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Objectives: Vitamin D modulates inflammation, and this may explain the observed associations between vitamin D status and disorders driven by systemic inflammation, such as coronary artery disease (CAD) and inflammatory rheumatic diseases (IRDs). The aims of this study were to assess vitamin D status in patients with CAD alone and in patients with CAD and IRD, and to explore potential associations between vitamin D status and the presence of mononuclear cell infiltrates (MCIs) in the aortic adventitia of these patients.Method: Plasma levels of 25-hydroxyvitamin D3 [(25(OH)D3] were determined by radioimmunoassay and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by enzyme immunoassay in the 121 patients from the Feiring Heart Biopsy Study (FHBS) who had available histology data on adventitial MCIs; 53 of these had CAD alone and 68 had CAD and IRD.Results: In the crude analysis, vitamin D levels were similar in CAD patients with and without IRD. After adjustment for potential confounders, IRD was associated with an increase of 8.8 nmol/L [95% confidence interval (CI) 1.0-16.6; p = 0.027] in 25(OH)D3 and an increase of 18.8 pmol/L (95% CI 4.3-33.3; p = 0.012) in 1,25(OH)2D3, while MCIs in the aortic adventitia were associated with lower levels of 1,25(OH)2D3 (β = -18.8, 95% CI -33.6 to -4.0; p = 0.014).Conclusions: IRD was associated with higher levels of both 25(OH)D3 and 1,25(OH)2D3. These findings argue against the hypothesis that patients with high systemic inflammatory burden (CAD+IRD) should have lower vitamin D levels than those with less inflammation (CAD only). Of note, when controlled for potential confounders, low 1,25(OH)2D3 levels were associated with adventitial aortic inflammation. [ABSTRACT FROM AUTHOR]

Objectives: Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients. Method: In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3-5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15. Results: By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08-1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups. Conclusions: Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Gastric bypass and duodenal switch are currently performed bariatric surgical procedures. Uncontrolled studies suggest that duodenal switch induces greater weight loss than gastric bypass.Objective: To determine whether duodenal switch leads to greater weight loss and more favorable improvements in cardiovascular risk factors and quality of life than gastric bypass.Design: Randomized, parallel-group trial. (ClinicalTrials.gov registration number: NCT00327912)Setting: 2 academic medical centers (1 in Norway and 1 in Sweden).Patients: 60 participants with a body mass index (BMI) between 50 and 60 kg/m(2).Intervention: Gastric bypass (n = 31) or duodenal switch (n = 29).Measurements: The primary outcome was the change in BMI after 2 years. Secondary outcomes included anthropometric measures; concentrations of blood lipids, glucose, insulin, C-reactive protein, and vitamins; and health-related quality of life and adverse events.Results: Fifty-eight of 60 participants (97%) completed the study. The mean reductions in BMI were 17.3 kg/m(2) (95% CI, 15.7 to 19.0 kg/m(2)) after gastric bypass and 24.8 kg/m(2) (CI, 23.0 to 26.5 kg/m(2)) after duodenal switch (mean between-group difference, 7.44 kg/m(2) [CI, 5.24 to 9.64 kg/m(2)]; P < 0.001). Total cholesterol concentration decreased by 0.24 mmol/L (CI, -0.03 to 0.50 mmol/L) (9.27 mg/dL [CI, -1.16 to 19.3 mg/dL]) after gastric bypass and 1.07 mmol/L (CI, 0.79 to 1.35 mmol/L) (41.3 mg/dL [CI, 30.5 to 52.1 mg/dL]) after duodenal switch (mean between-group difference, 0.83 mmol/L [CI, 0.48 to 1.18 mmol/L]; 32.0 mg/dL [CI, 18.5 to 45.6 mg/dL]; P ≤ 0.001). Reductions in low-density lipoprotein cholesterol concentration, anthropometric measures, fat mass, and fat-free mass were also greater after duodenal switch (P ≤ 0.010 for each between-group comparison). Both groups had reductions in blood pressure and mean concentrations of glucose, insulin, and C-reactive protein, with no between-group differences. The duodenal switch group, but not the gastric bypass group, had reductions in concentrations of vitamin A and 25-hydroxyvitamin D. Most Short Form-36 Health Survey dimensional scores improved in both groups, with greater improvement in 1 of 8 domains (bodily pain) after gastric bypass. From surgery until 2 years, 10 participants (32%) had adverse events after gastric bypass and 18 (62%) after duodenal switch (P = 0.021). Adverse events related to malnutrition occurred only after duodenal switch.Limitation: Clinical experience was greater with gastric bypass than with duodenal switch at the study centers.Conclusion: Duodenal switch surgery was associated with greater weight loss, greater reductions of total and low-density lipoprotein cholesterol concentrations, and more adverse events. Improvements in other cardiovascular risk factors and quality of life were similar after both procedures.Primary Funding Source: South-Eastern Norway Regional Health Authority. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear whether moderate-to-vigorous physical activity (MVPA) is associated with a lower mortality risk, over and above its contribution to total physical activity volume., Methods: 46,682 adults (mean age: 64 years) were included in a meta-analysis of nine prospective cohort studies. Each cohort generated tertiles of accelerometry-measured physical activity volume and volume-adjusted MVPA. Hazard ratios (HR, with 95% confidence intervals) for mortality were estimated separately and in joint models combining volume and MVPA. Data was collected between 2001 and 2019 and analyzed in 2023., Results: During a mean follow-up of 9 years, 4,666 deaths were recorded. Higher physical activity volume, and a greater contribution from volume-adjusted MVPA, were each associated with lower mortality hazard in multivariable-adjusted models. Compared to the least active tertile, higher physical activity volume was associated with a lower mortality (HRs: 0.62; 0.58, 0.67 and 0.50; 0.42, 0.60 for ascending tertiles). Similarly, a greater contribution from MVPA was associated with a lower mortality (HRs: 0.94; 0.85, 1.04 and 0.88; 0.79, 0.98). In joint analysis, a lower mortality from higher volume-adjusted MVPA was only observed for the middle tertile of physical activity volume., Conclusions: The total volume of physical activity was associated with a lower risk of mortality to a greater extent than the contribution of MVPA to physical activity volume. Integrating any intensity of physical activity into daily life may lower mortality risk in middle-aged and older adults, with a small added benefit if the same amount of activity is performed with a higher intensity., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to compare the incidence of knee osteoarthritis (OA) between the anatomic single-bundle (SB) and anatomic double-bundle (DB) anterior cruciate ligament (ACL) reconstruction technique after 5-year follow-up (FU). Secondary objectives were to compare patient-reported outcome measures (PROMs), clinical examination, activity level, functional tests and graft failures between the two groups., Methods: The study was a secondary analysis after 5-year FU of a randomized controlled trial (RCT) (Clinical Trials NCT01033188). One hundred and twenty patients between 18 and 40 years were randomized to either anatomic SB or anatomic DB reconstruction. The Kellgren-Lawrence (KL) classification grade ≥2 and the Osteoarthritis Research Society International (OARSI) atlas criteria score ≥2 were used for defining OA. Additionally, PROMs were obtained and clinical examinations of the knees were performed. Finally, the number of patients experiencing graft failure in each group was recorded., Results: Radiographic imaging was performed in 39 patients in the SB group and in 37 patients in the DB group. Four patients (10%) in the SB group and two (5%) in the DB group developed osteoarthritis according to the KL classification (p = 0.28). Five (13%) in the SB group and three (8%) in the DB group developed osteoarthritis according to the OARSI atlas criteria (p = 0.59; difference 5.0% [95% confidence interval, CI: -0.10 to 0.20]). There were no significant differences in the PROMs, clinical examinations, activity levels, or functional tests when comparing the two groups. Of initially 62 SB patients, 14 (23%) experienced graft failure compared to 4 (7%) of the 58 DB patients (p = 0.015; difference 