Search

IntroductionUsing a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size and lower cost. However, there is currently no consensus-driven guideline for the reporting of RCTs using a surrogate endpoint as a primary outcome; therefore, we seek to develop SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extensions to improve the design and reporting of these trials. As an initial step, scoping and targeted reviews will identify potential items for inclusion in the extensions and participants to contribute to a Delphi consensus process.Methods and analysisThe scoping review will search and include literature reporting on the current understanding, limitations and guidance on using surrogate endpoints in trials. Relevant literature will be identified through: (1) bibliographic databases; (2) grey literature; (3) handsearching of reference lists and (4) solicitation from experts. Data from eligible records will be thematically analysed into potential items for inclusion in extensions. The targeted review will search for RCT reports and protocols published from 2017 to 2021 in six high impact general medical journals. Trial corresponding author contacts will be listed as potential participants for the Delphi exercise.Ethics and disseminationEthical approval is not required. The reviews will support the development of SPIRIT and CONSORT extensions for reporting surrogate primary endpoints (surrogate endpoint as the primary outcome). The findings will be published in open-access publications.This review has been prospectively registered in the OSF Registration DOI: 10.17605/OSF.IO/WP3QH.

The health research agenda has historically been led by researchers; however, their priorities may not necessarily align with those of patients, caregivers and clinicians. Research priority setting initiatives identify and prioritise topics which lack evidence. This is particularly important in plastic surgery, a speciality lacking high-quality evidence to definitively answer many common clinical questions. Research priorities direct research activity and funding, so their selection process must be representative and transparent. This review appraised all priority setting initiatives in plastic surgery using the reporting guideline for priority setting of health research (REPRISE).OVID Medline, EMBASE, CINAHL and the James Lind Alliance (JLA) repository were searched (inception - 11/06/21) using search terms for 'research priority setting' and 'plastic and reconstructive surgery'. Dual-author screening and data extraction were conducted, according to PRISMA.Of 3899 de-duplicated citations, 17 were included. Most studies were conducted in national (14/17), high-income (16/17) settings. More priority setting initiatives focussed on burns (6/17) and hand surgery (4/17) than other subspecialties. The JLA (5/17) and qualitative (5/17) approaches were most used for prioritisation, followed by Delphi techniques (3/17), other surveys (3/17) and mixed methods (1/17). A minority included patient (8/17) or multi-disciplinary (8/17) stakeholders. Few reported strategies for implementing research priorities (6/17) or measuring their impact (2/17).Stakeholders from lower-income countries are underrepresented in priority setting initiatives for plastic surgery, despite the global burden of disease. Future studies should recruit more patient and multidisciplinary stakeholders, to achieve meaningful consensus. Clear implementation strategies are needed to maximise impact.

BackgroundPaediatric abusive head trauma (AHT) occurs in young children due to violent shaking or blunt impact. Educational and behavioural programmes modifying parent/infant interactions may aid primary prevention. This systematic review aims to assess the effectiveness of such interventions to prevent AHT in infants.MethodsWe searched Embase, MEDLINE, PsycINFO, The Cochrane library, CINAHL databases and trial registries to September 2021, for studies assessing the effectiveness of educational and behavioural interventions in preventing AHT. Eligible interventions had to include messaging about avoiding or dangers of infant shaking. Randomised controlled trials (RCTs) reporting results for primary (AHT, infant shaking) or secondary outcomes (including parental responses to infant crying, mental wellbeing), and non-randomised studies (NRSs) reporting primary outcomes were included. Evidence from combinable studies was synthesised using random-effects meta-analyses. Certainty of evidence was assessed using GRADE framework. PROSPERO registration CRD42020195644.FindingsOf 25 identified studies, 16 were included in meta-analyses. Five NRSs reported results for AHT, of which four were meta-analysed (summary odds ratio [OR] 0.95, 95 % confidence intervals [CI] 0.80–1.13). Two studies assessed self-reported shaking (one cluster-RCT, OR 0.11, 95 % CI 0.02–0.53; one cohort study, OR 0.36, 95 % CI 0.20–0.64, not pooled). Meta-analyses of secondary outcomes demonstrated marginal improvements in parental response to inconsolable crying (summary mean difference 1.58, 95 % CI 0.11–3.06, on a 100-point scale) and weak evidence that interventions increased walking away from crying infants (summary incidence rate ratio 1.52, 95 % CI 0.94–2.45). No intervention effects were found in meta-analyses of parental mental wellbeing or other responses to crying.InterpretationLow certainty evidence suggests that educational programmes for AHT prevention are not effective in preventing AHT. There is low to moderate certainty evidence that educational interventions have no effect or only marginally improve some parental responses to infant crying.

