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The trace plot is seldom used in meta-analysis, yet it is a very informative plot. In this article, we define and illustrate what the trace plot is, and discuss why it is important. The Bayesian version of the plot combines the posterior density of [tau], the between-study standard deviation, and the shrunken estimates of the study effects as a function of [tau]. With a small or moderate number of studies, [tau] is not estimated with much precision, and parameter estimates and shrunken study effect estimates can vary widely depending on the correct value of [tau]. The trace plot allows visualization of the sensitivity to [tau] along with a plot that shows which values of [tau] are plausible and which are implausible. A comparable frequentist or empirical Bayes version provides similar results. The concepts are illustrated using examples in meta-analysis and meta-regression; implementation in R is facilitated in a Bayesian or frequentist framework using the bayesmeta and metafor packages, respectively.

Abstract Background Patients with advanced chronic non-malignant conditions often experience significant symptom burden. Therefore, overcoming barriers to interprofessional collaboration between general practitioners (GPs) and specialist palliative home care (SPHC) teams is essential to facilitate the timely integration of palliative care elements. The KOPAL trial aimed to examine the impact of case conferences between GPs and SPHC teams on symptom burden and pain in patients with advanced chronic heart failure, chronic obstructive pulmonary disease, and dementia. Methods The cluster-randomised controlled trial compared a structured palliative care nurse visit followed by an interprofessional case conference to usual care. Data were collected from GPs at baseline and 48 weeks, while standardised patient interviews were conducted at baseline, 6, 12, 24, and 48 weeks. Results We analysed 172 patients from 49 German GP practices. Both groups showed marginal improvement in symptom burden; however, no statistically significant between-group difference was found ( $$\:{\Delta\:}$$ =-0.561, 95% CI: -3.201–2.079, p = .68). Patients with dementia experienced a significant pain reduction ( $$\:{\Delta\:}$$ =2.187, 95% CI: 0.563–3.812, p = .009). Conversely, the intervention did not have a significant effect on pain severity ( $$\:{\Delta\:}$$ =-0.711, 95% CI: -1.430 − 0.008, p=.053) or pain interference ( $$\:{\Delta\:}$$ =-0.036, 95% CI:-0.797 − 0.725, p=.926) in other patient groups. Conclusions The intervention showed promise in the timely introduction of palliative care elements to address pain management in patients with dementia. Further studies are needed to identify and effectively address symptom burden and pain in other patient groups. Trial registration German Clinical Trials Register: https://www.drks.de/DRKS00017795 (Registration date: 9th January 2020).

Abstract Aims Chronic systolic heart failure (CHF) is a major health burden. A relevant number of patients shows asymptomatic left ventricular dysfunction (ALVSD) before symptomatic CHF or becomes asymptomatic after initiating heart failure therapy. Clinical course, prognosis, and response to pharmacological and device‐based treatment are largely unknown in these two distinct groups of patients. Current pharmacological and interventional therapies do neither properly address the underlying pathophysiology nor prevent malignant loss of function. New therapeutic paradigms are needed to stop the progression from asymptomatic to symptomatic heart failure. Key questions are what causes progression of clinically asymptomatic New York Heart Association (NYHA) I heart failure to overt heart failure (>NYHA I) in some but not all patients and the underlying reasons for this transition. This requires the identification of disease mechanisms and biomarkers that predict outcome in well‐defined cohorts for innovative preclinical and clinical trials. Methods and results TransitionCHF is a prospective, multicentre, longitudinal pathophysiological evaluation cohort study in patients with asymptomatic systolic dysfunction NYHA I and left ventricular ejection fraction ≤40%. The cohort comprises both incidental findings and patients who had become asymptomatic after a previous symptomatic event. TransitionCHF has recruited 1000 patients with ALVSD caused by various aetiologies in 20 university heart failure clinics across Germany. Both patients with and without comorbidities at study entry will be recruited. Patients will be systematically investigated and followed up annually over the course of the study. The primary composite endpoint is time to hospitalization for heart failure and cardiovascular death. The secondary endpoints assess time to all‐cause mortality, to cardiovascular mortality, to heart failure mortality, to all‐cause hospitalization, to heart failure hospitalization, and to recurrent heart failure hospitalizations, as well as time to assist device implantation/transplantation. Additional investigations focusing on biomarkers, comorbidities, gender aspects, nutrition, and functional parameters including quality of life will be performed. Conclusions TransitionCHF will provide a more thorough pathophysiological understanding of the progression of asymptomatic systolic dysfunction into symptomatic heart failure that will help develop therapies tailored to prevent progressive heart failure.

In Bayesian random-effects meta-analysis, the use of weakly informative prior distributions is of particular benefit in cases where only a few studies are included, a situation often encountered in health technology assessment (HTA). Suggestions for empirical prior distributions are available in the literature but it is unknown whether these are adequate in the context of HTA. Therefore, a database of all relevant meta-analyses conducted by the Institute for Quality and Efficiency in Health Care (IQWiG, Germany) was constructed to derive empirical prior distributions for the heterogeneity parameter suitable for HTA. Previously, an extension to the normal-normal hierarchical model had been suggested for this purpose. For different effect measures, this extended model was applied on the database to conservatively derive a prior distribution for the heterogeneity parameter. Comparison of a Bayesian approach using the derived priors with IQWiG's current standard approach for evidence synthesis shows favorable properties. Therefore, these prior distributions are recommended for future meta-analyses in HTA settings and could be embedded into the IQWiG evidence synthesis approach in the case of very few studies.

Abstract Background The SAVVY project aims to improve the analyses of adverse events (AEs) in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). This paper summarizes key features and conclusions from the various SAVVY papers. Methods Summarizing several papers reporting theoretical investigations using simulations and an empirical study including randomized clinical trials from several sponsor organizations, biases from ignoring varying follow-up times or CEs are investigated. The bias of commonly used estimators of the absolute (incidence proportion and one minus Kaplan-Meier) and relative (risk and hazard ratio) AE risk is quantified. Furthermore, we provide a cursory assessment of how pertinent guidelines for the analysis of safety data deal with the features of varying follow-up time and CEs. Results SAVVY finds that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard. Conclusions The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. Whenever varying follow-up times and/or CEs are present in the assessment of AEs, SAVVY recommends using the Aalen-Johansen estimator (AJE) with an appropriate definition of CEs to quantify AE risk. There is an urgent need to improve pertinent clinical trial reporting guidelines for reporting AEs so that incidence proportions or one minus Kaplan-Meier estimators are finally replaced by the AJE with appropriate definition of CEs.

