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  • 151. Ingelsson, E
    et al.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, J
    Risérus, U
    Michaelsson, K
    Byberg, L
    Relative importance and conjoint effects of obesity and physical inactivity for development of insulin resistance.2009Inngår i: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 16, nr 1, s. 28-33Artikkel i tidsskrift (Fagfellevurdert)
  • 152. Ingelsson, E
    et al.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala University, Department of Health and Social Sciences.
    Zethelius, B
    Vasan, RS
    Flyvbjerg, A
    Frystyk, J
    Berne, C
    Hänni, A
    Lind, L
    Sundström, J
    Associations of serum adiponectin with skeletal muscle morphology and insulin sensitivity2009Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, nr 3, s. 953-957Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Skeletal muscle morphology and function are strongly associated with insulin sensitivity.

    Objective: The objective of the study was to test the hypothesis that circulating adiponectin is associated with skeletal muscle morphology and that adiponectin mediates the relation of muscle morphology to insulin sensitivity.

    Design, Settings, and Participants: This was a cross-sectional investigation of 461 men aged 71 yr, participants of the community-based Uppsala Longitudinal Study of Adult Men study.

    Main Outcome Measures: Measures included serum adiponectin, insulin sensitivity measured with euglycemic insulin clamp technique, and capillary density and muscle fiber composition determined from vastus lateralis muscle biopsies.

    Results: In multivariable linear regression models (adjusting for age, physical activity, fasting glucose, and pharmacological treatment for diabetes), serum adiponectin levels rose with increasing capillary density (β, 0.30 per 50 capillaries per square millimeter increase; P = 0.041) and higher proportion of type I muscle fibers (β, 0.27 per 10% increase; P = 0.036) but declined with a higher proportion of type IIb fibers (β, −0.39 per 10% increase; P = 0.014). Using bootstrap methods to examine the potential role of adiponectin in associations between muscle morphology and insulin sensitivity and the associations of capillary density (β difference, 0.041; 95% confidence interval 0.001, 0.085) and proportion of type IIb muscle fibers (β difference, −0.053; 95% confidence interval −0.107, −0.002) with insulin sensitivity were significantly attenuated when adiponectin was included in the models.

    Conclusions: Circulating adiponectin concentrations were higher with increasing skeletal muscle capillary density and in individuals with higher proportion of slow oxidative muscle fibers. Furthermore, our results indicate that adiponectin could be a partial mediator of the relations between skeletal muscle morphology and insulin sensitivity.

    Circulating adiponectin concentrations are associated with skeletal muscle morphology and could be involved in the relations between muscle morphology and insulin sensitivity.

  • 153. Ivert, Torbjörn
    et al.
    Malmström, Håkan
    Hammar, Niklas
    Carlsson, Axel C
    Wändell, Per E
    Holzmann, Martin J
    Jungner, Ingmar
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska Institutet.
    Walldius, Göran
    Cardiovascular events in patients under age fifty with early findings of elevated lipid and glucose levels - The AMORIS study2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 8, artikkel-id e0201972Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The long-term trajectories of lipid and glucose levels in subjects who experience a major cardiovascular (CV) event at a young age has not been well studied. Our objective was to investigate lipid, lipoprotein, apolipoprotein (apo), and glucose levels in individuals experiencing a CV event before 50 years of age.

    METHODS AND FINDINGS: A first CV event [non-fatal myocardial infarction (MI), coronary revascularisation, or CV related death] before age 50 was recorded in 2,939 (cumulative incidence 1.2% in males and 0.3% in females) of 361,353 individuals included in the prospective Swedish AMORIS (Apolipoprotein-related MOrtality RISk) study with health examinations 1985-1996 and follow-up through 2011. In a nested case-control analysis, cases with a CV event were matched to randomly selected controls. Population risk factor trajectories were calculated up to 20 years prior to an event. Total cholesterol (TC), triglyceride (TG), and glucose levels were higher in cases than in controls as early as 20 years prior to the event with differences increasing over time. Low density lipoprotein, apoB, and the apoB/apoA-1 ratio were higher and increased over time, while HDL and apoA-1 were lower in cases compared to controls. The odds ratio was 2.5 (95% confidence interval 1.6-3.7) for TC ≥5 mmol/L and TG ≥1.7 mmol/L in cases versus controls. The adjusted population-attributable fractions including lipids, glucose, diabetes, smoking, hypertension, and obesity indicated that about 50% of CV events before age 50 may be associated with elevated lipid and glucose levels.

    CONCLUSIONS: Elevated TC, TG, LDL, apoB, and glucose levels and high apoB/apo A-1 ratio documented two decades before a CV event in subjects younger than 50 years may account for about half of CV events before age 50, which calls for early recognition and possibly treatment of modifiable CV risk factors in young individuals.

  • 154. James, Matthew T
    et al.
    Grams, Morgan E
    Woodward, Mark
    Elley, C Raina
    Green, Jamie A
    Wheeler, David C
    de Jong, Paul
    Gansevoort, Ron T
    Levey, Andrew S
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury2015Inngår i: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 66, nr 4, s. 552-554Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain.

    STUDY DESIGN: Meta-analysis of cohort studies.

    SETTING & POPULATION: 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts.

    SELECTION CRITERIA FOR STUDIES: Cohorts participating in the CKD Prognosis Consortium.

    PREDICTORS: Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions.

    OUTCOME: Hospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.

    RESULTS: During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80mL/min/1.73m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs>60mL/min/1.73m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension.

    LIMITATIONS: AKI identified by diagnostic code.

    CONCLUSIONS: Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.

  • 155. James, Spencer L. G
    et al.
    Abate, Degu
    Abate, Kalkidan Hessen
    Abay, Solomon M
    Abbafati, Cristiana
    Abbasi, Nooshin
    Abbastabar, Hedayat
    Abd-Allah, Foad
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Murray, Christopher J. L
    Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 20172018Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 392, nr 10159, s. 1789-1858Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. 

    Methods We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. 

    Findings Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 39% (95% uncertainty interval [UI] 3.1-4. 6) from 1990 to 2017; however, the all-age YLD rate increased by 7.2% (6.0-8.4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7.9% (6 6-9. 2) for males and 6.5% (5.4-7.7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-hatin and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). 

    Interpretation Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury.