Purpose On 24/04/2018, the United Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA) clarified previous policies by issuing a statement, that the use of sodium valproate is contraindicated in women of childbearing potential unless the conditions of a pregnancy prevention programme are met, and only if other treatments are ineffective or not tolerated. We evaluated the impact of this over the first year of implementation in a tertiary epilepsy centre. Methods Cross-sectional study of all women under active follow up, or newly referred, of childbearing age (16–55 years), taking valproate for the treatment of epilepsy, over 12 months from 01/05/2018. Results We identified 125 cases, with 31 newly referred in response to MHRA regulations. 9.6% of patients did not attend their appointment, 35.2% had a learning disability (LD), which in 19.2% was sufficiently severe that they could not consent to a sexual relationship. Patients with LD prescribed valproate were significantly younger, and more likely to have a focal or uncharacterised epilepsy than patients without LD. In 46.4% of patients, MHRA regulations were followed: women were already using highly active contraception (HAC), HAC was started, or valproate withdrawn. In 24.8% of cases, women elected to continue valproate, and were not willing to use HAC. Conclusions In 53.6% of cases, MHRA regulations contraindicating the use valproate in women of childbearing potential could not be followed fully, due to lack of patient attendance, lack of applicability in severe LD, or ethical concerns relating to patient choice.

ObjectivesThis qualitative study aimed to investigate: (1) priorities of patients and healthcare professionals during recovery from a burn injury, (2) how priorities change over time and (3) how priorities map to outcomes currently reported in burns research.DesignSemi-structured interviews were conducted. Interviews were audio recorded, transcribed and analysed thematically.Setting, participantsA total of 53 patients and healthcare professionals were recruited from four National Health Service (NHS) burn services across England and Wales across England and Wales. Patient participants (n=32) included adults, adolescents and parents of paediatric patients, with a variety of burn injuries in terms of severity and cause of burn injury. Healthcare professionals (n=21) were NHS staff members involved in burn care and included professionals with a range of clinical experience and roles (eg, nurses, surgeons, occupational therapists, physiotherapist, administration).ResultsTen themes relating to priorities (outcomes) during recovery from a burn injury were identified for patients and professionals. Of those, six were identified for patients and professionals (‘pain and discomfort’, ‘psychological well-being’, ‘healing’, ‘scarring’, ‘function’, ‘infection’), three were unique to professionals (‘patient knowledge, understanding and support’, ‘sense of control’, ’survival’) and one was unique to patients (‘uncertainty’). Results highlighted that importance of these priorities changes over time (eg, ‘survival’ was only a concern in the short term). Likewise, priorities differed between patients and professionals (eg, ‘pain’ was important to patients throughout their recovery, but not for professionals). Seven out of 10 themes overlapped with outcomes commonly assessed in burn research.ConclusionProfessionals’ and patients’ priorities (important outcomes) change over time after burn injury and differ between those groups. Burn care research should consider measuring outcomes at different time points during the recovery from a burn injury to accurately reflect complexity of burn recovery.

IntroductionRandomised controlled trials (RCTs) may use surrogate endpoints as substitutes and predictors of patient-relevant/participant-relevant final outcomes (eg, survival, health-related quality of life). Translation of effects measured on a surrogate endpoint into health benefits for patients/participants is dependent on the validity of the surrogate; hence, more accurate and transparent reporting on surrogate endpoints is needed to limit misleading interpretation of trial findings. However, there is currently no explicit guidance for the reporting of such trials. Therefore, we aim to develop extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines to improve the design and completeness of reporting of RCTs and their protocols using a surrogate endpoint as a primary outcome.Methods and analysisThe project will have four phases: phase 1 (literature reviews) to identify candidate reporting items to be rated in a Delphi study; phase 2 (Delphi study) to rate the importance of items identified in phase 1 and receive suggestions for additional items; phase 3 (consensus meeting) to agree on final set of items for inclusion in the extensions and phase 4 (knowledge translation) to engage stakeholders and disseminate the project outputs through various strategies including peer-reviewed publications. Patient and public involvement will be embedded into all project phases.Ethics and disseminationThe study has received ethical approval from the University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee (project no: 200210051). The findings will be published in open-access peer-reviewed publications and presented in conferences, meetings and relevant forums.

