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Background and Aims: Few population-based cohort studies, including both men and women, have explored circulating proteins associated with incident myocardial infarction (MI). This study investigated the relationships between circulating cardiometabolic-related proteins and MI risk using cohort-based and Mendelian randomization (MR) analyses and explored potential sex-specific differences., Methods: The discovery cohort included 11 751 Swedish adults (55-93 years). Data on 259 proteins assessed with Olink proximity extension assays, biochemical, and questionnaire-based information were used. Participants were followed up for incident MI and death over 8 years through linkage to Swedish registers. Replication analyses were conducted on the UK Biobank sample (n = 51 613). In MR analyses, index cis-genetic variants strongly related to the proteins were used as instrumental variables. Genetic association summary statistic data for MI were obtained from the CARDIoGRAMplusC4D consortium and FinnGen., Results: Forty-five proteins were associated with incident MI in discovery and replication samples following adjustment for potential confounders and multiple testing. In the secondary analysis, 13 of the protein associations were sex-specific, with most associations identified among women. In MR analysis, genetically predicted higher levels of renin, follistatin, and retinoic acid receptor responder protein 2 were linked to an increased risk of MI. Tissue factor pathway inhibitor, tumor necrosis factor receptors 1 and 2, placenta growth factor had an inverse association with MI., Conclusions: This study identified both new and confirmed previously established associations between circulating proteins and incident MI and, for the first time, suggested sex-specific patterns in multiple protein-MI associations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims/hypothesis: Parenting a child with type 1 diabetes has been associated with stress-related symptoms. This study aimed to elucidate the potential impact on parental risk of major cardiovascular events (MCE) and death., Methods: In this register-based study, we included the parents of 18,871 children, born 1987-2020 and diagnosed with type 1 diabetes in Sweden at <18 years. The median parental age at the child's diagnosis was 39.0 and 41.0 years for mothers and fathers, respectively. The cohort also encompassed 714,970 population-based matched parental control participants and 12,497 parental siblings. Cox proportional hazard regression models were employed to investigate the associations between having a child with type 1 diabetes and incident MCE and all-cause death, and, as secondary outcomes, acute coronary syndrome and ischaemic heart disease (IHD). We adjusted for potential confounders including parental type 1 diabetes and country of birth., Results: During follow-up (median 12 years, range 0-35), we detected no associations between parenting a child with type 1 diabetes and MCE in mothers (adjusted HR [aHR] 1.02; 95% CI 0.90, 1.15) or in fathers (aHR 1.01; 95% CI 0.94, 1.08). We noted an increased hazard of IHD in exposed mothers (aHR 1.21; 95% CI 1.05, 1.41) with no corresponding signal in fathers (aHR 0.97; 95% CI 0.89, 1.05). Parental sibling analysis did not confirm the association in exposed mothers (aHR 1.01; 95% CI 0.73, 1.41). We further observed a slightly increased hazard of all-cause death in exposed fathers (aHR 1.09; 95% CI 1.01, 1.18), with a similar but non-significant estimate noted in exposed mothers (aHR 1.07; 95% CI 0.96, 1.20). The estimates from the sibling analyses of all-cause death in fathers and mothers were 1.12 (95% CI 0.90, 1.38) and 0.73 (95% CI 0.55, 0.96), respectively., Conclusions/interpretation: Having a child diagnosed with type 1 diabetes in Sweden was not associated with MCE, but possibly with all-cause mortality. Further studies are needed to disentangle potential underlying mechanisms, and to investigate parental health outcomes across the full lifespan., (© 2024. The Author(s).)

Background: Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches., Methods: This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity., Findings: Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I 2 =61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I 2 =59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I 2 =68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes., Interpretation: The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines., Funding: The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre., Competing Interests: Declaration of interests J-PD-C received research grants and consulting fees from the Dairy Farmers of Canada, research grants from The Weston Family Foundation, and travel support from the International Dairy Federation in the past 5 years, unrelated to the submitted work. SS-M received research funding (2019 and 2023 unrestricted grants) for epidemiological studies on dairy products and cardiometabolic diseases from the Dutch Dairy Association and the Danish Dairy Research Foundation, and funds from Nutrimedes (Affligem, Belgium)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To study the association between meat intake (predominantly red and processed meats) and the risk of hip fracture, as well as the association between meat intake and biomarkers of inflammation, oxidative stress, bone turnover, body composition, and bone mineral density (BMD)., Methods: Data from the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men) with repeated investigations and their respective clinical sub-cohorts was utilised. Incident hip fractures were ascertained through individual linkage to registers. Associations were investigated using multivariable Cox and linear regression analyses., Results: During up to 23 years of follow-up (mean 18.2 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. Each daily serving of meat intake conferred a hazard ratio (HR) of 1.03 (95% confidence interval [CI] 1.00; 1.06) for hip fracture. In quintile 5, compared to quintile 2, the HR was 1.11 (95% CI 1.01; 1.21) among all participants. In the sub-cohorts, meat intake was directly associated with circulating levels of interleukin-6, C-reactive protein, leptin, ferritin, parathyroid hormone, and calcium., Conclusion: A modest linear association was found between a higher meat intake and the risk of hip fractures. Our results from the sub-cohorts further suggest that possible mechanisms linking meat intake and hip fracture risk may be related to the regulation of bone turnover, subclinical inflammation, and oxidative stress. Although estimates are modest, limiting red and processed meat intake in a healthy diet is advisable to prevent hip fractures., (© 2024. The Author(s).)

Objectives: Hip fractures are associated with a high burden of morbidity and mortality. Diet is essential for preventing fragility fractures, but the role of dietary fatty acids on the risk of hip fracture is uncertain. The aim was to investigate how intake of different dietary fatty acids relates to the risk of hip fracture. A relative validation of the long-term intake of dietary fatty acids estimated from food frequency questionnaires (FFQs) was also performed., Design, Settings and Participants: We used data collected in two population-based cohorts, the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men, aged 45-82 years). Data from the repeated investigations in the cohorts and cross-sectional data from their clinical sub-cohorts were used., Measurements: Diet data was collected in FFQs. Incident hip fractures were gathered by individual linkage to national registers. We performed Cox regression analysis to investigate associations between dietary fatty acids and hip fracture. Follow-up time was between January 1st, 1998 and December 31st, 2020. The validation was performed using correlation analyses, comparing fatty acids measured in adipose tissue with estimated fatty acid intakes from FFQs., Results: During up to 23 years of follow-up (mean 18 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. A low linoleic acid (LA) and high intakes of long-chain n-3 fatty acids were associated with higher hip fracture risk in a non-linear way. In quartile 4 compared to quartile 1 of LA, the multivariable-adjusted hazard ratio of hip fracture was 0.89 (95% Confidence Interval: 0.81, 0.97). The study confirmed the validity of FFQs to capture the intake of the specific dietary long-chain n-3 fatty acids. The estimated intake of LA, α-linolenic acid, and myristic acid were also adequately captured by the FFQs. Validity was confirmed in both women and men., Conclusion: A low to moderate intake of linoleic acid and a higher intake of long-chain n-3 fatty acids were associated with a higher risk of hip fractures. The results indicate that attention should be paid to dietary fatty acid composition for the optimal prevention of fragility fractures., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins., Methods: We used data from a population-based cohort of 4950 Swedish women (55-85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins., Results: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures., Conclusions: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis., (© 2023. The Author(s).)