  • 156.
    Jia, Ting
    et al.
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Huang, Xiaoyan
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden ; Division of Nephrology, Peking University Shenzhen Hospital, Peking University, Shenzhen, China..
    Qureshi, Abdul R
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Xu, Hong
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden ; Division of Renal Medicine, Peking Union Medical College Hospital, Beijing, China.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Department of Public Health and Caring Sciences, Section of Geriatrics, Uppsala University, Uppsala, Sweden.
    Lindholm, Bengt
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Stenvinkel, Peter
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Risérus, Ulf
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Carrero, Juan J
    Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden ; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function2014Inngår i: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 86, nr 2, s. 383-391Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As chronic kidney disease (CKD) progresses with abnormalities in glucose and insulin metabolism, commonly used insulin sensitivity indices (ISIs) may not be applicable in individuals with CKD. Here we sought to validate surrogate ISIs against the glucose disposal rate by the gold-standard hyperinsulinemic euglycemic glucose clamp (HEGC) technique in 1074 elderly men of similar age (70 years) of whom 495 had and 579 did not have CKD (estimated glomerular filtration rate (eGFR) under 60 ml/min per 1.73 m(2) (median eGFR of 46 ml/min per 1.73 m(2))). All ISIs provided satisfactory (weighted κ over 0.6) estimates of the glucose disposal rate in patients with CKD. ISIs derived from oral glucose tolerance tests (OGTTs) agreed better with HEGC than those from fasting samples (higher predictive accuracy). Regardless of CKD strata, all ISIs allowed satisfactory clinical discrimination between the presence and absence of insulin resistance (glucose disposal rate under 4 mg/kg/min). We also assessed the ability of both HEGC and ISIs to predict all-cause and cardiovascular mortality during a 10-year follow-up. Neither HEGC nor ISIs independently predicted mortality. Adjustment for renal function did not materially change these associations. Thus, ISIs can be applied in individuals with moderately impaired renal function for diagnostic purposes. For research matters, OGTT-derived ISIs may be preferred. Our data do not support the hypothesis of kidney function mediating insulin sensitivity (IS)-associated outcomes nor a role for IS as a predictor of mortality.Kidney International advance online publication, 29 January 2014; doi:10.1038/ki.2014.1.

  • 157. Jia, Ting
    et al.
    Risérus, Ulf
    Xu, Hong
    Lindholm, Bengt
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Sjögren, Per
    Cederholm, Tommy
    Larsson, Tobias E
    Ikizler, Talat A
    Carrero, Juan J
    Kidney function, β-cell function and glucose tolerance in older men2015Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 2, s. 587-593Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Kidney dysfunction induces insulin resistance, but it is unknown if β cell function is affected.

    Objective: To investigate insulin release (β cell function) and glucose tolerance following a standardized oral glucose tolerance test (OGTT) across kidney function strata.

    Setting and Design: Community-based cohort study from the Uppsala Longitudinal Study of Adult Men (ULSAM).

    Participants and Main Outcome Measure: Included were 1015 non-diabetic Swedish men aged 70-71 years. All participants underwent OGTT and euglycaemic hyperinsulinaemic clamp (HEGC) tests, allowing determination of insulin sensitivity, β cell function and glucose tolerance. Kidney function was estimated by cystatin C-algorithms. Mixed models were used to identify determinants of insulin secretion after the hyperglycemic load.

    Results: As many as 466 (46%) of participants presented moderate-advanced kidney disease. Insulin sensitivity (by HEGC) decreased across decreasing kidney function quartiles. After the OGTT challenge, however, β cell function indices (area under the curve for insulin release, the estimated first phase insulin release and the insulinogenic index) were incrementally higher. Neither the oral disposition index nor ths 2-hour post-load glucose tolerance differed across kidney function strata. Mixed models showed that dynamic insulin release during the OGTT was inversely associated to kidney function despite correction for each individual's insulin sensitivity or its risk factors.

    Conclusions: In older men, β cell function after a hyperglycemic load appropriately compensated the loss in insulin sensitivity that accompanies kidney dysfunction. As a result, the net balance between insulin sensitivity and β cell function was preserved.

  • 158.
    Jobs, Elisabeth
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala University.
    Cathepsin S as a biomarker of low-grade inflammation, insulin resistance, and cardiometabolic disease risk2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.

       The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.

       This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.

       In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.

       Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations. 

  • 159.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitetet.
    Adamsson, Viola
    Larsson, Anders
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Ingelsson, Erik
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Risérus, Ulf
    Influence of a prudent diet on circulating cathepsin S in humans2014Inngår i: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 13, nr 84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Increased circulating cathepsin S levels have been linked to increased risk of cardiometabolic diseases and cancer. However, whether cathepsin S is a modifiable risk factor is unclear. We aimed to investigate the effects of a prudent diet on plasma cathepsin S levels in healthy individuals.

    FINDINGS: Explorative analyses of a randomized study were performed in 88 normal to slightly overweight and hyperlipidemic men and women (aged 25 to 65) that were randomly assigned to ad libitum prudent diet, i.e. healthy Nordic diet (ND) or a control group (habitual Western diet) for 6 weeks. Whereas all foods in the ND were provided, the control group was advised to consume their habitual diet throughout the study. The ND was in line with dietary recommendations, e.g. low in saturated fats, sugars and salt, but high in plant-based foods rich in fibre and unsaturated fats.The ND significantly decreased cathepsin S levels (from 20.1 (+/-4.0 SD) to 19.7 μg/L (+/-4.3 SD)) compared with control group (from 18.2 (+/-2.9 SD) to 19.1 μg/L (+/-3.8 SD)). This difference remained after adjusting for sex and change in insulin sensitivity (P = 0.03), and near significant after adjusting for baseline cathepsin S levels (P = 0.06), but not for change in weight or LDL-C. Changes in cathepsin S levels were directly correlated with change in LDL-C.

    CONCLUSIONS: Compared with a habitual control diet, a provided ad libitum healthy Nordic diet decreased cathepsin S levels in healthy individuals, possibly mediated by weight loss or lowered LDL-C. These differences between groups in cathepsin S were however not robust and therefore need further investigation.

  • 160.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, Johan
    Basu, Samar
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Association between serum cathepsin S and mortality in older adults2011Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, nr 10, s. 1113-1121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking. Objective To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women.

    Design, Setting, and Participants: Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S.

    Main Outcome Measure Total mortality.

    Results: During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P = .009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P = .04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P = .01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P = .01).

    Conclusions Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

  • 161.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Serum cathepsin S levels independently predicts total- and cardiovascular mortality in elderly men2011Inngår i: European Society of Cardiology Congress 2011, Stockholm, 2011Konferansepaper (Annet vitenskapelig)
  • 162.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Serum cathepsin S levels independently predicts total- and cardiovascular mortality in elderly men2010Inngår i: Kardiovaskulära vårmötet, Göteborg, 2010Konferansepaper (Annet vitenskapelig)
  • 163.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Serum cathepsin S predicts the risk for mortality in elderly men and women2011Inngår i: Kardiovaskulära vårmötet, Örebro, 2011Konferansepaper (Annet vitenskapelig)
  • 164.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Ingelsson, Erik
    Risérus, Ulf
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Serum cathepsin S predicts the risk for mortality in elderly men and women2011Konferansepaper (Annet vitenskapelig)
  • 165.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Risérus, U
    Ingelsson, E
    Helmersson, J
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, J
    Lind, L
    Larsson, A
    Basu, S
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Serum cathepsin S is associated with serum C-reactive protein and interleukin-6 independently of obesity in elderly men2010Inngår i: Journal of Clinical Epidemiology, ISSN 0895-4356, E-ISSN 1878-5921, Vol. 95, nr 9, s. 4460-4464Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants.

    Methods: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr.

    Results: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 SD increase, 0.13; 95% confidence interval 0.07–0.19; P < 0.001) and higher serum IL-6 (regression coefficient for 1 SD increase, 0.08; 95% confidence interval 0.01–0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index <25 kg/m2, n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr.

