Bayesian nonparametric (BNP) approaches for meta-analysis have been developed to relax distributional assumptions and handle the heterogeneity of random effects distributions. These models account for possible clustering and multimodality of the random effects distribution. However, when we combine studies of varying quality, the resulting posterior is not only a combination of the results of interest but also factors threatening the integrity of the studies' results. We refer to these factors as the studies' internal validity biases (e.g., reporting bias, data quality, and patient selection bias). In this paper, we introduce a new meta-analysis model called the bias-corrected Bayesian nonparametric (BC-BNP) model, which aims to automatically correct for internal validity bias in meta-analysis by only using the reported effects and their standard errors. The BC-BNP model is based on a mixture of a parametric random effects distribution, which represents the model of interest, and a BNP model for the bias component. This model relaxes the parametric assumptions of the bias distribution of the model introduced by Verde. Using simulated data sets, we evaluate the BC-BNP model and illustrate its applications with two real case studies. Our results show several potential advantages of the BC-BNP model: (1) It can detect bias when present while producing results similar to a simple normal-normal random effects model when bias is absent. (2) Relaxing the parametric assumptions of the bias component does not affect the model of interest and yields consistent results with the model of Verde. (3) In some applications, a BNP model of bias offers a better understanding of the studies' biases by clustering studies with similar biases. We implemented the BC-BNP model in the R package jarbes, facilitating its practical application.

Background: Sports scientists have studied in-season training periodization with elite soccer teams obtaining some calculations such as relative accumulated load. However, to the best of the authors' knowledge, there is scarce literature about training programs related to the loads imposed during matches in non-starter vs. starter players during different in-season periods. Objective: The main aim of the present study was to compare accumulative match and training load rates and the corresponding training/match ratio (TMr) between non-starters and starters players of an Argentine professional soccer team during two in-season periods (regular competition period vs. match congested period). Methods: Ten players were considered starters if they started the match and completed at least 60 min in three consecutive matches while the other 10 were classified as non-starters (most of the matches played as substitute players) over two 8-week periods. The external load of each player during typical practice sessions and official matches was monitored by GPS. Data on total distance (TD), high-intensity load rate (distance covered at speed > 14.9 km/h per minute, HILR) and high-speed load rate (distance covered at speed > 19.9 km/h per minute, HSLR), number of runs during the load rates (#HILR and #HSLR), high-intensity accelerations and decelerations (> 2.5 m/s2, HIA; < -2.5 m/s(2), HID) and high metabolic load distance (HMLD) were monitored. An individual TMr was calculated for each external load measure. Results: There were no significant differences in accumulative match and training load rates between non-starters and starters. Regarding TMr, non-starters presented a lower value in HILR (-12.9%, p = .039), #HILR (-7.7%, p = .032), and HMLD (-9.8%, p = .024). Conclusions: The main finding of this study showed that non-starters did not present an improvement or deterioration in physical performance in the main physical metrics analysed, compared to starter players in both periods. In addition, non-starters presented lower values of TMr for high-intensity patterns during the regular period. This could be attributed to the fact that non-starting players have achieved higher performance in various physical metrics, compared to players who were substituted or completed the entire match.

The José Carreras Cord Blood Bank (CBB) located in Düsseldorf as of today stores 21 215 active cryopreserved cord blood units (CBUs) applicable as a source for hematopoietic stem cell (HSC) transplantation. Since the success of transplantation outcomes is mainly dependent on the cord blood quality, typical parameters are evaluated by a Stability Monitoring Program specified by the FACT Standards. The longest expiration time determined to date is 29 years for unseparated units, 25 years for manual and 18 years for automated volume-reduced units licensed by the Paul-Ehrlich Institute. According to the CBB stability program TNC count, TNC recovery, TNC viability, CD34+7AAD- viability, CD45+7AAD- viability and CFC count were determined for all 3 processing methods applied over time. As a measure of stability, unseparated units (processed 1993-1998) revealed a mean TNC viability of 88.91 ± 5.01% after 29 years of cryopreservation versus manual volume-reduced CBUs (processed 1998-2005) with a mean of 84.22 ± 10.02% after 25 years of cryopreservation versus automated volume-reduced CBUs (processed since 2005) with a mean of 88.64.91 ± 3.91% after 18 years of cryopreservation. In addition, these relevant parameters were retrospectively analyzed for released transplants in correlation to the storage time. Moreover, the follow-up data of recipients from CBUs cryopreserved directly (unseparated) versus CBUs cryopreserved after manual versus automated volume-reduction are presented here demonstrating an earlier engraftment in both volume-reduced groups as compared to unseparated CBUs. By this retrospective analysis, key questions are discussed regarding cord blood parameters in relation to processing methods, engraftment, and patient age (children and adults).

