2008, followed up for CMM incidence through 2009 (maximum age 37 years) to examine season of birth and other perinatal factors.
Results: There were 1595 CMM cases in 63.9 million person-years of follow-up. We found a sinusoidal pattern in CMM risk by season of birth (P = 0.006), with peak risk corresponding to birthdates in spring (March–May). Adjusted odds ratios for CMM by season of birth were 1.21 [95% confidence interval (CI), 1.05–1.39; P = 0.008] for spring, 1.07 (95% CI, 0.92–1.24; P = 0.40) for summer and 1.12 (95% CI, 0.96–1.29; P = 0.14) for winter, relative to fall. Spring birth was associated with superficial spreading subtype of CMM (P = 0.02), whereas there was no seasonal association with nodular subtype (P = 0.26). Other CMM risk factors included family history of CMM in a sibling (>6-fold) or parent (>3-fold), female gender, high fetal growth and high paternal education level.
Conclusions: In this large cohort study, persons born in spring had increased risk of CMM in childhood through young adulthood, suggesting that the first few months of life may be a critical period of UVR susceptibility. Sun avoidance in early infancy may play an important role in the prevention of CMM in high-risk populations.
PMCID: PMC4052134  PMID: 24453238
fetal development; melanoma; risk factors; seasons
10.  Intrauterine Factors and Risk of Nonepithelial Ovarian Cancers 
Gynecologic oncology  2014;133(2):293-297.
The majority of ovarian tumors in girls and young women are nonepithelial in origin. The etiology of nonepithelial ovarian tumors remains largely unknown, and intrauterine exposures may play an important role. We examined the association of perinatal factors with risk of nonepithelial ovarian tumors in girls and young women.
National cohort study of 1,536,057 women born in Sweden during 1973–2004 and followed for diagnoses of nonepithelial ovarian tumors through 2009 (attained ages 5–37 years). Perinatal and maternal characteristics, and cancer diagnoses were ascertained using nationwide health registry data.
147 women were diagnosed with nonepithelial ovarian tumors in 31.6 million person-years of follow-up, including 94 with germ cell tumors and 53 with sex-cord stromal tumors. Women born preterm (<37 weeks of gestation) had significantly increased risk of developing nonepithelial ovarian tumors (adjusted hazard ratio 1.86, 95% CI 1.03–3.37; p=0.04). Histological subgroup analyses showed that preterm birth was associated with increased risk of sex-cord stromal tumors (4.39, 2.12–9.10; p<0.001), but not germ cell tumors (0.68, 0.21–2.15; p=0.51). No significant associations were found with fetal growth, birth order, and maternal age at birth.
This large cohort study provides the first evidence that preterm birth is a risk factor for developing sex cord-stromal tumors. Ovarian hyperstimulation in response to high gonadotropin levels in preterm girls could mediate disease risk through the proliferative and steroidogenic effects of FSH and LH on granulosa and theca cells, from which most sex-cord stromal tumors are derived.
PMCID: PMC4006291  PMID: 24530563
nonepithelial ovarian cancers; sex-cord stromal tumors; germ cell tumors; perinatal factors; gestational age; preterm birth
11.  End stage renal disease risk and neighbourhood deprivation: A nationwide cohort study in Sweden 
Chronic kidney disease has been associated with socioeconomic disparities and neighbourhood deprivation. We aimed to determine whether there is an association between neighbourhood deprivation and end stage renal disease (ESRD), and whether this association is independent of individual-level sociodemographic factors and comorbidities.
National Swedish data registers were used. The entire Swedish population aged 20–69 years was followed from January 1, 2001 until December 31, 2010. Data were analysed by multilevel logistic regression, with individual-level sociodemographic factors (age, marital status, family income, education level, country of birth, urban/rural status, and mobility) and comorbidities at the first level and neighbourhood deprivation at the second level.
Neighbourhood deprivation was significantly associated with ESRD (age-adjusted odds ratio [OR] 1.45, 95% confidence interval [CI] 1.34–1.56 in men and OR 1.59, 95% CI 1.44–1.75 in women). The ORs for ESRD in men and women living in the most deprived neighbourhoods remained significantly increased when adjusted for age and individual-level sociodemographic factors (OR 1.25, 95% CI 1.15–1.35 in men and OR 1.30, 95% CI 1.17–1.44 in women). In the full model, which took account of sociodemographic factors and comorbidities, the ORs for ESRD remained significantly increased (OR 1.17, 95% CI 1.07–1.27 in men and OR 1.18, 95% CI 1.06–1.31 in women).
