Oral magnesium supplementation does not affect insulin sensitivity in people with insulin-treated type 2 diabetes and a low serum magnesium: a randomised controlled trial.

AIMS/HYPOTHESIS: Hypomagnesaemia has been associated with insulin resistance and an increased risk of type 2 diabetes. Whether magnesium supplementation improves insulin sensitivity in people with type 2 diabetes and a low serum magnesium level is unknown. METHODS: Using a randomised, double-blind (both participants and investigators were blinded to the participants' treatment sequences), placebo-controlled, crossover study design, we compared the effect of oral magnesium supplementation (15 mmol/day) for 6 weeks with that of matched placebo in individuals with insulin-treated type 2 diabetes (age ≥18 years, BMI 18-40 kg/m2, HbA1c <100 mmol/mol [11.3%], serum magnesium ≤0.79 mmol/l). Participants were recruited from the outpatient clinic and through advertisements. Randomisation to a treatment sequence order was done using a randomisation list. We used block randomisation and the two possible treatment sequences were evenly distributed among the trial population. The primary outcome was the mean glucose infusion rate during the final 30 min of a hyperinsulinaemic-euglycaemic clamp (i.e. M value). Secondary outcomes included variables of glucose control, insulin need, BP, lipid profile and hypomagnesaemia-related symptoms during follow-up. RESULTS: We recruited 14 participants (50% women, 100% White, mean ± SD age 67±6 years, BMI 31±5 kg/m2, HbA1c 58±9 mmol/mol [7.4±0.9%]) with insulin-treated type 2 diabetes. Magnesium supplementation increased both mean ± SEM serum magnesium level (0.75±0.02 vs 0.70±0.02 mmol/l, p=0.016) and urinary magnesium excretion (magnesium/creatinine ratio, 0.23±0.02 vs 0.15±0.02, p=0.005), as compared with placebo. The M value of the glucose clamp did not differ between the magnesium and placebo study arms (4.6±0.5 vs 4.4±0.6 mg kg-1 min-1, p=0.108). During the 6 weeks of treatment, continuous glucose monitoring outcomes, HbA1c, insulin dose, lipid profile and BP also did not differ, except for a lower HDL-cholesterol concentration after magnesium compared with placebo (1.14±0.08 vs 1.20±0.09 mmol/l, p=0.026). Symptoms potentially related to hypomagnesaemia were similar for both treatment arms. CONCLUSIONS/INTERPRETATION: Despite an albeit modest increase in serum magnesium concentration, oral magnesium supplementation does not improve insulin sensitivity in people with insulin-treated type 2 diabetes and low magnesium levels. TRIAL REGISTRATION: EudraCT number 2021-001243-27. FUNDING: This study was supported by a grant from the Dutch Diabetes Research Foundation (2017-81-014).

Effectiveness of aortic valve replacement in Heyde syndrome: a meta-analysis.

AIMS: Heyde syndrome is the co-occurrence of aortic stenosis, acquired von Willebrand syndrome, and gastrointestinal bleeding. Aortic valve replacement has been demonstrated to resolve all three associated disorders. A systematic review and meta-analysis were performed to obtain best estimates of the effect of aortic valve replacement on acquired von Willebrand syndrome and gastrointestinal bleeding. METHODS AND RESULTS: A literature search was performed to identify articles on Heyde syndrome and aortic valve replacement up to 25 October 2022. Primary outcomes were the proportion of patients with recovery of acquired von Willebrand syndrome within 24 h (T1), 24-72 h (T2), 3-21 days (T3), and 4 weeks to 2 years (T4) after aortic valve replacement and the proportion of patients with cessation of gastrointestinal bleeding. Pooled proportions and risk ratios were calculated using random-effects models. Thirty-three studies (32 observational studies and one randomized controlled trial) on acquired von Willebrand syndrome (n = 1054), and 11 observational studies on gastrointestinal bleeding (n = 300) were identified. One study reported on both associated disorders (n = 6). The pooled proportion of Heyde patients with acquired von Willebrand syndrome recovery was 86% (95% CI, 79%-91%) at T1, 90% (74%-96%) at T2, 92% (84%-96%) at T3, and 87% (67%-96%) at T4. The pooled proportion of Heyde patients with gastrointestinal bleeding cessation was 73% (62%-81%). Residual aortic valve disease was associated with lower recovery rates of acquired von Willebrand syndrome (RR 0.20; 0.05-0.72; P = 0.014) and gastrointestinal bleeding (RR 0.57; 0.40-0.81; P = 0.002). CONCLUSION: Aortic valve replacement is associated with rapid recovery of the bleeding diathesis in Heyde syndrome and gastrointestinal bleeding cessation. Residual valve disease compromises clinical benefits.

