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Anna-Lena Klauser,1 Marc Hirschfeld,1– 3 Andrea Ritter,1,2 Gerta Rücker,1,4 Markus Jäger,1,2 Julia Gundarova,1 Daniela Weiss,1,2 Ingolf Juhasz-Böss,1,2 Kai Berner,1,2 Thalia Erbes,1,2 Jasmin Asberger1,2 1Faculty of Medicine, University of Freiburg, Freiburg, Germany; 2Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany; 3Institute of Veterinary Medicine, University of Göttingen, Göttingen, Germany; 4Institute of Medical Biometry and Statistics, Medical Center – University of Freiburg, Freiburg, GermanyCorrespondence: Jasmin AsbergerDepartment of Obstetrics and Gynecology, Faculty of Medicine and Medical Center – University of Freiburg, Hugstetterstr. 55, Freiburg, 79106, GermanyTel +49 761 270 30020Fax +49 761 270 30370Email jasmin.asberger@uniklinik-freiburg.dePurpose: In 2020, breast cancer still represents the most common type of cancer in women worldwide. Depending on the specific molecular subtype, clinical breast cancer management comprises surgery, radiotherapy, chemotherapy and targeted therapy. Furthermore, there are some therapeutic approaches from the field of complementary and alternative medicine. Current research focuses on the elucidation of new therapeutic targets for treatment development. Odorant substances affect apoptosis, proliferation and cell cycle in healthy and cancerous cells. Exact signalling pathways involved are not entirely clear. The present study aims to analyse their therapeutic potential in breast cancer.Methods: This study focuses on the effect of commonly used odorant substances (citral, citrathal R, cyclovertal, para-cymol, hexylacetat, herbavert, dihydromyrcerol and limonen) on the breast cancer cell lines MDA-MB-231, T47-D and BT474. Methodologically, this study applied cell culturing, MTT assay for detection of IC50 of the odorant substance, RNA purification followed by qRT-PCR, protein isolation and Western Blot, as well as immunocytochemistry. Further, this study investigates the role of transient receptor potential channel V1 (TRPV1), involved in the mechanisms of action for some odorant substances. Therefore, capsazepine, a TRPV1 antagonist, was used.Results: The odorant substances citral, citrathal R and cyclovertal have significant pro-apoptotic (p < 0.001), anti-proliferative (p < 0.001) and cell cycle-arresting effects measurable in RNA expression as well as in protein levels and immunocytochemical staining. The combination of citral and capsazepine no longer showed significant pro-apoptotic, antiproliferative, and cell cycle inhibitory effects compared to the compounds alone. This indicates that TRPV1 is necessary for the signal transduction of citral.Conclusion: This present study reveals three odorant substances with effects on cell viability, indicating their potential use in breast cancer therapy.Keywords: citral, citrathal R, cyclovertal, odorant substances, olfactory receptor and breast cancer

Ravindra Gopaul,1 Robert A Waller,1 Ricci Kalayanamitra,2 Garrett Rucker,3 Andrew Foy4 1Department of Emergency Medicine, Penn State Hershey Medical Center, Hershey, PA, USA; 2Department of Emergency Medicine, Staten Island University Hospital, New York, NY, USA; 3Penn State Milton S. Hershey College of Medicine, Hershey, PA, USA; 4Department of Internal Medicine, Division of Cardiology, Penn State Hershey Medical Center, Hershey, PA, USACorrespondence: Ravindra Gopaul, Email rgopaul@pennstatehealth.psu.eduObjective: The HEART Score is a clinically validated risk stratification tool for patients with chest pain. Using five parameters (History, Electrocardiogram, Age, Risk factors, and Troponin), this instrument categorizes patients as low, moderate, or high risk for major adverse cardiac events within six weeks after evaluation. Of these parameters, History is the most subjective, as providers independently assign their level of clinical suspicion. Overestimation of history, and ultimately the HEART Score, can result in increased resource utilization, expense, and patient risk. We sought to evaluate bias in provider assessment of history when determining the HEART Score.Methods: Emergency medicine (EM) and Cardiology providers received surveys with one of two versions of clinical vignettes randomized at the question level and were asked to estimate the history component of the HEART Score. Vignettes differed by age, risk factors, sex, and socioeconomic status (SES), but both versions should have received the same score for history. Statistical analysis was then used to assess differences in history assessment between vignettes.Results: Of the 884 responses analyzed, most providers overestimated the historical portion of the HEART Score when assessing risk factors, patient distress, age, and lower SES. Many underestimated history with knowledge of a previous negative stress test. When controlling for specialty, the universal theme was overestimation by EM providers and underestimation by cardiologists. Despite the presence of hypertension, gender differences, and the appearance of mild distress, cardiologists were more likely to correctly estimate history compared to EM providers. SES consideration generally led to an underestimation of history by cardiologists. These findings were all statistically significant.Conclusion: Our study demonstrates that both EM and cardiology providers overestimate history when considering prognosticators that are frequently viewed as concerning. Further education on proper usage of the HEART Score is needed for more appropriate scoring of history and improved resource allocation for hospital systems.Keywords: HEART score, physician, provider, history

To address the challenges of effective data handling faced by Small and Medium Sized Enterprises (SMEs) a cloud-based infrastructure for accessing and processing of Earth Observation(EO)-data has been developed within the project APPS4GMES(www.apps4gmes.de). To gain homogenous multi mission data access an Input Data Portal (IDP) been implemented on this infrastructure. The IDP consists of an Open Geospatial Consortium (OGC) conformant catalogue, a consolidation module for format conversion and an OGC-conformant ordering framework. Metadata of various EO-sources and with different standards is harvested and transferred to an OGC conformant Earth Observation Product standard and inserted into the catalogue by a Metadata Harvester. The IDP can be accessed for search and ordering of the harvested datasets by the services implemented on the cloud infrastructure. Different land-surface services have been realised by the project partners, using the implemented IDP and cloud infrastructure. Results of these are customer ready products, as well as pre-products (e.g. atmospheric corrected EO data), serving as a basis for other services. Within the IDP an automated access to ESA's Sentinel-1 Scientific Data Hub has been implemented. Searching and downloading of the SAR data can be performed in an automated way. With the implementation of the Sentinel-1 Toolbox and own software, for processing of the datasets for further use, for example for Vista's snow monitoring, delivering input for the flood forecast services, can also be performed in an automated way. For performance tests of the cloud environment a sophisticated model based atmospheric correction and pre-classification service has been implemented. Tests conducted an automated synchronised processing of one entire Landsat 8 (LS-8) coverage for Germany and performance comparisons to standard desktop systems. Results of these tests, showing a performance improvement by the factor of six, proved the high flexibility and computing power of the cloud environment. To make full use of the cloud capabilities a possibility for automated upscaling of the hardware resources has been implemented. Together with the IDP infrastructure fast and automated processing of various satellite sources to deliver market ready products can be realised, thus increasing customer needs and numbers can be satisfied without loss of accuracy and quality. [ABSTRACT FROM AUTHOR]

Landscape fires show large variability in the amount of biomass or fuel consumed per unit area burned. Fuel consumption (FC) depends on the biomass available to burn and the fraction of the biomass that is actually combusted, and can be combined with estimates of area burned to assess emissions. While burned area can be detected from space and estimates are becoming more reliable due to improved algorithms and sensors, FC is usually modeled or taken selectively from the literature. We compiled the peer-reviewed literature on FC for various biomes and fuel categories to understand FC and its variability better, and to provide a database that can be used to constrain biogeochemical models with fire modules. We compiled in total 77 studies covering 11 biomes including savanna (15 studies, average FC of 4.6 t DM (dry matter) ha-1 with a standard deviation of 2.2), tropical forest (n =19, FC=126±77), temperate forest (n =12, FC=58±72), boreal forest (n =16, FC=35±24), pasture (n =4, FC=28±9.3), shifting cultivation (n =2, FC=23, with a range of 4.0-43), crop residue (n =4, FC=6.5±9.0), chaparral (n =3, FC=27±19), tropical peatland (n =4, FC=314±196), boreal peatland (n =2, FC=42 [42-43]), and tundra (n =1, FC=40). Within biomes the regional variability in the number of measurements was sometimes large, with e.g. only three measurement locations in boreal Russia and 35 sites in North America. Substantial regional differences in FC were found within the de?ned biomes: for example, FC of temperate pine forests in the USA was 37% lower than Australian forests dominated by eucalypt trees. Besides showing the differences between biomes, FC estimates were also grouped into different fuel classes. Our results highlight the large variability in FC, not only between biomes but also within biomes and fuel classes. This implies that substantial uncertainties are associated with using biome-averaged values to represent FC for whole biomes. Comparing the compiled FC values with co-located Global Fire Emissions Database version 3 (GFED3) FC indicates that modeling studies that aim to represent variability in FC also within biomes, still require improvements as they have dif?culty in representing the dynamics governing FC. [ABSTRACT FROM AUTHOR]

