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Background Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear. Methods We performed an analysis of the Scientific Registry of Transplant Recipients database. Kidney transplant recipients were categorized according to body mass index (BMI) categories and immunosuppressive protocols: (i) tacrolimus/mycophenolate mofetil (Tac-MMF), (ii) mTOR-inhibitor/Tac (mTORi-Tac), (iii) mTORi/cyclosporin (mTORi-Cyc) and (iv) mTORi-MMF. Results Graft recipients with advanced obesity (BMI ≥35 kg/m2) exhibited significantly lower rates of acute rejection during the first year after transplantation in the mTORi-Tac (6.4%) group compared with Tac-MMF (11.2%). Obesity class 1 (30 Conclusion These results are critical for the growing number of obese graft recipients and warrant prospective evaluation.

This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-β (Aβ). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aβ to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.

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.

Extracorporeal circulation (ECC) is frequently used in intensive care patients with impaired lung or cardiac function. Despite being a life-saving therapeutic option, ECC is associated with increased risk for both bleeding and thrombosis. The management of bleeding and thromboembolic events in ECC patients is still challenging partly due to the lack of information on the pathophysiological changes in hemostasis and platelet function during the procedure. Using a combination of an ex vivo model for shear stress and a sensitive and easy-to-use laboratory method, we analyzed platelet responsiveness during ECC. After shear stress simulation in an ex vivo closed-loop ECC model, we found a significantly decreased response of α-granules after activation with adenosine diphosphate and thrombin receptor activating peptide (TRAP-6) and CD63 expression after activation with TRAP-6. Mepacrine uptake was also significantly reduced in the ex vivo shear stress model.In the same line, platelets from patients under ECC with venovenous systems and venoarterial systems showed impaired CD62P degranulation after stimulation with ADP and TRAP-6 compared with healthy control on day 1, 6, and 10 after implantation of ECC. However, no correlation between platelet degranulation and the occurrence of bleeding or thromboembolic events was observed.The used whole blood flow cytometry with immediate fixation after drawing introduces a sensitive and easy-to-use method to determine platelet activation status and our data confirm that increased shear stress conditions under ECC can cause impaired degranulation of platelet.

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 143 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: Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. 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. Conclusions: Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity. Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity and emphasizes the importance of timely initiation of treatment in these critically ill patients.

This study aimed to compare an individual weight-machine-based strengthening program (MbT) with a group-/homebased training offering strengthening/functional exercises (GHT) in a general health care setting. A total of 657 participants (GHT = 521, MbT = 136) suffering from hip/knee OA were included and analysed with a pre–post design (baseline (T0)/3-months (T1)). Primary outcomes were pain and physical functioning (Western Ontario and McMaster Universities Osteoarthritis Index, range 0–10). Additionally, adherence and perceived patient benefit were measured (T1). Data were analysed with linear mixed models (time, treatment, baseline pain/physical impairment severity) adjusted for patient characteristics. No significant between-group differences in pain reduction/functional improvements (time*treatment*baseline pain/physical impairment severity, pain/function: n.s.; time*treatment, pain: p = 0.884, function: p = 0.067). Within-group improvements were dependent on baseline severity: Higher severity levels demonstrated larger changes from baseline. Perceived patient-benefit (very high to high, GHT: 78%, MbT: 92%) and exercise adherence (Dropouts T1: GHT: 27.8%, MbT: 16.2%; adherence to supervised sessions: GHT: 89%, MbT: 92%) was slightly better in the MbT. In summary, both MbT and GHT, showed positive results for patients with at least moderate disease symptoms. Findings for physical functioning, perceived patient-benefit, exercise adherence hint towards a superiority of MbT. Individual preferences should be considered when prescribing exercise therapy. Trial registration: (1) German Clinical Trial Register DRKS00009251. Registered 10 September 2015. (2) German Clinical Trial Register DRKS00009257. Registered 11 September 2015.

Purpose The extent of lymphadenectomy and clinical features influence the risk of occult nodes in node-negative prostate cancer. We derived a simple estimation model for the negative predictive value (npv) of histopathologically node-negative prostate cancer patients (pN0) to guide adjuvant treatment. Methods Approximations of sensitivities in detecting lymph node metastasis from current publications depending on the number of removed lymph nodes were used for a theoretical deduction of a simplified formulation of npv assuming a false node positivity of 0. Results A theoretical formula of npv = p(N0IpN0) = (100 − prevalence) / (100 − sensitivity × prevalence) was calculated (sensitivity and preoperative prevalence in %). Depending on the number of removed lymph nodes (nLN), the sensitivity of pN0-staged prostate cancer was derived for three sensitivity levels accordingly: sensitivity = f(nLN) = 9 × nLN /100 for 0 ≤ nLN ≤ 8 and f(nLN) = (nLN + 70) /100 for 9 ≤ nLN ≤ 29 and f(nLN) = 1 for nLN ≥ 30. Conclusion We developed a theoretical formula for estimation of the npv in pN0-staged prostate cancer patients. It is a sine qua non to use the formula in a clinically experienced context before deciding to electively irradiate pelvic lymph nodes or to intensify adjuvant systemic treatment.

