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.

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).

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

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

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

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

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

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

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

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

Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer.

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.

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis.

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.

IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid 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.

Predicting Response to Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia Using Structural Magnetic Resonance Imaging: A Multisite Machine Learning Analysis.

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.

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 expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas.

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.

Survivin and XIAP - two potential biological targets in follicular thyroid carcinoma.

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.

Preclinical assesement of survivin and XIAP as prognostic biomarkers and therapeutic targets in gastroenteropancreatic neuroendocrine neoplasia.

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.

Red cell distribution width in anemic patients undergoing transcatheter aortic valve implantation.

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.

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.

Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham-Controlled Trial.

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.