Abstract Background Several systematic reviews have summarized the evidence for specific treatments of primary care patients suffering from depression. However, it is not possible to answer the question how the available treatment options compare with each other as review methods differ. We aim to systematically review and compare the available evidence for the effectiveness of pharmacological, psychological, and combined treatments for patients with depressive disorders in primary care. Methods/Design To be included, studies have to be randomized trials comparing antidepressant medication (tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), hypericum extracts, other agents) and/or psychological therapies (e.g. interpersonal psychotherapy, cognitive therapy, behavioural therapy, short dynamically-oriented psychotherapy) with another active therapy, placebo or sham intervention, routine care or no treatment in primary care patients in the acute phase of a depressive episode. Main outcome measure is response after completion of acute phase treatment. Eligible studies will be identified from available systematic reviews, from searches in electronic databases (Medline, Embase and Central), trial registers, and citation tracking. Two reviewers will independently extract study data and assess the risk of bias using the Cochrane Collaboration's corresponding tool. Meta-analyses (random effects model, inverse variance weighting) will be performed for direct comparisons of single interventions and for groups of similar interventions (e.g. SSRIs vs. tricyclics) and defined time-windows (up to 3 months and above). If possible, a global analysis of the relative effectiveness of treatments will be estimated from all available direct and indirect evidence that is present in a network of treatments and comparisons. Discussion Practitioners do not only want to know whether there is evidence that a specific treatment is more effective than placebo, but also how the treatment options compare to each other. Therefore, we believe that a multiple treatment systematic review of primary-care based randomized controlled trials on the most important therapies against depression is timely.

Abstract Background The heterogeneity statistic I2, interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error, depends on precision, that is, the size of the studies included. Methods Based on a real meta-analysis, we simulate artificially 'inflating' the sample size under the random effects model. For a given inflation factor M = 1, 2, 3,... and for each trial i, we create a M-inflated trial by drawing a treatment effect estimate from the random effects model, using si2 MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGaem4Cam3aa0baaSqaaiabdMgaPbqaaiabikdaYaaaaaa@2FBE@/M as within-trial sampling variance. Results As precision increases, while estimates of the heterogeneity variance τ2 remain unchanged on average, estimates of I2 increase rapidly to nearly 100%. A similar phenomenon is apparent in a sample of 157 meta-analyses. Conclusion When deciding whether or not to pool treatment estimates in a meta-analysis, the yard-stick should be the clinical relevance of any heterogeneity present. τ2, rather than I2, is the appropriate measure for this purpose.

Abstract Background Simpson's paradox is sometimes referred to in the areas of epidemiology and clinical research. It can also be found in meta-analysis of randomized clinical trials. However, though readers are able to recalculate examples from hypothetical as well as real data, they may have problems to easily figure where it emerges from. Method First, two kinds of plots are proposed to illustrate the phenomenon graphically, a scatter plot and a line graph. Subsequently, these can be overlaid, resulting in a overlay plot. The plots are applied to the recent large meta-analysis of adverse effects of rosiglitazone on myocardial infarction and to an example from the literature. A large set of meta-analyses is screened for further examples. Results As noted earlier by others, occurrence of Simpson's paradox in the meta-analytic setting, if present, is associated with imbalance of treatment arm size. This is well illustrated by the proposed plots. The rosiglitazone meta-analysis shows an effect reversion if all trials are pooled. In a sample of 157 meta-analyses, nine showed an effect reversion after pooling, though non-significant in all cases. Conclusion The plots give insight on how the imbalance of trial arm size works as a confounder, thus producing Simpson's paradox. Readers can see why meta-analytic methods must be used and what is wrong with simple pooling.

Abstract Background Citation counts are often regarded as a measure of the utilization and contribution of published articles. The objective of this study is to assess whether statistical reporting and statistical errors in the analysis of the primary outcome are associated with the number of citations received. Methods We evaluated all original research articles published in 1996 in four psychiatric journals. The statistical and reporting quality of each paper was assessed and the number of citations received up to 2005 was obtained from the Web of Science database. We then examined whether the number of citations was associated with the quality of the statistical analysis and reporting. Results A total of 448 research papers were included in the citation analysis. Unclear or inadequate reporting of the research question and primary outcome were not statistically significantly associated with the citation counts. After adjusting for journal, extended description of statistical procedures had a positive effect on the number of citations received. Inappropriate statistical analysis did not affect the number of citations received. Adequate reporting of the primary research question, statistical methods and primary findings were all associated with the journal visibility and prestige. Conclusion In this cohort of published research, measures of reporting quality and appropriate statistical analysis were not associated with the number of citations. The journal in which a study is published appears to be as important as the statistical reporting quality in ensuring dissemination of published medical science.

Background: The heterogeneity statistic I(2), interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error, depends on precision, that is, the size of the studies included.Methods: Based on a real meta-analysis, we simulate artificially 'inflating' the sample size under the random effects model. For a given inflation factor M = 1, 2, 3,... and for each trial i, we create a M-inflated trial by drawing a treatment effect estimate from the random effects model, using s(i)(2)/M as within-trial sampling variance.Results: As precision increases, while estimates of the heterogeneity variance tau(2) remain unchanged on average, estimates of I(2) increase rapidly to nearly 100%. A similar phenomenon is apparent in a sample of 157 meta-analyses.Conclusion: When deciding whether or not to pool treatment estimates in a meta-analysis, the yard-stick should be the clinical relevance of any heterogeneity present. tau(2), rather than I(2), is the appropriate measure for this purpose. [ABSTRACT FROM AUTHOR]

Background: Simpson's paradox is sometimes referred to in the areas of epidemiology and clinical research. It can also be found in meta-analysis of randomized clinical trials. However, though readers are able to recalculate examples from hypothetical as well as real data, they may have problems to easily figure where it emerges from.Method: First, two kinds of plots are proposed to illustrate the phenomenon graphically, a scatter plot and a line graph. Subsequently, these can be overlaid, resulting in a overlay plot. The plots are applied to the recent large meta-analysis of adverse effects of rosiglitazone on myocardial infarction and to an example from the literature. A large set of meta-analyses is screened for further examples.Results: As noted earlier by others, occurrence of Simpson's paradox in the meta-analytic setting, if present, is associated with imbalance of treatment arm size. This is well illustrated by the proposed plots. The rosiglitazone meta-analysis shows an effect reversion if all trials are pooled. In a sample of 157 meta-analyses, nine showed an effect reversion after pooling, though non-significant in all cases.Conclusion: The plots give insight on how the imbalance of trial arm size works as a confounder, thus producing Simpson's paradox. Readers can see why meta-analytic methods must be used and what is wrong with simple pooling. [ABSTRACT FROM AUTHOR]

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Network meta-analysis (NMA) allows estimating and ranking the effects of several interventions for a clinical condition. Component network meta-analysis (CNMA) is an extension of NMA which considers the individual components of multicomponent interventions. CNMA allows to "reconnect" a disconnected network with common components in subnetworks. An additive CNMA assumes that component effects are additive. This assumption can be relaxed by including interaction terms in the CNMA., Methods: We evaluate a forward model selection strategy for component network meta-analysis to relax the additivity assumption that can be used in connected or disconnected networks. In addition, we describe a procedure to create disconnected networks in order to evaluate the properties of the model selection in connected and disconnected networks. We apply the methods to simulated data and a Cochrane review on interventions for postoperative nausea and vomiting in adults after general anaesthesia. Model performance is compared using average mean squared errors and coverage probabilities., Results: CNMA models provide good performance for connected networks and can be an alternative to standard NMA if additivity holds. For disconnected networks, we recommend to use additive CNMA only if strong clinical arguments for additivity exist., Conclusions: CNMA methods are feasible for connected networks but questionable for disconnected networks., (© 2023. The Author(s).)