Introduction Adherence to COPD management strategies is complex, and it is unclear which intervention may enhance it. Objectives We aim to evaluate the effectiveness of adherence-enhancing interventions, alone or compared to interventions, for patients with COPD. Methods This review comprises a component network meta-analysis with a structured narrative synthesis. We searched MEDLINE, Embase, CENTRAL, CINAHL and trial registries on 9 September 2023. We included controlled studies that explored adherence in patients with COPD. Two review authors independently performed the study selection, data extraction and the risk of bias assessment. We involved patients with COPD in developing this systematic review through focus group interviews and displayed the findings in pre-designed logic models. Results We included 33 studies with 5775 participants. We included 13 studies in the component network meta-analysis that explored adherence. It was mainly assessed through questionnaires. As a continuous outcome, there was a tendency mainly for education (standardised mean difference 1.26, 95% CI 1.13–1.38, very low certainty of evidence) and motivation (mean difference 1.85, 95% CI 1.19–2.50, very low certainty of evidence) to improve adherence. As a dichotomous outcome (e.g. adherent/non-adherent), we found a possible benefit with education (odds ratio 4.77, 95% CI 2.25–10.14, low certainty of evidence) but not with the other components. We included six studies that reported quality of life in the component network meta-analysis. Again, we found a benefit of education (mean difference −9.70, 95% CI −10.82– −8.57, low certainty of evidence) but not with the other components. Conclusions Education may improve adherence and quality of life in COPD patients. Patient focus group interviews indicated that interventions that strengthen patients’ self-efficacy and help them to achieve individual goals are the most helpful.

Abstract Background Integrated care, in particular the ‘Blended Collaborative Care (BCC)’ strategy, may have the potential to improve health-related quality of life (HRQoL) in multimorbid patients with heart failure (HF) and psychosocial burden at no or low additional cost. The ESCAPE trial is a randomised controlled trial for the evaluation of a BCC approach in five European countries. For the economic evaluation of alongside this trial, the four main objectives were: (i) to document the costs of delivering the intervention, (ii) to assess the running costs across study sites, (iii) to evaluate short-term cost-effectiveness and cost-utility compared to providers’ usual care, and (iv) to examine the budgetary implications. Methods The trial-based economic analyses will include cross-country cost-effectiveness and cost-utility assessments from a payer perspective. The cost-utility analysis will calculate quality-adjusted life years (QALYs) using the EQ-5D-5L and national value sets. Cost-effectiveness will include the cost per hospital admission avoided and the cost per depression-free days (DFD). Resource use will be measured from different sources, including electronic medical health records, standardised questionnaires, patient receipts and a care manager survey. Uncertainty will be addressed using bootstrapping. Discussion The various methods and approaches used for data acquisition should provide insights into the potential benefits and cost-effectiveness of a BCC intervention. Providing the economic evaluation of ESCAPE will contribute to a country-based structural and organisational planning of BCC (e.g., the number of patients that may benefit, how many care managers are needed). Improved care is expected to enhance health-related quality of life at little or no extra cost. Trial registration The study follows CHEERS2022 and is registered at the German Clinical Trials Register (DRKS00025120).

Abstract Objective Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state‐of‐the‐art clinical settings and trials applying combined outcome parameters. Methods Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed‐25‐foot walk test (T25FW), and nine‐hole‐peg‐test (9HPT)). Results 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7–61.2], 135 female, median follow‐up: 29.3 months [17.9–40.9]) were included. NfL (age‐) and GFAP (age‐ and sex‐) adjusted Z scores were higher in pwPMS compared to HC (p 3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12–5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21–6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53–12.13], p = 0.006). Interpretation Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non‐active pwPMS with particularly high progression risk.

Background New methods to identify patients who benefit from a primary prophylactic implantable cardioverter‐defibrillator (ICD) are needed. T‐wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. Methods and Results In the EU‐CERT‐ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter‐Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24‐hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all‐cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points

Abstract Background Chronic obstructive pulmonary disease (COPD) is characterised by hyperinflation and expiratory airflow limitation due to long-term exposure to irritants. The variety and complexity of COPD treatment and the possible added comorbidities may make the patients find it difficult to cope with the required medications. That is why supporting patients’ adherence is critical because not taking medications correctly increases the risk of complications and creates an additional financial burden. A range of interventions aiming to improve patient adherence were used, and most of them are complex since they involve a mix of elements. Furthermore, despite the variety of available tools, assessing adherence is challenging because clinicians usually do not get a concrete judgement if their patients followed their treatment plan reliably. We aim to evaluate the effectiveness of adherence-enhancing interventions for COPD patients, explore which intervention (component) works for which patients and check the factors influencing the implementation and participant responses. Methods We will perform a comprehensive literature search (Medline, Embase, Cochrane Library, trial registries) without restrictions on language and publication status, and we will include all controlled studies investigating the effect of adherence-enhancing intervention on patients with COPD. We plan to involve COPD patients in the systematic review development through two patient interviews (one before and one after the systematic review). Two reviewers will perform the screening, data extraction and risk of bias (ROB) assessment. For ROB, we will use ROB 2.0 to assess randomised controlled trials, and ROBINS-I to assess non-randomised studies. We will perform pair-wise random-effects meta-analyses and component network meta-analyses to identify the most effective components and combinations of components. We will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. To determine the degree of complexity, we will use the iCAT_SR checklist, and then, following a logical model, we will group the interventions according to prespecified criteria. Discussion This systematic review aims to point out the most effective and implementable adherence-enhancing interventions by using methods for synthesising evidence on complex interventions and involving COPD patients all along with the review process. Systematic review registration PROSPERO CRD42022353977

