Guideline appraisal with AGREE II: online survey of the potential influence of AGREE II items on overall assessment of guideline quality and recommendation for use.

BACKGROUND: The AGREE II instrument is the most commonly used guideline appraisal tool. It includes 23 appraisal criteria (items) organized within six domains. AGREE II also includes two overall assessments (overall guideline quality, recommendation for use). Our aim was to investigate how strongly the 23 AGREE II items influence the two overall assessments. METHODS: An online survey of authors of publications on guideline appraisals with AGREE II and guideline users from a German scientific network was conducted between 10th February 2015 and 30th March 2015. Participants were asked to rate the influence of the AGREE II items on a Likert scale (0 = no influence to 5 = very strong influence). The frequencies of responses and their dispersion were presented descriptively. RESULTS: Fifty-eight of the 376 persons contacted (15.4%) participated in the survey and the data of the 51 respondents with prior knowledge of AGREE II were analysed. Items 7-12 of Domain 3 (rigour of development) and both items of Domain 6 (editorial independence) had the strongest influence on the two overall assessments. In addition, Items 15-17 (clarity of presentation) had a strong influence on the recommendation for use. Great variations were shown for the other items. The main limitation of the survey is the low response rate. CONCLUSIONS: In guideline appraisals using AGREE II, items representing rigour of guideline development and editorial independence seem to have the strongest influence on the two overall assessments. In order to ensure a transparent approach to reaching the overall assessments, we suggest the inclusion of a recommendation in the AGREE II user manual on how to consider item and domain scores. For instance, the manual could include an a-priori weighting of those items and domains that should have the strongest influence on the two overall assessments. The relevance of these assessments within AGREE II could thereby be further specified.

NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

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<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 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 × 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 system and 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.

Single-incision versus standard multi-incision laparoscopic colectomy in patients with malignant or benign colonic disease: a systematic review, meta-analysis and assessment of the evidence.

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.

Approaches to assessing the benefits and harms of medical devices for application in surgery.

BACKGROUND: 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. PURPOSE: 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. CONCLUSIONS: 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.

The single-incision laparoscopic surgery technique has questionable advantages in colorectal surgery.

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.

Guideline appraisal with AGREE II: Systematic review of the current evidence on how users handle the 2 overall assessments.

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.

Information on new drugs at market entry: retrospective analysis of health technology assessment reports versus regulatory reports, journal publications, and registry reports.

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.

Posttraumatic stress disorder and not depression is associated with shorter leukocyte telomere length: findings from 3,000 participants in the population-based KORA F4 study.

BACKGROUND: A 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. METHODS: Data 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. RESULTS: The 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. CONCLUSIONS: Participants 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.