Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study.

BACKGROUND: Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. Their role in defining subphenotypes of AF is not known. METHODS AND RESULTS: This prespecified analysis of the EAST-AFNET4 biomolecule study assigned patients to clusters using polytomous variable latent class analysis (poLCA) based on baseline concentrations of thirteen precisely-quantified biomolecules potentially reflecting ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome, the primary outcome of EAST-AFNET 4, were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow up 2.9 years).Unsupervised biomolecule analysis assigned 1586 patients (71 years old, 46% women) into four clusters. The highest-risk cluster was dominated by elevated BMP10, IGFBP7, NT-proBNP, ANGPT2 and GDF15. Patients in the lowest-risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of hsCRP, IL-6, and D-dimer. Patients in the highest-risk cluster had a 5-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control was effective across clusters (pinteraction = 0.63). Sensitivity analyses and external validation in BBC-AF replicated clusters and risk gradients. CONCLUSIONS: Biomolecule concentrations identify cardiometabolic subphenotypes in patients with atrial fibrillation at high and low cardiovascular risk.

Diagnostic test accuracy in longitudinal study settings: theoretical approaches with use cases from clinical practice.

OBJECTIVES: In this study, we evaluate how to estimate diagnostic test accuracy (DTA) correctly in the presence of longitudinal patient data (ie, repeated test applications per patient). STUDY DESIGN AND SETTING: We used a nonparametric approach to estimate the sensitivity and specificity of three tests for different target conditions with varying characteristics (ie, episode length and disease-free intervals between episodes): 1) systemic inflammatory response syndrome (n = 36), 2) depression (n = 33), and 3) epilepsy (n = 30). DTA was estimated on the levels 'time', 'block', and 'patient-time' for each diagnosis, representing different research questions. The estimation was conducted for the time units per minute, per hour, and per day. RESULTS: A comparison of DTA per and across use cases showed variations in the estimates, which resulted from the used level, the time unit, the resulting number of observations per patient, and the diagnosis-specific characteristics. Intra- and inter-use-case comparisons showed that the time-level had the highest DTA, particularly the larger the time unit, and that the patient-time-level approximated 50% sensitivity and specificity. CONCLUSION: Researchers need to predefine their choices (ie, estimation levels and time units) based on their individual research aims, estimands, and diagnosis-specific characteristics of the target outcomes to make sure that unbiased and clinically relevant measures are communicated. In cases of uncertainty, researchers could report the DTA of the test using more than one estimation level and/or time unit.

Clinical effectiveness of patient-targeted feedback following depression screening in general practice (GET.FEEDBACK.GP): an investigator-initiated, prospective, multicentre, three-arm, observer-blinded, randomised controlled trial in Germany.