0.016 [95% CI: 0.03-0.29])., Conclusion: At 5-year FU, there were no significant differences in the incidence of OA, PROMS, or other clinical findings comparing the anatomic DB to anatomic SB ACL reconstructed patients. There were fewer graft failures among patients treated with anatomic DB ACL reconstruction., Level of Evidence: II., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin-kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety., Objectives: This double blind, randomized trial was conducted to test whether evolocumab reduces the burden of cardiac allograft vasculopathy., Methods: Patients who had received a cardiac allograft at 1 of the Nordic transplant centers within the prior 4 to 8 weeks were randomized to monthly subcutaneous injections of evolocumab 420 mg or matching placebo. The primary endpoint was the baseline-adjusted maximal intimal thickness as measured by intracoronary ultrasound after 12 months' treatment., Results: The trial enrolled 128 patients between June 2019 and May 2022. Matched pairs of coronary ultrasound images were available for 56 patients assigned to evolocumab and 54 patients assigned to placebo. At 12 months, the adjusted mean difference in the maximal intimal thickness between the 2 arms was 0.017 mm (95% CI: -0.006 to 0.040; P = 0.14). The mean reduction in low-density lipoprotein cholesterol with evolocumab compared with placebo was 1.11 mmol/L (95% CI: 0.86-1.37 mmol/L). The use of evolocumab was not associated with an increase in adverse events., Conclusions: Twelve months of treatment with evolocumab substantially reduced low-density lipoprotein cholesterol but did not reduce maximal coronary intimal thickness in HTx recipients. (Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients [EVOLVD]; NCT03734211)., Competing Interests: Funding Support and Author Disclosures This work was funded by Amgen, the South-Eastern Norway Regional Health Authority, and the Kardimmun foundation. Amgen provided the investigational medicinal products and an unrestricted grant. The funders had no role in the trial design or data collection, analysis, and interpretation. The funders had no role in the preparation or review of the manuscript, or in the decision to publish, but were allowed to read the manuscript for approval prior to publication. Dr Broch has received lecture fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Orion Pharma, Pfizer, Pharmacosmos, and Vifor Pharma. Dr Gullestad has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Amgen; and has been a member of local advisory board in AstraZeneca and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether decompression alone is non-inferior to decompression with instrumented fusion five years after primary surgery in patients with degenerative lumbar spondylolisthesis., Design: Five year follow-up of a randomised, multicentre, non-inferiority trial (Nordsten-DS)., Setting: 16 public orthopaedic and neurosurgical clinics in Norway., Participants: Patients aged 18-80 years with symptomatic lumbar spinal stenosis and a spondylolisthesis of 3 mm or more at the stenotic level., Interventions: Decompression surgery alone and decompression with additional instrumented fusion (1:1)., Main Outcome Measures: The primary outcome was a 30% or more reduction in Oswestry disability index from baseline to five year follow-up. The predefined non-inferiority margin was a -15 percentage point difference in the proportion of patients who met the primary outcome. Secondary outcomes included the mean change in Oswestry disability index, Zurich claudication questionnaire, numeric rating scale for leg and back pain, and EuroQol Group 5-Dimension (EQ-5D-3L) questionnaire., Results: From 12 February 2014 to 18 December 2017, 267 participants were randomly assigned to decompression alone (n=134) and decompression with instrumented fusion (n=133). Of these, 230 (88%) responded to the five year questionnaire: 121 in the decompression group and 109 in the fusion group. Mean age at baseline was 66.2 years (SD 7.6), and 69% were women. In the modified intention-to-treat analysis with multiple imputation of missing data, 84 (63%) of 133 people in the decompression alone group and 81 (63%) of 129 people in the fusion group had a at least a 30% reduction in Oswestry disability index, a difference of 0.4 percentage points. (95% confidence interval (CI) -11.2 to 11.9). The respective results of the per protocol analysis were 65 (65%) of 100 in the decompression alone group and 59 (66%) of 89 in the fusion group, a difference of -1.3 percentage points (95% CI -14.5 to 12.2). Both 95% CIs were higher than the predefined non-inferiority margin of -15%. The mean change in Oswestry disability index from baseline to five years was -17.8 in both groups (mean difference 0.02 (95% CI -3.8 to 3.9)). Results of the other secondary outcomes were in the same direction as the primary outcome. From two to five year follow-up, a new lumbar operation occurred in six (5%) of 123 people in the decompression group and 11 (10%) of 113 people in the fusion group, with a total from baseline to five years of 21 (16%) of 129 people and 23 (18%) of 125, respectively., Conclusions: In participants with degenerative spondylolisthesis, decompression alone was non-inferior to decompression with instrumented fusion five years after primary surgery. Proportions of subsequent surgeries at the index level or an adjacent lumbar level were no different between the groups., Trial Registration: ClinicalTrials.gov NCT02051374., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form www.icmje.org/disclosure-of-interest/ and declared that they have had no financial relationships with any organisation that may have a financial interest in the submitted work in the previous three years and no relationships or activities that could have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values., Methods and Results: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%., Conclusion: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Results from long-term follow-up after biliopancreatic diversion with duodenal switch (DS) are scarce., Objective: To compare weight loss, health outcomes, and quality of life 10 years or more after Roux-en-Y-gastric bypass (RYGB) and DS surgery in patients with severe obesity-that is, a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 50 to 60., Design, Setting, and Participants: This open-label randomized clinical trial was conducted at 2 academic bariatric centers in Sweden and Norway. Sixty patients with a BMI of 50 to 60 were included from March 1, 2006, to August 31, 2007. Data were analyzed from August 12, 2022, to January 25, 2023., Interventions: Laparoscopic RYGB or laparoscopic DS., Main Outcomes and Measures: The main outcome was change in BMI after 10 or more years. Secondary outcomes included anthropometric measures, lipid and glycemic profiles, bone mass density, adverse events, gastrointestinal tract symptoms, and health-related quality of life., Results: Forty-eight of the original 60 patients (80%) were assessed after a median of 12 (range, 9-13) years (mean [SD] age, 48.0 [6.0] years; 35 women [73%]). At follow-up, the mean BMI reductions were 11.0 (95% CI, 8.3-13.7) for RYGB and 20.3 (95% CI, 17.6-23.0) for DS, with a mean between-group difference of 9.3 (95% CI, 5.4-13.1; P < .001). Total weight loss was 20.0% (95% CI, 15.3%-24.7%) for RYGB and 33.9% (95% CI, 27.8%-40.0%) for DS (P = .001). Mean serum lipid levels, except high-density lipoprotein cholesterol and hemoglobin A1c, improved more in the DS group during follow-up. Bone mass was reduced for both groups from 5 to 10 years, with lower bone mass after DS at 10 years. Quality-of-life scores (Obesity-Related Problem Scale and the 36-Item Short Form Health Survey) were comparable across groups at 10 years. The total number of adverse events was higher after DS (135 vs 97 for RYGB; P = .02). More patients in the DS group developed vitamin deficiencies (21 vs 11 for RYGB; P = .008) including 25-hydroxyvitamin D deficiency (19 for DS vs 9 for RYGB; P = .005). Four of 29 patients in the DS group (14%) developed severe protein-caloric malnutrition, of whom 3 (10%) underwent revisional surgery., Conclusions and Relevance: In this randomized clinical trial, BMI reduction was greater after DS, but RYGB had a better risk profile over 10 years. Biliopancreatic diversion with DS may not be a better surgical strategy than RYGB for patients with a BMI of 50 to 60., Trial Registration: ClinicalTrials.gov Identifier: NCT00327912.