Introduction: Patients with inflammatory bowel diseases (IBD) often report psychological problems, unemployment, disability, sick leave and compromised quality of life. The effect of psychological interventions on health-related outcomes in IBD is controversial as previous reviews faced the obstacle of high heterogeneity among provided multimodular interventions. The heterogeneity can be addressed with network meta-analysis (NMA) and (multi)component NMA (CNMA). We aim to investigate whether psychological interventions can improve quality of life, clinical and social outcomes in IBD using NMA and CNMA. This is the study protocol., Methods and Analysis: We will consider randomised, quasi-randomised and non-randomised controlled trials, including cluster randomised and cross-over trials with 2 months of minimum follow-up. The conditions to be studied comprise Crohn's disease and ulcerative colitis in children, adolescents and adults. We will include any psychological intervention aiming to change the health status of the study participant.We will search Medline, Embase, Web of Science, CENTRAL, LILACS, Psyndex, PsycINFO, Google Scholar and trial registries from inception (the search will be updated before the review completion). Two authors will independently screen all references based on titles and abstracts. For data extraction, standard forms are developed and tested before extraction. All information will be assessed independently by at least two reviewers, and disagreements solved by consensus discussion or a third rater if necessary.The data synthesis will include a pairwise meta-analysis supported by meta-regression. We will conduct NMA (all treatments will constitute single nodes of the network) and CNMA (we will define all treatments as sums of core components, eg, cognitive +behaviour, or cognitive +behaviour + relaxation, and additionally consider interactions) using the R Package netmeta., Ethics and Dissemination: No ethical approval is required. Reports will include the final report to the funder, conference presentation, peer-reviewed publication and a patient report., Prospero Registration Number: CRD42021250446., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Network meta-analysis estimates all relative effects between competing treatments and can produce a treatment hierarchy from the most to the least desirable option according to a health outcome. While about half of the published network meta-analyses present such a hierarchy, it is rarely the case that it is related to a clinically relevant decision question., Methods: We first define treatment hierarchy and treatment ranking in a network meta-analysis and suggest a simulation method to estimate the probability of each possible hierarchy to occur. We then propose a stepwise approach to express clinically relevant decision questions as hierarchy questions and quantify the uncertainty of the criteria that constitute them. The steps of the approach are summarized as follows: a) a question of clinical relevance is defined, b) the hierarchies that satisfy the defined question are collected and c) the frequencies of the respective hierarchies are added; the resulted sum expresses the certainty of the defined set of criteria to hold. We then show how the frequencies of all possible hierarchies relate to common ranking metrics., Results: We exemplify the method and its implementation using two networks. The first is a network of four treatments for chronic obstructive pulmonary disease where the most probable hierarchy has a frequency of 28%. The second is a network of 18 antidepressants, among which Vortioxetine, Bupropion and Escitalopram occupy the first three ranks with frequency 19%., Conclusions: The developed method offers a generalised approach of producing treatment hierarchies in network meta-analysis, which moves towards attaching treatment ranking to a clear decision question, relevant to all or a subset of competing treatments., (© 2022. The Author(s).)

Background: Network meta-analysis (NMA) has attracted growing interest in evidence-based medicine. Consistency between different sources of evidence is fundamental to the reliability of the NMA results. The purpose of the present study was to estimate the prevalence of evidence of inconsistency and describe its association with different NMA characteristics., Methods: We updated our collection of NMAs with articles published up to July 2018. We included networks with randomised clinical trials, at least four treatment nodes, at least one closed loop, a dichotomous primary outcome, and available arm-level data. We assessed consistency using the design-by-treatment interaction (DBT) model and testing all the inconsistency parameters globally through the Wald-type chi-squared test statistic. We estimated the prevalence of evidence of inconsistency and its association with different network characteristics (e.g., number of studies, interventions, intervention comparisons, loops). We evaluated the influence of the network characteristics on the DBT p-value via a multivariable regression analysis and the estimated Pearson correlation coefficients. We also evaluated heterogeneity in NMA (consistency) and DBT (inconsistency) random-effects models., Results: We included 201 published NMAs. The p-value of the design-by-treatment interaction (DBT) model was lower than 0.05 in 14% of the networks and lower than 0.10 in 20% of the networks. Networks including many studies and comparing few interventions were more likely to have small DBT p-values (less than 0.10), which is probably because they yielded more precise estimates and power to detect differences between designs was higher. In the presence of inconsistency (DBT p-value lower than 0.10), the consistency model displayed higher heterogeneity than the DBT model., Conclusions: Our findings show that inconsistency was more frequent than what would be expected by chance, suggesting that researchers should devote more resources to exploring how to mitigate inconsistency. The results of this study highlight the need to develop strategies to detect inconsistency (because of the relatively high prevalence of evidence of inconsistency in published networks), and particularly in cases where the existing tests have low power., (© 2021. The Author(s).)

Background: Healthcare decisions are ideally based on clinical trial results, published in study registries, as journal articles or summarized in secondary research articles. In this research project, we investigated the impact of academically and commercially sponsored clinical trials on medical practice by measuring the proportion of trials published and cited by systematic reviews and clinical guidelines., Methods: We examined 691 multicenter, randomized controlled trials that started in 2005 or later and were completed by the end of 2016. To determine whether sponsorship/funding and place of conduct influence a trial's impact, we created four sub-cohorts of investigator initiated trials (IITs) and industry sponsored trials (ISTs): 120 IITs and 171 ISTs with German contribution compared to 200 IITs and 200 ISTs without German contribution. We balanced the groups for study phase and place of conduct. German IITs were funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), or by another non-commercial research organization. All other trials were drawn from the German Clinical Trials Register or ClinicalTrials.gov. We investigated, to what extent study characteristics were associated with publication and impact using multivariable logistic regressions., Results: For 80% of the 691 trials, results were published as result articles in a medical journal and/or study registry, 52% were cited by a systematic review, and 26% reached impact in a clinical guideline. Drug trials and larger trials were associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as a journal article while results of ISTs were more often published in study registries. International ISTs less often gained impact by inclusion in systematic reviews or guidelines than IITs., Conclusion: An encouraging high proportion of the clinical trials were published, and a considerable proportion gained impact on clinical practice. However, there is still room for improvement. For publishing study results, study registries have become an alternative or complement to journal articles, especially for ISTs. IITs funded by governmental bodies in Germany reached an impact that is comparable to international IITs and ISTs., (© 2021. The Author(s).)

Background: Overweight and obesity in children and adolescents are major public health challenges affecting quality of life and representing important risk factors in the development of non-communicable diseases. School environments provide great possibilities for the primary prevention of overweight and obesity and different school-based nutrition interventions are available. However, existing research on school-based nutrition interventions has important limitations and no network meta-analysis (NMA) has been performed yet to compare all available interventions. Therefore, the present research project aims to investigate the impact of different nutrition interventions in the school setting by comparing and ranking them using NMA methodology., Methods/design: A systematic literature search will be performed in 11 electronic databases (PubMed, the Cochrane Library, Web of Science, ERIC, PsycINFO, CAB Abstracts, Campbell Library, BiblioMap EPPI, Australian Education Index, Joanna Briggs Institute Evidence-Based Practice Database and Practice-based Evidence in Nutrition Database). Parallel or cluster randomized controlled trials (RCTs) meeting the following criteria will be included: (1) generally healthy school students aged 4-18 years, (2) school-based intervention with ≥ 1 nutrition component, and (3) assessed anthropometric (overweight/obesity risk, body weight change, weight Z-score, [standardized] body mass index, body fat, waist circumference) and/or diet-quality measures (daily intake of fruits and vegetables, fat, and sugar-sweetened beverages). Random effects pairwise and NMA will be performed for these outcomes and surface under the cumulative ranking curve (SUCRA) estimated (P-score). Where possible, component NMA (CNMA) will be used additionally. Subgroup analyses are carried out for intervention duration, gender, age of school students, socioeconomic status, and geographical location, and sensitivity analyses by excluding high risk of bias RCTs., Discussion: This systematic review and NMA will be the first to both directly and indirectly compare and rank different school-based nutrition interventions for the primary prevention of overweight and obesity in childhood and adolescence. Our analyses will provide important insights about the effects of the different interventions and show which are the most promising. The results of our study can help inform the design of new studies and will be of value to anyone interested in developing successful, evidence-based nutrition interventions in school settings., Systematic Review Registration: PROSPERO: CRD42020220451 .

Many healthcare interventions are complex, consisting of multiple, possibly interacting, components. Several methodological articles addressing complex interventions in the meta-analytical context have been published. We hereby provide an overview of methods used to evaluate the effects of complex interventions with meta-analytical models. We summarized the methodology, highlighted new developments, and described the benefits, drawbacks, and potential challenges of each identified method. We expect meta-analytical methods focusing on components of several multicomponent interventions to become increasingly popular due to recently developed, easy-to-use, software tools that can be used to conduct the relevant analyses. The different meta-analytical methods are illustrated through two examples comparing psychotherapies for panic disorder., Competing Interests: The authors have declared that no competing interests exist.

Breast cancer (BC) represents the most common type of cancer in females worldwide. Endocrine therapy evolved as one of the main concepts in treatment of hormone-receptor positive BC. Current research focuses on the elucidation of tumour resistance mechanisms against endocrine therapy. In a translational in vitro approach, potential regulatory effects of clinically implemented BC anti-oestrogens on ERα, its coactivators DDX5, DDX17 and other DEADbox proteins as well as on the proliferation markers cyclin D1 and Ki67 were investigated on both the RNA and protein level. BC in vitro models for hormone-receptor positive (MCF-7, T-47D) and hormone-receptor negative cells (BT-20) were subjected to endocrine therapy. Anti-oestrogen-dependent expression regulation of target genes on the transcriptional and translational level was quantified and statistically assessed. Endocrine therapy decreases the expression levels of Ki67, cyclin D1 and ERα in hormone-receptor positive cells. In the hormone-receptor negative cells, the three parameters remained stable after endocrine therapy. Endoxifen triggers a downregulation of DDX5 and DDX23 in MCF-7 cells. Fulvestrant treatment downregulates the expression levels of all investigated DEADbox proteins in MCF-7 cells. In T-47D cells, endoxifen and fulvestrant lead to a decrease of all target gene expression levels. Interestingly, endocrine therapy affects DEADbox RNA expression levels in BT-20 cells, too. However, this result could only be confirmed for DDX1, immunocytologically. The investigated DEADbox proteins appear to correlate with the oestrogen-dependent tumourigenesis in hormone-receptor positive BC and show expression alterations after endocrine treatment.