Rule-out of non-ST-segment elevation acute coronary syndrome by a single, pre-hospital troponin measurement: a randomized trial.

AIMS: Patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are routinely transferred to the emergency department (ED). A clinical risk score with point-of-care (POC) troponin measurement might enable ambulance paramedics to identify low-risk patients in whom ED evaluation is unnecessary. The aim was to assess safety and healthcare costs of a pre-hospital rule-out strategy using a POC troponin measurement in low-risk suspected NSTE-ACS patients. METHODS AND RESULTS: This investigator-initiated, randomized clinical trial was conducted in five ambulance regions in the Netherlands. Suspected NSTE-ACS patients with HEAR (History, ECG, Age, Risk factors) score ≤3 were randomized to pre-hospital rule-out with POC troponin measurement or direct transfer to the ED. The sample size calculation was based on the primary outcome of 30-day healthcare costs. Secondary outcome was safety, defined as 30-day major adverse cardiac events (MACE), consisting of ACS, unplanned revascularization or all-cause death. : A total of 863 participants were randomized. Healthcare costs were significantly lower in the pre-hospital strategy (€1349 ± €2051 vs. €1960 ± €1808) with a mean difference of €611 [95% confidence interval (CI): 353-869; P < 0.001]. In the total population, MACE were comparable between groups [3.9% (17/434) in pre-hospital strategy vs. 3.7% (16/429) in ED strategy; P = 0.89]. In the ruled-out ACS population, MACE were very low [0.5% (2/419) vs. 1.0% (4/417)], with a risk difference of -0.5% (95% CI -1.6%-0.7%; P = 0.41) in favour of the pre-hospital strategy. CONCLUSION: Pre-hospital rule-out of ACS with a POC troponin measurement in low-risk patients significantly reduces healthcare costs while incidence of MACE was low in both strategies. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT05466591 and International Clinical Trials Registry Platform id NTR 7346.

Upper extremity versus lower extremity for secondary access during transcatheter aortic valve implantation: rationale and design of the randomised TAVI XS trial.

BACKGROUND: During transcatheter aortic valve implantation (TAVI), secondary access is required for angiographic guidance and temporary pacing. The most commonly used secondary access sites are the femoral artery (angiographic guidance) and the femoral vein (temporary pacing). An upper extremity approach using the radial artery and an upper arm vein instead of the lower extremity approach using the femoral artery and femoral vein may reduce clinically relevant secondary access site-related bleeding complications, but robust evidence is lacking. TRIAL DESIGN: The TAVI XS trial is a multicentre, randomised, open-label clinical trial with blinded evaluation of endpoints. A total of 238 patients undergoing transfemoral TAVI will be included. The primary endpoint is the incidence of clinically relevant bleeding (i.e. Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding) of the randomised secondary access site (either diagnostic or pacemaker access, or both) within 30 days after TAVI. Secondary endpoints include time to mobilisation after TAVI, duration of hospitalisation, any BARC type 2, 3 or 5 bleeding, and early safety at 30 days according to Valve Academic Research Consortium­3 criteria. CONCLUSION: The TAVI XS trial is the first randomised trial comparing an upper extremity approach to a lower extremity approach with regard to clinically relevant secondary access site-related bleeding complications. The results of this trial will provide important insights into the safety and efficacy of an upper extremity approach in patients undergoing transfemoral TAVI.

No insulin degludec dose adjustment required after aerobic exercise for people with type 1 diabetes: the ADREM study.

