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ObjectiveTo provide insights into women’s attitudes towards a human papillomavirus (HPV)-based cervical cancer screening strategy.Data sourcesMedline, Web of Science Core Collection, Cochrane Library, PsycINFO, CINAHL and ClinicalTrials.gov were systematically searched for published and ongoing studies (last search conducted in August 2021).Methods of study selectionThe search identified 3162 references. Qualitative and quantitative studies dealing with women’s attitudes towards, and acceptance of, an HPV-based cervical cancer screening strategy in Western healthcare systems were included. For data analysis, thematic analysis was used and synthesised findings were presented descriptively.Tabulation, integration, and resultsTwelve studies (including 9928 women) from USA, Canada, UK and Australia met the inclusion criteria. Women’s attitudes towards HPV-based screening strategies were mainly affected by the understanding of (i) the personal risk of an HPV infection, (ii) the implication of a positive finding and (iii) the overall screening purpose. Women who considered their personal risk of HPV to be low and women who feared negative implications of a positive finding were more likely to express negative attitudes, whereas positive attitudes were particularly expressed by women understanding the screening purpose. Overall acceptance of an HPV-based screening strategy ranged between 13% and 84%.ConclusionThis systematic review provides insights into the attitudes towards HPV-based cervical cancer screening and its acceptability based on studies conducted with women from USA, Canada, UK and Australia. This knowledge is essential for the development of education and information strategies to support the implementation of HPV-based cervical cancer screening.Systematic review registrationPROSPERO (CRD42020178957).

Zusammenfassung. Kürzlich hat ein Cochrane-Review das aktuelle Wissen über die Auswirkungen von Massnahmen zur Unterstützung depressiver Patienten bei der Rückkehr zur Arbeit zusammengefasst. Die Evidenzbasis – 45 randomisierte, kontrollierte Studien – war umfangreich und führte häufig zu einer mittelgradigen oder sogar hohen Robustheit der Evidenz. Für die Endpunkte «Rückkehr zur Arbeit» sowie «Depressive Symptome» zeigte die Integration von Massnahmen am Arbeitsplatz kombiniert mit klinisch-psychologischer Behandlung den grössten Nutzen. Verglichen mit der üblichen Versorgung könnte dies bei depressiven Patienten zu einer Senkung krankheitsbedingter Absenzen um 25 Tage pro Jahr führen. Für Hausärzte lohnt es sich, in die Organisation einer verbesserten Versorgung mit psychologischer Behandlung in Verbindung mit Massnahmen zur Rückkehr an den Arbeitsplatz zu investieren. Einfache Massnahmen am Arbeitsplatz, wie zum Beispiel die Verkürzung der Arbeitszeit oder die Verschlankung der Arbeitsanforderungen, können helfen, wenn sie in die medizinische Versorgung integriert werden. Die Anpassungen am Arbeitsplatz werden in der Regel durch den Vorgesetzten oder die Personalabteilung realisiert. Ein gutes Verhältnis zum Vorgesetzten ist daher unerlässlich. Es gibt keine Hinweise, dass antidepressive Medikamente die Zeit bis zur Rückkehr an den Arbeitsplatz verkürzen.

The National Institute for Health and Care Excellence (NICE) invited Alimera Sciences, the company manufacturing fluocinolone acetonide intravitreal implant (FAc) 0.19 mg (tradename ILUVIEN), to submit evidence on the clinical and cost-effectiveness of FAc for treating recurrent non-infectious uveitis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre + , was commissioned to act as the independent Evidence Review Group (ERG). This paper contains a summary of the clinical and cost-effectiveness evidence submitted by the company, the ERG's critique on the submitted evidence, and the guidance issued by the NICE Appraisal Committee (AC). The company submission (CS) was mainly informed by the PSV-FAI-001 trial in which FAc was compared with (limited) current practice [(L)CP], which was not considered to be representative of UK clinical practice by the ERG. There was no comparison of FAc to any treatment listed in the final scope, and especially to the dexamethasone intravitreal implant (dexamethasone), which was considered to be a relevant comparator by the AC. The primary outcome of the PSV-FAI-001 was recurrence of uveitis in the treated eye. Most of the events for the primary outcome were imputed during the PSV-FAI-001 trial, which probably led to an overestimation of the number of recurrences of disease, and a biased estimate of the relative effectiveness of FAc versus (L)CP. Finally, the place of FAc in the treatment pathway was not clearly defined by the company. Substantial uncertainty surrounded the cost-effectiveness results due to the shortcomings of the clinical evidence. Additionally, the quality of life of patients was not measured during the PSV-FAI-001 trial and long-term effectiveness data of FAc were lacking. The ERG adjusted several issues identified in the CS and added dexamethasone as a comparator in the decision analytic model. The ERG presented multiple analyses as base-cases because several elements of the assessment remained uncertain. The fully incremental ERG results ranged from dexamethasone (extendedly) dominating FAc (when assuming a hazard ratio of 1 or 0.7 for dexamethasone versus FAc) to an incremental cost-effectiveness ratio (ICER) of 30,153 pound per quality-adjusted life-year (QALY) gained for FAc versus (L)CP [when assuming a hazard ratio of 0.456 for dexamethasone versus (L)CP]. The ICER of FAc versus (L)CP ranged from 12,325 pound to 30,153 pound per QALY gained. After a second AC meeting where alternative company scenarios comparing FAc with dexamethasone were considered by the AC, the AC concluded that "the results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an ICER of 29,461 pound per QALY gained, and most of the ICERs were below 20,000 pound per QALY gained". Therefore, the AC recommended FAc as a cost-effective use of National Health Service (NHS) resources for treating recurrent non-infectious uveitis affecting the posterior segment of the eye in the final TA590 guidance (published July 2019).

