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  • 401.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Sahlin, Kent
    Actively phosphorylating mitochondria are more resistant to lactic acidosis than inactive mitochondria.1999Ingår i: American Journal of Physiology. Cell Physiology, ISSN  0363-6143, Vol. 277, nr 2, s. C288-C293Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxidative phosphorylation of isolated rat skeletal muscle mitochondria after exposure to lactic acidosis in either phosphorylating or nonphosphorylating states has been evaluated. Mitochondrial respiration and transmembrane potential (Delta Psi m) were measured with pyruvate and malate as the substrates. The addition of lactic acid decreased the pH of the reaction medium from 7.5 to 6.4. When lactic acid was added to nonphosphorylating mitochondria, the subsequent maximal ADP-stimulated respiration decreased by 27% compared with that under control conditions (P < 0.05), and the apparent Michaelis-Menten constant (Km) for ADP decreased to 10 µM vs. 20 µM (P < 0.05) in controls. In contrast, maximal respiration and ADP sensitivity were not affected when mitochondria were exposed to acidosis during active phosphorylation in state 3. Acidosis significantly increased mitochondrial oxygen consumption in state 4 (post-state 3), irrespective of when acidosis was induced. This effect of acidosis was attenuated in the presence of oligomycin. The addition of lactic acid during state 4 respiration decreased Delta Psi m by 19%. The ratio between added ADP and consumed oxygen (P/O) was close to the theoretical value of 3 in all conditions. The addition of potassium lactate during state 3 (i.e., medium pH unchanged) had no effect on the parameters measured. It is concluded that lactic acidosis has different effects when induced on nonphosphorylating vs. actively phosphorylating mitochondria. On the basis of these results, we suggest that the influence of lactic acidosis on muscle aerobic energy production depends on the physiological conditions at the onset of acidity.

  • 402.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Sahlin, Kent
    Physical exercise and mitochondrial function in human skeletal muscle.2002Ingår i: Exercise and Sport Sciences Reviews, ISSN  0091-6331, Vol. 30, nr 3, s. 129-137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Muscle adaptation to endurance training involves qualitative changes in intrinsic properties of mitochondria. After training, the ADP sensitivity of mitochondrion is decreased whereas the effect of creatine on respiration is increased. This results in an improved control of aerobic energy production. Acute exercise does not adversely affect mitochondrial function.

  • 403.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Sahlin, Kent
    Rate of oxidative phosphorylation in isolated mitochondria from human skeletal muscle: effect of training status.1997Ingår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 161, s. 345-353Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Muscle oxidative function has been investigated in subjects with various training status (VO2 max, 41–72 mL O2 kg-1 body wt min-1, n=10). Mitochondria were isolated from biopsies taken from m. vastus lateralis. Maximal mitochondrial oxygen consumption (QO2) and ATP production (MAPR) were measured with polarographic and bioluminometric techniques, respectively. The yield of mitochondria, calculated from the fractional activity of citrate synthase (CS), averaged 26%. With pyruvate + malate, the respiratory control ratio was 5.7 ± 0.4 (X ± SE) and the P/O ratio was 2.83 ± 0.02, which demonstrates that the isolated mitochondria were functionally intact. QO2 was significantly correlated to aerobic training status expressed as muscle CS activity (r=0.86), VO2 max (r=0.84) and lactate threshold (r=0.83) but not to the fibre type composition. A highly significant correlation (r=0.93) was observed between ATP production calculated from QO2 and MAPR, but ATP production derived from QO2 was higher than MAPR both for pyruvate + malate (255%) and for a-ketoglutarate (23%). QO2 extrapolated to a temperature of 38 °C averaged 68 mL O2 min-1 kg-1 wet wt, which is similar to previous findings in vitro and in vivo during the post-exercise period. However, calculated muscle O2 utilization during exercise was three- to fivefold higher than QO2 measured on isolated mitochondria. It is suggested that additional factors exist for activation of mitochondrial respiration during exercise. It is concluded that muscle oxidative function can be quantitatively assessed from the respiration of mitochondria isolated from needle biopsy specimens and that QO2 is closely correlated to whole-body VO2 max.

  • 404.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Sahlin, Kent
    Fernström, Maria
    The leaky mitochondrion2004Ingår i: Physiology News, ISSN 1476-7996, Vol. 56, s. 27-28Artikel i tidskrift (Refereegranskat)
  • 405.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Tonkonogi, Aleksandra
    Grundläggande muskel- och neurofysiologi2019Ingår i: Motorisk kontroll och inlärning: Med inriktning på muskoloskeletal rehabilitering / [ed] Ulrik Röijezon, Studentlitteratur AB, 2019, 1, s. 25-36Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 406.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Walsh, Brandon
    Svensson, Michael
    Sahlin, Kent
    Mitochondrial function and antioxidative defence in human muscle: Effects of endurance training and oxidative stress.2000Ingår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 528, nr 2, s. 379-388Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1. The influence of endurance training on oxidative phosphorylation and the susceptibility of mitochondrial oxidative function to reactive oxygen species (ROS) was investigated in skeletal muscle of four men and four women. Mitochondria were isolated from muscle biopsies taken before and after 6 weeks of endurance training. Mitochondrial respiration was measured before and after exposure of mitochondria to exogenous ROS (H2O2+ FeCl2). 2. Endurance training increased peak pulmonary O2 uptake (VO2,peak) by 24 % and maximal ADP-stimulated mitochondrial oxygen consumption (state 3) by 40 % (P< 0.05). Respiration in the absence of ADP (state 4), the respiratory control ratio (RCR = state 3/state 4) and the ratio between added ADP and consumed oxygen (P/O) remained unchanged by the training programme. 3. Exposure to ROS reduced state 3 respiration but the effect was not significantly different between pre- and post-training samples. State 4 oxygen consumption increased after exposure to ROS both before (+189 %, P< 0.05) and after training (+243 %, P< 0.05) and the effect was significantly higher after training (P< 0.05, pre- vs. post-training). The augmented state 4 respiration could in part be attenuated by atractyloside, which indicates that ADP/ATP translocase was affected by ROS. The P/O ratio in ROS-treated mitochondria was significantly lower (P< 0.05) compared to control conditions, both before (-18.6 ± 2.2 %) and after training (-18.5 ± 1.1 %). 4. Muscle activities of superoxide dismutase (mitochondrial and cytosolic), glutathione peroxidase and muscle glutathione status were unaffected by training. There was a positive correlation between muscle superoxide dismutase activity and age (r= 0.75; P< 0.05; range of age 20–37 years), which may reflect an adaptation to increased generation of ROS in senescent muscle. The muscle glutathione pool was more reduced in subjects with high activity of glutathione peroxidase (r= 0.81; P< 0.05). 5. The influence of short-term training on mitochondrial oxygen consumption has for the first time been investigated in human skeletal muscle. The results showed that maximal mitochondrial oxidative power is increased after endurance training but that the efficiency of energy transfer (P/O ratio) remained unchanged. Antioxidative defence was unchanged after training when expressed relative to muscle weight. Although this corresponds to a reduced antioxidant protection per individual mitochondrion, the sensitivity of aerobic energy transfer to ROS was unchanged. However, the augmented ROS-induced non-coupled respiration after training indicates an increased susceptibility of mitochondrial membrane proton conductance to oxidative stress.

  • 407.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Walsh, Brandon
    Söderlund, Karin
    Hultman, Erik
    Saks, Valdur
    Sahlin, Kent
    The role of phosphorylcreatine in the regulation of mitochondrial respiration in human skeletal muscle.2001Ingår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 537, nr 3, s. 971-978Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1. The role of phosphorylcreatine (PCr) and creatine (Cr) in the regulation of mitochondrial respiration was investigated in permeabilised fibre bundles prepared from human vastus lateralis muscle. 2. Fibre respiration was measured in the absence of ADP (V0) and after sequential additions of submaximal ADP (0.1 mm ADP, Vsubmax), PCr (or Cr) and saturating [ADP] (Vmax). 3. Vsubmax increased by 55% after addition of saturating creatine (P< 0.01; n = 8) and half the maximal effect was obtained at 5 mm [Cr]. In contrast, Vsubmax decreased by 54% after addition of saturating phosphorylcreatine (P< 0.01; n = 8) and half the maximal effect was obtained at 1 mm [PCr]. Vmax was not affected by Cr or PCr. 4. Vsubmax was similar when PCr and Cr were added simultaneously at concentrations similar to those in muscle at rest (PCr/Cr = 2) and at low-intensity exercise (PCr/Cr = 0.5). At conditions mimicking high-intensity exercise (PCr/Cr = 0.1), Vsubmax increased to 60% of Vmax (P< 0.01) vs. rest and low-intensity exercise). 5. Eight of the subjects participated in a 16 day Cr supplementation programme. Following Cr supplementation, V0 decreased by 17% (P< 0.01) vs. prior to Cr supplementation), whereas ADP-stimulated respiration (with and without Cr or PCr) was unchanged. 6. For the first time evidence is given that PCr is an important regulator of mitochondrial ADP-stimulated respiration. Phosphorylcreatine decreases the sensitivity of mitochondrial respiration to ADP whereas Cr has the opposite effect. During transition from rest to high-intensity exercise, decreases in the PCr/Cr ratio will effectively increase the sensitivity of mitochondrial respiration to ADP. The decrease in V0 after Cr supplementation indicates that intrinsic changes in membrane proton conductance occur.

