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Abstract Background There is a vicious cycle between unemployment and mental health issues. Unemployed individuals with mental health issues require individualized support at multiple levels in order to promote their mental health, and obtain and retain employment. The 3for1-intervention program aims to provide such support with three components (short-term psychotherapy, job coaching based on the Individual Placement and Support approach, and peer support). This study protocol outlines how the effectiveness of this three-component intervention program in terms of re-employment, mental health, and psychosocial outcomes will be evaluated. Methods The 3for1-intervention program will be evaluated with a non-randomized controlled trial design in a multi-center study. 500 eligible participants aged between 18 and 60 years from six job centers in Southern Germany will be allocated to a control group or an intervention group. Allocation is time-based, with the control group being recruited first, followed by recruitment of the intervention group. The control group will receive treatment as usual, whereas the intervention group will receive treatment as usual as well as access to the three intervention components over a period of 12 months. Assessment will be conducted at baseline (t0), and 12 (t1) and 18 (t3) months later. The primary outcome will be the proportion of participants who are in employment subject to social insurance contributions at t1. Differences between control and intervention group will be tested with logistic regression analysis, controlling for relevant covariates. Analyses of secondary outcomes will relate to group differences regarding re-employment, health and well-being, social integration, help-seeking, and self-stigma at t1 and t2, applying logistic regression analysis or analysis of covariance. Additionally, usage of health services will be measured to evaluate the intervention program’s cost effectiveness. Discussion The 3for1-intervention aims to improve employability and mental health outcomes of a vulnerable population with high need for assistance. Improvements for this population would benefit the German welfare state as well. This study could provide valuable insights into the feasibility, implementation, and sustainability of this individualized, multi-level support program within German job centers. Trial registration This trial is registered with the German Clinical Trials Register: DRKS00029002 (registered on 11 May 2022).

Abstract Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response and recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed and 321 liquid biopsies of 87 patients sequenced. Mean sequencing depth after deduplication using UMIs was 6000x and the error rate of UMI-corrected reads was 2.47×10−4. Variant allele fractions correlated with PET/CT MTV (rho=0.69), S100 (rho=0.72), and LDH (rho=0.54). A decrease of allele fractions between T1 and T2 was associated with improved PFS and OS in the palliative cohort (p = 0.008 and p

Cancer peptide vaccination represents a promising therapeutic approach, but has been hampered by lack of suitable antigens and restricted applicability due to different HLA backgrounds of individual patients. We here introduce a novel warehouse-based concept for composition of personalized peptide vaccines and report on its successful application in a Phase II clinical trial in patients with chronic lymphocytic leukemia (CLL) after first-line therapy. 26 CLL patients in at least partial remission (PR) after 6 months of immuno-chemotherapy were vaccinated with a personalized vaccine compiled from a premanufactured peptide warehouse comprising immunopeptidome-defined CLL-associated peptides. Primary objective was evaluation of immunogenicity, secondary objectives were safety and minimal residual disease (MRD) response. Immunopeptidome-guided vaccine composition was throughout successful, proving the feasibility of warehouse-based vaccine design. Vaccination was well tolerated, with local injection site reactions being the most common adverse event. Only few patients showed vaccine-induced T cell responses, attributable to their inability to mount strong immune responses due to immune-chemotherapy and lack of potent adjuvant formulations. Both issues are addressed within a follow-up trial (NCT04688385), combining the immunopeptidome-guided warehouse-based vaccine design reported here with a potent novel adjuvant evaluating personalized multi- peptide vaccination in CLL patients under T cell supportive BTK inhibitor therapies.Clinical trial registrationwww.clinicaltrialsregister.eu, identifier NCT02802943.

IntroductionAcute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome.MethodsBased on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial’s primary objectives are the assessment of the vaccine’s immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy.Ethics and disseminationThe AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.

IntroductionDuring the communicable coronavirus disease (COVID-19) pandemic, organizational infection control measures (oICMs) were introduced in the workplace. The employees’ positive attitudes and active participation are relevant for full effectiveness regarding disease prevention. Therefore, we explore changes in employees’ attitudes toward oICM at work from August–October 2020 (T0) over January 2021 (T1) to October–November 2021 (T2). We further investigate the role an organization can play in supporting health-related preventive behavior.MethodsWe considered repeated cross-sectional and longitudinal panel survey data from 5,554 employees of a global supplier of technology and services in Germany. A total of 16 items constitute the attitude scores toward oICM (5-point Likert scale). Via mixed-effect model, aspects associated with employees’ attitudes toward oICM were explored. Via ‘extreme-group’ approach, we compared the 20% of participants with the largest changes into less favorable to the 20% with the largest changes into more favorable attitudes toward oICM over time.ResultsThe overall positive attitudes toward work-related oICM were more favorable at T1 (mean ± SD: 4.2 ± 0.6, median (IQR): 4.3 (0.8), n = 2,515) compared to T0 (4.1 ± 0.6, 4.1 (0.8), n = 2,417) but less favorable at T2 (3.9 ± 0.7, 4.0 (0.9), n = 2,062). Among others, feeling well-informed about possible work-related risks of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), perceived psychosocial demands through work environment aspects, and perceived management’s commitment to safety and health were associated with long-term positive attitudes toward oICM. Individuals developing more favorable attitudes toward oICM reported feeling well-informed about possible work-related SARS-CoV-2 infection risks and improved COVID-19-specific resilience over time. Individuals developing less favorable attitudes toward oICM reported decreased perceptions of COVID-19-associated risks.ConclusionoICMs in the workplace were perceived appropriate even after COVID-19 vaccines were widely available although the perceived affective risks about SARS-CoV-2 decreased. Taken together, our findings highlight how organizations can support employees in adopting health-related preventive behavior. Among others, we found that feeling well-informed about possible work-related health risks was positively associated with long-term favorable attitudes toward work-related oICM. We expect that the results contribute to the development of interventions to prepare and adapt to future global public health concerns.