Background AMSTAR-2 is a 16-item assessment tool to check the quality of a systematic review and establish whether the most important elements are reported. ROBIS is another assessment tool which was designed to evaluate the level of bias present within a systematic review. Our objective was to compare, contrast and establish both inter-rater reliability and usability of both tools as part of two overviews of systematic reviews. Strictly speaking, one tool assesses methodological quality (AMSTAR-2) and the other assesses risk of bias (ROBIS), but there is considerable overlap between the tools in terms of the signalling questions. Methods Three reviewers independently assessed 31 systematic reviews using both tools. The inter-rater reliability of all sub-sections using each instrument (AMSTAR-2 and ROBIS) was calculated using Gwet’s agreement coefficient (AC1 for unweighted analysis and AC2 for weighted analysis). Results Thirty-one systematic reviews were included. For AMSTAR-2, the median agreement for all questions was 0.61. Eight of the 16 AMSTAR-2 questions had substantial agreement or higher (> 0.61). For ROBIS, the median agreement for all questions was also 0.61. Eleven of the 24 ROBIS questions had substantial agreement or higher. Conclusion ROBIS is an effective tool for assessing risk of bias in systematic reviews and AMSTAR-2 is an effective tool at assessing quality. The median agreement between raters for both tools was identical (0.61). Reviews that included a meta-analysis were easier to rate with ROBIS; however, further developmental work could improve its use in reviews without a formal synthesis. AMSTAR-2 was more straightforward to use; however, more response options would be beneficial.

BackgroundInfantile colic is a distressing condition characterised by excessive crying in the first few months of life. The aim of this research was to update the synthesis of evidence of complementary and alternative medicine (CAM) research literature on infantile colic and establish what evidence is currently available.MethodsMedline, Embase and AMED (via Ovid), Web of Science and Central via Cochrane library were searched from their inception to September 2018. Google Scholar and OpenGrey were searched for grey literature and PROSPERO for ongoing reviews. Published systematic reviews that included randomised controlled trials (RCTs) of infants aged up to 1 year, diagnosed with infantile colic using standard diagnostic criteria, were eligible. Reviews of RCTs that assessed the effectiveness of any individual CAM therapy were included. Three reviewers were involved in data extraction and quality assessment using the AMSTAR-2 scale and risk of bias using the ROBIS tool.ResultsSixteen systematic reviews were identified. Probiotics, fennel extract and spinal manipulation show promise to alleviate symptoms of colic, although some concerns remain. Acupuncture and soy are currently not recommended. The majority of the reviews were assessed as having high or unclear risk of bias and low confidence in the findings.ConclusionThere is clearly a need for larger and more methodologically sound RCTs to be conducted on the effectiveness of some CAM therapies for IC. Particular focus on probiotics in non-breastfed infants is pertinent.Systematic review registrationPROSPERO: CRD42018092966.

Significance: Keloid and hypertrophic scarring are common following acute wounds. However, the variability in scarring outcomes between individuals and in particular, the association between genetic factors and scarring, is not well understood. This scoping review aims to summarize the methodology used in studies of genetic influences on the development of keloid or hypertrophic scarring in adults and children after acute wounding. The objectives were to determine the study designs used, the characteristics of participants included, the tools used to assess scarring and the length of follow-up after wounding. Recent Advances: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Excerpta Medica Database (EMBASE), Web of Science, Biosciences Information Service (BIOSIS), Prospective Register of Systematic Reviews (PROSPERO), The Human Genetic Epidemiology (HuGE) Navigator (database of genetic association studies), and the genome-wide association study Catalog were searched from January 2008 to April 2020. Cohort studies and case-control studies that examined the association between one or more genetic variations and the development of keloid or hypertrophic scarring were eligible for inclusion. A narrative synthesis that grouped studies by wound type was conducted. Critical Issues: Nine studies met the inclusion criteria (five in burns, four surgical wounds, and none in other types of acute wounds). Seven assessed hypertrophic scarring, one keloid scarring, and one both scar types. Seven studies used a prospective cohort design. All studies used subjective methods (clinician or patient observation) to assess scarring. There was considerable variation in how scar scales were operationalized. Future Directions: This review identified a small body of evidence on genetic susceptibility to scarring after acute wounding. Further studies are needed, and in a wide range of populations, including patients with wounds caused by trauma.

