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.).

Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24†h.

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients. METHODS: This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with 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 electrocardiogram (ECG)-diagnosed atrial fibrillation. RESULTS: Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE ≥24 h were present at baseline in 259/2389 patients (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE ≥24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .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.

Does breast cancer modify the long-term relationship between lifestyle behaviors and mortality? A prospective analysis of breast cancer survivors and population-based controls.

BACKGROUND: Modifiable lifestyle factors are known to impact survival. It is less clear whether this differs between postmenopausal women ever diagnosed with breast cancer and unaffected women. METHODS: Women diagnosed with breast cancer and unaffected women of comparable age were recruited from 2002 to 2005 and followed up until 2020. Using baseline information, a lifestyle adherence score (range 0-8; categorized as low [0-3.74], moderate [3.75-4.74], and high [≥4.75]) was created based on the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. Cox regression and competing risks analysis were used to analyze the association of adherence to WCRF/AICR lifestyle recommendations with overall mortality and with death due to cardiovascular diseases and cancer, respectively. RESULTS: A total of 8584 women were included (2785 with breast cancer and 5799 without). With a median follow-up of 16.1 years there were 2006 total deaths. Among the deaths of known causes (98.6%), 445 were cardiovascular-related and 1004 were cancer-related. The average lifestyle score was 4.2. There was no differential effect of lifestyle score by case-control status on mortality. After adjusting for covariates, moderate (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57-0.76) and high (HR, 0.54; 95% CI, 0.47-0.63) adherence to WCRF/AICR lifestyle recommendations were significantly associated with a decrease in overall mortality. Similarly, in competing risks analysis, moderate and high adherence were associated with decreased mortality from cardiovascular diseases and from cancer. CONCLUSIONS: A healthy lifestyle can substantially reduce mortality risk in women. With low adherence to all WCRF/AICR guidelines in about a third of study participants, health interventions are warranted.

Radiofrequency ablation via catheter and transpapillary access in patients with cholangiocarcinoma (ACTICCA-2 trial) - a multicenter, randomized, controlled, open-label investigator-initiated trial.

BACKGROUND: Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. METHODS/DESIGN: ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. DISCUSSION: ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024.

Dual-Energy CT muscle fat fraction as a new imaging biomarker of body composition and survival predictor in critically ill patients.

OBJECTIVE: To analyze changes in the muscular fat fraction (FF) during immobilization at the intensive care unit (ICU) using dual-energy CT (DECT) and evaluate the predictive value of the DECT FF as a new imaging biomarker for morbidity and survival. METHODS: Immobilized ICU patients (n = 81, 43.2% female, 60.3 ± 12.7 years) were included, who received two dual-source DECT scans (CT1, CT2) within a minimum interval of 10 days between 11/2019 and 09/2022. The DECT FF was quantified for the posterior paraspinal muscle by two radiologists using material decomposition. The skeletal muscle index (SMI), muscle radiodensity attenuation (MRA), subcutaneous-/ visceral adipose tissue area (SAT, VAT), and waist circumference (WC) were assessed. Reasons for ICU admission, clinical scoring systems, therapeutic regimes, and in-hospital mortality were noted. Linear mixed models, Cox regression, and intraclass correlation coefficients were employed. RESULTS: Between CT1 and CT2 (median 21 days), the DECT FF increased (from 20.9% ± 12.0 to 27.0% ± 12.0, p = 0.001). The SMI decreased (35.7 cm2/m2 ± 8.8 to 31.1 cm2/m2 ± 7.6, p < 0.001) as did the MRA (29 HU ± 10 to 26 HU ± 11, p = 0.009). WC, SAT, and VAT did not change. In-hospital mortality was 61.5%. In multivariable analyses, only the change in DECT FF was associated with in-hospital mortality (hazard ratio (HR) 9.20 [1.78-47.71], p = 0.008), renal replacement therapy (HR 48.67 [9.18-258.09], p < 0.001), and tracheotomy at ICU (HR 37.22 [5.66-245.02], p < 0.001). Inter-observer reproducibility of DECT FF measurements was excellent (CT1: 0.98 [0.97; 0.99], CT2: 0.99 [0.96-0.99]). CONCLUSION: The DECT FF appears to be suitable for detecting increasing myosteatosis. It seems to have predictive value as a new imaging biomarker for ICU patients. CLINICAL RELEVANCE STATEMENT: The dual-energy CT muscular fat fraction appears to be a robust imaging biomarker to detect and monitor myosteatosis. It has potential for prognosticating, risk stratifying, and thereby guiding therapeutic nutritional regimes and physiotherapy in critically ill patients. KEY POINTS: The dual-energy CT muscular fat fraction detects increasing myosteatosis caused by immobilization. Change in dual-energy CT muscular fat fraction was a predictor of  in-hospital morbidity and mortality. Dual-energy CT muscular fat fraction had a predictive value superior to established CT body composition parameters.