  • 408.
    Tonkonogi, Michail
    et al.
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Walsh, Brandon
    Tiivel, Toomas
    Saks, Valdur
    Sahlin, Kent
    Mitochondrial function in human skeletal muscle is not impaired by high intensity exercise.1999Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 437, nr 4, s. 562-568Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hypothesis that high-intensity (HI) intermittent exercise impairs mitochondrial function was investigated with different microtechniques in human muscle samples. Ten male students performed three bouts of cycling at 130% of peak O2 consumption (V·O2,peak). Muscle biopsies were taken from the vastus lateralis muscle at rest, at fatigue and after 110 min recovery. Mitochondrial function was measured both in isolated mitochondria and in muscle fibre bundles made permeable with saponin (skinned fibres). In isolated mitochondria there was no change in maximal respiration, rate of adenosine 5'-triphosphate (ATP) production (measured with bioluminescence) and respiratory control index after exercise or after recovery. The ATP production per consumed oxygen (P/O ratio) also remained unchanged at fatigue but decreased by 4% (P<0.05) after recovery. In skinned fibres, maximal adenosine 5'-diphosphate (ADP)-stimulated respiration increased by 23% from rest to exhaustion (P<0.05) and remained elevated after recovery, whereas the respiratory rates in the absence of ADP and at 0.1 mM ADP (submaximal respiration) were unchanged. The ratio between respiration at 0.1 and 1 mM ADP (ADP sensitivity index) decreased at fatigue (P<0.05) but after the recovery period was not significantly different from that at rest. It is concluded that mitochondrial oxidative potential is maintained or improved during exhaustive HI exercise. The finding that the sensitivity of mitochondrial respiration to ADP is reversibly decreased after strenuous exercise may indicate that the control of mitochondrial respiration is altered.

  • 409. Torell, Matilda F
    et al.
    Strömsöe, Anneli
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Zagerholm, Ellen
    Herlitz, Johan
    Claesson, Andreas
    Svensson, Leif
    Börjesson, Mats
    Higher survival rates in exercise-related out-of-hospital cardiac arrests, compared to non-exercise-related - a study from the Swedish Register of Cardiopulmonary Resuscitation2017Ingår i: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 24, nr 15, s. 1673-1679Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Despite the positive effects of physical activity, the risk of sudden cardiac arrest is transiently increased during and immediately after exercise. The purpose of this study was to assess the incidence of exercise-related out-of-hospital cardiac arrest in the general population and to compare characteristics and prognosis of these cardiac arrests with non-exercise-related out-of-hospital cardiac arrests.

    Methods: Data from all cases of treated out-of-hospital cardiac arrest outside of home reported to the Swedish Register of Cardiopulmonary Resuscitation from 2011-2015 in three counties of Sweden were investigated (population 2.1 m). This registry captures almost 100% of all out-of-hospital cardiac arrests in Sweden. Results Of 1825 out-of hospital cardiac arrests, 137 (7.5%) were exercise-related, resulting in an incidence of 1.2 per 100,000 person-years. The 30-day survival rate was significantly higher among exercise-related out-of hospital cardiac arrests compared to non-exercise-related out-of-hospital cardiac arrests (54.3 % vs 19.4%, p < 0.0001). Patients suffering an exercise-related out-of-hospital cardiac arrest were on average 10 years younger than those who had a non-exercise-related out-of-hospital cardiac arrest, 56.4 years compared to 67.2 years. Exercise-related out-of-hospital cardiac arrests were more often witnessed (89.4% vs 78.6%, p = 0.002), had higher rates of bystander cardiopulmonary resuscitation (80.3% vs 61.0%, p < 0.0001) and were more frequently connected to an automated external defibrillator (20.4% vs 4.6%, p < 0.0001).

    Conclusions: Cardiac arrests that occur in relation to exercise have a significantly better prognosis and outcome than non-exercise-related cardiac arrests. This may be explained by favourable circumstances but may also reflect that these persons experience a sudden cardiac arrest at a lower degree of coronary artery disease, due to their younger age and to exercise being a trigger.

  • 410. Torstensen, Tom Arild
    et al.
    Grooten, Wilhelmus J A
    Østerås, Håvard
    Heijne, Annette
    Harms-Ringdahl, Karin
    Äng, Björn
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    How does exercise dose affect patients with long-term osteoarthritis of the knee? A study protocol of a randomised controlled trial in Sweden and Norway: the SWENOR Study2018Ingår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, nr 5, artikel-id e018471Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Osteoarthritis (OA) of the knee is characterised by knee pain, disability and degenerative changes, and places a burden on societies all over the world. Exercise therapy is an often-used modality, but there is little evidence of what type of exercise dose is the most effective, indicating a need for controlled studies of the effect of different dosages. Thus, the aim of the study described in this protocol is to evaluate the effects of high-dose versus low-dose medical exercise therapy (MET) in patients with knee OA.

    METHODS AND ANALYSIS: This is a multicentre prospective randomised two-arm trial with blinded assessment and data analysis. We are planning to include 200 patients aged 45-85 years with symptomatic (pain and decreased functioning) and X-ray verified diagnosis of knee OA. Those eligible for participation will be randomly allocated to either high-dose (n=100) or low-dose (n=100) MET. All patients receive three supervised treatments each week for 12 weeks, giving a total of 36 MET sessions. The high-dose group exercises for 70-90 min compared with 20-30 min for the low-dose group. The high-dose group exercises for a longer time, and receives a greater number of exercises with more repetitions and sets. Background and outcome variables are recorded at inclusion, and outcome measures are collected after every sixth treatment, at the end of treatment, and at 6-month and 12-month follow-ups. Primary outcome is self-rated knee functioning and pain using the Knee Injury and Osteoarthritis Outcome Score (KOOS). The primary end point is at the end of treatment after 3 months, and secondary end points are at 6 months and 12 months after the end of treatment.

    ETHICS AND DISSEMINATION: This project has been approved by the Regional Research Ethics Committees in Stockholm, Sweden, and in Norway. Our results will be submitted to peer-reviewed journals and presented at national and international conferences.

    TRIAL REGISTRATION NUMBER: NCT02024126; Pre-results.

  • 411. Tseli, Elena
    et al.
    Grooten, Wilhelmus Johannes Andreas
    Stålnacke, Britt-Marie
    Boersma, Katja
    Enthoven, Paul
    Gerdle, Björn
    Äng, Björn
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Predictors of multidisciplinary rehabilitation outcomes in patients with chronic musculoskeletal pain: protocol for a systematic review and meta-analysis2017Ingår i: Systematic Reviews, E-ISSN 2046-4053, ISSN 2046-4053, Vol. 6, nr 1, artikel-id 199Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Chronic musculoskeletal pain is a major public health problem. Early prediction for optimal treatment results has received growing attention, but there is presently a lack of evidence regarding what information such proactive management should be based on. This study protocol, therefore, presents our planned systematic review and meta-analysis on important predictive factors for health and work-related outcomes following multidisciplinary rehabilitation (MDR) in patients with chronic musculoskeletal pain.

    METHODS: We aim to perform a synthesis of the available evidence together with a meta-analysis of published peer-reviewed original research that includes predictive factors preceding MDR. Included are prospective studies of adults with benign, chronic (> 3 months) musculoskeletal pain diagnoses who have taken part in MDR. In the studies, associations between personal and rehabilitation-based factors and the outcomes of interest are reported. Outcome domains are pain, physical functioning including health-related quality of life, and work ability with follow-ups of 6 months or more. We will use a broad, explorative approach to any presented predictive factors (demographic, symptoms-related, physical, psychosocial, work-related, and MDR-related) and these will be analyzed through (a) narrative synthesis for each outcome domain and (b) if sufficient studies are available, a quantitative synthesis in which variance-weighted pooled proportions will be computed using a random effects model for each outcome domain. The strength of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation.

    DISCUSSION: The strength of this systematic review is that it aims for a meta-analysis of prospective cohort or randomized controlled studies by performing an extensive search of multiple databases, using an explorative study approach to predictive factors, rather than building on single predictor impact on the outcome or on predefined hypotheses. In this way, an overview of factors central to MDR outcome can be made and will help strengthen the evidence base and inform a wide readership including health care practitioners and policymakers.

    SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016025339.

  • 412. Tseli, Elena
    et al.
    Stålnacke, Britt-Marie
    Boersma, Katja
    Enthoven, Paul
    Gerdle, Björn
    Äng, Björn
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet; Center for Clinical Research Dalarna.
    Grooten, Wilhelmus Johannes Andreas
    Prognostic factors for physical functioning after multidisciplinary rehabilitation in patients with chronic musculoskeletal pain: a systematic review and meta-analysis2019Ingår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 35, nr 2, s. 148-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: This systematic review aimed to identify and evaluate prognostic factors for long-term (≥6▒mo) physical functioning in patients with chronic musculoskeletal pain following multidisciplinary rehabilitation (MDR).

    METHODS: Electronic searches conducted in MEDLINE, PsycINFO, EMBASE, CINAHL, Web of Science, and Cochrane CENTRAL revealed 25 original research reports, published 1983-2016, (n=9436). Potential prognostic factors relating to initial pain and physical and psychological functioning were synthesized qualitatively and quantitatively in random effects meta-analyses. The level of evidence (LoE) was evaluated with GRADE.