Background: Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause of patient dissatisfaction and may lead to prolonged hospital stay and higher costs of care along with more severe complications. Many antiemetic drugs are available for prophylaxis. They have various mechanisms of action and side effects, but there is still uncertainty about which drugs are most effective with the fewest side effects., Objectives: • To compare the efficacy and safety of different prophylactic pharmacologic interventions (antiemetic drugs) against no treatment, against placebo, or against each other (as monotherapy or combination prophylaxis) for prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia • To generate a clinically useful ranking of antiemetic drugs (monotherapy and combination prophylaxis) based on efficacy and safety • To identify the best dose or dose range of antiemetic drugs in terms of efficacy and safety SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and reference lists of relevant systematic reviews. The first search was performed in November 2017 and was updated in April 2020. In the update of the search, 39 eligible studies were found that were not included in the analysis (listed as awaiting classification)., Selection Criteria: Randomized controlled trials (RCTs) comparing effectiveness or side effects of single antiemetic drugs in any dose or combination against each other or against an inactive control in adults undergoing any type of surgery under general anaesthesia. All antiemetic drugs belonged to one of the following substance classes: 5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, corticosteroids, antihistamines, and anticholinergics. No language restrictions were applied. Abstract publications were excluded., Data Collection and Analysis: A review team of 11 authors independently assessed trials for inclusion and risk of bias and subsequently extracted data. We performed pair-wise meta-analyses for drugs of direct interest (amisulpride, aprepitant, casopitant, dexamethasone, dimenhydrinate, dolasetron, droperidol, fosaprepitant, granisetron, haloperidol, meclizine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, promethazine, ramosetron, rolapitant, scopolamine, and tropisetron) compared to placebo (inactive control). We performed network meta-analyses (NMAs) to estimate the relative effects and ranking (with placebo as reference) of all available single drugs and combinations. Primary outcomes were vomiting within 24 hours postoperatively, serious adverse events (SAEs), and any adverse event (AE). Secondary outcomes were drug class-specific side effects (e.g. headache), mortality, early and late vomiting, nausea, and complete response. We performed subgroup network meta-analysis with dose of drugs as a moderator variable using dose ranges based on previous consensus recommendations. We assessed certainty of evidence of NMA treatment effects for all primary outcomes and drug class-specific side effects according to GRADE (CINeMA, Confidence in Network Meta-Analysis). We restricted GRADE assessment to single drugs of direct interest compared to placebo., Main Results: We included 585 studies (97,516 randomized participants). Most of these studies were small (median sample size of 100); they were published between 1965 and 2017 and were primarily conducted in Asia (51%), Europe (25%), and North America (16%). Mean age of the overall population was 42 years. Most participants were women (83%), had American Society of Anesthesiologists (ASA) physical status I and II (70%), received perioperative opioids (88%), and underwent gynaecologic (32%) or gastrointestinal surgery (19%) under general anaesthesia using volatile anaesthetics (88%). In this review, 44 single drugs and 51 drug combinations were compared. Most studies investigated only single drugs (72%) and included an inactive control arm (66%). The three most investigated single drugs in this review were ondansetron (246 studies), dexamethasone (120 studies), and droperidol (97 studies). Almost all studies (89%) reported at least one efficacy outcome relevant for this review. However, only 56% reported at least one relevant safety outcome. Altogether, 157 studies (27%) were assessed as having overall low risk of bias, 101 studies (17%) overall high risk of bias, and 327 studies (56%) overall unclear risk of bias. Vomiting within 24 hours postoperatively Relative effects from NMA for vomiting within 24 hours (282 RCTs, 50,812 participants, 28 single drugs, and 36 drug combinations) suggest that 29 out of 36 drug combinations and 10 out of 28 single drugs showed a clinically important benefit (defined as the upper end of the 95% confidence interval (CI) below a risk ratio (RR) of 0.8) compared to placebo. Combinations of drugs were generally more effective than single drugs in preventing vomiting. However, single NK₁ receptor antagonists showed treatment effects similar to most of the drug combinations. High-certainty evidence suggests that the following single drugs reduce vomiting (ordered by decreasing efficacy): aprepitant (RR 0.26, 95% CI 0.18 to 0.38, high certainty, rank 3/28 of single drugs); ramosetron (RR 0.44, 95% CI 0.32 to 0.59, high certainty, rank 5/28); granisetron (RR 0.45, 95% CI 0.38 to 0.54, high certainty, rank 6/28); dexamethasone (RR 0.51, 95% CI 0.44 to 0.57, high certainty, rank 8/28); and ondansetron (RR 0.55, 95% CI 0.51 to 0.60, high certainty, rank 13/28). Moderate-certainty evidence suggests that the following single drugs probably reduce vomiting: fosaprepitant (RR 0.06, 95% CI 0.02 to 0.21, moderate certainty, rank 1/28) and droperidol (RR 0.61, 95% CI 0.54 to 0.69, moderate certainty, rank 20/28). Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol showed clinically important benefit, but low doses showed no clinically important benefit. Aprepitant was used mainly at high doses, ramosetron at recommended doses, and fosaprepitant at doses of 150 mg (with no dose recommendation available). Frequency of SAEs Twenty-eight RCTs were included in the NMA for SAEs (10,766 participants, 13 single drugs, and eight drug combinations). The certainty of evidence for SAEs when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to low. Droperidol (RR 0.88, 95% CI 0.08 to 9.71, low certainty, rank 6/13) may reduce SAEs. We are uncertain about the effects of aprepitant (RR 1.39, 95% CI 0.26 to 7.36, very low certainty, rank 11/13), ramosetron (RR 0.89, 95% CI 0.05 to 15.74, very low certainty, rank 7/13), granisetron (RR 1.21, 95% CI 0.11 to 13.15, very low certainty, rank 10/13), dexamethasone (RR 1.16, 95% CI 0.28 to 4.85, very low certainty, rank 9/13), and ondansetron (RR 1.62, 95% CI 0.32 to 8.10, very low certainty, rank 12/13). No studies reporting SAEs were available for fosaprepitant. Frequency of any AE Sixty-one RCTs were included in the NMA for any AE (19,423 participants, 15 single drugs, and 11 drug combinations). The certainty of evidence for any AE when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to moderate. Granisetron (RR 0.92, 95% CI 0.80 to 1.05, moderate certainty, rank 7/15) probably has no or little effect on any AE. Dexamethasone (RR 0.77, 95% CI 0.55 to 1.08, low certainty, rank 2/15) and droperidol (RR 0.89, 95% CI 0.81 to 0.98, low certainty, rank 6/15) may reduce any AE. Ondansetron (RR 0.95, 95% CI 0.88 to 1.01, low certainty, rank 9/15) may have little or no effect on any AE. We are uncertain about the effects of aprepitant (RR 0.87, 95% CI 0.78 to 0.97, very low certainty, rank 3/15) and ramosetron (RR 1.00, 95% CI 0.65 to 1.54, very low certainty, rank 11/15) on any AE. No studies reporting any AE were available for fosaprepitant. Class-specific side effects For class-specific side effects (headache, constipation, wound infection, extrapyramidal symptoms, sedation, arrhythmia, and QT prolongation) of relevant substances, the certainty of evidence for the best and most reliable anti-vomiting drugs mostly ranged from very low to low. Exceptions were that ondansetron probably increases headache (RR 1.16, 95% CI 1.06 to 1.28, moderate certainty, rank 18/23) and probably reduces sedation (RR 0.87, 95% CI 0.79 to 0.96, moderate certainty, rank 5/24) compared to placebo. The latter effect is limited to recommended and high doses of ondansetron. Droperidol probably reduces headache (RR 0.76, 95% CI 0.67 to 0.86, moderate certainty, rank 5/23) compared to placebo. We have high-certainty evidence that dexamethasone (RR 1.00, 95% CI 0.91 to 1.09, high certainty, rank 16/24) has no effect on sedation compared to placebo. No studies assessed substance class-specific side effects for fosaprepitant. Direction and magnitude of network effect estimates together with level of evidence certainty are graphically summarized for all pre-defined GRADE-relevant outcomes and all drugs of direct interest compared to placebo in http://doi.org/10.5281/zenodo.4066353., Authors' Conclusions: We found high-certainty evidence that five single drugs (aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron) reduce vomiting, and moderate-certainty evidence that two other single drugs (fosaprepitant and droperidol) probably reduce vomiting, compared to placebo. Four of the six substance classes (5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, and corticosteroids) were thus represented by at least one drug with important benefit for prevention of vomiting. Combinations of drugs were generally more effective than the corresponding single drugs in preventing vomiting. NK₁ receptor antagonists were the most effective drug class and had comparable efficacy to most of the drug combinations. 5-HT₃ receptor antagonists were the best studied substance class. For most of the single drugs of direct interest, we found only very low to low certainty evidence for safety outcomes such as occurrence of SAEs, any AE, and substance class-specific side effects. Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol were more effective than low doses for prevention of vomiting. Dose dependency of side effects was rarely found due to the limited number of studies, except for the less sedating effect of recommended and high doses of ondansetron. The results of the review are transferable mainly to patients at higher risk of nausea and vomiting (i.e. healthy women undergoing inhalational anaesthesia and receiving perioperative opioids). Overall study quality was limited, but certainty assessments of effect estimates consider this limitation. No further efficacy studies are needed as there is evidence of moderate to high certainty for seven single drugs with relevant benefit for prevention of vomiting. However, additional studies are needed to investigate potential side effects of these drugs and to examine higher-risk patient populations (e.g. individuals with diabetes and heart disease)., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: Obesity is highly prevalent in older adults aged 65 years or older. Different lifestyle interventions (diet, exercise, self-management) are available but benefits and harms have not been fully quantified comparing all available health promotion interventions. Special consideration must be given to functional outcomes and possible adverse effects (loss of muscle and bone mass, hypoglycaemia) of weight loss interventions in this age group. The objective of this study is to synthesise the evidence regarding the effects of different types and modalities of lifestyle interventions, or their combinations, on physical function and obesity-related outcomes such as body composition in older adults with obesity., Methods and Analyses: Six databases (Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Psychinfo and Web of Science) and two trial registries (Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform) will be searched for randomised controlled trials of lifestyle interventions in older adults with obesity. Screening (title/abstract and full-text) and data extraction of references as well as assessment of risk of bias and rating of the certainty of evidence (Grading of Recommendations, Assessment, Development and Evaluation for network meta-analyses) will be performed by two reviewers independently. Frequentist random-effects network meta-analyses will be conducted to determine the pooled effects from each intervention., Ethics and Dissemination: We will submit our findings to peer-reviewed journals and present at national and international conferences as well as in scientific medical societies. Patient-targeted dissemination will involve local and national advocate groups., Prospero Registration Number: CRD42019147286., Competing Interests: Competing interests: LS is a member of the GRADE working group. JAB is funded by the National Institute on Aging and Office of Dietary Supplements of the National Institutes of Health under Award Number K23AG051681, and the R01 AG067416., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In pairwise meta-analysis, the contribution of each study to the pooled estimate is given by its weight, which is based on the inverse variance of the estimate from that study. For network meta-analysis (NMA), the contribution of direct (and indirect) evidence is easily obtained from the diagonal elements of a hat matrix. It is, however, not fully clear how to generalize this to the percentage contribution of each study to a NMA estimate., Methods: We define the importance of each study for a NMA estimate by the reduction of the estimate's variance when adding the given study to the others. An equivalent interpretation is the relative loss in precision when the study is left out. Importances are values between 0 and 1. An importance of 1 means that the study is an essential link of the pathway in the network connecting one of the treatments with another., Results: Importances can be defined for two-stage and one-stage NMA. These numbers in general do not add to one and thus cannot be interpreted as 'percentage contributions'. After briefly discussing other available approaches, we question whether it is possible to obtain unique percentage contributions for NMA., Conclusions: Importances generalize the concept of weights in pairwise meta-analysis in a natural way. Moreover, they are uniquely defined, easily calculated, and have an intuitive interpretation. We give some real examples for illustration.