    Conclusions: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.

  • 166.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Risérus, Ulf
    Ingelsson, Erik
    Helmersson, Johanna
    Nerpin, Elisabet
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Sundström, Johan
    Lind, Lars
    Larsson, Anders
    Basu, Samar
    Ärnlöv, Johan
    Cathepsin S is independently associated with cytokine mediated inflammation in elderly men2009Inngår i: European Society of Cardiology Congress, Uppsala, 2009Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Cathepsin S is independently associated with cytokine mediated inflammation in elderly men Conclusion: Higher serum levels of Cathepsin S were independently associated with higher CRP and IL-6 in a community– based sample of elderly men. Our data provides support for the notion that Cathepsin S is involved in inflammatory processes, possibly leading to atherosclerosis and cardiovascular disease. Background: Cathepsin S is a lysosomal protease that has been suggested to play a key role in the development of atherosclerosis and cardiovascular disease by degradation of vascular extracellular matrix. Previous studies have suggested that cathepsin S provides a molecular link between obesity and atherosclerosis, possibly via increased inflammatory activity. Yet, the association between circulating cathepsin S and inflammation markers has not previously been reported in the community. Aim: To investigate the association between plasma levels of cathepsin- S, C-reactive protein (CRP) and Interleukin 6 (IL-6), in the community. Methods: Serum levels of cathepsin S, CRP, IL-6 were measured in frozen samples from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (n=999, mean age 71 years). Results: Cross-sectional association between Cathepsin S, CRP and IL-6 at age 70 showed that one standard deviation (SD) higher serum Cathepsin S was significantly associated with 0.14 SD higher serum CRP and 0.07-0.08 SD higher serum IL-6 when adjusting for age, life style factors (body mass index, physic activity and smoking), cardiovascular risk factors (hypertension, dyslipidemia, previous cardiovascular disease and diabetes and smoking), and the combination of all covariates

  • 167.
    Jobs, Elisabeth
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Risérus, Ulf
    Ingelsson, Erik
    Sundström, Johan
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Nerpin, Elisabet
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Iggman, David
    Basu, Samar
    Larsson, Anders
    Lind, Lars
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men2012Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 1, s. 163-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE. To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

    RESEARCH DESIGN AND METHODS. Serum cathepsin S, insulin sensitivity (euglycaemic-hyperinsulinaemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

    RESULTS. After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).

    CONCLUSIONS. Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.

  • 168.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Broad-spectrum pathogen detection using padlock probes and suspension micro-array technology.2007Inngår i: Fifth annual planet xmap europe 2007, Amsterdam, 2007Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    A technique for multiplex detection of pathogens based on padlock probes and Luminex technology has been developed. Here detection data from a panel of pathogenic fungi is presented. Most nucleic acid based techniques in use for clinical pathogen detection (diagnosis) can reveal one to a few pathogens in each test. Techniques revealing several pathogens at a time are often problematic due to inherent difficulties with multiplex PCR. The padlock probe (PLP) based detection method, presented here, avoids such problems and has potential for developing highly multiplexed assays. A PLP is an oligonucleotide designed to hybridize to a target sequence so that the 5’ and 3’ end of the probe meet with only a nick separating them. A ligase can close the nick, forming a closed DNA circle of the probe. In the case presented here the internal parts of the probe (the parts not participating in target hybridization) have a general PCR primer target region and a DNA address region (tag region). General PCR primers, that are labelled, can amplify circularized probes and the products can be detected in a Luminex™ machine via the address tags.

  • 169.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Creating Arrays by Centrifugation2002Inngår i: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 32, nr 6, s. 1322-1329Artikkel i tidsskrift (Fagfellevurdert)
  • 170.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Dynamic Allele-Specific Hybridisation: A New Method for Scoring Single Nucleotide Polymorphisms.1999Inngår i: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 17, s. 87-88Artikkel i tidsskrift (Fagfellevurdert)
  • 171.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Effect of Oligonucleotide Truncation on Single-nucleotide Distinction by Solid Phase Hybridization2002Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 74, nr 1, s. 199-202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligonucleotide microarrays are used to analyze target sequences on the basis of differences in hybridization stability between matched and mismatched probe-target duplexes. DNA microarray manufacture via photolithographic synthesis generates a minority of full-length oligonucleotide probes along with a series of 5'-truncated contaminants. In a model experiment, we now investigate the effect of truncated oligonucleotides on the ability to distinguish target sequence variants that differ in a single nucleotide position. A series of oligonucleotides, mixed in proportions simulating stepwise synthetic yields of between 82 and 100%, were bound to a solid support and allowed to hybridize to a target molecule. The extent of hybridization was monitored over a range of temperatures via the fluorescence of a double-strand-specific dye. The discriminatory power of pure oligonucleotide probes was found to be significantly greater than that of a population of truncated probes, but only over a limited temperature interval. We conclude that at optimal temperatures greater oligonucleotide quality can improve the performance of oligonucleotide hybridization microarrays.

  • 172.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Identification of 167 Polymorphisms in 88 Genes from Candidate Neurodegeneration Pathways1999Inngår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 238, nr 2, s. 315-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Catalogs of intra-gene polymorphisms are needed to facilitate wide-ranging candidate gene-based association studies in common complex diseases. With this in mind, we have scanned multiple alignments of expressed sequence tags and of genomic DNA sequences (PCR products from four to eight unrelated individuals) to find polymorphisms in 195 genes putatively involved in neurodegenerative illness (including components of oxidative stress, excitotoxicity, inflammation, apoptosis and aging). This led to the discovery of 167 polymorphisms in 88 genes. These comprised 163 single nucleotide polymorphisms, one insertion/deletion, and three other variations involving more than one base pair. The polymorphisms were distributed in the exons (87), introns (70), and gene flanking regions (10). Of the exonic polymorphisms, 17 would give rise to non-synonymous amino acid substitutions. These findings now provide a valuable resource for association studies in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease.

  • 173.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    iFRET: An Improved Fluorescence System for DNA Melting Analysis2002Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 12, nr 9, s. 1401-1407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fluorescence resonance energy transfer (FRET) is a powerful tool for detecting spatial relationships between macromolecules, one use of which is the tracking of DNA hybridization status. The process involves measuring changes in fluorescence as FRET donor and acceptor moieties are brought closer together or moved farther apart as a result of DNA hybridization/denaturation. In the present study, we introduce a new version of FRET, which we term induced FRET (iFRET), that is ideally suited for melting curve analysis. The innovation entails using a double-strand, DNA-specific intercalating dye (e.g., SYBR Green I) as the FRET donor, with a conventional FRET acceptor affixed to one of the DNA molecules. The SNP genotyping technique dynamic allele specific hybridization (DASH) was used as a platform to compare iFRET to two alternative fluorescence strategies, namely, the use of the intercalating dye alone and the use of a standard FRET pair (fluorescein as donor, 6-rhodamine as acceptor). The iFRET configuration combines the advantages of intercalating dyes, such as high signal strengths and low cost, with maintaining the specificity and multiplex potential afforded by traditional FRET detection systems. Consequently, iFRET represents a fresh and attractive schema for monitoring interactions between DNA molecules.

