Assessing the impact of sex on high-frequency repetitive transcranial magnetic stimulation´s clinical response in schizophrenia - results from a secondary analysis.

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.

An assessment of the informative value of data sharing statements in clinical trial registries.

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 ).

Long-Term Stability of Cord Blood Units After 29 Years of Cryopreservation: Follow-Up Data From the José Carreras Cord Blood Bank.

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 ±â€…5.01% after 29 years of cryopreservation versus manual volume-reduced CBUs (processed 1998-2005) with a mean of 84.22 ±â€…10.02% after 25 years of cryopreservation versus automated volume-reduced CBUs (processed since 2005) with a mean of 88.64.91 ±â€…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).

Delineation of the adult phenotype of Coffin-Siris syndrome in 35 individuals.

Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.

An iterative and interdisciplinary categorisation process towards FAIRer digital resources for sensitive life-sciences data.

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.

Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

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. FUNDING: German Federal Ministry of Education and Research.

Prognostic Discrimination of Alternative Lymph Node Classification Systems for Patients with Radically Resected Non-Metastatic Colorectal Cancer: A Cohort Study from a Single Tertiary Referral Center.

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.

Peridural Anesthesia and Cancer-Related Survival after Surgery for Pancreatic Cancer-A Retrospective Cohort Study.

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.

Effects of high-frequency prefrontal rTMS on heart frequency rates and blood pressure in schizophrenia.

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.

Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial.

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/m2 Age > 65 years with at least one other risk factor (BMI > 35 kg/m2, 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/m2 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: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. 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) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. 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: 1) 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 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) 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).

A Bayesian risk analysis for Trisomy 21 in isolated choroid plexus cyst: combining a prenatal database with a meta-analysis.

OBJECTIVE: The purpose of this study was to quantify the possible additional risk of a fetus with an isolated choroid plexus cyst (ICPC) for Trisomy 21 by combining a large controlled cohort study with data from existent studies. METHODS: We searched our prenatal database between 2000 and 2014 for all singleton pregnancies between 18 + 0 and 26 + 6 gestational weeks with either an isolated choroid plexus cyst (study group) or no abnormality found in the detailed ultrasound scan (control group). We assessed all prenatal karyotyping results if invasive testing was performed and attempted to collect the postnatal outcome reports of all patients. The prevalence of Down syndrome was calculated. By using previous studies that met our inclusion criteria, a meta-analysis following the Bayesian Independent Model was created. From this meta-analysis, we computed the posterior predictive distribution of the probability (Trisomy 21 | ICPC) = P1 including posterior means, standard deviations, quantiles (2.5, 50, and 97.5%). By calculating the posterior of the difference (Δ) between the probability (Trisomy 21 | ICPC) and the probability (Trisomy 21 | Normal Ultrasound) = P2, we investigated the additional risk of an ICPC (ΔB = P1-P2). RESULTS: Overall, we detected 1220 fetuses with an isolated plexus cyst at 19-27 weeks of gestational age (GA). In our study group, the prevalence of Trisomy 21 was 2/1220 (0.16, 95% CI: 0.1-0.6%). The median of the pooled probability of Trisomy 21 given isolated PC across the studies included in the meta-analysis was 0.2% (CI: 0.1-0.4%). In the given periods (GA and time), 66,606 (74.8%) out of 89,056 investigated fetuses met the inclusion criteria and had a normal ultrasound result without any abnormality. The Δ between our study group and the control group was 0.08% (CIΔA: 0-0.5%). Including the meta-analysis, the median of the posterior distribution of Δ between P1 and P2 was 0.08% (CIΔB: 0-0.4%) (ΔB = P1-P2). CONCLUSION: The posterior distribution of Δ between P1 and P2 including the meta-analysis corresponds to showing no difference between the cases and controls (95% CIΔB: 0-0.4%). The additional risk of a fetus with an ICPC for Trisomy 21 is 97.5% likely to be lower than 0.4% (about 1/250). However, in our collective, the positive predictive value of ICPC for Down syndrome was 0.16% (about 1/625). In prenatal counseling, the additional risk should be added to the individual risk (based on maternal age, earlier screening test results, and sonographic markers) and the diagnostic options including fetal DNA and diagnostic procedures should be discussed according to the posterior individual risk.