Insomnia is a prevalent disorder and it leads to relevant impairment in health-related quality of life. Recent clinical guidelines pointed out that Cognitive-Behavior Therapy for Insomnia (CBT-I) should be considered as first-line intervention. Nevertheless, many other interventions are commonly used by patients or have been proposed as effective for insomnia. These include melatonin, light exposure, exercise, and complementary and alternative medicine. Evaluation of comparable effectiveness of these interventions with first-line intervention for insomnia is however still lacking. We conducted a systematic review and network meta-analysis on the effects of these interventions. PubMed, PsycInfo, PsycArticles, MEDLINE, and CINAHL were systematically searched and 40 studies were included in the systematic review, while 36 were entered into the meta-analysis. Eight network meta-analyses were conducted. Findings support effectiveness of melatonin in improving sleep-onset difficulties and of meditative movement therapies for self-report sleep efficiency and severity of the insomnia disorder. Some support was observed for exercise, hypnotherapy, and transcranial magnetic resonance, but the number of studies for these interventions is still too small. None of the considered interventions received superior evidence to CBT-I, which should be more widely disseminated in primary care.

The present study examined the predictive values of amyloid PET, 18 F-FDG PET, and nonimaging predictors (alone and in combination) for development of Alzheimer dementia (AD) in a large population of patients with mild cognitive impairment (MCI). Methods: The study included 319 patients with MCI from the Alzheimer Disease Neuroimaging Initiative database. In a derivation dataset ( n = 159), the following Cox proportional-hazards models were constructed, each adjusted for age and sex: amyloid PET using 18 F-florbetapir (pattern expression score of an amyloid-β AD conversion-related pattern, constructed by principle-components analysis); 18 F-FDG PET (pattern expression score of a previously defined 18 F-FDG-based AD conversion-related pattern, constructed by principle-components analysis); nonimaging (functional activities questionnaire, apolipoprotein E, and mini-mental state examination score); 18 F-FDG PET + amyloid PET; amyloid PET + nonimaging; 18 F-FDG PET + nonimaging; and amyloid PET + 18 F-FDG PET + nonimaging. In a second step, the results of Cox regressions were applied to a validation dataset ( n = 160) to stratify subjects according to the predicted conversion risk. Results: On the basis of the independent validation dataset, the 18 F-FDG PET model yielded a significantly higher predictive value than the amyloid PET model. However, both were inferior to the nonimaging model and were significantly improved by the addition of nonimaging variables. The best prediction accuracy was reached by combining 18 F-FDG PET, amyloid PET, and nonimaging variables. The combined model yielded 5-y free-of-conversion rates of 100%, 64%, and 24% for the low-, medium- and high-risk groups, respectively. Conclusion: 18 F-FDG PET, amyloid PET, and nonimaging variables represent complementary predictors of conversion from MCI to AD. Especially in combination, they enable an accurate stratification of patients according to their conversion risks, which is of great interest for patient care and clinical trials., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Results of medical research should be made publicly available in a timely manner to enable patients and health professionals to make informed decisions about health issues. We aimed to apply a multi-state model to analyze the overall time needed to publish study results, and to examine predictors of the timing of transitions within the research process from study initiation through completion/discontinuation to eventual publication., Methods: Using a newly developed multi-state model approach, we analysed the effect of different study-related factors on each of the transitions from study approval to eventual publication, using a data set of clinical studies approved by a German research ethics committee between 2000 and 2002., Results: Of 917 approved studies, 806 were included in our analyses. About half of the clinical studies which began were subsequently published as full articles, and the median time from study approval to publication was 10 years. Differences across model states were apparent; several factors were predictive of the transition from study approval to completion, while funding source and collaboration were predictive of the transition from completion to publication., Conclusions: The proposed multi-state model approach permits a more comprehensive analysis of time to publication than a simple examination of the transition from approval to publication, and thus the findings represent an advance on previous studies of this aspect of the research process., Competing Interests: The authors have declared that no competing interests exist.

Objective: Meta-analysis is of fundamental importance to obtain an unbiased assessment of the available evidence. In general, the use of meta-analysis has been increasing over the last three decades with mental health as a major research topic. It is then essential to well understand its methodology and interpret its results. In this publication, we describe how to perform a meta-analysis with the freely available statistical software environment R, using a working example taken from the field of mental health., Methods: R package meta is used to conduct standard meta-analysis. Sensitivity analyses for missing binary outcome data and potential selection bias are conducted with R package metasens. All essential R commands are provided and clearly described to conduct and report analyses., Results: The working example considers a binary outcome: we show how to conduct a fixed effect and random effects meta-analysis and subgroup analysis, produce a forest and funnel plot and to test and adjust for funnel plot asymmetry. All these steps work similar for other outcome types., Conclusions: R represents a powerful and flexible tool to conduct meta-analyses. This publication gives a brief glimpse into the topic and provides directions to more advanced meta-analysis methods available in R., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Traditional pairwise meta-analysis (PMA) is a very useful method that pools evidence from one study design type if appropriate; its widespread use in nutrition research is an important phenomenon. Recently, a promising method for more advanced evidence-synthesis, called network meta-analysis (NMA), was introduced. NMA is an extension of PMA that enables simultaneous comparison of multiple interventions. NMA combines direct evidence (i.e., trials comparing 2 interventions directly) and indirect evidence (i.e., from a connected route via ≥1 comparators, e.g. placebo) in a network of studies. NMAs have the potential to advance knowledge in the field of nutrition as they provide insights that cannot be obtained by individual 2-arm randomized controlled trials or PMA. Thus, in this perspective paper, we aim to summarize the current (methodologic) status of published NMAs in nutrition research and emphasize advances and strengths in comparison with traditional PMA through specific examples, and highlight potential pitfalls and limitations. NMA is an emerging methodology in the field of nutrition research. A PubMed search identified only 23 nutrition research-related NMAs published since the inception of journals up to January 8, 2019 (61% of them published since 2017), compared with >5000 published PMAs. Moreover, we aim to highlight the scientific concepts and standards through the use of the following NMA example: "Which type of oils/solid fats offers the greatest impact on blood lipids?" In this regard, we discuss intervention definitions, transitivity/similarity, statistical methods, description and visualization of results, inconsistency, ranking, dissemination bias, assessing the certainty of evidence by Grading of Recommendations Assessment, Development and Evaluation, and reporting guidelines. We expect that rigorously conducted NMAs based on high-quality systematic reviews will become the new evidence synthesis benchmark in nutrition research. However, caution is warranted because abuse and misinterpretations of PMA and NMA findings could hamper the scientific field and possibly decision-making regarding public policy., (Copyright © American Society for Nutrition 2019.)