Neighbourhood deprivation is independently associated with ESRD in both men and women irrespective of individual-level sociodemographic factors and comorbidities.
PMCID: PMC4374981  PMID: 25294596
Neighbourhood deprivation; Socioeconomic factors; End stage renal disease; Risk factors
12.  Familial transmission of chronic obstructive pulmonary disease in adoptees: a Swedish nationwide family study 
BMJ Open  2015;5(4):e007310.
Familial clustering of chronic obstructive pulmonary disease (COPD) is well established, but the familial risk of COPD has not been determined among adoptees. The aim was to determine whether the familial transmission of COPD is related to disease in biological and/or adoptive parents.
Historic cohort study.
80 214 (50% females).
The Swedish Multi-Generation Register was used to follow all Swedish-born adoptees born in 1932–2004 (n=80 214) between 1 January 1964 and 31 December 2010 for COPD (n=1978). The risk of COPD was estimated in adoptees with at least one biological parent with COPD but no adoptive parent with COPD (n=162) compared with adoptees without a biological or adoptive parent with COPD. The risk of COPD was also determined in adoptees with at least one adoptive parent but no biological parent with COPD (n=110), and in adoptees with both affected biological and adoptive parents (n=162).
Primary outcome measure
COPD in adoptees.
Adoptees with COPD in at least one biological parent but no adoptive parent were more likely to have COPD than adoptees without a biological or adoptive parent with COPD (standardised incidence ratio, SIR=1.98 (95% CI 1.69 to 2.31)). The familial SIR for adoptees with both a biological parent and an adoptive parent with COPD was 1.68 (95% CI 1.39 to 2.00). Adoptees with at least one adoptive parent with COPD but no biological parent with COPD were not at an increased risk of COPD (SIR=1.12 (95% CI 0.92 to 1.35)).
The findings of the study show that the familial transmission of COPD is associated with COPD in biological but not adoptive parents, suggesting that genetic or early life factors are important in the familial transmission of COPD.
PMCID: PMC4401855  PMID: 25869691
13.  Digested wheat gluten inhibits binding between leptin and its receptor 
BMC Biochemistry  2015;16:3.
Leptin resistance is considered a primary risk factor for obesity. It has been hypothesized that dietary cereal grain protein could cause leptin resistance by preventing leptin from binding to its receptor. Non-degraded dietary wheat protein has been found in human serum at a mean level of 41 ng/mL. Here, we report our findings from testing whether enzymatically digested gluten from wheat prevents leptin from binding to the leptin receptor in vitro.
Gluten from wheat was digested with pepsin and trypsin under physiological conditions. Pepsin and trypsin activity was removed from the gluten digest with a 10 kDa spin-filter or by heat treatment at 100°C for 30 min. Binding to the leptin receptor of leptin mixed with gluten digest at a series of concentrations was measured using surface plasmon resonance technology.
Binding of the gluten digest to the leptin receptor was not detected. Spin-filtered gluten digest inhibited binding of leptin to the leptin receptor, with 50% inhibition at a gluten digest concentration of ~10 ng/mL. Heat-treated gluten digest did not inhibit leptin binding.
Digested wheat gluten inhibits binding of leptin to the leptin receptor, with half-maximal inhibition at 10 ng/mL. The inhibition is significant at clinically relevant concentrations and could therefore serve as a novel pathway to investigate to understand the molecular basis of leptin resistance, obesity and associated disorders.
PMCID: PMC4308898  PMID: 25600821
Gluten; Leptin; Leptin resistance; Obesity
14.  Age, period and cohort trends in drug abuse hospitalizations within the total Swedish population (1975-2010)* 
Drug and alcohol dependence  2013;134:355-361.
The societal consequences of drug abuse (DA) are severe and well documented, the World Health Organization recommending tracking of population trends for effective policy responses in treatment of DA and delivery of health care services. However, to correctly identify possible sources of DA change, one must first disentangle three different time-related influences on the need for treatment due to DA: age effects, period effects and cohort effects.
We constructed our main Swedish national DA database (spanning four decades) by linking healthcare data from the Swedish Hospital Discharge Register to individuals, which included hospitalisations in Sweden for 1975-2010. All hospitalized DA cases were identified by ICD codes. Our Swedish national sample consisted of 3,078,129 men and 2,921,816 women. We employed a cross-classified multilevel logistic regression model to disentangle any net age, period and cohort effects on DA hospitalization rates.