Background The provision of data sharing statements (DSS) for clinical trials has been made mandatory by different stakeholders. DSS are a device to clarify whether there is intention to share individual participant data (IPD). What is missing is a detailed assessment of whether DSS are providing clear and understandable information about the conditions for data sharing of IPD for secondary use. Methods A random sample of 200 COVID-19 clinical trials with explicit DSS was drawn from the ECRIN clinical research metadata repository. The DSS were assessed and classified, by two experienced experts and one assessor with less experience in data sharing (DS), into different categories (unclear, no sharing, no plans, yes but vague, yes on request, yes with specified storage location, yes but with complex conditions). Results Between the two experts the agreement was moderate to substantial (kappa=0.62, 95% CI [0.55, 0.70]). Agreement considerably decreased when these experts were compared with a third person who was less experienced and trained in data sharing (“assessor”) (kappa=0.33, 95% CI [0.25, 0.41]; 0.35, 95% CI [0.27, 0.43]). Between the two experts and under supervision of an independent moderator, a consensus was achieved for those cases, where both experts had disagreed, and the result was used as “gold standard” for further analysis. At least some degree of willingness of DS (data sharing) was expressed in 63.5% (127/200) cases. Of these cases, around one quarter (31/127) were vague statements of support for data sharing but without useful detail. In around half of the cases (60/127) it was stated that IPD could be obtained by request. Only in in slightly more than 10% of the cases (15/127) it was stated that the IPD would be transferred to a specific data repository. In the remaining cases (21/127), a more complex regime was described or referenced, which could not be allocated to one of the three previous groups. As a result of the consensus meetings, the classification system was updated. Conclusion The study showed that the current DSS that imply possible data sharing are often not easy to interpret, even by relatively experienced staff. Machine based interpretation, which would be necessary for any practical application, is currently not possible. Machine learning and / or natural language processing techniques might improve machine actionability, but would represent a very substantial investment of research effort. The cheaper and easier option would be for data providers, data requestors, funders and platforms to adopt a clearer, more structured and more standardised approach to specifying, providing and collecting DSS. Trial registration The protocol for the study was pre-registered on ZENODO ( https://zenodo.org/record/7064624#.Y4DIAHbMJD8 ).

BACKGROUND:The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. METHODS:Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS:157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION:In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Background: In elite soccer, many teams routinely use positional games (PGs) in their practice sessions, striving to simulate competition situations, although some debate exists about the application's usefulness. Objective: The main aim of this descriptive study was to compare the physical demands among three different formats of PGs within the competitive profile. Methods: A descriptive study was conducted with 19 Argentinian professional soccer players (age 23.7 +/- 4.7 years, body mass 73.6 +/- 7.0 kg, height 177.2 +/- 5.6 cm). External load was monitored by GPS (Catapult (TM)) during typical practice sessions with PGs designs (7 vs. 7 + 1 Floater [F], 9 vs. 9 + 2F + 2 goalkeepers [GK], 10 vs. 10 + 1F + 2GK) and during 10 official matches. Data on total distance (TD), player-load (PL), HILR (distance covered at speed > 14.9 km/h per minute), HSSL (distance covered at speed > 19.9 km/h per minute), number of runs during HILR and HSSL, very high-intensity accelerations (> 3.5 m/s(2); VHIA) and decelerations (< -3.5 m/s(2); VHID) and maximal speed (MS) were measured. In addition, rates of perceived exertion (RPE) were also monitored. Results: The mean values of TD and PL were similar to those of match status in every format. With respect to HILR and HSSL, the average values were significantly lower than those obtained in matches for 7 vs. 7 + 1F and 9 vs. 9 + 2F + 2GK formats (p < .001). The MS was the other variable in the study that differed notably from the values obtained during matches in each format (p < .001). The VHIA values were significantly higher than matches in 7 vs. 7 + 1F, while VHID presented statistical differences in both formats, 7 vs. 7 + 1F and 10 vs. 10 + 1F + 2GK. Regarding RPE, 10 vs. 10 + 1F + 2GK was the only format without statistical difference in comparison with matches (p < .001). Conclusions: The findings suggest that smaller-sized PGs could be used to stimulate intensity in terms of acceleration/deceleration demands, whereas larger-sized PGs are the optimum format to reach a similar performance in a competitive situation.