  • 174.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Latest Advances in SNP Genotyping by Dynamic Allele Specific Hybridization (DASH)2001Inngår i: Genome Sequencing & Biology, Cold Spring Harbour, New York, USA , 2001Konferansepaper (Fagfellevurdert)
  • 175.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Ongoing Development of Dynamic Allele Specific Hybridization (DASH) for Polymorphism Analysis2001Inngår i: 4th International Meeting on Single Nucleotide polymorphism and Complex Genome Analysis, Stockholm, 2001Konferansepaper (Fagfellevurdert)
  • 176.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Robust and Accurate Single Nucleotide Polymorphism Genotyoing by Dynamic Allelespecific Hybridization (DASH): Design criteria and Assay Validation2001Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 11, nr 1, s. 152-162Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We recently introduced a generic single nucleotide polymorphism (SNP) genotyping method, termed DASH (dynamic allele-specific hybridization), which entails dynamic tracking of probe (oligonucleotide) to target (PCR product) hybridization as reaction temperature is steadily increased. The reliability of DASH and optimal design rules have not been previously reported. We have now evaluated crudely designed DASH assays (sequences unmodified from genomic DNA) for 89 randomly selected and confirmed SNPs. Accurate genotype assignment was achieved for 89% of these worst-case-scenario assays. Failures were determined to be caused by secondary structures in the target molecule, which could be reliably predicted from thermodynamic theory. Improved design rules were thereby established, and these were tested by redesigning six of the failed DASH assays. This involved reengineering PCR primers to eliminate amplified target sequence secondary structures. This sophisticated design strategy led to complete functional recovery of all six assays, implying that SNPs in most if not all sequence contexts can be effectively scored by DASH. Subsequent empirical support for this inference has been evidenced by ~30 failure-free DASH assay designs implemented across a range of ongoing genotyping programs. Structured follow-on studies employed standardized assay conditions, and revealed that assay reproducibility (733 duplicated genotypes, six different assays) was as high as 100%, with an assay accuracy (1200 genotypes, three different assays) that exceeded 99.9%. No post-PCR assay failures were encountered. These findings, along with intrinsic low cost and high flexibility, validate DASH as an effective procedure for SNP genotyping.

  • 177.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Robust and Accurate Single Nucleotide Polymorphism Genotyping by Dynamic Allele Specific Hybridization (DASH)2001Inngår i: SNP 2000 : Third International Meeting on Single Nucleotide polymorphism and Complex Genome Analysis, Taos, New Mexico, USA, 2001Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Dynamic allele specific hybridization (DASH) [1] is a method for genotyping single nucleotide polymorphisms (SNPs), insertion/deletions (indels), and other subtle sequence variations. Allele discrimination is based upon the detection of stability differences in duplex DNAs (oligonucleotide probes hybridized to PCR product targets) involving fully matched or allelic-mismatched structures. The procedure involves PCR amplification of a short sequence spanning a variant position. One PCR primer is biotinylated allowing subsequent facile affinity (streptavidin) capture of one strand of the PCR product onto a solid support. An unlabelled oligonucleotide probe, complementary to one of the alleles, is then annealed to this target DNA at low temperature in the presence of a double-strand specific intercalating dye. Samples are then steadily heated through a temperature range while continually monitoring fluorescence, i.e., the amount of duplexed probe-target material. A melting temperature profile is thus derived, indicating the presence of perfectly matched or subtly mismatch probe-target duplexes, or a heterozygous mixture of the two. An extensive testing and validation study was performed in order to maximize the utility of DASH. This study involved design and application of DASH assays for 89 randomly selected SNPs. Nonoptimized assay designs (worst-case scenario) resulted in 79 functional assays from which genotypes could be clearly determined. Statistical analysis of many variables in these assays revealed that the presence or absence of secondary structures in the target sequence was a critical factor for DASH performance. By identifying key bases involved in secondary structure formation and then by altering these in the PCR primers, the formation of secondary structure could be minimized. Six of the failed DASH assays were redesigned following this strategy, and full recovery of all six assays was achieved (bestcase scenario). Subsequent replication and method comparison studies demonstrated that DASH achieves a genotyping accuracy better than 99.9%, and a reproducibility of 100%. No post-PCR assay failures have yet been encountered. These findings, along with intrinsic low cost (less than 25c/genotype) and high flexibility, validate DASH as an effective procedure for SNP genotyping.

  • 178.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    SNP association studies in Alzheimer's disease highlight problems for complex disease analysis2001Inngår i: Trends in Genetics, ISSN 0168-9479, Vol. 17, nr 7, s. 407-413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic linkage and association analyses are two distinct approaches to understanding the genetic etiology of complex disease. Association analysis has become particularly popular in recent times, but the true utility of the strategy remains uncertain. To try to gain better insight into the relevant issues, we have used genetic association analysis to explore the etiology of Alzheimer's disease. Our empirical findings supplement the theoretical debate, illustrating the general doubtfulness of previous positive findings and the limited ability of typical association studies based on candidate genes to discern true medium-sized signals from false positives. Improvements in genotyping technologies and increasing the number of SNPs tested, without sophisticated allowance for all other issues, could simply lead to an unmanageable overload of false-positive signals, themselves obscuring true disease associations

  • 179.
    Jobs, Magnus
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    SNP Genotyping by Dynamic Allele Specific Hybridization (DASH)2001Inngår i: 7th Conference on Methods and Applications of Fluorescence: Spectroscopy, Imaging and Probes, Amsterdam, The Nederlands , 2001Konferansepaper (Fagfellevurdert)
  • 180.
    Jobs, Magnus
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Eriksson, Ronnie
    Blomberg, Jonas
    Multiplex and quantifiable detection of infectious fungi using padlock probes, general qPCR and suspension microarray readout2013Inngår i: Laboratory protocols in fungal biology current methods in fungal biology / [ed] Gupta, Vijai Kumar; Tuohy, Mari, New York: Springer , 2013Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 181. Johnson, CO
    et al.
    Nguyen, M
    Roth, GA
    Nichols, E
    Alam, T
    Abate, D
    Abd-Allah, F
    Abdelalim, A
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Murray, CJL
    Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 20162019Inngår i: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, nr 5, s. 439-458Artikkel i tidsskrift (Fagfellevurdert)
  • 182. Järnbert-Pettersson, Hans
    et al.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Labour pain - poorly analysed and reported: a systematic review2018Inngår i: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 18, nr 1, artikkel-id 483Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Modelling and analysing repeated measures data, such as women's experiences of pain during labour, is a complex topic. Traditional end-point analyses such as t-tests, ANOVA, or repeated measures [rANOVA] have known disadvantages. Modern and more sophisticated statistical methods such as mixed effect models provide flexibility and are more likely to draw correct conclusions from data. The aim of this study is to study how labour pain is analysed in repeated measures design studies, and to increase awareness of when and why modern statistical methods are suitable with the aim of encouraging their use in preference of traditional methods.