Systematic comparison of approaches to analyze clustered competing risks data.

BACKGROUND: In many clinical trials the study interest lies in the comparison of a treatment to a control group regarding a time to event endpoint like time to myocardial infarction, time to relapse, or time to a specific cause of death. Thereby, an event can occur before the primary event of interest that alters the risk for or prohibits observing the latter, i.e. a competing event. Furthermore, multi-center studies are often conducted. Hence, a cluster structure might be observed. However, commonly only the aspect of competing events or the aspect of the cluster structure is modelled within primary analysis, although both are given within the study design. Methods to adequately analyze data in such a design were recently described but were not systematically compared yet. METHODS: Within this work we provide a systematic comparison of four approaches for the analysis of competing events where a cluster structure is present based on a real life data set and a simulation study. The considered methods are the commonly applied cause-specific Cox proportional hazards model with a frailty, the Fine and Gray model for considering competing risks, and extensions of the latter model by Katsahian et al. and Zhou et al. RESULTS: Based on our simulation results, the model by Katsahian et al. showed the best performance in bias, square root of mean squared error, and power in nearly all scenarios. In contrast to the other three models this approach allows both unbiased effect estimation and prognosis. CONCLUSION: The provided comparison and simulations help to guide applied researchers to choose an adequate method for the analysis of competing events where a cluster structure is present. Based on our simulation results the approach by Katsahian et al. can be recommended.

Disentangling pharmacological and expectation effects in antidepressant discontinuation among patients with fully remitted major depressive disorder: study protocol of a randomized, open-hidden discontinuation trial.

BACKGROUND: Antidepressants are established as an evidence-based, guideline-recommended treatment for Major Depressive Disorder. Prescriptions have markedly increased in past decades, with a specific surge in maintenance prescribing. Patients often remain on antidepressants longer than clinically necessary. When attempting to stop, many patients experience adverse discontinuation symptoms. Discontinuation symptoms can be debilitating and hinder successful discontinuation. While discontinuation symptoms can result from pharmacological effects, evidence on nocebo-induced side effects of antidepressant use suggests that patients' expectations may also influence occurrence. METHODS: To disentangle pharmacological and expectation effects in antidepressant discontinuation, patients with fully remitted Major Depressive Disorder who fulfill German guideline recommendations to discontinue will either remain on or discontinue their antidepressant. Participants' expectations will be manipulated by varying verbal instructions using an open-hidden paradigm. Within the open trial arms, participants will receive full information about treatment, i.e., high expectation. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant, i.e., moderate expectation. A total of N = 196 participants will be randomly assigned to either of the four experimental groups: open discontinuation (OD; n = 49), hidden discontinuation (HD; n = 49), open continuation (OC; n = 49), or hidden continuation (HC; n = 49). Discontinuation symptom load during the 13-week experimental phase will be our primary outcome measure. Secondary outcome measures include discontinuation symptom load during the subsequent 39-week clinical observation phase, recurrence during the 13-week experimental period, recurrence over the course of the complete 52-week trial evaluated in a time-to-event analysis, and stress, anxiety, and participants' attentional and emotional processing at 13 weeks post-baseline. Blood and saliva samples will be taken as objective markers of antidepressant blood serum level and stress. Optional rsfMRI measurements will be scheduled. DISCUSSION: Until today, no study has explored the interplay of pharmacological effects and patients' expectations during antidepressant discontinuation. Disentangling their effects has important implications for understanding mechanisms underlying adverse discontinuation symptoms. Results can inform strategies to manage discontinuation symptoms and optimize expectations in order to help patients and physicians discontinue antidepressants more safely and effectively. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05191277), January 13, 2022.

The Freestyle Valve in Severe Necrotizing Aortic Root Endocarditis: Comorbidity Upon Outcome.