Background: Many specific games are practiced with the aim of maintaining the possession of the ball by the team. Among them, possession games (POG) are similar to small-sided games (SSG), and as such, have a few different characteristics. Objective: The aim of this study was to compare high-intensity patterns of professional soccer players in relation to the positional role between POG and SSG in professional soccer. Methods: A descriptive analysis was conducted over one season, during typical training sessions with 5 vs. 5 designs and 10 official matches. Twenty-six male professional players (age 24.7 +/- 5 years, body mass 73.6 +/- 7 kg, body height 178.4 +/- 6.2 cm) were classified into five positional roles: central defender, wide defender, midfielder, wing and forward. Players' locomotor activity was recorded using GPS (Openfield-CatapultTM). Data on total distance, player-load, work rates (distance covered at speed > 14.9 km/h per min and distance covered at speed > 19.9 km/h per min), the number of runs in work rates, very high-intensity accelerations-decelerations (> 3.5 / < -3.5 m/s(2)) and maximal speed were measured. Results: The analysis of the data showed higher performance for POG in seven of the nine study variables (p <.01), except in accelerations where the SSG were higher than POG (p <.01), while no significant difference was obtained in decelerations. When comparing performance among playing positions, significantly higher values were observed in POG (p <.05) in the same variables (no differences for the wingers in total distance and player-load; wide defenders and forwards in distance covered at speed > 19.9 km/h per min). Regarding accelerations, SSG outperformed POG in almost all game positions (p <.05, except for wide defenders). No significant differences were found in decelerations for all positions. Conclusions: The findings suggest that POG could be used to stimulate the physical demands to which players are exposed to competitions. Moreover, SSG could be used as an exercise with greater intentionality when it comes to stimulating a significant number of accelerations per unit time.

Sharing sensitive data is a specific challenge for research infrastructures in the field of life sciences. For that reason a toolbox has been developed, providing resources for researchers who wish to share and use sensitive data, to support the workflows for handling these kinds of digital objects. Common and community approved annotations are required to be compliant with FAIR principles (Findability, Accessibility, Interoperability, Reusability). The toolbox makes use of a tagging (categorisation) system, allowing consistent labelling and categorisation of digital objects, in terms relevant to data sharing tasks and activities. A pilot study was performed within the Horizon 2020 project EOSC-Life, in which 2 experts from 6 life sciences research infrastructures were recruited to independently assign tags to the same set of 10 to 25 resources related to sensitive data management and data sharing (in total 110). Summary statistics of agreement and observer variation per research infrastructure are provided. The pilot study has shown that experts were able to attribute tags but in most cases with a considerable observer variation between experts. In the context of CWFR (Canonical Workflow Frameworks for Research), this indicates the necessity for careful definition, evaluation and validation of parameters and processes related to workflow descriptions. The results from this pilot study were used to tackle this issue by revising the categorisation system and providing an updated version.

Background Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. Methods A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. Findings Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40.2 years (SD 11.7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29.6 [SD 14.5]) than in the olanzapine plus placebo group (-24.1 [13.4], p=0.049, Cohen's d=0.396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25.2 [SD 15 .9], p=0.095, Cohen's d=0.29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). Interpretation The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