Background and Aims: The evidence for beta-blocker therapy after myocardial infarction (MI) is randomized trials conducted more than 30 years ago, and the continued efficacy has been questioned., Design and Methods: The ongoing Danish (DANBLOCK) and Norwegian (BETAMI) randomized beta-blocker trials are joined to evaluate the effectiveness and risks of long-term beta-blocker therapy after MI. Patients with normal or mildly reduced left ventricular ejection fraction (LVEF ≥ 40%) will be randomized to open-label treatment with beta-blockers or no such therapy. The event-driven trial will randomize ∼5700 patients and continue until 950 primary endpoints have occurred. As of July 2023, 5228 patients have been randomized. Of the first 4000 patients randomized, median age was 62 years, 79% were men, 48% had a ST-segment elevation myocardial infarction (STEMI), and 84% had a normal LVEF. The primary endpoint is a composite of adjudicated recurrent MI, incident heart failure (HF), coronary revascularization, ischaemic stroke, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest. The primary safety endpoint includes a composite of recurrent MI, HF, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest 30 days after randomization. Secondary endpoints include each of the components of the primary endpoint, patient-reported outcomes, and other clinical outcomes linked to beta-blocker therapy. The primary analysis will be conducted according to the intention-to-treat principle using a Cox proportional hazards regression model. End of follow-up is expected in December 2024., Conclusion: The combined BETAMI-DANBLOCK trial will have the potential to affect current clinical practice for beta-blocker therapy in patients with normal or mildly reduced LVEF after MI., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The aim was to determine how jump load affects knee complaints in elite men's volleyball. We collected data from four men's premier league volleyball teams through three seasons in a prospective cohort study (65 players, 102 player-seasons). Vert inertial measurement devices captured the jump load (jump frequency and jump height) from 21 088 daily player sessions, and knee complaints were reported in 3568 weekly OSTRC-O questionnaires. Mixed complementary log-log regression models described the probability of (i) experiencing symptoms if players were currently asymptomatic, (ii) worsening symptoms if players had symptoms, and (iii) recovery from knee complaints. Based on our causal assumptions, weekly jump load was modeled as the independent variable, adjusted for age (years), weight (kg), position on volleyball team, and past jump load. No certain evidence of an association was found between weekly jump load and probability of (i) knee complaints (p from 0.10 to 0.32 for three restricted cubic splines of load), (ii) worsening symptoms if the player already had symptoms (p from 0.11 to 0.97), (iii) recovery (p from 0.36 to 0.63). The probability of knee complaints was highest for above-average weekly jump load (~1.2% for an outside hitter with mean age and height) compared with low loads (~1%) and very high loads (→ ~ 0%). The association between jump load and knee complaints risk remains unclear. Small differences in risk across observed jump load levels were observed. It would likely require substantially increased sample sizes to detect this association with certainty., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The relationship between recent (acute) training load relative to long-term (chronic) training load may be associated with sports injury risk. We explored the potential for modelling acute and chronic loads separately to address current statistical methodology limitations. We also determined whether there was any evidence of an interaction in the association between acute and chronic training loads and injury risk in football. A men's Qatar Stars League football cohort (1 465 players, 1 977 injuries), where training load was defined as the number of minutes of activity, and a Norwegian elite U-19 football cohort (81 players, 60 injuries), where training load was defined as the session rating of perceived exertion (sRPE). Mixed logistic regression was run with training load on the current day (acute load) and cumulative past training load estimated by distributed lag non-linear models (chronic load) as independent variables. Injury was the outcome. An interaction between acute and chronic training load was modelled. In both football populations, we observed that the risk of injury on the current day for different values of acute training load was highest for players with low chronic load, followed by high and then medium chronic load. The slopes varied substantially between different levels of chronic training load, indicating an interaction. Modelling acute and chronic loads separately in regression models is a suitable statistical approach for analysing the association between relative training load and injury risk in injury prevention research. Sports scientists should also consider the potential for interactions between acute and chronic load., Competing Interests: The authors declare no conflict of interest., (Copyright © Biology of Sport 2024.)