Serum 25-hydroxyvitamin D (S-25OHD) is used to assess vitamin D status and is known to be affected by season and fat mass. Because these factors are often ignored when interpreting S-25OHD, assessment of vitamin D associations with disease outcomes may be distorted. We aimed to investigate the impact of season of blood draw and fat mass on the association of S25OHD with fracture risk. We enrolled 5000 women, mean ± SD age 68 ± 7 years, with dual-energy x-ray absorptiometry (DXA) scans and blood collection in a population-based cohort. Proportional hazards regression, stratified by season and fat mass, was used to determine hazard ratios (HRs) of fracture according to categories of S-25OHD. Our secondary exposures were serum 1,25-dihydroxycholecalciferol (1,25-(OH) 2 D 3 ), the most active vitamin D metabolite and plasma parathyroid hormone (P-PTH). During an average of 9.2 years of follow-up, 1080 women had a fracture. Women with S-25OHD <30 nmol/L drawn during sunny months (May-October) had a multivariable-adjusted fracture HR of 2.06 (95% CI, 1.27-3.35) compared with those with S-25OHD >60 nmol/L; those with S-25OHD 30-40 nmol/L had an HR of 1.59 (95% CI, 1.12-2.26). In contrast, S-25OHD drawn during November through April was unrelated to fracture risk. The increased risk with low sunny season S-25OHD was seen only among women with body mass index (BMI) ≥25 kg/m 2 or fat mass index (FMI) ≥9.8 kg/m 2 . High fat mass and low S-25OHD were independently related to lower S-1,25-dihydroxycholecalciferol, which itself predicted fracture risk with samples collected during the sunny season. Irrespective of season, P-PTH was unrelated to fracture risk. We conclude that S-25OHD is associated with fracture risk only if drawn during periods of seasonally high levels in women with a high BMI. These results have implications for the evaluation of vitamin D status and can explain the lack of effect seen with vitamin D supplementation in many fracture trials. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

The role of diet in sarcopenia is unclear, and results from studies using dietary patterns (DP) are inconsistent. We assessed how adherences to a posteriori DP are associated with the prevalence of sarcopenia and its components 16 years later. Four DP were defined in the Uppsala Longitudinal Study of Adult Men at baseline (n 1133, average age 71 years). Among 257 men with information at follow-up, 19 % (n 50) had sarcopenia according to the European Working Group on sarcopenia in Older People 2 definition. Adherence to DP2 (mainly characterised by high intake of vegetables, green salad, fruit, poultry, rice and pasta) was non-linearly associated with sarcopenia; adjusted OR and 95 % CI for medium and high v. low adherence: 0·41 (0·17, 0·98) and 0·40 (0·17, 0·94). The OR per standard deviation (sd) higher adherence to DP2 was 0·70 (0·48, 1·03). Adjusted OR (95 % CI) for 1 sd higher adherence to DP1 (mainly characterised by high consumption of milk and cereals), DP3 (mainly characterised by high consumption of bread, cheese, marmalade, jam and sugar) and DP4 (mainly characterised by high consumption of potatoes, meat and egg and low consumption of fermented milk) were 1·04 (0·74, 1·46), 1·19 (0·71, 2·00) and 1·08 (0·77, 1·53), respectively. There were no clear associations between adherence to the DP and muscle strength, muscle mass, physical performance or sarcopenia using EWGSOP1 (sarcopenia n 54). Our results indicate that diet may be a potentially modifiable risk factor for sarcopenia in old Swedish men.

Context: In a cross-sectional study, we found an association between type 2 diabetes mellitus (T2DM) and smaller bone area together with greater bone mineral density (BMD) at the total hip., Objective: This work aims to investigate these associations longitudinally, by studying T2DM status (no T2DM n = 1521, incident T2DM n = 119, or prevalent T2DM n = 106) in relation to changes in total hip bone area and BMD., Methods: In 3 cohorts, the Swedish Mammography Cohort Clinical (SMCC; n = 1060), Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 483), and Uppsala Longitudinal Study of Adult Men (ULSAM; n = 203), with repeat assessment of T2DM status and dual energy x-ray absorptiometry (DXA) measurements of total hip bone area and BMD on average 8 years apart, a linear regression model was used to assess the effect of T2DM status on change in bone area and BMD at the total hip., Results: After meta-analysis, the change in bone area at the total hip was 0.5% lower among those with incident T2DM compared to those without T2DM (-0.18 cm2; 95% CI, -0.30 to -0.06). The change in bone area was similar among those with prevalent T2DM compared to those without (0.00 cm2; 95% CI, -0.13 to 0.13). For BMD, the combined estimate was 0.004 g/cm2 (95% CI, -0.006 to 0.014) among those with incident T2DM and 0.010 g/cm2 (95% CI, -0.000 to 0.020) among those with prevalent T2DM, compared to those without T2DM., Conclusion: Those with incident T2DM have a lower expansion in bone area at the total hip compared to those without T2DM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

