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OBJECTIVES: Traffic-related pollution is associated with cardiovascular disease in general, but previous studies suggested that low socioeconomic status (SES) groups might be more susceptible towards a negative impact. We examined whether the association between long-term exposure to high traffic and early signs of coronary artery disease is modified by SES. METHODS: Individual-level medical and social data from a population-based study were linked with census information on neighbourhood socioeconomic characteristics. Residential exposure to traffic was defined as proximity to major roads using a geographical information system. We studied associations between high traffic and coronary artery calcification (CAC) within strata of SES to examine effect modification. Data stem from an epidemiological study in Germany including 2264 women and 2037 men (45-75 years). RESULTS: High traffic and low SES were both associated with higher amounts of calcification (>or=75th age-specific percentile). More participants with low SES lived close to major roads while stratified analyses did not indicate higher susceptibility in low SES groups. Participants with low SES and simultaneous exposure to high traffic had highest levels of CAC. For example, the prevalence of high calcification was 23.9% in better-educated men with low traffic exposure but 37.7% in lower-educated men with high traffic exposure (women: 22.0% vs 28.1%). CONCLUSIONS: High traffic exposure was associated with coronary calcification in all social groups, but as low SES individuals had higher calcification in general and were also more often exposed to traffic, existing inequalities could be further shaped by traffic exposure. [ABSTRACT FROM AUTHOR]

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: 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 )., (© 2024. The Author(s).)

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)., (© The Author(s) 2023. Published by Oxford University Press.)

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., (© 2022. The Author(s).)

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., Competing Interests: Declaration of interests CUC has been a consultant and advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen Pharmaceuticals, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Seqirus, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. MK received honoraria from Roche, Servier, and Tromssdorff and a travel grant from Janssen Cilag. MZ received scientific grants from the German Research Foundation and Servier; and speaker and travel grants from Otsuka, Lundbeck, Roche, Recordati, Ferrer and Trommsdorff. BL received honoraria and speaker's fees from ANM, AstraZeneca, Autifony Therapeutics, Desyncra, Lundbeck, Merz, MagVenture, Neurolite, Neuromod, Novartis, Pfizer, and Servier; research funding from the Tinnitus Research Initiative, the German Research Foundation, the German Bundesministerium für Bildung und Forschung, the American Tinnitus Association, AstraZeneca, and cerbomed; funding for equipment from MagVenture and Deymed Diagnostic; and travel and accommodation payments from Eli Lilly, Lundbeck, Servier, and Pfizer. TBP has served as a consultant for Rovi and received travel compensation from AstraZeneca and Pfizer. GG has served as a consultant for Allergan, Boehringer Ingelheim, Institute for Quality and Efficiency in Health Care, Janssen-Cilag, Lundbeck, Otsuka, Recordati, ROVI, Sage, and Takeda. He has served on the speakers' bureau of Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck and Saladax. He is co-founder or shareholder, or both, of Mind and Brain Institute GmbH, Brainfoods GmbH, OVID Health Systems GmbH, and MIND Foundation gGmbH. AH was on the advisory board of Janssen-Cilag, Lunbeck, Roche, and Otsuka and has accepted paid speaking engagements for Janssen-Cilag, Lunbeck, and Otsuka. SL has received honoraria as a consultant or advisor, or for lectures, from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitshubishi. JC was a member of an advisory board of Roche; accepted travel or hospitality not related to a speaking engagement from Servier; received support for symposia from Inomed, Localite, Magventure, Roche, Mag & More, NeuroConn, Syneika, FBI Medizintechnik, Spitzer Arzneimittel and Diamedic; and was involved in research and participated in studies funded by the German Research Foundation and the German Bundesministerium für Bildung und Forschung, Foundation European Group for Research In Schizophrenia, ACADIA Pharmaceuticals, Boehringer Ingelheim Pharma GmbH KG, Otsuka Pharmaceutical Europe, and EnVivo Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

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: 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to investigate the inflammatory infiltrate, osteoclast formation, and expression of MMP-9 during the healing phase following root canal treatment in teeth with apical periodontitis., Materials and Methods: Apical periodontitis was induced in dogs teeth, and root canal treatment was performed in a single visit or using calcium hydroxide as intracanal medication. One hundred and eighty days following treatment the presence of inflammation was examined, and the tissues were stained to detect osteoclasts by means of a tartrate resistant alkaline phosphatase (TRAP) assay. Synthesis of MMP-9 was detected using Western blotting and immunohistochemistry., Results: Teeth with apical periodontitis that had root canal therapy performed in a single visit presented a higher synthesis of MMP-9 compared with root canal treatment using calcium hydroxide. Treatment with calcium hydroxide resulted in a reduced amount of inflammatory cells and MMP-9 positive cells. Osteoclast formation, the number of MMP-9 positive osteoclasts and cementocytes, was reduced following root canal treatment, regardless of the root canal treatment protocol used., Conclusion: Root canal treatment reduced the amount of inflammatory cells and osteoclasts in periapical area. The use of calcium hydroxide as intracanal medication resulted in a lower synthesis of MMP-9, though the number of osteoclasts and MMP-9 positive osteoclasts were similar between the groups., Clinical Relevance: Periapical bone repair following root canal treatment is impacted by therapy performed either in single visit or using calcium hydroxide dressing measured by inflammatory cell recruitment, osteoclast formation, and MMP-9 synthesis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