Aims: Currently, no incident heart failure (HF) risk score that is in regular use in a general population is available. We aimed to develop this and compare with existing HF risk scores., Methods and Results: Participants in the third wave (2006-08) of the population-based Trøndelag Health Study 3 (HUNT3) were included if they reported no previous HF. Any hospital diagnoses captured during follow-up (until the end of 2018) of HF, cardiomyopathy, or hypertensive heart disease were assessed by an experienced cardiologist. Valid HF events were defined as symptoms/signs of HF and objective evidence of structural/functional abnormality of the heart at rest. The model was compared with slightly modified HF risk scores (the Health Aging and Body Composition HF risk score, the Framingham HF risk score, the Pooled Cohort equations to Prevent HF risk score, and NORRISK 2). Among 36 511 participants (mean ± SD age of 57.9 ± 13.3 years, 55.4% female), with a mean follow-up of 10.2 ± 1.3 years, 1366 developed HF (incidence rate of 3.66 per 1000 participant years). Out of the 38 relevant clinical variables assessed, we identified 12 (atrial fibrillation being the strongest) that independently predicted an HF event. The final model demonstrated good discrimination (C statistics = 0.904) and calibration, was stable in internal validation, and performed well compared with existing risk scores. The model identified that, at enrolment, 31 391 (86%), 2386 (7%), 1246 (3%), and 1488 (4%) had low, low-intermediate, high-intermediate, and high 10-year HF risk, respectively., Conclusions: Twelve clinical variables independently predicted 10-year HF risk. The model may serve well as the foundation of a practical, online risk score for HF in general practice., Trial Registration: ClinicalTrials.gov Identifier: NCT04648852., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: We studied associations between the burden of health problems and athlete burnout in a population of athletes from Norwegian Sport Academy High Schools., Methods: This is a mixed prospective/retrospective cohort study. We included 210 athletes, 135 boys and 75 girls, from endurance, technical and team sports. We used the Oslo Sports Trauma Centres Questionnaire for Health Problems to collect 124 weeks of health data. During the first 26 weeks, athletes reported the health data prospectively using a smartphone app. For the following 98 weeks, we collected health data by interviewing athletes at the end of their third year in Sport Academy High School. At the time of the interview, the athletes also completed a web-based questionnaire, including the Athlete Burnout Questionnaire and covering social relations in sports and school, coach relations and living conditions., Results: A greater burden of health problems was associated with a higher score for athlete burnout (B: 0.16, 95% CI 0.09 to 0.22, p<0.001). In a multivariable model, this was true for both illnesses (B: 0.21, 95% CI 0.10 to 0.32, p<0.001), acute injuries (B: 0.16, 95% CI 0.04 to 0.27, p=0.007) and overuse injuries (B: 0.10, 95% CI 0.002 to 0.18, p=0.011). This was also true in gender and sports category subgroups. The coach having a high influence on training week was associated with a lower score for athlete burnout., Conclusion: A greater burden of health problems was associated with greater symptoms of athlete burnout in athletes attending Sport Academy High Schools., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mild or asymptomatic disease is now the dominating presentation of primary hyperparathyroidism (PHPT). However, bone involvement with decreased bone mineral density (BMD) and an increased risk of fractures has been demonstrated. Indications for parathyroidectomy (PTX) in mild PHPT have been debated for years. There is a need of long-term randomized studies comparing PTX with observation without intervention (OBS). Here, we present bone health data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), a randomized controlled trial, comparing PTX to OBS. This study included 191 patients (96 OBS/95 PTX), and 129 patients (64 OBS/65 PTX) were followed for 10 years to the end of study (EOS). BMD was measured with dual-energy X-ray absorptiometry (DXA), peripheral fractures were noted, and spine radiographs were obtained for vertebral fracture assessment. There was a significant treatment effect of PTX on BMD compared with OBS for all analyzed compartments, most explicit for the lumbar spine (LS) and femoral neck (FN) (p < 0.001). The mean changes in T-score from baseline to 10 years were from 0.41 for radius 33% (Rad33) to 0.58 for LS greater in the PTX group than in the OBS group. There was a significant decrease in BMD for all compartments in the OBS group, most pronounced for FN, Rad33, and ultradistal radius (UDR) (p < 0.001). Even though there was a significant treatment effect of PTX compared with OBS, there was only a significant increase in BMD over time for LS (p < 0.001). We found no difference between groups in fracture frequency in the 10-year cohort, neither with modified intention-to-treat (mITT) analysis nor per protocol analysis. Because BMD is only a surrogate endpoint of bone health and PTX did not reduce fracture risk, observation could be considered a safe option for many patients with mild PHPT regarding bone health in a 10-year perspective. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Objective: To investigate whether high-sensitivity cardiac troponin T (hsTnT) correlates to markers of disease activity in inflammatory arthritis (IA), and whether antirheumatic treatment influences hsTnT levels., Methods: We assessed 115 patients with active IA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosing spondylitis) before and after using methotrexate (MTX) alone or tumor necrosis factor inhibitor (TNFi) with or without MTX co-medication (TNFi±MTX). All patients starting with TNFi had been previously unsuccessfully treated with MTX monotherapy. HsTnT (measured in serum by electro-chemiluminescence immunoassay (Roche Elecsys® Troponin T- high-sensitivity)), and other clinical and laboratory parameters were evaluated at baseline, and after 6 weeks and 6 months of treatment., Results: Of markers of disease activity, baseline levels of hsTnT positively correlated with Physicians' Global Assessment Score of disease activity in the total patient cohort (p = 0.039). In RA group, hsTnT positively correlated with swollen joints, Disease Activity Score for 28 joints with ESR and serum tumor necrosis factor levels (p = 0.025, p = 0.008, p = 0.01, respectively). Median hsTnT at baseline was 5.0 ng/L, and did not change significantly at 6-week visit (6.0 ng/L, p = 0.37) and 6-month visit (6.0 ng/L, p = 0.18) with either antirheumatic therapy., Conclusions: HsTnT levels were associated with inflammatory markers for IA disease activity. However, while inflammatory markers significantly improved after antirheumatic treatment, hsTnT did not change during the 6-month follow-up period., Competing Interests: The authors have declared that no competing interests exist. We confirm that AbbVie does not alter our adherence to all PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Nguyen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Weight loss failure or weight regain may occur after Roux-en-Y gastric bypass (RYGB). Revisional surgery includes distalization. However, few studies have looked at the associations between the total alimentary limb length (TALL) and weight loss outcomes, none with long-term results., Objectives: Peri- and postoperative outcomes were assessed after employing TALL of either 250 cm or 300 cm in the failed RYGB., Methods: This study is a retrospective cohort analysis of 90 patients that underwent laparoscopic distalization between January 2006 and January 2016 due to failed RYBG. The index RYGB was modified to TALL of 250 cm (n = 48) or of 300 cm (n = 42) which entailed elongating the bilio-pancreatic limb (BPL) and transposing the Roux limb (RL) to a common limb (CL) of 100 cm and 150 cm, respectively. Long-term weight loss outcomes along with nutritional and vitamin status were analyzed., Results: Preoperative BMI at distalization was 38.6 kg/m 2 . After 8 years, excess weight loss (EWL) was 61.8%. No differences between the two groups were seen in weight loss outcomes or early surgical complication rates (6.7%). However, more vitamin and nutritional deficiencies were present in the TALL 250-cm group (50.0% and 35.4%, respectively) versus the TALL 300-cm group (33.3% and 14.3% respectively), which led to laparoscopic revision in 27 patients by lengthening the TALL with 100 cm. Patients with weight regain after index RYGB had in average 59.9% higher EWL than patients with EWL failure., Conclusion: Distalization of the failed RYGBP is safe and effective, but TALL should not be shorter than 300 cm (and CL 150 cm) due to high rates of malnutrition. Adequate supplementation and long-term follow-up are mandatory to prevent serious malnutrition., (© 2022. The Author(s).)

