Randomized Trial of Cholesterol Lowering With Evolocumab for Cardiac Allograft Vasculopathy in Heart Transplant Recipients.

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 one 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).

Ten-Year Outcomes Following Roux-en-Y Gastric Bypass vs Duodenal Switch for High Body Mass Index: A Randomized Clinical Trial.

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.

Bacterial growth in patients with low back pain and Modic changes: protocol of a multicentre, case-control biopsy study.

INTRODUCTION: Bacterial infection and Modic changes (MCs) as causes of low back pain (LBP) are debated. Results diverged between two randomised controlled trials examining the effect of amoxicillin with and without clavulanic acid versus placebo on patients with chronic LBP (cLBP) and MCs. Previous biopsy studies have been criticised with regard to methods, few patients and controls, and insufficient measures to minimise perioperative contamination. In this study, we minimise contamination risk, include a control group and optimise statistical power. The main aim is to compare bacterial growth between patients with and without MCs. METHODS AND ANALYSIS: This multicentre, case-control study examines disc and vertebral body biopsies of patients with cLBP. Cases have MCs at the level of tissue sampling, controls do not. Previously operated patients are included as a subgroup. Tissue is sampled before antibiotic prophylaxis with separate instruments. We will apply microbiological methods and histology on biopsies, and predefine criteria for significant bacterial growth, possible contamination and no growth. Microbiologists, surgeons and pathologist are blinded to allocation of case or control. Primary analysis assesses significant growth in MC1 versus controls and MC2 versus controls separately. Bacterial disc growth in previously operated patients, patients with large MCs and growth from the vertebral body in the fusion group are all considered exploratory analyses. ETHICS AND DISSEMINATION: The Regional Committees for Medical and Health Research Ethics in Norway (REC South East, reference number 2015/697) has approved the study. Study participation requires written informed consent. The study is registered at ClinicalTrials.gov (NCT03406624). Results will be disseminated in peer-reviewed journals, scientific conferences and patient fora. TRIAL REGISTRATION NUMBER: NCT03406624.

Causal inference did not detect any effect of jump load on knee complaints in elite men's volleyball.

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.

A new statistical approach to training load and injury risk: separating the acute from the chronic load.

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.

Validation of a novel direct method to determine reduced adherence to atorvastatin therapy.

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 Danish-Norwegian randomized trial on beta-blocker therapy after myocardial infarction: Design, rationale, and baseline characteristics.

AIM: 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. This 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 STEMI, and 84% had a normal LVEF. The primary endpoint is a composite of adjudicated recurrent MI, incident heart failure, coronary revascularization, ischemic stroke, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest. The primary safety endpoint includes a composite of recurrent MI, heart failure, 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.

Development of a tool to predict the risk of incident heart failure in a general population: the HUNT for HF risk score.

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.

Associations between health problems and athlete burnout: a cohort study in 210 adolescent elite athletes.

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.

High-sensitivity cardiac troponin T is associated with disease activity in patients with inflammatory arthritis.

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.

Positive Effect of Parathyroidectomy Compared to Observation on BMD in a Randomized Controlled Trial of Mild Primary Hyperparathyroidism.

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).

Failed Roux-en-Y Gastric Bypass-Long-Term Results of Distalization with Total Alimentary Limb Length of 250 or 300 cm.

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/m2. 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.

Post-acute symptoms 3-15 months after COVID-19 among unvaccinated and vaccinated individuals with a breakthrough infection.

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.

Effects of Antirheumatic Treatment on Cell Cholesterol Efflux and Loading Capacity of Serum Lipoproteins in Spondylarthropathies.

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.

Handling and reporting missing data in training load and injury risk research.

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.

Exploring cardiac effects after oxytocin 2.5 IU or carbetocin 100 µg: A randomised controlled trial in women undergoing planned caesarean delivery.

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.

Assessing the cumulative effect of long-term training load on the risk of injury in team sports.

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.

Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for transcatheter aortic valve implantation: results of the IIISAS randomised trial.

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.

Exercise-induced change in circulating NT-proBNP could not distinguish between patients with and without coronary artery disease: the CADENCE study.

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.