We aimed to comprehensively evaluate the association of body composition with fracture risk using longitudinal data from a Swedish cohort of 44,366 women and men (mean age of 70 years) and a subcohort of 5022 women. We estimated hazard ratios (HRs) of fracture for baseline body mass index (BMI), BMI change during the prior 12 and 18 years, baseline waist-to-height ratio, total and regional distribution of fat and lean mass, with and without areal bone mineral density (BMD) adjustment. During follow-up (median 8.7 years), 7290 individuals sustained a fracture, including 4279 fragility fractures, of which 1813 were hip fractures. Higher baseline BMI and prior gain in BMI were inversely associated with all types of fracture. Lower fracture rate with higher baseline BMI was seen within every category of prior BMI change, whereas higher prior BMI gain conferred a lower rate of fracture within those with normal baseline BMI. Each standard deviation (SD) higher baseline waist-to-height ratio, after adjustment for BMI, was associated with higher rates of hip fracture in both women and men (HR 1.12; 95% CI, 1.05-1.19). In the subcohort (median follow-up 10 years), higher baseline fat mass index (FMI) and appendicular lean mass index (LMI) showed fracture-protective effects. After BMD adjustment, higher baseline BMI, total LMI, FMI, and higher prior BMI gain were associated with higher fracture rate. Baseline fat distribution also was associated with fracture rate; a 1-SD higher android to gynoid fat mass ratio in prior BMI gainers was associated with BMD-adjusted HRs of 1.16 (95% CI, 1.05-1.28) for any fracture and 1.48 (95% CI, 1.16-1.89) for hip fracture. This pattern was not observed among prior BMI losers. These findings indicate that for optimal fracture prevention, low baseline BMI, prior BMI loss and high baseline central obesity should be avoided in both women and men. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background and Aims: Each year, millions of people suffer from fragility fractures. Hip fractures are the most devastating type of such fractures. We aimed to investigate whether the association of dietary calcium intake with hip fracture risk can be modified by a healthy diet, herein defined as the modified Mediterranean diet score (mMED), in Swedish adults., Methods: The study included 82,092 men and women at baseline. Diet and covariate data were collected twice, 12 years apart, using questionnaires. Information on incident hip fractures was collected from a national registry. Dietary calcium intake and mMED were each categorized into low, medium and high categories, and in nine combined strata of the two exposures. Multivariable adjusted hazard ratios (HR) of hip fracture with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression analysis, with time-updated information on exposures and covariates. Non-linear trends were assessed using restricted cubic splines., Results: During 20 years of follow-up including 1,367,260 person-years at risk, 5938 individuals experienced a hip fracture. Dietary calcium intake and hip fracture were non-linearly associated, whereas adherence to mMED decreased hip fracture rates in a dose-response pattern. The lowest hip fracture rates were observed among women and men who reported a calcium intake of 800 mg or more, combined with a high adherence to mMED. In each stratum of calcium intake, the HRs of hip fracture were increasingly higher with lower adherence to mMED, compared with the reference level (high calcium and high mMED). Individuals with low calcium intake (<800 mg/day) or high calcium intake (>1200 mg/day) combined with low adherence to mMED had a HR of 1.54 (95% CI 1.28-1.85) and 1.50 (95% CI 1.26-1.77), respectively. No major differences in the hip fracture risk patterns were discerned between women and men., Conclusion: A moderate to high dietary calcium intake in the context of an overall healthy diet were associated with lower hip fracture rates., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims/hypothesis: Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip., Methods: We selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10 -8 ) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men., Results: In a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (-0.67 cm 2 [95% CI -1.30, -0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm 2 [95% CI -0.00, 0.07; p = 0.060])., Conclusions/interpretation: Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.

Purpose: Comorbidity indices are often used to measure comorbidities in register-based research. We aimed to adapt the Charlson comorbidity index (CCI) to a Swedish setting., Methods: Four versions of the CCI were compared and evaluated by disease-specific experts., Results: We created a cohesive coding system for CCI to 1) harmonize the content between different international classification of disease codes (ICD-7,8,9,10), 2) delete incorrect codes, 3) enhance the distinction between mild, moderate or severe disease (and between diabetes with and without end-organ damage), 4) minimize duplication of codes, and 5) briefly explain the meaning of individual codes in writing., Conclusion: This work may provide an integrated and efficient coding algorithm for CCI to be used in medical register-based research in Sweden., Competing Interests: Ludvigsson coordinates an unrelated study on behalf of the Swedish Inflammatory Bowel Disease Quality Register that has received funding from the Janssen Corporation. Askling is the principal investigator for Abbvie, BMS, Eli Lilly, Merck, Pfizer, Roche, Samsung Bioepis, and Sanofi mainly pertaining to a national safety surveillance of rheumatology drugs. The other authors report no conflicts of interest in this work., (© 2021 Ludvigsson et al.)

Aims: We aimed to discover and replicate associations between leisure-time physical activity and cardiovascular candidate plasma protein biomarkers and to examine whether the associations were independent of body fat., Methods: We used cross-sectional data from two population-based cohorts, the EpiHealth (discovery cohort; n  = 2239) and the Swedish Mammography Cohort - Clinical (SMCC; replication cohort; n  = 4320). Physical activity during leisure time was assessed using questionnaires, and plasma concentrations of 184 proteins were assayed using the Olink Proseek Multiplex Cardiovascular 2 and 3 kits. We applied adjusted linear regression models using the False Discovery Rate to control for multiple testing in discovery., Results: In EpiHealth, physical activity was associated with 75 cardiovascular plasma biomarkers, of which 28 associations were verified (replicated) in SMCC. Findings include seven novel associations in human: paraoxonase 3, cystatin B, cathepsin Z, alpha-L-iduronidase, prostasin, growth differentiation factor 2 and tumour necrosis factor alpha receptor superfamily member 11A. Estimates for associations were similar across tertiles of body fat and physical activity was associated with four biomarkers independent of body fat percentage: paraoxonase 3, cystatin B, fatty acid-binding protein 4 and interleukin-1 receptor antagonist., Conclusion: Leisure-time physical activity was associated with 28 cardiovascular-specific proteins; four associations were independent of body fat. Biomarkers in novel associations are involved in several atherosclerotic processes including regulation of low-density lipoprotein oxidation, protein degradation and immune cell adhesion and migration. Further research into these pathways may yield new insights into how physical activity affects cardiovascular health.

Background Mechanisms related to the influence of diet on the development of cardiovascular disease are not entirely understood, and protein biomarkers may help to understand these pathways. Studies of biomarkers identified with multiplex proteomic methods and dietary patterns are largely lacking. Methods and Results Dietary patterns were generated through principal component analysis in 2 population-based Swedish cohorts, the EpiHealth (EpiHealth study; n=20 817 men and women) and the SMCC (Swedish Mammography Cohort Clinical [n=4650 women]). A set of 184 protein cardiovascular disease biomarkers were measured with 2 high-throughput, multiplex immunoassays. Discovery and replication multivariable linear regression analyses were used to investigate the associations between the principal component analysis-generated dietary patterns and the cardiovascular disease-associated protein biomarkers, first in the EpiHealth (n=2240) and then in the Swedish Mammography Cohort Clinical. Four main dietary patterns were identified in the EpiHealth, and 3 patterns were identified in the Swedish Mammography Cohort Clinical. The healthy and the Western/traditional patterns were found in both cohorts. In the EpiHealth, 57 protein biomarkers were associated with 3 of the dietary patterns, and 41 of these associations were replicated in the Swedish Mammography Cohort Clinical, with effect estimates ranging from 0.057 to 0.083 (P-value range, 5.0×10 -2 -1.4×10 -9 ) for each SD increase in the relative protein concentration. Independent associations were established between dietary patterns and the 21 protein biomarkers. Two proteins, myeloperoxidase and resistin, were associated with both the healthy and the light meal pattern but in opposite directions. Conclusions We have discovered and replicated independent associations between dietary patterns and 21 biomarkers linked to cardiovascular disease, which have a role in the pathways related to inflammation, endothelial and immune function, cell adhesion, and metabolism.