BACKGROUND: Screening for depression in primary care alone is not sufficient to improve clinical outcomes. However, targeted feedback of the screening results to patients might result in beneficial effects. The GET.FEEDBACK.GP trial investigated whether targeted feedback of the depression screening result to patients, in addition to feedback to general practitioners (GPs), leads to greater reductions in depression severity than GP feedback alone or no feedback. METHODS: The GET.FEEDBACK.GP trial was an investigator-initiated, multicentre, three-arm, observer-blinded, randomised controlled trial. Depression screening was conducted electronically using the Patient Health Questionnaire-9 (PHQ-9) in 64 GP practices across five regions in Germany while patients were waiting to see their GP. Currently undiagnosed patients (aged ≥18 years) who screened positive for depression (PHQ-9 score ≥10), were proficient in the German language, and had a personal consultation with a GP were randomly assigned (1:1:1) into a group that received no feedback on their depression screening result, a group in which only the GP received feedback, or a group in which both GP and patient received feedback. Randomisation was stratified by treating GP and PHQ-9 depression severity. Trial staff were masked to patient enrolment and study group allocation and GPs were masked to the feedback recieved by the patient. Written feedback, including the screening result and information on depression, was provided to the relevant groups before the consultation. The primary outcome was PHQ-9-measured depression severity at 6 months after randomisation. An intention-to-treat analysis was conducted for patients who had at least one follow-up visit. This study is registered at ClinicalTrials.gov (NCT03988985) and is complete. FINDINGS: Between July 17, 2019, and Jan 31, 2022, 25 279 patients were approached for eligibility screening, 17 150 were excluded, and 8129 patients completed screening, of whom 1030 (12·7%) screened positive for depression. 344 patients were randomly assigned to receive no feedback, 344 were assigned to receive GP-targeted feedback, and 339 were assigned to receive GP-targeted plus patient-targeted feedback. 252 (73%) patients in the no feedback group, 252 (73%) in the GP-targeted feedback group, and 256 (76%) in the GP-targeted and patient-targeted feedback group were included in the analysis of the primary outcome at 6 months, which reflected a follow-up rate of 74%. Gender was reported as female by 637 (62·1%) of 1025 participants, male by 384 (37·5%), and diverse by four (0·4%). 169 (16%) of 1026 patients with available migration data had a migration background. Mean age was 39·5 years (SD 15·2). PHQ-9 scores improved for each group between baseline and 6 months by -4·15 (95% CI -4·99 to -3·30) in the no feedback group, -4·19 (-5·04 to -3·33) in the GP feedback group, and -4·91 (-5·76 to -4·07) in the GP plus patient feedback group, with no significant difference between the three groups (global p=0·13). The difference in PHQ-9 scores when comparing the GP plus patient feedback group with the no feedback group was -0·77 (-1·60 to 0·07, d=-0·16) and when comparing with the GP-only feedback group was -0·73 (-1·56 to 0·11, d=-0·15). No increase in suicidality was observed as an adverse event in either group. INTERPRETATION: Providing targeted feedback to patients and GPs after depression screening does not significantly reduce depression severity compared with GP feedback alone or no feedback. Further research is required to investigate the potential specific effectiveness of depression screening with systematic feedback for selected subgroups. FUNDING: German Innovation Fund. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Statistical inference for diagnostic test accuracy studies with multiple comparisons.

Diagnostic accuracy studies assess the sensitivity and specificity of a new index test in relation to an established comparator or the reference standard. The development and selection of the index test are usually assumed to be conducted prior to the accuracy study. In practice, this is often violated, for instance, if the choice of the (apparently) best biomarker, model or cutpoint is based on the same data that is used later for validation purposes. In this work, we investigate several multiple comparison procedures which provide family-wise error rate control for the emerging multiple testing problem. Due to the nature of the co-primary hypothesis problem, conventional approaches for multiplicity adjustment are too conservative for the specific problem and thus need to be adapted. In an extensive simulation study, five multiple comparison procedures are compared with regard to statistical error rates in least-favourable and realistic scenarios. This covers parametric and non-parametric methods and one Bayesian approach. All methods have been implemented in the new open-source R package cases which allows us to reproduce all simulation results. Based on our numerical results, we conclude that the parametric approaches (maxT and Bonferroni) are easy to apply but can have inflated type I error rates for small sample sizes. The two investigated Bootstrap procedures, in particular the so-called pairs Bootstrap, allow for a family-wise error rate control in finite samples and in addition have a competitive statistical power.

Discrimination of benign, atypical, and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 using diffusion-weighted MRI.

Background: Neurofibromatosis type 1 (NF1) is associated with the development of benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumors. Recently described atypical neurofibromas (ANF) are considered pre-malignant precursor lesions to MPNSTs. Previous studies indicate that diffusion-weighted magnetic resonance imaging (DW-MRI) can reliably discriminate MPNSTs from BPNSTs. We therefore investigated the diagnostic accuracy of DW-MRI for the discrimination of benign, atypical, and malignant peripheral nerve sheath tumors. Methods: In this prospective explorative single-center phase II diagnostic study, 44 NF1 patients (23 male; 30.1 ±â€…11.8 years) underwent DW-MRI (b-values 0-800 s/mm²) at 3T. Two radiologists independently assessed mean and minimum apparent diffusion coefficients (ADCmean/min) in areas of largest tumor diameters and ADCdark in areas of lowest signal intensity by manual contouring of the tumor margins of 60 BPNSTs, 13 ANFs, and 21 MPNSTs. Follow-up of ≥ 24 months (BPNSTs) or histopathological evaluation (ANFs + MPNSTs) served as diagnostic reference standard. Diagnostic ADC-based cut-off values for discrimination of the three tumor groups were chosen to yield the highest possible specificity while maintaining a clinically acceptable sensitivity. Results: ADC values of pre-malignant ANFs clustered between BPNSTs and MPNSTs. Best BPNST vs. ANF + MPNST discrimination was obtained using ADCdark at a cut-off value of 1.6 × 10-3 mm2/s (85.3% sensitivity, 93.3% specificity), corresponding to an AUC of 94.3% (95% confidence interval: 85.2-98.0). Regarding BPNST + ANF vs. MPNST, best discrimination was obtained using an ADCdark cut-off value of 1.4 × 10-3 mm2/s (83.3% sensitivity, 94.5% specificity). Conclusions: DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Background: Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. Methods/design: The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). Discussion: This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. Clinical Trial Registration: EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Biomarkers for predicting atrial fibrillation: An explorative sub-analysis of the randomised SCREEN-AF trial.