Platelets express the transmembrane chemokine SR-PSOX/CXCL16, proteolytic cleavage of which generates the sCXCL16 soluble-(s) chemokine. The sCXCL16 engages CXCR6 on platelets to synergistically propagate degranulation, aggregation and thrombotic response. Currently, we have investigated the pro-thrombotic and prognostic association of platelet CXCL16–CXCR6 axis in CAD-(n = 240; CCS n = 62; ACS n = 178) patients. Platelet surface-associated-CXCL16 and CXCR6 surface expression ascertained by flow cytometry correlated significantly with platelet activation markers (CD62P denoting degranulation and PAC-1 binding denoting α2bβ3-integrin activation). Higher platelet CXCL16 surface association (1st quartile vs. 2nd–4th quartiles) corresponded to significantly elevated collagen-induced platelet aggregation assessed by whole blood impedance aggregometry. Platelet-CXCL16 and CXCR6 expression did not alter with dyslipidemia, triglyceride, total cholesterol, or LDL levels, but higher (>median) plasma HDL levels corresponded with decreased platelet-CXCL16 and CXCR6. Although platelet-CXCL16 and CXCR6 expression did not change significantly with or correlate with troponin I levels, they corresponded with higher Creatine Kinase-(CK) activity and progressively deteriorating left ventricular ejection fraction (LVEF) at admission. Elevated-(4th quartile) platelet-CXCL16 (p = 0.023) and CXCR6 (p = 0.030) measured at admission were significantly associated with a worse prognosis. However, after Cox-PH regression analysis, only platelet-CXCL16 was ascertained as an independent predictor for all-cause of mortality. Therefore, the platelet CXCL16–CXCR6 axis may influence thrombotic propensity and prognosis in CAD patients.

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.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

AimsTo determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582).MethodsDetails of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy.ResultsNo adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye.ConclusionThe results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.

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

Objectives To evaluate the influence of audio-guided self-hypnosis on claustrophobia in a high-risk cohort undergoing magnetic resonance (MR) imaging. Methods In this prospective observational 2-group study, 55 patients (69% female, mean age 53.6 ± 13.9) used self-hypnosis directly before imaging. Claustrophobia included premature termination, sedation, and coping actions. The claustrophobia questionnaire (CLQ) was completed before self-hypnosis and after MR imaging. Results were compared to a control cohort of 89 patients examined on the same open MR scanner using logistic regression for multivariate analysis. Furthermore, patients were asked about their preferences for future imaging. Results There was significantly fewer claustrophobia in the self-hypnosis group (16%; 9/55), compared with the control group (43%; 38/89; odds ratio .14; p = .001). Self-hypnosis patients also needed less sedation (2% vs 16%; 1/55 vs 14/89; odds ratio .1; p = .008) and non-sedation coping actions (13% vs 28%; 7/55 vs 25/89; odds ratio .3; p = .02). Self-hypnosis did not influence the CLQ results measured before and after MR imaging (p = .79). Self-hypnosis reduced the frequency of claustrophobia in the subgroup of patients above an established CLQ cut-off of .33 from 47% (37/78) to 18% (9/49; p = .002). In the subgroup below the CLQ cut-off of 0.33, there were no significant differences (0% vs 9%, 0/6 vs 1/11; p = 1.0). Most patients (67%; 35/52) preferred self-hypnosis for future MR examinations. Conclusions Self-hypnosis reduced claustrophobia in high-risk patients undergoing imaging in an open MR scanner and might reduce the need for sedation and non-sedation coping actions. Key Points • Forty percent of the patients at high risk for claustrophobia may also experience a claustrophobic event in an open MR scanner. • Self-hypnosis while listening to an audio in the waiting room before the examination may reduce claustrophobic events in over 50% of patients with high risk for claustrophobia. • Self-hypnosis may also reduce the need for sedation and other time-consuming non-sedation coping actions and is preferred by high-risk patients for future examinations.

Background Accumulating evidence indicates toward an association between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis.Objectives We investigated the hypothesis that the procoagulatory state in COVID-19 patients is associated with impaired fibrinolysis system.Methods Altogether, 29 COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in this descriptive study. Whole blood samples were investigated by thromboelastography to assess coagulation and fibrinolysis. Additionally, standard routine coagulation testing and immunoassays for factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and α2-antiplasmin (A2AP) were performed.Results A significantly increased lysis resistance and a significantly longer time of lysis after adding tissue plasminogen activator were observed in blood samples from ICU COVID-19 patients compared with healthy controls (maximal lysis: 3.25 ± 0.56 vs. 6.20 ± 0.89%, p = 0.0127; lysis time: 365.7 ± 44.6 vs. 193.2 ± 16.3 seconds, p = 0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92 ± 0.91 vs. 1.28 ± 0.33 U/mL, p = 0.001). A positive correlation between the activity of PAI-1 and lysis time of the formed clot (r = 0.70, p = 0.0006) was observed.Conclusion Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Thromboelastography could offer a tool to investigate the contribution of the fibrinolytic status to the procoagulatory condition in COVID-19.

