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Background:Laparoscopic procedures have increasingly been accepted as standard in surgical treatment of benign and malignant entities, resulting in a continuous evolution of operative techniques. Since one of the aims in laparoscopic colorectal surgery is to reduce access trauma, one possible way is to further reduce the surgical site by the single-incision laparoscopic surgery technique (SLS). One of the main criticisms concerning the use of SLS is its questionable benefit combined with its technical demands for the surgeon. These questions were addressed by comparing SLS versus conventional laparoscopic multitrocar surgery (LMS) in benign and malignant conditions with respect to technical operative parameters and early postoperative outcome of the patients.Methods:Between 2010 and 2013, we performed SLS for colorectal disease. Of the 111 patients who underwent colorectal resection, 47 patients were operated by SLS and 31 using the LMS technique. The collected data for our patients were compared according to operating time, postoperative morbidity and mortality, pain score numeric rating scale on day 1 and day 5 postoperatively and postoperative hospital stay. To complement the pain scores, the required pain medication for adequate pain relief on these days was given.Results:There was no significant difference in age, BMI or sex ratio between the two groups. The intraoperative and early postoperative course was comparable as well. Postoperative hospital stay was the only parameter with a significant difference, showing an advantage for SLS.Conclusion:SLS is a feasible surgical method and a technical option in laparoscopic colorectal surgery. However, we were not able to identify substantial advantages of SLS that would favor this technique.

For the calculation of relative measures such as risk ratio (RR) and odds ratio (OR) in a single study, additional approaches are required for the case of zero events. In the case of zero events in one treatment arm, the Peto odds ratio (POR) can be calculated without continuity correction, and is currently the relative effect estimation method of choice for binary data with rare events. The aim of this simulation study is a variegated comparison of the estimated OR and estimated POR with the true OR in a single study with two parallel groups without confounders in data situations where the POR is currently recommended. This comparison was performed by means of several performance measures, that is the coverage, confidence interval (CI) width, mean squared error (MSE), and mean percentage error (MPE). We demonstrated that the estimator for the POR does not outperform the estimator for the OR for all the performance measures investigated. In the case of rare events, small treatment effects and similar group sizes, we demonstrated that the estimator for the POR performed better than the estimator for the OR only regarding the coverage and MPE, but not the CI width and MSE. For larger effects and unbalanced group size ratios, the coverage and MPE of the estimator for the POR were inappropriate. As in practice the true effect is unknown, the POR method should be applied only with the utmost caution.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P-6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 3 x 10-5), with combined stages 1 and 2 genomewide significance of P=5.6 x 10-10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous systemand relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Meta-analysis has generally been accepted as a fundamental tool for combining effect estimates from several studies. For binary studies with rare events, the Peto odds ratio (POR) method has become the relative effect estimator of choice. However, the POR leads to biased estimates for the OR when treatment effects are large or the group size ratio is not balanced. The aim of this work is to derive the limit of the POR estimator for increasing sample size, to investigate whether the POR limit is equal to the true OR and, if this is not the case, in which situations the POR limit is sufficiently close to the OR. It was found that the derived limit of the expected POR is not equivalent to the OR, because it depends on the group size ratio. Thus, the POR represents a different effect measure. We investigated in which situations the POR is reasonably close to the OR and found that this depends only slightly on the baseline risk within the range (0.001; 0.1) yet substantially on the group size ratio and the effect size itself. We derived the maximum effect size of the POR for different group size ratios and tolerated amounts of bias, for which the POR method results in an acceptable estimator of the OR. We conclude that the limit of the expected POR can be regarded as a new effect measure, which can be used in the presented situations as a valid estimate of the true OR.

Introduction The Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument is the most commonly used guideline appraisal tool. It includes 23 appraisal criteria (items) organized within 6 domains and 2 overall assessments (1. overall guideline quality; 2. recommendation for use). The aim of this systematic review was twofold. Firstly, to investigate how often AGREE II users conduct the 2 overall assessments. Secondly, to investigate the influence of the 6 domain scores on each of the 2 overall assessments. Materials and methods A systematic bibliographic search was conducted for publications reporting guideline appraisals with AGREE II. The impact of the 6 domain scores on the overall assessment of guideline quality was examined using a multiple linear regression model. Their impact on the recommendation for use (possible answers: “yes”, “yes, with modifications”, “no”) was examined using a multinomial regression model. Results 118 relevant publications including 1453 guidelines were identified. 77.1% of the publications reported results for at least one overall assessment, but only 32.2% reported results for both overall assessments. The results of the regression analyses showed a statistically significant influence of all domains on overall guideline quality, with Domain 3 (rigour of development) having the strongest influence. For the recommendation for use, the results showed a significant influence of Domains 3 to 5 (“yes” vs. “no”) and Domains 3 and 5 (“yes, with modifications” vs. “no”). Conclusions The 2 overall assessments of AGREE II are underreported by guideline assessors. Domains 3 and 5 have the strongest influence on the results of the 2 overall assessments, while the other domains have a varying influence. Within a normative approach, our findings could be used as guidance for weighting individual domains in AGREE II to make the overall assessments more objective. Alternatively, a stronger content analysis of the individual domains could clarify their importance in terms of guideline quality. Moreover, AGREE II should require users to transparently present how they conducted the assessments.

