Aims Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE−/− FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). Methods and results Compared with normo-ferremic ApoE−/− mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE−/− FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE−/− FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. Conclusion Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.

BackgroundStandard random-effects meta-analysis methods perform poorly when applied to few studies only. Such settings however are commonly encountered in practice. It is unclear, whether or to what extent small-sample-size behaviour can be improved by more sophisticated modeling.MethodsWe consider likelihood-based methods, the DerSimonian-Laird approach, Empirical Bayes, several adjustment methods and a fully Bayesian approach. Confidence intervals are based on a normal approximation, or on adjustments based on the Student-t-distribution. In addition, a linear mixed model and two generalized linear mixed models (GLMMs) assuming binomial or Poisson distributed numbers of events per study arm are considered for pairwise binary meta-analyses. We extract an empirical data set of 40 meta-analyses from recent reviews published by the German Institute for Quality and Efficiency in Health Care (IQWiG). Methods are then compared empirically as well as in a simulation study, based on few studies, imbalanced study sizes, and considering odds-ratio (OR) and risk ratio (RR) effect sizes. Coverage probabilities and interval widths for the combined effect estimate are evaluated to compare the different approaches.ResultsEmpirically, a majority of the identified meta-analyses include only 2 studies. Variation of methods or effect measures affects the estimation results. In the simulation study, coverage probability is, in the presence of heterogeneity and few studies, mostly below the nominal level for all frequentist methods based on normal approximation, in particular when sizes in meta-analyses are not balanced, but improve when confidence intervals are adjusted. Bayesian methods result in better coverage than the frequentist methods with normal approximation in all scenarios, except for some cases of very large heterogeneity where the coverage is slightly lower. Credible intervals are empirically and in the simulation study wider than unadjusted confidence intervals, but considerably narrower than adjusted ones, with some exceptions when considering RRs and small numbers of patients per trial-arm. Confidence intervals based on the GLMMs are, in general, slightly narrower than those from other frequentist methods. Some methods turned out impractical due to frequent numerical problems.ConclusionsIn the presence of between-study heterogeneity, especially with unbalanced study sizes, caution is needed in applying meta-analytical methods to few studies, as either coverage probabilities might be compromised, or intervals are inconclusively wide. Bayesian estimation with a sensibly chosen prior for between-trial heterogeneity may offer a promising compromise.Electronic supplementary materialThe online version of this article (10.1186/s12874-018-0618-3) contains supplementary material, which is available to authorized users.

Decreased oxygen availability at high altitude requires physiological adjustments allowing for adequate tissue oxygenation. One such mechanism is a slow increase in the hemoglobin concentration ([Hb]) resulting in elevated [Hb] in high-altitude residents. Diagnosis of anemia at different altitudes requires reference values for [Hb]. Our aim was to establish such values based on published data of residents living at different altitudes by applying meta-analysis and multiple regressions. Results show that [Hb]is increased in all high-altitude residents. However, the magnitude of increase varies among the regions analyzed and among ethnic groups within a region. The highest increase was found in residents of the Andes (1 g/dL/1000 m), but this increment was smaller in all other regions of the world (0.6 g/dL/1000 m). While sufficient data exist for adult males and females showing that sex differences in [Hb] persist with altitude, data for infants, children, and pregnant women are incomplete preventing such analyses. Because WHO reference values were originally based on [Hb] of South American people, we conclude that individual reference values have to be defined for ethnic groups to reliably diagnose anemia and erythrocytosis in high-altitude residents. Future studies need to test their applicability for children of different ages and pregnant women.

BackgroundGiven both the increase of nursing home residents forecast and challenges of current interprofessional interactions, we developed and tested measures to improve collaboration and communication between nurses and general practitioners (GPs) in this setting. Our multicentre study has been funded by the German Federal Ministry of Education and Research (FK 01GY1124).MethodsThe measures were developed iteratively in a continuous process, which is the focus of this article. In part 1 “exploration of the situation”, interviews were conducted with GPs, nurses, nursing home residents and their relatives focusing on interprofessional interactions and medical care. They were analysed qualitatively. Based on these results, in part 2 “development of measures to improve collaboration”, ideas for improvement were developed in nine focus groups with GPs and nurses. These ideas were revisited in a final expert workshop. We analysed the focus groups and expert workshop using mind mapping methods, and finally drew up the compilation of measures. In an exploratory pilot study "study part 3" four nursing homes chose the measures they wanted to adopt. These were tested for three months. Feasibility and acceptance of the measures were evaluated via guideline interviews with the stakeholders which were analysed by content analyses.ResultsSix measures were generated: meetings to establish common goals, main contact person, standardised pro re nata medication, introduction of name badges, improved availability of nurse/GP and standardised scheduling/ procedure for nursing home visits. In the pilot study, the measures were implemented in four nursing homes. GPs and nurses reviewed five measures as feasible and acceptable, only the designation of a “main contact person” was not considered as an improvement.ConclusionsSix measures to improve collaboration and communication could be compiled in a multistep qualitative process respecting the perspectives of involved stakeholders. Five of the six measures were positively assessed in an exploratory pilot study. They could easily be transferred into the daily routine of other nursing homes, as no special models have to exist in advance. Impact of the measures on patient oriented outcomes should be examined in further research.Trial registrationNot applicable.Electronic supplementary materialThe online version of this article (10.1186/s12875-017-0678-1) contains supplementary material, which is available to authorized users.