    METHODS: Six databases were searched with the English language as a restriction. Study eligibility criteria included: Original studies published between 1999 and 2016, studying pregnant women in labour with the aim to compare at least two methods for labour pain management, with at least two measurements of labour pain separated by time, and where labour pain was analysed. After deduplication, all records (n = 2800) were screened by one of the authors who excluded ineligible publication types, leaving 737 records remaining for full-text screening. A sample of 309 studies was then randomly selected and screened by both authors.

    RESULTS: Among the 133 (of 309) studies that fulfilled the study eligibility criteria, 7% used mixed effect models, 20% rANOVA, and 73% used end-point analysis to draw conclusions regarding treatment effects for labour pain between groups. The most commonly used end-point analyses to compare groups regarding labour pain were t-tests (57, 43%) and ANOVA (41, 31%). We present a checklist for clinicians to clarify when mixed effect models should be considered as the preferred choice for analysis, in particular when labour pain is measured.

    CONCLUSIONS: Studies that aim to compare methods for labour pain management often use inappropriate statistical methods, and inaccurately report how the statistical analyses were carried out. The statistical methods used in analyses are often based on assumptions that are not fulfilled or described. We recommend that authors, reviewers, and editors pay greater attention to the analysis when designing and publishing studies evaluating methods for pain relief during labour.

  • 183.
    Karlsson, Maria
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Karlsson, Peter
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Patienters delaktighet i beslut om den egna omvårdnaden på en kirurgavdelning.: En empirisk studie2006Independent thesis Basic level (degree of Bachelor)Oppgave
  • 184. Kassebaum, Nicholas
    et al.
    Bertozzi-Villa, Amelia
    Coggeshall, Megan S
    Shackelford, Katya A
    Steiner, Caitlyn
    Heuton, Kyle R
    Gonzalez-Medina, Diego
    Barber, Ryan
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Lozano, Rafael
    Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 20132014Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 384, nr 9947, s. 980-1004Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery. 

    Methods: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values. 

    Findings: 292 982 (95% UI 261017-327792) maternal deaths occurred in 2013, compared with 376 034 (343483-407574) in 1990. The global annual rate of change in the MMR was -0.3% (-1.1 to 0.6) from 1990 to 2003, and -2.7% (-3.9 to -1.5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0.4% (-0.2-0.6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956.8 (685.1-1262.8) in South Sudan to 2.4 (1.6-3.6) in Iceland. 

    Interpretation: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.

  • 185. Kassebaum, Nicholas J
    et al.
    Arora, Megha
    Barber, Ryan M
    Bhutta, Zulficar
    Carter, Austin
    Casey, Daniel C
    Charlson, Fiona J
    Coates, Matthew M
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Murray, Christopher J. L
    Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 20152016Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, nr 10053, s. 1603-1658Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development.

    Methods

    We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate.

    Findings

    Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval 2·9–3·0) for men and 3·5 years (3·4–3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78–0·92) and 1·2 years (1·1–1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs.

    Interpretation

    Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum.

    Funding

    Bill & Melinda Gates Foundation

  • 186. Kassebaum, Nicholas J
    et al.
    Barber, Ryan M
    Bhutta, Zulfiqar
    Dandona, Lalit
    Gething, Peter W
    Hay, Simon I
    Kinfu, Yohannes
    Larson, Heidi J
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Remuzzi, Giuseppe
    Global, regional, and national levels of maternal mortality, 1990-2015: a systematic analysis for the Global Burden of Disease Study 20152016Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, nr 10053, s. 1775-1812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    In transitioning from the Millennium Development Goal to the Sustainable Development Goal era, it is imperative to comprehensively assess progress toward reducing maternal mortality to identify areas of success, remaining challenges, and frame policy discussions. We aimed to quantify maternal mortality throughout the world by underlying cause and age from 1990 to 2015.

    Methods

    We estimated maternal mortality at the global, regional, and national levels from 1990 to 2015 for ages 10–54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories, 11 of which were analysed at the subnational level. We quantified eight underlying causes of maternal death and four timing categories, improving estimation methods since GBD 2013 for adult all-cause mortality, HIV-related maternal mortality, and late maternal death. Secondary analyses then allowed systematic examination of drivers of trends, including the relation between maternal mortality and coverage of specific reproductive health-care services as well as assessment of observed versus expected maternal mortality as a function of Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility.

    Findings

    Only ten countries achieved MDG 5, but 122 of 195 countries have already met SDG 3.1. Geographical disparities widened between 1990 and 2015 and, in 2015, 24 countries still had a maternal mortality ratio greater than 400. The proportion of all maternal deaths occurring in the bottom two SDI quintiles, where haemorrhage is the dominant cause of maternal death, increased from roughly 68% in 1990 to more than 80% in 2015. The middle SDI quintile improved the most from 1990 to 2015, but also has the most complicated causal profile. Maternal mortality in the highest SDI quintile is mostly due to other direct maternal disorders, indirect maternal disorders, and abortion, ectopic pregnancy, and/or miscarriage. Historical patterns suggest achievement of SDG 3.1 will require 91% coverage of one antenatal care visit, 78% of four antenatal care visits, 81% of in-facility delivery, and 87% of skilled birth attendance.

    Interpretation

    Several challenges to improving reproductive health lie ahead in the SDG era. Countries should establish or renew systems for collection and timely dissemination of health data; expand coverage and improve quality of family planning services, including access to contraception and safe abortion to address high adolescent fertility; invest in improving health system capacity, including coverage of routine reproductive health care and of more advanced obstetric care—including EmOC; adapt health systems and data collection systems to monitor and reverse the increase in indirect, other direct, and late maternal deaths, especially in high SDI locations; and examine their own performance with respect to their SDI level, using that information to formulate strategies to improve performance and ensure optimum reproductive health of their population.

    Funding

    Bill & Melinda Gates Foundation.

  • 187. Kassebaum, Nicholas
    et al.
    Kyu, Hmwe Hmwe
    Zoeckler, Leo
    Olsen, Helen
    Thomas, Katie
    Pinho, Christine
    Bhutta, Zulfiqar
    Dandona, Lalit
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Vos, Theo
    Child and adolescent health from 1990 to 2015: Findings from the Global Burden of Diseases, Injuries and Risk Factors 2015 study2017Inngår i: JAMA pediatrics, ISSN 2168-6203, E-ISSN 2168-6211, Vol. 171, nr 6, s. 573-592Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance  Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health.

    Objective  To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion.

    Evidence Review  Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss.

    Findings  Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries.

    Conclusions and Relevance  Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.

  • 188. Kirn, D.R.
    et al.
    Koochek, A.
    Reid, K.F.
    von Berens, Å.
    Travison, T.G.
    Folta, S.
    Sacheck, J.
    Nelson, M.
    Åberg, Anna Cristina
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Fielding, R.A.
    The vitality, independence, and vigor in the elderly 2 study (VIVE2): design and methods2015Inngår i: Contemporary Clinical Trials, ISSN 1551-7144, E-ISSN 1559-2030, Vol. 43, s. 164-171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Nutritional supplementation may potentiate the increase in skeletal muscle protein synthesis following exercise in healthy older individuals. Whether exercise and nutrition act synergistically to produce sustained changes in physical functioning and body composition has not been well studied, particularly in mobility-limited older adults.