    RESULTS: Pain related factors (intensity and chronicity) were not associated with function/disability at long-term follow up, OR=0.84, 95% CI: 0.65-1.07 and OR=0.97, 95% CI: 0.93-1.00 respectively (moderate LoE). A better function at follow up was predicted by Physical factors; higher levels of initial self-reported functioning, OR=1.07, 95% CI: 1.02-1.13 (low LoE), and Psychological factors; low initial levels of emotional distress, OR=0.77, 95% CI: 0.65-0.92, low levels of cognitive behavioural risk factors, OR 0.85, 95% CI: 0.77-0.93 and high levels of protective cognitive behavioural factors, OR=1.49; 95% CI: 1.17-1.90 (moderate LoE).

    DISCUSSION: While pain intensity and long-term chronicity did not predict physical functioning in chronic pain patients after MDR, poor pre-treatment physical and psychological functioning influenced the prognosis negatively. Thus, treatment should further target and optimize these modifiable factors and an increased focus on positive, psychological protective factors may perhaps provide an opening for yet untapped clinical gains.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

  • 413. Tärnqvist, J.
    et al.
    Dahlén, E.
    Norberg, G.
    Magnusson, C.
    Herlitz, J.
    Strömsöe, Anneli
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Axelsson, C.
    Andersson Hagiwara, M.
    On-scene and final assessments and their interrelationship among patients who use the EMS on multiple occasions2017Ingår i: Prehospital and Disaster Medicine, ISSN 1049-023X, E-ISSN 1945-1938, Vol. 32, nr 5, s. 528-535Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The use of Emergency Medical Services (EMS) is increasing. A number of patients call repeatedly for EMS. Early studies of frequent callers show that they form a heterogenous group. Problem: There is a lack of research on frequent EMS callers. There is furthermore a lack of knowledge about characteristics and the prehospital assessment of the patients who call for EMS on several occasions. Finally, there is a general lack of knowledge with regard to the association between the prehospital assessment by health care providers and the final diagnosis. Method: Patients in Skaraborg in Western Sweden, who used the EMS at least four times in 2014, were included, excluding transport between hospitals. Information on the prehospital assessment on-scene and the final diagnosis was collected from the EMS and hospital case records. Results: In all, 339 individual patients who used the EMS on 1,855 occasions were included, accounting for five percent of all missions. Fifty percent were women. The age range was 10-98 years, but more than 50.0% were in the age range of 70-89 years. The most common emergency signs and symptoms (ESS) codes on the scene were dyspnea, chest pain, and abdominal pain. The most common final diagnosis was chronic obstructive pulmonary disease (eight percent). Thirteen percent of all cases had a final diagnosis defined as a potentially life-threatening condition. Among these, 22.0% of prehospital assessments were retrospectively judged as potentially inappropriate. Forty-nine percent had a defined final diagnosis not fulfilling the criteria for a potentially life-threatening condition. Among these cases, 30.0% of prehospital assessments were retrospectively judged as potentially inappropriate. Conclusion:: Among patients who used EMS on multiple occasions, the most common symptoms on-scene were dyspnea, chest pain, and abdominal pain. The most common final diagnosis was chronic obstructive pulmonary disease. In 13.0%, the final diagnosis of a potentially life-threatening condition was indicated. In a minority of these cases, the assessment on-scene was judged as potentially inappropriate. 

  • 414.
    Ursing, Johan
    et al.
    Projecto de Saúde de Bandim, Indepth Network, Bissau, Guinea-Bissau, Malaria Research Laboratory, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Eksborg, Staffan
    Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.
    Rombo, Lars
    Malaria Research Laboratory, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, Centre for Clinical Research, Sörmland, Uppsala University, Sweden.
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Blessborn, Daniel
    Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
    Rodrigues, Amabelia
    Projecto de Saúde de Bandim, Indepth Network, Bissau, Guinea-Bissau.
    Kofoed, Poul-Erik
    Projecto de Saúde de Bandim, Indepth Network, Bissau, Guinea-Bissau, Department of Paediatrics, Kolding Hospital, Kolding, Denmark.
    Chloroquine is grossly under dosed in young children with malaria: implications for drug resistance2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 1, artikel-id e86801Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations.

    Methods and Findings: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent.

    Conclusions: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.

  • 415. Ursing, Johan
    et al.
    Kofoed, Poul-Erik
    Rodrigues, Amabelia
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Rombo, Lars
    Chloroquine is grossly overdosed and overused but well tolerated in Guinea-Bissau2009Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 53, nr 1, s. 180-185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg(-1), respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg(-1) each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg(-1)) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of high-dose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.

  • 416. Ursing, Johan
    et al.
    Kofoed, Poul-Erik
    Rodrigues, Amabelia
    Blessborn, Daniel
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Thoft-Nielsen, Rikke
    Bjorkman, Anders
    Rombo, Lars
    Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial2011Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 203, nr 1, s. 109-116Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. In 2008. Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.

    Methods. In a randomized open-label clinical trial, artemether-lumefantrine or chloroquine (50 mg/kg) were given as 6 divided doses over 3 days to children aged 6 months - 15 years who had uncomplicated P. falciparum monoinfection. Drug concentrations were measured on day 7. P. falciparum multidrug resistance gene N86Y and pfcrt K76T alleles were identified.

    Results. The polymerase chain reaction adjusted day 28 and 42 treatment efficacies were 162 (97%) of 168 and 155 (97%) of 161, respectively, for artemether-lumefantrine and 150 (95%) of 158 and 138 (94%) of 148, respectively, for chloroquine. When parasites with resistance-associated pfcrt 76T were treated, the day 28 efficacy of chloroquine was 87%. No severe drug-related adverse events were detected. Symptom resolution was similar with both treatments.

    Conclusions. Both treatments achieved the World Health Organization recommended efficacy for antimalarials that will be adopted as policy. High-dose chloroquine treatment regimes should be further evaluated with the aim of assessing chloroquine as a potential partner drug to artemisinin derivatives.

  • 417. Ursing, Johan
    et al.
    Rombo, Lars
    Bergqvist, Yngve
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Rodrigues, Amabelia
    Kofoed, Poul-Erik
    High-Dose Chloroquine for Treatment of Chloroquine Resistant Plasmodium falciparum Malaria2016Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 213, nr 8, s. 1315-1321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:  Due to development of multidrug resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard dose chloroquine remained effective for decades despite the existence of "chloroquine resistant" P. falciparum. This study aimed to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance conferring genotypes.

    METHODS:  Standard or double dose chloroquine was given to 892 children aged <15 years with uncomplicated malaria during three clinical trials (2001-2008) with at least 35 days follow up. The P. falciparum resistance conferring genotype (pfcrt 76T) and day seven chloroquine concentrations were determined. Data were divided into age groups <5, 5-9 and 10-14 years as concentrations increase with age when chloroquine is prescribed according to body weight.

    RESULTS:  Adequate clinical and parasitological responses were 14%, 38%, and 39% after standard dose and 66%, 84%, and 91% after double dose chloroquine in children aged <5, 5-9 and 10-14 years and infected with P. falciparum with chloroquine resistance conferring genotypes (n=195, p<0.001). In parallel, median chloroquine concentrations were 471, 688, and 809 (standard dose), 1040, 1494 and 1585 (double dose) nmol/l.

    CONCLUSIONS:  Chloroquine resistance is dose dependent and can be overcome by higher still well tolerated doses.

  • 418. van der Laan, S.W
    et al.
    Fall, T
    Soumaré, A
    Teumer, A
    Sedaghat, S
    Baumert, J
    Zabaneh, D
    van Setten, J
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Asselbergs, F. W
    Cystatin C and cardiovascular disease: A mendelian randomization study2016Ingår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 68, nr 9, s. 934-945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.

    OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n ¼ 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n ¼ 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.

    RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p ¼ 2.12 1014). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p ¼ 5.95 10211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p ¼ 0.994), which was statistically different from the observational estimate (p ¼ 1.6 105 ). A causal effect of cystatin C was not detected for any individual component of CVD.

    CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. 

  • 419. Velasquez, Ilais Moreno
    et al.
    Kumar, Jitender
    Bjorkbacka, Harry
    Nilsson, Jan
    Silveira, Angela
    Leander, Karin
    Berglund, Anita
    Strawbridge, Rona J.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Melander, Olle
    Duffy antigen receptor genetic variant and the association with Interleukin 8 levels2015Ingår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 72, nr 2, s. 178-184Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study is to identify loci associated with circulating levels of Interleukin 8 (IL8). We investigated the associations of 121,445 single nucleotide polymorphisms (SNPs) from the Illumina 200K CardioMetabochip with IL8 levels in 1077 controls from the Stockholm Heart Epidemiology Program (SHEEP) study, using linear regression under an additive model of inheritance. Five SNPs (rs12075A/G, rs13179413C/T, rs6907989T/A, rs9352745A/C, rs1779553T/C) reached the predefined threshold of genome-wide significance (p < 1.0 x 10(-5)) and were tested for in silico replication in three independent populations, derived from the PIVUS, MDC-CC and SCARF studies. IL8 was measured in serum (SHEEP, PIVUS) and plasma (MDC-CC, SCARF). The strongest association was found with the SNP rs12075 A/G, Asp42Gly (p = 1.6 x 10(-6)), mapping to the Duffy antigen receptor for chemokines (DARC) gene on chromosome 1. The minor allele G was associated with 15.6% and 10.4% reduction in serum IL8 per copy of the allele in SHEEP and PIVUS studies respectively. No association was observed between rs12075 and plasma IL8. Conclusion: rs12075 was associated with serum levels but not with plasma levels of IL8. It is likely that serum IL8 represents the combination of levels of circulating plasma IL8 and additional chemokine liberated from the erythrocyte DARC reservoir due to clotting. These findings highlight the importance of understanding ILS as a biomarker in cardiometabolic diseases.