BACKGROUND: Atrial fibrillation (AF) is a common treatable risk factor for stroke. Screening for paroxysmal AF in general practice is difficult, but biomarkers might help improve screening strategies. OBJECTIVES: We investigated six blood biomarkers for predicting paroxysmal AF in general practice. METHODS: This was a pre-specified sub-study of the SCREEN-AF RCT done in Germany. Between 12/2017-03/2019, we enrolled ambulatory individuals aged 75 years or older with a history of hypertension but without known AF. Participants in the intervention group received active AF screening with a wearable patch, continuous ECG monitoring for 2x2 weeks and usual care in the control group. The primary endpoint was ECG-confirmed AF within six months after randomisation. High-sensitive Troponin I (hsTnI), brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), N-terminal pro atrial natriuretic peptide (NT-ANP), mid-regional pro atrial natriuretic peptide (MR-pro ANP) and C-reactive protein (CRP) plasma levels were investigated at randomisation for predicting AF within six months after randomisation. RESULTS: Blood samples were available for 291 of 301 (96.7%) participants, including 8 with AF (3%). Five biomarkers showed higher median results in AF-patients: BNP 78 vs. 41 ng/L (p = 0.012), NT-pro BNP 273 vs. 186 ng/L (p = 0.029), NT-proANP 4.4 vs. 3.5 nmol/L (p = 0.027), MR-pro ANP 164 vs. 125 pmol/L (p = 0.016) and hsTnI 7.4 vs. 3.9 ng/L (p = 0.012). CRP levels were not different between groups (2.8 vs 1.9 mg/L, p = 0.1706). CONCLUSION: Natriuretic peptide levels and hsTnI are higher in patients with AF than without and may help select patients for AF screening, but larger trials are needed.

BNP, NT-pro BNP, NT-ANP and MR-pro ANP and hsTnI levels are higher in patients with AF than without AFWith a sensitivity at 100%, BNP had the highest specificity of 60% (BNP level 50.1ng/L), followed by NT-pro BNP with a specificity of 53% (179ng/l).

A diagnostic phase III/IV seamless design to investigate the diagnostic accuracy and clinical effectiveness using the example of HEDOS and HEDOS II.

The development process of medical devices can be streamlined by combining different study phases. Here, for a diagnostic medical device, we present the combination of confirmation of diagnostic accuracy (phase III) and evaluation of clinical effectiveness regarding patient-relevant endpoints (phase IV) using a seamless design. This approach is used in the Thyroid HEmorrhage DetectOr Study (HEDOS & HEDOS II) investigating a post-operative hemorrhage detector named ISAR-M THYRO® in patients after thyroid surgery. Data from the phase III trial are reused as external controls in the control group of the phase IV trial. An unblinded interim analysis is planned between the two study stages which includes a recalculation of the sample size for the phase IV part after completion of the first stage of the seamless design. The study concept presented here is the first seamless design proposed in the field of diagnostic studies. Hence, the aim of this work is to emphasize the statistical methodology as well as feasibility of the proposed design in relation to the planning and implementation of the seamless design. Seamless designs can accelerate the overall trial duration and increase its efficiency in terms of sample size and recruitment. However, careful planning addressing numerous methodological and procedural challenges is necessary for successful implementation as well as agreement with regulatory bodies.

Different perspectives in psychiatry: how family-oriented are professionals in Germany?