    Methods: The VIVE2 study was a multi-center, randomized controlled trial, conducted in the United States and Sweden. This study was designed to compare the effects of a 6-month intervention with a once daily, experimental, 4fl. oz. liquid nutritional supplement providing 150kcal, whey protein (20g), vitamin D (800IU) (Nestlé Health Science, Vevey, Switzerland), to a low calorie placebo drink (30kcal, non-nutritive; identical format) when combined with group-based exercise in 150 community-dwelling, mobility-limited older adults. All participants participated in a structured exercise program (3 sessions/week for 6months), which included aerobic, strength, flexibility, and balance exercises.

    Results: The primary outcome was 6-month change in 400m walk performance (m/s) between supplement and placebo groups. Secondary outcomes included 6month change in: body composition, muscle cross-sectional area, leg strength, grip strength, stair climb time, quality of life, physical performance, mood/depressive symptoms and nutritional status. These outcomes were selected based on their applicability to the health and well-being of older adults.

    Conclusions: The results of this study will further define the role of nutritional supplementation on physical functioning and restoration of skeletal muscle mass in older adults. Additionally, these results will help refine the current physical activity and nutritional recommendations for mobility-limited older adults.

  • 189. Klatte, Derk C F
    et al.
    Gasparini, Alessandro
    Xu, Hong
    de Deco, Pietro
    Trevisan, Marco
    Johansson, Anna L V
    Wettermark, Björn
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Janmaat, Cynthia J
    Carrero, Juan J
    Association between proton pump inhibitor use and risk of progression of chronic kidney disease2017Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, nr 3, s. 702-710Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND & AIMS: Proton pump inhibitors (PPI) have been associated with acute kidney injury (AKI) and recent studies suggest that they may be associated with the risk of chronic kidney disease (CKD).

    METHODS: We performed a retrospective analysis using the Stockholm creatinine measurements database, which contains information on diagnoses, dispensation claims, and laboratory test results for all citizens in the Stockholm region from 2007 through 2010. We identified new users of PPIs (n= 105305) and new users of H2 blockers (H2B; n= 9578); data on renal outcomes were collected for a median 2.7 years. The primary outcome was progression CKD, defined as doubling of creatinine or decrease in estimated glomerular filtration rate of 30% or more. Secondary outcomes were end-stage renal disease and acute kidney injury (AKI). Complete collection of repeated PPI and H2B dispensations at pharmacies in Sweden allowed modeling the time-dependent risk associated to cumulative PPI exposure.

    RESULTS: Users of PPIs, compared to users of H2Bs, had an increased risk for doubled levels of creatinine (1985 events; adjusted hazard ratio [HR], 1.26; 95% CI, 1.05-1.51) and decrease in estimated glomerular filtration rate of 30% or more (11045 events; 1.26; 95% CI, 1.16-1.36). PPI use also associated with development of end-stage renal disease (HR, 2.40; 0.76-7.58) and AKI (HR, 1.30; 95% CI, 1.00-1.69). There was a graded association between cumulative exposure to PPIs and risk of CKD progression. This was not the case for cumulative H2B use.

    CONCLUSIONS: Initiation of PPI therapy and cumulative PPI exposure associate with increased risk of CKD progression in a large, North European healthcare system. Although consistent, the association was modest in magnitude, and cannot exclude residual confounding.

  • 190. Koochek, A
    et al.
    von Berens, Å
    Gustafsson, T
    Kirn, D.R
    Laussen, J
    Reid, K.F
    Åberg, Anna Cristina
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Nydahl, M
    Cederholm, T
    Fielding, A
    Serum 25-hydroxy vitamin D and physical performance in community-dwelling old mobility limited adults in Sweden and USA2014Konferansepaper (Fagfellevurdert)
  • 191. Kovesdy, Csaba P
    et al.
    Coresh, Josef
    Ballew, Shoshana H
    Woodward, Mark
    Levin, Adeera
    Naimark, David M J
    Nally, Joseph
    Rothenbacher, Dietrich
    Stengel, Benedicte
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Past Decline Versus Current eGFR and Subsequent ESRD Risk2016Inngår i: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, nr 8, s. 2447-2455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    eGFR is a robust predictor of ESRD risk. However, the prognostic information gained from the past trajectory (slope) beyond that of the current eGFR is unclear. We examined 22 cohorts to determine the association of past slopes and current eGFR level with subsequent ESRD. We modeled hazard ratios as a spline function of slopes, adjusting for demographic variables, eGFR, and comorbidities. We used random effects meta-analyses to combine results across studies stratified by cohort type. We calculated the absolute risk of ESRD at 5 years after the last eGFR using the weighted average baseline risk. Overall, 1,080,223 participants experienced 5163 ESRD events during a mean follow-up of 2.0 years. In CKD cohorts, a slope of -6 versus 0 ml/min per 1.73 m(2) per year over the previous 3 years (a decline of 18 ml/min per 1.73 m(2) versus no decline) associated with an adjusted hazard ratio of ESRD of 2.28 (95% confidence interval, 1.88 to 2.76). In contrast, a current eGFR of 30 versus 50 ml/min per 1.73 m(2) (a difference of 20 ml/min per 1.73 m(2)) associated with an adjusted hazard ratio of 19.9 (95% confidence interval, 13.6 to 29.1). Past decline contributed more to the absolute risk of ESRD at lower than higher levels of current eGFR. In conclusion, during a follow-up of 2 years, current eGFR associates more strongly with future ESRD risk than the magnitude of past eGFR decline, but both contribute substantially to the risk of ESRD, especially at eGFR<30 ml/min per 1.73 m(2).

  • 192. Kyu, Hmwe Hmwe
    et al.
    Abate, Degu
    Abate, Kalkidan Hassen
    Abay, Solomon
    Abbafati, Cristiana
    Abbasi, Nooshin
    Abbastabar, Hedayat
    Abd-Allah, Foad
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Murray, Christopher J. L
    Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 20172018Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 392, nr 10159, s. 1859-1922Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background How long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years. 

    Methods We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Sociodemographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males. 

    Findings Globally, from 1990 to 2017, life expectancy at birth increased by 7.4 years (95% uncertainty interval 74-7.8), from 65.6 years (65.3-65- 8) in 1990 to 73.0 years (72.7-73.3) in 2017. The increase in years of life varied from 5.1 years (5.0-5.3) in high SDI countries to 12.0 years (11.3-12.8) in low SDI countries. Of the additional years of life expected at birth, 26.3% (20.1-33.1) were expected to be spent in poor health in high SDI countries compared with 11.7% (8.8-15.1) in low-middle SDI countries. HALE at birth increased by 6.3 years (5.9-6.7), from 57.0 years (54.6-59.1) in 1990 to 63.3 years (60.5-65.7) in 2017. The increase varied from 3.8 years (3.4-4.1) in high SDI countries to 10.5 years (9.8-11.2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1.0 year (0.4-1.7) in Saint Vincent and the Grenadines (62.4 years [59.9-64.7] in 1990 to 63.5 years [60.9-65.8] in 2017) to 23.7 years (21.9-25.6) in Eritrea (30.7 years [28.9-32.2] in 1990 to 54.4 years [51.5-57.1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1.4 years (0.6-2.3) in Algeria to 11.9 years (10.9-12.9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75.8 years [72.4-78.7]) and males (72.6 years [69 " 8-75.0]) and the lowest estimates were in Central African Republic (47.0 years [43.7-50.2] for females and 42.8 years [40.1-45.6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41.3% (38.8-43.5) for communicable diseases and by 49"8% (47.9-51.6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40.1% (36.8-43.0), although age-standardised DALY rates decreased by 18.1% (16.0-20.2). 