We found distinct net age, period and cohort effects, each influencing the predicted probability ofhospitalisation for DA in men and women. Peak age for DA in both sexes was 33-35 years; net period effects showed an increase in hospitalisation for DA from 1996 to 2001; and in birth cohorts 1968-74, we saw a considerable reduction (around 75%) in predicted probability of hospitalisation for DA.
The use of hospital admissions could be regarded as a proxy of the population's health service use for DA. Our results may thus constitute a basis for effective prevention planning, treatment and other appropriate policy responses.
PMCID: PMC3909834  PMID: 24300899
Sweden; drug abuse; age-period-cohort effects; longitudinal; trends
15.  The longitudinal exercise trend among older Swedes aged 53–84 years – a 16-year follow-up study 
BMC Public Health  2014;14:1327.
Many older adults are physically inactive and inactivity increases with age. This knowledge comes from cross-sectional studies. Cross-sectional studies may miss important trajectories within the older adults as a result of retirements, and poor health impact of promotional efforts. The aim of this study was to analyse, longitudinally, the annual effects of age group and birth cohort on self-reported regular exercise in the Swedish population aged 53–84 years during a 16-year period, for each sex separately.
A random sample of non-institutionalized persons was interviewed three times from 1988 to 2004 by professional interviewers. In addition to three time-related variables – year of interview, age at the time of the interview, and year of birth – we included the following explanatory variables in the analyses: educational level, body mass index, smoking, and self-reported health status. The data were analysed by a mixed model with a random intercept.
The total prevalence of self-reported regular exercise increased between 1988/89 and 2004/05 among both men and women, from 27.1 to 43.1% and from 21.1 to 41.1%, respectively. There was a mean annual change in all age-groups in exercise of between 0.76 and 1.24% among men and between 0.86 and 1.38% among women. Low prevalence of self-reported regular exercise was associated with low educational level, obesity, smoking, and poor self-reported health, although those with poor self-reported health the greatest increase of physical activity.
There was a steady, albeit inadequate, increase in self-reported regular exercise in older adults between 1988 and 2004. Physical activity promotion in older adults should be of high priority for both primary and secondary prevention of diseases, especially among groups with known risk factors for low levels of exercise.
PMCID: PMC4391333  PMID: 25547275
Exercise; Older adults; Longitudinal studies; Cohort effect; Mixed models
16.  Statin use and risk of depression: a Swedish national cohort study 
BMC Psychiatry  2014;14:348.
Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n = 4,607,990).
National register data for adults ≥40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression.
Use of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR = 0.92, 95% CI, 0.89-0.96; p < 0.001). Simvastatin had a protective effect (OR = 0.93, 95% CI, 0.89-0.97; p = 0.001), whereas atorvastatin was associated with increased risk of depression (OR = 1.11, 95% CI, 1.01-1.22; p = 0.032). There was a stepwise decrease in odds ratio with increasing age (OR ≥ 40 years = 0.95, OR ≥ 50 years = 0.91, OR ≥ 60 years = 0.85, OR ≥ 70 years = 0.81).
The use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.
PMCID: PMC4266881  PMID: 25471121
Statins; Atorvastatin; Simvastatin; Depression; Aetiology; Inflammation; Oxidative stress
17.  Familial Risks of Kidney Failure in Sweden: A Nationwide Family Study 
PLoS ONE  2014;9(11):e113353.
The value of family history as a risk factor for kidney failure has not been determined in a nationwide setting.
This nationwide family study aimed to determine familial risks for kidney failure in Sweden.
The Swedish multi-generation register on 0–78-year-old subjects were linked to the Swedish patient register and the Cause of death register for 1987–2010. Individuals diagnosed with acute kidney failure (n = 10063), chronic kidney failure (n = 18668), or unspecified kidney failure (n = 3731) were included. Kidney failure patients with cystic kidney disease, congenital kidney and urinary tract malformations, urolithiasis, and rare inherited kidney syndromes, and hyperoxaluria were excluded. Standardized incidence ratios (SIRs) were calculated for individuals whose parents/siblings were diagnosed with kidney failure compared to those whose parents or siblings were not.