ΒACKGROUND: Children of parents with a mental illness have up to 50% chance of developing a mental illness themselves. Numerous studies have shown that preventive family-oriented interventions can decrease the risk by 40% and that professionals are a decisive factor influencing family-oriented practice. There are also substantial differences between professions in terms of their family-oriented practices. This study examines the level of family-oriented practice for different professional groups in Germany. METHODS: Data were used from the baseline assessment of the two-group randomized controlled multicenter trial ci-chimps as a subproject of CHIMPS-NET, which took place from January 2020 to May 2021 in 18 clinical centers in Germany. Child and adolescent mental health systems as well as adult mental health systems took part and every professional involved in the treatment was invited to participate. Data was used from 475 mental health professionals including physicians, psychologists, psychotherapists for adults and for children and adolescents, occupational/ music/ physio/ art therapists/ (social) education workers and nursing/ education service. Family-oriented mental health practice was examined using the translated version of the Family-Focused Mental Health Practice Questionnaire (FFMHPQ) with means and standard deviations calculated for each of the 18 FFMHPQ-GV subscales. ANOVAs were computed to compare professions and significant differences were examined via post hoc analyses (Scheffé). Additionally, effect sizes were calculated (Omega squared). RESULTS: Differences were seen between the professions in all aspects of family-oriented practice: Both regarding organizational policy and support aspects, issues concerning working with parent-clients, as well as professional skills and knowledge aspects. Psychotherapists for children and adolescents scored the highest family-oriented practices compared to all other professional groups on almost all subscales. CONCLUSION: This study examines the level of family-oriented practice for different professional groups in Germany. Apart from skills and knowledge about the impact of mental illness and parenting, psychotherapists for children and adolescents had the highest scores and engaged most in family-oriented practice. Psychotherapists for adults got the least workplace support for family-oriented practice but were competent providing resources and referral information to the concerned families and feel confidence working with them. Due to these results, a training need exists to improve skills and knowledge about the impact of mental illness and parenting. Additionally, there is still potential for institutional support in promoting family-oriented work. TRIAL REGISTRATION: The CHIMPS-NET-study was registered with the German Clinical Trials Register on 2019-12-19 (DRKS00020380) and with Clinical Trials on 2020-4-30 (NCT04369625), the ci-chimps-study was registered with the German Clinical Trials Register (DRKS00026217) on 2021-08-27 and with Clinical Trials on 2021-11-04 (NCT05106673).

The impact of inaccurate assumptions about antibody test accuracy on the parametrisation and results of infectious disease models of epidemics.

The parametrisation of infectious disease models is often done based on epidemiological studies that use diagnostic and serology tests to establish disease prevalence or seroprevalence in the population being modelled. During outbreaks of an emerging infectious disease, tests are often used, both for disease control and epidemiological studies, before studies evaluating their accuracy in the population have concluded, with assumptions made about accuracy parameters like sensitivity and specificity. In this simulation study, we simulated such an outbreak, based on the case study of COVID-19, and found that inaccurate parametrisation of infectious disease models due to assumptions about antibody test accuracy in a seroprevalence study can cause modelling results that inform public health decisions to be inaccurate; for example, in our simulation setup, assuming that antibody test specificity was 0.99 instead of 0.90 when it was in fact 0.90 led to an average relative difference of 0.78 in model-projected peak hospitalisations, even when test sensitivity and all other parameters were accurately characterised. We therefore suggest that methods to speed up test evaluation studies are vitally important in the public health response to an emerging outbreak.

Regression Analyses and Their Particularities in Observational Studies.

BACKGROUND: Regression analysis is a standard method in medical research. It is often not clear, however, how the individual components of regression models are to be understood and interpreted. In this article, we provide an overview of this type of analysis and discuss its special features when used in observational studies. METHODS: Based on a selective literature review, the individual components of a regression model for differently scaled outcome variables (metric: linear regression; binary: logistic regression; time to event: Cox regression; count variable: Poisson or negative binomial regression) are explained, and their interpretation is illustrated with respect to a study on multiple sclerosis. The prerequisites for the use of each of these models, their applications, and their limitations are described in detail. RESULTS: Regression analyses are used to quantify the relation between several variables and the outcome variable. In randomized clinical trials, this flexible statistical analysis method is usually lean and prespecified. In observational studies, where there is a need to control for potential confounders, researchers with knowledge of the topic in question must collaborate with experts in statistical modeling to ensure high model quality and avoid errors. Causal diagrams are an increasingly important basis for evaluation. They should be constructed in collaboration and should differentiate between confounders, mediators, and colliders. CONCLUSION: Researchers need a basic understanding of regression models so that these models will be well defined and their findings will be fully reported and correctly interpreted.