AIMS/HYPOTHESIS: It is generally recommended to reduce basal insulin doses after exercise to reduce the risk of post-exercise nocturnal hypoglycaemia. Based on its long t½, it is unknown whether such adjustments are required or beneficial for insulin degludec. METHODS: The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was a randomised controlled, crossover study in which we compared 40% dose reduction (D40), or postponement and 20% dose reduction (D20-P), with no dose adjustment (CON) in adults with type 1 diabetes at elevated risk of hypoglycaemia, who performed a 45 min aerobic exercise test in the afternoon. All participants wore blinded continuous glucose monitors for 6 days, measuring the incidence of (nocturnal) hypoglycaemia and subsequent glucose profiles. RESULTS: We recruited 18 participants (six women, age 38 ± 13 years, HbA1c 56 ± 8 mmol/mol [7.3 ± 0.8%], mean ± SD). Time below range (i.e. glucose <3.9 mmol/l) the night after the exercise test was generally low and occurrence did not differ between the treatment regimens. During the subsequent whole day, time below range was lower for D40 compared with CON (median [IQR], 0 [0-23] vs 18 [0-55] min, p=0.043), without differences in the number of hypoglycaemic events. Time above range (i.e. glucose >10 mmol/l) was greater for D20-P vs CON (mean ± SEM, 584 ± 81 vs 364 ± 66 min, p=0.001) and D40 (385 ± 72 min, p=0.003). CONCLUSIONS/INTERPRETATION: Post-exercise adjustment of degludec does not mitigate the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Although reducing degludec reduced next-day time below range, this did not translate into fewer hypoglycaemic events, while postponing degludec should be avoided because of increased time above range. Altogether, these data do not support degludec dose adjustment after a single exercise bout. TRIAL REGISTRATION: EudraCT number 2019-004222-22 FUNDING: The study was funded by an unrestricted grant from Novo Nordisk, Denmark.

Exercise-induced release of cardiac troponin is attenuated with repeated bouts of exercise: impact of cardiovascular disease and risk factors.

Prolonged exercise can induce cardiac troponin release. As single bouts of exercise may protect against cardiac injury, we explored the hypothesis that the magnitude of exercise-induced release of troponin attenuates upon successive days of exercise. We also examined whether effects of successive exercise bouts differ between healthy participants and individuals with cardiovascular risk factors (CVRFs) and established cardiovascular disease (CVD). We examined cardiac troponin I (cTnI) concentrations from whole venous blood samples collected from the antecubital vein (10 mL) in 383 participants (61 ± 14 yr) at rest and immediately following four consecutive days of long-distance walking (30-50 km/day). Participants were classified as either healthy (n = 222), CVRF (n = 75), or CVD (n = 86). Baseline cTnI concentrations were significantly higher in participants with CVD and CVRF compared with healthy (P < 0.001). Exercise-induced elevations in cTnI were observed in all groups following all days of walking compared with baseline (P < 0.001). Tobit regression analysis on absolute cTnI concentrations revealed a significant day × group interaction (P = 0.04). Following day 1 of walking, post hoc analysis showed that exercise-induced elevations in cTnI attenuated on subsequent days in healthy and CVRF, but not in CVD. Odds ratios for incident cTnI concentrations above the upper reference limit were significantly higher compared with baseline on day 1 for healthy participants (4.90 [95% CI, 1.58-15.2]) and participants with CVD (14.9 [1.86-125]) and remained significantly higher than baseline on all subsequent days in CVD. The magnitude of postexercise cTnI concentrations following prolonged walking exercise significantly declines upon repeated days of exercise in healthy individuals and those with CVRF, whereas this decline is not present in patients with CVD.NEW & NOTEWORTHY We show the magnitude of postexercise cardiac troponin concentrations following prolonged walking exercise significantly declines upon repeated days of exercise in healthy individuals and those with cardiovascular risk factors, while this decline is not present in patients with established cardiovascular disease.

Handgrip exercise in patients scheduled for cardiac surgery to attenuate troponin release: a feasibility study.

Cardiac surgery, including surgical aortic valve repair (SAVR) and coronary artery bypass grafting (CABG), are associated with ischemia-reperfusion (I/R) injury. Single bouts of exercise, including handgrip exercise, may protect against I/R injury. This study explored 1) the feasibility of daily handgrip exercise in the week before SAVR and/or CABG and 2) its impact on cardiac I/R injury, measured as postoperative cardiac troponin-T (cTnT) release. Sixty-five patients undergoing elective SAVR and/or CABG were randomized to handgrip exercise + usual care (intervention, n = 33) or usual care alone (control, n = 32). Handgrip exercise consisted of daily 4 × 5-min handgrip exercise (30% maximal voluntary contraction) for 2-7 days before cardiac surgery. Feasibility was assessed using validated questionnaires. Postoperative cTnT release was assessed at 0, 6, 12, 18, and 24 h [primary outcome area under the curve (cTnTAUC)]. Most patients (93%) adhered to handgrip exercise and 77% was satisfied with this intervention. Handgrip exercise was associated with lower cTnTAUC (402,943 ± 225,206 vs. 473,300 ± 232,682 ng · min/L), which is suggestive of a medium effect size (Cohen's d 0.31), and lower cTnTpeak (313 [190-623] vs. 379 [254-699] ng/L) compared with controls. We found that preoperative handgrip exercise is safe and feasible for patients scheduled for SAVR and/or CABG and is associated with a medium effect size to reduce postoperative cardiac I/R injury. This warrants future studies to assess the potential clinical impact of exercise protocols before cardiac surgery.NEW & NOTEWORTHY Daily handgrip exercise in the week before elective cardiac surgery is safe and feasible. Handgrip exercise is associated with a medium effect size for less troponin-T release. Future larger-sized studies are warranted to explore the impact of (handgrip) exercise prior to cardiac surgery on clinical outcomes and direct patient benefits.