The value of 18 F-FDG PET for predicting conversion from mild cognitive impairment (MCI) to Alzheimer dementia (AD) is currently under debate. We used a principal components analysis (PCA) to identify a metabolic AD conversion-related pattern (ADCRP) and investigated the prognostic value of the resulting pattern expression score (PES). Methods: 18 F-FDG PET scans of 544 MCI patients were obtained from the Alzheimer Disease Neuroimaging Initiative database and analyzed. We implemented voxel-based PCA and standard Statistical Parametric Mapping analysis (as a reference) to disclose cerebral metabolic patterns associated with conversion from MCI to AD. By Cox proportional hazards regression, we examined the prognostic value of candidate predictors. Also, we constructed prognostic models with clinical, imaging, and clinical and imaging variables in combination. Results: PCA revealed an ADCRP that involved regions with relative decreases in metabolism (temporoparietal, frontal, posterior cingulate, and precuneus cortices) and relative increases in metabolism (sensorimotor and occipital cortices, cerebellum, and left putamen). Among the predictor variables age, sex, Functional Activities Questionnaire, Mini-Mental State Examination, apolipoprotein E, PES, and normalized 18 F-FDG uptake (regions with significant hypo- and hypermetabolism in patients with conversion vs. those without conversion), PES was the best independent predictor of conversion (hazard ratio, 1.77, per z score increase; 95% CI, 1.24-2.52; P < 0.001). Moreover, adding PES to the model including the clinical variables significantly increased its prognostic value. Conclusion: The ADCRP expression score was a valid predictor of conversion. A combination of clinical variables and PES yielded a higher accuracy than each single tool in predicting conversion from MCI to AD, underlining the incremental utility of 18 F-FDG PET., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Length of stay evaluations are very common to determine the burden of nosocomial infections. However, there exist fundamentally different methods to quantify the prolonged length of stay associated with nosocomial infections. Previous methodological studies emphasized the need to account for the timing of infection in order to differentiate the length of stay before and after the infection., Methods: We derive four different approaches in a simple multi-state framework, display their mathematical relationships in a multiplicative as well as additive way and apply them to a real cohort study (n=756 German intensive-care unit patients of whom 124 patients acquired a nosocomial infection)., Results: The first approach ignores the timing of infection and quantifies the difference of eventually infected and eventually uninfected; it is 12.31 days in the real data. The second approach compares the average sojourn time with infection with the average sojourn time of being hypothetically uninfected; it is 2.12 days. The third one compares the average length of stay of a population in a world with nosocomial infections with a population in a hypothetical world without nosocomial infections; it is 0.35 days. Finally, approach four compares the mean residual length of stay between currently infected and uninfected patients on a daily basis; the difference is 1.77 days per infected patient., Conclusions: The first approach should be avoided because it compares the eventually infected with the eventually uninfected, but has no prospective interpretation. The other approaches differ in their interpretation but are suitable because they explicitly distinguish between the pre- and post-time of the nosocomial infection.

The objective of this study is to describe the general approaches to network meta-analysis that are available for quantitative data synthesis using R software. We conducted a network meta-analysis using two approaches: Bayesian and frequentist methods. The corresponding R packages were "gemtc" for the Bayesian approach and "netmeta" for the frequentist approach. In estimating a network meta-analysis model using a Bayesian framework, the "rjags" package is a common tool. "rjags" implements Markov chain Monte Carlo simulation with a graphical output. The estimated overall effect sizes, test for heterogeneity, moderator effects, and publication bias were reported using R software. The authors focus on two flexible models, Bayesian and frequentist, to determine overall effect sizes in network meta-analysis. This study focused on the practical methods of network meta-analysis rather than theoretical concepts, making the material easy to understand for Korean researchers who did not major in statistics. The authors hope that this study will help many Korean researchers to perform network meta-analyses and conduct related research more easily with R software.

Aim: The value of 18 F-fluorodeoxyglucose (FDG) PET for the prognosis of conversion from mild cognitive impairment (MCI) to Alzheimer's dementia (AD) is controversial. In the present work, the identification of cerebral metabolic patterns with significant prognostic value for conversion of MCI patients to AD is investigated with voxel-based Cox regression, which in contrast to common categorical comparisons also utilizes time information., Methods: FDG PET data of 544 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were randomly split into two equally-sized datasets (training and test). Within a median follow-up duration of 47 months (95% CI: 46-48 months) 181 patients developed AD. In the training dataset, voxel-wise Cox regressions were used to identify regions associated with conversion of MCI to AD. These were compared to regions identified by a classical group comparison (analysis of covariance (ANCOVA) with statistical parametric mapping (SPM) 8) between converters and non-converters (both adjusted for apolipoprotein E (APOE) genotype, mini-mental state examination (MMSE) score, age, sex and education). In the test dataset, normalized FDG uptake within significant brain regions from voxel-wise Cox- and ANCOVA analyses (Cox- and ANCOVA- regions of interest (ROI), respectively) and clinical variables APOE status, MMSE score and education were tested in different Cox models (adjusted for age, sex) including: (1) only clinical variables, (2) only normalized FDG uptake in ANCOVA-ROI, (3) only normalized FDG uptake from Cox-ROI, (4) clinical variables plus FDG uptake in ANCOVA-ROI, (5) clinical variables plus FDG uptake from Cox-ROI., Results: Conversion-related regions with relative hypometabolism comprised parts of the temporo-parietal and posterior cingulate cortex/precuneus for voxel-wise ANCOVA, plus frontal regions for voxel-wise Cox regression (both p < .01, false discovery rate (FDR) corrected). The clinical-only model (1) and the models based on normalized FDG uptake from Cox-ROI only (2) and ANCOVA-ROI only (3) all significantly predicted conversion to AD (Wald Test (WT): p < .001). The clinical model (1) was significantly improved by adding imaging information in model (4) (Akaike information criterion (AIC) relative likelihood (RL) (1) vs (4): RL < 0.018). There were no significant differences between models (2) and (3), as well as (4) and (5)., Conclusions: Voxel-wise Cox regression identifies conversion-related patterns of cerebral glucose metabolism, but is not superior to classical group contrasts in this regard. With imaging information from both FDG PET patterns, the prediction of conversion to AD was improved., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aetiology of dementia is not yet fully understood. Stress can have a damaging effect on brain health. The prognostic effect of anxiety is still unclear regarding Alzheimer's disease as well as vascular dementia.AimsTo explore the association between anxiety and future dementia., Method: Medline, PsycINFO, CINAHL, Web of Science and ALOIS were searched for publications up to 12 January 2018. Longitudinal studies with a follow-up of at least 2 years were included, if the trait or state anxiety had been assessed at baseline. Studies with cognitive impairment at baseline were not included. We used a random effects model to calculate the pooled time to Alzheimer's disease and incidence of vascular dementia., Results: Anxiety predicts risk of Alzheimer's disease (n = 26 193 out of seven studies, hazard ratio1.53, 95% CI 1.16-2.01, P < 0.01) and vascular dementia (n = 4916 out of two studies, odds ratio1.88, 95% CI 1.05-3.36, P < 0.01). The pooled hazard ratio regarding risk of Alzheimer's disease was still significant when excluding studies with critical risk of bias (n = 14 110 out of six studies, hazard ratio 1.35, 95% CI 1.08-1.70, P < 0.01)., Conclusions: Anxiety is a risk factor for both types of dementia. The temporal and functional relation between anxiety and dementia needs investigation in future studies. The protective value of treating anxiety should be explored further.Declaration of interestNone.