Direct Oral Anticoagulants for Stroke Prevention in Patients with Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials.

Background: Device-detected atrial fibrillation (AF) (also known as subclinical AF or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear. Methods: We performed a systematic review of MEDLINE and Embase for randomized trials comparing oral anticoagulation to antiplatelet or no antithrombotic therapy in adults with device-detected AF recorded by a pacemaker, implantable cardioverter-defibrillator, cardiac resynchronization therapy device or implanted cardiac monitor. We used random-effects models for meta-analysis and rated the quality of evidence using the GRADE framework. The review was pre-registered (PROSPERO CRD42023463212). Results: From 785 unique citations, we identified two randomized trials with relevant clinical outcome data; NOAH-AFNET 6 (2,536 participants) evaluated edoxaban and ARTESiA (4,012 participants) evaluated apixaban. Meta-analysis demonstrated that oral anticoagulation with these agents reduced ischemic stroke (relative risk [RR] 0.68, 95% confidence interval [CI] 0.50-0.92; high-quality evidence). The results from the two trials were consistent (I2 statistic for heterogeneity=0%). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction or pulmonary embolism (RR 0.85, 95% CI 0.73-1.00, I2=0%; moderate-quality evidence). There was no reduction in cardiovascular death (RR 0.95, 95% CI 0.76-1.17, I2=0%; moderate-quality evidence) or all-cause mortality (RR 1.08, 95% CI 0.96-1.21 I2=0%; moderate-quality evidence). Oral anticoagulation increased major bleeding (RR 1.62, 95% CI 1.05-2.5 I²=61%; high-quality evidence). Conclusions: The results of the NOAH-AFNET 6 and ARTESiA trials are consistent with each other. Meta-analysis of these two large randomized trials provides high-quality evidence that oral anticoagulation with edoxaban or apixaban reduces the risk of stroke in patients with device-detected AF and increases the risk of major bleeding.

Anticoagulation with edoxaban in patients with long Atrial High-Rate Episodes ≥24†hours.

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHRE) ≥ 24 hours and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared to no anticoagulation in these patients. METHODS: This secondary prespecified analysis of NOAH-AFNET 6 examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared to placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and ECG-diagnosed atrial fibrillation. RESULTS: AHRE ≥24 hours were present at baseline in 259/2389 patients enrolled in NOAH-AFNET 6 (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc score 4). Clinical characteristics were not different from patients with shorter AHRE. During a median follow-up of 1.8 years, the primary outcome occurred in 9/132 patients with AHRE ≥24 hours (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). AHRE duration did not interact with the efficacy (p-interaction = 0.65) or safety (p-interaction = 0.98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 hours developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; p < 0.001). CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

Psychological risk factors for Long COVID and their modification: study protocol of a three-arm, randomised controlled trial (SOMA.COV).

BACKGROUND: Growing evidence suggests that in addition to pathophysiological, there are psychological risk factors involved in the development of Long COVID. Illness-related anxiety and dysfunctional symptom expectations seem to contribute to symptom persistence. AIMS: With regard to the development of effective therapies, our primary aim is to investigate whether symptoms of Long COVID can be improved by a targeted modification of illness-related anxiety and dysfunctional symptom expectations. Second, we aim to identify additional psychosocial risk factors that contribute to the persistence of Long COVID, and compare them with risk factors for symptom persistence in other clinical conditions. METHOD: We will conduct an observer-blinded, three-arm, randomised controlled trial. A total of 258 patients with Long COVID will be randomised into three groups of equal size: targeted expectation management in addition to treatment as usual (TAU), non-specific supportive treatment plus TAU, or TAU only. Both active intervention groups will comprise three individual online video consultation sessions and a booster session after 3 months. The primary outcome is baseline to post-interventional change in overall somatic symptom severity. CONCLUSIONS: The study will shed light onto the action mechanisms of a targeted expectation management intervention for Long COVID, which, if proven effective, can be used stand-alone or in the context of broader therapeutic approaches. Further, the study will enable a better understanding of symptom persistence in Long COVID by identifying additional psychological risk factors.

Factors influencing the duration of untreated illness among patients with anorexia nervosa: A multicenter and multi-informant study.