Objective: To study the association between dog ownership and cardiovascular risk factors., Design: A nationwide register-based cohort study and a cross-sectional study in a subset., Setting: A cohort of 2 026 865 participants was identified from the Register of the Total Population and linked to national registers for information on dog ownership, prescribed medication, hospital admissions, education level, income and country of birth. Participants were followed from 1 October, 2006, to the end of the study on 31 December, 2012, assessing medication for a cardiovascular risk factor, emigration and death. Cross-sectional associations were further assessed in 10 110 individuals from the TwinGene study with additional adjustment for professional level, employment status, Charlson comorbidity index, disability and tobacco use., Participants: All Swedish residents aged 45-80 years on 1 October, 2006., Main Outcome Measures: Initiation of medication for hypertension, dyslipidaemia and diabetes mellitus., Results: After adjustment for confounders, the results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95% CI, 1.01 to 1.03) and lipid-lowering treatment (HR, 1.02; 95% CI, 1.01 to 1.04) in dog owners than in non-owners, particularly among those aged 45-60 years and in those owning mixed breed or companion/toy breed dogs. No association of dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.95 to 1.01). Sensitivity analyses in the TwinGene cohort indicated confounding of the association between dog ownership and prevalent treatment for hypertension, dyslipidaemia and diabetes mellitus, respectively, from factors not available in the national cohort, such as employment status and non cardiovascularchronic disease status., Conclusions: In this large cohort study, dog ownership was associated with a minimally higher risk of initiation of treatment for hypertension and dyslipidaemia implying that the previously reported lower risk of cardiovascular mortality among dog owners in this cohort is not explained by reduced hypertension and dyslipidaemia. These observations may suffer from residual confounding despite access to multiple important covariates, and future studies may add valuable information., Competing Interests: Competing interests: EI is a scientific advisor for Precision Wellness and Olink Proteomics for work unrelated to the present project., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It is not known how physical exercise affects the risk of different types of fractures, especially in highly active individuals. To investigate this association, we studied a cohort of 118,204 men and 71,757 women who from 1991 to 2009 participated in Vasaloppet, a long-distance cross-country skiing race in Sweden, and 505,194 nonparticipants frequency-matched on sex, age, and county of residence from the Swedish population. Participants ranged from recreational exercisers to world-class skiers. Race participation, distance of race run, number of races participated in, and finishing time were used as proxies for physical exercise. Incident fractures from 1991 to 2010 were obtained from national Swedish registers. Over a median follow-up of 8.9 years, 53,175 fractures of any type, 2929 hip, 3107 proximal humerus, 11,875 lower leg, 11,733 forearm, and 2391 vertebral fractures occurred. In a Cox proportional hazard regression analysis using time-updated exposure and covariate information, participation in the race was associated with an increased risk of any type of fracture (hazard ratio [HR], 1.02; 95% CI, 1.00 to 1.05); forearm fractures had an HR, 1.11 with a 95% CI, 1.06 to 1.15. There was a lower risk of hip (HR, 0.75; 95% CI, 0.67 to 0.83), proximal humerus (HR, 0.90; 95% CI, 0.82 to 0.98), and lower leg fractures (HR, 0.93; 95% CI, 0.89 to 0.97), whereas the HR of vertebral fracture was 0.97 with a 95% CI, 0.88 to 1.07. Among participants, the risk of fracture was similar irrespective of race distance and number of races run. Participants close to the median finishing time had a lower risk of fracture compared with faster and slower participants. In summary, high levels of physical exercise were associated with a slightly higher risk of fractures of any type, including forearm fractures, but a lower risk of hip, proximal humerus, and lower leg fractures. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

It is presently unclear whether free serum 25-hydroxyvitamin D (S-25(OH)D) better reflects bone health than total S-25(OH)D. We have previously shown that summer total S-25(OH)D values are more useful to predict bone mineral density (BMD) than winter values. Our objective was therefore to compare the relative importance of free and total S-25(OH)D for BMD by season. BMD was measured by dual-energy X-ray absorptiometry (DXA) in 5002 Swedish women (mean age 68 years) randomly selected from a large population-based longitudinal cohort study. Free S-25(OH)D was analyzed by a commercial ELISA and total S-25(OH)D by HPLC-tandem mass spectrometry (MS/MS). Free and total S-25(OH)D co-varied with season, with 26% and 29% higher values in August compared with those in January-March (nadir). There were no differences in mean BMD between categories of free or total S-25(OH)D in samples collected during winter. Women with higher total S-25(OH)D measured during summer had higher BMD at the total hip. Compared with women who had total S-25(OH)D values above 80 nmol/L during summer, adjusted BMD at the total hip was 6% (95% CI, 1% to 11%) lower for S-25(OH)D concentrations between 30 and 40 mmol/L, and 11% (95% CI, 3% to 19%) lower for those with total S-25(OH)D <30 nmol/L. In contrast, free S-25(OH)D measured during summer was not associated with BMD. Compared with women who had highest free S-25(OH)D measured during summer (>8.8 pmol/L), those with intermediate (2.4-3.5 pmol/L) and lowest (<2.4 pmol/L) free S-25(OH)D during summer did not have lower total hip BMD values (3% [95% CI, -2% to 7%] and -2% [95% CI, -8% to 4%]). In addition, we found no added value for the prediction of BMD with the combined measurement of total and free S-25(OH)D during summer or winter. We conclude that vitamin D status assessed by direct measurements of free S-25(OH)D does not reflect BMD better than total S-25(OH)D. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Coffee's long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = -0.0007, 95% C.I. -0.009 to 0.008, P = 0.87; β = -0.001, 95% C.I. -0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (P heterogeneity  > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.