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. 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 oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p = 0·17). 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. Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with 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. 2016-003168-37) and registered at clinicaltrials.gov (NCT03111212).

IntroductionMany patients with cancer experience severe psychological distress, but as a result of various barriers, few of them receive psycho-oncological support. E-mental health interventions try to overcome some of these barriers and the limitation of healthcare offers, enabling patients with cancer to better cope with psychological distress. In the proposed trial, we aim to assess the efficacy and cost-effectiveness of the manualised e-mental health intervention Make It Training- Mindfulness-Based and Skills-Based Distress Reduction in Oncology. Make It Training is a self-guided and web-based psycho-oncological intervention, which includes elements of cognitive behavioural therapy, mindfulness-based stress reduction and acceptance and commitment therapy. The training supports the patients over a period of 4 months. We expect the Make It Training to be superior to treatment as usual optimised (TAU-O) in terms of reducing distress after completing the intervention (T1, primary endpoint).Methods and analysisThe study comprises a multicentre, prospective, randomised controlled confirmatory interventional trial with two parallel arms. The proposed trial incorporates four distinct measurement time points: the baseline assessment before randomisation, a post-treatment assessment and 3 and 6 month follow-up assessments. We will include patients who have received a cancer diagnosis in the past 12 months, are in a curative treatment setting, are 18–65 years old, have given informed consent and experience high perceived psychological distress (Hospital Anxiety and Depression Scale ≥13) for at least 1 week. Patients will be randomised into two groups (Make It vs TAU-O). The aim is to allocate 600 patients with cancer and include 556 into the intention to treat analysis. The primary endpoint, distress, will be analysed using a baseline-adjusted ANCOVA for distress measurement once the intervention (T1) has been completed, with study arm as a binary factor, baseline as continuous measurement and study centre as an additional categorical covariate.Ethics and disseminationThe Ethics Committee of the Medical Faculty Essen has approved the study (21-10076-BO). Results will be published in peer-reviewed journals, conference presentations, the project website, and among self-help organisations.Trial registration numberGerman Clinical Trial Register (DRKS); DRKS-ID: DRKS00025213.

Cardiovascular risk factors and comorbidities are highly prevalent among COVID-19 patients and are associated with worse outcomes.We therefore investigated if established cardiovascular risk assessment models could efficiently predict adverse outcomes in COVID-19. Furthermore, we aimed to generate novel risk scores including various cardiovascular parameters for prediction of short- and midterm outcomes in COVID-19.We included 441 consecutive patients diagnosed with SARS-CoV-2 infection. Patients were followed-up for 30 days after the hospital admission for all-cause mortality (ACM), venous/arterial thromboembolism, and mechanical ventilation. We further followed up the patients for post-COVID-19 syndrome for 6 months and occurrence of myocarditis, heart failure, acute coronary syndrome (ACS), and rhythm events in a 12-month follow-up. Discrimination performance of DAPT, GRACE 2.0, PARIS-CTE, PREDICT-STABLE, CHA2-DS2-VASc, HAS-BLED, PARIS-MB, PRECISE-DAPT scores for selected endpoints was evaluated by ROC-analysis.Out of established risk assessment models, GRACE 2.0 score performed best in predicting combined endpoint and ACM. Risk assessment models including age, cardiovascular risk factors, echocardiographic parameters, and biomarkers, were generated and could successfully predict the combined endpoint, ACM, venous/arterial thromboembolism, need for mechanical ventilation, myocarditis, ACS, heart failure, and rhythm events. Prediction of post-COVID-19 syndrome was poor.Risk assessment models including age, laboratory parameters, cardiovascular risk factors, and echocardiographic parameters showed good discrimination performance for adverse short- and midterm outcomes in COVID-19 and outweighed discrimination performance of established cardiovascular risk assessment models.