BACKGROUND: Treatment of severe necrotizing aortic root endocarditis (SNARE) carries a substantial perioperative risk. As an alternative to homografts, we assessed short-term outcome and future prognosis in patients undergoing root replacement using the Freestyle valve. METHODS: Between 2000 and 2018, a total of 45 patients (mean age 70.9 ± 8.3 years, 66% men) underwent aortic root replacement for SNARE using the Freestyle valve. Mean Society of Thoracic Surgeons mortality score and EuroScore II were 22.6% ± 17.1 and 29.3% ± 20.9, respectively. Prosthetic endocarditis was present in 70.1%, and aortic annulus patch repair was performed in 64% of the patients. Median follow-up was 3.6 years (range: 0.1-14.5) and was 100% complete. RESULTS: The 30-day mortality was 15.5%. During follow-up, there were no reoperations, while reinfection was suspected in one patient. Survival was significantly inferior to the general population with a standardized mortality ratio of 10.7 (95% confidence interval [CI]: 9.1-12.6) (p < 0.0001). In 30-day survivors and after correction for significant comorbidities in a Cox proportional hazards model, estimated survival probabilities at 1, 5, and 10 years were 98.7 (95% CI: 92.5-99.8%), 94.1 (77.9-98.5%), and 63.8 (28.4-85.2%). Estimated mean difference in survival probability was better for the general population after postoperative year 6, but within the 95% CI for no difference. CONCLUSION: Use of the Freestyle valve is reliable solution for the most complex cases with a low rate of reinfection. Early mortality is substantial and caused by the patient's condition and severity of the infection. Excess late mortality can be attributed to patient-specific comorbidities.

Gender differences and cooperation in medical authorships - an analysis of the recent ten years in five key medical disciplines.

BACKGROUND: Career prospects in academic medicine are strongly linked to scientific authorship and this marker has been widely used as an indicator of gender equity in academia. However, direct comparisons of medical disciplines regarding their proportion of female physicians (FP) in different countries are missing. This study examines the gender parity and gender cooperation using first authorships (FA) and senior authorships (SA) of scientific publications in five medical disciplines and six different OECD countries over a 10-year time-trend. METHODS: Articles from three high-impact journals in each of the medical discipline radiology, urology, surgery, gynecology, and pediatrics from the years 2007/8 and 2017/18 were retrospectively reviewed. The gender and affiliation location of the FA and SA of original research articles and reviews were assigned and compared with the proportion of in each discipline for the United States of America, Canada, United Kingdom, France, Germany, and Japan. Mantel-Haenszel test and multinomial logistic regression models were used to calculate differences in proportions of women authors and FP and to assess trends and proportions of FA and SA. RESULTS: 30,803 articles were evaluated. Equally, with rising proportions of FP in all disciplines, the number of women authors increased across years. The shares of women FAs were either significantly higher (urology/surgery/gynecology) or balanced (pediatrics/radiology) compared to the proportion of FP. In contrast, the shares of women SA were balanced only in disciplines with a low proportion of FP (urology and surgery) and otherwise reduced. Women same-gender cooperation was as common as men same-gender cooperation and preferred over a women-led mixed gender cooperation in disciplines where this seemed to be practicable due to the high proportions of FP. CONCLUSION: In contrast to FA, a significant disparity persists in SA, particularly in disciplines with a high proportion of FP. The discrepancy between FA and SA may reflect, among others, dropout from an academic career in early or mid-academic levels, for example, due to structural inequality; together with the findings on gender preference in authorship collaborations, this may inform future strategies for promoting equal career advancement for women physicians.

Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure.

BACKGROUND: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction. METHODS: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF] <50%. RESULTS: This analysis included 798 patients (300 [37.6%] female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had heart failure and preserved LVEF (LVEF≥50%; mean LVEF 61±6.3%), the others had heart failure with midrange ejection fraction (n=211; LVEF 40%-49%; mean LVEF 44 ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31±5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomly assigned to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomly assigned to usual care (130/402; 7.9 per 100 patient-years; hazard ratio, 0.74 [0.56-0.97]; P=0.03), not altered by heart failure status (interaction P value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71 of 396 (17.9%) patients with heart failure randomly assigned to ERC and in 87 of 402 (21.6%) patients with heart failure randomly assigned to usual care (hazard ratio, 0.85 [0.62-1.17]; P=0.33). LVEF improved in both groups (LVEF change at 2 years: ERC 5.3±11.6%, usual care 4.9±11.6%, P=0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure. CONCLUSIONS: Rhythm control therapy conveys clinical benefit when initiated within 1 year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01288352. URL: http://www.controlled-trials.com; Unique identifier: ISRCTN04708680. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20.