Objective: We aimed to describe post-acute sequelae of SARS-CoV-2 infection (PASC) related symptoms 3-15 months after a positive test in SARS-CoV-2 unvaccinated and vaccinated participants with a breakthrough infection., Methods: Participants of the Norwegian COVID-19 cohort, without a positive SARS-CoV-2 test, completed a questionnaire about PASC-related symptoms between November 2020 and January 2021. About a year later, a second questionnaire (which also included the Everyday Memory Questionnaire [EMQ]-13) was completed by the same participants, most still without a positive SARS-CoV-2 test, but also by unvaccinated and vaccinated participants with a positive test 3-15 months before the questionnaire. Laboratory-confirmed SARS-CoV-2 status (positive or negative swab test determined by reverse transcriptase quantitative polymerase chain reaction) at the time of completing the questionnaire was ascertained from the Mandatory Norwegian Surveillance System for Communicable Diseases., Results: No differences were found in the self-reported PASC symptoms, dyspnea, fatigue, smell/taste changes, concentration problems, or the EMQ-13 score between unvaccinated and vaccinated participants 3-15 months after the positive test. Fewer memory problems were reported among vaccinated than unvaccinated participants., Conclusion: SARS-CoV-2 vaccines offer minor protection against PASC symptoms, although fewer memory problems were reported among the vaccinated than the unvaccinated participants., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Spondyloarthropathies (SpA) are associated with increased cardiovascular risk. Among possible mechanisms is the dysfunction of serum lipoproteins in regulating cell cholesterol homeostasis. Cholesterol efflux capacity (CEC)-the atheroprotective ability of HDL (high density lipoproteins) to accept cholesterol from macrophages-might predict cardiovascular disease independently of HDL-cholesterol levels. We aimed at evaluating modifications of CEC and of the atherogenic cholesterol loading capacity (CLC) of serum lipoproteins in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) following anti-rheumatic treatment. A total of 62 SpA patients (37 PsA and 25 AS) were evaluated before and after treatment with tumor necrosis factor inhibitor and/or methotrexate. CEC and CLC were measured by radioisotopic and fluorometric techniques, respectively. Endothelial function was assessed by finger plethysmography (Endopat). In the whole SpA group, total and HDL-cholesterol increased after treatment, while lipoprotein(a) decreased and CLC was unchanged. Treatment was associated with increased Scavenger Receptor class B type I (SR-BI)-mediated CEC in the AS group. SR-BI- and ABCG1-mediated CEC were negatively associated with inflammatory parameters and positively related to coffee consumption. SR-BI CEC and CLC were positively and negatively associated with endothelial function, respectively. Our pilot study suggests that anti-rheumatic treatment is associated with favorable modulation of lipoprotein quality and function in SpA, particularly in AS, in spite of the induced increase in total cholesterol levels. If confirmed in a larger population, this might represent an atheroprotective benefit beyond what is reflected by conventional serum lipid profile.

Background: Oxytocin can stimulate release of myocardial biomarkers troponin I and T, prolong QTc and induce ST-depression., Objective: To explore cardiac changes after either intravenous carbetocin or oxytocin., Study Design: Exploratory phase 4 randomised controlled trial., Setting: Obstetrics units of Oslo University Hospital, Norway between September 2015 and May 2018., Participants: Forty healthy, singleton pregnant women aged 18 to 50 years at gestational age at least 36 weeks with a planned caesarean delivery., Interventions: Participants were randomised to receive either oxytocin 2.5 IU or carbetocin 100 μg immediately after delivery., Main Outcome Measures: The primary endpoint was the assessment of troponin I within 48 h of study drug administration. Troponin I and T, and creatine kinase myocardial band assessments were measured before spinal anaesthesia (baseline), and again at 4, 10 and 24 h after delivery. QTc, ST-depression and relative increase in heart rate were recorded from start of study drug administration to 10 min after delivery. All adverse events were monitored., Results: Compared with the carbetocin group, higher troponin I levels were observed in the oxytocin group at 4 h and 10 h after delivery. For both treatment groups, an increase from baseline in troponin I and T was most pronounced at 10 h after delivery, and it had begun to decline by 24 h. QTc increased with time after administration of both study drugs, with a mean maximum increase of 10.4 ms observed at 9 min (P   <  0.001). No statistical differences were observed in QTc ( P  = 0.13) or ST-depression ( P  = 0.11) between the treatment groups., Conclusions: Oxytocin 2.5 IU and carbetocin 100 μg caused a similar increase in QTc. The trial was underpowered with regards to ST-depression and the release of myocardial biomarkers and these warrant further investigation. Data from this trial will inform a larger phase 4 trial to determine potential drug differences in troponin release., Trial Registration: ClinicalTrials.gov Identifier: NCT02528136., (Copyright © 2022 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Objective. In patients with chest pain, exercise stress test has a moderate accuracy for coronary artery disease (CAD). Adding a reliable cardiac biomarker to the exercise test could potentially improve the precision of the test. We investigated circulating NT-proBNP levels before and during exercise stress test in patients with and without angiographically verified CAD. We hypothesized that NT-proBNP would give an additive diagnostic value to the exercise stress test. Methods . In patients presenting with symptoms of stable CAD, venous blood samples were taken at rest and within 5 min of termination of a maximal stress test on a bicycle ergometer. All study participants underwent coronary angiography. Significant CAD was defined as ≥75% stenosis in one or more segments of the coronary arteries. Results . Of the 297 participants, significant CAD was found in 111 (37%) patients. Resting levels of NT-proBNP were significantly higher in patients with CAD compared with patients without CAD (74.18 vs. 56.03 ng/L), p  = .005. During exercise, NT-proBNP levels increased in the total population ( p  < .001). The rise was, however, not significantly different between the two groups (8.24 vs. 8.51 ng/L), p  = .700. Combining resting NT-proBNP with positive exercise stress test was superior to exercise test alone in predicting CAD, AUC = 0.68 vs. 0.64. Conclusion . Exercise-induced change in circulating NT-proBNP could not distinguish between patients with or without CAD. However, resting levels of NT-proBNP were significantly higher in patients with CAD than those without CAD.