High adherence to healthy diets has the potential to prevent disease and prolong life span, and healthy dietary pattern scores have each been associated with disease and mortality. We studied two commonly promoted healthy diet scores (modified Mediterranean diet score (mMED) and the Healthy Nordic Food Index (HNFI)) and the combined effect of the two scores in association with all-cause and cause-specific mortality (cancer, CVD and ischaemic heart disease). The study included 38 428 women (median age of 61 years) from the Swedish Mammography Cohort. Diet and covariate data were collected in a questionnaire. mMED and HNFI were generated and categorised into low-, medium- and high-adherence groups, and in nine combinations of these. Multivariable-adjusted hazard ratios (HR) of register-ascertained mortality and 95 % CI were calculated in Cox proportional hazards regression analysis. During follow-up (median: 17 years), 10 478 women died. In the high-adherence categories compared with low-adherence categories, the HR for all-cause mortality was 0·76 (95 % CI 0·70, 0·81) for mMED and 0·89 (95 % CI 0·83, 0·96) for HNFI. Higher adherence to mMED was associated with lower mortality in each stratum of HNFI in the combined analysis. In general, mMED, compared with HNFI, was more strongly associated with a lower cause-specific mortality. In Swedish women, both mMED and HNFI were inversely associated with all-cause and cardiovascular mortality. The combined analysis, however, indicated an advantage to be adherent to the mMED. The present version of HNFI did not associate with mortality independent of mMED score.

Milk products may differ in pro-oxidant properties and their effects on fracture risk could potentially be modified by the intake of foods with antioxidant activity. In the population-based Swedish Mammography Cohort study, we aimed to determine how milk and fermented milk combined with fruit and vegetable consumption are associated with hip fracture. Women born in 1914-1948 (n = 61,240) answered food frequency and lifestyle questionnaires in 1987-1990 and 38,071 women contributed with updated information in 1997. During a mean follow-up of 22 years, 5827 women had a hip fracture (ascertained via official register data). Compared with a low intake of milk (<1 glass/day) and a high intake of fruits and vegetables (≥5 servings/day), a high intake of milk (≥3 glasses/day) with a concomitant low intake of fruits and vegetables (<2 servings/day) resulted in a hazard ratio (HR) of 2.49 (95% CI, 2.03 to 3.05). This higher hip fracture rate among high consumers of milk was only modestly attenuated with a concomitant high consumption of fruit and vegetables (HR, 2.14; 95% CI, 1.69 to 2.71). The combination of fruits and vegetables with fermented milk (yogurt or soured milk) yielded a different pattern with lowest rates of hip fracture in high consumers: HR, 0.81 (95% CI, 0.68 to 0.97) for ≥2 servings/day of fermented milk and ≥5 servings/day of fruits and vegetables compared with low consumption of both fruit and vegetables and fermented milk. We conclude that the amount and type of dairy products as well as fruit and vegetable intake are differentially associated with hip fracture rates in women. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objectives: To examine the longitudinal associations between aging with preserved functionality, i.e. independent aging and survival, and lifestyle variables, dietary pattern and cardiovascular risk factors., Design: Cohort study., Setting: Uppsala Longitudinal Study of Adult Men, Sweden., Participants: Swedish men (n = 1,104) at a mean age of 71 (range 69.4-74.1) were investigated, 369 of whom were evaluated for independent aging 16 years later, at a mean age of 87 (range 84.8-88.9)., Measurements: A questionnaire was used to obtain information on lifestyle, including education, living conditions, and physical activity. Adherence to a Mediterranean-like diet was assessed according to a modified Mediterranean Diet Score derived from 7-day food records. Cardiovascular risk factors were measured. Independent aging at a mean age of 87 was defined as lack of diagnosed dementia, a Mini-Mental State Examination score of 25 or greater, not institutionalized, independence in personal activities of daily living, and ability to walk outdoors alone. Complete survival data at age 85 were obtained from the Swedish Cause of Death Register., Results: Fifty-seven percent of the men survived to age 85, and 75% of the participants at a mean age of 87 displayed independent aging. Independent aging was associated with never smoking (vs current) (odds ratio (OR) = 2.20, 95% confidence interval (CI) = 1.05-4.60) and high (vs low) adherence to a Mediterranean-like diet (OR = 2.69, 95% CI = 1.14-6.80). Normal weight or overweight and waist circumference of 102 cm or less were also associated with independent aging. Similar associations were observed with survival., Conclusion: Lifestyle factors such as never smoking, maintaining a healthy diet, and not being obese at age 71 were associated with survival and independent aging at age 85 and older in men., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Dietary pattern analysis is a useful tool to study the importance of food components in the context of a diet and how they relate to health and disease. The association between dietary patterns and fractures is at present uncertain. We aimed to study associations between dietary patterns and risk of hip fracture in the Swedish Mammography Cohort, including 56,736 women (median baseline age 52 years). Diet data was collected in food frequency questionnaires at two investigations and dietary patterns were defined by principal component analysis using 31 food groups. Information on hip fractures was collected from the Swedish National Patient Register. Multivariable adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated in Cox proportional hazards regression analysis. The two patterns identified-the healthy and Western/convenience dietary patterns-were time-updated and analysed. During a median follow-up time of 25.5 years, 4997 women experienced a hip fracture. Hip fracture rate was 31% lower in the highest compared to the lowest quartile of the healthy dietary pattern [HR (95% CI) 0.69 (0.64; 0.75)]. In contrast, women in the highest compared to the lowest quartile of the Western/convenience dietary pattern had a 50% higher [HR (95% CI) 1.50 (1.38; 1.62)] hip fracture rate. Further, in each stratum of a Western/convenience dietary pattern a higher adherence to a healthy dietary pattern was associated with less hip fractures. The present results suggest that a varied healthy diet may be beneficial for the prevention of fragility fractures in women.