Background Single-incision laparoscopic colectomy (SILC) requires only one umbilical port site and (depending on technique) a specimen extraction site. The aim of this study was the assessment of the available evidence for the comparison of SILC to conventional multi-port laparoscopic colectomy (MLC) in adult patients, in whom elective colectomy is indicated because of malignant or benign disease. First, previous meta-analyses on this topic were assessed. Secondly, a systematic review and meta-analysis of randomised controlled trials, was performed. Methods Electronic literature searches (CENTRAL, MEDLINE and EMBASE; up to March 2016) were performed. Additionally, we searched clinical trials registries and abstracts from surgical society meetings. For meta-analysis, risk ratios (RR) or mean differences (MD) with 95 % confidence intervals were calculated and pooled. The quality of previous meta-analyses was evaluated against established criteria (AMSTAR) and their reported results were investigated for consistency. Results We identified 6 previous meta-analyses of mostly low methodological quality (AMSTAR total score: 2 − 5 out of 11 items). To fill the evidence gaps, all these meta-analyses had included non-randomised studies, but usually without assessing their risk of bias. In our systematic review and meta-analysis of randomised controlled trials exclusively, we included two randomised controlled trials with a total of 82 colorectal cancer patients. There was insufficient evidence to clarify whether SILC leads to less local complications (RR = 0.52, 95 % CI 0.14 − 1.94) or lower mortality (1 death per treatment group). Length of hospital stay was significantly shorter in the SILC group (MD = -1.20 days, 95 % CI -1.95 to -0.44). One of the two studies found postoperative pain intensity to be lower at the first day. We also identified 7 ongoing trials with a total sample size of over 1000 patients. Conclusion The currently available study results are too sparse to detect (or rule out) relevant differences between SILC and MLC. The quality of the current evidence is low, and the additional analysis of non-randomised data attempts, but does not solve this problem. SILC should still be considered as an experimental procedure, since the evidence of well-designed randomised controlled trials is too sparse to allow any recommendation.

For the calculation of relative measures such as risk ratio (RR) and odds ratio (OR) in a single study, additional approaches are required for the case of zero events. In the case of zero events in one treatment arm, the Peto odds ratio (POR) can be calculated without continuity correction, and is currently the relative effect estimation method of choice for binary data with rare events. The aim of this simulation study is a variegated comparison of the estimated OR and estimated POR with the true OR in a single study with two parallel groups without confounders in data situations where the POR is currently recommended. This comparison was performed by means of several performance measures, that is the coverage, confidence interval (CI) width, mean squared error (MSE), and mean percentage error (MPE). We demonstrated that the estimator for the POR does not outperform the estimator for the OR for all the performance measures investigated. In the case of rare events, small treatment effects and similar group sizes, we demonstrated that the estimator for the POR performed better than the estimator for the OR only regarding the coverage and MPE, but not the CI width and MSE. For larger effects and unbalanced group size ratios, the coverage and MPE of the estimator for the POR were inappropriate. As in practice the true effect is unknown, the POR method should be applied only with the utmost caution.