Purpose: To map the current practice of handling missing data in the field of training load and injury risk and to determine how missing data in training load should be handled., Methods: A systematic review of the training load and injury risk literature was performed to determine how missing data are reported and handled. We ran simulations to compare the accuracy of modelling a predetermined relationship between training load and injury risk following handling missing data with different methods. The simulations were based on a Norwegian Premier League men's football dataset (n = 39). Internal training load was measured with the session Rating of Perceived Exertion (sRPE). External training load was the total distance covered measured by a global positioning systems (GPS) device., Results: Only 37 (34%) of 108 studies reported whether training load had any missing observations. Multiple Imputation using Predicted Mean Matching was the best method of handling missing data across multiple scenarios., Conclusion: Studies of training load and injury risk should report the extent of missing data, and how they are handled. Multiple Imputation with Predicted Mean Matching should be used when imputing sRPE and GPS variables.

Background: Poor statin adherence remains a public health concern associated with adverse outcomes. We evaluated the use of pharmacokinetic measurements to monitor adherence to simvastatin in patients with coronary heart disease (CHD)., Methods: Eighteen patients with CHD taking an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5), or 80 mg (n = 6) were examined at steady-state pharmacokinetics. Ten patients were instructed to interrupt simvastatin dosing and return for blood sampling for the subsequent 3 days. Dose-normalized plasma concentrations of simvastatin lactone and simvastatin acid and the sum of the 2 were evaluated to discriminate between adherent dosing and dose omission. Bioanalytical quantification was performed using liquid chromatography-tandem mass spectrometry., Results: A simvastatin acid cutoff of 1.0 × 10 -2 nmol -1 ·L -1 ·mg -1 identified 100% of those omitting 2 doses and 60% of those omitting a single dose. Simvastatin acid showed superior ability to discriminate dose omission, as well as the best agreement between samples handled at ambient and cool temperatures (median deviation 3.5%; interquartile range -2.5% to 13%). The cutoff for a morning dose schedule, with a similar ability to discriminate, was estimated at 2.0 × 10 -3 nmol -1 ·L -1 ·mg -1 ., Conclusions: The present method discriminated between adherence and reduced adherence to simvastatin therapy in patients with CHD. Sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurement of simvastatin acid in a blood sample, according to defined cutoff values. Further studies validating the cutoff value and utility for clinical application are encouraged., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The joint associations of total and intensity-specific physical activity with obesity in relation to all-cause mortality risk are unclear., Methods: We included 34 492 adults (72% women, median age 62.1 years, 2034 deaths during follow-up) in a harmonised meta-analysis of eight population-based prospective cohort studies with mean follow-up ranging from 6.0 to 14.5 years. Standard body mass index categories were cross-classified with sample tertiles of device-measured total, light-to-vigorous and moderate-to-vigorous physical activity and sedentary time. In five cohorts with waist circumference available, high and low waist circumference was combined with tertiles of moderate-to-vigorous physical activity., Results: There was an inverse dose-response relationship between higher levels of total and intensity-specific physical activity and mortality risk in those who were normal weight and overweight. In individuals with obesity, the inverse dose-response relationship was only observed for total physical activity. Similarly, lower levels of sedentary time were associated with lower mortality risk in normal weight and overweight individuals but there was no association between sedentary time and risk of mortality in those who were obese. Compared with the obese-low total physical activity reference, the HRs were 0.59 (95% CI 0.44 to 0.79) for normal weight-high total activity and 0.67 (95% CI 0.48 to 0.94) for obese-high total activity. In contrast, normal weight-low total physical activity was associated with a higher risk of mortality compared with the obese-low total physical activity reference (1.28; 95% CI 0.99 to 1.67)., Conclusions: Higher levels of physical activity were associated with lower risk of mortality irrespective of weight status. Compared with obesity-low physical activity, there was no survival benefit of being normal weight if physical activity levels were low., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The aim of this trial was to evaluate whether intravenous iron could provide benefit beyond transcatheter aortic valve implantation (TAVI) in iron-deficient patients with severe aortic stenosis., Methods and Results: In this randomised, placebo-controlled, double-blind, single-centre trial, we enrolled patients with severe aortic stenosis and iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with a transferrin saturation <20%) who were evaluated for TAVI. Patients were randomly assigned (1:1) to receive intravenous ferric derisomaltose or placebo ∼3 months before TAVI. The primary endpoint was the between-group, baseline-adjusted 6-min walk distance measured 3 months after TAVI. Secondary outcomes included quality of life, iron stores, hand grip strength, New York Heart Association (NYHA) class, and safety. Between January 2020 and September 2021, we randomised 74 patients to ferric derisomaltose and 75 patients to placebo. The modified intention-to-treat population comprised the 104 patients who completed the 6-min walk test at baseline and 3 months after successful TAVI. Iron stores were restored in 76% of the patients allocated to iron and 13% of the patients allocated to placebo (p < 0.001). There was no difference in the baseline-adjusted 6-min walk distance between the two treatment arms (p = 0.82). The number of serious adverse events, quality of life, hand grip strength, and NYHA class did not differ between the treatment arms., Conclusion: Treatment with intravenous iron did not provide clinical benefit beyond TAVI in iron-deficient patients with severe aortic stenosis., Clinical Trial Registration: ClinicalTrials.gov NCT04206228., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed., Objective: To examine the effect of PTX on mild PHPT with regard to mortality (primary end point) and key morbidities (secondary end point)., Design: Prospective randomized controlled trial. (ClinicalTrials.gov: NCT00522028)., Setting: Eight Scandinavian referral centers., Patients: From 1998 to 2005, 191 patients with mild PHPT were included., Intervention: Ninety-five patients were randomly assigned to PTX, and 96 were assigned to observation without intervention (OBS)., Measurements: Date and causes of death were obtained from the Swedish and Norwegian Cause of Death Registries 10 years after randomization and after an extended observation period lasting until 2018. Morbidity events were prospectively registered annually., Results: After 10 years, 15 patients had died (8 in the PTX group and 7 in the OBS group). Within the extended observation period, 44 deaths occurred, which were evenly distributed between groups (24 in the PTX group and 20 in the OBS group). A total of 101 morbidity events (cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones) were also similarly distributed between groups (52 in the PTX group and 49 in the OBS group). During the study, a total of 16 vertebral fractures occurred in 14 patients (7 in each group)., Limitation: During the study period, 23 patients in the PTX group and 27 in the OBS group withdrew., Conclusion: Parathyroidectomy does not appear to reduce morbidity or mortality in mild PHPT. Thus, no evidence of adverse effects of observation was seen for at least a decade with respect to mortality, fractures, cancer, cardiovascular and cerebrovascular events, or renal morbidities., Primary Funding Source: Swedish government, Norwegian Research Council, and South-Eastern Norway Regional Health Authority.