Background: We aimed to investigate associations between combinations of body mass index (BMI)-categories, levels of physical activity and long-term risk of cardiovascular disease., Method and Results: At age 50 years, cardiovascular risk factors were assessed in 2196 participating men of the ULSAM-study. This investigation was repeated at age 60, 70, 77 and 82 years. Being physically active (PA) was defined as three hours of recreational or hard physical training per week. The men were categorized according to BMI/PA-status, as PA/normal weight (n = 593 at baseline), non-PA/normal weight (BMI < 25 kg/m(2), n = 580), PA/overweight (n = 418), non-PA/overweight (BMI 25-30 kg/m(2), n = 462), PA/obese (n = 62), non-PA/obese (BMI >30 kg/m(2), n = 81). We used updated data on BMI and physical activity obtained at all examinations. During follow-up (median 30 years) 850 individuals suffered a cardiovascular disease (myocardial infarction, stroke or heart failure). Using updated data on BMI/PA categories, an increased risk for cardiovascular disease was seen with increasing BMI, but a high physical activity was associated with a lower risk of cardiovascular disease within each BMI category: non-PA/normal weight (hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.04-1.66), PA/overweight (HR 1.52, 95% CI 1.20-1.94), non-PA/overweight (HR 1.65, 95% CI 1.31-2.07) PA/obese (HR 2.05, 95% CI 1.44-2.92) and non-PA/obese (HR 2.39, 95% CI 1.74-3.29), using PA/normal weight men as referent., Conclusions: Although physical activity was beneficial at all levels of BMI regarding the risk of future cardiovascular disease, there was still a substantial increased risk associated with being overweight or obese during 30 years of follow-up., (© The European Society of Cardiology 2015.)

Background: An association between obstructive sleep apnea and the incidence of heart failure has been reported in men but not in women. The aim of this study was to investigate whether a combination of snoring and excessive daytime sleepiness, the two main symptoms of obstructive sleep apnea syndrome, was able to predict incident heart failure in a population-based sample of women., Methods: The population-based cohort study Sleep and Health in Women (SHE; n = 5990 women born between 1901 and 1980) was used, with baseline questionnaire data from April 2000 relating to snoring, excessive daytime sleepiness, and covariates. Using data retrieved from the Swedish National Patient Register and Cause of Death Register, the follow-up of incident heart failure continued until 31 December 2011., Results: Among women with both snoring and excessive daytime sleepiness at baseline, 5.3% developed heart failure during follow-up compared with 0.9% in the reference group with neither snoring nor excessive daytime sleepiness. After adjustment for age, waist circumference, smoking, alcohol, hypertension, diabetes, previous myocardial infarction, physical inactivity, depressive symptoms, menopausal status, and hormone replacement therapy, women with the combination of snoring and excessive daytime sleepiness had a twofold increase in the risk of incident heart failure (hazard ratio [HR] 2.2 95% confidence interval [CI] 1.1-4.4)., Conclusion: Symptoms of obstructive sleep apnea, that is, the combination of snoring and excessive daytime sleepiness, are associated with an increased risk of developing heart failure in women., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To study the association between self-reported sleep disturbances and dementia risk., Methods: Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years., Results: Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels., Conclusion: Improving sleep quality may help reduce the neurodegenerative risk in older men., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-therapeutic use of anabolic androgenic steroids (AAS) has been associated with various adverse effects; one of the most serious being direct cardiovascular effects with unknown long-term consequences. Therefore, large studies of the association between AAS and cardiovascular outcomes are warranted. We investigated cardiovascular morbidity and mortality in individuals who tested positive for AAS., Methods and Results: Between 2002 and 2009, a total of 2013 men were enrolled in a cohort on the date of their first AAS test. Mortality and morbidity after cohort entry was retrieved from national registries. Of the 2013 individuals, 409 (20%) tested positive for AAS. These men had twice the cardiovascular morbidity and mortality rate as those with negative tests (adjusted hazard ratio (aHR) 2.0; 95% confidence interval (CI) 1.2-3.3). Compared to the Swedish population, all tested men had an increased risk of premature death from all causes (standardized mortality ratio for AAS-positive: 19.3, 95% CI 12.4-30.0; for AAS-negative: 8.3, 95% CI 6.1-11.0)., Conclusion: Non-therapeutic exposure to AAS appears to be an independent risk factor for cardiovascular morbidity and premature death., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To examine whether high milk consumption is associated with mortality and fractures in women and men., Design: Cohort studies., Setting: Three counties in central Sweden., Participants: Two large Swedish cohorts, one with 61,433 women (39-74 years at baseline 1987-90) and one with 45,339 men (45-79 years at baseline 1997), were administered food frequency questionnaires. The women responded to a second food frequency questionnaire in 1997., Main Outcome Measure: Multivariable survival models were applied to determine the association between milk consumption and time to mortality or fracture., Results: During a mean follow-up of 20.1 years, 15,541 women died and 17,252 had a fracture, of whom 4259 had a hip fracture. In the male cohort with a mean follow-up of 11.2 years, 10,112 men died and 5066 had a fracture, with 1166 hip fracture cases. In women the adjusted mortality hazard ratio for three or more glasses of milk a day compared with less than one glass a day was 1.93 (95% confidence interval 1.80 to 2.06). For every glass of milk, the adjusted hazard ratio of all cause mortality was 1.15 (1.13 to 1.17) in women and 1.03 (1.01 to 1.04) in men. For every glass of milk in women no reduction was observed in fracture risk with higher milk consumption for any fracture (1.02, 1.00 to 1.04) or for hip fracture (1.09, 1.05 to 1.13). The corresponding adjusted hazard ratios in men were 1.01 (0.99 to 1.03) and 1.03 (0.99 to 1.07). In subsamples of two additional cohorts, one in males and one in females, a positive association was seen between milk intake and both urine 8-iso-PGF2α (a biomarker of oxidative stress) and serum interleukin 6 (a main inflammatory biomarker)., Conclusions: High milk intake was associated with higher mortality in one cohort of women and in another cohort of men, and with higher fracture incidence in women. Given the observational study designs with the inherent possibility of residual confounding and reverse causation phenomena, a cautious interpretation of the results is recommended., (© Michaëlsson et al 2014.)

Context: The importance of dietary vitamin D for osteoporotic fracture prevention is uncertain., Objective: Our objective was to investigate associations between dietary vitamin D intake with risk of fracture and osteoporosis., Design and Participants: In the population-based Swedish Mammography Cohort (including 61 433 women followed for 19 years), diet was assessed by repeated food frequency questionnaires., Setting: The study was conducted in 2 municipalities in central Sweden., Main Outcome Measure: Incident fractures were identified from registry data. In a subcohort (n = 5022), bone mineral density was determined by dual-energy x-ray absorptiometry and serum 25-hydroxyvitamin D was measured using HPLC-tandem mass spectrometry., Results: A total of 14 738 women experienced any type of first fracture during follow-up, and 3871 had a hip fracture. Multivariable-adjusted hazard ratio (HR) for any first fracture was 0.96 (95% confidence interval, 0.92-1.01) for the lowest (mean, 3.1 μg/d) and 1.02 (0.96-1.07) for the highest (mean, 6.9 μg/d) quintile compared with the third quintile of vitamin D intake. The corresponding HR for a first hip fracture was 1.02 (0.96-1.08) for the lowest and 1.14 (1.03-1.26) for the highest quintile. Intakes >10 μg/d, compared with <5 μg/d, conferred an HR of 1.02 (0.92-1.13) for any fracture and an HR of 1.27 (1.03-1.57) for hip fracture. The intake of vitamin D did not affect the odds for osteoporosis, although higher levels were associated with higher bone mineral density (0.3%-2%, P < .0001). A positive association was observed between vitamin D intake and serum 25-hydroxyvitamin D., Conclusions: Dietary intakes of vitamin D seem of minor importance for the occurrence of fractures and osteoporosis in community-dwelling Swedish women.