Metabolic Syndrome Is Associated with Impaired Survival after Surgery for Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms. Surgery is the only curative treatment option. However, our understanding of predictors of survival after surgery remains incomplete. The aim of the study was to evaluate metabolic syndrome (MetS) as a prognostic factor in pNET. METHODS: In a retrospective single-center cohort study, we examined the influence of MetS in 120 patients with curative intended resection of pNETs on overall survival (OS), recurrence-free survival, and outcome after recurrence. RESULTS: MetS was present in 32 patients (26.6%). Patients with MetS had an impaired OS after curative intended surgery compared to patients without MetS (median OS 72 months [95% CI 13.3-130.7] vs. not reached, p < 0.001). The shortest survival was observed in patients with MetS in the presence of oligometastatic disease at time of surgery. In a multivariable Cox regression analysis, MetS was identified as an independent risk factor for mortality (hazard ratio [HR] = 4.54, 95% CI [1.88-11.00], p = 0.01). In our dataset, MetS was not associated with tumor recurrence or recurrence-free survival. Nevertheless, in patients with recurrence, MetS was associated with shorter time to recurrence (median 3.4 months, 95% CI [2.48-4.24], vs. 20.1 months, 95% CI [10.8-29.49], p < 0.001), and poor outcome (HR = 5.03, 95% CI [1.25-20.20], p = 0.01). CONCLUSIONS: We identified MetS as a negative prognostic factor after curative intended surgery for pNET. In particular, patients with oligometastatic disease might not benefit from extensive surgery in the presence of MetS. Furthermore, MetS had a strong impact on survival after recurrence.

Weighted composite time to event endpoints with recurrent events: comparison of three analytical approaches.

BACKGROUND: In clinical trials the study interest often lies in the comparison of a treatment to a control regarding a time to event endpoint. A composite endpoint allows to consider several time to event endpoints at once. Usually, only the time to the first occurring event for a patient is thereby analyzed. However, an individual may experience more than one non-fatal event. Including all observed events in the analysis can increase the power and provides a more complete picture of the disease. Thus, analytical methods for recurrent events are required. A challenge is that the different event types belonging to the composite often are of different clinical relevance. In this case, weighting the event types according to their clinical relevance is an option. Different weight-based methods for composite time to event endpoints were proposed. So far, there exists no systematic comparison of these methods. METHODS: Within this work we provide a systematic comparison of three methods proposed for weighted composite endpoints in a recurrent event setting combining non-fatal and fatal events of different clinical relevance. We consider an extension of an approach proposed by Wei and Lachin, an approach by Rauch et al., and an approach by Bakal et al.. Comparison is done based on a simulation study and based on a clinical study example. RESULTS: For all three approaches closed formula test statistics are available. The Wei-Lachin approach and the approach by Rauch et al. show similar results in mean squared error. For the approach by Wei and Lachin confidence intervals are provided. The approach by Bakal et al. is not related to a quantifiable estimand. The relevance weights of the different approaches work on different level, i.e. either on cause-specific hazard ratios or on event count. CONCLUSION: The provided comparison and simulations can help to guide applied researchers to choose an adequate method for the analysis of composite endpoints combining (recurrent) events of different clinical relevance. The approach by Wei and Lachin and Rauch et al. can be recommended in scenarios where the composite effect is time-independent. The approach by Bakal et al. should be applied carefully.

Study protocol of a randomized controlled trial evaluating home treatment with peer support for acute mental health crises (HoPe).