Abstract Background Accurate assessment and enhancement of health-related skills among oncology patients are pivotal for optimizing cancer care. The Patient Activation Measure (PAM-13), a questionnaire designed to reflect an individual’s knowledge, skills, and confidence in self-healthcare management, has been validated across diverse countries and settings. Concerns have been raised regarding the cross-situational applicability, as patients with specific diseases and cultural backgrounds interpret questionnaire items differently. This study aimed to examine the structural validity and psychometric properties of the PAM-13 in an oncological patient cohort. Methods Baseline data from a longitudinal non-randomized controlled study involving cancer out-patients (n = 1,125) from Comprehensive Cancer Centres in Southern Germany were analysed. The German version of the PAM-13 was employed. With classical test and item response theory methods data quality, reliability, convergent and structural validity, as well as psychometric properties were assessed. Exploratory (EFA) and confirmatory factor analyses (CFA) were employed to investigate the postulated unidimensionality of the underlying construct. With a partial credit model (PCM) we examined item fit, targeting, local independence and differential item functioning. Results Participants were predominantly female (73.0%) with a breast cancer diagnosis (41.3%). While items were generally well-accepted, ceiling effects were observed and a high mean PAM-13 score (69.7, SD = 14.2) was noted, potentially compromising responsiveness to interventions. Reliability was adequate (Cronbach’s α = 0.81), person and item separation reliability were good to excellent (0.81 and 0.99, respectively). Explorations of the unidimensionality of the construct (EFA, CFA, PCM) yielded inconclusive results, hinting towards a two-factor solution. Item difficulty rankings deviated from the original. No differential item functioning was identified, and local independence was confirmed. Conclusions While the PAM-13 serves as a valuable instrument for comprehending and promoting health-related skills in cancer patients, the identification of ceiling effects, disordered item-difficulty rankings, and inconclusive findings regarding unidimensionality contribute to the expanding body of evidence, emphasizing the dependency of PAM-13’s validity and reliability on distinctive characteristics within the population under investigation. Future research should prioritize refining or adding PAM-13 items to better capture the specific health-related challenges within diverse populations, paving the way for more effective patient engagement strategies in oncology. Trial registration number DRKS00021779

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton’s tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured “peptide warehouse” based on the patient’s individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.

Abstract Objective To assess the effectiveness of exercise and education in addition to standard care (SC) compared to SC alone in patients with hip or knee osteoarthritis (OA) during 24 months follow-up. Design We conducted a quasi-experimental pragmatic clinical trial in care centers of a health insurance company. Overall, 1,030 subjects with hip and/or knee OA were included. The intervention group was recruited from clients participating in a hip/knee training (HKT, n = 515) in addition to SC. The control group (CO, n = 515) receiving SC only was recruited from the insurance database. HKT comprised 8 group sessions (1/week) of exercise and education, complemented by a 11-week structured home-exercise program (2/week). Primary endpoints were change of joint-related pain and function (WOMAC Index, score 0–10) after 3 months. Secondary endpoints related to follow-ups at 6, 12 and 24 months. All patient reported outcome measures were analyzed using linear mixed models (LMMs) investigating a time x treatment effect. A multivariable cox proportional hazards regression model was used to identify differences of joint replacement during follow-up between groups. Results LMMs revealed statistically significant differences in favor of HKT for the primary outcomes WOMAC pain = 0.47 (CI 0.27–0.66; Effect Size (ES) = 0.22, p

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals.Trial registration numbersEU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Abstract Background Current health care demonstrates an insufficient provision and utilization of physical exercises despite their recommendation as a first-line treatment in clinical guidelines for patients with knee osteoarthritis (OA). Mobile health (m-health) technologies offer new opportunities to guide and monitor home-based exercise programs by using mobile devices and inertial sensors in combination with a digital application (app). This study will evaluate patient benefits resulting from the use of the specific digital health application re.flex for patients with knee OA. Methods This monocentric, two-arm, randomized controlled parallel-group trial will evaluate the effectiveness of the app- and sensor-guided exercise program re.flex for patients with moderate-to-severe knee OA. We aim to recruit 200 participants via newspapers, newsletters and information events. Participants will be randomly allocated to the intervention group and the control group in a 1:1 ratio. Participants in the control group will not receive any study intervention or instruction for any change to their previous health care utilization. Despite this, they are allowed to make use of usual care provided by their treating physician. The intervention group comprises a 12-week home training program with three sessions per week in addition to usual care. Exercises will be guided and monitored by use of the training app (re.flex) and two accelerometers that are attached proximally and distally to the affected knee joint. Pre- and postmeasurements will take place at baseline (t0) and after 12 weeks (t1). Primary outcomes will be osteoarthritis-specific pain and physical function measured with the Knee Osteoarthritis Outcome Score (KOOS) subscales Pain and Function in daily living (ADL). Second, further self-reported health outcomes, a performance measurement, app logfiles and safety will be assessed. Intervention effects will be calculated by baseline-adjusted analysis of covariance (ANCOVA) using an intention-to-treat approach. Multiple imputation will be applied. Discussion Re.flex can bridge part of the gap between recommendations for strengthening exercises in patients with knee OA and the insufficient actual care situation. This randomized controlled trial is designed to provide conclusions on the effectiveness of the health application re.flex for the population under study and will provide further insight into adherence rates and the safety of its use. Trial registration The trial was registered on 20/01/2023 at www.drks.de (ID: DRKS00030932).

Abstract Background Venovenous extracorporeal membrane oxygenation (vvECMO) is used to treat hypoxia in patients with severe acute respiratory distress syndrome (ARDS). Nevertheless, uncertainty exists regarding the optimal timing of initiation of vvECMO therapy. We aimed to investigate the association between number of days of invasive mechanical ventilation (IMV) prior to vvECMO implantation and mortality. Methods In this retrospective observational study, we included patients treated at an academic intensive care unit with vvECMO for severe ARDS. The primary outcome was all-cause 28-day mortality. We conducted a multivariate logistic regression analysis to estimate the association between number of days of IMV prior to vvECMO implantation and mortality after adjustment for confounders. Results Out of 274 patients who underwent ECMO for severe ARDS, 158 patients (median age: 58 years) with relevant data were included in the analysis. The mean duration of IMV prior to vvECMO was significantly shorter in survivors than in nonsurvivors [survivors median: 1; interquartile range: 1–3; non-survivors median 4; interquartile range: 1–5.75; p = 0.0001). Logistic regression showed an association between the duration of ventilation prior to vvECMO and patient mortality. The odds ratio for the all-cause 28-day mortality and in-hospital mortality was significantly reduced in patients who received vvECMO within the first 5 days of IMV. Conclusions Early vvECMO implantation may be associated with lower mortality in ARDS.

Before revascularization, moyamoya patients require hemodynamic evaluation. In this study, we evaluated the scoring system Prior Infarcts, Reactivity and Angiography in Moyamoya Disease (PIRAMID). We also devised a new scoring system, MRI-Based Assessment of Risk for Stroke in Moyamoya Angiopathy (MARS-MMA), and compared the scoring systems with respect to the capability to predict impaired [15O]water PET cerebral perfusion reserve capacity (CPR). We evaluated 69 MRI, 69 DSA and 38 [15O]water PET data sets. The PIRAMID system was validated by ROC curve analysis with neurological symptomatology as a dependent variable. The components of the MARS-MMA system and their weightings were determined by binary logistic regression analysis. The comparison of PIRAMID and MARS-MMA was performed by ROC curve analysis. The PIRAMID score correlated well with the symptomatology (AUC = 0.784). The MARS-MMA system, including impaired breath-hold-fMRI, the presence of the Ivy sign and arterial wall contrast enhancement, correlated slightly better with CPR impairment than the PIRAMID system (AUC = 0.859 vs. 0.827, Akaike information criterion 140 vs. 146). For simplified clinical use, we determined three MARS-MMA grades without loss of diagnostic performance (AUC = 0.855). The entirely MRI-based MARS-MMA scoring system might be a promising tool to predict the risk of stroke.