Abstract Background Maintaining the ability to perform self‐care is a critical goal in patients with cancer. We assessed whether the patient‐reported ability to walk 4 m and wash oneself predict survival in patients with pre‐terminal cancer. Methods We performed a prospective observational study on 169 consecutive hospitalized patients with cancer (52% female, 64 ± 12 years) and an estimated 1–12 months prognosis at an academic, inpatient palliative care unit. Patients answered functional questions for ‘today’, ‘last week’, and ‘last month’, performed patient‐reported outcomes (PROs), and physical function assessments. Results Ninety‐two (54%) patients reported the ability to independently walk 4 m and 100 (59%) to wash ‘today’. The median number of days patients reported the ability to walk 4 m and wash were 6 (IQR 0–7) and 7 (0–7) days (‘last week’); and 27 (5–30) and 26 (10–30) days (‘last month’). In the last week, 32% of patients were unable to walk 4 m on every day and 10% could walk on 1–3 days; 30% were unable to wash on every day and 10% could wash on 1–3 days. In the last months, 14% of patients were unable to walk 4 m on every day and 10% could only walk on 1–10 days; 12% were unable to wash on every day and 11% could wash on 1–10 days. In patients who could walk ‘today’ average 4 m gait speed was 0.78 ± 0.28 m/s. Patients who reported impaired walking and washing experienced more symptoms (dyspnoea, exertion, and oedema) and decreased physical function (higher Eastern Cooperative Oncology Group Performance Status, and lower Karnofsky Performance Status and hand‐grip strength [unable vs. able to walk ‘today’: 205 ± 87 vs. 252 ± 78 Newton, P = 0.001; unable vs. able to wash ‘today’: 204 ± 86 vs. 250 ± 80 Newton, P = 0.001]). During the 27 months of observation, 152 (90%) patients died (median survival 46 days). In multivariable Cox proportional hazards regression analyses, all tested parameters were independent predictors of survival: walking 4 m ‘today’ (HR 0.63, P = 0.015), ‘last week’ (per 1 day: HR 0.93, P = 0.011), ‘last month’ (per 1 day: HR 0.98, P = 0.012), 4 m gait speed (per 1 m/s: HR 0.45, P = 0.002), and washing ‘today’ (HR 0.67, P = 0.024), ‘last week (per 1 day HR 0.94, p=0.019), and ‘last month’ (per 1 day HR 0.99, P = 0.040). Patients unable to walk and wash experienced the shortest survival and most reduced functional status. Conclusions In patients with pre‐terminal cancer, the self‐reported ability to walk 4 m and wash were independent predictors of survival and associated with decreased functional status.

Abstract ESCAPE Evaluation of a patient‐centred biopsychosocial blended collaborative care pathway for the treatment of multimorbid elderly patients. Therapeutic Area Healthcare interventions for the management of older patients with multiple morbidities. Aims Multi‐morbidity treatment is an increasing challenge for healthcare systems in ageing societies. This comprehensive cohort study with embedded randomized controlled trial tests an integrated biopsychosocial care model for multimorbid elderly patients. Hypothesis A holistic, patient‐centred pro‐active 9‐month intervention based on the blended collaborative care (BCC) approach and enhanced by information and communication technologies can improve health‐related quality of life (HRQoL) and disease outcomes as compared with usual care at 9 months. Methods Across six European countries, ESCAPE is recruiting patients with heart failure, mental distress/disorder plus ≥2 medical co‐morbidities into an observational cohort study. Within the cohort study, 300 patients will be included in a randomized controlled assessor‐blinded two‐arm parallel group interventional clinical trial (RCT). In the intervention, trained care managers (CMs) regularly support patients and informal carers in managing their multiple health problems. Supervised by a clinical specialist team, CMs remotely support patients in implementing the treatment plan—customized to the patients' individual needs and preferences—into their daily lives and liaise with patients' healthcare providers. An eHealth platform with an integrated patient registry guides the intervention and helps to empower patients and informal carers. HRQoL measured with the EQ‐5D‐5L as primary endpoint, and secondary outcomes, that is, medical and patient‐reported outcomes, healthcare costs, cost‐effectiveness, and informal carer burden, will be assessed at 9 and ≥18 months. Conclusions If proven effective, the ESCAPE BCC intervention can be implemented in routine care for older patients with multiple morbidities across the participating countries and beyond.

Abstract Background In out-of-hours urgent care practices in Germany, physicians of different specialties care for a large number of patients, most of all unknown to them, resulting in a high workload and challenging diagnostic decision-making. As there is no common patient file, physicians have no information about patients’ previous conditions or received treatments. In this setting, a digital tool for medical history taking could improve the quality of medical care. This study aims to implement and evaluate a software application (app) that takes a structured symptom-oriented medical history from patients in urgent care settings. Methods We conduct a time-cluster-randomized trial in two out-of-hours urgent care practices in Germany for 12 consecutive months. Each week during the study defines a cluster. We will compare participants with (intervention group) and without app use (control group) prior to consultation and provision of the self-reported information for the physician. We expect the app to improve diagnostic accuracy (primary outcome), reduce physicians’ perceived diagnostic uncertainty, and increase patients’ satisfaction and the satisfaction with communication of both physician and patient (secondary outcomes). Discussion While similar tools have only been subject to small-scale pilot studies surveying feasibility and usability, the present study uses a rigorous study design to measure outcomes that are directly associated with the quality of delivered care. Trial registration The study was registered at the German Clinical Trials Register (No. DRKS00026659 registered Nov 03 2021. World Health Organization Trial Registration Data Set, https://trialsearch.who.int/Trial2.aspx? TrialID = DRKS00026659.

Summary: Background: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. Methods: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. Findings: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37–9·27], p

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing–remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender ( p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score ( p = 0.004), and the presence of monitoring ( p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 – UK portal 0.311). Those with higher EDSS at index ( p

Introduction People receiving home care usually have complex healthcare needs requiring the involvement of informal caregivers and various health professionals. In this context, successful collaboration is an important element of person-centred care, which is often insufficiently implemented. Consequences might be found in avoidable hospitalisations. The aim of the study is to develop a care concept to improve person-centred interprofessional collaboration for people receiving home care considering the perspectives of all person groups involved.Methods and analysis This study uses a mixed-methods design consisting of a literature review, several qualitative inquiries, a cross-sectional quantitative study and a final structured workshop. After a literature review (work package (WP) 1), we will explore the perspectives of people receiving home care (n=20), their relatives (n=20) and representatives of statutory health insurances (n=5) in semistructured interviews (WP2). Moreover, 100 individuals of each group (people receiving home care, relatives, registered nurses, general practitioners and therapists) involved in home care will answer a survey on collaboration that will be analysed descriptively (WP3). Additionally, monoprofessional focus groups (n=9) of registered nurses, general practitioners and therapists, respectively, will discuss current practices. Data will be analysed by qualitative content analysis. Best practice cases (n=8) will be analysed by a case-based qualitative content analysis based on data of observations of home visits and interviews (WP4). The findings of WP2 will be discussed in mixed focus groups (n=4) with 10 participants each (WP5). Considering the results of joint displays of WP3, WP4 and WP5, the interprofessional care concept and its implementation will be elaborated in an expert workshop (WP6).Ethics and dissemination Ethical approval was obtained from all ethics committees of the project partners. Study results will be disseminated through publications, conference presentations, student education and advanced training of health professionals.Trial registration number NCT05149937.