Background: A reduction in the formation of free radicals and oxidative stress might reduce the rate of bone loss and muscle wasting., Objective: The objective was to determine whether α-tocopherol intake or serum concentrations are associated with fracture risk in older women and men., Design: Two cohort studies, the Swedish Mammography Cohort (SMC; n = 61,433 women) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1138 men), were used., Results: During 19 y of follow-up, 14,738 women in the SMC experienced a first fracture at any site (3871 hip fractures). A higher hip fracture rate was observed with lower intakes of α-tocopherol. Compared with the highest quintile of intake, the lowest quintile had a multivariable-adjusted HR of 1.86 (95% CI: 1.67, 2.06). The HR of any fracture was 1.20 (95% CI: 1.14, 1.28). α-Tocopherol-containing supplement use was associated with a reduced rate of hip fracture (HR: 0.78; 95% CI: 0.65, 0.93) and any fracture (HR: 0.86; 95% CI: 0.78, 0.94). Compared with the highest quintile of α-tocopherol intake in ULSAM (follow-up: 12 y), lower intakes (quintiles 1-4) were associated with a higher rate of hip fracture (HR: 3.33; 95% CI: 1.43, 7.76) and any fracture (HR: 1.84; 95% CI: 1.18, 2.88). The HR for hip fracture in men for each 1-SD decrease in serum α-tocopherol was 1.58 (95% CI: 1.13, 2.22) and for any fracture was 1.23 (95% CI: 1.02, 1.48)., Conclusion: Low intakes and low serum concentrations of α-tocopherol are associated with an increased rate of fracture in elderly women and men.

Objective: To investigate the association between long term intake of dietary and supplemental calcium and death from all causes and cardiovascular disease., Design: Prospective longitudinal cohort study., Setting: Swedish mammography cohort, a population based cohort established in 1987-90., Participants: 61 433 women (born between 1914 and 1948) followed-up for a median of 19 years., Main Outcome Measures: Primary outcome measures, identified from registry data, were time to death from all causes (n=11 944) and cause specific cardiovascular disease (n=3862), ischaemic heart disease (n=1932), and stroke (n=1100). Diet was assessed by food frequency questionnaires at baseline and in 1997 for 38 984 women, and intakes of calcium were estimated. Total calcium intake was the sum of dietary and supplemental calcium., Results: The risk patterns with dietary calcium intake were non-linear, with higher rates concentrated around the highest intakes (≥1400 mg/day). Compared with intakes between 600 and 1000 mg/day, intakes above 1400 mg/day were associated with higher death rates from all causes (hazard ratio 1.40, 95% confidence interval 1.17 to 1.67), cardiovascular disease (1 49, 1.09 to 2.02), and ischaemic heart disease (2.14, 1.48 to 3.09) but not from stroke (0.73, 0.33 to 1.65). After sensitivity analysis including marginal structural models, the higher death rate with low dietary calcium intake (<600 mg/day) or with low and high total calcium intake was no longer apparent. Use of calcium tablets (6% users; 500 mg calcium per tablet) was not on average associated with all cause or cause specific mortality but among calcium tablet users with a dietary calcium intake above 1400 mg/day the hazard ratio for all cause mortality was 2.57 (95% confidence interval 1.19 to 5.55)., Conclusion: High intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke.

Objective: To assess whether higher mortality rates among individuals in motor vehicle crashes in areas with low population density depend on injury type and severity or are related to the performance of emergency medical services (EMS)., Methods: Prehospital and hospital deaths were studied in a population-based cohort of 41,243 motor vehicle crashes that occurred in Sweden between 1998 and 2004. The final multivariable analysis was restricted to 6884 individuals in motor vehicle crashes, to minimise the effects of confounding factors., Results: Crude mortality rates following motor vehicle crashes were inversely related to regional population density. In regions with low population density, the unadjusted rate ratio for prehospital death was 2.2 (95% CI 1.9 to 2.5) and for hospital death 1.5 (95% CI 1.1 to 1.9), compared with a high-density population. However, after controlling for regional differences in age, gender and the type/severity of injuries among 6884 individuals in motor vehicle crashes, low population density was no longer associated with increased mortality. At 25 years of age, predicted prehospital mortality was 9% lower (95% CI 5% to 12%) in regions with low population density compared with high population density. This difference decreased with increasing age, but was still 3% lower (95% CI 0.5% to 5%) at 65 years of age., Conclusions: The inverse relationship between population density and mortality among individuals in motor vehicle crashes is related to pre-crash factors that influence the type and severity of injuries and not to differences in EMS.

Background: Comparative studies on dietary patterns and long-term mortality are sparse., Objective: The objective was to examine the relations between 10-y mortality and adherence to the World Health Organization dietary guidelines [Healthy Diet Indicator (HDI)], a Mediterranean-like diet, and a carbohydrate-restricted (CR) diet in elderly Swedish men., Design: Dietary habits were determined by 7-d dietary records in a population-based longitudinal study of 924 Swedish men (age: 71 ± 1 y). The HDI score (-1 to 8 points), the Mediterranean Diet Score (MDS; 0-8 points), and the CR score (2-20 points) were calculated for each participant. Nonadequate reporters of energy intake were identified (n = 413). Mortality was registered during a median follow-up of 10.2 y. Cox proportional hazards regression, with multivariable adjustments, was used to determine the effects of adherence to each dietary pattern., Results: Two hundred fifteen and 88 subjects died of all-cause and cardiovascular disease, respectively. In all individuals, risk relations to mortality for each SD increment in the scores were observed for only MDS, with an adjusted hazard ratio (HR) of 0.83 (95% CI: 0.70, 0.99). Among adequate dietary reporters (n = 511), adjusted HRs for each SD increment in scores were enhanced for MDS (ie, 0.71; 95% CI: 0.55, 0.92) for all-cause mortality and 0.63 (95% CI: 0.42, 0.96) for cardiovascular mortality. Corresponding HRs for CR diet score were 1.19 (95% CI: 0.97, 1.45) for all-cause mortality and 1.44 (95% CI: 1.03, 2.02) for cardiovascular mortality., Conclusion: Adherence to a Mediterranean-like dietary pattern reduced mortality, whereas adherence to a CR dietary pattern appeared to increase mortality in elderly Swedish men, especially when only adequate dietary reporters were considered.