Abstract Background Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. Methods An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and

Abstract Background This primary analysis evaluated the “PREVenting the impairment of primary Osteoarthritis by high-impact long-term Physical exercise regimen—Psychological Adherence Program” (PrevOP-PAP), designed to support patients with osteoarthritis of the knee (OAK) to engage in regular moderate-to-vigorous physical activity (MVPA) to reduce OAK symptoms (WOMAC scores). Theory-based on the health action process approach (HAPA), the intervention targeted volitional precursors of MVPA change: action and coping planning, maintenance and recovery self-efficacy, action control, and social network formation. We hypothesized that compared to an active control condition, increases in MVPA at the end of the 12-month intervention would translate into lower WOMAC scores at 24 months in the intervention condition. Methods Participants with radiographically verified moderate OAK (N = 241; 62.66% female; M(SD) = 65.60(7.61) years) were randomly assigned to the intervention (51%) or the active control condition. WOMAC scores (24 months) were the primary -, accelerometer-assessed MVPA (12 months) the key secondary outcomes. The PrevOP-PAP was a 12-month intervention with computer-assisted face-to-face and phone-based sessions designed to increase HAPA-proposed volitional precursors of MVPA change (up to 24 months; secondary outcomes). Intent-to-treat analyses included multiple regression and manifest path models. Results MVPA (12 months) did not mediate effects of the PrevOP-PAP on WOMAC scores (24 months). Compared to the active control condition, WOMAC scores (24 months) were lower in the intervention condition, but this effect did not remain stable in sensitivity analyses (b(SE) = -8.41(4.66), 95%-CI [-17.53; 0.71]). However, exploratory analyses revealed significantly stronger reductions in WOMAC-pain (24 months) in the intervention condition (b(SE) = -2.99(1.18), 95%-CI [-5.36; -0.63]). Groups did not differ in MVPA at 12 months (b(SE) = -3.78(3.42), 95%-CI [-10.80; 2.58]). Of the proposed precursors of MVPA change, action planning was higher in the intervention than in the control condition (24 months; b(SE) = 0.64(0.26), 95%-CI [0.14; 1.15]). Conclusions Compared to an active control condition, the PrevOP-PAP did not produce reliable effects on WOMAC scores and none on preceding MVPA. Of the HAPA-proposed volitional precursors, only action planning was sustainably increased. Future interventions should use m-health applications to digitally support long-term changes in proposed volitional precursors of MVPA change. Trial registration German Clinical Trials Register; https://drks.de/search/de/trial/DRKS00009677 ; also available at http://apps.who.int/trialsearch/ ; registration number: DRKS00009677; date of registration: 26/01/2016.

Abstract Background Stroke is a major cause of death and the most frequent cause of permanent disability in western countries. Repetitive transcranial brain stimulation (rTMS) has been used to enhance neuronal plasticity after stroke, yet with only moderate effect sizes. Here we will apply a highly innovative technology that synchronizes rTMS to specific brain states identified by real-time analysis of electroencephalography. Methods One hundred forty-four patients with early subacute ischemic motor stroke will be included in a multicenter 3-arm parallel, randomized, double-blind, standard rTMS and sham rTMS-controlled exploratory trial in Germany. In the experimental condition, rTMS will be synchronized to the trough of the sensorimotor µ-oscillation, a high-excitability state, over ipsilesional motor cortex. In the standard rTMS control condition the identical protocol will be applied, but non-synchronized to the ongoing µ-oscillation. In the sham condition, the same µ-oscillation-synchronized protocol as in experimental condition will be applied, but with ineffective rTMS, using the sham side of an active/placebo TMS coil. The treatment will be performed over five consecutive work days (1,200 pulses per day, 6,000 pulses total). The primary endpoint will be motor performance after the last treatment session as measured by the Fugl-Meyer Assessment Upper Extremity. Discussion This study investigates, for the first time, the therapeutic efficacy of personalized, brain-state-dependent rTMS. We hypothesize that synchronization of rTMS with a high-excitability state will lead to significantly stronger improvement of paretic upper extremity motor function than standard or sham rTMS. Positive results may catalyze a paradigm-shift towards personalized brain-state-dependent stimulation therapies. Trial registration This study was registered at ClinicalTrials.gov (NCT05600374) on 10–21-2022.

Despite of contact restrictions, population mobility remains the main reason for the spread of SARS-CoV-2. The state of Baden-Württemberg (BW), Germany, approved a model study in Tübingen (TÜMOD) to evaluate how mandatory rapid diagnostic tests (RDT) could reduce transmission. Between 16 March and 24 April 2021, approximately 165,000 residents and visitors to the city were screened for SARS CoV-2 infection using Abbott Panbio™ COVID-19 Antigen rapid test device. We assessed incidences and recorded epidemiological characteristics in a subset of 4,118 participants recruited at three of the nine testing stations. PCR tests were performed in RDT-positives to determine the positive predictive value (PPV), and circulating variants of SARS-CoV-2 were identified by whole-genome sequencing. 2,282 RDT-negative samples were tested by pooled PCR to calculate the false negative rate (FNR). Viral load was compared between variants. 116 (3%) participants were positive by RDT, and of these, 57 (49%) were positive by PCR, 55 (47%) were negative. This resulted in a PPV of 51%. Of the 57 positives, 52 SARS-CoV-2 genomes were successfully sequenced. Of these, 50 belonged to the B.1.1.7 lineage, which had a high viral load (average Ct = 19). Of the 2,282 RDT negatives tested, all were PCR negative (FNR 0%). At the end of TÜMOD, the incidence in Tübingen, which was initially lower, had reached the incidence in the state of BW. While it is difficult to assess the impact of TÜMOD on incidence independent of confounding factors, further studies are needed to identify the effect of close-meshed testing on infection rates.