In this study, the effects of lyophilized Euterpe oleracea (LEO) as a dietary antioxidant additive were assessed on growth, skin coloration, bioactive muscle properties, metabolic parameters, and antioxidant status of tambaqui ( Colossoma macropomum ). Fish (initial body weight 0.92 ± 0.01 g) were fed five isoproteic (40% of crude protein) and isocaloric (20 kJ/g gross energy) diets (three replicates each) with graded LEO levels (6.3, 13, 25, 50, and 100 g per kg of diet), and a control group (0 g kg −1 LEO) at 10% of total biomass each day during 30 days. The experiment was conducted in a semistatic system (18 tanks of 200 L; N = 50 fish per tank). The results showed that the greatest final body length (7.92 ± 0.08 cm) was obtained in fish fed 50 g kg −1 LEO ( p < 0.05). Fish fed 50 g and 100 g kg −1 LEO had higher final body weight (FBW, 115% and 119%, respectively) and weight gain (WG, 118% and 124%, respectively) than control group ( p < 0.05). Feed conversion ratio (0.73–0.78), protein efficiency ratio (3.44–3.48), and feed intake (3.85–4.01% day −1 ) were improved in fish fed 13 g to 100 g kg −1 LEO ( p < 0.05). Condition factor (K) and proximate carcass composition were not altered by feeding treatments ( p > 0.05). LEO-enriched diets (50 g to 100 g kg −1 LEO) intensified the cyan color in the fish skin ( p < 0.05). The DPPH • scavenging activity, total polyphenols, and flavonoids in the muscle were not changed ( p > 0.05). Dietary LEO did not alter the muscle’s cholesterol, glucose, glycogen, and total protein levels compared to the control group ( p > 0.05). However, the muscle triglyceride in the LEO treatments was significantly lower (40.5%) than in the control ( p < 0.05). The electron transport system activity in muscle was significantly increased (76.3%) with dietary LEO of 13 g to 100 g kg −1 . LEO boosted the total antioxidant capacity (ACAP) in the intestine (39.6%) ( p < 0.05); however, there were no differences in liver and muscle ( p > 0.05). The malondialdehyde (MDA) concentrations showed no differences in the intestine, liver, and muscle regardless of treatments ( p > 0.05). A fitted second-order polynomial estimated that 54.7 g kg −1 LEO results in lower intestine MDA levels. Overall, 50 g kg −1 LEO promoted tambaqui growth, improved the skin color, adjusted hypolipidemic and bioenergetics in the muscle, enhanced intestinal ACAP, and minimized MDA levels in this tissue. Therefore, LEO is a potential feed supplement used in tambaqui production.

For life science infrastructures, sensitive data generate an additional layer of complexity. Cross-domain categorisation and discovery of digital resources related to sensitive data presents major interoperability challenges. To support this FAIRification process, a toolbox demonstrator aiming at support for discovery of digital objects related to sensitive data (e.g., regulations, guidelines, best practice, tools) has been developed. The toolbox is based upon a categorisation system developed and harmonised across a cluster of 6 life science research infrastructures. Three different versions were built, tested by subsequent pilot studies, finally leading to a system with 7 main categories (sensitive data type, resource type, research field, data type, stage in data sharing life cycle, geographical scope, specific topics). 109 resources attached with the tags in pilot study 3 were used as the initial content for the toolbox demonstrator, a software tool allowing searching of digital objects linked to sensitive data with filtering based upon the categorisation system. Important next steps are a broad evaluation of the usability and user-friendliness of the toolbox, extension to more resources, broader adoption by different life-science communities, and a long-term vision for maintenance and sustainability.

Background: Lymph node ratio (LNR) and the Log odds of positive lymph nodes (LODDS) have been proposed as a new prognostic indicator in surgical oncology. Various studies have shown a superior discriminating power of LODDS over LNR and lymph node category (N) in diverse cancer entities, when examined as a continuous variable. However, for each of the classification systems various cut-off values have been defined, with the question of the most appropriate for patients with CRC still remaining open. The present study aimed to compare the predictive impact of different lymph node classification systems and to define the best cut-off values regarding accurate evaluation of overall survival in patients with resectable, non-metastatic colorectal cancer (CRC). Methods: CRC patients who underwent surgical resection from 1996 to 2018 were extracted from our medical data base. Cox proportional hazards regression models and C-statistics were performed to assess the discriminative power of 25 LNR and 26 LODDS classifications. Regression models were adjusted for age, sex, extent of the tumor, differentiation, tumor size and localization. Results: Our study group consisted of 654 consecutive patients with non-metastatic CRC. C-statistic revealed 2 LNR and 5 LODDS classifications that demonstrated superior prognostic performance in patients with UICC III CRC, compared to the N category. No clear advantage of one classification over another could be demonstrated in any other patient subgroup. Conclusions: Distinct LNR and LODDS classifications demonstrate a prognostic superiority over the N category only in patients with Stage III radically resected CRC.