INTRODUCTION: The duration of untreated illness (DUI), that is, the interval between the onset of anorexia nervosa (AN) symptoms and start of specialized treatments, has a strong influence on the prognosis. OBJECTIVE: To quantify modifiable predictors of the DUI and to derive recommendations for secondary prevention strategies. METHODS: Within a multicenter, multi-informant study, DUI was assessed in interviews with patients undergoing first specialized AN treatment. Modifiable factors were assessed perspectives of AN-patients, their relatives, and primary care practitioners [PCPs]) with the FABIANA-checklist (Facilitators and barriers in anorexia nervosa treatment initiation). The effect of FABIANA-items on the DUI for each perspective was calculated using Cox Regression (control variables: age, eating disorder pathology, health care status, migration background, body mass index [BMI]). RESULTS: We included data from N = 125 female patients with AN (72 adults, 53 adolescents, Mage = 19.2 years, SD = 4.2, MBMI = 15.7 kg/m2 , SD = 1.9), N = 89 relatives (81.8% female, 18.2% male, Mage = 46.0 years, SD = 11.0) and N = 40 PCPs (Mage = 49.7 years, SD = 9.0). Average DUI was 12.0 months. Watching or reading articles about the successful treatment of other individuals with AN (patients' perspective) and regular appointments with a PCP (PCPs' perspective) were related to a shorter DUI (HR = 0.145, p = .046/ HR = 0.395, p = .018). Patients whose relatives rated that PCPs trivialized patients' difficulties had a longer DUI (HR = -0.147, p = .037). PCPs and relatives rated PCPs' competence higher than patients did. DISCUSSION: It is recommended (a) to incorporate treatment success stories in prevention strategies, (b) to inform PCPs about potential benefits of regular appointments during the transition to specialized care, and (c) to train PCPs in dealing with patients' complaints. PUBLIC SIGNIFICANCE: Many individuals with AN seek treatment very late. Our study shows that a promising approach to facilitate earlier AN treatment is to inform patients about successful treatments of affected peers, to foster regular appointments with a PCP and, to motivate these PCPs to take individuals' with AN difficulties seriously. Thus, our study provides important suggestions for interventions that aim to improve early treatment in AN.

Impact of Introducing a PACU24 Concept on the Perioperative Outcome of Patients with Advanced Ovarian Cancer Treated with Cytoreductive Surgery.

Introduction: Patients with ovarian cancer who undergo multivisceral surgery usually require intensive care monitoring postoperatively. In view of the ever-fewer numbers of high-care/intensive care beds and the introduction of fast-track treatment concepts, it is increasingly being suggested that these patients should be cared for postoperatively in 24-h Post Anesthesia Care Units (PACU24). No analyses have been carried out to date to investigate whether such a postoperative care concept might be associated with a potential increase in postoperative complications in this patient cohort. Methods: A PACU24 unit was set up in our institution in 2015 and it has become the primary postoperative care pathway for patients with ovarian cancer who have undergone cytoreductive (debulking) surgery. A structured, retrospective analysis of data from patients treated before (control group) and after (PACU group) the introduction of this care concept was carried out, with a particular focus on postoperative complications and secondary admission to an intensive care unit where necessary. Results: The data of 42 patients were analyzed for the PACU group and 45 patients for the control group. According to the analysis, the preoperative and surgical data of both groups were comparable (age, ASA, BMI, FIGO stage, duration of surgery, blood loss). The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM score) as a measure for the risk of postoperative complications was higher in the PACU group (11.1% vs. 9.7%, p = 0.001). Patients in the PACU group underwent bowel resection with anastomosis significantly more often (76.3% vs. 33.3%, p < 0.001), although the extent of surgery was otherwise comparable. The total number, type and severity of postoperative complications and the duration of the overall stay in hospital did not differ between the two groups. None of the patients required secondary transfer from the PACU or normal ward to an intensive care unit (ICU). Summary: Our data support the assumption that the care concept of transferring patients to a PACU24 represents a safe and cost-saving care pathway for the postoperative care of patients even after complex gynecological-oncological procedures.

Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes.

BACKGROUND: Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known. METHODS: We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding. RESULTS: The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year). CONCLUSIONS: Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups. (Funded by the German Center for Cardiovascular Research and others; NOAH-AFNET 6 ClinicalTrials.gov number, NCT02618577; ISRCTN number, ISRCTN17309850.).