Abstract Background Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. Methods We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. Results Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. Conclusions The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. Trial registration: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Abstract Rationale Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. Objectives A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. Methods Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. Measurements Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. Main results The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. Conclusions Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

Abstract Background Childhood and adolescent overweight and obesity are among the most serious health challenges today. Structured weight reduction programs can be helpful to reduce severe health consequences but evidence is partly scarce. The STARKIDS program aims to improve on some of these limitations and is designed to be a structured, stepwise, digitally supported intervention program for the whole family. It is divided into two intervention steps spanning over 1.5 years and aims at promoting a healthy weight development of children/adolescents with overweight/obesity and an increase in quality of life. Methods The STARKIDS intervention is evaluated in a cluster-randomized study design by comparing it with a control group receiving a one-time structured counselling in the pediatric practice. The study aims to include 1000 families with children/adolescents with overweight/obesity from 100 pediatric practices. The main outcomes are reduction in body mass index percentiles and improvements in children’s/adolescent’s quality of life, secondary outcomes refer to the contents of the intervention such as diet, physical activity, stress, and media habits. All outcomes are measured on three measurement time points: (T0) at baseline/inclusion in the study, (T1) baseline + 12 months which is the end of step 1 of the STARKIDS intervention, and (T2) baseline + 18 months which is the end of step 2 of the STARKIDS intervention. Discussion The stepwise, e-health-supported STARKIDS program is a low-threshold intervention program for families with children/adolescents with overweight/obesity. With the proof of concept, STARKIDS provides the potential to be implemented as a standard care tool for the prevention and intervention of childhood/adolescence obesity in the German health system. Trial registration German Clinical Trials Register (DRKS) DRKS00022813 (acknowledged primary register of the World Health Organization). Registered on 27 November 2020 (Universal Trial Number U1111-1254-9536).

Abstract Background Multimorbidity is a major problem in Europe, increasing the need for prevention and rehabilitation programs. In Germany no guidelines have been developed that focus on patients with multiple chronic non-communicable diseases (NCDs). Benefits of physical activity (PA) and exercise in NCDs have been proven, but most interventions focus on single conditions. The evaluation of the effectiveness, efficiency and safety of PA programs in patients suffering from multiple NCDs and the feasibility of the implementation within the health care service remain open research questions. Methods The multi-site randomized controlled pragmatic trial includes 320 sedentary subjects with at least two of the following NCDs, either manifested or in a pre-stage with evident risk factors: Cardio-vascular disease, Diabetes mellitus type 2, knee/ hip osteoarthritis and obesity. Participants will be recruited from general practitioners and medical specialists and randomized to standard care of a statutory health insurance or MultiPill-Exercise. Standard care includes a choice of one or a maximum of two 8- to 12-week health programs, including nutrition, exercise, relaxation or special disease management programs. MultiPill-Exercise is based on the bio-psycho-social health model, considering a person-oriented perspective in light of given individual characteristics and context factors. The 24-weeks intervention focuses on aerobic and strengthening exercises in line with the WHO PA recommendations. Psychological and pedagogical elements along with behavior change techniques are implemented to ease the initiation and maintenance of exercise participation and lifestyle change, including nutrition. Primary outcome will be short- and long-term PA measured with the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ). Secondly, the effectiveness of the program on generic, disease specific, economic, and exercise behavioral parameters, as well as program adherence and safety will be evaluated. Discussion Results of this trial evaluate the PA intervention program in people with multiple NCDs in a real-life scenario. It will serve as a proof of concept with the opportunity of translation into routine practice. This approach, as a multi-site RCT with its rigorous methods and standardized operating procedures for the conduction of the intervention, will allow valid conclusions for the implementation of PA interventions in people with multimorbidity. Trial registration The trial was registered at www.drks.de (ID: DRKS00025033 ) on 30th September 2021.

Abstract Objective While the anticipated rise of disease‐modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. Methods: We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1‐year follow‐up and 2‐year follow‐up visit. Results Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross‐sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels. Interpretation: Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.

Abstract Background The current first-line treatment for binge eating disorder (BED), which is psychotherapy, is moderately effective in terms of abstinence from binge-eating. Neurobiological evidence suggests that people affected by BED show difficulties along the spectrum of impulsivity, including inhibitory control impairments and highlights the potential of novel treatment approaches directly targeting inhibitory control, including cognitive training approaches and non-invasive brain stimulation. Methods ACCElect is a prospective, randomized controlled pilot trial investigating a novel, food-related inhibitory control training combined with transcranial direct current stimulation (tDCS). 40 patients with BED will be randomly assigned to receive the training either combined with verum or with sham stimulation (control condition). The inhibitory control training is based on principles of the antisaccade paradigm and comprises six training sessions over two weeks. Core aims are the investigation of feasibility and clinically relevant effects of a tDCS-enhanced inhibitory control training in BED patients and the establishment of a data basis for a larger efficacy trial. The primary clinical endpoint is binge-eating (BE) frequency in terms of changes in BE episodes four weeks after treatment termination as compared to baseline. Key secondary outcomes comprise ED pathology and general psychopathology, inhibitory control capacities, quality of life as well as acceptability and satisfaction with the intervention. Discussion The results of the present trial will contribute to the development of novel neurobiologically informed treatment approaches for patients suffering from BED. Trial registration The ACCElect trial was prospectively registered on October 1, 2020, under the registration number NCT04572087 at ClinicalTrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04572087 ).

Abstract Plasma clearance of iohexol is a pivotal metric to quantify glomerular filtration rate (GFR), but the optimal timing and frequency of plasma sampling remain to be assessed. In this study, we evaluated the impact of a Bayesian estimation procedure on iohexol clearance estimates, and we identified an optimal sampling strategy based on data in individuals aged 70+. Assuming a varying number of random effects, we re-estimated previously developed population pharmacokinetic two- and three-compartment models in a model development group comprising 546 patients with iohexol concentration data up to 300 min post injection. Model performance and optimal sampling times were assessed in an evaluation group comprising 104 patients with reduced GFR and concentration data up to 1440 min post injection. Two- and three-compartment models with random effects for all parameters overestimated clearance values (bias 5.07 and 4.40 mL/min, respectively) and underpredicted 24-h concentrations (bias − 14.5 and − 12.0 µg/ml, respectively). Clearance estimates improved distinctly when limiting random effects of the three-compartment model to clearance and central volume of distribution. Two blood samples, one early and one 300 min post injection, were sufficient to estimate iohexol clearance. A simplified three-compartment model is optimal to estimate iohexol clearance in elderly patients with reduced GFR.

Plain English summary Patients with a severe form of anorexia nervosa (AN) are often treated as inpatients. Many of them benefit from this acute treatment. Unfortunately, a significant number of patients experience relapse after discharge. This problem could be addressed by specific treatments directly following inpatient therapy, so called aftercare interventions, which are tailored to patients’ needs in this treatment period. This review looks at studies which have investigated the efficacy of aftercare interventions for patients with AN directly after inpatient treatment. We included any studies which compared a novel aftercare intervention to a control treatment and where patients were randomly assigned to either of these treatments, as this procedure is considered to reduce bias. We found seven studies that investigated different aftercare intervention approaches, including medication, guided self-help and psychotherapy, and three ongoing studies. Based on the very limited evidence so far, no clear recommendations can be made favoring a specific approach for post-inpatient aftercare in adult patients with AN. The review shows that it should be a priority to increase uptake of aftercare interventions and to reduce dropout rates. This could be achieved by a better tailoring of interventions to patient needs and the integration of patient perspectives in intervention design. More studies are needed to find interventions which allow patients with AN to maintain treatment gains after intensive inpatient treatment.