Background: A tactical factor such as playing formation seems to be another influencing factor in the physical performance of elite soccer players during the match. Some researchers have suggested that distances covered during high-intensity running in matches are valid measures of physical performance. They concluded that players covered greater distances of high-intensity activities during some team formations in comparison to others. Objective: The aim of this study was to examine high-intensity patterns of professional soccer players in relation to the positional role with two different playing formations. Methods: Match data were collected during official games systematically playing in 1-3-4-3 and 1-4-2-1-3 formations. Nineteen professional players (age 24.7 ± 4.8 years, body mass 74.5 ± 6.2 kg, height 176.3 ± 5.3 cm, percentage of body fat 9.7 ± 2.5%) were classified into five positional roles: central defender, wide defender, midfielder, wing and forward. Match performance variables included moderate-intensity running (14.9–19.8 km/h), high-speed running (19.9–25.2 km/h) and sprinting (> 25.2 km/h). The number of runs (#HSR, #SPR) and metabolic rates as HILR ([MIR + HSR + SPR]/min) and HSSL ([HSR + SPR]/min) were determined. Results: The statistical analysis revealed that #SPR (p = .045), HILR (p = .022) and HSSL (p = .019) were higher in 1-4-2-1-3 than 1-3-4-3 formation. According to the playing position, significant differences were found in HILR (p = .045) and HSSL (p = .028) for forwards during 1-4-2-1-3 and midfielders amounted more HILR than others in that team formation (p = .047). Additionally, wings amounted significantly higher #HSR (p = .011) and #SPR (p = .010) in 1-4-2-1-3, as long as forwards was the other position with more #SPR during that formation (p = .023). Conclusions: The players performed more high-intensity patterns in 1-4-2-1-3. Attackers and midfielders were the playing positions that held the most statistical differences comparing both team formations. These findings reveal that playing formation seems to be another potential factor of influence with respect to the physical performance of elite players if we consider their high-intensity profile in particular.

Background: In patients with prostatic and breast cancer the application of peridural anesthesia (PDA) showed a beneficial effect on prognosis. This was explained by reduced requirements for general anesthetics and perioperative opioids as well as a lower perioperative stress level. The impact of PDA in patients with more aggressive types of cancer has not been completely elucidated. Here, we analyzed the prognostic influence of PDA on overall survival after surgery as primary in patients that underwent radical resection of pancreatic adenocarcinoma. Methods: Records of 98 consecutive patients were reviewed. In 70 of these cases PDA was applied. Patient characteristics such as demographics, TNM stage, and operative data were retrospectively collected from medical records and analyzed. Survival data were analyzed by Cox’s proportional hazard regression model. Results: Overall, no significant prognostic influence of PDA on recurrence or overall survival (p = 0.762, Hazard Ratio [HR] 0.884, 95% confidence interval [CI] 0.398–1.961) was found. However, there was a trend towards a longer overall survival (p = 0.069, HR 0.394, 95% CI 0.144–1.078) associated with PDA in a subgroup of patients with better differentiation of pancreatic adenocarcinoma. Conclusion: The observation of longer survival associated with PDA in our subgroup of patients with better-differentiated pancreatic carcinomas is in line with previous reports on various other less aggressive tumor entities. Our results indicate that PDA might improve the oncological outcome of patients with pancreatic adenocarcinoma.