Abstract Background Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system with an increasing worldwide prevalence. Since 1993, more than 15 disease-modifying immunotherapies (DMTs) have been licenced and have shown moderate efficacy in clinical trials. Based on the heterogeneity of the disease and the partial effectiveness of therapies, a personalised medicine approach would be valuable taking individual prognosis and suitability of a chosen therapy into account to gain the best possible treatment effect. The primary objective of this review is to assess the differential treatment effects of all approved DMTs in subgroups of adults with clinically isolated syndrome or relapsing forms of MS. We will analyse possible treatment effect modifiers (TEM) defined by baseline demographic characteristics (gender, age), and diagnostic (i.e. MRI measures) and clinical (i.e. relapses, disability level) measures of MS disease activity. Methods We will include all published and accessible unpublished primary and secondary analyses of randomised controlled trials (RCTs) with a follow-up of at least 12 months investigating the efficacy of at least one approved DMT, with placebo or other approved DMTs as control intervention(s) in subgroups of trial participants. As the primary outcome, we will address disability as defined by the Expanded Disability Status Scale or multiple sclerosis functional composite scores followed by relapse frequency, quality of life measures, and side effects. MRI data will be analysed as secondary outcomes. MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL and major trial registers will be searched for suitable studies. Titles and abstracts and full texts will be screened by two persons independently using Covidence. The risk of bias will be analysed based on the Cochrane “Risk of Bias 2” tool, and the certainty of evidence will be assessed using GRADE. Treatment effects will be reported as rate ratio or odds ratio. Primary analyses will follow the intention-to-treat principle. Meta-analyses will be carried out using random-effects models. Discussion Given that individual patient data from clinical studies are often not available, the review will allow to analyse the evidence on TEM in MS immunotherapy and thus support clinical decision making in individual cases. Systematic review registration PROSPERO CRD42021279665 .

Abstract Background To improve interprofessional collaboration between registered nurses (RNs) and general practitioners (GPs) for nursing home residents (NHRs), the interprof ACT intervention package was developed. This complex intervention includes six components (e.g., shared goal setting, standardized procedures for GPs’ nursing home visits) that can be locally adapted. The cluster-randomized interprof ACT trial evaluates the effects of this intervention on the cumulative incidence of hospital admissions (primary outcome) and secondary outcomes (e.g., length of hospital stays, utilization of emergency care services, and quality of life) within 12 months. It also includes a process evaluation which is subject of this protocol. The objectives of this evaluation are to assess the implementation of the interprof ACT intervention package and downstream effects on nurse–physician collaboration as well as preconditions and prospects for successive implementation into routine care. Methods This study uses a mixed methods triangulation design involving all 34 participating nursing homes (clusters). The quantitative part comprises paper-based surveys among RNs, GPs, NHRs, and nursing home directors at baseline and 12 months. In the intervention group (17 clusters), data on the implementation of preplanned implementation strategies (training and supervision of nominated IPAVs, interprofessional kick-off meetings) and local implementation activities will be recorded. Major outcome domains are the dose, reach and fidelity of the implementation of the intervention package, changes in interprofessional collaboration, and contextual factors. The qualitative part will be conducted in a subsample of 8 nursing homes (4 per study group) and includes repeated non-participating observations and semistructured interviews on the interaction between involved health professionals and their work processes. Quantitative and qualitative data will be descriptively analyzed and then triangulated by means of joint displays and mixed methods informed regression models. Discussion By integrating a variety of qualitative and quantitative data sources, this process evaluation will allow comprehensive assessment of the implementation of the interprof ACT intervention package, the changes induced in interprofessional collaboration, and the influence of contextual factors. These data will reveal expected and unexpected changes in the procedures of interprofessional care delivery and thus facilitate accurate conclusions for the further design of routine care services for NHRs. Trial registration ClinicalTrials.gov NCT03426475 . Registered on 07/02/2018.

Abstract Fragmented QRS (fQRS) is an electrocardiographic (ECG) marker of myocardial conduction abnormality, characterized by additional notches in the QRS complex. The presence of fQRS has been associated with an increased risk of all-cause mortality and arrhythmia in patients with cardiovascular disease. However, current binary visual analysis is prone to intra- and inter-observer variability and different definitions are problematic in clinical practice. Therefore, objective quantification of fQRS is needed and could further improve risk stratification of these patients. We present an automated method for fQRS detection and quantification. First, a novel robust QRS complex segmentation strategy is proposed, which combines multi-lead information and excludes abnormal heartbeats automatically. Afterwards extracted features, based on variational mode decomposition (VMD), phase-rectified signal averaging (PRSA) and the number of baseline-crossings of the ECG, were used to train a machine learning classifier (Support Vector Machine) to discriminate fragmented from non-fragmented ECG-traces using multi-center data and combining different fQRS criteria used in clinical settings. The best model was trained on the combination of two independent previously annotated datasets and, compared to these visual fQRS annotations, achieved Kappa scores of 0.68 and 0.44, respectively. We also show that the algorithm might be used in both regular sinus rhythm and irregular beats during atrial fibrillation. These results demonstrate that the proposed approach could be relevant for clinical practice by objectively assessing and quantifying fQRS. The study sets the path for further clinical application of the developed automated fQRS algorithm.