The stress response to the COVID-19 pandemic might differ between early and later stages. Longitudinal data on the development of population mental health during COVID-19 pandemic is scarce. We have investigated mental health trajectories and predictors for change in a probability sample of the general population in Germany at the beginning and after 6 months of the pandemic. We conducted a longitudinal survey in a population-based probability sample of German adults. The current study analyzed data from a first assessment in May 2020 (T1; N = 1,412) and a second in November 2020 (T2; N = 743). Mental health was assessed in terms of anxiety and depression using the Patient Health Questionnaire-4 (PHQ-4). Mental health outcomes at T1 were compared with PHQ-4 norm data. Trajectories over time were investigated based on outcome classifications of PHQ-4 scores. Predictors of mental health outcomes and change were identified using multiple regression analysis. In spring 2020, participants showed significantly higher PHQ-4 scores as compared to the norm data, however, overall anxiety and depression remained low also 6 months later. 6.6% of respondents showed a mental health deterioration in autumn 2020, entering subclinical and clinical ranges, outweighing the proportion of people with improved outcomes. Sociodemographic variables associated with mental distress at T1 were mainly not predictive for change at T2. Even under prolonged pandemic-related stress, mental health remained mainly stable in the general population. Further development of the considerable subgroup experiencing deterioration of depression and anxiety should be monitored, in order to tailor prevention and intervention efforts.

Abstract Objective Despite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors. Methods The study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme‐linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed). Results Levels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p

Abstract Background A major barrier to long-term recovery from anorexia nervosa (AN) are early and frequent relapses after inpatient treatment. There is an urgent need for enhanced continuity of specialized care involving effective aftercare interventions and relapse prevention strategies in order to improve the long-term outcome for patients with AN. Methods SUSTAIN is a multi-center, prospective, randomized-controlled trial investigating the efficacy of a novel post-inpatient aftercare intervention for patients with AN as compared to optimized treatment-as-usual (TAU-O). The SUSTAIN aftercare intervention is based on the cognitive-interpersonal maintenance model of AN and specifically tailored to achieve sustained recovery in AN following inpatient treatment. The SUSTAIN aftercare intervention comprises 20 treatment sessions over eight months and will be predominantly delivered via videoconference to overcome discontinuity of care. TAU-O refers to routine outpatient psychotherapy as generally offered in the German health care system. A total number of 190 patients receiving inpatient or day-hospital treatment for AN will be randomized and assessed over a 14-month period following randomization including a 6 months follow-up. Minimum Body Mass Index (BMI) is 15 kg/m2 at trial inclusion. The primary efficacy endpoint is the change in BMI between baseline (T0) and end of treatment (T2) adjusted for baseline BMI. Key secondary outcomes comprise eating disorder and general psychopathology, quality of life, proportion of relapse and of weight restoration, and cost-effectiveness. Discussion The results of the present trial will provide evidence if the novel aftercare intervention fosters sustained recovery in patients affected by severe courses of AN. Trial registration The SUSTAIN trial was prospectively registered on November 18, 2020, under the registration number DRKS00023372 at the German Clinical Trials Register ( https://www.drks.de/drks_web/ ) which is an acknowledged primary register of the World Health Organization ( http://apps.who.int/trialsearch/ ). Protocol version: 1.2.

Abstract Food-related impulsivity, i.e. a food-related attentional bias proposed to be due to increased reward sensitivity and diminished inhibitory control, has been cross-sectionally associated with binge eating disorder. To analyze changes in food-related impulsivity, we implemented longitudinal analyses of objective laboratory tasks in a randomized controlled trial called IMPULS. Patients who attended an impulsivity-focused group intervention (IG N = 31) and control patients who did not take part in the intervention (CG N = 25) were compared before (T0) and after the intervention period (T1) and at three months follow-up (T2). Patients’ impulsive gaze behavior towards food vs. neutral stimuli was measured in two eye tracking paradigms, one addressing reward sensitivity and another addressing inhibitory control. Initial fixations of food vs. neutral stimuli were increased at T0 (IG: p = .014, CG: p = .001), but not at T1 and T2 in IG (T1: p = .178, T2: p = .203) and in CG after Bonferroni correction only at T2 (T1: p = .031, T2: p = .002). Patients from IG increased dwell time on neutral stimuli at T1 contrary to patients from CG (p = .016) and rated the presented food stimuli as less positive (e.g. pleasantness p

Zusammenfassung Zielsetzung In dieser Studie untersuchten wir, wie häufig Mitglieder eines Best-Practice-Modells der Integrierten Versorgung in Deutschland ihre subjektive künftige Arbeitsfähigkeit mit ihrem Hausarzt (GP) besprechen; darüber hinaus untersuchten wir unabhängige Variablen, die erklären, ob die künftige Arbeitsfähigkeit thematisiert wird. Methoden In einer Querschnittserhebung beantworteten 1168 (von 3218 Eingeladenen) Mitglieder der Integrierten Versorgung einen standardisierten Fragebogen. Diese Studie umfasst n = 475 berufstätige Befragte, die höchstens 65 Jahre alt waren. Wir ermittelten die Häufigkeit von erwerbstätigen Mitgliedern bis 65 Jahre, die ihre subjektive künftige Arbeitsfähigkeit bereits mit ihrem Hausarzt besprochen hatten. Mit Hilfe einer logistischen Regressionsanalyse wurden Prädiktoren ermittelt, die erklären, ob die künftige Arbeitsfähigkeit mit dem Hausarzt besprochen wird. Ergebnisse N = 80 (16,8%) der Befragten gaben an, ihre künftige Arbeitsfähigkeit mit ihrem Hausarzt besprochen zu haben. Eine multiple logistische Regressionsanalyse ergab folgende Ergebnisse: Die Odds Ratio für die Besprechung der künftigen Arbeitsfähigkeit ist umso höher, je zufriedener die Befragten mit ihrem Hausarzt sind, je schlechter sie selbst ihre derzeitige Arbeitsfähigkeit in Bezug auf die körperlichen Arbeitsanforderungen einschätzen und wenn die Befragten chronisch krank sind (Nagelkerke-Pseudo-R2 = 0,13). Schlussfolgerungen Selbst im hier vorliegenden Versorgungskontext besprachen Erwerbstätige bis zum Alter von 65 Jahren ihre künftige Arbeitsfähigkeit nur selten mit ihrem Hausarzt. Dies deutet darauf hin, dass das Thema “künftige Arbeitsfähigkeit” in anderen populationsbezogenen Settings der Gesundheitsversorgung in Deutschland noch seltener besprochen wird. Es scheint, dass in der Akutversorgung tätige Leistungserbringer dieses Thema nur sporadisch berücksichtigen - trotz der großen Bedeutung des Erhalts der Arbeitsfähigkeit.