The concordant (same disease) familial risks (sibling/parent history) were increased for chronic kidney failure SIR = 2.02 (95% confidence interval, CI 1.90–2.14) but not for acute kidney failure SIR = 1.08 (95% CI 0.94–1.22) and for unspecified kidney failure SIR = 1.25 (95% CI 0.94–1.63). However, the discordant (different disease) familial risk for acute kidney failure SIR = 1.19 (95% CI 1.06–1.32) and unspecified kidney failure SIR = 1.63 (95% CI 1.40–1.90) was significantly increased in individuals with a family history of chronic kidney failure. The familial risk for chronic kidney failure was similar for males SIR = 2.04 (95% CI 1.90–2.20) and females SIR = 1.97 (95% CI 1.78–2.17). Familial risks for chronic kidney failure were highest at age of 10–19 years SIR = 6.33 (95% CI 4.16–9.22).
The present study shows that family history is an important risk factor for chronic kidney failure but to a lower degree for acute kidney failure and unspecified kidney failure.
PMCID: PMC4244139  PMID: 25423475
18.  Immigrant enclaves and risk of diabetes: a prospective study 
BMC Public Health  2014;14:1093.
The diversity of the Swedish population has increased substantially over the past three decades. The aim of this study was to assess whether living in an ethnic enclave is associated with risk of diabetes mellitus (DM) among first and second-generation immigrants and native Swedes.
Cumulative incidence of DM in three urban municipalities was assessed from 2006–2010 by linking records from the national census, multi-generational family register, and prescription drug register. Immigrant enclaves were identified using Moran’s Index. Multi-level logistic regression was used to assess the relationship between enclave residence and risk of DM for three groups: Iraqi immigrants, non-Iraqi immigrants, and native Swedes (N = 887,603).
The cumulative incidence of DM was greater in Iraqi enclaves compared to other neighborhoods (4.7% vs. 2.3%). Among Iraqi immigrants, enclave residence was not associated with odds of DM (Odds ratio (OR): 1.03, 95% Confidence Interval (CI): 0.86 – 1.24). Among other immigrants, enclave residence was not associated with DM after accounting for neighborhood deprivation. Among native Swedes, enclave residence was associated with elevated risk of DM even after accounting for neighborhood deprivation and individual-level characteristics (OR: 1.23, 95% CI: 1.11 – 1.36).
Residential ethnic composition is associated with DM but this relationship differs across ethnic group. Enclave residence is not associated with increased odds of DM for immigrants, regardless of their nation of origin, but it is associated with increased likelihood of DM for native Swedes.
PMCID: PMC4221671  PMID: 25335856
Journal of psychiatric research  2013;47(10):1298-1303.
Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N=7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001–2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85–5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08–5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (~20–30%) or excluded (~25–40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies.
PMCID: PMC3746500  PMID: 23806577
mental disorders; mortality; suicide
20.  Subsequent brain tumors in patients with autoimmune disease 
Neuro-Oncology  2013;15(9):1142-1150.
Previous studies have reported increased risk of brain tumors after allergic conditions, but no systematic analyses of these tumors in patients with autoimmune disease (AId) have been performed. No data are available on survival among patients with AId from brain tumors. We analyzed systematically risks and survival in histological types of brain tumors among patients who received a diagnosis of 33 different AIds.
Patients and Methods
Standardized incidence ratios (SIRs) for brain tumors or hazard ratios (HRs) of deaths after brain tumors were calculated up to 2008 in 402 462 patients hospitalized for AId after 1964 and were compared with data on the population not hospitalized for AIds.
Brain tumors were diagnosed in 880 patients with AId. No increased or decreased risks (SIRs) were noted for glioma, whereas the increased SIRs for meningioma after many AIds were likely to be attributable to surveillance bias. The data on survival showed overall decreases for glioma (HR, 1.15) and meningioma (HR, 1.26). The survival in both was decreased in patients with chronic rheumatic heart disease, multiple sclerosis, and rheumatoid arthritis. Overall, HRs were increased for glioma after 6 AIds and for meningioma after 7 AIds.
The present data showed that none of the 33 AIds influenced the risk of glioma. However, many AIds negatively influence survival in glioma and meningioma, probably through added physical burden or therapeutic limitations. Information of an existing AId in patients with newly diagnosed brain tumors should help the prognostic assessment and the design of treatment.
PMCID: PMC3748918  PMID: 23757294
comorbidity; glioma; hazard ratio; meningioma; standardized incidence ratio
21.  Depression, neighborhood deprivation and risk of type 2 diabetes 
Health & place  2013;23:63-69.
