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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.

Background: Evidence-based clinical practice is challenging in all fields, but poses special barriers in the field of rare diseases. The present paper summarises the main barriers faced by clinical research in rare diseases, and highlights opportunities for improvement., Methods: Systematic literature searches without meta-analyses and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project., Results: Barriers specific to rare diseases comprise the difficulty to recruit participants because of rarity, scattering of patients, limited knowledge on natural history of diseases, difficulties to achieve accurate diagnosis and identify patients in health information systems, and difficulties choosing clinically relevant outcomes., Conclusions: Evidence-based clinical practice for rare diseases should start by collecting clinical data in databases and registries; defining measurable patient-centred outcomes; and selecting appropriate study designs adapted to small study populations. Rare diseases constitute one of the most paradigmatic fields in which multi-stakeholder engagement, especially from patients, is needed for success. Clinical research infrastructures and expertise networks offer opportunities for establishing evidence-based clinical practice within rare diseases.

Background: Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices., Methods: Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project., Results: In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency., Conclusions: The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices.

Background: Postoperative respiratory complications (PRCs) are associated with significant morbidity, mortality, and hospital costs. Obstructive sleep apnea (OSA), often undiagnosed in the surgical population, may be a contributing factor. Thus, we aimed to develop and validate a score for preoperative prediction of OSA (SPOSA) based on data available in electronic medical records preoperatively., Methods: OSA was defined as the occurrence of an OSA diagnostic code preceded by a polysomnography procedure. A priori defined variables were analyzed by multivariable logistic regression analysis to develop our score. Score validity was assessed by investigating the score's ability to predict non-invasive ventilation. We then assessed the effect of high OSA risk, as defined by SPOSA, on PRCs within seven postoperative days and in-hospital mortality., Results: A total of 108,781 surgical patients at Partners HealthCare hospitals (2007-2014) were studied. Predictors of OSA included BMI >25 kg*m -2 and comorbidities, including pulmonary hypertension, hypertension, and diabetes. The score yielded an area under the curve of 0.82. Non-invasive ventilation was significantly associated with high OSA risk (OR 1.44, 95% CI 1.22-1.69). Using a dichotomized endpoint, 26,968 (24.8%) patients were identified as high risk for OSA and 7.9% of these patients experienced PRCs. OSA risk was significantly associated with PRCs (OR 1.30, 95% CI 1.19-1.43)., Conclusion: SPOSA identifies patients at high risk for OSA using electronic medical record-derived data. High risk of OSA is associated with the occurrence of PRCs.

Background: Patients admitted to intensive care units (ICU) are often treated with intravenous (IV) vasopressors. Persistent hypotension and dependence on IV vasopressors in otherwise resuscitated patients lead to delay in discharge from ICU. Midodrine is an oral alpha-1 adrenergic agonist approved for treatment of symptomatic orthostatic hypotension. This trial aims to evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV vasopressor treatment, and allow earlier discharge from ICU and hospital., Methods: The MIDAS trial is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial being conducted in the USA and Australia. We are targeting 120 patients. Adult patients admitted to the ICU who are resuscitated and otherwise stable on low dose IV vasopressors for at least 24 h will be considered for recruitment. Participants will be randomized to receive midodrine (20 mg) or placebo three times a day, in addition to standard care. The primary outcome is time (hours) from initiation of midodrine or placebo to discontinuation of IV vasopressors. Secondary outcomes include time (hours) from ICU admission to discharge readiness, ICU length of stay (LOS) (days), hospital LOS (days), rates of ICU readmission, and rates of adverse events related to midodrine administration., Discussion: Midodrine is approved by the Food and Drug Administration (FDA) for the treatment of symptomatic orthostatic hypotension. In August 2010, FDA proposed to withdraw approval of midodrine because of lack of studies that verify the clinical benefit of the drug. We obtained Investigational New Drug (IND 113,330) approval to study its effects in critically ill patients who require IV vasopressors but are otherwise ready for discharge from the ICU. A pilot observational study in a cohort of surgical ICU patients showed that the rate of decline in vasopressor requirements increased after initiation of midodrine treatment. We hypothesize that midodrine administration is effective to wean IV vasopressors and shorten ICU and hospital LOS. This trial may have significant implications on lowering costs of hospital care and obtaining FDA approval for new indications for midodrine., Trial Registration: This study has been registered at clinicaltrials.gov on 02/09/2012 (NCT01531959).

The rise of electronic medical records has led to a proliferation of large observational studies that examine the perioperative period. In contrast to randomized controlled trials, these studies have the ability to provide quick, cheap and easily obtainable information on a variety of patients and are reflective of everyday clinical practice. However, it is important to note that the data used in these studies are often generated for billing or documentation purposes such as insurance claims or the electronic anesthetic record. The reliance on codes to define diagnoses in these studies may lead to false inferences or conclusions. Researchers should specify the code assignment process and be aware of potential error sources when undertaking studies using secondary data sources. While misclassification may be a short-coming of using large databases, it does not prevent their use in conducting meaningful effectiveness research that has direct consequences on medical decision making.