Abstract Background Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS. Methods The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO2/FiO2. Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany. Discussion The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS. Trial registration EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017.

In the original publication of this article [1], the authors missed that reverse coding was necessary for the item “Do you work separate from your colleagues?” before calculating the scale ‘social relations’. So they corrected the analysis accordingly. The results with the revised scale show that there are no longer any significant differences between nurses and physicians with regard to this scale.

Abstract Background Older adults have the highest drug utilization due to multimorbidity. Although the number of people over age 70 is expected to double within the next decades, population-based data on their medication patterns are scarce especially in combination with polypharmacy and potentially inappropriate medication (PIM). Our objective was to analyse the frequency of polypharmacy, pattern of prescription (PD) and over-the-counter (OTC) drug usage, and PIMs according to age and gender in a population-based cohort of very old adults in Germany. Methods Cross-sectional baseline data of the Berlin Initiative Study, a prospective cohort study of community-dwelling adults aged ≥70 years with a standardized interview including demographics, lifestyle variables, co-morbidities, and medication assessment were analysed. Medication data were coded using the Anatomical Therapeutic Chemical (ATC) classification. Age- and sex-standardized descriptive analysis of polypharmacy (≥5 drugs, PD and OTC vs. PD only and regular and on demand drugs vs regular only), medication frequency and distribution, including PIMs, was performed by age (

Abstract Background Surgical site infections (SSI) are the most common health care associated infections in German acute hospitals and can result in prolonged hospital stays, increased use of antibiotics and utilisation of care. Staphylococcus aureus bacteria (methicillin-resistant S Aureus (MRSA) and methicillin-susceptible S Aureus (MSSA)) are amongst the most prominent causes of SSI. While up to 90% of documented S Aureus colonization is already detectable prior to hospital admission, the majority of hygiene measures in Germany is focused on the hospital setting. It is hypothesized that early detection and decontamination of S Aureus colonization in primary care can prevent health care associated infections and reduce the number of S Aureus isolates in the hospital setting. Methods This study is a controlled interventional study (N = 13,260) with a pre-post comparison. The intersectoral intervention (over 2 years) will encompass the following elements: ambulatory detection and decontamination of MRSA and MSSA prior to elective surgery combined with a structured follow-up care. Patients from the control group will be screened in the hospital setting, in accordance with the standard operating procedure (SOP) in routine care. The primary endpoint is the reduction of MRSA and MSSA colonization upon hospital admission. Secondary endpoints are complication rate (SSI), length of stay, recolonization of patients (3 and 6 months after release), patient and provider satisfaction, patient compliance and cost development. Discussion In case of positive results, the chance of a widespread uptake and implementation in routine care are considered high. The active involvement of primary care providers in the implementation of screening and decontamination as well as follow-up care is a unique feature of this study. The positive resonance of primary care providers during the recruitment phase highlights the relevance of the topic to the participating actors. These efforts are coupled with patient education and specifically trained medical staff, promising a sustained impact. The STAUfrei care pathway can homogenize current practices in routine care and provide a template for further intersectoral cooperation. Trial registration German Clinical Trials Register (DRKS), DRKS00016615. Registered on April 1st, 2019.

ObjectiveThe role of resection in progressive glioblastoma (GBM) to prolong survival is still controversial. The aim of this study was to determine 1) the predictors of post-progression survival (PPS) in progressive GBM and 2) which subgroups of patients would benefit from recurrent resection.MethodsWe have conducted a retrospective bicentric cohort study on isocitrate dehydrogenase (IDH) wild-type GBM treated in our hospitals between 2006 and 2015. Kaplan-Maier analyses and univariable and multivariable Cox regressions were performed to identify predictors and their influence on PPS.ResultsOf 589 patients with progressive IDH wild-type GBM, 355 patients were included in analyses. Median PPS of all patients was 9 months (95% CI 8.0-10.0), with complete resection 12 months (95% CI 9.7-14.3, n=81), incomplete resection 11 months (95% CI 8.9-13.1, n=70) and without resection 7 months (95% CI 06-08, n=204). Multivariable Cox regression demonstrated a benefit for PPS with complete (HR 0.67, CI 0.49-0.90) and incomplete resection (HR 0.73, 95% CI 0.51-1.04) and confirmed methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter, lower age at diagnosis, absence of deep brain and multilocular localization, higher Karnofsky Performance Status (KPS) and recurrent therapies to be associated with longer PPS. In contrast, traditional eloquence and duration of progression-free survival had no effect on PPS. Subgroup analyses showed that all subgroups of confirmed predictors benefited from resection, except for patients in poor condition with a KPS

As the Corona Disease 2019 (COVID-19) caused by SARS-CoV-2 persists, vaccination is one of the key measures to contain the spread. Side effects (SE) from vaccination are one of the reasons for reluctance to vaccinate. We systematically investigated self-reported SE after the first, second, and booster vaccinations. The data were collected during the TüSeRe: exact study (Tübinger Monitoring Studie zur exakten Analyse der Immunantwort nach Vakzinierung). Employees of health and research institutions were invited to participate. Study participants were asked to fill out an online questionnaire and report their SE after each dose of SARS-CoV-2 vaccination. A total of 1046 participants (mean age: 44 ± 12.9 years; female, n = 815 (78%); male, n = 231 (22%)) were included in the analysis. Local and systemic SE were more frequent after receiving the vector-based vaccine ChAdOx1 nCoV-19 in the first vaccination. However, local and systemic SE were more common after receiving mRNA vaccines (BNT162b2, mRNA-1273) in the second vaccination. Compared to the BNT162b2 vaccine, more SE have been observed after receiving the mRNA-1273 vaccine in the booster vaccination. In multivariate analysis, local and systemic side effects were associated with vaccine type, age and gender. Local and systemic SE are common after SARS-CoV-2 vaccines. The frequency of self-reported local and systemic SE differ significantly between mRNA and vector-based vaccines.

