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Contains fulltext : 252137.pdf (Publisher’s version ) (Open Access) BACKGROUND: Left atrial appendage occlusion (LAAO) provides an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). In patients with a long-term or permanent contraindication for OAC randomized controlled trial (RCT) data is lacking. STUDY OBJECTIVES: To assess the efficacy and safety of LAAO in AF patients who are ineligible to use OAC. The co-primary efficacy endpoint is (1) time to first occurrence of stroke (ischemic, hemorrhagic, or undetermined) and (2) time to first occurrence of the composite of stroke, transient ischemic attack (TIA), and systemic embolism (SE). The primary safety endpoint is the 30-day rate of peri-procedural complications. STUDY DESIGN: This is a multicenter, investigator-initiated, open-label, blinded endpoint (PROBE), superiority-driven RCT. Patients with AF, a CHA₂DS₂-VASc score ≥2 for men and ≥3 for women and a long-term or permanent contraindication for OAC will be randomized in a 2:1 fashion to the device- or control arm. Patients in the device arm will undergo percutaneous LAAO and will receive post-procedural dual antiplatelet therapy (DAPT) per protocol, while those in the control arm will continue their current treatment consisting of no antithrombotic therapy or (D)APT as deemed appropriate by the primary responsible physician. In this endpoint-driven trial design, assuming a 50% lower stroke risk of LAAO compared to conservative treatment, 609 patients will be followed for a minimum of 1 and a maximum of 5 years. Cost-effectiveness and budget impact analyses will be performed to allow decision-making on reimbursement of LAAO for the target population in the Netherlands. SUMMARY: The COMPARE LAAO trial will investigate the clinical superiority in preventing thromboembolic events and cost-effectiveness of LAAO in AF patients with a high thromboembolic risk and a contraindication for OAC use. NCT TRIAL NUMBER: NCT04676880.

Background and Aims Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC. Methods In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis. Results Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1–59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline. Conclusions Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

In many European societies, the demand for health and social care for people in vulnerable positions are increasing. Together with a lack of personal and growing societal care costs, it is warranted to look for innovative ways to better support people in vulnerable positions in their care. People in vulnerable positions often face challenges in the timely access to various forms of care they need, for example due an intellectual disability, autism spectrum disorder (ASD) or a mental disorder. This project examines the possibility of a virtual assistant to improve access to care for people in vulnerable positions. Innovative in this project is the study of whether and how a ‘sensitive’ virtual assistant can be developed, i.e., a virtual assistant that modifies to the different needs of the target group through adaptive and inclusive artificial intelligence technology. The sensitive virtual assistant will be developed through a design thinking method, in which 1) the current and desired experiences of the target group regarding their care and support are mapped, and 2) the sensitive virtual assistant's ability to address these needs and adapt its functionalities to different users will be explored. Interestingly, this study takes place in close collaboration with ‘citizen scientists’ who have a cognitive impairment such as intellectual disability or ASD. In this inclusive research trajectory, they ensure that the virtual assistant will fit the needs and lifeworld of the target population. This project is expected to generate theoretical, methodological and technological contributions to the field of chatbot research, citizen science and inclusive research.

IntroductionTotal mesorectal excision is the standard of care for rectal cancer, which can be performed using open, laparoscopic, robot-assisted and transanal technique. Large prospective (randomised controlled) trials comparing these techniques are lacking, do not take into account the learning curve and have short-term or long-term oncological results as their primary endpoint, without addressing quality of life, functional outcomes and cost-effectiveness. Comparative data with regard to these outcomes are necessary to identify the optimal minimally invasive technique and provide guidelines for clinical application.Methods and analysisThis trial will be a prospective observational multicentre cohort trial, aiming to compare laparoscopic, robot-assisted and transanal total mesorectal excision in adult patients with rectal cancer performed by experienced surgeons in dedicated centres. Data collection will be performed in collaboration with the prospective Dutch ColoRectal Audit and the Prospective Dutch ColoRectal Cancer Cohort. Quality of life at 1 year postoperatively will be the primary outcome. Functional outcomes, cost-effectiveness, short-term outcomes and long-term oncological outcomes will be the secondary outcomes. In total, 1200 patients will be enrolled over a period of 2 years in 26 dedicated centres in the Netherlands. The study is registered at https://www.trialregister.nl/9734 (NL9734).Ethics and disseminationData will be collected through collaborating parties, who already obtained approval by their medical ethical committee. Participants will be included in the trial after having signed informed consent. Results of this study will be disseminated to participating centres, patient organisations, (inter)national society meetings and peer-reviewed journals.

We investigated whether intrahepatic markers could predict response in chronic hepatitis B virus (HBV) patients treated with peg-interferon and adefovir for 48 weeks.Intrahepatic covalently closed circular DNA (cccDNA), total intrahepatic HBV DNA and the proportion of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) positive hepatocytes in 16 hepatitis B e antigen (HBeAg) positive and 24 HBeAg negative patients were measured at baseline and at end of treatment.Baseline intrahepatic markers were not associated with sustained virological response (SVR) defined as HBV DNA2000 IU/mL and persistent normal alanine aminotransferase levels at the end of follow-up (week 72). At end of treatment, intrahepatic cccDNA and total intrahepatic HBV DNA in HBeAg positive patients were significantly lower in patients with HBeAg seroconversion (P = 0.016 and P = 0.010) with positive predictive values (PPV) for SVR of 80% and 80%, respectively. In HBeAg negative patients, intrahepatic cccDNA and total intrahepatic HBV DNA had declined significantly at end of treatment (P = 0.035 and P = 0.041) and corresponding PPV for SVR was 73% and 82%. In HBeAg positive patients, median proportion of HBcAg positive hepatocytes declined significantly (P = 0.002) at end of treatment. In HBeAg negative patients, the proportion of HBsAg positive hepatocytes had declined significantly at end of treatment (P = 0.0009). Using HBsAg ≤ 7.5% as a limit, PPV for SVR in HBeAg negative patients was 83%.At end of treatment in HBeAg positive patients, intrahepatic cccDNA and total intrahepatic HBV DNA were predictive for SVR. In HBeAg negative patients a proportion of7.5% HBsAg positive hepatocytes at end of treatment was a strong predictor for SVR.

This paper describes how to estimate the prevalence of chronic diseases in a population using data from contact registrations in general practice with a limited time length. Instead of using only total numbers of observed patients adjusted for the length of the observation period, we propose the use of (i) the time of the first contact of patients, (ii) the joint total numbers of patients and contacts, and (iii) the sets of patients in distinct time intervals, to generate prevalence rate estimates. The three new prevalence rate estimators have been developed assuming either a homogeneous or a parameterized heterogeneous patient population. Systematic and stochastic components of the estimators have been analysed by cross-validation for five chronic diseases using data from the Dutch 'Study on Chronic Conditions'. The results show that the first two estimators work well for diseases with a relatively structured visiting behaviour, such as hypertension and diabetes mellitus, assuming a time-constant contact rate and homogeneous patient population. For diseases such as ischaemic heart disease, chronic non-specific respiratory diseases and osteoarthritis, that do not satisfy these assumptions, the methods generally result in underestimations.