BACKGROUND AND AIMS Data on the estimated glomerular filtration rate (eGFR) over time in older populations are scarce. Identifying patterns of eGFR progression is essential for a better understanding of chronic kidney disease (CKD) in older adults. METHOD We used data from the BIS, a community-dwelling cohort of 2069 people aged 70 or older. Participants were recruited between 2009 and 2011. After baseline assessment, four follow-up visits were conducted biennially over a total observation period of 8 years. During all study visits, eGFR and CKD stages based on KIDGO guidelines were assessed using the creatinine and cystatin C-based BIS2 equation (eGFRBIS2). Additionally, we used the creatinine-based EKFC equation (eGFREKFC). In a sub-analysis, we included only non-deceased participants with complete attendance at all study visits and valid eGFR values at all measurements. RESULTS At baseline, the mean age was 80.4 years (SD = 6.7), and 52.6 % were females. Prevalence was highest for CKD stage 2 (45.4%) and 3 (49.3%). After 8 years, the prevalence for CKD stages 1 and 2 decreased, whereas stages 3 and 4 showed a consistent upward trend resulting in 18.4%, 72.4% and 8.9% of participants in stages 2, 3 and 4, respectively. Mean eGFRBIS2 decreased from 58.1 (SD = 15.2) to 48.3 (SD = 13.3) mL/min/1.73 m² after 8 years. Mean eGFREKFC showed a similar trend with estimates being slightly higher (60.4 versus 54.2 mL/min/1.73 m2 after 8 years). Same trends applied to the subgroup with complete attendance (mean age: 77.4 years). However, compared with the total population they showed a higher mean eGFRBIS2 (63.3 versus 58.1 mL/min/1.73 m²) and lower prevalence of CKD stages 3 and 4 (stage 2: 59.4 versus 45.4%; stage 3: 37.1 versus 49.3% stage 4: 1.2 versus 3.6%) at baseline. CONCLUSION We found that over the observation period of 8 years, mean eGFRBIS2 decreased by 9.8 mL/min/1.73 m2 resulting in an increasing prevalence of CKD stages 3 and 4 by 23.1 and 5.3%, respectively. This was observed in the total population as well as in the subgroup with complete study attendance.

BACKGROUND AND AIMS Decreased kidney function is an established risk factor of cardiovascular morbidity including heart failure (HF) as well as cardiovascular and all-cause mortality among adults. However, the role of decreased kidney function with regard to these outcomes among old and very old adults remains poorly understood. This is an important knowledge gap given the common decline of kidney function in advanced age, which can affect both healthy individuals and patients with significant morbidity. To this end, we conducted a population-based study to assess whether decreased kidney function is associated with an increased risk of HF, cardiovascular and all-cause mortality in a prospective cohort of community-dwelling older adults. METHOD We included participants of the Berlin Initiative Study (BIS), age ≥70 years, with estimated glomerular filtration rate (eGFRBIS2) at baseline (between 2009 and 2011) and information on prior diagnosis of HF. Participants were followed from baseline until the occurrence of one of the study outcomes (see below) or December 2020, the latest date of data availability. Potential confounders included demographic characteristics, anthropometrics (body mass index), lifestyle factors (alcohol consumption, smoking, physical exercise), proxies of socioeconomic status (education, income), medications (major classes of antihypertensive drugs, oral anticoagulants, antiplatelet agents), and comorbidities measured at baseline using face-to-face interviews and administrative healthcare data. The three study outcomes were hospitalization for HF (HHF), cardiovascular death and all-cause mortality. HHF was defined based on inpatient diagnostic codes, and the mortality outcomes were defined based on a combination of administrative healthcare data, death certificates and hospital discharge notes. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of the three outcomes associated with decreased kidney function (eGFRBIS2 RESULTS Our study cohort included 1466 HF free older adults (mean age 79 years; 55% female). Compared with retained kidney function, decreased kidney function was associated with increased risks of HHF (crude incidence rates per 100/year: 2.7 versus 1.1; adjusted HR, 1.48; 95% CI, 1.06–2.07), cardiovascular death (crude incidence rates per 100/year: 2.7 versus 0.9; adjusted HR, 1.49; 95% CI, 1.06–2.09), and all-cause mortality (crude incidence rates per 100/year: 6.3 versus 2.8; adjusted HR, 1.27; 95% CI, 1.03–1.57). Kaplan-Meier curves for the three study outcomes are shown in Figure 1. Among the 590 older adults with prior HF (mean age 83 years; 54% female), the effect estimates were similar albeit less precise (HHF: HR, 1.32; 95% CI, 0.88–1.98/cardiovascular death: HR, 1.67; 95% CI, 1.06–2.63/all-cause mortality: HR, 1.22; 95% CI, 0.91–1.63). CONCLUSION Our population-based study showed that decreased kidney function is associated with increased risks of cardiovascular morbidity and cardiovascular and all-cause mortality among older adults, corroborating findings in younger populations.

To improve performance in endurance sports, it is important to include both high-intensity and low-intensity training, but there is neither a universally accepted practice nor clear scientific evidence that allows reliable statements about the predominance of a specific training method. This randomized controlled trial compared the effects of a polarized training model (POL) to a low-intensity training model (LIT) on physiological parameters and mountain bike cross-country Olympic (XCO) race performance in eighteen competitive XCO athletes (17.9 ± 3.6 years). The superiority of one of the two methods could not be shown in this study. The results did not show statistically significant differences between POL and LIT, as both interventions led to slight improvements. However, a small tendency toward better effects for POL was seen for cycling power output during the race (4.4% vs. –2.2%), at the 4 mmol/L (6.1% vs. 2.8%) and individual anaerobic lactate threshold (5.1% vs. 2.3%), and for maximal aerobic performance (4.4% vs. 2.6%), but not for maximal efforts lasting 10 to 300 s. Despite the lack of significant superiority in this and some other studies, many athletes and coaches prefer POL because it produces at least equivalent effects and requires less training time.