Introduction The actual prevalence of a SARS-CoV-2 infection and the individual assessment of being or having been infected may differ. Facing the great uncertainty—especially at the beginning of the pandemic—and the possibility of asymptomatic or mildly symptomatic, subclinical infections, we evaluate the experience of SARS-CoV-2 antibody screening at a tertiary clinical setting.Methods and analysis All employees of a tertiary eye centre and a research institute of ophthalmology were offered antibody testing in May 2020, using a sequential combination of different validated assays/antigens and point-of-care (POC) testing for a subset (NCT04446338). Before taking blood, a systematic inquiry into past symptoms, known contacts and a subjective self-assessment was documented. The correlations between serostatus, patient contacts and demographic characteristics were analysed. Different tests were compared by Kappa statistics.Results Among 318 participants, SARS-CoV-2 antibodies were detected in 9 employees. Chemiluminescence assays (chemiluminescence immunoassay and electrochemiluminescence) showed superior specificity and high reproducibility, compared with ELISA and POC results.In contrast to the low seropositivity (2.8%) of healthcare workers, higher than that of the other departments of the hospital, a large proportion mistakenly assumed that they might have already been infected. Antiviral antibody titres increased and remained on a plateau for at least 3 months.Conclusions The great demand and acceptance confirmed the benefit of highly sensitive testing methods in the early phase of the pandemic. The coincidence of low seroprevalence and anxious employees may have contributed to internalising the need of hygiene measures.

Affect experienced during an exercise session is supposed to predict future exercise behavior. However, empirical evidence reveals high variability in affective response to different exercise modalities. Thus, the purpose of the present study was to compare acute affective response and its variation during three different endurance exercise modalities: (a) moderate-intensity continuous exercise (MICE), (b) vigorous-intensity continuous exercise (VICE), and (c) high-intensity interval exercise (HIIE). Using the dual-mode theory as a theoretical framework, cognitive and interoceptive factors were considered as potential predictors of in-task affective response. In a within-subject design, 40 insufficiently active healthy participants (aged from 20 to 40 years) attended three sessions per exercise modality on a cycle ergometer. Affective valence (measured by the Feeling Scale), two cognitive factors (perceived competence and awareness of interoceptive cues), and one interoceptive factor (heart rate) were assessed before, during, and after each exercise session. Mixed models with three levels (subject, exercise session, and time point) revealed more positive affective valence during MICE compared with VICE (p < 0.001) and HIIE (p < 0.01), while there was no significant difference between the latter two. Levene's test results showed the highest variability of in-task affective valence during VICE (ps < 0.01). Regarding the course across the session, MICE was associated with a constant slight increase in affective valence from pre- to post-exercise (p < 0.05), whereas VICE and HIIE caused a decline in pleasure, followed by an affective rebound immediately after exercise termination (ps < 0.01). The highest importance of cognitive and interoceptive factors for in-task affective valence was observed in VICE (ps < 0.05). The current findings provide support for the tenets of the dual-mode theory, however, indicating that there may be differences in the affect-intensity relationship between continuous and interval exercise. In conclusion, the study results concerning previously insufficiently active individuals extend the knowledge of how exercise can positively shape affective well-being depending on exercise modality and psychophysiological influences. This knowledge enables public health practitioners to design more individualized activity recommendations, thereby improving the subjective experience of exercise.

COVID-19 may lead to severe acute respiratory distress syndrome (ARDS) resulting in increased morbidity and mortality. Heart failure and/or pre-existing cardiovascular disease may correlate with poor outcomes and thus require special attention from treating physicians. The present study sought to investigate a possible impact of impaired myocardial function as well as myocardial distress markers on mortality or ARDS with need for mechanical ventilation in 157 consecutive patients with confirmed SARS-CoV-2 infection. All patients were admitted and treated at the University Hospital of Tübingen, Germany, during the first wave of the pandemic. Electrocardiography, echocardiography, and routine blood sampling were performed at hospital admission. Impaired left-ventricular and right-ventricular function, tricuspid regurgitation > grade 1, and elevated RV-pressure as well as thrombotic and myocardial distress markers (D-dimers, NT-pro-BNP, and troponin-I) were associated with mechanical ventilation and/or all-cause mortality. Impaired cardiac function is more frequent amidst ARDS, leading to subsequent need for mechanical ventilation, and thus denotes a poor outcome in COVID-19. Since a causal treatment for SARS-CoV-2 infection is still lacking, guideline-compliant cardiovascular evaluation and treatment remains the best approach to improve outcomes in COVID-19 patients with cardiovascular comorbidities.

Abstract Background Metastasized or unresectable melanoma has been the first malignant tumor to be successfully treated with checkpoint inhibitors. Nevertheless, about 40–50% of the patients do not respond to these treatments and severe side effects are observed in up to 60%. Therefore, there is a high need to identify reliable biomarkers predicting response. Tumor Mutation Burden (TMB) is a debated predictor for response to checkpoint inhibitors and early measurement of ctDNA can help to detect treatment failure to immunotherapy in selected melanoma patients. However, it has not yet been clarified how TMB and ctDNA can be used to estimate response to combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma. Patients and methods In this prospective biomarker study, we included 35 melanoma patients with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy. In all patients, a tumor panel of 710 tumor-associated genes was applied (tumor vs. reference tissue comparison), followed by repetitive liquid biopsies. Cell-free DNA was extracted and at least one driver mutation was monitored. Treatment response was evaluated after about three months of therapy. Results TMB was significantly higher in responders than in nonresponders and TMB > 23.1 Mut/Mb (TMB-high) was associated with a survival benefit compared to TMB ≤ 23.1 Mut/Mb (TMB-low or TMB-intermediate). Furthermore, a > 50% decrease of cell-free DNA concentration or undetectable circulating tumor DNA (ctDNA), measured by tumor-specific variant copies/ml of plasma at first follow-up three weeks after treatment initiation were significantly associated with response to combined immunotherapy and improved overall survival, respectively. It is noticeable that no patient with TMB ≤ 23.1 Mut/Mb and detectable or increasing ctDNA at first follow-up responded to immunotherapy. Conclusion High TMB, > 50% decrease of cell-free DNA concentration, and undetectable ctDNA at first follow-up seem to be associated with response and overall survival under combined immunotherapy. The evaluation of ctDNA and cell-free DNA three weeks after treatment initiation may be suitable for early assessment of efficacy of immunotherapy.