In network meta-analysis, it is important to assess the influence of the limitations or other characteristics of individual studies on the estimates obtained from the network. The percentage contribution matrix, which shows how much each direct treatment effect contributes to each treatment effect estimate from network meta-analysis, is crucial in this context. We use ideas from graph theory to derive the percentage that is contributed by each direct treatment effect. We start with the 'projection' matrix in a two-step network meta-analysis model, called the H matrix, which is analogous to the hat matrix in a linear regression model. We develop a method to translate H entries to percentage contributions based on the observation that the rows of H  can be interpreted as flow networks, where a stream is defined as the composition of a path and its associated flow. We present an algorithm that identifies the flow of evidence in each path and decomposes it into direct comparisons. To illustrate the methodology, we use two published networks of interventions. The first compares no treatment, quinolone antibiotics, non-quinolone antibiotics and antiseptics for underlying eardrum perforations and the second compares 14 antimanic drugs. We believe that this approach is a useful and novel addition to network meta-analysis methodology, which allows the consistent derivation of the percentage contributions of direct evidence from individual studies to network treatment effects., Competing Interests: No competing interests were disclosed.

Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. In addition, with the development of invasive therapies and novel disease-specific therapies, strategies for patient enrichment in trial populations are of growing importance. Imaging disease-specific patterns of regional glucose metabolism with PET and 18 F-FDG allows for a highly accurate distinction between Parkinson disease (PD) and atypical parkinsonian syndromes, including multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. On the basis of a preliminary metaanalysis of currently available studies with inclusion of multiple disease groups, we estimated that the diagnostic sensitivity and specificity for visual PET readings supported by voxel-based statistical analyses for diagnosis of atypical parkinsonian syndromes are 91.4% and 90.6%, respectively. The diagnostic specificity of 18 F-FDG PET for diagnosing multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration was consistently shown to be high (>90%), whereas sensitivity was more variable (>75%). It is increasingly acknowledged that cognitive impairment represents a major challenge in PD, with mild cognitive impairment being a prodromal stage of PD with dementia (PDD). In line with clinical and neuropsychologic studies, recent PET studies demonstrated that posterior cortical dysfunction in nondemented PD patients precedes cognitive decline and the development of PDD by several years. Taken together, the current literature underscores the utility of 18 F-FDG PET for diagnostic evaluation of parkinsonism and the promising role of 18 F-FDG PET for assessment and risk stratification of cognitive impairment in PD., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusions. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone are effective; however, a review of the effectiveness and safety of the newer oral chelator deferasirox in people with thalassaemia is needed., Objectives: To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and iron overload., Search Methods: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 August 2016.We also searched MEDLINE, Embase, the Cochrane Library, Biosis Previews, Web of Science Core Collection and three trial registries: ClinicalTrials.gov; the WHO International Clinical Trials Registry Platform; and the Internet Portal of the German Clinical Trials Register: 06 and 07 August 2015., Selection Criteria: Randomised controlled studies comparing deferasirox with no therapy or placebo or with another iron-chelating treatment., Data Collection and Analysis: Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information., Main Results: Sixteen studies involving 1807 randomised participants (range 23 to 586 participants) were included. Twelve two-arm studies compared deferasirox to placebo (two studies) or deferoxamine (seven studies) or deferiprone (one study) or the combination of deferasirox and deferoxamine to deferoxamine alone (one study). One study compared the combination of deferasirox and deferiprone to deferiprone in combination with deferoxamine. Three three-arm studies compared deferasirox to deferoxamine and deferiprone (two studies) or the combination of deferasirox and deferiprone to deferiprone and deferasirox monotherapy respectively (one study). One four-arm study compared two different doses of deferasirox to matching placebo groups.The two studies (a pharmacokinetic and a dose-escalation study) comparing deferasirox to placebo (n = 47) in people with transfusion-dependent thalassaemia showed that deferasirox leads to net iron excretion. In these studies, safety was acceptable and further investigation in phase II and phase III studies was warranted.Nine studies (1251 participants) provided data for deferasirox versus standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared. In the phase III study, similar or superior efficacy for the intermediate markers ferritin and liver iron concentration (LIC) could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg per day and 51.6 mg per day respectively. The pooled effects across the different dosing ratios are: serum ferritin, mean difference (MD) 454.42 ng/mL (95% confidence interval (CI) 337.13 to 571.71) (moderate quality evidence); LIC evaluated by biopsy or SQUID, MD 2.37 mg Fe/g dry weight (95% CI 1.68 to 3.07) (moderate quality evidence) and responder analysis, LIC 1 to < 7 mg Fe/g dry weight, risk ratio (RR) 0.80 (95% CI 0.69 to 0.92) (moderate quality evidence). The substantial heterogeneity observed could be explained by the different dosing ratios. Data on mortality (low quality evidence) and on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was better with deferasirox among those who had previously received deferoxamine treatment, RR 2.20 (95% CI 1.89 to 2.57) (moderate quality evidence). The rate of discontinuations was similar for both drugs (low quality evidence).For the remaining comparisons in people with transfusion-dependent thalassaemia, the quality of the evidence for outcomes assessed was low to very low, mainly due to the very small number of participants included. Four studies (205 participants) compared deferasirox to deferiprone; one of which (41 participants) revealed a higher number of participants experiencing arthralgia in the deferiprone group, but due to the large number of different types of adverse events reported and compared this result is uncertain. One study (96 participants) compared deferasirox combined with deferiprone to deferiprone with deferoxamine. Participants treated with the combination of the oral iron chelators had a higher adherence compared to those treated with deferiprone and deferoxamine, but no participants discontinued the study. In the comparisons of deferasirox versus combined deferasirox and deferiprone and that of deferiprone versus combined deferasirox and deferiprone (one study, 40 participants), and deferasirox and deferoxamine versus deferoxamine alone (one study, 94 participants), only a few patient-relevant outcomes were reported and no significant differences were observed.One study (166 participants) included people with non-transfusion dependent thalassaemia and compared two different doses of deferasirox to placebo. Deferasirox treatment reduced serum ferritin, MD -306.74 ng/mL (95% CI -398.23 to -215.24) (moderate quality evidence) and LIC, MD -3.27 mg Fe/g dry weight (95% CI -4.44 to -2.09) (moderate quality evidence), while the number of participants experiencing adverse events and rate of discontinuations (low quality evidence) was similar in both groups. No participant died, but data on mortality were limited due to a follow-up period of only one year (moderate quality evidence)., Authors' Conclusions: Deferasirox offers an important treatment option for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy and will translate to similar benefits in the long term, as has been shown for deferoxamine, needs to be confirmed. Data from randomised controlled trials on rare toxicities and long-term safety are still limited. However, after a detailed discussion of the potential benefits and risks, deferasirox could be offered as the first-line option to individuals who show a strong preference for deferasirox, and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine.

Background: Low cardiac output syndrome remains a serious complication, and accounts for substantial morbidity and mortality in the postoperative course of paediatric patients undergoing surgery for congenital heart disease. Standard prophylactic and therapeutic strategies for low cardiac output syndrome are based mainly on catecholamines, which are effective drugs, but have considerable side effects. Levosimendan, a calcium sensitiser, enhances the myocardial function by generating more energy-efficient myocardial contractility than achieved via adrenergic stimulation with catecholamines. Thus potentially, levosimendan is a beneficial alternative to standard medication for the prevention of low cardiac output syndrome in paediatric patients after open heart surgery., Objectives: To review the efficacy and safety of the postoperative prophylactic use of levosimendan for the prevention of low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease., Search Methods: We identified trials via systematic searches of CENTRAL, MEDLINE, Embase, and Web of Science, as well as clinical trial registries, in June 2016. Reference lists from primary studies and review articles were checked for additional references., Selection Criteria: We only included randomised controlled trials (RCT) in our analysis that compared prophylactic levosimendan with standard medication or placebo, in infants and children up to 18 years of age, who were undergoing surgery for congenital heart disease., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias according to a pre-defined protocol. We obtained additional information from all but one of the study authors of the included studies. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of evidence from the studies that contributed data to the meta-analyses for the prespecified outcomes. We created a 'Summary of findings' table to summarise the results and the quality of evidence for each outcome., Main Results: We included five randomised controlled trials with a total of 212 participants in the analyses. All included participants were under five years of age. Using GRADE, we assessed there was low-quality evidence for all analysed outcomes. We assessed high risk of performance and detection bias for two studies due to their unblinded setting. Levosimendan showed no clear effect on risk of mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.12 to 1.82; participants = 123; studies = 3) and no clear effect on low cardiac output syndrome (RR 0.64, 95% CI 0.39 to 1.04; participants = 83; studies = 2) compared to standard treatments. Data on time-to-death were not available from any of the included studies.There was no conclusive evidence on the effect of levosimendan on the secondary outcomes. The length of intensive care unit stays (mean difference (MD) 0.33 days, 95% CI -1.16 to 1.82; participants = 188; studies = 4), length of hospital stays (MD 0.26 days, 95% CI -3.50 to 4.03; participants = 75; studies = 2), duration of mechanical ventilation (MD -0.04 days, 95% CI -0.08 to 0.00; participants = 208; studies = 5), and the risk of mechanical circulatory support or cardiac transplantation (RR 1.49, 95% CI 0.19 to 11.37; participants = 60; studies = 2) did not clearly differ between the groups. Published data about adverse effects of levosimendan were limited. A meta-analysis of hypotension, one of the most feared side effects of levosimendan, was not feasible because of the heterogeneous expression of blood pressure values., Authors' Conclusions: The current level of evidence is insufficient to judge whether prophylactic levosimendan prevents low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease. So far, no significant differences have been detected between levosimendan and standard inotrope treatments in this setting.The authors evaluated the quality of evidence as low, using the GRADE approach. Reasons for downgrading were serious risk of bias (performance and detection bias due to unblinded setting of two RCTs), serious risk of inconsistency, and serious to very serious risk of imprecision (small number of included patients, low event rates).