Objectives Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression. Trial design This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested. Participants The trial is conducted at 10–15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m 2 Age > 65 years with at least one other risk factor (BMI > 35 kg/m 2 , coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m 2 with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: Age < 18 years Unable to give informed consent Pregnant women or breastfeeding mothers Previous transfusion reaction or other contraindication to a plasma transfusion Known hypersensitivity to camostat mesylate and/or severe pancreatitis Volume stress due to CP administration would be intolerable Known IgA deficiency Life expectancy < 6 months Duration SARS-CoV-2 typical symptoms > 3 days SARS-CoV-2 PCR detection older than 3 days SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) Previously or currently hospitalized due to SARS-CoV-2 Previous antiviral therapy for SARS-CoV-2 ALT or AST > 5 x ULN at screening Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) Chronic kidney disease with GFR < 30 ml/min Concurrent or planned anticancer treatment during trial period Accommodation in an institution due to legal orders (§40(4) AMG). Any psycho-social condition hampering compliance with the study protocol. Evidence of current drug or alcohol abuse Use of other investigational treatment within 5 half-lives of enrolment is prohibited Previous use of convalescent plasma for COVID-19 Concomitant proven influenza A infection Patients with organ or bone marrow transplant in the three months prior to screening visit Intervention and comparator Participants will be randomized to the following 4 groups: Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1–7) Standard of care (SOC, control for CP) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1–7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety. Main outcomes The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization. Randomization Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center. Blinding (masking) The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded. Numbers to be randomized (sample size) Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate. Trial status The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021. Trial registration EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020). Full protocol The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions. METHODS:Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia. RESULTS:157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found. CONCLUSION:These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period.

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400–800 mg/day), and olanzapine (10–20 mg/day) and amisulpride–olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

Objective: Concordance-analysis and evaluation of existing algorithms detecting late-onset preeclampsia during first trimester screeningMethods: Retrospective cohort study investigating risk algorithms of late-onset preeclampsia during first trimester screening in a German prenatal center. Three previously developed algorithms including anamnestic factors (Apriori) and biophysical markers (BioM) were investigated by using detection rates (DR) with fixed FPR 10% and fixed cutoff >1:100. Furthermore, we set up a concordance-analysis of test results in late-onset preeclampsia cases to examine the effect of influencing factors and to detect potential weaknesses of the algorithms. Therefore, we modeled the probability of discordances as a function of the influencing factors based on a logistic regression, that was fitted using a Bayesian approach.Results: 6,113 pregnancies were considered, whereof 700 have been excluded and 5,413 pregnancies were analyzed. 98 (1.8%) patients developed preeclampsia (79 late-onsets, 19 early-onsets). The Apriori-algorithm reaches a DR of 34.2%, by adding BioM (MAP and UtA-PI) the DR improves to 57.0% (FPR of 10%). In concordance-analysis of Apriori algorithm and Apriori+BioM algorithms, influencing factor BMI<25 increases the chance of discordances sigificantly. Additional, in the subgroup of late-onset preeclampsias with BMI<25 the DR is higher in Apriori+BioM algorithms than in Apriori algorithm alone. If both compared algorithms include BioM, influencing factor MAP decreases the chance of discordances significantly. All other tested influencing factors do not have a statistically significant effect on discordancesConclusion: Normal-weight patients benefit more from the integration of MAP and UtA-PI compared to overweight/obese patients.

Public health researchers may have to decide whether to perform a meta-analysis including only high-quality randomized clinical trials (RCTs) or whether to include a mixture of all the available evidence, namely RCTs of varying quality and observational studies (OS). The main hurdle when combining disparate evidence in a meta-analysis is that we are not only combining results of interest but we are also combining multiple biases. Therefore, commonly applied meta-analysis methods may lead to misleading conclusions. In this paper, we present a new Bayesian hierarchical model, called the bias-corrected (BC) meta-analysis model, to combine different study types in meta-analysis. This model is based on a mixture of two random effects distributions, where the first component corresponds to the model of interest and the second component to the hidden bias structure. In this way, the resulting model of interest is adjusted by the internal validity bias of the studies included in a systematic review. We illustrate the BC model with two meta-analyses: The first one combines RCTs and OS to assess effectiveness of vaccination to prevent invasive pneumococcal disease. The second one investigates the effectiveness of stem cell treatment in heart disease patients. Our results show that ignoring internal validity bias in a meta-analysis may lead to misleading conclusions. However, if a meta-analysis model contemplates a bias adjustment, then RCTs results may increase their precision by including OS in the analysis. The BC model has been implemented in JAGS and R, which facilitate its application in practice.