BACKGROUND: Home treatment (HT) is a treatment modality for patients with severe mental illness (SMI) in acute mental crises. It is frequently considered equivalent to psychiatric inpatient treatment in terms of treatment outcome. Peer Support (PS) means that people with lived experience of a mental illness are trained to support others on their way towards recovery. While PS is growing in international importance and despite a growing number of studies supporting its benefits, it is still not comprehensively implemented into routine care. The HoPe (Home Treatment with Peer Support) study investigates a combination of both - HT and PS - to provide further evidence for a recovery-oriented treatment of psychiatric patients. METHODS: In our randomized controlled trial (RCT), HT with PS is compared with HT without PS within a network of eight psychiatric clinical centers from the North, South and East of Germany. We investigate the effects of a combination of both approaches with respect to the prevention of relapse/recurrence defined as first hospitalization after randomization (primary outcome), disease severity, general functioning, self-efficacy, psychosocial health, stigma resistance, recovery support, and service satisfaction (secondary outcomes). A sample of 286 patients will be assessed at baseline after admission to HT care (data point t0) and randomized into the intervention (HT + PS) and control arm (HT). Follow-Up assessments will be conducted 2, 6 and 12 months after admission (resulting in three further data points, t1 to t3) and will be analyzed via intention-to-treat approach. DISCUSSION: This study may determine the positive effects of PS added to HT, prove additional evidence for the efficacy of PS and thereby facilitate its further implementation into psychiatric settings. The aim is to improve quality of mental health care and patients' recovery as well as to reduce the risk of relapses and hospitalizations for patients with SMI. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov: NCT04336527 , April 7, 2020.

Comparison of four diagnostic criteria for invasive pulmonary aspergillosis-A diagnostic accuracy study in critically ill patients.

BACKGROUND: In the absence of lung biopsy, there are various algorithms for the diagnosis of invasive pulmonary aspergillosis (IPA) in critically ill patients that rely on clinical signs, underlying conditions, radiological features and mycology. The aim of the present study was to compare four diagnostic algorithms in their ability to differentiate between probable IPA (i.e., requiring treatment) and colonisation. METHODS: For this diagnostic accuracy study, we included a mixed ICU population with a positive Aspergillus culture from respiratory secretions and applied four different diagnostic algorithms to them. We compared agreement among the four algorithms. In a subgroup of patients with lung tissue histopathology available, we determined the sensitivity and specificity of the single algorithms. RESULTS: A total number of 684 critically ill patients (69% medical/31% surgical) were included between 2005 and 2020. Overall, 79% (n = 543) of patients fulfilled the criteria for probable IPA according to at least one diagnostic algorithm. Only 4% of patients (n = 29) fulfilled the criteria for probable IPA according to all four algorithms. Agreement among the four diagnostic criteria was low (Cohen's kappa 0.07-0.29). From 85 patients with histopathological examination of lung tissue, 40% (n = 34) had confirmed IPA. The new EORTC/MSGERC ICU working group criteria had high specificity (0.59 [0.41-0.75]) and sensitivity (0.73 [0.59-0.85]). CONCLUSIONS: In a cohort of mixed ICU patients, the agreement among four algorithms for the diagnosis of IPA was low. Although improved by the latest diagnostic criteria, the discrimination of invasive fungal infection from Aspergillus colonisation in critically ill patients remains challenging and requires further optimization.

SARS-CoV-2 infection in patients with autoimmune hepatitis.

BACKGROUND & AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH). METHODS: Data for patients with AIH and SARS-CoV-2 infection were combined from 3 international reporting registries and outcomes were compared to those in patients with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD). RESULTS: Between 25th March and 24th October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) patients with AIH were taking ≥1 immunosuppressive drug. There were no differences in rates of major outcomes between patients with AIH and non-AIH CLD, including hospitalization (76% vs. 85%; p = 0.06), intensive care unit admission (29% vs. 23%; p = 0.240), and death (23% vs. 20%; p = 0.643). Factors associated with death within the AIH cohort included age (odds ratio [OR] 2.16/10 years; 1.07-3.81), and Child-Pugh class B (OR 42.48; 4.40-409.53), and C (OR 69.30; 2.83-1694.50) cirrhosis, but not use of immunosuppression. Propensity score matched (PSM) analysis comparing patients with AIH with non-AIH CLD demonstrated no increased risk of adverse outcomes including death (+3.2%; -9.2%-15.7%). PSM analysis of patients with AIH vs. non-CLD (n = 769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6-31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%-15.6%). CONCLUSION: Patients with AIH were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease. LAY SUMMARY: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from 3 large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.

Do Children With Functional Abdominal Pain Benefit More From a Pain-Specific Cognitive-Behavioral Intervention Than From an Unspecific Attention Control Intervention? Results of a Randomized Controlled Trial.