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., (© 2020 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Objective : Concordance-analysis and evaluation of existing algorithms detecting late-onset preeclampsia during first trimester screening Methods : 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 discordances Conclusion : Normal-weight patients benefit more from the integration of MAP and UtA-PI compared to overweight/obese patients.

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., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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.

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.

Objective To investigate the clinical relevance of an isolated echogenic cardiac focus (iECF) as a marker for trisomy 21 using a large second-trimester collective including a low-risk subgroup. Materials and Methods We retrospectively evaluated 1 25 211 pregnancies from 2000-2016 and analyzed all iECF cases with regard to chromosomal anomalies. It consisted of an early second-trimester collective from 14+0-17+6 weeks (n=34 791) and a second-trimester anomaly scan collective from 18+0-21+6 weeks. Two a priori risk subgroups (high and low risk) of the latter were built based on maternal age and previous screening test results using a cut-off of 1:300. Likelihood ratios (LR) of iECF for the detection of trisomy 21, trisomy 13, trisomy 18 and structural chromosomal anomalies were estimated. Results In total, 1 04 001 patients were included. An iECF was found in 4416 of 1 02 847 euploid fetuses (4.29%) and in 64 of 557 cases with trisomy 21 (11.49%) giving a positive LR of 2.68 (CI: 2.12-3.2). The sensitivity was 11.5% at a false-positive rate of 4.29% (CI:4.17-4.42) with p≤0.01%. In the high-and low-risk subgroups, the prevalence of iECF was comparable: 5.08% vs. 5.05%. The frequency of trisomy 21 was 0.39%, 98/24 979 vs 0.16%, 69/44 103. LR+was 3.86 (2.43-5.14) and 2.59 (1.05-4). For both subgroups the association of iECF with trisomy 21 was statistically significant. The prevalence of structural chromosomal anomalies in the second-trimester anomaly scan collective was 0.08% (52/68 967), of which 2 showed an iECF. Conclusion The detection of an iECF at the time of 14+0-21+6 weeks significantly increases the risk for trisomy 21 in the high-risk and in the low-risk subgroups and does not statistically change the risks for trisomy 13/18 or structural abnormalitie., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.

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.

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.

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., (Copyright © 2019. Published by Elsevier B.V.)

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., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

AIMThe study aims to test whether simultaneous measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) is feasible, safe and effective during regadenoson-induced hyperemia.METHODS AND RESULTSFFR, CFR and IMR were measured simultaneously during regadenoson (Rapiscan 400 μg) -induced hyperemia in 50 patients with stable coronary artery disease with a SYNTAX score of <22. Simultaneous measurement of FFR, CFR and IMR was technically feasible in all cases (50/50). No side effects occurred and even patients fulfilling classical contraindications for the use of adenosine (10/50) could be included. Regadenoson-induced hyperemia remained stable after maximal pressure drop for more than 35 sec as measured by systemic aortic and distal coronary pressure. There was a significant drop in transit mean time from baseline to hyperemia of more than 50% (1.0 ± 0.6 s vs. 0.4 ± 0.2 s, p <  0.01). Patients' mean IMR value was 23.4, and IMR values above 75th percentile significantly correlated with metformin demanding diabetes mellitus with OR 21.76 and nicotine abuse with OR 10.28.CONCLUSIONA single intravenous regadenoson bolus via peripheral line increases coronary blood flow without harmful systemic side effects enabling interventionists to simultaneously assess FFR, CFR and IMR in patients with stable coronary artery disease.

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS., Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction., Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern., Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.