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction.

Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.

Editor's Choice - Therapeutic Options and Outcomes in Midaortic Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: Midaortic syndrome (MAS) is narrowing of the distal thoracic and or abdominal aorta with congenital, inflammatory, or idiopathic aetiology. If left untreated, the prognosis is poor due to hypertensive complications. Follow up data after treatment are sparse, contrary to aortic coarctation. This study aimed to investigate hypertension during follow up after medical, endovascular, and surgical therapy in juveniles and adults. DATA SOURCES: A meta-analysis of case series and reports was performed, focusing on the incidence of hypertension during the follow up of juvenile (i.e., age 0-17 years) and adult MAS patients after medical, endovascular, or surgical therapy. REVIEW METHODS: Search queries were performed in PubMed, Embase, and Web of Science, and eligible articles underwent quality control. Descriptive statistics were reported based on available data, and individual patient data meta-analyses were performed using a one stage approach, accounting for clustering by case series or decades of reporting for case reports. For the meta-analysis, missing outcome and aetiology data were multiply imputed. RESULTS: The number of juveniles and adults who underwent endovascular therapy (33.7% vs. 27.3%; p = .42) and surgery (52.2% vs. 58.0%; p = .46) was similar. At baseline, 92.4% of juveniles and 87.5% of adults were hypertensive, decreasing to 23.2% and 24.1% during a follow up of 23 months (juveniles) and 18 months (adults), respectively. More hypertension was found compared with surgery in juveniles after endovascular therapy (38.1% vs. 10.8%; p = .020). Meta-analysis also demonstrated a trend for hypertension after endovascular therapy in juveniles, whereas hypertension was more prevalent following surgery in adults compared with endovascular therapy or medication. CONCLUSION: This review and meta-analysis investigated therapeutic options for MAS in juveniles and adults. It found that complications and hypertension during follow up were more common in juveniles after endovascular treatment, whereas surgery in adults was associated with more hypertension.

Timing of cardiac surgery during pregnancy: a patient-level meta-analysis.

AIMS: To investigate the association between the timing of cardiac surgery during pregnancy and both maternal and foetal outcomes. METHODS AND RESULTS: Studies published up to 6 February 2021 on maternal and/or foetal mortality after cardiac surgery during pregnancy that included individual patient data were identified. Maternal and foetal mortality was analysed per trimester for the total population and stratified for patients who underwent caesarean section (CS) prior to cardiac surgery (Caesarean section (CaeSe) group) vs. patients who did not (Cardiac surgery (CarSu) group). Multivariable logistic regression analysis was performed to evaluate predictors of both maternal and foetal mortality. In total, 179 studies were identified including 386 patients of which 120 underwent CS prior to cardiac surgery. Maternal mortality was 7.3% and did not differ significantly among trimesters of pregnancy (P = 0.292) nor between subgroup CaeSe and CarSu (P = 0.671). Overall foetal mortality was 26.5% and was lowest when cardiac surgery was performed during the third trimester (10.3%, P < 0.01). CS prior to surgery was significantly associated with a reduced risk of foetal mortality in a multivariable model [odds ratio 0.19, 95% confidence interval [0.06-0.56)]. Trimester was not identified as an independent predictor for foetal nor maternal mortality. CONCLUSION: Maternal mortality after cardiac surgery during pregnancy is not associated with the trimester of pregnancy. Cardiac surgery is associated with high foetal mortality but is significantly lower in women where CS is performed prior to cardiac surgery. When the foetus is viable, CS prior to cardiac surgery might be safe. When CS is not feasible, trimester stage does not seem to influence foetal mortality.

Screening and prevalence of cardiac abnormalities on electro- and echocardiography in a large cohort of patients with mitochondrial disease.

