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Aims: To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF)., Methods and Results: ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation., Conclusion: ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF., (© 2022 European Society of Cardiology.)

Purpose: The purpose of this study was to determine the learning curve for total operative time using a novel cutting guide positioning robotic assistant for total knee arthroplasty (raTKA). Additionally, we compared complications and final limb alignment between raTKA and manual TKA (mTKA), as well as accuracy to plan for raTKA cases., Methods: We performed a retrospective cohort study on a series of patients (n = 180) that underwent raTKA (n = 90) using the ROSA Total Knee System or mTKA (n = 90) by one of three high-volume (> 200 cases per year) orthopaedic surgeons between December 2019 and September 2020, with minimum three-month follow-up. To evaluate the learning curve surgical times and postoperative complications were reviewed., Results: The cumulative summation analysis for total operative time revealed a change point of 10, 6, and 11 cases for each of three surgeons, suggesting a rapid learning curve. There was a significant difference in total operative times between the learning raTKA and both the mastered raTKA and mTKA groups (p = 0.001) for all three surgeons combined. Postoperative complications were minimal in all groups. The proportion of outliers for the final hip-knee-ankle angle compared to planned was 5.2% (3/58) for the mastered raTKA compared to 24.1% (19/79) for mTKA (p = 0.003). The absolute mean difference between the validated and planned resections for all angles evaluated was < 1 degree for the mastered raTKA cases., Conclusion: As the digital age of medicine continues to develop, advanced technologies may disrupt the industry, but should not disrupt the care provided. This cutting guide positioning robotic system can be integrated relatively quickly with a rapid initial learning curve (6-11 cases) for operative times, similar 90-day complication rates, and improved component positioning compared to mTKA. Proficiency of the system requires additional analysis, but it can be expected to improve over time., Level of Evidence: Level III Retrospective Therapeutic Cohort Study., (© 2021. The Author(s).)

Biomarkers play a key role in the monitoring of disease progression. The time taken for an individual to reach a biomarker exceeding or lower than a meaningful threshold is often of interest. Due to the inherent variability of biomarkers, persistence criteria are sometimes included in the definitions of progression, such that only two consecutive measurements above or below the relevant threshold signal that "true" progression has occurred. In previous work, a novel approach was developed, which allowed estimation of the time to threshold using the parameters from a linear mixed model where the residual variance was assumed to be pure measurement error. In this paper, we extend this methodology so that serial correlation can be accommodated. Assuming that the Markov property holds and applying the chain rule of probabilities, we found that the probability of progression at each timepoint can be expressed simply as the product of conditional probabilities. The methodology is applied to a cohort of HIV positive individuals, where the time to reach a CD4 count threshold is estimated. The second application we present is based on a study on abdominal aortic aneurysms, where the time taken for an individual to reach a diameter exceeding 55 mm is studied. We observed that erroneously ignoring the residual correlation when it is strong may result in substantial overestimation of the time to threshold. The estimated probability of the biomarker reaching a threshold of interest, expected time to threshold, and confidence intervals are presented for selected patients in both applications., (© 2019 John Wiley & Sons, Ltd.)

Background: Obesity is a major risk factor for cardiovascular diseases. In this study, we aimed to investigate the maternal circulatory differences during pregnancy between obese and normal weight women., Materials and Methods: The functioning of the maternal circulation (arteries, veins, heart and body fluid) was assessed by ECG-Doppler ultrasound, impedance cardiography (ICG) and bio-impedance during pregnancy in obese women (BMI ≥30 kg/m 2 ) and normal weight, nonobese women (BMI 20-25 kg/m 2 ). In this observational study, 232 assessments were performed in the obese group, whereas 919 assessments were performed in the nonobese group., Results: Relative to nonobese women, the overall cardiovascular function in obese women during first and second trimester is consistent with a high volume/low-resistance circulation. In third trimester, cardiac output of obese women decreases from 9.2 (8.2-10.7) L/min to 8.5 (7.6-9.6) L/min (P = .037) whereas this is not true in the nonobese women (from 7.8 (7-8.5) L/min to 7.8 (6.8-8.9) L/min, P = .536). Simultaneously, the persistently lower peripheral vascular resistance in obese vs nonobese women disappears (880 (761-1060) dyn.sec/cm 5 vs 928 (780-1067)., Conclusions: The circulatory gestational adaptations between nonobese and obese women were generally similar. The findings in the third trimester suggest that a pregnancy in obese women start as a state of high volume/low resistance, gradually shifting to a volume overload with decrease of cardiac output and disappearance of low vascular resistance. This evolution makes obese women vulnerable for gestational hypertensive diseases., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Purpose: To assess the risk of femoral tunnel convergence in combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstructions. The hypothesis was that a more proximal and anterior orientation of the ALL femoral tunnel should reduce the risk of convergence with the ACL femoral tunnel., Methods: 15 fresh-frozen cadaver knees were examined. An anatomic ACL femoral tunnel was drilled arthroscopically in each specimen and ALL tunnels were made in two directions: (1) 0° coronal angulation and 20° axial angulation, (2) 30° coronal angulation and 30° axial angulation. Computed tomography scans were performed to investigate tunnel convergence and to measure the minimal distance between tunnels, tunnel length and the LFC width., Results: Tunnel convergence occurred in 20 of 30 cases (67%). Convergence was significantly reduced when tunnels were drilled at 30° coronal and 30° axial angulation (p < 0.05). The mean length of the ALL tunnel was 15.9 mm [95% CI (13.6; 18.1)] and was independent of ALL tunnel angulation. The mean minimal distance between the ALL and ACL tunnel was 3.1 mm [95% CI (2.1; 4.1)]. The odds ratio for tunnel convergence was 3.5 for small LFC, relative to large LFC (n.s.) CONCLUSION: A high risk of tunnel convergence was observed when performing combined ACL and ALL reconstructions. The clinical relevance of this work is that the occurrence of tunnel conflicts can be reduced by aiming the ALL tunnel in a more proximal and anterior direction. Surgeons should be aware of this, since tunnel convergence could jeopardize the ACL reconstruction and fixation.

Aims: Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes., Methods: The ADVOR trial is set up as a multicentre, randomized, double-blind, placebo-controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high-dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction (< 40% vs. ≥ 40%). The primary endpoint is successful decongestion with no more than trace oedema assessed on the third morning after hospital admission, with good diuretic efficacy defined as a urine output > 3.5 L during the first 30-48 h of decongestive treatment. Secondary endpoints include all-cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire., Conclusion: ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

In 1985-1986, a hepatitis B vaccination programme was conducted in a Belgian institution for the mentally handicapped. A group of 97 residents was followed up for 11 years in order to characterize the long-term persistence of hepatitis B antibodies after vaccination. This paper proposes the use of linear mixed-effects models to account for serial correlation and between-individual heterogeneity in the data, while adjusting the analysis for various individual characteristics and important risk factors in the response to vaccination. We propose several model building strategies and focus on the prediction of future levels of antibodies., (Copyright 2001 John Wiley & Sons, Ltd.)