Abstract Aims Recent trials have evaluated sodium–glucose co‐transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI). Methods and results Fragility index is defined as the minimum number of patients that must be moved from the ‘non‐event’ to the ‘event’ group to turn a statistically significant result to non‐significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non‐significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all‐cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all‐cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta‐analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all‐cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile. Conclusion Improvement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium–glucose co‐transporter 2 inhibitor trials. In contrast, secondary endpoints of all‐cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

Abstract The presence of acute infectious respiratory diseases (ARD) is one of the main reasons why recently arrived refugees seek medical help. This paper investigates the incidence rates of acute respiratory diseases in an adult refugee population as well as associated sociodemographic factors and drug treatments. We conducted a retrospective observational study of deidentified medical records. The data were collected between 2015 and 2019 in the health care centers of two large German initial reception centers for refugees. Multivariable analyses controlling for sociodemographics were carried out using generalized estimating equations. Out of 10,431 eligible residents, 6965 medical encounters of 2840 adult patients were recorded over 30 months. Of all the adult patients, 34.4% sought medical help for a respiratory symptom or diagnosis at least once. Older patients and patients from Sub-Saharan Africa sought help less often. The occurrence of ARD showed a typical distribution over the course of the year. Facility occupancy was not associated with ARD occurrence. Acute respiratory symptoms are a leading cause for adult refugee patients to seek medical care. The doctor contact rates due to ARD were consistently two to three times higher among refugees than among German residents.

Abstract Background The SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups. Methods Estimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment. Results Ten sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs. Conclusions The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly.

Abstract In 2001, the German Multiple Sclerosis Society, facing lack of data, founded the German MS Registry (GMSR) as a long-term data repository for MS healthcare research. By the establishment of a network of participating neurological centres of different healthcare sectors across Germany, GMSR provides observational real-world data on long-term disease progression, sociodemographic factors, treatment and the healthcare status of people with MS. This paper aims to illustrate the framework of the GMSR. Structure, design and data quality processes as well as collaborations of the GMSR are presented. The registry’s dataset, status and results are discussed. As of 08 January 2021, 187 centres from different healthcare sectors participate in the GMSR. Following its infrastructure and dataset specification upgrades in 2014, more than 196,000 visits have been recorded relating to more than 33,000 persons with MS (PwMS). The GMSR enables monitoring of PwMS in Germany, supports scientific research projects, and collaborates with national and international MS data repositories and initiatives. With its recent pharmacovigilance extension, it aligns with EMA recommendations and helps to ensure early detection of therapy-related safety signals.

Abstract Aims The Carillon Mitral Contour System has been shown to reduce mitral regurgitation and left ventricular volumes in symptomatic heart failure patients with functional mitral regurgitation. We sought to evaluate the effects of the Carillon device on quality of life and functional capacity in these patients. Methods and results An individual participant data meta‐analysis was conducted utilizing data from REDUCE‐FMR, TITAN, and TITAN II studies. The main outcomes assessed were changes from baseline in Kansas City Cardiomyopathy Questionnaire overall summary scores (KCCQ‐OSS), 6 min walk test (6MWT) distance, and New York Heart Association (NYHA) classification at Months 1 and 12 after device implantation. Subgroup analyses were conducted for patients with severe functional mitral regurgitation (Grade 3 or 4). Pooled estimates were calculated using a random‐effects model and are presented as weighted proportions or weighted mean differences along with 95% confidence intervals (CIs). Among 139 patients included in the analysis, Carillon device significantly improved the 6MWT distance (63.0 m; 95% CI 18.8–107.2, P = 0.0056) and KCCQ‐OSS score (15.1; 95% CI 5.6–24.7, P = 0.0022) at 1 month from baseline. These benefits were sustained at 12 months (64.1 m; 95% CI 13.2–115.0, P = 0.0141, for 6MWT distance, and 12.3; 95% CI 4.7–19.8, P = 0.0019, for KCCQ‐OSS score). More than 50% of the patients had improvements in KCCQ‐OSS by ≥5 (60.4%; 95% CI 47.4–72.1) and 10 points (50.5%; 95% CI 34.9–66.0) at 12 months. Almost half of the patients experienced a ≥1 class improvement in NYHA class after implantation of the device at 1 month (67.9%; 95% CI 37.3–88.3) and at 12 months (48.8%; 95% CI 31.8–66.2). Results remained similar for KCCQ‐OSS, 6MWT distance, and NYHA classification when only patients with Grade 3 or 4 mitral regurgitation were analysed. The pooled estimates of 30 day and 1 year all‐cause mortality were 2.2% (95% CI 0.7–6.5) and 17.3% (95% CI 11.8–24.5), respectively. Conclusions The Carillon Mitral Contour System significantly improved patient‐reported quality‐of‐life outcomes in heart failure patients with functional mitral regurgitation.

Abstract Background Conventional methods for phase I dose-escalation trials in oncology are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial. Methods Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. The aim is to utilize the information from both the completed and the ongoing schedules to inform decisions on the dose level for the next dose cohort. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results In a simulation study, the developed approach is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-predictive prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The R and Stan code for the implementation of an illustrative sequential phase I trial example in oncology is publicly available ( https://github.com/gunhanb/TITEPK_sequential ). Conclusion In phase I oncology trials with sequential multiple schedules, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.

Abstract Aims The objective of this study was to compare functional outcomes through 1 year in patients with core‐lab verified moderate to severe (Grades 2+ to 4+) functional mitral regurgitation (FMR) treated with the Carillon device or control in the blinded sham‐controlled REDUCE‐FMR (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation) study. Methods and results The main outcomes of this analysis were the change in 6 min walk test (6MWT) distance, incidence of heart failure hospitalization or death, change in New York Heart Association (NYHA) class, and change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score through 1 year of follow‐up. The minimum clinically important difference (MCID) was defined as a ≥30 m increase in 6MWT distance, an NYHA decrease in ≥1 class, and a ≥3 point increase in KCCQ score. The proportion of patients achieving the MCID in each treatment group was compared using Fisher's exact test, and the number needed to treat (NNT) with the Carillon device was calculated. Among 83 patients (62 Carillon and 21 sham), no statistically significant group differences were observed in the baseline characteristics. All outcomes at 1 year numerically favoured the Carillon group, including MCID for the 6MWT distance (59% vs. 23%, P = 0.029; NNT = 2.8), NYHA class (48% vs. 33%, P = 0.38; NNT = 6.9), KCCQ score (69% vs. 47%, P = 0.14; NNT = 4.5), and freedom from heart failure hospitalization or death (60% vs. 48%, P = 0.45; NNT = 8.3). Conclusions REDUCE‐FMR was the first blinded sham‐controlled trial to report outcomes with percutaneous therapy for the treatment of FMR. Trends towards improvement in mean 6MWT distance, KCCQ score, and NYHA class were observed with the Carillon device. A substantially higher number of patients achieved MCID for all patient‐centred outcomes with the Carillon device compared with the sham procedure.