Background treatment goals for blood pressure (BP) lowering in older patients with heart failure (HF) are unclear. Objective to assess whether BP control < 140/90 mmHg is associated with a decreased risk of mortality in older HF patients. Design population-based prospective cohort study. Setting/subjects participants of the Berlin Initiative Study, a prospective cohort of community-dwelling older adults launched in 2009. Clinical information was obtained in face-to-face interviews and linked to administrative healthcare data. Methods Cox proportional hazards models estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular death and all-cause mortality associated with normalised BP (systolic BP < 140 mmHg and diastolic BP < 90 mmHg) compared with non-normalised BP (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) in HF patients. The primary analysis considered only baseline BP (‘time-fixed’); an additional analysis updated BP during follow-up (‘time-dependent’). Results at baseline, 544 patients were diagnosed with HF and treated with antihypertensive drugs (mean age 82.8 years; 45.4% female). During a median follow-up of 7.5 years and compared with non-normalised BP, normalised BP was associated with similar risks of cardiovascular death (HR, 1.24; 95% CI, 0.84–1.85) and all-cause mortality (HR, 1.16; 95% CI, 0.89–1.51) in the time-fixed analysis but with increased risks of cardiovascular death (HR, 1.79; 95% CI, 1.23–2.61) and all-cause mortality (HR, 1.48; 95% CI, 1.15–1.90) in the time-dependent analysis. Conclusions BP control < 140/90 mmHg was not associated with a decreased risk of mortality in older HF patients. The increased risk in the time-dependent analysis requires further corroboration.

ObjectiveLymphadenectomy is an integral part of surgical staging and treatment for patients with gynecologic malignancies. Since its introduction, laparoscopic lymphadenectomy has proved feasible, safe, and oncologically adequate compared with open surgery while morbidity is lower and hospital stay considerably shorter. The aim of this study was to examine if surgical outcomes may be improved after the initial learning curve is complete.MethodsAn analysis of 2535 laparoscopic pelvic and/or para-aortic lymphadenectomies was performed between July 1994 and March 2018 by one team of gynecologic oncology surgeons but with the consistent supervision of a consultant surgeon. Data were collected prospectively evaluating operative time, intra-operative and post-operative complications, number of lymph nodes, and body mass index (BMI). Previously published data of 650 patients treated after introduction of the method (period 1, 1994–2003) were compared with the latter 524 patients (period 2, 2014–2018).ResultsThe median age of the 2535 patients was 43 years (IQR 34–57). The most common indication for pelvic and/or para-aortic lymphadenectomy was cervical cancer (n=1893). Operative time for para-aortic lymph node dissection was shorter in period 2 (68 vs 100 min, p2. In contrast to period 1 (n=18, 2.9%), there were no intra-operative complications in period 2 (n=0, 0.0%, pConclusionIn this large cohort of patients who underwent laparoscopic transperitoneal lymphadenectomy, lymph node count and peri-operative complications improved after the initial learning curve.

PURPOSE We aimed to investigate differences between high-intensity interval exercise (HIIE, including high-intensity interval training and sprint interval training) and moderate-intensity continuous training (MICT) on physical fitness, body composition, blood pressure, blood lipids, insulin and glucose metabolism, inflammation, and endothelial function. METHODS Differences between HIIE and MICT were summarized using a random-effects meta-analysis on the effect size (Cohen's d). A meta-regression was conducted using the following subgroups: population, age, training duration, men ratio, exercise type, baseline values (clinical relevant ranges), and type of HIIE. Studies were included if at least one of the following outcomes were reported: maximal oxygen uptake (V˙O2max), flow-mediated dilation (FMD), body mass index (BMI), body mass, percent body fat, systolic and diastolic blood pressure, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, total cholesterol, C-reactive protein (CRP), fasting glucose and insulin, glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR). A total of 55 studies were included. RESULTS Overall, HIIE was superior to MICT in improving V˙O2max (d = 0.40, P < 0.001) and FMD (d = 0.54, P < 0.05). Oppositely, MICT was superior to HIIE in improving HbA1c (d = -0.27, P < 0.05). No differences were observed in BMI (d = -0.02), body mass (d = -0.05), percent body fat (d = 0.04), systolic blood pressure (d = -0.04), diastolic blood pressure (d = 0.03), HDL (d = -0.05), LDL (d = 0.08), triglycerides (d = 0.03), total cholesterol (d = 0.14), CRP (d = -0.11), fasting insulin (d = 0.02), fasting glucose (d = 0.02), and HOMA-IR (d = -0.04). Moderator analyses indicated that the difference between HIIE and MICT was affected by different subgroups. CONCLUSION Overall, HIIE showed to be more effective in improving cardiovascular health and cardiorespiratory fitness, whereas MICT was superior in improving long-term glucose metabolism. In the process of personalized training counseling, health-enhancing effects of exercise training may be improved by considering the individual risk profiles.

PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma. PATIENTS AND METHODS The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data. RESULTS For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data. CONCLUSION The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.

Radiolabeled bisphosphonates such as 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) typically show intense uptake in skeletal metastases from metastatic castration-resistant prostate cancer (mCRPC). Extensive bone involvement is regarded as a risk factor for mCRPC patients treated with 223Ra-dichloride (223Ra). The aim of this study was to quantify 99mTc-DPD uptake by means of SPECT/CT before 223Ra and compare the results with the feasibility of treatment and overall survival (OS). Methods: Sixty consecutive mCRPC patients were prospectively included in this study. SPECT/CT of the central skeleton covering the skull to the mid-femoral level was performed before the first cycle of 223Ra. The bone compartment was defined by means of low-dose CT. Emission data were corrected for scatter, attenuation, and decay supplemented by resolution recovery using dedicated software. The Kaplan-Meier estimator, U test, and Cox regression analysis were used for statistics. Results: Total 99mTc-DPD uptake of the central skeleton varied between 11% and 56% of injected dose (%ID) or between 1.8 and 10.5 %ID/1,000 mL of bone volume (%ID/L). SUVmean ranged from 1.9 to 7.4, whereas the SUVmax range was 18-248. Patients unable to complete 223Ra treatment because of progression and/or cytopenia (n = 23) showed significantly higher uptake (31.9 vs. 25.4 %ID and 6.0 vs. 4.7 %ID/L; P < 0.02). OS after 223Ra (median, 15.2 mo) was reduced to 7.3 mo in cases of skeletal uptake that was 26 %ID or higher, as compared with 30.8 mo if lower than 26 %ID (P = 0.008). Similar results were obtained for %ID/L and SUVmean SUVmax did not correlate with survival. %ID/L was identified as an independent prognostic factor for OS (hazard ratio, 1.381 per unit), along with number of previous treatment lines. Conclusion: Quantitative SPECT/CT of bone scans performed at baseline is prognostic for survival in mCRPC patients treated with 223Ra.

Purpose Active surveillance (AS) strategies for patients with low- and early intermediate-risk prostate cancer are still not consistently defined. Within a controlled randomized trial, active surveillance was compared to other treatment options for patients with prostate cancer. Aim of this analysis was to report on termination rates of patients treated with AS including different grade groups. Methods A randomized trial comparing radical prostatectomy, active surveillance, external beam radiotherapy and brachytherapy was performed from 2013 to 2016 and included 345 patients with low- and early intermediate-risk prostate cancer (ISUP grade groups 1 and 2). The trial was prematurely stopped due to slow accrual. A total of 130 patients were treated with active surveillance. Among them, 42 patients were diagnosed with intermediate-risk PCA. Reference pathology and AS quality control were performed throughout. Results After a median follow-up time of 18.8 months, 73 out of the 130 patients (56%) terminated active surveillance. Of these, 56 (77%) patients were histologically reclassified at the time of rebiopsy, including 35% and 60% of the grade group 1 and 2 patients, respectively. No patients who underwent radical prostatectomy at the time of reclassification had radical prostatectomy specimens ≥ grade group 3. Conclusion In this prospectively analyzed subcohort of patients with AS and conventional staging within a randomized trial, the 2-year histological reclassification rates were higher than those previously reported. Active surveillance may not be based on conventional staging alone, and patients with grade group 2 cancers may be recommended for active surveillance in carefully controlled trials only.

To evaluate the clinical benefit of positron emission tomography (PET)/computed tomography (CT) in patients with advanced melanoma, primarily not selected for surgery based on management changes and survival data using the linked evidence approach (LEA). A total of 201 18F-FDG PET/CT examinations (n = 33, stage III and n = 168, stage IV) in 119 melanoma patients, primarily not scheduled for surgery, were analysed regarding their impact on clinical management. Patients were selected from a prospective oncological PET/CT registry. The three PET/CT indication groups included unclear lesions in conventional imaging (n = 8), routine follow-up after multiple surgeries (n = 115) and therapy response evaluation of systemic therapy (n = 78). PET/CT-induced management changes were categorized either as major (change from follow-up to surgical or systemic treatment or vice versa, change from surgery to systemic therapy or vice versa) or minor (modifications in systemic therapy). The expected benefit of changes was determined via the linked evidence approach (LEA) connecting registry data, outcome data including overall survival and evidence of diagnostic accuracy of PET/CT based on existing literature. Related to the total study cohort, a change of management after PET/CT was observed in 48% of scans, including 10% minor and 38% major changes. Major changes involved a shift either from follow-up (33/201) or therapy pause (7/201) to systemic therapy, to surgical or other local therapy (26/201) and BSC (2/201). Nine out of 201 cases resulted in treatment pause of systemic therapy. We could confirm the prognostic value of PET/CT-based management by observing a 5-year survival rate more than roughly doubled in patients followed up after tumour exclusion or under local therapy compared with patients under systemic therapy. We could argue for a patient benefit from PET/CT-based management changes using results on accuracy and therapeutic effects from the literature. The use of PET/CT in advanced melanoma patients, primarily not considered for surgery, resulted in frequent changes of management associated with a relevant expected clinical benefit especially in patients classified by PET/CT as tumour-free or eligible for radical surgery.