Abstract Background To evaluate outcome and toxicity of High-dose methotrexate (HDMTX)-based induction therapy followed by consolidation with conventional systemic chemotherapy and facultative intraventricular therapy (modified Bonn protocol) in patients with primary CNS lymphoma (PCNSL). Methods Between 01/2005 and 12/2013 113 patients with newly diagnosed PCNSL presented at our center; 98 of those qualified for HDMTX based chemotherapy, received a modified Bonn protocol and were included in the analysis. The treatment regimen was based on the “Bonn protocol”, but modified by omission of systemic drugs not able to cross the intact blood brain barrier. Intraventricular therapy was postponed until completion of three induction chemotherapy cycles or was replaced by intrathecal liposomal AraC and rituximab was added to induction from 2010 onwards. Results Median patient age was 67 years (range 38–83). Complete response/complete response unconfirmed (CR/CRu) was achieved in 59/98 patients (60%), partial response (PR) in 9/98 patients (9%). Twenty-four patients (23%) had progressive disease (PD), 6 (6%) died on therapy. Median progression-free survival (PFS) for all patients was 11.4 months, median overall survival (OS) 29.1 months. A trend to better outcome for intraventricular therapy versus intrathecal liposomal AraC was found in patients

Background: Disease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome. Methods: Data were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blinded and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24–48 h, 6–8 days, 12–15 days and 6–12 months) after the initial hemorrhage. Volume of brain with apparent pathology and/or BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the World Federation of Neurosurgical Societies and Rosen-Macdonald scores. Outcome at ≥6 months was assessed using the extended Glasgow outcome scale and disease course (progressive or non-progressive based on imaging-detected loss of normal brain tissue in consecutive scans). Logistic regression was used to define biomarkers that best predict outcomes. Receiver operating characteristic analysis was performed to assess accuracy of outcome prediction models. Findings: In the present cohort, 63% of patients had progressive and 37% non-progressive disease course. Progressive course was associated with worse outcome at ≥6 months (sensitivity of 98% and specificity of 97%). Brain volume with BBBD was significantly larger in patients with progressive course already 24–48 h after admission (2.23 (1.23–3.17) folds, median with 95%CI), and persisted at all time points. The highest probability of a BBB-disrupted voxel to become pathological was found at a distance of ≤1 cm from the brain with apparent pathology (0·284 (0·122–0·594), p

Keratinocyte cancer is the most common malignancy in Caucasians. The aim of this study was to investigate risk-factors responsible for development of keratinocyte cancer in Australia. A case-control study was conducted, including 112 cases of squamous cell carcinoma (SCC), 95 cases of basal cell carcinoma (BCC) and 122 controls. Freckling during adolescence (SCC: odds ratio (OR) 1.04, p

Besides deficits in memory and cognition, impaired visual processing is common for Alzheimer's disease (AD) patients and mouse models of AD but underlying mechanisms still remain unclear. Using in vivo Ca2+ imaging of the mouse primary visual cortex (V1) we tested whether such impairment is caused by neuronal hyperactivity, an emerging functional hallmark of AD. Profound neuronal hyperactivity was indeed found in V1 of APPSWE/PS1G384A and even of PS1G384A mice, presenting neither with plaque accumulation nor with neuroinflammation. This hyperactivity was accompanied by over-responsiveness to visual stimuli and impaired visual tuning properties of individual neurons, largely caused by insufficient suppression of responses to non-preferred orientation/direction stimuli. Moreover, visual stimulation robustly suppressed the ongoing spontaneous activity in WT but not in APPSWE/PS1G384A mice. Emptying intracellular Ca2+ stores significantly reduced neuronal hyperactivity and the pathological over-responsiveness to visual stimuli, but could not rescue stimulus-induced suppression of spontaneous activity and impaired tuning properties of individual cells. Thus, our data identify the AD-mediated dysfunction of intracellular Ca2+ stores as a main cause of pathologically increased visual responsiveness in APPSWE/PS1G384A mice. At the same time, the impairment of visual tuning and the stimulus-induced suppression of spontaneous activity, identified in this study, are likely caused by different mechanisms as, for example, dysfunction of local interneurons.

Abstract Background Promoting patient and occupational safety are two key challenges for hospitals. When aiming to improve these two outcomes synergistically, psychosocial working conditions, leadership by hospital management and supervisors, and perceptions of patient and occupational safety climate have to be considered. Recent studies have shown that these key topics are interrelated and form a critical foundation for promoting patient and occupational safety in hospitals. So far, these topics have mainly been studied independently from each other. The present study investigated hospital staffs’ perceptions of four different topics: (1) psychosocial working conditions, (2) leadership, (3) patient safety climate, and (4) occupational safety climate. We present results from a survey in two German university hospitals aiming to detect differences between nurses and physicians. Methods We performed a cross-sectional study using a standardized paper-based questionnaire. The survey was conducted with nurses and physicians to assess the four topics. The instruments mainly consisted of scales of the German version of the COPSOQ (Copenhagen Psychosocial Questionnaire), one scale of the Copenhagen Burnout Inventory (CBI), scales to assess leadership and transformational leadership, scales to assess patient safety climate using the Hospital Survey on Patient Safety Culture (HSPSC), and analogous items to assess occupational safety climate. Results A total of 995 completed questionnaires out of 2512 distributed questionnaires were returned anonymously. The overall response rate was 39.6%. The sample consisted of 381 physicians and 567 nurses. We found various differences with regard to the four topics. In most of the COPSOQ and the HSPSC-scales, physicians rated psychosocial working conditions and patient safety climate more positively than nurses. With regard to occupational safety, nurses indicated higher occupational risks than physicians. Conclusions The WorkSafeMed study combined the assessment of the four topics psychosocial working conditions, leadership, patient safety climate, and occupational safety climate in hospitals. Looking at the four topics provides an overview of where improvements in hospitals may be needed for nurses and physicians. Based on these results, improvements in working conditions, patient safety climate, and occupational safety climate are required for health care professionals in German university hospitals – especially for nurses.

This cross-sectional study explored factors associated with the corona virus disease 2019 (COVID-19) vaccination acceptance among higher education students in southwestern Germany. We conducted a cross-sectional online survey at six state-approved higher education institutions (HEIs) between July and November 2021. In addition to descriptive analyses, univariate as well as multivariate binary logistic regression analyses were conducted. A total of 6556 higher education students aged 18 years and older participated in our survey; 91.4% of participating students had been vaccinated against COVID-19 at least once. The factors that significantly contributed to the explanation of higher education students’ vaccination status in the multivariate analysis (area under curve—AUC = 0.94) were variables on the perception of the virus SARS-CoV-2 (affective risk perception: Adjusted odds ratio—aOR = 1.2; perception of the outbreak as a media-hype: aOR = 0.8), attitudes towards personal (aOR = 0.7) and study-related (aOR = 0.8) health and safety measures to prevent transmission of SARS-CoV-2, and attitudes towards COVID-19 vaccination (preservation of own health: aOR = 1.3; confidence in vaccine safety: aOR = 1.7; supporting higher education through vaccination: aOR = 1.2; own contribution to the containment of the pandemic: aOR = 1.7). The findings target assisting HEIs in returning to face-to-face teaching after previous semesters of online teaching.