Abstract Introduction Multiple sclerosis is a chronic inflammatory, degenerative disease of the central nervous system manifesting at first with relapses in about 85% of cases. In Germany, intravenous therapy with high-dose corticosteroids is the treatment standard of acute relapses. The treatment leads to a faster reduction of symptoms in about 25 of 100 treated patients but has no proven long-term benefits over placebo treatment. Intravenous treatment is not superior to oral treatment. Therefore, informed decisions on relapse management are required. An earlier randomised controlled trial showed that evidence-based patient information and education on relapse management leads to more informed decisions and more relapses not treated or treated with oral corticosteroids. This study aims to evaluate whether a web-based relapse management programme will positively change relapse management and strengthen autonomy in people with multiple sclerosis. Methods The pragmatic double-blind randomised controlled trial is accompanied by a mixed-methods process evaluation and a health economic evaluation and follows the UK Medical Research Council guidance on developing and evaluating complex interventions. A total of 188 people with possible or relapsing-remitting multiple sclerosis with ≥ 1 relapse within the last year and/or ≥ 2 relapses within the last 2 years will be recruited and randomised using blocks. The intervention group receives a web- and dialogue-based decision aid on relapse management, a nurse-led webinar and access to a monitored chat forum. The control group receives standard information, which will be made available via the same online platform as the intervention. The primary endpoint is the proportion of relapses not treated or treated with oral corticosteroids. Key secondary endpoints are the annualised relapse rate, decision-making, empowerment, quality of life and cost-effectiveness. Facilitators and barriers will be assessed by mixed-methods process evaluation measures. The study ends when 81 relapses have been documented or after 24 months of observation per individual patient. Analyses will follow the intention-to-treat principle. Discussion We hypothesise that the intervention will enhance patient empowerment and have a positive impact on patients’ relapse management. Trial registration ClinicalTrials.gov NCT04233970 . Registered on 18 January 2020

Abstract Aims This study aimed to investigate the reporting of subgroup analyses in heart failure (HF) randomized controlled trials (RCTs) and to determine the strength and credibility of subgroup claims. Methods and results All primary HF RCTs published in nine high‐impact journals from 1 January 2008 to 31 December 2017 were included. Multivariable regression analysis was used to identify factors that may favour the reporting of results in specific subgroups. Strength of the subgroup effect claimed was classified into (i) strong, (ii) likely, or (iii) suggestive. Credibility of subgroup claim was scored using a pre‐specified 10 pointer criteria. Of the 261 HF RCTs studied, 107 (41%) reported subgroup analyses. Twenty‐five (23%) RCTs claimed a subgroup effect for the primary outcome of which six (24%) made a strong claim, eight (32%) claimed a likely effect, and 11 (44%) suggested a possible subgroup effect. Seven of the 25 RCTs did not employ interaction testing for subgroup claims of the primary outcome. Three out of 10 pre‐specified credibility criteria were satisfied by half of the trials. Fourteen trials justified the choice of subgroups, and 10 explicitly stated they were underpowered to detect differences within subgroups. Source of funding did not influence the frequency of reporting subgroup analyses (OR 0.53, 95% CI 0.78–3.62, P = 0.52). Conclusions Appropriate credibility criteria were rarely met even by HF RCTs that held strong subgroup claims. Subgroup analyses should be pre‐specified, be adequately powered, present interaction terms, and be replicated in independent data before being integrated into clinical decision making.

Abstract Background Proven treatments for low back pain, at best, only provide modest overall benefits. Matching people to treatments that are likely to be most effective for them may improve clinical outcomes and makes better use of health care resources. Methods We conducted an individual participant data meta-analysis of randomised controlled trials of three types of therapist delivered interventions for low back pain (active physical, passive physical and psychological treatments). We applied two statistical methods (recursive partitioning and adaptive risk group refinement) to identify potential subgroups who might gain greater benefits from different treatments from our individual participant data meta-analysis. Results We pooled data from 19 randomised controlled trials, totalling 9328 participants. There were 5349 (57%) females with similar ratios of females in control and intervention arms. The average age was 49 years (standard deviation, SD, 14). Participants with greater psychological distress and physical disability gained most benefit in improving on the mental component scale (MCS) of SF-12/36 from passive physical treatment than non-active usual care (treatment effects, 4.3; 95% confidence interval, CI, 3.39 to 5.15). Recursive partitioning method found that participants with worse disability at baseline gained most benefit in improving the disability (Roland Morris Disability Questionnaire) outcome from psychological treatment than non-active usual care (treatment effects, 1.7; 95% CI, 1.1 to 2.31). Adaptive risk group refinement did not find any subgroup that would gain much treatment effect between psychological and non-active usual care. Neither statistical method identified any subgroups who would gain an additional benefit from active physical treatment compared to non-active usual care. Conclusions Our methodological approaches worked well and may have applicability in other clinical areas. Passive physical treatments were most likely to help people who were younger with higher levels of disability and low levels of psychological distress. Psychological treatments were more likely to help those with severe disability. Despite this, the clinical importance of identifying these subgroups is limited. The sizes of sub-groups more likely to benefit and the additional effect sizes observed are small. Our analyses provide no evidence to support the use of sub-grouping for people with low back pain.