ObjectiveEvaluation of the specificity and accuracy of four CE-approved SARS-CoV-2 antigen rapid self-tests (AG-ST) Anbio, Clungene, Hotgene and Mexacare.Method1015 asymptomatic volunteers were screened for SARS-CoV-2 by means of an oropharyngeal swab taken by qualified personnel and subsequent RT-PCR testing. Each participant additionally performed nasal self-swabs for two of the four rapid antigen tests at the same day according to the manufacturers’ instructions. Study participants transmitted a photo and own interpretation of their test results to the study center. The results of the two self-tests provided by the participants were correlated with the results of the SARS-CoV-2 RT-PCR and independently assessed and evaluated by the study center.ResultsNone of the volunteers tested positive upon RT-PCR, whereas 13 AG-ST showed a false positive test result (0.7 %). The highest false positivity rate was found for the Clungene test (2.1 % compared to 0.2 % for the other tests), while the highest test failure rate (invalid) was found for the Mexacare test (3.7%). The Anbio and Hotgene tests produced the fewest false positive results when evaluated by the participants and also showed the best agreement among themselves.ConclusionSARS-CoV-2 Antigen rapid self-tests with higher false positive test rates, such as the Clungene test, or with high rates of invalid test results, such as the Mexacare test, are less suitable for screening purposes of asymptomatic study participants especially in low-prevalence settings. False positive or inadequate test results increase the burden on certified test laboratories due to verification PCR tests and cause a substantial economic loss due to unnecessary quarantine measurements and cause psychological stress in the affected study participants. In addition to earlier defined requirements for sensitivity for SARS-CoV-2 detection, a lower acceptance boundary for the false positivity rate of < 0.3% should be demanded.

According to international literature, patients with cancer wish to have information on complementary and integrative healthcare (CIH). Medical guidelines recommend actively approaching patients with cancer discussing potential benefits and risks of individual CIH methods. While some CIH methods, for example, acupuncture and yoga, have been proven effective in high-quality studies, other CIH methods lack studies or bear the risk of interactions with chemotherapeutics, for example, herbal drugs. Therefore, an evidence-based interprofessional counselling programme on CIH will be implemented at four Comprehensive Cancer Centres in the federal state of Baden-Wuerttemberg, Germany.A complex intervention consisting of elements on patient, provider and system levels will be developed and evaluated within a multilayer evaluation design with confirmatory evaluation on patient level. Patients with a cancer diagnosis within the last 6 months will receive three individual counselling sessions on CIH within 3 months (=intervention on patient level). The counselling will be provided by an interprofessional team of medical and nursing staff. For this purpose, an intensive online training programme, a CIH knowledge database and an interprofessional team-building process were developed and implemented (=intervention on provider level). Moreover, training events on the basics of CIH are offered in the outpatient setting (=intervention on system level). Primary outcome of the evaluation at the patient level is patient activation measured (PAM) with the PAM-13 after 3 months. Secondary outcomes, for example, quality of life, self-efficacy and clinical parameters, will be assessed at baseline, after 3 months and at 6 months follow-up. The intervention group (n=1000) will be compared with a control group (n=500, treatment as usual, no CIH counselling. The outcomes and follow-up times in the control group are the same as in the intervention group. Moreover, the use of health services will be analysed in both groups using routine data. A qualitative-quantitative process evaluation as well as a health economic evaluation will identify relevant barriers and enabling factors for later roll-out.The study has been approved by the appropriate Institutional Ethical Committee of the University of Tuebingen, No. 658/2019BO1. The results of these studies will be disseminated to academic audiences and in the community.DRKS00021779; Pre-results.

