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 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 ).

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.

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.

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.

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.

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.

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.

Prevalence of Propionibacterium acnes in the glenohumeral compared with the subacromial space in primary shoulder arthroscopies.

HYPOTHESIS: We hypothesized that the prevalence of Propionibacterium acnes in patients undergoing primary shoulder arthroscopy is equal in the glenohumeral space compared with the subacromial space. METHODS: Patients aged 18 years or older with shoulder arthroscopies were included. The exclusion criteria were prior shoulder operations, complete rotator cuff tears, systemic inflammatory diseases, tumors, shoulder injections within 6 months of surgery, and antibiotic therapy within 14 days preoperatively. After standardized skin disinfection with Kodan Tinktur Forte Gefärbt, a skin swab was taken at the posterior portal. Arthroscopy was performed without cannulas, prospectively randomized to start either in the glenohumeral space or in the subacromial space, with direct harvesting of a soft-tissue biopsy specimen. Sample cultivation was conducted according to standardized criteria for bone and joint aspirate samples and incubated for 14 days. Matrix-assisted laser desorption-ionization time-of-flight spectrometry was used for specimen identification in positive culture results. RESULTS: The study prospectively included 115 consecutive patients with normal C-reactive protein levels prior to surgery (54.8% men; mean age, 47.2 ± 14.6 years). P acnes was detected on the skin after disinfection in 36.5% of patients, in the glenohumeral space in 18.9%, and in the subacromial space in 3.5% (P = .016). CONCLUSION: The prevalence of P acnes is significantly higher in the glenohumeral space compared with the subacromial space in primary shoulder arthroscopies. The results do not confirm the contamination theory but also cannot clarify whether P acnes is a commensal or enters the joint hematologically or even lymphatically or via an unknown pathway. Despite standardized surgical skin disinfection, P acnes can be detected in skin swab samples in more than one-third of patients.

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC. METHODS: Eighty-six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated. RESULTS: High CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1α stimulated invasive growth, caused cell cycle activation and induced EMT. CONCLUSIONS: The CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC.

Survivin and XIAP: two valuable biomarkers in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) accounts for ∼5% of all thyroid malignancies. To date, surgery is the first-line therapy with curative intention. However, for advanced MTC, conventional chemotherapeutic agents do not provide convincing results. Therefore, the identification of biomarkers that can be antagonised by small-molecule therapeutics may lead to novel encouraging treatment options. METHODS: Seventy-nine patients with surgically resected and histologically confirmed MTC were included in this study. Tissue microarrays were constructed to assess the relationship between inhibitor of apoptosis proteins (IAPs) survivin or XIAP expression levels and clinicopathological variables as well as overall survival. RESULTS: High survivin or XIAP expression was associated with an advanced T-stage and metastatic disease. Whereas tissue expression levels of survivin correlated with serum calcitonin levels, XIAP was overexpressed in the subgroup of patients with sporadic MTC. Both IAPs were negatively associated with patient survival in the multivariate Cox regressions analysis (survivin: hazard ratio (HR) 1.62; 95% confidence interval (CI): 1.21-2.16; P=0.001; XIAP: HR 1.78; 95% CI: 1.16-2.72; P=0.008). CONCLUSIONS: Survivin and XIAP demonstrate distinct expression patterns in MTCs, which are associated with advanced disease and poor prognosis. We thus provide first evidence that both IAPs might serve as viable targets in patients with MTC.

Bayesian evidence synthesis for exploring generalizability of treatment effects: a case study of combining randomized and non-randomized results in diabetes.

In this paper, we present a unified modeling framework to combine aggregated data from randomized controlled trials (RCTs) with individual participant data (IPD) from observational studies. Rather than simply pooling the available evidence into an overall treatment effect, adjusted for potential confounding, the intention of this work is to explore treatment effects in specific patient populations reflected by the IPD. In this way, by collecting IPD, we can potentially gain new insights from RCTs' results, which cannot be seen using only a meta-analysis of RCTs. We present a new Bayesian hierarchical meta-regression model, which combines submodels, representing different types of data into a coherent analysis. Predictors of baseline risk are estimated from the individual data. Simultaneously, a bivariate random effects distribution of baseline risk and treatment effects is estimated from the combined individual and aggregate data. Therefore, given a subgroup of interest, the estimated treatment effect can be calculated through its correlation with baseline risk. We highlight different types of model parameters: those that are the focus of inference (e.g., treatment effect in a subgroup of patients) and those that are used to adjust for biases introduced by data collection processes (e.g., internal or external validity). The model is applied to a case study where RCTs' results, investigating efficacy in the treatment of diabetic foot problems, are extrapolated to groups of patients treated in medical routine and who were enrolled in a prospective cohort study.

