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Aims: In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown., Methods and Results: In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10-0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22-0.73; P = 0.002]., Conclusions: Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF., Study Registration: ClinicalTrials.gov Identifier: NCT02137187., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: To develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity., Methods: A machine learning approach was used to develop a model that can identify patients without disease progression. SSc patients included in the prospective Leiden SSc cohort and fulfilling the ACR/EULAR 2013 criteria were included. Disease progression was defined as progression in ≥1 organ system, and/or start of immunosuppression or death. Using elastic-net-regularisation, and including 90 independent clinical variables (100% complete), we trained the model on 75% and validated it on 25% of the patients, optimising on negative predictive value (NPV) to minimise the likelihood of missing progression. Probability cutoffs were identified for low and high risk for disease progression by expert assessment., Results: Of the 492 SSc patients (follow-up range: 2-10 years), disease progression during follow-up was observed in 52% (median time 4.9 years). Performance of the model in the test set showed an AUC-ROC of 0.66. Probability score cutoffs were defined: low risk for disease progression (<0.197, NPV:1.0; 29% of patients), intermediate risk (0.197-0.223, NPV:0.82; 27%) and high risk (>0.223, NPV:0.78; 44%). The relevant variables for the model were: previous use of cyclophosphamide or corticosteroids, start with immunosuppressive drugs, previous gastrointestinal progression, previous cardiovascular event, pulmonary arterial hypertension, modified Rodnan Skin Score, creatine kinase and diffusing capacity for carbon monoxide., Conclusion: Our machine-learning-assisted model for progression enabled us to classify 29% of SSc patients as 'low risk'. In this group, annual assessment programmes could be less extensive than indicated by international guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The classification of disease activity states in rheumatoid arthritis (RA) can be achieved through disease activity indices, such as the Disease Activity Score in 28 joints erythrocyte sedimentation rate (DAS28-ESR), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Subjective measurements, such as patient reported outcomes have been incorporated into several of these indices alongside more objective assessments, such as increases in the ESR and C-reactive protein. Moreover, while they use similar criteria, different indices weight these criteria to different extents. Therefore, the classifications based on each evaluation may not always be the same. We aim to compare the performance of the three indices and their individual components in two different populations., Methods: Data from Dutch and Portuguese adherent centers were extracted from the METEOR database, a multinational collaboration on RA. We included a total of 24,605 visits from Dutch centers (from 5,870 patients) and 20,120 visits from Portuguese centers (from 3,185 patients). We compared the disease activity states as evaluated by the DAS28-ESR, CDAI, and SDAI across the two populations. In addition, we analyzed the individual components of each evaluation, including their respective contributions to the outcome, in each population., Results: We found significant differences in the disease activity states classified with the DAS28-ESR between the two populations. SDAI and CDAI had more congruous results. While the proportion of visits to Dutch and Portuguese centers that were classified as "in remission" was very similar between the CDAI and SDAI, the DAS28-ESR gave discordant results. Dutch patients had lower ESRs, which is more heavily weighted in the DAS28-ESR. In addition, even though the mean physicians' global assessment values did not vary significantly for Dutch vs Portuguese physicians, we found that doctors at Portuguese centers overall scored the physician's global assessment lower than Dutch physicians for patient visits classified by disease activity state., Conclusion: While the CDAI and SDAI assigned disease activity states that were largely similar, the DAS28-ESR was often discordant across the two populations. Moreover, we found that physicians, more than patients, evaluated disease activity differently among the Portuguese and Dutch populations.

Background: Ibogaine is an agent that has been evaluated as an unapproved anti-addictive agent for the management of drug dependence. Sudden cardiac death has been described to occur secondary to its use. We describe the clinical effects and toxicokinetics of ibogaine and noribogaine in a single patient. For this purpose, we developed a LC-MS/MS-method to measure ibogaine and noribogaine plasma-concentrations. We used two compartments with first order absorption., Case Details: The maximum concentration of ibogaine was 1.45 mg/L. Our patient developed markedly prolonged QTc interval of 647ms maximum, several multiple cardiac arrhythmias (i.e., atrial tachycardia and ventricular tachycardia and Torsades des Pointes). QTc-prolongation remained present until 12 days after ingestion, several days after ibogaine plasma-levels were low, implicating clinically relevant noribogaine concentrations long after ibogaine had been cleared from the plasma. The ratio k 12 /k 21 for noribogaine was 21.5 and 4.28 for ibogaine, implicating a lower distribution of noribogaine from the peripheral compartment into the central compartment compared to ibogaine., Conclusions: We demonstrated a linear relationship between the concentration of the metabolite and long duration of action, rather than with parent ibogaine. Therefore, after (prolonged) ibogaine ingestion, clinicians should beware of long-term effects due to its metabolite.