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose Using evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patientʼs quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal extent of surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy if required. An evidence-based optimal use of different therapeutic modalities should improve the survival rates and quality of life of these patients. This S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources included reviews of evidence, which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one part of the guideline. Identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then subsequently modified during structured consensus conferences and/or additionally amended online using the DELPHI method, with consent between members achieved online. The guideline report is freely available online. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of endometrial cancer including precancers and early endometrial cancer as well as recommendations on palliative medicine, psycho-oncology, rehabilitation, patient information and healthcare facilities to treat endometrial cancer. The management of precancers of early endometrial precancerous conditions including fertility-preserving strategies is presented. The concept used for surgical primary therapy of endometrial cancer is described. Radiotherapy and adjuvant medical therapy to treat endometrial cancer and uterine carcinosarcomas are described. Recommendations are given for the follow-up care of endometrial cancer, recurrence and metastasis. Palliative medicine, psycho-oncology including psychosocial care, and patient information and rehabilitation are presented. Finally, the care algorithm and quality assurance steps for the diagnosis, therapy and follow-up of patients with endometrial cancer are outlined.

Background There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure. Objectives To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet®; Dova Pharmaceuticals, Durham, NC, USA) and lusutrombopag (Mulpleta®; Shionogi Inc., London, UK), in addition to established clinical management compared with established clinical management (no thrombopoietin receptor agonist) in the licensed populations. Design Systematic review and cost-effectiveness analysis. Setting Secondary care. Participants Severe thrombocytopenia (platelet count of Interventions Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is Main outcome measures Risk of platelet transfusion and rescue therapy or risk of rescue therapy only. Review methods Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019. Economic evaluation Model-based cost-effectiveness analysis. Results From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective. Limitations Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag. Conclusions Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost. Future work A head-to-head trial is warranted. Study registration This study is registered as PROSPERO CRD42019125311. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 51. See the NIHR Journals Library website for further project information.

Objective Asthma is associated with bronchial hyperresponsiveness, assessed by bronchial provocation tests such as the mannitol test. We aimed to assess the data on sensitivity and specificity of the mannitol test in diagnosing asthma. Data sources We searched electronically the Medline, Embase and Central databases from 1997 to 2019. Study selection Inclusion criteria were the assessment of the validity of the mannitol test. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). Data were extracted according to a prespecified list and analysed qualitatively. Results A total of 27 studies (4589 individuals, age 6n85 years, cross-sectional [n = 18] and case-controlled [n = 9] study design) were included. Overall sensitivity and specificity ranged from 8% (95% confidence interval [CI] 1n27) to 100% (95% CI 93n100) and 75% (95% CI 67n82) to 100% (95% CI 85n100). Excluding case-controlled design, studies conducted in a clinical setting showed a range from 19% (95% CI 14n27) to 91% (95% CI 59n100) for sensitivity and from 75% (95% CI 67n82) to 100% (95% CI 80n100) for specificity. Heterogeneity was high owing to differences in the populations examined and the methods used. Conclusions Studies on the accuracy of the mannitol test were heterogeneous. Overall specificity was higher than sensitivity and therefore the mannitol test seems to be a suitable diagnostic tool to confirm asthma. However, the high level of heterogeneity among the included studies makes a conclusive statement on the accuracy of the mannitol test difficult and further research is needed. As bronchial provocation tests can be especially useful in patients with an intermediate probability of asthma diagnosis, further studies are needed that include subjects with asthma symptoms but intermediate probability of asthma diagnosis.

Objectives\ud This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments (HTA) and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA).\ud Study Design and Setting\ud We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overiew of the domains and describe risk of bias and indirectness specifically.\ud Results\ud Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies.\ud Conclusions\ud Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

Objectives This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments (HTA) and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. Study Design and Setting We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Results Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. Conclusions Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. While several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

Background The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimerrs disease is inconclusive. Aims of the study We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is l20). Methods We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD m0.15, 95% CI m0.28 to m0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI m0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference m3.07, 95% CI m6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (g 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. Conclusions Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed. &nbsp.