Background: The transcatheter aortic valve implantation (TAVI), a minimally invasive surgical procedure to treat patients with severe symptomatic aortic stenosis, showed a rapid diffusion in Germany compared to the international level. The aim of this study is to identify and analyze factors affecting the implementation and diffusion of the procedure in hospitals using a qualitative application of the diffusion of innovations theory., Methods: We conducted problem-centered interviews with cardiologists and cardiac surgeons working in German hospitals. The multi-level model "diffusion of innovations in health services organizations" developed by Greenhalgh et al. was used to guide the research. Data was analyzed using content and a thematic analysis., Results: Among the ten participants who were interviewed, we found both barriers and facilitators related to the innovation itself, system readiness and antecedents, communication and influence, and the outer context. Key issues were the collaboration between cardiologists and cardiac surgeons, reimbursement policies, requirements needed to conduct the procedure, and medical advantages of the method., Conclusions: The findings show that there are multiple factors influencing the diffusion of TAVI that go beyond the reimbursement and cost issues. The diffusion of innovations model proved to be helpful in understanding the different aspects of the uptake of the procedure. A central theme that affected the implementation of TAVI was the collaboration and competition between involved medical departments: cardiology and cardiac surgery. Against this background, it seems especially important to moderate and coordinate the cooperation of the different medical disciplines.

Background: Exploring health-related information needs is necessary to better tailor information. However, there is a lack of systematic knowledge on how and in which groups information needs has been assessed, and which information needs have been identified. We aimed to assess the methodology of studies used to assess information needs, as well as the topics and extent of health-related information needs and associated factors in Germany., Methods: A systematic search was performed in Medline, Embase, Psycinfo, and all databases of the Cochrane Library. All studies investigating health-related information needs in patients, relatives, and the general population in Germany that were published between 2000 and 2012 in German or English were included. Descriptive content analysis was based on predefined categories., Results: We identified 19 studies. Most studies addressed cancer or rheumatic disease. Methods used were highly heterogeneous. Apart from common topics such as treatment, diagnosis, prevention and health promotion, etiology and prognosis, high interest ratings were also found in more specific topics such as complementary and alternative medicine or nutrition. Information needs were notable in all surveyed patient groups, relatives, and samples of the general population. Younger age, shorter duration of illness, poorer health status and higher anxiety and depression scores appeared to be associated with higher information needs., Conclusion: Knowledge about information needs is still scarce. Assuming the importance of comprehensive information to enable people to participate in health-related decisions, further systematic research is required.

Background: Several systematic reviews (SRs) of randomised controlled trials (RCTs) comparing laparoscopic versus open appendectomy have been published, but there has been no overview of SRs of these two interventions. This overview (review of review) aims to summarise the results of such SRs in order to provide the most up to date evidence, and to highlight discordant results., Methods: Medline, Embase, Cinahl, the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects were searched for SRs published up to August 2014. Study selection and quality assessment using the AMSTAR tool were carried out independently by two reviewers. We used standardised forms to extract data that were analysed descriptively., Results: Nine SRs met the inclusion criteria. All were of moderate to high quality. The number of randomized controlled trials (RCTs) they included ranged from eight to 67. The duration of surgery pooled by eight reviews was 7.6 to 18.3 minutes shorter using the open approach. Pain scores on the first postoperative day were lower after laparoscopic appendectomy in two out of three reviews. The risk of abdominal abscesses was higher for laparoscopic surgery in half of six meta-analyses. The occurrence of wound infections pooled by all reviews was lower after laparoscopic appendectomy. One review showed no difference in mortality. The laparoscopic approach shortened hospital stay from 0.16 to 1.13 days in seven out of eight meta-analyses, though the strength of the evidence was affected by strong heterogeneity., Conclusion: Laparoscopic and open appendectomy are both safe and effective procedures for the treatment of acute appendicitis. This overview shows discordant results with respect to the magnitude of the effect but not to the direction of the effect. The evidence from this overview may prove useful for the development of clinical guidelines and protocols.