Introduction Progressive chronic, non-malignant diseases (CNMD) like congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and dementia are of growing relevance in primary care. Most of these patients suffer from severe symptoms, reduced quality of life and increased numbers of hospitalisations. Outpatient palliative care can help to reduce hospitalisation rate by up to 50%. Due to the complex medical conditions and prognostic uncertainty of the course of CNMD, early interprofessional care planning among general practitioners who provide general palliative care and specialist palliative home care (SPHC) teams seems mandatory. The KOPAL study (a concept for strenghtening interprofessional collaboration for patients with palliative care needs) will test the effectiveness of a SPHC nurse–patient consultation followed by an interprofessional telephone case conference.Methods and analysis Multicentre two-arm cluster randomised controlled trial KOPAL with usual care as control arm. The study is located in Northern Germany and aims to recruit 616 patients in 56 GP practices (because of pandemic reasons reduced to 191 participants). Randomisation will take place on GP practice level immediately after inclusion (intervention group/control group). Allocation concealment is carried out on confirmation of participation. Patients diagnosed with CHF (New York Heart Association (NYHA) classification 3–4), COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage classification 3–4, group D) or dementia GDS stage 4 or above). Primary outcome is a reduced hospital admission within 48 weeks after baseline, secondary outcomes include symptom burden, quality of life and health costs. The primary analysis will follow the intention-to-treat principle. Intervention will be evaluated after the observation period using qualitative methods.Ethics and dissemination The responsible ethics committees of the cooperating centres approved the study. All steps of data collection, quality assurance and data analysis will continuously be monitored. The concept of KOPAL could serve as a blueprint for other regions and meet the challenges of geographical equity in end-of-life care.Trial registration number DRKS00017795; German Clinical Trials Register.

Abstract Aims We sought to conduct a meta‐analysis regarding the safety and efficacy of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors in patients with heart failure (HF). Methods and results MEDLINE, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched from their inception to November 2020 for placebo‐controlled randomized controlled trials of SGLT2 inhibitors. Randomized controlled trials were selected if they reported at least one of the prespecified outcomes in patients with HF. Hazard ratios (HRs) or risk ratios and their corresponding 95% confidence intervals were pooled using a random‐effects model. A total of seven trials including 16 820 HF patients (N = 8884 in the SGLT2 inhibitor arms; N = 7936 in the placebo arms) were included. In the overall HF cohort, SGLT2 inhibitors compared with placebo significantly reduced the risk of the composite endpoint of first HF hospitalization or cardiovascular death [HR: 0.77 (0.72–0.83); P

Abstract Background In Germany, up to 50% of nursing home residents are admitted to a hospital at least once a year. It is often unclear whether this is beneficial or even harmful. Successful interprofessional collaboration and communication involving general practitioners (GPs) and nurses may improve medical care of nursing home residents. In the previous interprof study, the six-component intervention package interprof ACT was developed to facilitate collaboration of GPs and nurses in nursing homes. The aim of this study is to evaluate the effectiveness of the interprof ACT intervention. Methods This multicentre, cluster randomised controlled trial compares nursing homes receiving the interprof ACT intervention package for a duration of 12 months (e.g. comprising appointment of mutual contact persons, shared goal setting, standardised GPs’ home visits) with a control group (care as usual). A total of 34 nursing homes are randomised, and overall 680 residents recruited. The intervention package is presented in a kick-off meeting to GPs, nurses, residents/relatives or their representatives. Nursing home nurses act as change agents to support local adaption and implementation of the intervention measures. Primary outcome is the cumulative incidence of hospitalisation within 12 months. Secondary outcomes include admissions to hospital, days admitted to hospital, use of other medical services, prevalence of potentially inappropriate medication and quality of life. Additionally, health economic and a mixed methods process evaluation will be performed. Discussion This study investigates a complex intervention tailored to local needs of nursing homes. Outcomes reflect the healthcare and health of nursing home residents, as well as the feasibility of the intervention package and its impact on interprofessional communication and collaboration. Because of its systematic development and its flexible nature, interprof ACT is expected to be viable for large-scale implementation in routine care services regardless of local organisational conditions and resources available for medical care for nursing home residents on a regular basis. Recommendations will be made for an improved organisation of primary care for nursing home residents. In addition, the results may provide important knowledge and data for the development and evaluation of further strategies to improve outpatient care for elderly care-receivers. Trial registration ClinicalTrials.gov NCT03426475 . Initially registered on 7 February 2018.

We investigated sporadic Creutzfeldt-Jakob disease (sCJD) among physicians in Germany by analyzing occupational information of patients with sCJD recorded by the German CJD Surveillance Unit (1993–2005; 1,250 patients, of whom 4 [0.32%] were physicians) and the National Reference Center for Human Spongiform Encephalopathies (2006–2016; 1,491 patients, of whom 13 [0.87%] were physicians). Among the physicians, we did not identify any neurologists, neurosurgeons, psychiatrists, or pathologists. A cumulative sum test showed an increase in reported physicians over time. Data for 2017–2018 indicated an increased rate of physicians among all notified sCJD cases (5/239 [2.1%]) when we used the total population of Germany as control group. Our data suggest the possibility of an increased risk for sCJD among physicians in Germany. However, we can only speculate about the reasons, and larger multinational studies are needed to replicate the finding and to clarify whether this finding is a general or a country-specific phenomenon.

Background: To support innovative trial designs in a regulatory setting for pediatric-onset multiple sclerosis (MS), the study aimed to perform a systematic literature review and meta-analysis of relapse rates with interferon β (IFN β), fingolimod, and natalizumab and thereby demonstrate potential benefits of Bayesian and non-inferiority designs in this population. Methods: We conducted a literature search in MEDLINE and EMBASE from inception until 17 June 2020 of all studies reporting annualized relapse rates (ARR) in IFN β-, fingolimod-, or natalizumab-treated patients with pediatric-onset relapsing–remitting MS. These interventions were chosen because the literature was mainly available for these treatments, and they are currently used for the treatment of pediatric MS. Two researchers independently extracted data and assessed study quality using the Cochrane Effective Practice and Organization of Care – Quality Assessment Tool. The meta-analysis estimates were obtained by Bayesian random effects model. Data were summarized as ARR point estimates and 95% credible intervals. Results: We found 19 articles, including 2 randomized controlled trials. The baseline ARR reported was between 1.4 and 3.7. The meta-analysis-based ARR was significantly higher in IFN β-treated patients (0.69, 95% credible interval: 0.51–0.91) versus fingolimod (0.11, 0.04–0.27) and natalizumab (0.17, 0.09–0.31). Based on the meta-analysis results, an appropriate non-inferiority margin versus fingolimod could be in the range of 2.29–2.67 and for natalizumab 1.72–2.29 on the ARR ratio scale. A Bayesian design, which uses historical information for a fingolimod or natalizumab control arm, could reduce the sample size of a new trial by 18 or 14 patients, respectively. Conclusion: This meta-analysis provides evidence that relapse rates are considerably higher with IFNs versus fingolimod or natalizumab. The results support the use of innovative Bayesian or non-inferiority designs to avoid exposing patients to less effective comparators in trials and bringing new medications to patients more efficiently.