INTRODUCTION: We aimed to compare the efficacy of cognitive-behavioral therapy (CBT) among children with functional abdominal pain with an attention control (AC), hypothesizing the superiority of CBT group intervention regarding pain intensity (primary outcome), pain duration and frequency (further primary outcomes), functional disability, and quality of life and coping strategies (key secondary outcomes). METHODS: We conducted a prospective, multicenter, randomized controlled efficacy trial (RCT) with 4 time points (before intervention, after intervention, 3-month follow-up, and 12-month follow-up). One hundred twenty-seven children aged 7-12 years were randomized to either the CBT (n = 63; 55.6% girls) or the AC (n = 64; 57.8% girls). RESULTS: Primary endpoint analysis of the logarithmized area under the pain intensity curve showed no significant difference between groups (mean reduction = 49.04%, 95% confidence interval [CI] -19.98%-78.36%). Treatment success rates were comparable (adjusted odds ratio = 0.53, 95% CI 0.21-1.34, number needed to treat = 16). However, time trend analyses over the course of 1 year revealed a significantly greater reduction in pain intensity (40.9%, 95% CI 2.7%-64.1%) and pain duration (43.6%, 95% CI 6.2%-66.1%) in the CBT compared with the AC, but not in pain frequency per day (1.2, 95% CI -2.7 to 5.2). In the long term, children in the CBT benefitted slightly more than those in the AC with respect to functional disability, quality of life, and coping strategies. DISCUSSION: Both interventions were effective, which underlines the role of time and attention for treatment efficacy. However, in the longer term, CBT yielded more favorable results.

Hepatitis E seroprevalence and viremia rate in immunocompromised patients: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Hepatitis E is an infectious disease of the liver caused by the hepatitis E virus (HEV). Immunocompromised patients present a particular risk group, as chronification of hepatitis E leading to life-threatening cirrhosis occurs when these patients are infected. Therefore, this study aims to estimate and compare the anti-HEV seroprevalence and the rate of HEV RNA positivity in transplant recipients and patients with human immunodeficiency virus (HIV). METHODS: This systematic review and meta-analysis involved a literature search (PubMed, Scopus; 1,138 studies) including 120 studies from 1996 to 2019, reporting anti-HEV seroprevalence and/or HEV-RNA positivity. Statistical analysis was performed using a linear mixed-effects meta regression model. RESULTS: Anti-HEV seroprevalence in 14 626 transplant recipients ranged from 6% (95% CI: 1.9-17.2) to 29.6% (95% CI: 21.6-39.) in different commercially available assays and did not differ significantly compared to 20 825 HIV positive patients (range: 3.5% (95% CI: 0.9-12.8) - 19.4% (95% CI: 13.5-26.9). In contrast, HEV-RNA positivity rate was significantly higher in transplant recipients than in HIV positive patients (1.2% (95% CI: 0.9-1.6) vs 0.39% (95% CI: 0.2-0.7); P-value = 0.0011). CONCLUSION: Anti-HEV seroprevalence did not differ significantly between transplant recipients and HIV positive patients. Interestingly, rates of HEV-RNA positivity, indicating ongoing infection, were significantly higher in transplant recipients. These findings demonstrate that transplant patients have an elevated risk of chronic infection in comparison to HIV patients at comparable risk of HEV-exposure.

Gender trends in authorships and publication impact in Academic Radiology-a 10-year perspective.