PURPOSE: We aimed to assess the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis. METHODS: An international expert panel determined diagnoses and clinical management in patients with suspected large vessel vasculitis, with and without the results of (18)F-FDG PET, respectively. The accuracy of the clinical diagnosis and the resulting clinical management with and without the (18)F-FDG PET results were compared using logistic regression models. RESULTS: The analysis included 30 patients referred to a tertiary care centre with large vessel vasculitis and 31 controls. (18)F-FDG PET had an overall sensitivity of 73.3% [95% confidence interval (CI) 54.1-87.7%], a specificity of 83.9% (95% CI 66.3-94.5%), a positive predictive value of 81.5% (95% CI 61.9-93.7%) and a negative predictive value of 76.5% (95% CI 58.8-89.3%). The diagnostic accuracy of (18)F-FDG PET was higher in patients not receiving immunosuppressive drugs (93.3 vs 64.5%, p = 0.006). Taken in context with other available diagnostic modalities, the addition of (18)F-FDG PET increased the clinical diagnostic accuracy from 54.1 to 70.5% (p = 0.04). The addition of (18)F-FDG PET increased the number of indicated biopsies from 22 of 61 patients (36.1%) to 25 of 61 patients (41.0%) and changed the treatment recommendation in 8 of 30 patients (26.7%) not receiving immunosuppressive medication and in 7 of 31 patients (22.6%) receiving immunosuppressive medication. CONCLUSION: (18)F-FDG PET is a sensitive and specific imaging tool for large vessel vasculitis, especially when performed in patients not receiving immunosuppressive drugs. It increases the overall diagnostic accuracy and has an impact on the clinical management in a significant proportion of patients.

OBJECTIVES The aims of this study were to (a) identify and assess the quality of reporting of published cost-effectiveness studies of bariatric surgery, (b) assess their transferability to Switzerland, and (c) adapt transferable cost-effectiveness results to Switzerland. METHODS A systematic literature search was performed in Medline, Embase and other databases. Two reviewers independently undertook screening, extraction, assessment of reporting quality utilising the Consolidated Health Economic Evaluation Reporting Standards, transferability, adaptation of cost data and recalculation of cost-effectiveness results. Cost data were adapted in three steps: correction for different levels of resource utilisation, for different prices of healthcare services and for change in costs over time. RESULTS Fifteen studies fulfilled criteria for adaptation of cost data to Switzerland. Four out of fifteen adapted studies with a long time-horizon for patients with a body mass index (BMI) >35kg/m2 indicated bariatric surgery to be a cost-saving (dominant) approach compared with conventional treatment. Other studies for patients with BMI >35kg/m2 showed cost-effective results, with incremental cost-effectiveness ratios (ICERs) below CHF 50,000 per quality adjusted life-year (QALY) gained. Two studies assessed cost-effectiveness for patients with BMI

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patientʼs quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy where required. The evidence-based optimal use of different therapeutic modalities should improve survival rates and the quality of life of these patients. The S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources include reviews of evidence which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one area of the guideline. The identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then modified during structured consensus conferences and/or additionally amended online using the DELPHI method with consent being reached online. The guideline report is freely available online. Recommendations Part 1 of this short version of the guideline presents recommendations on epidemiology, screening, diagnosis and hereditary factors, The epidemiology of endometrial cancer and the risk factors for developing endomentrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer including the pathology of the cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer.

Objectives To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. Study design A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. Results We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Conclusion Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.

Importance Feedback interventions using routinely collected health data might reduce antibiotic use nationwide without requiring the substantial resources and structural efforts of other antibiotic stewardship programs. Objective To determine if quarterly antibiotic prescription feedback over 2 years reduces antibiotic use when implemented in a complex health care system. Design, Setting, and Participants Pragmatic randomized trial using routinely collected claims data on 2900 primary care physicians with the highest antibiotic prescription rates in Switzerland. Interventions Physicians were randomized to quarterly updated personalized antibiotic prescription feedback over 2 years (n = 1450) or usual care (n = 1450). Feedback was provided both by mail and online from October 2013 to October 2015 and was supported by an initial 1-time provision of evidence-based guidelines. Main Outcomes and Measures The primary outcome was the prescribed defined daily doses (DDD) of any antibiotic to any patient per 100 consultations in the first year analyzed by intention-to-treat. We further analyzed prescriptions of specific antibiotics, age groups, and sex for the first and second year to investigate persistency of effects over time. Results The 2900 physicians had 10 660 124 consultations over 2 years of follow-up, prescribed 1 175 780 packages of antibiotics with 10 290 182 DDD. Physicians receiving feedback prescribed the same amount of antibiotics to all patients in the first year (between-group difference, 0.81%; 95% CI, −2.56% to 4.30%; P = .64) and second year (between-group difference, −1.73%; 95% CI, −5.07% to 1.72%; P = .32) compared with the control group. Prescribing to children aged 6 to 18 years was −8.61% lower in the feedback than in the control group in the first year (95% CI, −14.87% to −1.90%; P = .01). This difference diminished in the second year (between-group difference, −4.10%; 95% CI, −10.78% to 3.07%; P = .25). Physicians receiving feedback prescribed fewer antibiotics to adults aged 19 to 65 years in the second year (between-group difference, −4.59%; 95% CI, −7.91% to −1.16%; P Conclusions and Relevance This nationwide antibiotic stewardship program with routine feedback on antibiotic prescribing was not associated with a change of antibiotic use. In older children, adolescents, and younger adults less antibiotics were prescribed, but not consistently over the entire intervention period. Trial Registration clinicaltrials.gov Identifier:NCT01773824