A decreasing trend in exacerbation rates has been observed in COPD. Because mortality is linked to exacerbations, it is of interest to investigate whether a similar time trend is also present in mortality rates. We performed a systematic review of placebo groups in published randomised controlled trials. Mortality rate was modelled based on a Poisson distribution for the event counts. Adding information on mortality as well as on newly published studies on a previous database, we performed a meta-regression. Among the 56 included studies representing 14 166 patients, an annual decrease in mortality rates of 6.1% (−0.6%, 12.6%) (p=0.073) was observed. Consistent results were obtained in subgroups as well as when adjusting for potential confounders. The correlation between exacerbation rate and mortality rate was positive but weak as well as insignificant. In summary, analysis of randomised controlled trials in COPD patients showed a decrease in mortality in the placebo arms over the last two decades. This effect is comparable to the previously observed decrease in annual exacerbation rate. Albeit insignificant, our results suggest that care is needed in the design of new trials or when comparing results from trials published many years apart.

Background: The German multi-centre cluster-randomised controlled trial interprof ACT investigated interventions to increase inter-professional collaboration between nursing home (NH) staff and local general practitioners to reduce hospitalisations and improve nursing homes residents’ (NHRs) quality of life. The trial was funded by the German Health Care Innovation Fund. Methods: Cost-effectiveness of interprof ACT interventions was evaluated and compared to current standard of care (SOC) over 12 months, including 622 NHRs in 34 NHs in Germany. Multiplying resource use of healthcare services with German-specific unit costs generated costs. Health outcome was measured in quality-adjusted life-years QALYs), utility by multiplying EQ-5D-5L values with German-specific utility weights. Incremental cost-effectiveness analysis used an intention-to-treat approach and scenario analyses (SAs). Net-benefit-regression and cost-effectiveness acceptability curves addressed uncertainty. A German healthcare insurance perspective was assumed. Results: Base case results showed non-significant cost savings of 851.88€ and non-significant QALY loss of –0,056. Discussion: Dependency levels at baseline were non-significantly higher in IG compared to control group (CG). Lack of baseline costing data eliminated possibility to evaluate changes in costs due to the interprof ACT measures for both groups. Conclusion: Interprof ACT interventions are not cost-effective compared to current SOC.

Abstract Background An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials. Methods We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (pB). Results Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); pB

Introduction Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that mainly affects young adults. Uncertainty is a major psychological burden of the disease from diagnosis to prognosis, enhanced by the pressure to make early decisions on a diverse set of immunotherapies. Watchful waiting for 1–2 years while adapting goals and lifestyle habits to life with a chronic disease represents another reasonable option for persons with MS (PwMS). A behaviour change programme based on evidence-based patient information (EBPI) is not available in standard care. This randomised controlled trial (RCT) with an embedded process evaluation investigates the efficacy and cost-effectiveness of a web-based behavioural lifestyle programme to change lifestyle behaviour and reduce inflammatory disease activity in PwMS.Methods and analysis A web-based behavioural intervention will be evaluated in an RCT aiming to recruit 328 persons with clinically isolated syndrome, suspected MS or confirmed MS for less than 1 year, who have not yet started immunotherapy. Moreover, a mixed-methods process evaluation and a health economic evaluation will be carried out. Participants will be recruited in at least 16 MS centres across Germany and randomised to an intervention group with 12 months of access to EBPI about lifestyle factors in MS, combined with a complex behaviour change programme or to a control group (optimised standard care). The combined primary endpoint is the incidence of new T2 lesions on MRI or confirmed relapses.Ethics and dissemination The study has been approved by the Ethics Committee of the Hamburg Chamber of Physicians (PV6015). Trial results will be communicated at scientific conferences and meetings and presented on relevant patient websites and in patient education seminars.Trial registration number ClinicalTrials.gov Registry (NCT03968172); Pre-results.

Background In patients with ST-segment elevation myocardial infarction (STEMI), it is unknown how patient delay modulates the beneficial effects of timely reperfusion.Aims To assess the prognostic significance of a contact-to-balloon time of less than 90 min on in-hospital mortality in different categories of symptom-onset-to-first-medical-contact (S2C) times.Methods A total of 20 005 consecutive patients from the Feedback Intervention and Treatment Times in ST-segment Elevation Myocardial Infarction (FITT-STEMI) programme treated with primary percutaneous coronary intervention (PCI) were included.Results There were 1554 deaths (7.8%) with a J-shaped relationship between mortality and S2C time. Mortality was 10.0% in patients presenting within 1 hour, and 4.9%, 6.0% and 7.3% in patient groups with longer S2C intervals of 1–2 hours, 2–6 hours and 6–24 hours, respectively. Patients with a short S2C interval of less than 1 hour (S2C

Background: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. ICD implantation decisions are currently based on reduced left ventricular ejection fraction (LVEF≤35%). However, in some patients, the non-arrhythmic death risk predominates thus diminishing ICD-therapy benefits. Based on previous observations, we tested the hypothesis that compared to the others, patients with nocturnal respiratory rate (NRR) ≥18 breaths per minute (brpm) benefit less from prophylactic ICD implantations. Methods: This prospective cohort study was a pre-defined sub-study of EU-CERT-ICD trial conducted at 44 centers in 15 EU countries between May 12, 2014, and September 6, 2018. Patients with ischaemic or non-ischaemic cardiomyopathy were included if meeting primary prophylactic ICD implantation criteria. The primary endpoint was all-cause mortality. NRR was assessed blindly from pre-implantation 24-hour Holters. Multivariable models and propensity stratification evaluated the interaction between NRR and the ICD mortality effect. This study is registered with ClinicalTrials.gov (NCT0206419). Findings: Of the 2,247 EU-CERT-ICD patients, this sub-study included 1,971 with complete records. In 1,363 patients (61.7 (12) years; 244 women) an ICD was implanted; 608 patients (63.2 (12) years; 108 women) were treated conservatively. During a median 2.5-year follow-up, 202 (14.8%) and 95 (15.6%) patients died in the ICD and control groups, respectively. NRR statistically significantly interacted with the ICD mortality effect (p = 0.0070). While the 1,316 patients with NRR