A bias-corrected meta-analysis model for combining, studies of different types and quality.

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.

Concordance-analysis and evaluation of different diagnostic algorithms used in first trimester screening for late-onset preeclampsia.

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.

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

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.

Immediate and Sustained Effect of Neonatal Teaching in a Perinatal Setting in Urban Laos.

OBJECTIVE: This study aimed to quantify knowledge on neonatal topics among obstetricians and pediatricians participating in a perinatal teaching program aimed at reducing neonatal mortality in Laos. STUDY DESIGN: Obstetricians and pediatricians from Vientiane and the surrounding areas participated in a 1-week teaching program in obstetric and neonatal topics and responded to pre- and posttests questionnaires to quantify their knowledge. RESULTS: Although questions were predominantly related to neonatal topics, obstetricians performed significantly better than pediatricians during the pretest. Both groups increased their knowledge significantly as quantified by the results of the posttest. CONCLUSION: The teaching program was effective in improving knowledge on perinatal mortality related topics of the participants. These results may be related to the fact that most of the obstetricians had participated in a structured teaching program previously, whereas the pediatricians did not. We thus speculate that there is a sustained effect of even a 1-week teaching program in neonatology even several years after the initial teaching.

Symptomatic medial synovial plica of the knee joint: an underestimated pathology in young patients.

INTRODUCTION: To prospectively evaluate the outcome of arthroscopic resection of a symptomatic medial plica in patients under 30 years with evaluating the influence of sports, knee trauma and plica type. METHODS: 35 consecutive patients (38 knees), mean age 16.2 ± 4.7 years (9-26 years), 28 females (73.7%) were prospectively included. Patients with any additional surgical procedures or cartilage lesions > ICRS grade I were excluded. The influence of trauma to the knee, level of sport and the morphologic plica type on the outcome was evaluated in addition to standard knee scores before and 20.1 ± 9.3 months (12-44 months) after surgery. RESULTS: The Knee Injury and Osteoarthritis Outcome Score improved significantly from 50.2 ± 19.1% (12.5-94.6) to 80.7 ± 15.3% (48.2-100; p < 0.001). The Tegner Activity Scale improved significantly from 2.2 ± 1.5 (0-6) to 4.9 ± 1.7 (3-10; p < 0.001) and the Kujala Anterior Knee Pain Scale improved significantly from 52.6 ± 16.6 (16-86) to 80.7 ± 16.5 (46-100; p < 0.001). The level of pain in the knee decreased from 7.9 ± 2.0 (1-10) to 3.1 ± 2.6 (0-9; p < 0.001) at follow-up on a numeric rating scale (0-10). Neither trauma to the knee, high impact sport, cartilage lesions to the medial femoral condyle nor the plica type or associated ICRS grade I cartilage lesion to the medial femoral condyle had a significant effect on the outcome parameters. CONCLUSION: Arthroscopic resection of a symptomatic medial plica provides excellent clinical results in young patients. Trauma, high impact sports, ICRS grade I cartilage lesions to the medial femoral condyle or the plica type are not associated with a poorer outcome. LEVEL OF EVIDENCE: Level IV, prospective case series with no control group.

The association between a low critical shoulder angle and SLAP lesions.