AIMS OF THE STUDY To assess the cost-effectiveness of primarily surgical treatment (PST) versus primarily conservative treatment (PCT) in adults with intermediate severity, acute or subacute, lumbar radicular syndrome due to intervertebral disc herniation. METHODS A decision analytic model from healthcare system and societal perspectives was used to compare outcomes and costs of PST with those of PCT (physiotherapy, epidural injection and medication). Treatment pathways and quality of life were obtained from published clinical trials. Costs were derived from Swiss health insurance claims data. Swiss clinical experts provided information on use of medication and physiotherapy. The main outcome of interest was incremental cost per quality-adjusted-life-year (QALY) gained over a period of 2 years. Costs and QALYs gained were discounted from the second year, at a rate of 2% per year. RESULTS In the base-case analysis from a healthcare system perspective, over 2 years, PST compared with PCT led to 0.0634 additional QALYs per person, at an additional net cost of CHF 7198 per person. The corresponding incremental cost effectiveness ratio (ICER) amounted to CHF 113 396 per QALY gained. From a societal perspective the ICER was CHF 70 711 per QALY gained. ICERs were subject to substantial uncertainty because of limitations in available data. CONCLUSION A PST approach, when compared with PCT, may be cost effective from a societal perspective based on a willingness-to-pay threshold of CHF 100 000 per QALY gained. However, it is less likely to be cost effective from the perspective of the Swiss healthcare system. More research is needed to understand the long-term economic implications among this patient group.

Das Lungenkarzinom gehört weltweit zu den führenden Todesursachen. Bei Diagnosestellung ist es oft weit fortgeschritten und die betroffenen PatientInnen haben eine sehr schlechte Prognose. In der Schweiz ist das Lungenkarzinom bei Männern die häufigste und bei Frauen die zweithäufigste Krebstodesursache. Hauptrisikofaktor ist das Rauchen. Es wäre daher von großer Bedeutung, in Zukunft nicht nur Rauchstopp-Maßnahmen durchzuführen, sondern bei Menschen mit einem erhöhten Lungenkrebs-Risiko auch frühzeitig diagnostische und therapeutische Maßnahmen ergreifen zu können. In diesem Übersichtsartikel werden zuerst die Grundlagen des Lungenkarzinom-Screenings erläutert und anschließend aktuelle Studien zum Thema vorgestellt. Insgesamt liegen fünf randomisierte Studien vor. Eine dieser Studien konnte keinen Vorteil von regelmäßig durchgeführten konventionellen Thorax-Aufnahmen im Vergleich zur normalen Versorgung zeigen. In vier weiteren Studien wurde die Durchführung von Low-Dose-Computertomografien im Vergleich zu konventionellen Thorax-Aufnahmen und zur normalen Versorgung untersucht. Nur eine Studie aus den USA konnte einen kleinen Vorteil dieser Screening-Maßnahme im Vergleich zu regelmäßigen konventionellen Thorax-Aufnahmen nachweisen. Die drei anderen europäischen Studien zeigten keinerlei Vorteile für eine der Methoden. Das Ergebnis der US-Studie ist aus verschiedenen Gründen kritisch zu beurteilen. Hauptkritikpunkt ist die eingeschränkte Übertragbarkeit der Ergebnisse auf die alltägliche Versorgung. Die Rate der falsch positiven Befunde ist sehr hoch. Auch der Kosten-Nutzen-Effekt von solchen Lungenkrebs-Screening-Untersuchungen ist weiterhin unklar.

BackgroundComputed tomography (CT) is important in diagnosing and managing many conditions, including coronary artery disease (CAD) and congenital heart disease. Current CT scanners can very accurately diagnose CAD requiring revascularisation in most patients. However, imaging technologies have developed rapidly and new-generation computed tomography (NGCCT) scanners may benefit patients who are difficult to image (e.g. obese patients, patients with high or irregular heart beats and patients who have high levels of coronary calcium or a previous stent or bypass graft).ObjectiveTo assess the clinical effectiveness and cost-effectiveness of NGCCT for diagnosing clinically significant CAD in patients who are difficult to image using 64-slice computed tomography and treatment planning in complex congenital heart disease.Data sourcesBibliographic databases were searched from 2000 to February/March 2011, including MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) database and Science Citation Index (SCI). Trial registers and conference proceedings were searched.Review methodsSystematic review methods followed published guidance. Risk of bias was assessed using QUADAS-2. Results were stratified by patient group. Summary sensitivity and specificity were calculated using a bivariate summary receiver operating characteristic, or random effects model. Heterogeneity was assessed using the chi-squared statistic andI2-statistic. Cost-effectiveness of NGCCT was modelled separately for suspected and known CAD, evaluating invasive coronary angiography (ICA) only, ICA after positive NGCCT (NGCCT–ICA), and NGCCT only. The cost-effectiveness of NGCCT, compared with 64-slice CT, in reducing imaging-associated radiation in congenital heart disease was assessed.ResultsTwenty-four studies reported accuracy of NGCCT for diagnosing CAD in difficult-to-image patients. No clinical effectiveness studies of NGCCT in congenital heart disease were identified. The pooled per-patient estimates of sensitivity were 97.7% [95% confidence interval (CI) 88.0% to 99.9%], 97.7% (95% CI 93.2% to 99.3%) and 96.0% (95% CI 88.8% to 99.2%) for patients with arrhythmias, high heart rates and previous stent, respectively. The corresponding estimates of specificity were 81.7% (95% CI 71.6% to 89.4%), 86.3% (95% CI 80.2% to 90.7%) and 81.6% (95% CI 74.7% to 87.3%), respectively. In patients with high coronary calcium scores, previous bypass grafts or obesity, only per-segment or per-artery data were available. Sensitivity estimates remained high (> 90% in all but one study). In patients with suspected CAD, the NGCCT-only strategy appeared most cost-effective; the incremental cost-effectiveness ratio (ICER) of NGCCT–ICA compared with NGCCT only was £71,000. In patients with known CAD, the most cost-effective strategy was NGCCT–ICA (highest cost saving, dominates ICA only). The ICER of NGCCT only compared with NGCCT–ICA was £726,230. For radiation exposure only, the ICER for NGCCT compared with 64-slice CT in congenital heart disease ranged from £521,000 for the youngest patients to £90,000 for adults.LimitationsAvailable data were limited, particularly for obese patients and patients with previous bypass grafts. All studies of the accuracy of NGCCT assume that the reference standard (ICA) is 100% sensitive and specific; however, there is some evidence that ICA may sometimes underestimate the extent and severity of stenosis. Patients with more than one criterion that could contribute to difficulty in imaging were often excluded from studies; the effect on test accuracy of multiple difficult to image criteria remains uncertain.ConclusionsNGCCT may be sufficiently accurate to diagnose clinically significant CAD in some or all difficult-to-image patient groups. Economic analyses suggest that NGCCT is likely to be considered cost-effective for difficult-to-image patients with CAD, at current levels of willingness to pay in the NHS. For patients with suspected CAD, NGCCT only would be most favourable; for patients with known CAD, NGCCT–ICA would be most favourable. No studies assessing the effects of NGCCT on therapeutic decision making, or subsequent patient outcomes, were identified. The ideal study to address these questions would be a large multi-centre RCT. However, one possible alternative might be to establish a multicentre tracker study. High-quality test accuracy studies, particularly in obese patients, patients with high coronary calcium, and those with previous bypass grafts are needed to confirm the findings of our systematic review. These studies should include patients with multiple difficult to image criteria.FundingThe National Institute for Health Research Health Technology Assessment programme. This project was funded by the HTA programme, on behalf of NICE, as project number 10/107/01.