OBJECTIVES: To analyze the development of publication numbers of female authors in high-, medium-, and low-impact radiological journals. METHODS: In this bibliometric analysis, gender of the first (FA) and senior author (SA) was assigned to all original research articles and reviews, published in 10 high-, medium-, and low-impact radiological journals in 2007/8 and 2017/18. The adjusted event rate (AER) and adjusted odds ratio (AOR) were calculated using mixed logistic and multinomial logistic regression models to assess and compare female publications according to impact factor, journal, author position, and combination. RESULTS: The proportion of female FA and female SA in N = 6979 (2007/2008) and N = 7383 (2017/2018) articles increased to 29.1% and 16.1% in 2017/2018, respectively. While most female authorships were continuously observed in medium-impact journals, the strongest increase occurred for both female FA (AOR 2.0; p < .0001) and SA (AOR 2.1; p < .0001) in low-impact journals. Female SA published significantly more often in a low- (AOR 1.5) or medium- (AOR 1.8) than in a high-ranking journal. Among the high-ranking journals, female FA published most frequently in European Radiology (32.4%; 95% CI [29.3-35.8]; p < .0001), female SA in Investigative Radiology (15.9%; 95% CI [13.7-18.4]; p < .0001). Male same-sex authorships decreased (AOR 0.9), but remained at least twice as common as all-female or mixed authorships. CONCLUSION: The increase in female authorship is reflected in all impact areas. Female FA and SA increased most in low-ranking journals but are most common in medium-ranking journals. Female SA remain rare, especially in high impact journals. KEY POINTS: • Compared to the proportion of female radiologists worldwide, female senior authors are underrepresented in all impact areas, in particular in high-impact journals. • Among the included high-ranking radiological journals, female first authors and senior authors were strongest represented in European Radiology and Investigative Radiology, while across all impact areas they mostly published in medium-ranking journals. • Female author combinations were more frequent in low- and medium- than in high-ranking journals, whereas male author combinations remained more common than female senior author collaborations in all impact areas.

Presence of donor specific HLA class 2 antibodies (DSA class 2) is associated with development of graft fibrosis more than 10 years after liver transplantation-a retrospective single center study.

Here the impact of donor specific human leukocyte antigen (HLA) class 2 antibodies (DSA cl 2) on long term outcome after liver transplantation (LT) was investigated. Altogether 156 (44 pediatric and 112 adult) LT recipients were included in the study. Graft fibrosis was assessed by liver elastography and biopsy. DSA cl 2 were determined by Luminex technology. 46% of LT recipients were positive for DSA cl 2 after a median follow-up of 15 years. In the multivariate analysis DSA cl 2 were significantly associated with immunosuppressive monotherapy (OR 5.42; 95% CI: 1.02-28.90; p = .048). Compared to DSA cl 2 negative patients, positive recipients had significantly more graft fibrosis based on the liver stiffness (mean 9.4 ± 9.0 kPa vs. 6.5 ± 6.3 kPa; p < .002) and fibrosis stages determined by liver elastography (p = .016) and the performed liver biopsies (p = .002). Also, a significantly higher incidence of chronic rejections (11% vs. 2%; p = .045) and graft losses (6% vs. 0%; p = .043) were found. In the multivariate regression analysis DSA cl 2 were significantly associated with graft fibrosis (OR 4.57; 95% CI 1.59-13.10; p = .005). So, these data suggest that development of DSA cl 2 occurs more often with immunosuppressive monotherapy and may ultimately result in chronic rejection and graft fibrosis.

Evolution of liver stiffness and post-treatment surveillance by liver elastography for HCV patients in the DAA era.

OBJECTIVE: Baseline liver stiffness (LS) is prognostically relevant in patients with chronic hepatitis C virus (HCV) infection but may change after successful HCV eradication. Data on post-treatment LS for a further risk stratification remain scarce. Here, we study the kinetics of LS and laboratory parameters in patients undergoing HCV treatment and analyze the association of post-treatment LS with outcome parameters. METHODS: In a cohort of 1011 chronic HCV patients undergoing DAA treatment, we identified 404 patients with sequential LS and laboratory assessments with or without viral eradication. Additionally, outcome parameters were correlated with post-treatment LS after successful HCV therapy. RESULTS: LS significantly decreased from a median of 8.8 to 6.1 kPa in 346 patients after HCV eradication, but significantly increased from a median of 10.5 to 11.9 kPa in 58 patients without viral clearance. In 78 patients with two sequential post-treatment measurements, LS decreased from 12.6 to 8.7 kPa after a median 344 d, with a further decrease to 7.0 kPa after a median of 986 d after end of treatment (EoT). In 400 patients with a post-treatment LS assessment after viral eradication, only 9 liver-related events occurred over a median follow-up (FU) of 23 months. All events were observed in patients with a post-treatment LS >20 kPa. CONCLUSIONS: After successful HCV eradication, LS improves sequentially, suggesting an initial phase of necroinflammation regression followed by a second phase of true fibrosis regression. Overall, liver-related events were rarely observed and seem to be limited to patients with a post-treatment LS >20 kPa, so that these patients require a closer clinical monitoring.