  • 420. Velders, Matthijs A
    et al.
    Calais, Fredrik
    Dahle, Nina
    Fall, Tove
    Hagström, Emil
    Leppert, Jerzy
    Nowak, Christoph
    Tenerz, Åke
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Hedberg, Pär
    Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction2019Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Newer therapeutic agents for type 2 diabetes mellitus can improve cardiovascular outcomes, but diabetes remains underdiagnosed in patients with myocardial infarction (MI). We sought to identify proteomic markers of undetected dysglycaemia (impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) to improve the identification of patients at highest risk for diabetes. Materials and methods: In this prospective cohort, 626 patients without known diabetes underwent oral glucose tolerance testing (OGTT) during admission for MI. Proximity extension assay was used to measure 81 biomarkers. Multivariable logistic regression, adjusting for risk factors, was used to evaluate the association of biomarkers with dysglycaemia. Subsequently, lasso regression was performed in a 2/3 training set to identify proteomic biomarkers with prognostic value for dysglycaemia, when added to risk factors, fasting plasma glucose, and glycated haemoglobin A1c. Determination of discriminatory ability was performed in a 1/3 test set. Results: In total, 401/626 patients (64.1%) met the criteria for dysglycaemia. Using multivariable logistic regression, cathepsin D had the strongest association with dysglycaemia. Lasso regression selected seven markers, including cathepsin D, that improved prediction of dysglycaemia (area under the receiver operator curve [AUC] 0.848 increased to 0.863). In patients with normal fasting plasma glucose, only cathepsin D was selected (AUC 0.699 increased to 0.704). Conclusions: Newly detected dysglycaemia, including manifest diabetes, is common in patients with acute MI. Cathepsin D improved the prediction of dysglycaemia, which may be helpful in the a priori risk determination of diabetes as a motivation for confirmatory OGTT.

  • 421. Venge, P
    et al.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Zethelius, B
    Seemingly healthy 71-year old men with minor elevations of cardiac troponin I and at risk of premature death in CVD have elevated levels of NT-proBNP Report from the ULSAM study.2009Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 69, nr 3, s. p418-424Artikel i tidskrift (Refereegranskat)
  • 422.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Acupuncture for labour pain2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: Acupuncture involves puncturing the skin with thin sterile needles at defined acupuncture points. Previous studies are inconclusive regarding the effect of acupuncture on labour pain, but some studies have found a reduction in the use of pharmacological pain relief when acupuncture is administered. The appropriate dose of acupuncture treatment required to elicit a potential effect on labour pain has not been fully explored. The dose is determined by many different factors, including the number of needles used and the intensity of the stimulation. In Sweden, manual stimulation of the needles is common practice when acupuncture is used for labour pain, but electrical stimulation of the needles, which gives a higher dose, could possibly be more effective. The overall aim of this thesis was to evaluate the effectiveness of acupuncture with manual stimulation (MA) of the needles as well as acupuncture with a combination of manual and electrical stimulation (EA) in reducing labour pain, compared with standard care without any form of acupuncture (SC).

    Methods: The study was designed as a three-armed randomised controlled trial in which 303 nulliparous women with normal pregnancies were randomised to MA, EA, or SC. The primary outcome was labour pain, assessed using the Visual Analogue Scale (VAS). Secondary outcomes were relaxation during labour, use of obstetric pain relief, and associations between maternal characteristics and labour pain and use of epidural analgesia respectively. Also, labour and infant outcomes, recollection of labour pain, and maternal experiences, such as birth experience and experience of the midwife, were investigated two months after the birth. The sample size calculation was based on the potential to discover a difference of 15 mm on the VAS. Data were collected during labour before the interventions, the day after birth, and two months later. Besides using the VAS, information was collected by means of study specific protocol, questionnaires and medical records.

    Results: The mean VAS scores were 66.4 in the MA group, 68.5 in the EA group, and 69.0 in the SC group (mean differences: MA vs. SC 2.6 95% CI -1.7 to 6.9, and EA vs. SC 0.6 95% CI -3.6 to 4.8). Other methods of pain relief were used less frequently in the EA group, including epidural analgesia, MA 61.4%, EA 46%, and SC 69.9%. (EA vs. SC OR 0.4 95% CI 0.2 to 0.7). No statistically significant differences were found in the recollection of labour pain between the three groups two months after birth (mean VAS score: MA 69.3, EA 68.7 and SC 70.1). A few maternal characteristics were associated with labour pain (age, dysmenorrhea, and cervix dilatation), but none of the investigated characteristics predicted the outcome of the acupuncture treatment in MA or EA. Women in the EA group experienced acupuncture as being effective for labour pain to a higher extent than women who received MA, MA 44.4%, EA 67.1% (EA vs. MA OR 2.4 95% CI 1.2 to 4.8). Women in the EA group also spent less time in labour (mean 500 min) than those who received MA (mean 619 min) and SC (mean 615 min) (EA vs. MA HR 1.4 95% CI 1.0 to1.9, EA vs. SC HR 1.4, 95% CI 1.1 to 2.0), and had less blood loss than women receiving SC, (EA vs. SC OR 0.1 95% CI 0.3 to 0.7). The women’s assessment of the midwife as being supportive during labour (MA 77.2%, EA 83.5%, SC 80%), overall satisfaction with midwife care (MA 100%, EA 97.5%, SC 98.7%), and having an overall positive childbirth experience (MA 64.6%, EA 61.0%, SC 54.3%) did not differ statistically. No serious side effects of the acupuncture treatment were reported.

    Conclusion: Acupuncture, regardless of type of stimulation, did not differ from standard care without acupuncture in terms of reducing women’s experience of pain during labour, or their memory of pain and childbirth overall two months after the birth. However, other forms of obstetric pain relief were less frequent in women receiving a combination of manual and electrical stimulation, suggesting that this method could facilitate coping with labour pain.

  • 423.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Acupuncture for Labour Pain2015Konferensbidrag (Övrigt vetenskapligt)
  • 424.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Acupuncture with manual and electrical stimulation for labour pain: A longitudinal randomised controlled trial2014Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Background Acupuncture using manual stimulation (MA) of the needles is commonly used to reduce labour pain despite contradictory results from studies of its effectiveness. A combination of manual and electrical stimulation (EA) could reduce labour pain more effectively than MA alone, by a higher treatment intensity.The aim was to evaluate the effectiveness of MA and EA compared with standard care without any acupuncture (SC) in reducing labour pain. Our hypothesis was that both acupuncture stimulation techniques were more effective than SC, and that EA was the most effective.

    Methods

    Nulliparous women (n=303) with a normal pregnancy were equally randomized to three groups receiving 40 minutes of either MA, EA or to SC. The recruitment of participants took place at the admission to the labour ward between November 2008 and October 2011 at two Swedish hospitals.

    The primary outcome was women’s assessment of labour pain; before and after the first treatment, every 30 minutes for five hours, and thereafter every hour until birth, or until epidural analgesia was administered. For the primary outcome, a linear mixed model for repeated measures was performed to investigate associations between treatment (MA, EA, SC) and pain scores on VAS over time. A difference of 15 mm on the visual analogue scale (VAS) was regarded as clinically relevant, and this required 41 women per group, and compensating for dropouts, in total 101 women in each group.

    Data on the primary outcome were obtained from 253 women: MA n=83, EA n=87, and SC n=83.

    Results

    Primary outcome:

    Mean estimated pain scores on VAS (SC: 69.0, MA: 66.4 and EA: 68.5), adjusted for: treatment, age, education, and time from baseline, with no interactions did not differ between the groups (SC vs MA: mean difference 2.6, 95 % confidence interval [CI] -1.7-6.9 and SC vs EA: mean difference 0.6 [95%CI] -3.6-4.8).

    Secondary outcomes:

    Use of epidural analgesia: MA 61%, EA 46%, SC 70%. EA vs SC: odds ratio (OR) 0.35; (95% CI) 0.19-0.67.

    EA vs MA: OR 0.57 (95% CI) 0.31-1.06.

    Duration of labour (min): MA 619, EA 500, SC 615. EA vs SC: Hazard Ratio (HR) 1.44; (95% CI) 1.06-1.97. EA vs MA: HR 1.41; (95% CI) 1.03-1.91.

    Sufficient pain relief (day after partus): MA 77%, EA 81%, SC 74% (ns).

    Positive experience of the midwife (day after partus): MA 100%, EA 97.5%, and SC 98.7% (ns).

    Support from the midwife to a high extent (day after partus): MA 77.2%, EA 83.5%, and SC 80% (ns).

    Conclusions

    Acupuncture does not reduce women’s experience of labour pain, however, women receiving a combination of manual and electro-acupuncture (EA) used less additional pain relief, including epidural analgesia, and had shorter labour than women in the standard care group (SC). Despite the lower use of other pain relief, a majority of the women who used EA were equally satisfied with their pain relief as the women receiving manual acupuncture alone (MA) or SC. They were also equally satisfied with the support from the midwife.

     

  • 425.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Acupuncture with manual and electrical stimulation for labour pain: A longitudinal randomised controlled trial2014Konferensbidrag (Övrigt vetenskapligt)
  • 426.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Associations between maternal characteristics and women’s responses to acupuncture during labour: a secondary analysis from a randomised controlled trial2017Ingår i: Acupuncture in Medicine, ISSN 0964-5284, E-ISSN 1759-9873, Vol. 35, nr 3, s. 180-188Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Patient characteristics are modulators of pain experience after acupuncture treatment for chronic pain. Whether this also applies to labour pain is unknown.