Neighborhood characteristics have been associated with both depression and diabetes, but to date little attention has been paid to whether the association between depression and diabetes varies across different types of neighborhoods. This prospective study examined the relationship between depression, neighborhood deprivation, and risk of type 2 diabetes among 336,340 adults from a national-representative sample of primary care centers in Sweden (2001–2007). Multi-level logistic regression models were used to assess associations between depression and risk of type 2 diabetes across affluent and deprived neighborhoods. After accounting for demographic, individual-level socioeconomic, and health characteristics, depression was significantly associated with risk of diabetes (odds ratio (OR): 1.10, 95% confidence interval (CI): 1.06–1.14), as was neighborhood deprivation (OR for high vs. low deprivation: 1.66, 95% CI: 1.22–1.34). The interaction term between depression and neighborhood deprivation was non-significant, indicating that the relationship between depression and diabetes risk is similar across levels of neighborhood socioeconomic deprivation.
PMCID: PMC3773725  PMID: 23771166
Depression; Type 2 diabetes mellitus; Residence characteristics; Multi-level analysis; Socioeconomic factors
22.  Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders 
eLife  2014;3:e02917.
Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34–1.44) and 2.19 (95% CI 2.15–2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36–1.58) and 2.70 (95% CI 2.59–2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.
eLife digest
Children learn to talk, manage their emotions, and control their behavior in a period when the brain is developing rapidly. The first signs of several developmental disorders, such as autism and attention-deficit/hyperactivity disorder (ADHD), may also emerge during this period. Children with autism may have difficulties with social interactions and communication, while those with attention-deficit/hyperactivity disorder may struggle to pay attention to a task and may be more active than other children.
Autism or ADHD are diagnosed based on the child's behavior because the underlying causes of the disorders are not well understood. Both genes and the environment have been linked to the conditions; and it was recently suggested that certain common genetic mutations are more common in children with ADHD or autism. However, as some of the mutations linked to autism are not found in the genes of the affected children's parents, it is likely that they occurred in either of the sperm or the egg cell from the parents.
Exposure to harmful substances in the environment can cause mutations in egg or sperm cells, or alter the expression of genes without changing the gene sequence. Excessive alcohol consumption is one environmental factor that can mutate genes or alter gene expression. Here, Sundquist et al. have looked to see if there is a relationship between a child having a parent with an alcohol use problem and the child's risk of developing autism or ADHD.
Examining national medical registries identified 24,157 people with autism and 49,348 with ADHD in Sweden between 1987 and 2010. Sundquist et al. discovered that autism and ADHD were more common in individuals who had a parent with a history of an alcohol use disorder than in those whose parents had no history of an alcohol use disorder. There was also an even greater risk of either condition if the parent had been diagnosed with an alcohol use problem before the birth of the child.
Adopted children who had a biological parent with an alcohol use disorder were at a greater risk of autism and ADHD than those whose adoptive parent had an alcohol use disorder. However, as very few adopted parents were diagnosed with an alcohol use problem, it is important to be cautious about drawing firm conclusions from this observation.
Sundquist et al. estimate that around 4% of autism cases and 11% of ADHD cases could be avoided if parents abstained from heavy alcohol consumption. Though these findings are consistent with parents with an alcohol use disorder being more likely to pass on mutations to their children, there are also other possible explanations. As such, further research examining the underlying cause is still needed.
PMCID: PMC4135348  PMID: 25139954
autism; ADHD; alcohol use disorders; human
23.  Venous Thromboembolism and Varicose Veins Share Familial Susceptibility: A Nationwide Family Study in Sweden 
Varicose veins (VVs) have been associated with venous thromboembolism (VTE), but whether these diseases share familial susceptibility has not been determined. This nationwide study aimed to determine whether VTE shares familial susceptibility with VVs.