BACKGROUND: In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current guidelines as structural cardiac abnormalities are frequent. This study aims to evaluate the cardiac phenotype of a large Dutch cohort of patients with MD and investigates whether ECG alone is sufficient for predicting structural cardiac abnormalities on TTE. METHODS: In this retrospective cohort study, genetically confirmed MD patients >18 years old with an available ECG and TTE were included. Newcastle Mitochondrial Disease Scale for Adults (NMDAS) scores were assessed. ECG's were evaluated for rhythm and conduction disorders, voltage criteria for left ventricular hypertrophy (LVH) and repolarization disorders. Echocardiographic evaluation included left and right ventricular volumes and function, and presence of LVH or concentric remodeling. RESULTS: In total, 200 MD patients were included with a median age of 45 years (IQR; 37-57) of whom 36% were male. Of all MD patients, 35% had abnormalities on ECG and 61% on TTE. Most frequent structural cardiac abnormalities on TTE were: global longitudinal strain > - 18% (54%), concentric remodeling (27%) and left ventricular (LV) ejection fraction <52% (14%). Patients with maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) had the highest prevalence of ECG abnormalities (50% and 47%). TTE abnormalities were most prevalent in patients with MIDD (75%), followed by mitochondrial myopathy (MM) (55%), MELAS (47%) and Mitochondrial Epilepsy and Ragged Red Fibers (MERRF) (47%). MD patients with a high disease severity (NMDAS ≥21) had a higher prevalence of ECG abnormalities (44%, p = 0.039) and structural cardiac abnormalities (72%, p = 0.004) compared to patients with a NMDAS score of 11-20 and ≤ 10 (ECG: 34% and 19%; TTE: 63% and 39%). ECG abnormalities had a positive predictive value of 74% and a negative predictive value of 53% for structural cardiac abnormalities on TTE. CONCLUSION: MD patients frequently have cardiac involvement especially patients with MIDD, MELAS or high NMDAS score. ECG as sole screening parameter is insufficient to detect structural cardiac abnormalities.

Fluid REStriction in Heart Failure vs Liberal Fluid UPtake: Rationale and Design of the Randomized FRESH-UP Study.

AIMS: It is common practice for clinicians to advise fluid restriction in patients with heart failure (HF), but data from clinical trials are lacking. Moreover, fluid restriction is associated with thirst distress and may adversely impact quality of life (QoL). To address this gap in evidence, the Fluid REStriction in Heart failure vs liberal fluid UPtake (FRESH-UP) study was initiated. METHODS: The FRESH-UP study is a randomized, controlled, open-label, multicenter trial to investigate the effects of a 3-month period of liberal fluid intake vs fluid restriction (1500 mL/day) on QoL in outpatients with chronic HF (New York Heart Association Classes II--III). The primary aim is to assess the effect on QoL after 3 months using the Overall Summary Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Thirst distress, as assessed by the Thirst Distress Scale for patients with HF, KCCQ Clinical Summary Score, each of the KCCQ domains and clinically meaningful changes in these scores, the EQ-5D-5L, patient-reported fluid intake and safety (ie, death, HF hospitalizations) are secondary outcomes. The FRESH-UP study is registered at ClinicalTrials.gov (NCT04551729). CONCLUSION: The results of the FRESH-UP study will add substantially to the level of evidence concerning fluid management in chronic HF and may impact the QoL of these patients.

Multiple imputation of semi-continuous exposure variables that are categorized for analysis.

Semi-continuous variables are characterized by a point mass at one value and a continuous range of values for remaining observations. An example is alcohol consumption quantity, with a spike of zeros representing non-drinkers and positive values for drinkers. If multiple imputation is used to handle missing values for semi-continuous variables, it is unclear how this should be implemented within the standard approaches of fully conditional specification (FCS) and multivariate normal imputation (MVNI). This question is brought into focus by the use of categorized versions of semi-continuous exposure variables in analyses (eg, no drinking, drinking below binge level, binge drinking, heavy binge drinking), raising the question of how best to achieve congeniality between imputation and analysis models. We performed a simulation study comparing nine approaches for imputing semi-continuous exposures requiring categorization for analysis. Three methods imputed the categories directly: ordinal logistic regression, and imputation of binary indicator variables representing the categories using MVNI (with two variants). Six methods (predictive mean matching, zero-inflated binomial imputation, and two-part imputation methods with variants in FCS and MVNI) imputed the semi-continuous variable, with categories derived after imputation. The ordinal and zero-inflated binomial methods had good performance across most scenarios, while MVNI methods requiring rounding after imputation did not perform well. There were mixed results for predictive mean matching and the two-part methods, depending on whether the estimands were proportions or regression coefficients. The results highlight the need to consider the parameter of interest when selecting an imputation procedure.