    Aim To examine for associations between maternal characteristics and response to acupuncture in terms of labour pain intensity in close proximity to the treatment (within 60 min) and over a longer time period (up to 240 min), and whether or not epidural analgesia is used, before and after adjustment for obstetric status upon admission to the labour ward.

    Methods Cohort study (n=253) using data collected for a randomised controlled trial. Associations were examined using linear mixed models and logistic regression analyses. Tests of interactions were also applied to investigate whether maternal characteristics were influenced by treatment group allocation.

    Results In close proximity to the treatment, advanced age and cervical dilation were associated with lower pain scores (mean difference (MD) −13.2, 95% CI −23.4 to −2.9; and MD −5.0, 95% CI −9.6 to −0.5, respectively). For the longer time period, labour pain was negatively associated with age (MD −11.8, 95% CI −19.6 to −3.9) and positively associated with dysmenorrhoea (MD 5.5, 95% CI 1.6 to 9.5). Previous acupuncture experience and advanced cervical dilatation were associated with higher and lower use of epidural analgesia (OR 2.7, 95% CI 1.3 to 5.9; and OR 0.3, 95% CI 0.1 to 0.5, respectively). No interactions with treatment allocation were found.

    Conclusions This study did not identify any maternal characteristics associated with women's responses to acupuncture during labour.

    Trial registration number NCT01197950; Post-results.

  • 427.
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska Institutet.
    Manual and electroacupuncture for labour pain. Study design of a longitudinal randomized controlled trial2013Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Introduction: Results from previous acupuncture studies for labour pain are contradictory and lack important information on methodology. The sample sizes are in general small, information about the intervention such as needle placement, number of acupuncture points, type of stimulation, and duration of treatment, is often sparse or lacking However, studies indicate that acupuncture has a positive effect on women’s experiences of labour pain.

     

    Aim: The aim of the present study was to evaluate the efficacy of two different acupuncture stimulations, manual or electrical stimulation, compared with standard care in the relief of labour pain. Our hypothesis is that acupuncture with manual or electrical stimulation is more effective than standard care in the relief of labor pain, and that acupuncture with electrical stimulation is the most effective.

    Outcome measures: Primary outcome: Labour pain measured with visual analogue scale (VAS). Secondary outcomes are use of epidural analgesia, experience of relaxation, labour outcomes and infant outcomes. Biochemical markers of proinflammatory cytokines, memory of labour pain and overall childbirth experience.

    Methods: The study was designed as a randomized controlled trial based on Western medical theories. Nulliparous women with normal pregnancies admitted to the delivery ward after a spontaneous onset of labour were randomly allocated into one of three groups: manual acupuncture, electroacupuncture or standard care. Sample size calculation gave 101 women in each group, including a total of 303 women. VAS was used for assessing pain every 30 minutes for five hours and thereafter every hour until birth. Questionnaires were distributed before treatment, directly after the birth, and at one day and two months postpartum. Blood samples were collected before and after the first treatment.

    At the conference, information on the design of the study will be presented and the considerations of whether to use placebo controls or not will be discussed.

    ClinicalTrials.gov: NCT01197950

  • 428.
    Vixner, Linda
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Mårtensson, Lena B
    Schytt, Erica
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Omvårdnad. Karolinska institutet.
    Acupuncture with manual and electrical stimulation for labour pain: a two month follow up of recollection of pain and birth experience.2015Ingår i: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 15, artikel-id 180Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In a previous randomised controlled trial we showed that acupuncture with a combination of manual- and electrical stimulation (EA) did not affect the level of pain, as compared with acupuncture with manual stimulation (MA) and standard care (SC), but reduced the need for other forms of pain relief, including epidural analgesia. To dismiss an under-treatment of pain in the trial, we did a long-term follow up on the recollection of labour pain and the birth experience comparing acupuncture with manual stimulation, acupuncture with combined electrical and manual stimulation with standard care. Our hypothesis was that despite the lower frequency of use of other pain relief, women who had received EA would make similar retrospective assessments of labour pain and the birth experience 2 months after birth as women who received standard care (SC) or acupuncture with manual stimulation (MA).

    METHODS: Secondary analyses of data collected for a randomised controlled trial conducted at two delivery wards in Sweden. A total of 303 nulliparous women with normal pregnancies were randomised to: 40 min of MA or EA, or SC without acupuncture. Questionnaires were administered the day after partus and 2 months later.

    RESULTS: Two months postpartum, the mean recalled pain on the visual analogue scale (SC: 70.1, MA: 69.3 and EA: 68.7) did not differ between the groups (SC vs MA: adjusted mean difference 0.8, 95 % confidence interval [CI] -6.3 to 7.9 and SC vs EA: mean difference 1.3 CI 95 % -5.5 to 8.1). Positive birth experience (SC: 54.3 %, MA: 64.6 % and EA: 61.0 %) did not differ between the groups (SC vs MA: adjusted Odds Ratio [OR] 1.8, CI 95 % 0.9 to 3.7 and SC vs EA: OR 1.4 CI 95 % 0.7 to 2.6).

    CONCLUSIONS: Despite the lower use of other pain relief, women who received acupuncture with the combination of manual and electrical stimulation during labour made the same retrospective assessments of labour pain and birth experience 2 months postpartum as those who received acupuncture with manual stimulation or standard care.

    TRIAL REGISTRATION: ClinicalTrials.gov: NCT01197950.

  • 429.
    Vixner, Linda
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Mårtensson, Lena B
    Stener-Victorin, Elisabet
    Schytt, Erica
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Omvårdnad. Division of Reproductive Health, Department of Women's and Children's Health, Karolinska Institutet.
    Manual and electroacupuncture for labour pain: study design of a longitudinal randomized controlled trial2012Ingår i: Evidence-based Complementary and Alternative Medicine, ISSN 1741-427X, E-ISSN 1741-4288, artikel-id 943198Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction. Results from previous studies on acupuncture for labour pain are contradictory and lack important information on methodology. However, studies indicate that acupuncture has a positive effect on women's experiences of labour pain. The aim of the present study was to evaluate the efficacy of two different acupuncture stimulations, manual or electrical stimulation, compared with standard care in the relief of labour pain as the primary outcome. This paper will present in-depth information on the design of the study, following the CONSORT and STRICTA recommendations. Methods. The study was designed as a randomized controlled trial based on western medical theories. Nulliparous women with normal pregnancies admitted to the delivery ward after a spontaneous onset of labour were randomly allocated into one of three groups: manual acupuncture, electroacupuncture, or standard care. Sample size calculation gave 101 women in each group, including a total of 303 women. A Visual Analogue Scale was used for assessing pain every 30 minutes for five hours and thereafter every hour until birth. Questionnaires were distributed before treatment, directly after the birth, and at one day and two months postpartum. Blood samples were collected before and after the first treatment. This trial is registered at ClinicalTrials.gov: NCT01197950.

  • 430.
    Vixner, Linda
    et al.
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Department of Women’s and Children’s Health, Division of Reproductive Health, Karolinska Institutet, Retzius väg 13A, 171 77 Stockholm, Sweden.
    Schytt, Erica
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Omvårdnad. Centre for Clinical Research Dalarna, Nissers väg 3, 791 82 Falun, Sweden.
    Stener-Victorin, Elisabet
    Department of Physiology, Sahlgrenska Academy, Institute of Neuroscience and Physiology, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Waldenström, Ulla
    Department of Women’s and Children’s Health, Division of Reproductive Health, Karolinska Institutet, Retzius väg 13A, 171 77 Stockholm, Sweden.
    Pettersson, Hans
    Department of Clinical Science and Education, Södersjukhuset Karolinska Institutet, Stockholm, Sweden.
    Mårtensson, Lena B.
    School of Health and Education, University of Skövde, P.O. Box 408, 541 28 Skövde, Sweden.
    Acupuncture with manual and electrical stimulation for labour pain: a longitudinal randomised controlled trial2014Ingår i: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 14, artikel-id 187Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Acupuncture is commonly used to reduce pain during labour despite contradictory results. The aim of this study is to evaluate the effectiveness of acupuncture with manual stimulation and acupuncture with combined manual and electrical stimulation (electro-acupuncture) compared with standard care in reducing labour pain. Our hypothesis was that both acupuncture stimulation techniques were more effective than standard care, and that electro-acupuncture was most effective. 

    Methods: A longitudinal randomised controlled trial. The recruitment of participants took place at the admission to the labour ward between November 2008 and October 2011 at two Swedish hospitals. 303 nulliparous women with normal pregnancies were randomised to: 40 minutes of manual acupuncture (MA), electro-acupuncture (EA), or standard care without acupuncture (SC). Primary outcome: labour pain, assessed by Visual Analogue Scale (VAS). Secondary outcomes: relaxation, use of obstetric pain relief during labour and post-partum assessments of labour pain. The sample size calculation was based on the primary outcome and a difference of 15 mm on VAS was regarded as clinically relevant, this gave 101 in each group, including a total of 303 women. 