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., (Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Based on their overexpression and important roles in progression and therapy-resistance in malignant diseases, the inhibitor of apoptosis protein family (IAP) members, survivin and X-linked inhibitor of apoptosis protein (XIAP), represent attractive candidates for targeted therapy. The present study investigated the prognostic and biological relevance of survivin and XIAP in esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Survivin and XIAP expression was analyzed by immunohistochemistry using tissue microarrays containing 120 ESCC and 90 EAC samples as well as the corresponding non-neoplastic esophageal mucosa samples. IAP expression levels were then correlated to clinicopathological parameters and overall survival to identify any associations. In addition, esophageal cancer cell lines were treated with the survivin inhibitor YM155, and the XIAP inhibitors Birinapant and GDC-0152 in vitro . Survivin and XIAP expression were significantly increased in EAC and ESCC when compared with tumor-adjacent mucosa. In patients with ESCC XIAP expression was associated with female gender and advanced tumor stages, and nuclear survivin expression was associated with poor grading. High XIAP expression was identified as an independent negative prognostic marker in ESCC. By contrast, XIAP inhibitors did not affect cancer cell viability in vitro , and the small molecule survivin inhibitor YM155 significantly reduced cell viability and proliferation in esophageal cancer cell lines. Western blot analysis revealed a dose dependent decrease of survivin accompanied by an increased poly (adenosine diphosphate-ribose) polymerase cleavage following YM155 treatment. These findings underline the potential role of survivin and XIAP in the oncogenesis of esophageal cancer and provide a rationale for future clinical studies investigating the therapeutic efficacy of IAP directed therapies in patients with esophageal cancer.

Follicular thyroid cancer's (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity in vitro Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144-1.826; P  < 0.001). In vitro , the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease., (© 2018 Society for Endocrinology.)

Background: Follicular thyroid carcinoma's (FTC) often benign course is partially due to adjuvant radioactive iodine (RAI) treatment. However, once the tumour has spread and fails to retain RAI, the therapeutic options are limited and the outcome is poor. In this subset of patients, the identification of novel druggable biomarkers appears invaluable. Here, we investigated the stage dependent expression and functional role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in FTC. Methods: CXCR4/7 expression was examined in 44 FTC and corresponding non-neoplastic thyroid specimens as well as 10 FTC distant metastases and 18 follicular adenomas using tissue microarray technology. Expression levels were correlated with clinicopathological variables as well as overall and recurrence free survival. Changes regarding cell cycle activation, tumour cell invasiveness and mRNA expression of genes related to epithelial-mesenchymal transition (EMT) were investigated after treatment with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Results: CXCR4/7 expression was associated with large tumour size, advanced UICC stage as well as shorter overall and recurrence free survival. CXCR4 was significantly higher expressed in distant metastases than in primary tumour cores. In addition, rh-SDF1α induced invasive growth, cell cycle activation and EMT, while CXCR4 antagonists significantly reduced FTC invasiveness in vitro . Conclusion: Here we provide first evidence of the biological importance of the CXCR4/CXCR7/CXCL12 axis in FTC. Our findings underscore the therapeutic potential of this chemokine receptor family in advanced FTC and offer new valuable insight into the oncogenesis of metastatic FTC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

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.

There is considerable evidence that the inhibitor of apoptosis protein (IAP) family serves a role in tumorigenesis. The most studied IAP family members, survivin and X-linked inhibitor of apoptosis (XIAP), have been demonstrated to serve as biomarkers in distinct tumor entities. Thus, the present study aimed to investigate the expression levels of both IAPs in the tumor center, invasion front and lymph node metastases of surgically resected gastric cancer (GC) specimens. Tissue microarrays containing samples from 201 primary GCs were analyzed. IAP expression was detected using immunohistochemistry in different tumor compartments, normal mucosa and lymph node metastases. In addition, the association between the expression levels of these proteins, and clinicopathological parameters and overall survival was investigated. High levels of survivin and XIAP were evident in GC, when compared with normal mucosa, and were correlated with intestinal-type and well-differentiated GC, as well as low International Union Against Cancer stages. Increased XIAP expression was detected in lymph node metastases as compared with corresponding primary tumors. XIAP overexpression was identified to be an independent negative prognostic marker in diffuse and mixed type GC. These results suggest a potential role of survivin and XIAP in the early phase of gastric carcinogenesis. In addition, increased XIAP expression in lymph node metastases supports the observation that IAPs serve an essential role in metastatic tumor disease. Since XIAP expression was identified to be associated with poor survival in diffuse and mixed type GC, XIAP may serve as a novel therapeutic target in these types of GC.