Background Antimicrobial resistance has become a serious worldwide public health problem and is associated with antibiotic overuses. Whether personalized prescription feedback to high antibiotic prescribers using routinely collected data can lower antibiotic use in the long run is unknown. Methods We describe the design and rationale of a nationwide pragmatic randomized controlled trial enrolling 2900 primary care physicians in Switzerland with high antibiotic prescription rates based on national reimbursement claims data. About 1450 physicians receive quarterly postal and online antibiotic prescription feedback over 24 months allowing a comparison of the individual prescription rates with peers. Initially, they also receive evidence based treatment guidelines. The 1450 physicians in the control group receive no information. The primary outcome is the amount of antibiotics prescribed over a one year-period, measured as defined daily doses per 100 consultations. Other outcomes include the amount of antibiotics prescribed to specific age groups (65 years), to male and female patients, in addition to prescriptions of specific antibiotic groups. Further analyses address disease-specific quality indicators for outpatient antibiotic prescriptions, the acceptance of the intervention, and the impact on costs. Discussion This trial investigates whether continuous personalized prescription feedback on a health system level using routinely collected health data reduces antibiotic overuse. The feasibility and applicability of a web-based interface for communication with primary care physicians is further assessed. Trial registration ClinTrials.gov NCT01773824 (Date registered: August 24, 2012).

Background Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees. Methods and Findings We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner’s right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements. Conclusions Publication agreements constraining academic authors’ independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol., In a document analysis of trial protocols and publications, Erik von Elm and colleagues investigate the potential impact of publication agreements between industry sponsors and academic investigators., Author Summary Why Was This Study Done? Many randomized trials are designed and sponsored by for-profit companies that contract academic investigators to recruit and manage patients. Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, in particular with respect to trial publication. Besides evidence from a small sample, it was unclear how often trial protocols included publication agreements between industry and academic investigators, whether these agreements constrained the investigators’ publication rights, and how consistent such agreements stated in trial protocols were with those reported in corresponding publications. What Did the Researchers Do and Find? We investigated publication agreements in 647 randomized trial protocols approved in 2000–2003 by six research ethics committees in Switzerland, Canada, and Germany, and in 388 corresponding journal publications. Seventy percent of protocols mentioned an agreement on publication rights between industry and academic investigators; in 86% of those agreements, industry retained the right to disapprove or at least review manuscripts before publication. Seventy-four percent of agreements documented in protocols were not mentioned in corresponding journal articles. What Do These Findings Mean? Publication agreements constraining academic investigators’ independence are incompletely reported in publications; this may compromise the scientific evidence base established by randomized clinical trials. More transparency on publication constraints is warranted. Half of the included journal articles were published before 2008, leaving open the possibility that these findings do not reflect current reporting practice.

OBJECTIVES Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

Life expectancy has dramatically increased in industrialized nations over the last 200 hundred years. The aging of populations carries over to clinical research and leads to an increasing representation of elderly and multimorbid individuals in study populations. Clinical research in these populations is complicated by the fact that individuals are likely to experience several potential disease endpoints that prevent some disease-specific endpoint of interest from occurrence. Large developments in competing risks methodology have been achieved over the last decades, but we assume that recognition of competing risks in the clinical community is still marginal. It is the aim of this article to address translational aspects of competing risks to the clinical community. We describe clinical populations where competing risks issues may arise. We then discuss the importance of agreement between the competing risks methodology and the study aim, in particular the distinction between etiologic and prognostic research questions. In a review of 50 clinical studies performed in individuals susceptible to competing risks published in high-impact clinical journals, we found competing risks issues in 70% of all articles. Better recognition of issues related to competing risks and of statistical methods that deal with competing risks in accordance with the aim of the study is needed. Copyright (C) 2011 John Wiley & Sons, Ltd.