    Results: Mean estimated pain scores on VAS (SC: 69.0, MA: 66.4 and EA: 68.5), adjusted for: treatment, age, education, and time from baseline, with no interactions did not differ between the groups (SC vs MA: mean difference 2.6, 95% confidence interval [CI] -1.7-6.9 and SC vs EA: mean difference 0.6 [95% CI] -3.6-4.8). Fewer number of women in the EA group used epidural analgesia (46%) than women in the MA group (61%) and SC group (70%) (EA vs SC: odds ratio [OR] 0.35; [95% CI] 0.19-0.67). 

    Conclusions: Acupuncture does not reduce women's experience of labour pain, neither with manual stimulation nor with combined manual and electrical stimulation. However, fewer women in the EA group used epidural analgesia thus indicating that the effect of acupuncture with electrical stimulation may be underestimated. These findings were obtained in a context with free access to other forms of pain relief.

  • 431. Vos, Theo
    et al.
    Allen, Christine
    Arora, Megha
    Barber, Ryan M
    Bhutta, Zulfiqar
    Brown, Alexandria
    Carter, Austin
    Casey, Daniel C
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Murray, Christopher J. L
    Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 20152016Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, nr 10053, s. 1545-1602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. 

    Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. 

    Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. 

    Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available.

  • 432. Waikar, Sushrut S
    et al.
    Sabbisetti, Venkata
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Carlsson, Axel C
    Coresh, Josef
    Feldman, Harold I
    Foster, Meredith C
    Fufaa, Gudeta D
    Helmersson-Karlqvist, Johanna
    Hsu, Chi-Yuan
    Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies2016Ingår i: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 31, nr 9, s. 1460-1470Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The primary biomarkers used to define CKD are serum creatinine and albuminuria. These biomarkers have directed focus on the filtration and barrier functions of the kidney glomerulus even though albuminuria results from tubule dysfunction as well. Given that proximal tubules make up ∼90% of kidney cortical mass, we evaluated whether a sensitive and specific marker of proximal tubule injury, urinary kidney injury molecule-1 (KIM-1), is elevated in individuals with CKD or with risk factors for CKD.

    METHODS: We measured urinary KIM-1 in participants of five cohort studies from the USA and Sweden. Participants had a wide range of kidney function and were racially and ethnically diverse. Multivariable linear regression models were used to test the association of urinary KIM-1 with demographic, clinical and laboratory values.

    RESULTS: In pooled, multivariable-adjusted analyses, log-transformed, creatinine-normalized urinary KIM-1 levels were higher in those with lower eGFR {β = -0.03 per 10 mL/min/1.73 m(2) [95% confidence interval (CI) -0.05 to -0.02]} and greater albuminuria [β = 0.16 per unit of log albumin:creatinine ratio (95% CI 0.15-0.17)]. Urinary KIM-1 levels were higher in current smokers, lower in blacks than nonblacks and lower in users versus nonusers of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

    CONCLUSION: Proximal tubule injury appears to be an integral and measurable element of multiple stages of CKD.

  • 433. Waldenström, U
    et al.
    Cnattingius, S
    Vixner, Linda
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Norman, M
    Advanced maternal age increases the risk of very preterm birth, irrespective of parity: a population-based register study2017Ingår i: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 124, nr 8, s. 1235-1244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To investigate whether advanced maternal age is associated with preterm birth, irrespective of parity.

    DESIGN: Population-based registry study.

    SETTING: Swedish Medical Birth Register.

    POPULATION: First, second, and third live singleton births to women aged 20 years or older in Sweden, from 1990 to 2011 (n = 2 009 068).

    METHODS: Logistic regression analysis was used in each parity group to estimate risks of very and moderately preterm births to women at 20-24, 25-29, 30-34, 35-39, and 40 years or older, using 25-29 years as the reference group. Odds ratios (ORs) were adjusted for year of birth, education, country of birth, smoking, body mass index, and history of preterm birth. Age-related risks of spontaneous and medically indicated preterm births were also investigated.

    MAIN OUTCOME MEASURES: Very preterm (22-31 weeks of gestation) and moderately preterm (32-36 weeks) births.

    RESULTS: Risks of very preterm birth increased with maternal age, irrespective of parity: adjusted ORs in first, second, and third births ranged from 1.18 to 1.28 at 30-34 years, from 1.59 to 1.70 at 35-39 years, and from 1.97 to 2.40 at ≥40 years. In moderately preterm births, age-related associations were weaker, but were statistically significant from 35-39 years in all parity groups. Advanced maternal age increased the risks of both spontaneous and medically indicated preterm births.

    CONCLUSIONS: Advanced maternal age is associated with an increased risk of preterm birth, irrespective of parity, especially very preterm birth. Women aged 35 years and older, expecting their first, second, or third births, should be regarded as a risk group for very preterm birth.

  • 434. Walsh, Brandon
    et al.
    Tiivel, Toomas
    Tonkonogi, Michail
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Sahlin, Kent
    Increased concentrations of Pi and lactic acid reduce creatine stimulated respiration in muscle fibres.2002Ingår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 92, s. 2273-2276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We tested the hypothesis that the respiratory function of skeletal muscle mitochondria is impaired by lactic acidosis and elevated concentrations of Pi. The rate of respiration of chemically skinned fiber bundles from rat soleus muscle was measured at [Pi] (brackets denote concentration) and pH values similar to those at rest (3 mM Pi, pH 7.0) and high-intensity exercise (20 mM Pi, pH 6.6). Respiration was measured in the absence of ADP and after sequential additions of 0.1 mM ADP, 20 mM creatine (Cr; VCr), and 4 mM ADP. Respiration at 0.1 mM ADP increased after addition of Cr. However, VCr was 23% lower (P < 0.05) during high-intensity conditions than during resting conditions. VCr was also reduced when Pi or H+ was increased separately (P < 0.05). Respiration in the absence of ADP and after additions of 0.1 mM ADP and 4 mM ADP was not affected by changes in [Pi] or [H+]. The response was similar, irrespective of when acidosis was induced (i.e., quiescent or actively respiring mitochondria). In conclusion, Cr-stimulated respiration is impaired by increases in [H+] and [Pi] corresponding to those in exercising muscle. Although the reduced Cr-stimulated respiration could be compensated for by increased [ADP], this might have implications for intracellular homeostasis.

  • 435. Walsh, Brandon
    et al.
    Tonkonogi, Michail
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Malm, Christer
    Ekblom, Björn
    Sahlin, Kent
    Effect of eccentric exercise on muscle oxidative function in man.2001Ingår i: Medicine & Science in Sports & Exercise, ISSN 0195-9131, E-ISSN 1530-0315, Vol. 33, nr 3, s. 436-441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: The purpose of this study was to evaluate the effects of eccentric exercise on muscle oxidative function. Methods: Thirteen subjects performed high-intensity eccentric cycling for 30 min. Muscle oxidative function in vastus lateralis was evaluated by measurements of respiration in permeabilized muscle fibers (skinned fibers) and from the kinetics of oxyhemoglobin (oxyHb) saturation measured with near infrared spectroscopy (NIRS). Results: After eccentric cycling, all subjects reported extensive delayed onset muscle soreness (DOMS), but plasma markers of muscle damage (creatine kinase and [beta]-glucuronidase activity) were not significantly altered. The half time of oxyHb desaturation after circulatory occlusion (128 +/- 11 s, mean +/- SE) and oxyHb resaturation after restoration of blood flow (13.8 +/- 0.7 s) were not significantly changed after eccentric cycling (N = 7). Respiration in skinned muscle fibers measured in the absence of ADP and in the presence of a submaximal (0.1 mM) or maximal ADP concentration (1 mM) was not significantly changed after eccentric cycling (N = 6). The sensitivity of respiration to ADP was not significantly changed after eccentric cycling. Conclusions: Muscle oxidative function (maximal respiration and respiratory control by ADP) was not compromised after high-intensity eccentric cycle exercise. Furthermore, NIRS indicates that after eccentric cycling muscle oxygen utilization and local oxygen transport at rest are unchanged. It is concluded that eccentric cycling, although causing DOMS, does not negatively affect skeletal muscle oxidative function.

  • 436. Walsh, Brandon
    et al.
    Tonkonogi, Michail
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Sahlin, Kent
    Effect of endurance training on oxidative and antioxidative function in human permeabilised muscle fibres.2001Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 442, s. 420-425Artikel i tidskrift (Refereegranskat)
  • 437. Wang, Haidong
    et al.
    Bhutta, Zulfiqar
    Coates, Matthew M
    Coggeshall, Megan
    Dandona, Lalit
    Diallo, Khassoum
    Franca, Elisabeth Barboza
    Fraser, Maya
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Murray, Christopher J. L
    Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 20152016Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, nr 10053, s. 1725-1774Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Established in 2000, Millennium Development Goal 4 (MDG4) catalysed extraordinary political, financial, and social commitments to reduce under-5 mortality by two-thirds between 1990 and 2015. At the country level, the pace of progress in improving child survival has varied markedly, highlighting a crucial need to further examine potential drivers of accelerated or slowed decreases in child mortality. The Global Burden of Disease 2015 Study (GBD 2015) provides an analytical framework to comprehensively assess these trends for under-5 mortality, age-specific and cause-specific mortality among children under 5 years, and stillbirths by geography over time.