PURPOSE: To evaluate the critical shoulder angle (CSA), acromion index (AI) and further acromion parameters in patients with isolated SLAP lesions compared with patients without SLAP lesions. METHODS: Between 2012 and 2016, the CSA, AI, lateral acromion angle (LAA) and acromion slope (AS) were radiologically examined in consecutive patients > 18 years having had a shoulder arthroscopy with isolated SLAP lesion types II-IV. These were compared to controls without SLAP lesions and without (control group I) or with (control group II) complete supraspinatus tendon (SSP) tears. RESULTS: 75/103 patients with isolated SLAP lesion types II-IV with a mean age of 46.5 years (± 13.0, 18.1-76.3) were analyzed, 61% of them being male. For control, n = 211 consecutive patients (47% male) with an intact SSP and SLAP complex and a mean age of 52.3 years (± 15.0, 18.6-88.4) and n = 115 patients (60% male) with an intact SLAP complex but complete SSP tears, mean age 66.6 years (± 9.3, 44.7-87.9) were examined. The CSA in SLAP patients was 29.6° (± 3.5, 21.0-38.0), 33.8° (± 3.7, 25.1-46.9) in no SLAP and no SSP (p < 0.001) and 36.7° (± 3.6, 29.1-46.6) in no SLAP but SSP (p < 0.001). The area under the curve (AUC) for CSA was 0.83 for SLAP lesions resulting in a probability of 83% for patients with SLAP lesion to be associated with a specific CSA. CONCLUSIONS: Isolated SLAP lesion types II-IV are associated with a low CSA < 30°. The AI, the AS as well as the LAA showed no correlation with SLAP lesions. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS. RESULTS: 26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p<0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group. CONCLUSIONS: In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

Biceps tenodesis versus tenotomy in isolated LHB lesions: a prospective randomized clinical trial.

INTRODUCTION: Currently there exists no clear evidence concerning the surgical treatment of LHB lesions with either tenotomy or tenodesis. The aim of the study is therefore to evaluate elbow flexion and forearm supination force as well as the biceps muscle distalization according to both techniques in isolated LHB lesions. METHODS: Consecutive patients aged 40-70 years with shoulder arthroscopies for isolated SLAP or biceps pulley lesions were prospectively randomized to arthroscopic suprapectoral intraosseous LHB tenodesis or tenotomy. Pre-, 6 and 12 months postoperatively, the SST, ASES, Constant-Murley and LHB scores were recorded. The elbow flexion force was measured in 10°/90° flexion, the supination force in neutral/pronation position. In addition, the maximum upper-arm circumference and its position relative to the radial epicondyle of the humerus were evaluated preoperatively and in follow-up. RESULTS: 20/22 patients (mean age 52.0 ± 8.5; range 36-63 years, 11 male) completed the follow-up. 9/20 were treated with LHB tenodesis (mean age 51.5 ± 9.5; range 37-63 years, 7 male) and 11/20 with tenotomy (mean age 52.8 ± 8.0; range 36-62 years, 4 male). The force measurements and scores showed no significant difference after 12 months. Tenodesis achieved a significant increase in force 6 months postoperatively compared to preoperatively. One tenodesis patient and three tenotomy patients showed a postoperative popeye-sign deformity. CONCLUSION: This prospective randomized study comparing LHB tenodesis and tenotomy in isolated LHB lesions has shown no significant difference in elbow flexion and forearm supination force and clinical scores after 12 months. After LHB tenotomy, there was a non-significant trend for a higher rate of popeye-sign deformities of the upper arm and biceps muscle cramps.

The hierarchical metaregression approach and learning from clinical evidence.

The hierarchical metaregression (HMR) approach is a multiparameter Bayesian approach for meta-analysis, which generalizes the standard mixed effects models by explicitly modeling the data collection process in the meta-analysis. The HMR allows to investigate the potential external validity of experimental results as well as to assess the internal validity of the studies included in a systematic review. The HMR automatically identifies studies presenting conflicting evidence and it downweights their influence in the meta-analysis. In addition, the HMR allows to perform cross-evidence synthesis, which combines aggregated results from randomized controlled trials to predict effectiveness in a single-arm observational study with individual participant data (IPD). In this paper, we evaluate the HMR approach using simulated data examples. We present a new real case study in diabetes research, along with a new R package called jarbes (just a rather Bayesian evidence synthesis), which automatizes the complex computations involved in the HMR.