Follicular thyroid carcinoma's (FTC) overall good prognosis deteriorates if the tumour fails to retain radioactive iodine. Therefore, new druggable targets are in high demand for this subset of patients. Here, we investigated the prognostic and biological role of survivin and XIAP in FTC. Survivin and XIAP expression was investigated in 44 FTC and corresponding non-neoplastic thyroid specimens using tissue microarrays. Inhibition of both inhibitor of apoptosis proteins (IAP) was induced by shRNAs or specific small molecule antagonists and functional changes were investigated in vitro and in vivo. Survivin and XIAP were solely expressed in FTC tissue. Survivin expression correlated with an advanced tumour stage and recurrent disease. In addition, survivin proved to be an independent negative prognostic marker. Survivin or XIAP knockdown caused a significant reduction in cell viability and proliferation, activated caspase3/7 and was associated with a reduced tumour growth in vivo. IAP-targeting compounds induced a decrease of cell viability, proliferation and cell cycle activity accompanied by an increase in apoptosis. Additionally, YM155 a small molecule inhibitor of survivin expression significantly inhibited tumour growth in vivo. Both IAPs demonstrate significant functional implications in the oncogenesis of FTCs and thus prove to be viable targets in patients with advanced FTC.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F (9, 207) =2.72, P=0.005, partial η 2 =0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a rare and heterogenous tumor entity. Importantly, the highly proliferative subgroup of neuroendocrine carcinoma (GEP-NEC) is characterized by high resistance to conventional chemotherapy. Consequently, there is an urgent need to identify novel therapeutic targets, especially for GEP-NEC. Thus, we focused on Inhibitor of apoptosis protein (IAP) family members survivin and XIAP that orchestrate inhibition of apoptosis, induce resistance against chemotherapeutics and facilitate tumor metastasis. Copy number gains (CNGs) could be detected by microarray comparative genomic hybridization for survivin and XIAP in 60 % and 26.7 % of all GEP-NENs, respectively. Immunohistochemical staining of tissue specimens from 77 consecutive patients with GEP-NEN demonstrated increased survivin protein expression levels in tissue specimens of highly proliferative GEP-NEC or GEP-NEN located in the stomach and colon. In contrast, XIAP overexpression was associated with advanced tumor stages. Knockdown of survivin and XIAP markedly reduced cell proliferation and tumor growth. In vitro, YM155 induced apoptotic cell death accompanied by a reduction in cell proliferation and inhibited GEP-NEC xenograft growth. Taken together, our data provide evidence for a biological relevance of these IAPs in GEP-NEN and support a potential role of survivin as therapeutic target especially in the subgroup of aggressive GEP-NEC.

Objective: Investigating the proportions of anamnestic and biochemical variables of the previous and current pregnancies for the prediction of small for gestational age (SGA) neonates in the current pregnancy., Methods: In this observational retrospective study, 45 029 pregnancies were examined, including 3862 patients with more than one pregnancy. Odds ratios for SGA using anamnestic parameters and pregnancy-associated plasma protein A (PAPP-A) values from all pregnancies were estimated by using a logistic regression model., Results: There were 2552 (5.7%) SGA neonates. Two threshold PAPP-A values were identified at 0.15 MoM and 0.33 MoM with probabilities for SGA of 23% and 17%, respectively. A previous SGA < 10th centile and a current PAPP-A MoM value < 5th centile result in odds ratios of 4.8 (95% CI: 3.5-6.5) and 3.0 (95% CI: 1.8-5.0), respectively. The parameters' combined odds ratio is 14.1 (95% CI: 3.9-50.3) with a number needed to screen of ten for one SGA neonate at a detection rate of 37%., Conclusion: Information on previous pregnancies affected by SGA and a current pregnancy's low PAPP-A value are reliable predictors for a SGA delivery. First-trimester biochemical analysis should be maintained to detect women at risk for delivering a SGA neonate.

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., (Copyright © 2015 John Wiley & Sons, Ltd.)

Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: To determine the impact of red blood cell distribution width on outcome in anemic patients undergoing transcatheter aortic valve implantation (TAVI)., Methods: In a retrospective single center cohort study we determined the impact of baseline red cell distribution width (RDW) and anemia on outcome in 376 patients with aortic stenosis undergoing TAVI. All patients were discussed in the institutional heart team and declined for surgical aortic valve replacement due to high operative risk. Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data. Blood samples for hematology and biochemistry analysis were taken from every patient before and at fixed intervals up to 72 h after TAVI including blood count and creatinine. Descriptive statistics were used for patient's characteristics. Kaplan-Meier survival curves were used for time to event outcomes. A recursive partitioning regression and classification was used to investigate the association between potential risk factors and outcome variables., Results: Mean age in our study population was 81 ± 6.1 years. Anemia was prevalent in 63.6% (n = 239) of our patients. Age and creatinine were identified as risk factors for anemia. In our study population, anemia per se did influence 30-d mortality but did not predict longterm mortality. In contrast, a RDW > 14% showed to be highly predictable for a reduced short- and longterm survival in patients with aortic valve disease after TAVI procedure., Conclusion: Age and kidney function determine the degree of anemia. The anisocytosis of red blood cells in anemic patients supplements prognostic information in addition to that derived from the WHO-based definition of anemia.

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.