    Methods

    Drawing from analytical approaches developed and refined in previous iterations of the GBD study, we generated updated estimates of child mortality by age group (neonatal, post-neonatal, ages 1–4 years, and under 5) for 195 countries and territories and selected subnational geographies, from 1980–2015. We also estimated numbers and rates of stillbirths for these geographies and years. Gaussian process regression with data source adjustments for sampling and non-sampling bias was applied to synthesise input data for under-5 mortality for each geography. Age-specific mortality estimates were generated through a two-stage age–sex splitting process, and stillbirth estimates were produced with a mixed-effects model, which accounted for variable stillbirth definitions and data source-specific biases. For GBD 2015, we did a series of novel analyses to systematically quantify the drivers of trends in child mortality across geographies. First, we assessed observed and expected levels and annualised rates of decrease for under-5 mortality and stillbirths as they related to the Soci-demographic Index (SDI). Second, we examined the ratio of recorded and expected levels of child mortality, on the basis of SDI, across geographies, as well as differences in recorded and expected annualised rates of change for under-5 mortality. Third, we analysed levels and cause compositions of under-5 mortality, across time and geographies, as they related to rising SDI. Finally, we decomposed the changes in under-5 mortality to changes in SDI at the global level, as well as changes in leading causes of under-5 deaths for countries and territories. We documented each step of the GBD 2015 child mortality estimation process, as well as data sources, in accordance with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).

    Findings

    Globally, 5·8 million (95% uncertainty interval [UI] 5·7–6·0) children younger than 5 years died in 2015, representing a 52·0% (95% UI 50·7–53·3) decrease in the number of under-5 deaths since 1990. Neonatal deaths and stillbirths fell at a slower pace since 1990, decreasing by 42·4% (41·3–43·6) to 2·6 million (2·6–2·7) neonatal deaths and 47·0% (35·1–57·0) to 2·1 million (1·8-2·5) stillbirths in 2015. Between 1990 and 2015, global under-5 mortality decreased at an annualised rate of decrease of 3·0% (2·6–3·3), falling short of the 4·4% annualised rate of decrease required to achieve MDG4. During this time, 58 countries met or exceeded the pace of progress required to meet MDG4. Between 2000, the year MDG4 was formally enacted, and 2015, 28 additional countries that did not achieve the 4·4% rate of decrease from 1990 met the MDG4 pace of decrease. However, absolute levels of under-5 mortality remained high in many countries, with 11 countries still recording rates exceeding 100 per 1000 livebirths in 2015. Marked decreases in under-5 deaths due to a number of communicable diseases, including lower respiratory infections, diarrhoeal diseases, measles, and malaria, accounted for much of the progress in lowering overall under-5 mortality in low-income countries. Compared with gains achieved for infectious diseases and nutritional deficiencies, the persisting toll of neonatal conditions and congenital anomalies on child survival became evident, especially in low-income and low-middle-income countries. We found sizeable heterogeneities in comparing observed and expected rates of under-5 mortality, as well as differences in observed and expected rates of change for under-5 mortality. At the global level, we recorded a divergence in observed and expected levels of under-5 mortality starting in 2000, with the observed trend falling much faster than what was expected based on SDI through 2015. Between 2000 and 2015, the world recorded 10·3 million fewer under-5 deaths than expected on the basis of improving SDI alone.

    Interpretation

    Gains in child survival have been large, widespread, and in many places in the world, faster than what was anticipated based on improving levels of development. Yet some countries, particularly in sub-Saharan Africa, still had high rates of under-5 mortality in 2015. Unless these countries are able to accelerate reductions in child deaths at an extraordinary pace, their achievement of proposed SDG targets is unlikely. Improving the evidence base on drivers that might hasten the pace of progress for child survival, ranging from cost-effective intervention packages to innovative financing mechanisms, is vital to charting the pathways for ultimately ending preventable child deaths by 2030.

    Funding

    Bill & Melinda Gates Foundation.

  • 438. Wang, Haidong
    et al.
    Naghavi, Mohsen
    Allen, Christine
    Barber, Ryan M
    Bhutta, Zulfiqar
    Carter, Austin
    Casey, Daniel C
    Charlson, Fiona J
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala university.
    Murray, Christopher J. L
    Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 20152016Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, nr 10053, s. 1459-1544Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.

    Methods

    We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography–year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).

    Findings

    Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4–61·9) in 1980 to 71·8 years (71·5–72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7–17·4), to 62·6 years (56·5–70·2). Total deaths increased by 4·1% (2·6–5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8–18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6–16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9–14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1–44·6), malaria (43·1%, 34·7–51·8), neonatal preterm birth complications (29·8%, 24·8–34·9), and maternal disorders (29·1%, 19·3–37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000–183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000–532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.

    Interpretation

    At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.

    Funding

    Bill & Melinda Gates Foundation.

  • 439. Wang, Haidong
    et al.
    Wolock, Tim M
    Carter, Austin
    Nguyen, Grant
    Kyu, Hmwe Hmwe
    Gakidou, Emmanuela
    Hay, Simon I
    Mills, Edward J
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Murray, Christopher J L
    Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 20152016Ingår i: The Lancet HIV, ISSN 2352-3018, Vol. 3, nr 8, s. E361-E387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.

    Methods

    For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassifi cation.

    Findings

    Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1–3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5–2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6–40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7–1·9 million) in 2005, to 1·2 million deaths (1·1–1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.

    Interpretation

    Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued eff orts from governments and international agencies in the next 15 years to end AIDS by 2030.

  • 440. Wierup, Ia
    et al.
    Carlsson, Axel C.
    Wändell, Per
    Riserus, Ulf
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Borné, Yan
    Low anthropometric measures and mortality: results from the Malmö Diet and Cancer Study2015Ingår i: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 47, nr 4, s. 325-331Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim. To study the association between anthropometric measures: body mass index (BMI), percent body fat, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist-to-hip-to-height ratio (WHHR), and A Body Shape Index (ABSI); to see if individuals in the lowest 5 percentiles for these measures have an increased risk of mortality.

    Methods. A population-based prospective cohort study ( 10,304 men and 16,549 women), the Malmo Diet and Cancer study (MDC), aged 45-73 years.

    Results. During a mean follow-up of 14 +/- 3 years, 2,224 men and 1,983 women died. There was a significant increased mortality risk after adjustments for potential confounders in the group with the 5% lowest BMI ( referent 25%-75%); hazard ratios (HR) with 95% confidence intervals were 1.33 (1.10-1.61) for women and 1.27 (1.07-1.52) for men. A similar significant increased mortality risk was seen with the 5% lowest percent body fat, HR 1.31 (1.07-1.60) for women and 1.25 (1.04-1.50) for men. Women with an ABSI in the lowest 5 percentiles had a lower mortality risk HR 0.64 (0.48-0.85).

    Conclusion. These results imply that BMI or percent body fat could be used to identify lean individuals at increased mortality risk.

  • 441. Winkel, Per
    et al.
    Jakobsen, Janus Christian
    Hilden, Jørgen
    Jensen, Gorm
    Kjøller, Erik
    Sajadieh, Ahmad
    Kastrup, Jens
    Kolmos, Hans Jørn
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Gluud, Christian
    Prognostic value of routinely available data in patients with stable coronary heart disease. A 10-year follow-up of patients sampled at random times during their disease course2018Ingår i: Open heart, E-ISSN 2053-3624, Vol. 5, nr 2, artikel-id 000808Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective To characterise the long-term prognosis of patients with stable coronary artery heart disease by means of ‘standard predictors’ defined as demographic, clinical and biochemical quantities routinely available in general practices and ascertained at an interview not prompted by renewed cardiac complaints.Methods This is an observational study based on data from 2199 Copenhagen placebo patients from the ‘clarithromycin for patients with stable coronary heart disease’ trial of patients with stable coronary heart disease. In the trial, we compared the effects of 14 days of clarithromycin treatment versus placebo. The predictors were based on the interview forms and blood samples collected at entry, along with demographic information from hospital files.We studied ‘standard predictors’ of a composite outcome (myocardial infarction, unstable angina, cerebrovascular disease or all-cause death) and of all-cause death. Using Cox regression, we compared predictions of status at 3, 6 and 9 years without and with the use of ‘standard predictors’ and used receiver operating characteristic statistic.Results Few ‘standard predictors’ were associated (p&amp;lt;0.01) with the composite outcome or with all-cause death. When no ‘standard predictors’ were included, 63.2% of the model-based predictions of the composite outcome and 79.9% of death predictions were correct. Including all ‘standard predictors’ in the model increased the figures to 68.4% and 83.4%, respectively. C indices were low, except when all-cause death was assessed as a single outcome where C was 0.79.Conclusion ‘Standard predictors’ routinely available in general practices contribute only modestly to risk assessment in consecutively sampled patients with stable coronary heart disease as ascertained at a contact not prompted by renewed cardiac complaints. Novel biomarkers may improve the assessment.Trial registration number NCT00121550.

  • 442.
    Witasp, Anna
    et al.
    Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden ; Division of Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Carrero, Juan Jesús
    Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden ; Division of Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden ; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Michaëlsson, Karl
    Department of Surgical Sciences, Section of Orthopaedics, Uppsala University, Uppsala, Sweden.
    Ahlström, Håkan
    Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Uppsala, Sweden.
    Kullberg, Joel
    Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Uppsala, Sweden.
    Adamsson, Viola
    Department of Public Health and Caring Sciences/Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Risérus, Ulf
    Department of Public Health and Caring Sciences/Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Helmersson-Karlqvist, Johanna
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden.
    Inflammatory biomarker pentraxin 3 (PTX3) in relation to obesity, body fat depots and weight loss2014Ingår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 22, nr 5, s. 1373-1379Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: The relation between inflammatory markers, adiposity and disease is under extensive study. Here we tested the hypothesis that the immunomodulatory protein pentraxin 3 (PTX3) is associated with adiposity in the general population.