Objectives: Determine how to assess the cumulative effect of training load on the risk of injury or health problems in team sports., Methods: First, we performed a simulation based on a Norwegian Premier League male football dataset (n players=36). Training load was sampled from daily session rating of perceived exertion (sRPE). Different scenarios of the effect of sRPE on injury risk and the effect of relative sRPE on injury risk were simulated. These scenarios assumed that the probability of injury was the result of training load exposures over the previous 4 weeks. We compared seven different methods of modelling training load in their ability to model the simulated relationship. We then used the most accurate method, the distributed lag non-linear model (DLNM), to analyse data from Norwegian youth elite handball players (no. of players=205, no. of health problems=471) to illustrate how assessing the cumulative effect of training load can be done in practice., Results: DLNM was the only method that accurately modelled the simulated relationships between training load and injury risk. In the handball example, DLNM could show the cumulative effect of training load and how much training load affected health problem risk depending on the distance in time since the training load exposure., Conclusion: DLNM can be used to assess the cumulative effect of training load on injury risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The complement system plays an important role in pathophysiology of cardiovascular disease (CVD), and might be involved in accelerated atherogenesis in rheumatoid arthritis (RA). The role of complement activation in response to treatment, and in development of premature CVD in RA, is limited. Therefore, we examined the effects of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) on complement activation using soluble terminal complement complex (TCC) levels in RA; and assessed associations between TCC and inflammatory and cardiovascular biomarkers., Methods: We assessed 64 RA patients starting with MTX monotherapy (n = 34) or TNFi with or without MTX co-medication (TNFi±MTX, n = 30). ELISA was used to measure TCC in EDTA plasma. The patients were examined at baseline, after 6 weeks and 6 months of treatment., Results: Median TCC was 1.10 CAU/mL, and 57 (89%) patients had TCC above the estimated upper reference limit (<0.70). Compared to baseline, TCC levels were significantly lower at 6-week visit (0.85 CAU/mL, p<0.0001), without significant differences between the two treatment regimens. Notably, sustained reduction in TCC was only achieved after 6 months on TNFi±MTX (0.80 CAU/mL, p = 0.006). Reductions in TCC after treatment were related to decreased C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and interleukin 6, and increased levels of total, high and low-density lipoprotein cholesterol. Similarly, baseline TCC was significantly related to baseline CRP, ESR and interleukin 6. Patients with endothelial dysfunction had higher baseline TCC than those without (median 1.4 versus 1.0 CAU/mL, p = 0.023)., Conclusions: Patients with active RA had elevated TCC, indicating increased complement activation. TCC decreased with antirheumatic treatment already after 6 weeks. However, only treatment with TNFi±MTX led to sustained reduction in TCC during the 6-month follow-up period. RA patients with endothelial dysfunction had higher baseline TCC compared to those without, possibly reflecting involvement of complement in the atherosclerotic process in RA., Competing Interests: The authors have declared that no competing interests exist. We confirm that AbbVie does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Background: Mental health among young people in many countries, including Norway, seems to be deteriorating. Physical activity (PA) has been positively associated with mental health. However, methodological issues related to study design and measurement of PA and mental health outcomes currently limits our understanding of the relationship. The purpose of the present study is to explore the prospective relationship between objectively measured PA and mental health outcomes. More specifically, volume (total PA), intensity (moderate-to-vigorous PA [MVPA]) and sedentary behaviour (SED) were explored in relation to mental health problems (MHP) and mental wellbeing (MWB)., Methods: Data from 599 adolescents (54.4% female, mean age at baseline ±SD 13.3 ± 0.3 years) were collected annually during their 3 years (T1, T2 and T3) at lower secondary school. PA was measured using accelerometry. MWB was measured using the 'Warwick-Edinburgh Mental Wellbeing Scale' and MHP by the 'Strengths and Difficulties Questionnaire'. Multiple linear regression was performed to explore relationships between changes in PA/SED (between T1-T3) and MWB/MHP (at T3). The term 'movement categories' was used to refer to components on the movement continuum and includes volume (total PA), intensity (MVPA) and SED., Results: Among boys, any increase in SED was positively associated with MWB (β = 0.05, 95% CI: 0.01 to 0.10), whereas a small positive association between an increase in total PA (volume) and MWB was found among girls (β = 1.13, 95% CI: 0.05 to 2.21). There were no associations between changes in any movement categories [total PA (volume), MVPA, SED] and score on MHP at T3, neither for girls nor boys., Conclusion: This study provided no clear evidence of any association between change in volume or intensity of PA and MHP among an overall healthy adolescent study sample. There was, however, evidence of a relationship between increased SED and MWB among boys and increased volume of PA and MWB among girls. The relationship between movement categories and mental health may depend on the measurement used to assess both PA/SED and variables of mental health. Future research would be strengthened by researchers clarifying what construct of mental health is being used and measured., (© 2021. The Author(s).)

Background: The optimal surgical weight loss procedure for patients with a BMI of 50 kg/m2 or more is uncertain. This study compared distal Roux-en-Y gastric bypass (RYGB) with standard RYGB., Methods: In this double-blind RCT, patients aged 18-60 years with a BMI of 50-60 kg/m2 were allocated randomly to receive standard (150 cm alimentary, 50 cm biliopancreatic limb) or distal (150 cm common channel, 50 cm biliopancreatic limb) RYGB. The primary outcome (change in BMI at 2 years) has been reported previously. Secondary outcomes 5 years after surgery, such as weight loss, health-related quality of life, and nutritional outcomes are reported., Results: Between May 2011 and April 2013, 123 patients were randomized, 113 received an intervention, and 92 attended 5-year follow-up. Mean age was 40 (95 per cent c.i. 38 to 41) years and 73 patients (65 per cent) were women; 57 underwent standard RYGB and 56 distal RYGB. BMI was reduced by 15.1 (95 per cent c.i. 13.9 to 16.2) kg/m2 after standard and 15.7 (14.5 to 16.9) kg/m2 after distal RYGB; the between-group difference was -0.64 (-2.3 to 1.0) kg/m2 (P = 0.447). Total cholesterol, low-density lipoprotein cholesterol, and haemoglobin A1c levels declined more after distal than after standard RYGB. High-density lipoprotein cholesterol levels increased more after standard RYGB. Vitamin A and vitamin D levels were lower after distal RYGB. Changes in bone mineral density, resting metabolic rate, and total energy intake were comparable., Conclusion: Distal RYGB did not enable greater weight loss than standard RYGB. Differences in other outcomes favouring distal RYGB may not justify routine use of this procedure in patients with a BMI of 50-60 kg/m2. Registration number: NCT00821197 (http://www.clinicaltrials.gov).Presented in part as abstract to the IFSO (International Federation for the Surgery of Obesity and Metabolic disorders) conference, Madrid, Spain, August 2019., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background and Aims: We aimed to determine the relationship between