Background: This multi-centre, prospective, randomized, double-blind, placebo-controlled study was designed to test the hypotheses that parecoxib improves patients' postoperative analgesia without increasing surgical blood loss following radical open prostatectomy., Methods: 105 patients (64 ± 7 years old) were randomized to receive either parecoxib or placebo with concurrent morphine patient controlled analgesia. Cumulative opioid consumption (primary objective) and the overall benefit of analgesia score (OBAS), the modified brief pain inventory short form (m-BPI-sf), the opioid-related symptom distress scale (OR-SDS), and perioperative blood loss (secondary objectives) were assessed., Results: In each group 48 patients received the study medication for 48 hours postoperatively. Parecoxib significantly reduced cumulative opioid consumption by 24% (43 ± 24.1 mg versus 57 ± 28 mg, mean ± SD, p=0.02), translating into improved benefit of analgesia (OBAS: 2(0/4) versus 3(1/5.25), p=0.01), pain severity (m-BPI-sf: 1(1/2) versus 2(2/3), p < 0.01) and pain interference (m-BPI-sf: 1(0/1) versus 1(1/3), p=0.001), as well as reduced opioid-related side effects (OR-SDS score: 0.3(0.075/0.51) versus 0.4(0.2/0.83), p=0.03). Blood loss was significantly higher at 24 hours following surgery in the parecoxib group (4.3 g⋅dL(-1) (3.6/4.9) versus (3.2 g⋅dL(-1) (2.4/4.95), p=0.02)., Conclusions: Following major abdominal surgery, parecoxib significantly improves patients' perceived analgesia. Parecoxib may however increase perioperative blood loss. Further trials are needed to evaluate the effects of selective cyclooxygenase-2 inhibitors on blood loss., Trial Registration: ClinicalTrials.gov Identifier: NCT00346268.

Background: To ensure that clinical practice guidelines (CPGs) form a sound basis for decision-making in health care, it is necessary to be able to reliably assess and ensure their quality. This results in the need to assess the content of guidelines systematically, particularly with regard to the validity of their recommendations.The aim of the present analysis was to determine the suitability and applicability of frequently used assessment tools for evidence syntheses with regard to the assessment of guideline content., Methods: We conducted a systematic comparison and analysis of established tools for the assessment of evidence syntheses (guidelines, systematic reviews, health technology assessments). The tools analyzed were: ADAPTE, AGREE II, AMSTAR, GLIA and the INAHTA checklist. We analyzed methodological steps related to the assessment of the reliability and validity of guideline recommendations. Data were extracted and analyzed by two persons independently of one another., Results: Widely used tools for the methodological assessment of evidence syntheses are not suitable for a comprehensive content-related assessment. They remain mostly at the level of assessment of the documentation of processes. Some tools assess selected content-related aspects, but operationalization is either unspecific or lacking., Conclusion: None of the tools analyzed enables the structured and comprehensive assessment of the content of guideline recommendations with special regard to their reliability and validity. All tools contribute towards the judicious use of evidence syntheses by supporting their systematic development or assessment. However, further progress is needed, particularly with regard to the assessment of content quality. This includes comprehensive operationalization and documentation of the assessment process to ensure reliability and validity, and therefore to enable the effective use of trustworthy guidelines in the health care system.

Background: There is a lack of an instrument to evaluate systematic reviews of non-randomized studies in epidemiological research. The Assessment of Multiple Systematic Reviews (AMSTAR) is widely used to evaluate the scientific quality of systematic reviews, but it has not been validated for SRs of non-randomized studies. The objective of this paper is to report our experience in applying AMSTAR to systematic reviews of non-randomized studies in terms of applicability, reliability and feasibility. Thus, we applied AMSTAR to a recently published review of 32 systematic reviews of non-randomized studies investigating the hospital volume-outcome relationship in surgery., Results: The inter-rater reliability was high (0.76), albeit items 8 (scientific quality used in formulating conclusions), 9 (appropriate method to combine studies), and 11 (conflicts of interest) scored moderate (≤0.58). However, there was a high heterogeneity between the two pairs of reviewers. In terms of feasibility, AMSTAR proved easy to apply to systematic reviews of non-randomized studies, each review taking 5-10 minutes to complete. We faced problems in applying three items, mainly related to scientific quality of the included studies., Conclusions: AMSTAR showed good psychometric properties, comparable to prior findings in systematic reviews of randomized controlled trials. AMSTAR can be applied to systematic reviews of non-randomized studies, although there are some item specific issues users should be aware of. Revisions and extensions of AMSTAR might be helpful.

Background: Oral medication for patients with type 2 diabetes mellitus plays an important role in diabetes care and is associated with a high level self-care behavior and self-management. However, poor adherence to diabetes treatment is common which causes severe health complications and increased mortality. Barriers to adherence may consist of complex treatment regimens often along with long-term multi-therapies, side effects due to the medication as well as insufficient, incomprehensible or confusing information or instructions provided by the health care provider. Multidisciplinary approaches can support adherence success and can enable a more effective management of diabetes care. One approach in diabetes care can be the involvement of a pharmacist. The aim was to analyze the effectiveness of adherence-enhancing pharmacist interventions for oral medication in type 2 diabetes mellitus., Methods: A systematic review of randomized controlled trials. The study quality was assessed with the Cochrane risk of bias tool., Results: Of 491 hits, six publications were included. Two studies mainly examining educational interventions showed a significant improvement in adherence. Moreover, the quality of the included studies was deficient., Conclusion: Although pharmacist interventions might potentially improve adherence to type 2 diabetes mellitus medication, high-quality studies are needed to assess effectiveness.