Background Systematic reviews are an important tool of evidence-based surgery. Surgical systematic reviews and trials, however, require a special methodological approach. Purpose This article provides recommendations for conducting state-of-the-art systematic reviews in surgery with or without meta-analysis. Conclusions For systematic reviews in surgery, MEDLINE (via PubMed), Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) should be searched. Critical appraisal is at the core of every surgical systematic review, with information on blinding, industry involvement, surgical experience, and standardisation of surgical technique holding special importance. Due to clinical heterogeneity among surgical trials, the random-effects model should be used as a default. In the experience of the Study Center of the German Society of Surgery, adherence to these recommendations yields high-quality surgical systematic reviews.

Surgical resection is crucial for curative treatment of rectal cancer. Through multidisciplinary treatment, including radiochemotherapy and total mesorectal excision, survival has improved substantially. Consequently, more patients have to deal with side effects of treatment. The most recently introduced surgical technique is robotic-assisted surgery (RAS) which seems equally effective in terms of oncological control compared to laparoscopy. However, RAS enables further advantages which maximize the precision of surgery, thus providing better functional outcomes such as sexual function or contience without compromising oncological results. This review was done according to the PRISMA and AMSTAR-II guidelines and registered with PROSPERO (CRD42018104519). The search was planned with PICO criteria and conducted on Medline, Web of Science and CENTRAL. All screening steps were performed by two independent reviewers. Inclusion criteria were original, comparative studies for laparoscopy vs. RAS for rectal cancer and reporting of functional outcomes. Quality was assessed with the Newcastle-Ottawa scale. The search retrieved 9703 hits, of which 51 studies with 24,319 patients were included. There was a lower rate of urinary retention (non-RCTs: Odds ratio (OR) [95% Confidence Interval (CI)] 0.

The performance of statistical methods is often evaluated by means of simulation studies. In case of network meta-analysis of binary data, however, simulations are not currently available for many practically relevant settings. We perform a simulation study for sparse networks of trials under between-trial heterogeneity and including multi-arm trials. Results of the evaluation of two popular frequentist methods and a Bayesian approach using two different prior specifications are presented. Methods are evaluated using coverage, width of intervals, bias, and root mean squared error (RMSE). In addition, deviations from the theoretical surface under the cumulative rankings (SUCRAs) or Pscores of the treatments are evaluated. Under low heterogeneity and when a large number of trials informs the contrasts, all methods perform well with respect to the evaluated performance measures. Coverage is observed to be generally higher for the Bayesian than the frequentist methods. The width of credible intervals is larger than those of confidence intervals and is increasing when using a flatter prior for between-trial heterogeneity. Bias was generally small, but increased with heterogeneity, especially in netmeta. In some scenarios, the direction of bias differed between frequentist and Bayesian methods. The RMSE was comparable between methods but larger in indirectly than in directly estimated treatment effects. The deviation of the SUCRAs or P-scores from their theoretical values was mostly comparable over the methods but differed depending on the heterogeneity and the geometry of the investigated network. Multivariate meta-regression or Bayesian estimation using a half-normal prior scaled to 0.5 seems to be promising with respect to the evaluated performance measures in network meta-analysis of sparse networks.

Various blood cell ratios exist which seem to have an impact on prognosis for resected gastric cancer patients. The aim of this systematic review was to investigate the prognostic role of blood cell ratios in patients with gastric cancer undergoing surgery in a curative attempt. A systematic literature search in MEDLINE (via PubMed), CENTRAL, and Web of Science was performed. Information on survival and cut-off values from all studies investigating any blood cell ratio in resected gastric cancer patients were extracted. Prognostic significance and optimal cut-off values were calculated by meta-analyses and a summary of the receiver operating characteristic. From 2831 articles, 65 studies investigated six different blood cell ratios (prognostic nutritional index (PNI), lymphocyte to monocyte ratio (LMR), systemic immune-inflammation index (SII), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR)). There was a significant association for the PNI and NLR with overall survival and disease-free survival and for LMR and NLR with 5-year survival. The used cut-off values had high heterogeneity. The available literature is flawed by the use of different cut-off values hampering evidence-based patient treatment and counselling. This article provides optimal cut-off values recommendations for future research.