Are park availability and satisfaction with neighbourhood parks associated with physical activity and time spent outdoors?

BACKGROUND: There is substantial scope for enhancing population health through increased park visits and active use of parks; however, a better understanding of factors that influence park visitation is needed. This cross-sectional study examined how parent-reported satisfaction and perceived availability of parks were associated with adults' physical activity and children's physical activity and time spent outdoors, and whether these associations were mediated by park visitation. METHODS: Self-reported surveys were completed by adults living within 5 km of two parks located in Melbourne, Australia. Participants reported their satisfaction with neighbourhood park quality, walking duration from home to the nearest park, and park visitation in the past 7 days. Participants with a child aged 2-15 years also answered similar questions in relation to their child. The primary outcome variable for adults was leisure-time physical activity (LTPA) and for children was proxy-reported time spent outside. The secondary outcome for adults was combined transportation and LTPA and for children (5-15 years) was the number of days physical activity recommendations were met in the past 7 days. RESULTS: Significant positive associations between park availability and park visitation in the past 7 days, and between park visitation and the outcome variables were observed among both adults (n = 1085, Mage = 48.9, SD 13.4) and children (n = 753, Mage = 8.8, SD = 3.7). The association between park satisfaction and park visitation was only significant among adults. Park visitation mediated associations between park availability and park satisfaction and the outcome variables among both adults and children. CONCLUSIONS: Improving park availability and users' satisfaction with parks may increase visitation and consequently increase physical activity and time spent outdoors.

Long-term efficacy and cost-effectiveness of blended cognitive behavior therapy for high fear of recurrence in breast, prostate and colorectal Cancer survivors: follow-up of the SWORD randomized controlled trial.

BACKGROUND: Blended cognitive behaviour therapy (bCBT) is an effective treatment for fear of cancer recurrence (FCR) in curatively-treated breast, colorectal and prostate cancer survivors with high FCR. However, long-term outcomes are unknown. This study investigated the long-term efficacy and cost-effectiveness of bCBT compared with care as usual (CAU). METHODS: Eighty-eight cancer survivors with high FCR (Cancer Worry Scale ≥14) were randomly assigned to bCBT (n = 45) or CAU (n = 43). Data were collected at baseline and at three, nine and fifteen months from baseline and analysed by modified intention-to-treat. Efficacy was investigated with linear mixed-effects models. Cost-effectiveness was investigated from a societal perspective by comparing costs with quality-adjusted life-years (QALYs). RESULTS: Participants who received bCBT reported significantly lower FCR compared with CAU (mean difference of - 1.787 [95% CI -3.251 to - 0.323, p = 0.017] at 15 months follow-up), and proportionally greater self-rated and clinically significant improvement at each follow-up measurement. Total QALYs were non-significantly different between conditions when adjusted for utility score baseline differences (0.984 compared to 0.957, p = 0.385), while total costs were €631 lower (95% CI -1737 to 2794, p = 0.587). Intervention costs of bCBT were €466. The incremental cost-effectiveness ratio amounted to an additional €2049 per QALY gained, with a 62% probability that bCBT is cost-effective at a willingness to pay (WTP) threshold of €20,000 per QALY. Results were confirmed in sensitivity analyses. CONCLUSIONS: bCBT for cancer survivors with FCR is clinically and statistically more effective than CAU on the long-term. In addition, bCBT is a relatively inexpensive intervention with similar costs and QALYs as CAU. TRIAL REGISTRATION: The RCT was registered in the Dutch National Trial Register ( NTR4423 ) on 12-Feb-2014. This abstract was previously presented at the International Psycho-Oncology Society conference of 2018 and published online. (Psycho-oncology, 27(S3):8-55; 2018).

Sample size calculation for stepped-wedge cluster-randomized trials with more than two levels of clustering.