Background When a new drug becomes available, patients and doctors require information on its benefits and harms. In 2011, Germany introduced the early benefit assessment of new drugs through the act on the reform of the market for medicinal products (AMNOG). At market entry, the pharmaceutical company responsible must submit a standardised dossier containing all available evidence of the drug’s added benefit over an appropriate comparator treatment. The added benefit is mainly determined using patient relevant outcomes. The “dossier assessment” is generally performed by the Institute for Quality and Efficiency in Health Care (IQWiG) and then published online. It contains all relevant study information, including data from unpublished clinical study reports contained in the dossiers. The dossier assessment refers to the patient population for which the new drug is approved according to the summary of product characteristics. This patient population may comprise either the total populations investigated in the studies submitted to regulatory authorities in the drug approval process, or the specific subpopulations defined in the summary of product characteristics (“approved subpopulations”). Objective To determine the information gain from AMNOG documents compared with non-AMNOG documents for methods and results of studies available at market entry of new drugs. AMNOG documents comprise dossier assessments done by IQWiG and publicly available modules of company dossiers; non-AMNOG documents comprise conventional, publicly available sources—that is, European public assessment reports, journal publications, and registry reports. The analysis focused on the approved patient populations. Design Retrospective analysis. Data sources All dossier assessments conducted by IQWiG between 1 January 2011 and 28 February 2013 in which the dossiers contained suitable studies allowing for a full early benefit assessment. We also considered all European public assessment reports, journal publications, and registry reports referring to these studies and included in the dossiers. Data analysis We assessed reporting quality for each study and each available document for eight methods and 11 results items (three baseline characteristics and eight patient relevant outcomes), and dichotomised them as “completely reported” or “incompletely reported (including items not reported at all).” For each document type we calculated the proportion of items with complete reporting for methods and results, for each item and overall, and compared the findings. Results 15 out of 27 dossiers were eligible for inclusion and contained 22 studies. The 15 dossier assessments contained 28 individual assessments of 15 total study populations and 13 approved subpopulations. European public assessment reports were available for all drugs. Journal publications were available for 14 out of 15 drugs and 21 out of 22 studies. A registry report in ClinicalTrials.gov was available for all drugs and studies; however, only 11 contained results. In the analysis of total study populations, the AMNOG documents reached the highest grade of completeness, with about 90% of methods and results items completely reported. In non-AMNOG documents, the rate was 75% for methods and 52% for results items; journal publications achieved the best rates, followed by European public assessment reports and registry reports. The analysis of approved subpopulations showed poorer complete reporting of results items, particularly in non-AMNOG documents (non-AMNOG versus AMNOG: 11% v 71% for overall results items and 5% v 70% for patient relevant outcomes). The main limitation of our analysis is the small sample size. Conclusion Conventional, publicly available sources provide insufficient information on new drugs, especially on patient relevant outcomes in approved subpopulations. This type of information is largely available in AMNOG documents, albeit only partly in English. The AMNOG approach could be used internationally to develop a comprehensive publication model for clinical studies and thus represents a key open access measure.

Meta-analysis has generally been accepted as a fundamental tool for combining effect estimates from several studies. For binary studies with rare events, the Peto odds ratio (POR) method has become the relative effect estimator of choice. However, the POR leads to biased estimates for the OR when treatment effects are large or the group size ratio is not balanced. The aim of this work is to derive the limit of the POR estimator for increasing sample size, to investigate whether the POR limit is equal to the true OR and, if this is not the case, in which situations the POR limit is sufficiently close to the OR. It was found that the derived limit of the expected POR is not equivalent to the OR, because it depends on the group size ratio. Thus, the POR represents a different effect measure. We investigated in which situations the POR is reasonably close to the OR and found that this depends only slightly on the baseline risk within the range (0.001; 0.1) yet substantially on the group size ratio and the effect size itself. We derived the maximum effect size of the POR for different group size ratios and tolerated amounts of bias, for which the POR method results in an acceptable estimator of the OR. We conclude that the limit of the expected POR can be regarded as a new effect measure, which can be used in the presented situations as a valid estimate of the true OR.

The surgical community and the medical device industry enjoy a fruitful cooperation for the benefit of patients, but during the last years several high-risk products have led to problems and scandals, thus highlighting the need for reforms in European CE marking requirements. In October 2013, the European Parliament voted on a draft regulation on medical devices that intends to replace the current directives in 2014. This article offers guidance to surgeons on how to select and assess medical devices for clinical use. Examples include artificial sphincters, surgical meshes, as well as single-incision and robot-assisted surgery. It is important that surgeons have a basic understanding of the requirements for CE marking of new medical devices. Because device performance rather than effectiveness is required for European market entry, surgeons (and their patients) are often left with the burden of using potentially harmful devices. In addition, potential problems concerning the safety or effectiveness of approved devices are concealed by the lack of data transparency. Because regulatory reforms were blocked at the European level, many member states will now seek other ways of restricting the use of medical devices with unknown effectiveness. One interesting model in this regard is to link the reimbursement of new medical devices to the conduct of clinical trials. Surgeons should develop a structured multidisciplinary approach to innovation management in their hospitals before using a new high-risk device. The key question is how to strike the right balance between innovation and safety.

BackgroundA link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD.MethodsData are derived from the population-based KORA F4 study (2006-2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed.ResultsThe multiple model revealed a significant association between partial PTSD and TL (beta = -0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = -0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations.ConclusionsParticipants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.

IntroductionTreatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood–brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by theABCB1gene.Materials and methodsWe aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encodingABCB1gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the humanABCB1gene (Abcb1abdouble knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case–control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selectedABCB1gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy.Resultsi) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood–brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found.DiscussionThis is the first study demonstrating that individualABCB1gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Background The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. Objective To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. Methods We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10 −5 in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. Results Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10 −5 : The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36–0.61; P = 6.9 × 10 −9 ). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25–1.69; P = 8.5 × 10 −7 ). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. Conclusions In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.