statin adherence measured directly, and by self-report measures and serum cholesterol levels., Methods: Patients prescribed atorvastatin (N = 373) participated in a cross-sectional study 2-36 months after a coronary event. Self-reported adherence included statin adherence the past week, the 8-item Morisky medication adherence scale (MMAS-8), and the Gehi et al. adherence question. Atorvastatin was measured directly in spot blood plasma by a novel liquid chromatography tandem mass-spectrometry method discriminating adherence (0-1 doses omitted) and reduced adherence (≥2 doses omitted). Participants were unaware of the atorvastatin analyses at study participation., Results: Mean age was 63 (SD 9) years and 8% had reduced atorvastatin adherence according to the direct method. In patients classified with reduced adherence by the direct method, 40% reported reduced statin adherence, 32% reported reduced adherence with the MMAS-8 and 22% with the Gehi question. In those adherent by the direct method, 96% also reported high statin adherence, 95% reported high adherence on the MMAS-8 whereas 94% reported high adherence on the Gehi question. Cohen's kappa agreement score with the direct method was 0.4 for self-reported statin adherence, 0.3 for the Gehi question and 0.2 for the MMAS-8. Adherence determined by the direct method, self-reported statin adherence last week, and the Gehi question was inversely related to LDL-cholesterol levels with a p-value of <0.001, 0.001 and 0.004, respectively., Conclusions: Plasma-statin measurements reveal reduced adherence with higher sensitivity than self-report measures, relate to cholesterol levels, and may prove to be a useful tool to improve lipid management., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: Sleep apnea (SA) is highly prevalent in patients with atrial fibrillation (AF), and both conditions are associated with adverse cardiovascular outcomes. Objectives: To determine the effect of continuous positive airway pressure (CPAP) on AF burden. Methods: This open-label, parallel-group, randomized controlled trial included patients with paroxysmal AF and moderate to severe SA (apnea-hypopnea index ⩾15). A computerized system randomized eligible patients (1:1) to 5 months' treatment with CPAP plus usual care (CPAP, n  = 55) or usual care alone (control, n  = 54). The outcome assessment was blinded. The planned primary outcome was the difference between CPAP treatment and control groups in change of AF burden (percentage of time in AF) as measured by implantable loop recorder. Measurements and Main Results: A total of 579 patients with paroxysmal AF had respiratory polygraphy, of whom 244 (42%) had moderate to severe SA. Of these, 158 (65%) participated in the CPAP run-in period, of whom 39 (25%) patients did not tolerate the treatment. A total of 108 patients were available for the primary analysis. The mean time in AF decreased from 5.6% at baseline to 4.1% during the last 3 months of CPAP intervention and from 5.0% to 4.3% in the control group. The adjusted between-group difference at follow-up was -0.63 (95% confidence interval, -2.55 to 1.30) percentage points ( P  = 0.52). Seven serious adverse events (13%) occurred in the CPAP group, and two (4%) occurred in the control group. Conclusions: In patients with paroxysmal AF and SA, treatment with CPAP did not result in a statistically significant reduction in the burden of AF.Clinical trial registered with www.clinicaltrials.gov (NCT02727192).

Objectives: To determine whether the relationship between training load and injury risk is non-linear and investigate ways of handling non-linearity., Methods: We analysed daily training load and injury data from three cohorts: Norwegian elite U-19 football (n=81, 55% male, mean age 17 years (SD 1)), Norwegian Premier League football (n=36, 100% male, mean age 26 years (SD 4)) and elite youth handball (n=205, 36% male, mean age 17 years (SD 1)). The relationship between session rating of perceived exertion (sRPE) and probability of injury was estimated with restricted cubic splines in mixed-effects logistic regression models. Simulations were carried out to compare the ability of seven methods to model non-linear relationships, using visualisations, root-mean-squared error and coverage of prediction intervals as performance metrics., Results: No relationships were identified in the football cohorts; however, a J-shaped relationship was found between sRPE and the probability of injury on the same day for elite youth handball players (p<0.001). In the simulations, the only methods capable of non-linear modelling relationships were the quadratic model, fractional polynomials and restricted cubic splines., Conclusion: The relationship between training load and injury risk should be assumed to be non-linear. Future research should apply appropriate methods to account for non-linearity, such as fractional polynomials or restricted cubic splines. We propose a guide for which method(s) to use in a range of different situations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In patients with lumbar spinal stenosis and degenerative spondylolisthesis, it is uncertain whether decompression surgery alone is noninferior to decompression with instrumented fusion., Methods: We conducted an open-label, multicenter, noninferiority trial involving patients with symptomatic lumbar stenosis that had not responded to conservative management and who had single-level spondylolisthesis of 3 mm or more. Patients were randomly assigned in a 1:1 ratio to undergo decompression surgery (decompression-alone group) or decompression surgery with instrumented fusion (fusion group). The primary outcome was a reduction of at least 30% in the score on the Oswestry Disability Index (ODI; range, 0 to 100, with higher scores indicating more impairment) during the 2 years after surgery, with a noninferiority margin of -15 percentage points. Secondary outcomes included the mean change in the ODI score as well as scores on the Zurich Claudication Questionnaire, leg and back pain, the duration of surgery and length of hospital stay, and reoperation within 2 years., Results: The mean age of patients was approximately 66 years. Approximately 75% of the patients had leg pain for more than a year, and more than 80% had back pain for more than a year. The mean change from baseline to 2 years in the ODI score was -20.6 in the decompression-alone group and -21.3 in the fusion group (mean difference, 0.7; 95% confidence interval [CI], -2.8 to 4.3). In the modified intention-to-treat analysis, 95 of 133 patients (71.4%) in the decompression-alone group and 94 of 129 patients (72.9%) in the fusion group had a reduction of at least 30% in the ODI score (difference, -1.4 percentage points; 95% CI, -12.2 to 9.4), showing the noninferiority of decompression alone. In the per-protocol analysis, 80 of 106 patients (75.5%) and 83 of 110 patients (75.5%), respectively, had a reduction of at least 30% in the ODI score (difference, 0.0 percentage points; 95% CI, -11.4 to 11.4), showing noninferiority. The results for the secondary outcomes were generally in the same direction as those for the primary outcome. Successful fusion was achieved with certainty in 86 of 100 patients (86.0%) who had imaging available at 2 years. Reoperation was performed in 15 of 120 patients (12.5%) in the decompression-alone group and in 11 of 121 patients (9.1%) in the fusion group., Conclusions: In this trial involving patients who underwent surgery for degenerative lumbar spondylolisthesis, most of whom had symptoms for more than a year, decompression alone was noninferior to decompression with instrumented fusion over a period of 2 years. Reoperation occurred somewhat more often in the decompression-alone group than in the fusion group. (NORDSTEN-DS ClinicalTrials.gov number, NCT02051374.)., (Copyright © 2021 Massachusetts Medical Society.)

The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration., Competing Interests: The authors have declared that no competing interests exist.