Tumor resistance to endocrine therapy triggers estrogen-independent cancer progression, which is a major obstacle to the successful treatment of hormone receptor positive breast cancer (BC). The underlying molecular mechanisms of endocrine resistance are not fully understood yet. The matricellular protein cysteine-rich angiogenic inducer 61 (Cyr61) is associated with tumor invasiveness and the induction of tumorigenesis in various malignancies in vivo and the induction of estrogen-independence and endocrine therapy resistance in BC. The present study evaluated the potential effects and clinical relevance of Cyr61 expression levels in 67 patients with primary non-metastatic BC. Immunohistochemical analysis of formalin-fixed paraffin-embedded tissue sections was performed, and the association between Cyr61 protein expression and clinicopathological factors and survival was analyzed. Cyr61 overexpression was revealed to be significantly associated with a positive estrogen receptor (ER)/progesterone receptor (PR) status (P=0.016) and to the molecular subtype of BC (P=0.039). Compared with patients without Cyr61 overexpression, patients with Cyr61 overexpression exhibited an increased recurrence rate (30.6 vs. 22.6%) and decreased long-term survival (10-year overall survival, 62.9 vs. 69.7%); however, these associations did not reach statistically significant levels in Cox regression model analysis. Similar results were identified in the subgroup analysis of patients with ER/PR positive BC. These results indicate that Cyr61 serves a role in the development of endocrine therapy resistance in BC and is thus a potential therapeutic target to overcome endocrine therapy resistance. However, additional long-term survival analyses with large patient populations are required.

Background: Incurable cancer, which often constitutes an enormous challenge for patients, their families, and medical professionals, profoundly affects the patient's physical and psychosocial well-being. In standard cancer care, palliative measures generally are initiated when it is evident that disease-modifying treatments have been unsuccessful, no treatments can be offered, or death is anticipated. In contrast, early palliative care is initiated much earlier in the disease trajectory and closer to the diagnosis of incurable cancer., Objectives: To compare effects of early palliative care interventions versus treatment as usual/standard cancer care on health-related quality of life, depression, symptom intensity, and survival among adults with a diagnosis of advanced cancer., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, OpenGrey (a database for grey literature), and three clinical trial registers to October 2016. We checked reference lists, searched citations, and contacted study authors to identify additional studies., Selection Criteria: Randomised controlled trials (RCTs) and cluster-randomised controlled trials (cRCTs) on professional palliative care services that provided or co-ordinated comprehensive care for adults at early advanced stages of cancer., Data Collection and Analysis: We used standard methodological procedures as expected by Cochrane. We assessed risk of bias, extracted data, and collected information on adverse events. For quantitative synthesis, we combined respective results on our primary outcomes of health-related quality of life, survival (death hazard ratio), depression, and symptom intensity across studies in meta-analyses using an inverse variance random-effects model. We expressed pooled effects as standardised mean differences (SMDs, or Hedges' adjusted g). We assessed certainty of evidence at the outcome level using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) and created a 'Summary of findings' table., Main Results: We included seven randomised and cluster-randomised controlled trials that together recruited 1614 participants. Four studies evaluated interventions delivered by specialised palliative care teams, and the remaining studies assessed models of co-ordinated care. Overall, risk of bias at the study level was mostly low, apart from possible selection bias in three studies and attrition bias in one study, along with insufficient information on blinding of participants and outcome assessment in six studies.Compared with usual/standard cancer care alone, early palliative care significantly improved health-related quality of life at a small effect size (SMD 0.27, 95% confidence interval (CI) 0.15 to 0.38; participants analysed at post treatment = 1028; evidence of low certainty). As re-expressed in natural units (absolute change in Functional Assessment of Cancer Therapy-General (FACT-G) score), health-related quality of life scores increased on average by 4.59 (95% CI 2.55 to 6.46) points more among participants given early palliative care than among control participants. Data on survival, available from four studies enrolling a total of 800 participants, did not indicate differences in efficacy (death hazard ratio 0.85, 95% CI 0.56 to 1.28; evidence of very low certainty). Levels of depressive symptoms among those receiving early palliative care did not differ significantly from levels among those receiving usual/standard cancer care (five studies; SMD -0.11, 95% CI -0.26 to 0.03; participants analysed at post treatment = 762; evidence of very low certainty). Results from seven studies that analysed 1054 participants post treatment suggest a small effect for significantly lower symptom intensity in early palliative care compared with the control condition (SMD -0.23, 95% CI -0.35 to -0.10; evidence of low certainty). The type of model used to provide early palliative care did not affect study results. One RCT reported potential adverse events of early palliative care, such as a higher percentage of participants with severe scores for pain and poor appetite; the remaining six studies did not report adverse events in study publications. For these six studies, principal investigators stated upon request that they had not observed any adverse events., Authors' Conclusions: This systematic review of a small number of trials indicates that early palliative care interventions may have more beneficial effects on quality of life and symptom intensity among patients with advanced cancer than among those given usual/standard cancer care alone. Although we found only small effect sizes, these may be clinically relevant at an advanced disease stage with limited prognosis, at which time further decline in quality of life is very common. At this point, effects on mortality and depression are uncertain. We have to interpret current results with caution owing to very low to low certainty of current evidence and between-study differences regarding participant populations, interventions, and methods. Additional research now under way will present a clearer picture of the effect and specific indication of early palliative care. Upcoming results from several ongoing studies (N = 20) and studies awaiting assessment (N = 10) may increase the certainty of study results and may lead to improved decision making. In perspective, early palliative care is a newly emerging field, and well-conducted studies are needed to explicitly describe the components of early palliative care and control treatments, after blinding of participants and outcome assessors, and to report on possible adverse events.

Background/aim: The pro-angiogenic Cyr61 protein has been associated with tumorigenesis and cancer progression in different gynecological carcinomas. In this study, we evaluated the potential impact and clinical relevance of Cyr61 expression in patients with primary non-metastatic cervical cancer (CC)., Patients and Methods: Cyr61 expression was assessed in tissue specimen of 48 patients with primary CC by immunohistochemical analysis. Expression levels were scored and correlated to clinico-pathological factors and outcome data., Results: High Cyr61 expression levels were present in 54.2% of CC tissues. Associations with histological grade (p=0.030), depth of tumor invasion (p=0.007) and GOG score (p=0.027) were observed. Patients who overexpressed Cyr61 displayed an increased death rate (30.8% vs. 18.2%) and a decreased 5-year-survival (76.9% vs. 86.4%)., Conclusion: Our data indicate a potential functional impact of Cyr61 in development and the progression of CC. The definite tumor-relevant function (suppressive/promoting) of Cyr61 in CC and the prognostic relevance of Cyr61 overexpression has to be evaluated in larger cohorts., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: During their early years at medical school, students repeatedly criticize their workload, time constraints and test associated stress. At the same time, depressiveness and anxiety among first and second year medical students are on the rise. We therefore hypothesized that test anxiety may be related to depressiveness and considered cognitive and academic performances as confounders for the former and psychosocial distress for the latter., Methods: A whole class of 200 second year students was invited to participate in the study. Anxiety as a trait, depressiveness, crystallized intelligence, verbal fluency and psychosocial distress were assessed using validated tests and questionnaires. Acute state anxiety and sympathetic stress parameters were measured in real life situations immediately before an oral and a written exam and paired tests were used to compare the individual anxieties at the various time points. Previous academic performances were self-reported, the results of the impending exams were monitored. Finally, correlations were performed to test for interrelatedness between academic performances and the various personal, cognitive and psychosocial factors., Results: Acute test anxiety did not correlate with depressiveness nor did it correlate with previous nor impending academic performances nor any of the expected confounders on academic performance. However both, depressiveness and test anxiety strongly correlated with the perceived imbalance between efforts spent and rewards received. Moreover, anxiety as a trait not only correlated with acute state anxiety before an exam but was also significantly correlated to the feeling of over-commitment., Conclusion: Depressiveness during the early years of medical school seems unrelated to test anxiety and academic performance. Instead, it strongly correlated with the psychosocial distress emanating from attending medical school and points at a perceived imbalance between efforts spent and rewards received., Competing Interests: The authors have declared that no competing interests exist.