Background: Vitamin D status is known to be important for bone health but may also affect the development of several chronic diseases, including cancer and cardiovascular diseases, which are 2 major causes of death., Objective: We aimed to examine how vitamin D status relates to overall and cause-specific mortality., Design: The Uppsala Longitudinal Study of Adult Men, a community-based cohort of elderly men (mean age at baseline: 71 y; n = 1194), was used to investigate the association between plasma 25-hydroxyvitamin D [25(OH)D] and mortality. Total plasma 25(OH)D was determined with HPLC atmospheric pressure chemical ionization mass spectrometry. Proportional hazards regression was used to compute hazard ratios (HRs)., Results: During follow-up (median: 12.7 y), 584 (49%) participants died. There was a U-shaped association between vitamin D concentrations and total mortality. An approximately 50% higher total mortality rate was observed among men in the lowest 10% (<46 nmol/L) and the highest 5% (>98 nmol/L) of plasma 25(OH)D concentrations compared with intermediate concentrations. Cancer mortality was also higher at low plasma concentrations (multivariable-adjusted HR: 2.20; 95% CI: 1.44, 3.38) and at high concentrations (HR: 2.64; 95% CI: 1.46, 4.78). For cardiovascular death, only low (HR: 1.89; 95% CI: 1.21, 2.96) but not high (HR: 1.33; 95% CI: 0.69, 2.54) concentrations indicated higher risk., Conclusions: Both high and low concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality. Low concentrations are associated with cardiovascular mortality.

Context: Blood levels of 25-hydroxyvitamin D [25(OH)D] is the generally accepted indicator of vitamin D status, but no universal reference level has been reached., Objective: The objective of the study was to determine the threshold at which low plasma 25(OH)D levels are associated with fractures in elderly men and clarify the importance of low levels on total fracture burden., Design and Participants: In the Uppsala Longitudinal Study of Adult Men, a population-based cohort (mean age, 71 yr, n = 1194), we examined the relationship between 25(OH)D and risk for fracture. Plasma 25(OH)D levels were measured with high-pressure liquid chromatography-mass spectrometry., Setting: The study was conducted in the municipality of Uppsala in Sweden, a country with a high fracture incidence., Main Outcome Measure: Time to fracture was measured., Results: During follow-up (median 11 yr), 309 of the participants (26%) sustained a fracture. 25(OH)D levels below 40 nmol/liter, which corresponded to the fifth percentile of 25(OH)D, were associated with a modestly increased risk for fracture, multivariable-adjusted hazard ratio 1.65 (95% confidence interval 1.09-2.49). No risk difference was detected above this level. Approximately 3% of the fractures were attributable to low 25(OH)D levels in this population., Conclusions: Vitamin D insufficiency is not a major cause of fractures in community-dwelling elderly men in Sweden. Despite the fact that cutaneous synthesis of previtamin D during the winter season is undetectable at this northern latitude of 60 degrees, only one in 20 had 25(OH)D levels below 40 nmol/liter, the threshold at which the risk for fracture started to increase. Genetic adaptations to limited UV light may be an explanation for our findings.

Objective: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation., Design: Population based cohort study with follow-up over 35 years., Setting: Municipality of Uppsala, Sweden., Participants: 2205 men aged 50 in 1970-3 who were re-examined at ages 60, 70, 77, and 82 years., Main Outcome Measure: Total (all cause) mortality., Results: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking)., Conclusions: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation.

The authors investigated the shape, sex- and age-dependency, and possible confounding of the association between birth weight and systolic blood pressure (SBP) in 197,954 adults from 20 Nordic cohorts (birth years 1910-1987), one of which included 166,249 Swedish male conscripts. Random-effects meta-regression analyses were performed on estimates obtained from age- and sex-stratified analyses within each of the cohorts. There was an inverse association between birth weight and SBP, irrespective of adjustment for concurrent body mass index. The association was linear for males, but for females with a birth weight greater than 4 kg, SBP increased with birth weight (p < 0.01). The association was stronger in the older age groups (p < 0.05), although this could have been a birth cohort effect. The association was stronger among females than among males (p = 0.005) when birth weight was less than or equal to 4 kg. The estimated effect of birth weight on SBP at age 50 years was -1.52 mmHg/kg (95% confidence interval: -2.27, -0.77) in men and -2.80 mmHg/kg (95% confidence interval: -3.85, -1.76) in women. Exclusion of the Swedish conscripts produced nearly identical results. This meta-analysis supports the evidence of an inverse birth weight-SBP association, regardless of adjustment for concurrent body size. It also reveals important heterogeneity in the shape and strength of the association by sex and age.

Objectives: To find out if the presence of the metabolic syndrome increases the risk of subsequent total and cardiovascular mortality, taking into account established risk factors for cardiovascular disease., Design: Prospective cohort study., Setting: General population., Participants: A community based sample of 2322 men followed since 1970 for a maximum of 32.7 years, investigated at ages 50 and 70., Main Outcome Measures: The relations of the metabolic syndrome defined by the national cholesterol education programme (NCEP) of the US National Heart, Lung, and Blood Institute or criteria of the World Health Organization (WHO) to subsequent total and cardiovascular mortality., Results: When adding the metabolic syndrome to models with established risk factors for cardiovascular disease (smoking, diabetes, hypertension, and serum cholesterol) at age 50, presence of the metabolic syndrome as defined in the NCEP significantly predicted total and cardiovascular mortality (Cox proportional hazard ratios 1.36, 95% confidence interval 1.17 to 1.58; and 1.59, 1.29 to 1.95, respectively). The metabolic syndrome added prognostic information to that of the established risk factors for cardiovascular disease (likelihood ratio tests, P < 0.0001 for both outcomes). Similar results were obtained in a subsample without diabetes or manifest cardiovascular disease., Conclusions: In a large, community based sample of middle aged men, the presence of the metabolic syndrome according to the definition of the NCEP gave long term prognostic information regarding total and cardiovascular mortality if the status of established risk factors for cardiovascular disease was known. If confirmed this may indicate clinical value in diagnosing the metabolic syndrome.