Methods and Results
Swedish Multigeneration Register data for persons aged 0 to 76 years during the period 1964–2008 were linked to the Swedish Inpatient and Outpatient Registers. Familial risks (standardized incidence ratios [SIRs]) of VTE and VVs were examined in 2 ways (ie, bidirectionally): risk of VTE in subjects whose siblings had been diagnosed with VVs and risk of VVs in persons whose siblings had been diagnosed with VTE. The analyses were repeated for spouses to determine the importance of shared adult family environment. In total, 96 810 siblings had VVs and 87 564 had VTE. An increased risk of VTE was observed in persons whose siblings had VVs (SIR 1.30, 95% CI 1.26 to 1.33), whereas persons whose siblings had VTE had an increased risk of VVs (SIR 1.30, 95% CI 1.27 to 1.34). If 2 or more siblings were affected by VTE, the risk for VVs was 1.70 (95% CI 1.53 to 1.88). Conversely, if 2 or more siblings were affected by VVs, the risk for VTE was 1.52 (95% CI 1.38 to 1.67). In spouses of VTE patients, a minor increased risk of VVs was observed (SIR 1.05 for husbands, SIR 1.06 for wives). The risk of VTE in spouses of VV patients was similarly small (SIR 1.01 for husbands, SIR 1.05 for wives).
VVs and VTE share familial susceptibility. This novel finding suggests the existence of shared familial and possibly genetic factors.
PMCID: PMC4310366  PMID: 25158864
embolism; epidemiology; genetics; thrombosis; veins
24.  Causes of death in patients with extranodal cancer of unknown primary: searching for the primary site 
BMC Cancer  2014;14:439.
Cancer of unknown primary (CUP) is a fatal cancer, accounting for 3–5% of all diagnosed cancers. Finding the primary site is important for therapeutic choices and we believe that the organ which is designated as the cause of death may give clues about the primary site.
A total of 20,570 patients with CUP were identified from the Swedish Family-Cancer Database. Causes of death – as reported in the death certificate - were investigated, analyzing reported metastatic sites and histological subtypes separately. Survival was compared with metastatic cancer with a known primary tumor.
An organ-specific cancer could be identified as a cause of death in approximately 60% of all CUP patients with adenocarcinoma or undifferentiated histology. In adenocarcinoma, lung cancer was the most frequent cause of death (20%), followed by pancreatic cancer (14%), and ovarian cancer (11%). Lung cancer was the most common cause of death in patients with CUP metastases diagnosed in the nervous system (69%), respiratory system (53%), and bone (47%), whereas ovarian cancer was the most common cause of death when CUP was diagnosed in the pelvis (47%) or the peritoneum (32%). In CUP diagnosed in the liver, liver and pancreatic cancers accounted for 26% and 22% of deaths, respectively. Also in squamous cell CUP, lung cancer was the most common cause of death (45%).
According to the causes of death, the primary site appeared frequently to be either the organ where CUP metastases were diagnosed or an organ which may be traced through the known metastatic patterns of different cancer types.
PMCID: PMC4077560  PMID: 24929562
Cancer of unknown primary; CUP; Cause of death
25.  Alcohol Consumption Has a Protective Effect against Hematological Malignancies: a Population-Based Study in Sweden Including 420,489 Individuals with Alcohol Use Disorders12345 
Neoplasia (New York, N.Y.)  2014;16(3):229-234.e1.
BACKGROUND: It has been suggested that alcohol consumption is associated with increased risk of a few solid cancers, although studies that examined the association with hematological malignancies have shown inconsistent results. In this study, we examined the risk of hematological malignancies among individuals who had alcohol use disorders (AUDs) in Sweden. METHODS: Individuals with AUDs were identified from the nationwide Swedish Hospital Discharge Register and Outpatient Register, the Crime Register, and the Prescription Drug Register, and they were linked to the Swedish Cancer Registry to calculate standardized incidence ratios (SIRs) of hematological malignancies, using those Swedes without AUDs as a reference. In addition, we used a quasi-experimental sibling design to investigate the odds ratios among sibling pairs who were discordant with AUDs. RESULTS: A total of 420,489 individuals were identified with AUDs. After more than 15 million person-years of follow-up, a total of 1755 individuals developed hematological malignancies demonstrating a low risk, i.e., SIR = 0.60 (95% confidence interval = 0.57-0.63). People with AUDs had low risks for developing specific types of malignancies. The lowest risk (0.51) was for leukemia, followed by myeloma (0.52), non-Hodgkin lymphoma (0.65), and Hodgkin disease (0.71). The risk was lower among AUDs identified at an older age. The low risks of hematological malignancies were also noted using sibling analysis. CONCLUSIONS: Our data suggest that alcohol consumption has a protective effect against hematological malignancies. However, further studies are needed to identity the underlying mechanisms of the protective effect of alcohol consumption against hematological malignancies.
PMCID: PMC4094792  PMID: 24783999

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