The ongoing COVID-19 pandemic requires wearing face masks in many areas of our daily life; hence, the potential side effects of mask use are discussed. Therefore, the present study explores whether wearing a medical face mask (MedMask) affects physical working capacity (PWC). Secondary, the influence of a filtering facepiece mask with exhalation valve class 2 (FFP2exhal) and a cotton fabric mask (community mask) on PWC was also investigated. Furthermore, corresponding physiological and subjective responses when wearing face masks as well as a potential moderating role of subjects’ individual cardiorespiratory fitness and sex on face mask effects were analyzed. Thirty-nine subjects (20 males, 19 females) with different cardiorespiratory fitness levels participated in a standardized submaximal bicycle ergometer protocol using either a MedMask, FFP2exhal, community mask, or no mask (control) on four days, in randomized order. PWC130 and PWC150 as the mechanical load at the heart rates of 130 and 150 beats per minute were measured as well as transcutaneous carbon dioxide partial pressure, saturation of peripheral capillary oxygen, breathing frequency, blood pressure, perceived respiratory effort, and physical exhaustion. Using the MedMask did not lead to changes in PWC or physiological response compared to control. Neither appeared changes exceeding normal ranges when the FFP2exhal or community mask was worn. Perceived respiratory effort was up to one point higher (zero-to-ten Likert scale) when using face masks (p < 0.05) compared to control. Sex and cardiorespiratory fitness were not factors influencing the effects of the masks. The results of the present study provide reason to believe that wearing face masks for infection prevention during the COVID-19 pandemic does not pose relevant additional physical demands on the user although some more respiratory effort is required.

Simple Summary Our aim was to check for possible associations between clinical parameters or NGS-based genetic alterations and the occurrence of immune-related adverse events (IRAE) in melanoma patients with immune checkpoint inhibitors (ICI). We analyzed 95 melanoma patients with ICI and were able to identify several biomarkers associated with the development of IRAE. Female sex was significantly associated with the development of hepatitis, increased total and relative monocytes at ICI initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Furthermore, the following genetic alterations were identified being associated with IRAE: SMAD3 (pancreatitis); CD274, SLCO1B1 (hepatitis); PRDM1, CD274 (encephalitis); PRDM1, CD274, TSHR, FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. Our findings can help to assess the risk for the development of IRAE in melanoma patients with ICI. Abstract Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.

Movement disorders 37(2), 405-410 (2022). doi:10.1002/mds.28844, Published by Wiley, New York, NY

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.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.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.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).

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.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.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.The trial was registered at www.drks.de (ID: DRKS00025033 ) on 30th September 2021.

Purpose Although multiple imputation is the state-of-the-art method for managing missing data, mixed models without multiple imputation may be equally valid for longitudinal data. Additionally, it is not clear whether missing values in multi-item instruments should be imputed at item or score-level. We therefore explored the differences in analyzing the scores of a health-related quality of life questionnaire (EQ-5D-5L) using four approaches in two empirical datasets. Methods We used simulated (GR dataset) and observed missingness patterns (ABCD dataset) in EQ-5D-5L scores to investigate the following approaches: approach-1) mixed models using respondents with complete cases, approach-2) mixed models using all available data, approach-3) mixed models after multiple imputation of the EQ-5D-5L scores, and approach-4) mixed models after multiple imputation of EQ-5D 5L items. Results Approach-1 yielded the highest estimates of all approaches (ABCD, GR), increasingly overestimating the EQ-5D-5L score with higher percentages of missing data (GR). Approach-4 produced the lowest scores at follow-up evaluations (ABCD, GR). Standard errors (0.006–0.008) and mean squared errors (0.032–0.035) increased with increasing percentages of simulated missing GR data. Approaches 2 and 3 showed similar results (both datasets). Conclusion Complete cases analyses overestimated the scores and mixed models after multiple imputation by items yielded the lowest scores. As there was no loss of accuracy, mixed models without multiple imputation, when baseline covariates are complete, might be the most parsimonious choice to deal with missing data. However, multiple imputation may be needed when baseline covariates are missing and/or more than two timepoints are considered.

The ongoing COVID-19 pandemic requires wearing face masks in many areas of our daily life; hence, the potential side effects of mask use are discussed. Therefore, the present study explores whether wearing a medical face mask (MedMask) affects physical working capacity (PWC). Secondary, the influence of a filtering facepiece mask with exhalation valve class 2 (FFP2exhal) and a cotton fabric mask (community mask) on PWC was also investigated. Furthermore, corresponding physiological and subjective responses when wearing face masks as well as a potential moderating role of subjects’ individual cardiorespiratory fitness and sex on face mask effects were analyzed. Thirty-nine subjects (20 males, 19 females) with different cardiorespiratory fitness levels participated in a standardized submaximal bicycle ergometer protocol using either a MedMask, FFP2exhal, community mask, or no mask (control) on four days, in randomized order. PWC130 and PWC150 as the mechanical load at the heart rates of 130 and 150 beats per minute were measured as well as transcutaneous carbon dioxide partial pressure, saturation of peripheral capillary oxygen, breathing frequency, blood pressure, perceived respiratory effort, and physical exhaustion. Using the MedMask did not lead to changes in PWC or physiological response compared to control. Neither appeared changes exceeding normal ranges when the FFP2exhal or community mask was worn. Perceived respiratory effort was up to one point higher (zero-to-ten Likert scale) when using face masks (p < 0.05) compared to control. Sex and cardiorespiratory fitness were not factors influencing the effects of the masks. The results of the present study provide reason to believe that wearing face masks for infection prevention during the COVID-19 pandemic does not pose relevant additional physical demands on the user although some more respiratory effort is required.

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.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.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 ).