    METHODS: Serum PTX3 concentrations, body mass index (BMI), waist circumference (WC) and fat depots, as quantified by dual-energy X-ray absorptiometry and magnetic resonance imaging, were assessed in three community-based cohorts: ULSAM, n = 790, mean age 78 years; PIVUS, n = 1003, mean age 70 years, women 50%; and the NORDIET-trial, n = 86, mean age 53 years, women 63%. Participants were re-examined after 5 years (PIVUS, n = 804) or following a 6-week randomized controlled dietary intervention (NORDIET).

    RESULTS: PTX3 levels were inversely associated with BMI and WC as well as with total and visceral fat (P < 0.05 for all; adjusted for age, inflammatory biomarkers and cardiovascular risk factors). The association between PTX3 and BMI appeared even stronger in nonobese individuals. A decrease in BMI over 5 years as well as weight loss following the NORDIET intervention were associated with increased serum PTX3 concentrations (P < 0.001).

    CONCLUSIONS: These consistent data support an inverse association between circulating PTX3 and anthropometrical measures, calling for further mechanistic studies of the link between PTX3 and fat.

  • 443. Wood, Andrew R
    et al.
    Esko, Tonu
    Yang, Jian
    Vedantam, Sailaja
    Pers, Tune H
    Gustafsson, Stefan
    Chu, Audrey Y
    Estrada, Karol
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Frayling, Timothy M
    Defining the role of common variation in the genomic and biological architecture of adult human height2014Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 11, s. 1173-1186Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.2014

  • 444. Wormser, David
    et al.
    Kaptoge, Stephen
    Di Angeloantonio, Emanuele
    Wood, Angela M
    Pennells, Lisa
    Thompson, Alex
    Sarwar, Nadeem
    Kizer, Jorge R
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Uppsala universitet.
    Danesh, J
    Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies2011Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 377, nr 9771, s. 1085-95Artikel i tidskrift (Refereegranskat)
  • 445. Wu, Jason H Y
    et al.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Riserus, Ulf
    Micha, Renata
    Schulze, M. B
    Lemaitre, R. N
    Chien, K. L
    Sun, Q
    Harris, W. S
    Mozaffarian, Dariush
    Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies2017Ingår i: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, nr 21, s. 965-974Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.

    METHODS: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis.

    FINDINGS: Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m(2), who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I(2)=53·9%, pheterogeneity=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I(2)=63·0%, pheterogeneity<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all pheterogeneity≥0·13).

    INTERPRETATION: Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful.

  • 446. Wuopio, Jonas
    et al.
    Hilden, Jørgen
    Bring, Carl
    Kastrup, Jens
    Sajadieh, Ahmad
    Jensen, Gorm Boje
    Kjøller, Erik
    Kolmos, Hans Jørn
    Larsson, Anders
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study2018Ingår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 278, s. 97-102Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND AIMS: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease.

    METHODS: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs.

    RESULTS: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events.

    CONCLUSIONS: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.

  • 447. Wuopio, Jonas
    et al.
    Östgren, Carl Johan
    Länne, Toste
    Lind, Lars
    Ruge, Toralph
    Carlsson, Axel C.
    Larsson, Anders
    Nyström, Fredrik H.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska Institutet.
    The association between circulating endostatin and a disturbed circadian blood pressure pattern in patients with type 2 diabetes2018Ingår i: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 27, nr 4, s. 215-221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Endostatin, cleaved from collagen XVIII in the extracellular matrix, is a promising circulating biomarker for cardiovascular damage. It possesses anti-angiogenic and anti-fibrotic functions and has even been suggested to be involved in blood pressure regulation. Less is known if endostatin levels relate to circadian blood pressure patterns. In the present paper we studied the association between circulating levels of endostatin and nocturnal dipping in blood pressure.

    METHODS: We used the CARDIPP-study, a cohort of middle aged, type 2 diabetics (n = 593, 32% women), with data on both 24-hour and office blood pressure, serum-endostatin, cardiovascular risk factors, and incident major cardiovascular events. Nocturnal dipping was defined as a >10% difference between day- and night-time blood pressures.

    RESULTS: Two-hundred four participants (34%) were classified as non-dippers. The mean endostatin levels were significantly higher in non-dippers compared to dippers (mean ± standard deviation: 62.6 ± 1.8 µg/l vs. 58.7 ± 1.6 µg/l, respectively, p = .007). Higher serum levels of endostatin were associated with a diminished decline in nocturnal blood pressure adjusted for age, sex, HbA1c, mean systolic day blood pressure, hypertension treatment, glomerular filtration rate, and prevalent cardiovascular disease (regression coefficient per SD increase of endostatin -0.01, 95% CI, -0.02-(-0.001), p = .03). Structural equation modelling analyses suggest that endostatin mediates 7% of the association between non-dipping and major cardiovascular events.

    CONCLUSION: We found an independent association between higher circulating levels of endostatin and a reduced difference between day- and night-time systolic blood pressure in patients with type 2 diabetes. Yet endostatin mediated only a small portion of the association between non-dipping and cardiovascular events arguing against a clinical utility of our findings.

  • 448. Wuttke, M
    et al.
    Li, Y
    Sieber, K. B
    Feitosa, M. F
    Gorski, M
    Tin, A
    Wang, L
    Chu, A. Y
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska institutet.
    Pattaro, C
    A catalog of genetic loci associated with kidney function from analyses of a million individuals2019Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, nr 6, s. 957-972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

  • 449. Wändell, P.
    et al.
    Carlsson, A. C.
    Holzmann, M. J.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska Institutet, Uppsala universitet.
    Sundquist, J.
    Sundquist, K.
    The association between relevant co-morbidities and prevalent as well as incident heart failure in patients with atrial fibrillation2018Ingår i: Journal of Cardiology, ISSN 0914-5087, E-ISSN 1876-4738, Vol. 72, nr 1, s. 26-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    Congestive heart failure (CHF) is a serious complication in patients with atrial fibrillation (AF).

    OBJECTIVE:

    To study associations between relevant co-morbidities and CHF in patients with AF.

    METHODS:

    Study population included all adults (n=12,283) ≥45 years diagnosed with AF at 75 primary care centers in Sweden 2001-2007. Logistic regression was used to calculate odds ratios with 95% confidence intervals (CIs) for the associations between co-morbidities, and prevalent CHF. In a subsample (n=9424), (excluding patients with earlier CHF), Cox regression was used to estimate hazard ratios with 95% CIs for the association between co-morbidities, and a first hospital diagnosis of CHF, after adjustment for age and socio-economic factors.

    RESULTS:

    During 5.4 years' follow-up (standard deviation 2.5), 2259 patients (24.0%; 1135 men, 21.8%, and 1124 women, 26.7%) were diagnosed with CHF. Patients with hypertension were less likely to have CHF, while a diagnosis of coronary heart disease, valvular heart disease, diabetes, or chronic obstructive pulmonary disease (COPD), was consistently associated with CHF among men and women. CHF was more common among women with depression. The relative fully adjusted risk of incident CHF was increased for the following diseases in men with AF: valvular heart disease, cardiomyopathy, and diabetes; and for the following diseases in women: valvular heart disease, diabetes, obesity, and COPD. The corresponding risk was decreased among women for hypertension.

    CONCLUSIONS:

    In this clinical setting we found hypertension to be associated with a decreased risk of CHF among women; valvular heart disease and diabetes to be associated with an increased risk of CHF in both sexes; and cardiomyopathy to be associated with an increased risk of CHF among men.

  • 450. Wändell, P.E.
    et al.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Hälsa och samhälle, Medicinsk vetenskap.
    Nixon Andreasson, A.
    Andersson, K.
    Törnkvist, L.
    Carlsson, A.C.
    Effects of tactile massage on metabolic biomarkers in patients with type 2 diabetes2013Ingår i: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 39, nr 5, s. 411-417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Tactile massage (TM) is a gentle and superficial form of massage. A pilot study of patients with type 2 diabetes in primary care reported a reduction of 0.8% in glycosylated haemoglobin (HbA1c), whereas a randomized study comparing the effects of 10 weeks of TM once per week with relaxation exercises performed once per week as per instructions on a CD found no effects of TM on HbA1c in an intention-to-treat analysis. However, a significant reduction in waist circumference (WC) was found between the groups. Methods: This was a secondary per-protocol analysis of the effect of TM (n = 21) compared with relaxation (n = 25) on other metabolic biomarkers. Anthropometrics (BMI and WC) and metabolic factors (B HbA1c, S IGF, fS insulin, S adiponectin, S leptin and fP ghrelin) were assessed, insulin resistance (IR) was determined by modified homoeostasis model assessment (HOMA2-IR) using fP glucose and fS insulin, and ratios of adiponectin-to-leptin, adiponectin-to-HOMA-IR, adiponectin-to-WC and adiponectin-to-HbA1c were calculated at baseline, and at 10 weeks and 6 months after the intervention. Results: Significant results adjusted for age, gender and changes in lifestyle and medical factors were shown for WC in women (-6.2 cm [95% CI: -10.4, -1.9]), but not in men. In addition, improvements in the TM group were found for adiponectin and ratios of adiponectin-to-leptin and adiponectin-to-HbA1c levels. Conclusion: Our data indicate that TM therapy may affect metabolic markers in type 2 diabetes despite the lack of significant effects on HbA1c. The clinical implications of our findings need to be evaluated in further studies. © 2013 Elsevier Masson SAS. All rights reserved.

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