Background: Little is known on how well targeted treatment, for instance targeting towards low DAS, is implemented in clinical practice. Our aim was to evaluate treatment adjustments in response to DAS in RA patients in clinical practice., Methods: We used data from one referral centre, multiple rheumatologists, from the METEOR database. Generalized Estimating Equations (GEE) were used to assess whether in case of non-low disease activity (DAS > 2.4) treatment intensifications in DMARD therapy occurred ((change or increase in dose or number of DMARDs, including synthetic (s)DMARDs, biologic (b)DMARDs and corticosteroids compared to the visit before)). Determinants of not intensifying the treatment when DAS > 2.4 were investigated using GEE., Results: Five thousand one hundred fifty-seven registered visits of 1202 patients were available for the analyses. A DAS > 2.4 was weakly (OR: 1.19; 95% CI 1.07-1.33) associated with a treatment intensification. In 69% (n = 3577) of the visits patients were in low disease activity. In 66% (n = 1028) of the visits with DAS > 2.4 treatment was not intensified. These patients had a higher tender joint count and received more often methotrexate plus a bDMARD, or csDMARD monotherapy, as compared to patients that received treatment intensification., Conclusion: In the majority of visits in the METEOR database patients were already in a state of low disease activity, reflecting appropriate treatment intensity. When DAS was greater than 2.4, treatment was often not intensified due to high tender joint count or specific treatment combinations. This data suggest that while aiming for low DAS, physicians per patient weigh whether all DAS elements indicate disease activity or will respond to DMARD adjustment or not, and make treatment decisions accordingly.

Background: Cardiac resynchronization therapy (CRT) is characterized by a approximately 30% non-response. Invasive haemodynamic measurements are a traditional method to evaluate response to CRT. This study evaluates the correlation between acute changes in dP/dt(max) and Stroke Work (SW) during CRT., Methods: Thirty-four CRT candidates were haemodynamically evaluated by pressure-volume loop analysis during biventricular pacing., Results: Mean dP/dt(max) and SW at baseline were 854 +/- 198 and 5186 +/- 2349, and displayed an increase during pacing of 106 +/- 117 mmHg/s (13% +/- 14%) and 1303 +/- 3039 mL/mmHg (30% +/- 52%), respectively. No correlation was found between the percentage change in dP/dt(max) and SW (R = 0.06, P = ns). When defining response an augmentation of 10% relative to baseline for both parameters, 16 patients demonstrated an ambiguous response., Conclusion: Although both parameters display an average increase during pacing, the change relative to baseline values of SW and dP/dt(max) is not related.

Objective: To determine the usefulness of a prediction model for making treatment decisions in early rheumatoid arthritis (RA)., Methods: In 152 patients with early RA, progression of radiological damage during the first year [Sharp-van der Heijde (SH) score > 0] was assessed and used to define actual disease outcome. Available variables at baseline were entered in a multivariate regression analysis with progression score as dependent variable. This model was used to predict disease outcome in every patient. Using the standard deviations of the predicted disease outcome, patients were divided into 3 groups: (1) severe disease: high probability (> or = 0.8) for progression > 0, (2) mild disease: high probability (> or =0.8) for progression < or = 0, and (3) not classified: no high probability for either option. It was determined how many patients could be classified by using this model., Results: One hundred nine patients (71.7%) showed joint damage progression during the first year. Baseline variables available were: age, sex, duration of symptoms, duration of morning stiffness, patient's global assessment of disease activity, Health Assessment Questionnaire score, swollen and painful joint count, bilateral compression pain in metatarsophalangeals, rheumatoid factor positivity, erythrocyte sedimentation rate, shared epitope positivity, SH-score, and the presence of erosions. The R2 value (approximately variation explained) of the prediction model was 0.36. By using this model 46.3% of patients could be classified as having severe disease, 0% as having mild disease, and 53.7% could not be classified., Conclusion: To be able to make treatment decisions in early RA based on predicted disease outcome, a better prediction of disease outcome is needed, making the search for better prognostic variables urgent.