    Interpretation With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low S DI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health.

  • 193. Lagali, Neil S
    et al.
    Badian, Reza A
    Liu, Xu
    Feldreich, Tobias R
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Utheim, Tor Paaske
    Dahlin, Lars B
    Rolandsson, Olov
    Dendritic cell maturation in the corneal epithelium with onset of type 2 diabetes is associated with tumor necrosis factor receptor superfamily member 92018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, nr 1, artikkel-id 14248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.

  • 194. Larsson, A.
    et al.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Rydén, I.
    Helmersson-Karlqvist, J.
    Lind, L.
    Associations between cathepsin B and inflammation markers in elderly males and females2015Inngår i: Horizons in World Cardiovascular Research, Nova Science Publishers, Inc., 2015, Vol. 8, s. 157-164Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Background: The association between cathepsin B and inflammatory disorders is being increasingly recognized, but the underlying mechanism is less understood. The aim of the present study was to study the association between cathepsin B and different inflammation markers in a community-based cohort of elderly males and females.

    Methods: Blood samples were collected from 729 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort at the age of 75 years. Cathepsin B and the inflammation markers CRP, Pentraxin 3, TNF receptor 1 and TNF receptor 2 were analyzed together with albumin, cholesterol, HDL-cholesterol, LDL-cholesterol, cholesterol, apolipoprotein A1, apolipoprotein B and triglycerides.

    Results: Cathepsin B was significantly associated with TNF receptor 1 and 2 (P<0.001) but not with CRP and pentraxin 3. There were also significant associations with cholesterol, LDL and apolipoprotein B.

    Conclusion: The type of inflammatory response is of importance for circulating cathepsin B. The association between cathepsin B and the cardiovascular risk markers cholesterol, LDL-cholesterol and apolipoprotein B could contribute to plaque destabilisation and ruptures by cathepsin B.

  • 195.
    Larsson, Catarina
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Lovén, Jessica
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Multimodal smärtrehabilitering i specialistvård: En kartläggning av fysioterapeutiska interventioner2018Independent thesis Advanced level (degree of Master (One Year)), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Bakgrund: Långvarig smärta har konsekvenser på såväl individ- som samhällsnivå och är ett stort folkhälsoproblem. Forskning har visat måttligt till starkt vetenskapligt stöd för multimodal rehabilitering (MMR) vid komplex smärtproblematik. Vad fysioterapeuten använder för åtgärder inom MMR och hur samarbetet med andra yrkeskategorier ser ut finns dåligt beskrivet.

    Syfte: Att kartlägga fysioterapeutens arbete inom ramen för multimodal smärtrehabilitering inom specialistvården (MMR2).

    Metod: Webbenkätstudie där data samlades in från 71 fysioterapeuter som arbetade på enheter anslutna till Nationella registret över smärtrehabilitering (NRS).

    Resultat: Fysioterapeuternas arbete bestod framförallt av undervisning/råd och olika former av träning. Strategier för beteendeförändring, övningar i medveten närvaro/kroppsmedvetenhet och hemövningar var andra vanliga åtgärder. Acceptance and Commitment Therapy (ACT) och Kognitiv beteendeterapi (KBT) användes i flera moment av rehabiliteringen på många enheter. Rehabilitering i grupp var vanligast med aktiva åtgärder som till exempel träning. Rehabiliteringsperioden var vanligen 8-11 veckor, under vilken patienten träffade en fysioterapeut flera gånger i veckan. Teamen hade ett tätt samarbete med regelbundna teamträffar, uppföljningar och gemensamma åtgärder.

    Slutsats: Fysioterapeutens arbete inom MMR2 utgår från ett biopsykosocialt perspektiv där tyngdpunkten ligger i att återställa och/eller förbättra kroppsfunktion. Fysioterapeuterna har bred kompetens och lång erfarenhet vilket möjliggör att deras kunskaper om kroppen och rörelsesystemet kan integreras med åtgärder för beteendeförändring. Tillsammans med övriga yrkeskategorier täcker fysioterapeutens arbete in alla domäner i Klassifikation av funktionstillstånd, funktionshinder och hälsa (ICF). För en ökad förståelse kring vad som styr valet av fysioterapeutiska åtgärder inom MMR2 och hur arbetet med dessa åtgärder ser ut i den kliniska vardagen behövs fortsatt forskning.

  • 196. Larsson, T
    et al.
    Olauson, H
    Hagström, E
    Ingelsson, E
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Lind, L
    Sundström, J
    Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community2010Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, nr 2, s. 333-U379Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Hyperphosphatemia is a cardiovascular risk factor in patients with chronic kidney disease. Relations of circulating calcium (Ca) and phosphorus (Pi) to long-term mortality risk in the community require further investigation. 

    Methods and Results: Associations of serum Ca and Pi to mortality were evaluated in a community-based cohort of 2176 men (mean age, 50.1 years). During follow-up (median, 29.8 years), 1009 men died, and 466 of these deaths resulted from cardiovascular causes. In Cox proportional hazards models, serum Pi and [CaxPi] were independent predictors of total mortality (hazard ratio per SD, 1.06; 95% CI, 1.01-1.12; P=0.03; 1.07; 95% CI, 1.01-1.12; P=0.01) and cardiovascular mortality (1.10; 95% CI, 1.02-1.18; P=0.01; 1.10; 95% CI, 1.03-1.19; P=0.008). Serum Ca was associated with risk of total mortality (1.08; 95% CI, 1.01-1.16; P=0.02) and noncardiovascular mortality (1.10; 95% CI, 1.01-1.21; P=0.04). Results were consistent after multivariate adjustments in subsamples of individuals with estimated glomerular filtration rate > 90 mL/min and low-to-normal serum Ca and Pi. 

    Conclusion: Circulating Ca and Pi levels are associated with risks of total, cardiovascular, and noncardiovascular mortality in the community, and their conjoint effects are additive. Additional studies are warranted to evaluate whether Ca and Pi are modifiable risk factors in the general population. (Arterioscler Thromb Vasc Biol. 2010;30:333-339.)

  • 197. Leavy, Breiffni
    et al.
    Byberg, Lisa
    Michaelsson, Karl
    Melhus, Håkan
    Åberg, Anna Cristina
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    The fall descriptions and health characteristics of older adults with hip fracture: a mixed methods study2015Inngår i: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 15, artikkel-id 40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In light of the multifactorial etiology of fall-related hip fracture, knowledge of fall circumstances may be especially valuable when placed in the context of the health of the person who falls. We aimed to investigate the circumstances surrounding fall-related hip fractures and to describe fall circumstances in relation to participants' health and functional characteristics.