Predictors of mortality for necrotizing soft-tissue infections: a retrospective analysis of 64 cases.

PURPOSE: Necrotizing soft-tissue infection (NSTI) is a rare, but rapidly progressive and life-threatening disease with a high morbidity and mortality. The aim of the present study was to evaluate predictors of mortality in a group of patients with NSTIs treated at a single center. METHODS: The medical records of all patients that were treated because of a NSTI at our department between 1996 and 2011 were retrospectively analyzed. To identify factors that were associated with patients' outcome variables including demographic, clinical, laboratory, and microbiologic parameters were compared between the group of survivors and non-survivors. RESULTS: Sixty-four patients with the diagnosis of a NSTI were identified. The overall mortality was 32.8 %. Multiple regression analyses identified the development of a renal failure during the hospital stay and more importantly, the presence of visible skin necrosis on the initial clinical examination as independent prognostic markers for NSTIs. CONCLUSION: In patients with NSTIs, skin necrosis may serve as an indicator for an advanced stage of the disease. Thus, the presence of visible skin necrosis as an independent predictor of mortality emphasizes the outstanding importance of early diagnosis and prompt treatment to improve the prognosis of patients with NSTIs.

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).

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.

Expression of TRAIL-splice variants in gastric carcinomas: identification of TRAIL-γ as a prognostic marker.

BACKGROUND: TNF-related apoptosis inducing ligand (TRAIL) belongs to the TNF-superfamily that induces apoptotic cell death in a wide range of neoplastic cells in vivo as well as in vitro. We identified two alternative TRAIL-splice variants, i.e. TRAIL-ß and TRAIL-γ that are characterized by the loss of their proapoptotic properties. Herein, we investigated the expression and the prognostic values of the TRAIL-splice variants in gastric carcinomas. METHODS: Real time PCR for amplification of the TRAIL-splice variants was performed in tumour tissue specimens and corresponding normal tissues of 41 consecutive patients with gastric carcinoma. Differences on mRNA-expression levels of the TRAIL-isoforms were compared to histo-pathological variables and correlated with survival data. RESULTS: All three TRAIL-splice variants could be detected in both non-malignant and malignant tissues, irrespective of their histological staging, grading or tumour types. However, TRAIL-ß exhibited a higher expression in normal gastric tissue. The proapoptotic TRAIL-α expression was increased in gastric carcinomas when compared to TRAIL-ß and TRAIL-γ. In addition, overexpression of TRAIL-γ was associated with a significant higher survival rate. CONCLUSIONS: This is the first study that investigated the expression of TRAIL-splice variants in gastric carcinoma tissue samples. Thus, we provide first data that indicate a prognostic value for TRAIL-γ overexpression in this tumour entity.

Role of survivin as prognostic and clinicopathological marker in gastric cancer: a meta-analysis.

Survivin has been implicated as a potential prognostic marker in a wide range of malignant tumours. However, the prognostic impact of survivin in gastric cancer remains to be controversial and published data are sometimes heterogeneous. Thus, aim of this study was to review the literature by performing an electronical database search via PubMed and EMBASE to identify eligible studies that assessed the impact of survivin as prognostic marker and its association with clinicopathological variables. Database search until November 21st 2012 retrieved 20 studies comprising 2,695 gastric cancer patients that assessed expression of survivin by immunohistochemistry or RT-PCR analyses in gastric cancer specimens. Meta-analyses of clinicopathological variables revealed an association between the expression of survivin and the presence of lymph node metastases (pooled OR: 0.58; 95 % CI 0.35-0.96). In addition, a correlation between the expression of survivin and overall survival for patients with gastric cancer (pooled HR 1.93; 95 % CI 1.51-2.48) became evident. More importantly, we were able to exclude a severe heterogeneity (I(2) = 31 %) or publication bias for the survival analyses. Furthermore, one-way sensitivity analysis and subgroup analyses regarding the method used to detect survivin, the type of survival analysis, the study quality and whether information was provided regarding neoadjuvant therapy supported our initial results. In conclusion, this meta-analysis indicates the prognostic significance of survivin in patients with gastric cancer.

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.