BACKGROUND Pneumocystis jiroveci pneumonia (PCP) remains the most common opportunistic infection in patients infected with the human immunodeficiency virus (HIV). Among patients with HIV infection and PCP the mortality rate is 10% to 20% during the initial infection and this increases substantially with the need for mechanical ventilation. It has been suggested that corticosteroids adjunctive to standard treatment for PCP could prevent the need for mechanical ventilation and decrease mortality in these patients. OBJECTIVES To assess the effects of adjunctive corticosteroids on overall mortality and the need for mechanical ventilation in HIV-infected patients with PCP and substantial hypoxaemia (arterial oxygen partial pressure < 70 mmHg or alveolar-arterial gradient > 35 mmHg on room air). SEARCH METHODS For the original review we searched The Cochrane Library (2004, Issue 4), MEDLINE (January 1980 to December 2004) and EMBASE (January 1985 to December 2004) without language restrictions. We further reviewed the reference lists from previously published overviews, searched UptoDate version 2005 and Clinical Evidence Concise (Issue 12, 2004), contacted experts in the field and searched the reference lists of identified publications for citations of additional relevant articles.In this update of our review, we searched the above-mentioned databases in September 2010 and April 2014 for trials published since our original review. We also searched for ongoing trials in ClinicalTrials.gov and the World Health Organization International Clinical Trial Registry Platform (ICTRP). We searched for conference abstracts via AEGIS. SELECTION CRITERIA Randomised controlled trials that compared corticosteroids to placebo or usual care in HIV-infected patients with PCP in addition to baseline treatment with trimethoprim-sulfamethoxazole, pentamidine or dapsone-trimethoprim, and reported mortality data. We excluded trials in patients with no or mild hypoxaemia (arterial oxygen partial pressure > 70 mmHg or an alveolar-arterial gradient < 35 mmHg on room air) and trials with a follow-up of less than 30 days. DATA COLLECTION AND ANALYSIS Two teams of review authors independently evaluated the methodology and extracted data from each primary study. We pooled treatment effects across studies and calculated a weighted average risk ratio of overall mortality in the treatment and control groups using a random-effects model.In this update of our review, we used the GRADE methodology to assess evidence quality. MAIN RESULTS Of 2029 screened records, we included seven studies in the review and six in the meta-analysis. Risk of bias varied: the randomisation and allocation process was often not clearly described, five of seven studies were double-blind and there was almost no missing data. The quality of the evidence for mortality was high. Risk ratios for overall mortality for adjunctive corticosteroids were 0.56 (95% confidence interval (CI) 0.32 to 0.98) at one month and 0.59 (95% CI 0.41 to 0.85) at three to four months of follow-up. In adults, to prevent one death, numbers needed to treat are nine patients in a setting without highly active antiretroviral therapy (HAART) available, and 23 patients with HAART available. The three largest trials provided moderate quality data on the need for mechanical ventilation, with a risk ratio of 0.38 (95% CI 0.20 to 0.73) in favour of adjunctive corticosteroids. One study was conducted in infants, suggesting a risk ratio for death in hospital of 0.81 (95% CI 0.51 to 1.29; moderate quality evidence). AUTHORS' CONCLUSIONS The number and size of trials investigating adjunctive corticosteroids for HIV-infected patients with PCP is small, but the evidence from this review suggests a beneficial effect for adult patients with substantial hypoxaemia. There is insufficient evidence on the effect of adjunctive corticosteroids on survival in infants.

Copyright © 2015 Wolters Kluwer Health Inc. All rights reserved. Objective: To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. Background: Trial discontinuation has significant scientific ethical and economic implications. To date the prevalence of discontinuation of surgical RCTs is unknown. Methods: All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada Germany and Switzerland were screened. Baseline characteristics were collected and if published full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. Results: In total 863 RCT protocols involving adult patients were identified 127 in surgery (15) and 736 in medicine (85). Surgical trials were discontinued for any reason more often than medical trials [43 vs 27 risk difference 16 (95 confidence interval [CI]: 5 26); P = 0.001] and more often discontinued for slow recruitment [18 vs 11 risk difference 8 (95 CI: 0.1 16); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44 vs 40 risk difference 4 (95 CI: 5 to 14); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18 95 CI: 1.45 12.06; P = 0.008). Conclusions: Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full scale trials.