BACKGROUND/AIMS: Power and sample size calculation formulas for stepped-wedge trials with two levels (subjects within clusters) are available. However, stepped-wedge trials with more than two levels are possible. An example is the CHANGE trial which randomizes nursing homes (level 4) consisting of nursing home wards (level 3) in which nurses (level 2) are observed with respect to their hand hygiene compliance during hand hygiene opportunities (level 1) in the care of patients. We provide power and sample size methods for such trials and illustrate these in the setting of the CHANGE trial. METHODS: We extend the original sample size methodology derived for stepped-wedge trials based on a random intercepts model, to accommodate more than two levels of clustering. We derive expressions that can be used to determine power and sample size for p levels of clustering in terms of the variances at each level or, alternatively, in terms of intracluster correlation coefficients. We consider different scenarios, depending on whether the same units in a particular level are repeatedly measured as a cohort sample or whether different units are measured cross-sectionally. RESULTS: A simple variance inflation factor is obtained that can be used to calculate power and sample size for continuous and by approximation for binary and rate outcomes. It is the product of (1) variance inflation due to the multilevel structure and (2) variance inflation due to the stepped-wedge manner of assigning interventions over time. Standard and non-standard designs (i.e. so-called "hybrid designs" and designs with more, less, or no data collection when the clusters are all in the control or are all in the intervention condition) are covered. CONCLUSIONS: The formulas derived enable power and sample size calculations for multilevel stepped-wedge trials. For the two-, three-, and four-level case of the standard stepped wedge, we provide programs to facilitate these calculations.

Comparison of methods for imputing limited-range variables: a simulation study.

BACKGROUND: Multiple imputation (MI) was developed as a method to enable valid inferences to be obtained in the presence of missing data rather than to re-create the missing values. Within the applied setting, it remains unclear how important it is that imputed values should be plausible for individual observations. One variable type for which MI may lead to implausible values is a limited-range variable, where imputed values may fall outside the observable range. The aim of this work was to compare methods for imputing limited-range variables, with a focus on those that restrict the range of the imputed values. METHODS: Using data from a study of adolescent health, we consider three variables based on responses to the General Health Questionnaire (GHQ), a tool for detecting minor psychiatric illness. These variables, based on different scoring methods for the GHQ, resulted in three continuous distributions with mild, moderate and severe positive skewness. In an otherwise complete dataset, we set 33% of the GHQ observations to missing completely at random or missing at random; repeating this process to create 1000 datasets with incomplete data for each scenario.For each dataset, we imputed values on the raw scale and following a zero-skewness log transformation using: univariate regression with no rounding; post-imputation rounding; truncated normal regression; and predictive mean matching. We estimated the marginal mean of the GHQ and the association between the GHQ and a fully observed binary outcome, comparing the results with complete data statistics. RESULTS: Imputation with no rounding performed well when applied to data on the raw scale. Post-imputation rounding and imputation using truncated normal regression produced higher marginal means than the complete data estimate when data had a moderate or severe skew, and this was associated with under-coverage of the complete data estimate. Predictive mean matching also produced under-coverage of the complete data estimate. For the estimate of association, all methods produced similar estimates to the complete data. CONCLUSIONS: For data with a limited range, multiple imputation using techniques that restrict the range of imputed values can result in biased estimates for the marginal mean when data are highly skewed.

Prediction of cardiovascular events in older patients with hypertension in primary care: a cohort study.

BACKGROUND: Accurate risk stratification identifying patients with hypertension at risk of future cardiovascular disease in primary care would be desirable. AIM: To investigate the association between elevated brain natriuretic peptide (BNP), left ventricular hypertrophy (LVH) on an electrocardiogram (ECG), and LVH on an echocardiogram and the development of cardiovascular events (CVEs), especially heart failure and all-cause mortality (ACM), in a primary care population with hypertension without symptoms of heart failure. DESIGN AND SETTING: A prospective cohort study in five Dutch general practices between 2010-2012 and 2020. METHOD: In total, 530 patients (aged 60-85 years) underwent laboratory testing, ECGs, and echocardiograms at baseline. The incidence of new CVEs and ACM at up to 9 years' follow-up was recorded by data extraction from the digital information systems. RESULTS: Among the 530 participants, 31 (5.8%) developed a coronary event, 44 (8.3%) a cerebrovascular accident, 53 (10.0%) atrial fibrillation, 23 (4.3%) heart failure, and 66 (12.5%) died. Cox regression analyses, adjusting for relevant Framingham covariates, showed that elevated BNP increased the risk of ACM, CVEs, and specifically heart failure independently by 44% (hazard ratio [HR] 1.44, 95% confidence interval [CI] = 1.07 to 1.94, P = -0.017), 45% (HR 1.45, 95% CI = 1.15 to 1.82, P = 0.002), and 288% (HR 3.88, 95% CI = 2.13 to 7.10, P<0.001), respectively. LVH on ECG increased the risk of ACM independently by 108% (HR 2.08, 95% CI = 1.14 to 3.81, P = 0.017). LVH either on an ECG and/or echocardiogram increased the risk of heart failure independently by 309% (HR 4.09, 95% CI = 1.34 to 12.49, P = 0.014). CONCLUSION: In primary care patients with hypertension, BNP seems to be an important marker predicting future CVEs, especially heart failure, as well as all-cause mortality.