    Methods: The fall circumstances of 125 individuals (age >= 50 years) with hip fracture were investigated using semi-structured interviews. Data concerning participants' health (comorbidities and medications) and function (self-reported performance of mobility, balance, personal activities of daily living and physical activity, previous falls and hand grip strength) were collected via medical records, questionnaires and dynamometry. Using a mixed methods design, both data sets were analysed separately and then merged in order to provide a comprehensive description of fall events and identify eventual patterns in the data.

    Results: Fall circumstances were described as i) Activity at the time of the fall: Positional change (n = 24, 19%); Standing (n = 16, 13%); Walking (n = 71, 57%); Balance challenging (n = 14, 11%) and ii) Nature of the fall: Environmental (n = 32, 26%); Physiological (n = 35, 28%); Activity-related indoor (n = 8, 6%) and outdoor (n = 8, 6%); Trips and slips on snow (n = 20, 16%) and in snow-free conditions (n = 12, 10%) and Unknown (n = 10, 8%). We observed the following patterns regarding fall circumstances and participants' health: those who fell i) during positional change had the poorest functional status; ii) due to environmental reasons (indoors) had moderate physical function, but high levels of comorbidity and fall risk increasing medications; iii) in snow-free environments (outdoors) appeared to have a poorer health and functional status than other outdoor groups.

    Conclusions: Our findings indicate that patterns exist in relation to the falls circumstances and health characteristics of people with hip fracture which build upon that previously reported. These patterns, when verified, can provide useful information as to the ways in which fall prevention strategies can be tailored to individuals of varying levels of health and function who are at risk for falls and hip fracture.

  • 198. Leavy, Breiffni
    et al.
    Michaëlsson, Karl
    Åberg, Anna Cristina
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Melhus, Håkan
    Byberg, Liisa
    The impact of disease and drugs on hip fracture risk2017Inngår i: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 100, nr 1, s. 1-12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report the risks of a comprehensive range of disease and drug categories on hip fracture occurrence using a strict population-based cohort design. Participants included the source population of a Swedish county, aged ≥50 years (n = 117,494) including all incident hip fractures during 1 year (n = 477). The outcome was hospitalization for hip fracture (ICD-10 codes S72.0-S72.2) during 1 year (2009-2010). Exposures included: prevalence of (1) inpatient diseases [International Classification of Diseases (ICD) codes A00-T98 in the National Patient Register 1987-2010] and (2) prescribed drugs dispensed in 2010 or the year prior to fracture. We present age- and sex-standardized risk ratios (RRs), risk differences (RDs) and population attributable risks (PARs) of disease and drug categories in relation to hip fracture risk. All disease categories were associated with increased risk of hip fracture. Largest risk ratios and differences were for mental and behavioral disorders, diseases of the blood and previous fracture (RRs between 2.44 and 3.00; RDs (per 1000 person-years) between 5.0 and 6.9). For specific drugs, strongest associations were seen for antiparkinson (RR 2.32 [95 % CI 1.48-1.65]; RD 5.2 [1.1-9.4]) and antidepressive drugs (RR 1.90 [1.55-2.32]; RD 3.1 [2.0-4.3]). Being prescribed ≥10 drugs during 1 year incurred an increased risk of hip fracture, whereas prescription of cardiovascular drugs or ≤5 drugs did not appear to increase risk. Diseases inferring the greatest PARs included: cardiovascular diseases PAR 22 % (95 % CI 14-29) and previous injuries (PAR 21 % [95 % CI 16-25]; for specific drugs, antidepressants posed the greatest risk (PAR 16 % [95 % CI 12.0-19.3]).

  • 199. LeBlanc, Neil
    et al.
    Leijon, Mikael
    Jobs, Magnus
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Blomberg, Jonas
    Belak, Sandor
    A novel combination of TaqMan RT-PCR and a suspension microarray assay for the detection and species identification of pestiviruses2010Inngår i: Veterinary Microbiology, ISSN 0378-1135, E-ISSN 1873-2542, Vol. 142, nr 1-2, s. 81-86Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genus pestivirus contains four recognized species: classical swine fever virus, border disease virus, bovine viral diarrhoea virus types 1 and 2. All are economically important and globally distributed but classical swine fever is the most serious, concerning losses and control measures. It affects both domestic pigs and wild boars. Outbreaks of this disease in domestic pigs call for the most serious measures of disease control, including a stamping out policy in Europe. Since all the members of the pestivirus genus can infect swine, differential diagnosis using traditional methods poses some problems. Antibody tests may lack specificity due to cross-reactions, antigen capture ELISAs may have low sensitivity, and virus isolation may take several days or even longer time to complete. PCR-based tests overcome these problems for the most part, but in general lack the multiplexing capability to detect and differentiate all the pestiviruses simultaneously. The assay platform described here addresses all of these issues by combining the advantages of real-time PCR with the multiplexing capability of microarray technology. The platform includes a TaqMan real-time PCR designed for the universal detection of pestiviruses and a microarray assay that can use the amplicons produced in the real-time PCR to identify the specific pestivirus. (C) 2009 Elsevier B.V. All rights reserved.

  • 200.
    Libungan, Berglind
    et al.
    Sahlgrens university hospital.
    Lindqvist, Jonny
    Sahlgrens university hospital.
    Strömsöe, Anneli
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Nordberg, Per
    Karolinska institutet.
    Hollenberg, Jacob
    Karolinska institutet.
    Albertsson, Per
    Sahlgrens university hospital.
    Karlsson, Thomas
    Göteborgs universitet.
    Herlitz, Johan
    Högskolan Väst.
    Out-of-hospital cardiac arrest in the elderly: a large-scale population-based study2015Inngår i: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 94, s. 28-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is little information on elderly people who suffer from out-of-hospital cardiac arrest (OHCA). Aim: To determine 30-day mortality and neurological outcome in elderly patients with OHCA.

    Methods: OHCA patients >= 70 years of age who were registered in the Swedish Cardiopulmonary Resuscitation Register between 1990 and 2013 were included and divided into three age categories (70-79, 80-89, and >= 90 years). Multiple logistic regression analyses were performed to identify independent predictors of 30-day survival.

    Results: Altogether, 36,605 cases were included in the study. Thirty-day survival was 6.7% in patients aged 70-79 years, 4.4% in patients aged 80-89 years, and 2.4% in those over 90 years. For patients with witnessed OHCA of cardiac aetiology found in a shockable rhythm, survival was higher: 20%, 15%, and 11%, respectively. In 30-day survivors, the distribution according to the cerebral performance categories (CPC) score at discharge from hospital was similar in the three age groups. In multivariate analysis, in patients over 70 years of age, the following factors were associated with increased chance of 30-day survival: younger age, OHCA outside the home, witnessed OHCA, CPR before arrival of EMS, shockable first-recorded rhythm, and short emergency response time.

    Conclusions: Advanced age is an independent predictor of mortality in OHCA patients over 70 years of age. However, even in patients above 90 years of age, defined subsets with a survival rate of more than 10% exist. In survivors, the neurological outcome remains similar regardless of age. 

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