Correction: Volume: 349 Article Number: g4921 DOI: 10.1136/bmj.g4921 OBJECTIVE: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN: Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING: Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P

IMPORTANCE: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs however remains unclear. OBJECTIVES To determine the prevalence characteristics and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland Germany and Canada between 2000 and 2003.We recorded trial characteristics and planned recruitment from included protocols. Last follow up of RCTs was April 27 2013. MAIN OUTCOMES AND MEASURES: Completion status reported reasons for discontinuation and publication status of RCTs as determined by correspondence with the research ethics committees literature searches and investigator surveys. RESULTS: After a median follow up of 11.6 years (range 8.8 12.6 years) 253 of 1017 included RCTs were discontinued (24.9 [95CI 22.3 27.6]). Only 96 of 253 discontinuations (37.9 [95CI 32.0 44.3]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9[95CI 8.2 12.0]). In multivariable analysis industry sponsorship vs investigator sponsorship (8.4 vs 26.5; odds ratio [OR] 0.25 [95CI 0.15 0.43]; P < .001) and a larger planned sample size in increments of 100 ( 0.7; OR 0.96 [95CI 0.92 1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1 vs 33.6; OR 3.19 [95CI 2.29 4.43]; P < .001). CONCLUSIONS AND RELEVANCE: In this sample of trials based on RCT protocols from 6 research ethics committees discontinuation was common with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials. Copyright 2014 American Medical Association. All rights reserved.

Lung cancer is a leading cause of death worldwide. Patients are usually diagnosed at an advanced stage and have a very poor prognosis. In Switzerland, lung cancer is the most frequent cause of cancer death in men and the second most frequent cause of cancer death in women. Programmes to prevent individuals from initiating to smoke and to support smokers to quit are the most effective lung cancer prevention strategy. Whether routine screening for lung cancer in smokers is effective to reduce lung cancer related morbidity and mortality remains questionable. We summarize the evidence of five recent randomised controlled trials on routine screening for lung cancer in smokers. One study found no benefit of periodic conventional chest X-rays as compared to usual care without regular imaging for reducing lung cancer death. In four other trials, low-dose computer tomography (LDCT) was compared to conventional chest X-rays and to usual care. Only the largest trial, the US based National Lung Cancer Screening Trial (NLST), demonstrated a statistically significant reduction of lung cancer mortality of LDCT compared to conventional chest X-rays whereas three European trials could not prove any benefit. The results of the NLST need to be interpreted with care due to limited generalizability to European settings. LDCT screening had an unacceptable high rate of false positive findings resulting in an enormous use of resources for diagnostic work-up. Whether LDCT screening is associated with an acceptable incremental cost-effectiveness ratio still warrants further investigation.

__Purpose:__ To assess the diagnostic performance of dual-source cardiac (DSC) computed tomography (CT) newer-generation CT instruments for identifying anatomically significant coronary artery disease (CAD) in patients who are difficult to image by using 64-section CT. __Materials and Methods:__ A literature search comprised bibliographic databases (January 1, 2000, to March 22, 2011, with a pragmatic update on September 6, 2012), trial registries, and conference proceedings. Only studies using invasive coronary angiography as reference standard were included. Risk of bias was assessed (QUADAS-2). Results were stratified according to patient group on the basis of clinical characteristics. Summary estimates of sensitivity and specificity of DSC CT for detecting 50% or greater arterial stenosis were calculated by using a bivariate summary receiver operating characteristic or random-effects model. __Results:__ Twenty-five studies reported accuracy of DSC CT for diagnosing CAD in difficult to image patients; in 22 studies, one of two CT units of the same manufacturer (Somatom Definition or Somatom Definition Flash) was used, and in the remaining three, a different CT unit of another manufacturer (Aquilion One) was used. The pooled, per-patient estimates of sensitivity were 97.7% (95% confidence interval [CI]: 88.0%, 99.9%) and 97.7% (95% CI: 93.2%, 99.3%) for patients with arrhythmias and high heart rates, respectively. The corresponding pooled estimates of specificity were 81.7% (95% CI: 71.6%, 89.4%) and 86.3% (95% CI: 80.2%, 90.7%), respectively. All data were acquired by using Somatom Definition. In two studies with Somatom and one study with Aquilion One, sensitivity estimates of 90% or greater were reported in patients with previous stent implantations; specificities were 81.7% and 89.5% for Somatom and 81.0% for Aquilion One. In patients with high coronary calcium scores, previous bypass grafts, or obesity, only per-segment or per-artery data were available. Sensitivity estimates remained high (.90% in all but one study), and specificities ranged from 79.1% to 100%. All data were acquired by using Somatom Definition. __Conclusion:__ DSC CT may be sufficiently accurate to diagnose clinically significant CAD in some or all difficult to image patients.