Assessment of paravalvular regurgitation after transcatheter aortic valve replacement using 2D multi-velocity encoding and 4D flow cardiac magnetic resonance.

AIMS: To compare the novel 2D multi-velocity encoding (venc) and 4D flow acquisitions with the standard 2D flow acquisition for the assessment of paravalvular regurgitation (PVR) after transcatheter aortic valve replacement (TAVR) using cardiac magnetic resonance (CMR)-derived regurgitant fraction (RF). METHODS AND RESULTS: In this prospective study, patients underwent CMR 1 month after TAVR for the assessment of PVR, for which 2D multi-venc and 4D flow were used, in addition to standard 2D flow. Scatterplots and Bland-Altman plots were used to assess correlation and visualize agreement between techniques. Reproducibility of measurements was assessed with intraclass correlation coefficients. The study included 21 patients (mean age ± SD 80 ± 5 years, 9 men). The mean RF was 11.7 ± 10.0% when standard 2D flow was used, 10.6 ± 7.0% when 2D multi-venc flow was used, and 9.6 ± 7.3% when 4D flow was used. There was a very strong correlation between the RFs assessed with 2D multi-venc and standard 2D flow (r = 0.88, P < 0.001), and a strong correlation between the RFs assessed with 4D flow and standard 2D flow (r = 0.74, P < 0.001). Bland-Altman plots revealed no substantial bias between the RFs (2D multi-venc: 1.3%; 4D flow: 0.3%). Intra-observer and inter-observer reproducibility for 2D multi-venc flow were 0.98 and 0.97, respectively, and 0.92 and 0.90 for 4D flow, respectively. CONCLUSION: Two-dimensional multi-venc and 4D flow produce an accurate quantification of PVR after TAVR. The fast acquisition of the 2D multi-venc sequence and the free-breathing acquisition with retrospective plane selection of the 4D flow sequence provide useful advantages in clinical practice, especially in the frail TAVR population.

Effects of age on microvascular function in patients with normal coronary arteries.

BACKGROUND: It has been suggested that coronary microvascular function decreases with age, irrespective of the presence of epicardial atherosclerosis. AIMS: Our aim is to quantitatively investigate the effects of age on microvascular function in patients with normal coronary arteries. METHODS: In 314 patients with angina with no obstructive coronary artery disease (ANOCA), microcirculatory function was tested using the continuous thermodilution method. In 305 patients, the association between age and both resting and hyperaemic myocardial blood flow (Q), microvascular resistance (Rµ), absolute coronary flow reserve (CFR) and microvascular resistance reserve (MRR) was assessed. In addition, patients were divided into 3 groups to test for differences based on age quartiles (≤52 years [24.9%], 53-64 years [49.2%], ≥65 years [25.9%]). RESULTS: The mean age was 59±9 years with a range from 22 to 79 years. The mean resting Q (Qrest) was not different in the 3 age groups (88±34 mL/min, 82±29 mL/min, and 86±38 mL/min, R2=0.001; p=0.62). A trend towards a decreasing mean hyperaemic Q (Qmax) was observed with increasing age (223±79 mL/min, 209±84 mL/min, 200±80 mL/min, R2=0.010; p=0.083). The mean resting Rµ (Rµ,rest) were 1,204±460 Wood units (WU), 1,260±411 WU, and 1,289±455 WU (p=0.23). The mean hyperaemic Rµ (Rµ,hyp) increased significantly with advancing age (429±149 WU, 464±164 WU, 503±162 WU, R2=0.026; p=0.005). Consequently, MRR decreased with age (3.2±1.2, 3.1±1.0, 2.9±0.9; p=0.038). This trend was present in both the patients with (n=121) and without (n=184) coronary microvascular dysfunction (CMD). CONCLUSIONS: There is an age-dependent physiological increase in minimal microvascular resistance and decrease in microvascular function, which is represented by a decreased MRR and is independent of atherosclerosis. The age-dependent decrease in MRR was present in both patients with and without CMD and was most evident in patients with smooth coronary arteries.