BACKGROUND: Medical imaging techniques are important in the management of many patients with liver disease. Unenhanced ultrasound examinations sometimes identify focal abnormalities in the liver that may require further investigation, primarily to distinguish liver cancers from benign abnormalities. One important factor in selecting an imaging test is the ability to provide a rapid diagnosis. Options for additional imaging investigations include computed tomography (CT) and/or magnetic resonance imaging (MRI) and biopsy when the diagnosis remains uncertain. CT and MRI usually require referral with associated waiting time and are sometimes contraindicated. The use of contrast agents may improve the ability of ultrasound to distinguish between liver cancer and benign abnormalities and, because it can be performed at the same appointment as unenhanced ultrasound, more rapid diagnoses may be possible.OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of contrast-enhanced ultrasound (CEUS) using SonoVue(®) with that of contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CEMRI) for the assessment of adults with focal liver lesions (FLLs) in whom previous liver imaging is inconclusive.DATA SOURCES: Eight bibliographic databases including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from 2000 to September/October 2011. Research registers and conference proceedings were also searched.REVIEW METHODS: Systematic review methods followed published guidance. Risk of bias was assessed using a modified version of the QUADAS-2 tool. Results were stratified by clinical indication for imaging (characterisation of FLLs detected on ultrasound surveillance of cirrhosis patients, detection of liver metastases, characterisation of incidentally detected FLLs, assessment of treatment response). For incidental FLLs, pooled estimates of sensitivity and specificity, with 95% CIs, were calculated using a random-effects model. For other clinical indications a narrative summary was used. The cost-effectiveness of CEUS was modelled separately for the three main clinical applications considered [characterisation of FLLs detected on ultrasound surveillance of cirrhosis patients, detection of liver metastases in patients with colorectal cancer (CRC), characterisation of incidentally detected FLLs].RESULTS: Of the 854 references identified, 19 (describing 18 studies) were included in the review. Hand searching of conference proceedings identified a further three studies. Twenty of the 21 studies included in the systematic review were diagnostic test accuracy studies. Studies in cirrhosis patients reported varying estimates of test performance. There was no consistent evidence of a significant difference in performance between imaging modalities. It was unclear whether or not CEUS alone is adequate to rule out hepatocellular carcinoma (HCC) for FLLs of < 30 mm; one study indicated that CEUS may be better at ruling out HCC for FLLs of 11-30 mm [very small FLLs (< 10 mm) excluded]. There was no consistent evidence of a difference in test performance between imaging modalities for the detection of metastases; CEUS alone may be adequate to rule out liver metastases in colorectal cancer. In patients with incidentally detected FLLs, the pooled estimates of sensitivity for any malignancy using CEUS and CECT were 95.1% and 94.6%, respectively, and the corresponding specificity estimates were 93.8% and 93.1% respectively. One study comparing CEUS with CEMRI reported similar sensitivity and lower specificity for both modalities. In the surveillance of cirrhosis, CEUS was as effective as but £379 less costly than CECT. CEMRI was £1063 more costly than CEUS and gained 0.022 QALYs. In the detection of liver metastases from CRC, CEUS cost £1 more than CECT, and at a lifetime time horizon they yielded equal QALYs. CEMRI was dominated by CECT. In the characterisation of incidentally detected FLLs, CEUS was slightly more effective than CECT and CEMRI (by 0.0002 QALYs and 0.0026 QALYs respectively) and less costly (by £52 and £131 respectively).LIMITATIONS: There were a number of methodological issues specific to the studies included in this review. The main indication for liver imaging in the populations considered is likely to be to rule out primary liver cancer or metastases. Therefore, patient-level analyses of test performance are of particular interest. Some of the studies included in this review reported per-patient analyses; however, no study clearly stated how results were defined (e.g. was the presence of any positive lesion regarded as a positive test for the whole patient). In addition, a number of studies reported data for one lesion per patient (treated as per-patient data in this assessment). These studies generally selected the largest lesion or the lesion 'most suspicious for malignancy' for inclusion in analyses, with the consequence that estimates of test performance may have been exaggerated. The applicability of studies included in this review may be limited, as the majority of imaging studies were interpreted by multiple, experienced operators and the prevalence of malignancy in included studies appeared higher than might be expected in clinical practice. The cost-effectiveness analyses did not take into account the potential benefits of reduced anxiety that may arise from potentially shorter waiting times associated with SonoVue CEUS.CONCLUSIONS: SonoVue CEUS could provide similar diagnostic performance to other imaging modalities (CECT and CEMRI) for the assessment of FLLs. Economic analyses indicated that CEUS was a cost-effective replacement for CEMRI. The use of CEUS instead of CECT was considered cost-effective in the surveillance of cirrhosis and the characterisation of incidentally detected FLLs, with similar costs and effects for the detection of liver metastases from CRC. Further research is needed to compare the effects of different imaging modalities (SonoVue CEUS, CECT, CEMRI) on therapeutic planning, treatment and clinical outcomes. Future test accuracy studies should provide standardised definitions of a positive imaging test, and compare all three imaging modalities in the same patient group.STUDY REGISTRATION: PROSPERO: CRD42011001694.FUNDING: The National Institute for Health Research Health Technology Assessment programme.

CONTEXT: Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping. OBJECTIVE: To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect. DATA SOURCES: Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008. STUDY SELECTION: Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs. DATA EXTRACTION: Reviewers with methodological expertise conducted data extraction independently. RESULTS: The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks

The call by the Institute for Quality and Efficiency in Health Care (IQWiG) for randomised controlled trials (RCTs) to prove the patient-relevant benefit of positron emission tomography (PET) is currently a controversial topic in Germany. From a methodological point of view there is essentially no difference between diagnostic procedures and therapeutic (drug or non-drug) interventions in proving their causal benefit. A broad consensus has been reached since the 1960s (e.g. FDA regulations) that RCTs are the methodological gold standard for therapeutic interventions. Nevertheless, the same arguments that were cited against RCTs in assessing the benefit of therapeutic interventions are now used against RCTs in evaluating diagnostic tests (e.g. ethical problems, feasibility, etc.). This paper summarizes the central methodological arguments of the discussion on the benefit assessment of PET in malignant lymphomas from the perspective of IQWiG and its external experts.

Background Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The St udy O f Trial P olicy Of I nterim T runcation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. Methods/Design We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation. Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. Discussion A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.

Objectives To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. Study Design and Setting We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. Results Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). Conclusion Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.