Researchers are increasingly encouraged to co-produce research, involving members of the public, service users, policy makers and practitioners in more equal relationships throughout a research project. The sharing of power is often highlighted as a key principle when co-producing research. However, health and social care research, as with many other academic disciplines, is carried out within embedded hierarchies and structural inequalities in universities, public service institutions, and research funding systems—as well as in society more broadly. This poses significant challenges to ambitions for co-production. This article explores the difficulties that are faced when trying to put ideal co-production principles into practice. A reflective account is provided of an interdisciplinary project that aimed to better understand how to reduce power differentials within co-produced research. The project facilitated five workshops, involving researchers from different disciplines, health, social care and community development staff and public contributors, who all had experience in co-production within research. In the workshops, people discussed how they had attempted to enable more equal relationships and shared ideas that supported more effective and equitable co-produced research. Shared interdisciplinary learning helped the project team to iteratively develop a training course, a map of resources and reflective questions to support co-produced research. The gap between co-production principles and practice is challenging. The article examines the constraints that exist when trying to share power, informed by multidisciplinary theories of power. To bring co-production principles into practice, changes are needed within research practices, cultures and structures; in understandings of what knowledge is and how different forms of knowledge are valued. The article outlines challenges and tensions when co-producing research and describes potential ideas and resources that may help to put co-production principles into practice. We highlight that trying to maintain all principles of co-production within the real-world of structural inequalities and uneven distribution of resources is a constant challenge, often remaining for now in the realm of aspiration.

IntroductionThe post-2005 rise in clinical trials and clinical research conducted in India was accompanied by frequent reports of unethical practices, leading to a series of regulatory changes. We conducted a systematic scoping review to obtain an overview of empirical research pertaining to the ethics of clinical trials/research in India.MethodsOur search strategy combined terms related to ethics/bioethics, informed consent, clinical trials/research and India, across nine databases, up to November 2019. Peer-reviewed research exploring ethical aspects of clinical trials/research in India with any stakeholder groups was included. We developed an evidence map, undertook a narrative synthesis and identified research gaps. A consultation exercise with stakeholders in India helped contextualise the review and identify additional research priorities.ResultsTitles/Abstracts of 9699 articles were screened, full text of 282 obtained and 80 were included. Research on the ethics of clinical trials/research covered a wide range of topics, often conducted with little to no funding. Studies predominantly examined what lay (patients/public) and professional participants (eg, healthcare staff/students/faculty) know about topics such as research ethics or understand from the information given to obtain their consent for research participation. Easily accessible groups, namely ethics committee members and healthcare students were frequently researched. Research gaps included developing a better understanding of the recruitment-informed consent process, including the doctor-patient interaction, in multiple contexts and exploring issues of equity and justice in clinical trials/research.ConclusionThe review demonstrates that while a wide range of topics have been studied in India, the focus is largely on assessing knowledge levels across different population groups. This is a useful starting point, but fundamental questions remain unanswered about informed consent processes and broader issues of inequity that pervade the clinical trials/research landscape. A priority-setting exercise and appropriate funding mechanisms to support researchers in India would help improve the clinical trials/research ecosystem.

Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.

Background Postoperative urinary retention (PO-UR) is an acute and painful inability to void after surgery that can lead to complications and delayed hospital discharge. Standard treatment with a urinary catheter is associated with a risk of infection and can be distressing, undignified and uncomfortable. This systematic review aimed to identify effective interventions for the prevention and treatment of PO-UR that might be alternatives to urinary catheterization. Methods Electronic databases were searched from inception to September 2017. Randomized trials of interventions for the prevention or treatment of PO-UR were eligible for inclusion. Studies were assessed for risk of bias using the Cochrane (2.0) tool. Two reviewers were involved at all review stages. Where possible, data were pooled using random-effects meta-analysis. The overall quality of the body of evidence was rated using the GRADE approach. Results Some 48 studies involving 5644 participants were included. Most interventions were pharmacological strategies to prevent PO-UR. Based on GRADE, there was high-certainty evidence to support replacing morphine in a regional anaesthetic regimen, using alpha-blockers (number needed to treat to prevent one case of PO-UR (NNT) 5, 95 per cent c.i. 5 to 7), the antispasmodic drug drotaverine (NNT 9, 7 to 30) and early postoperative mobilization (NNT 5, 4 to 8) for prevention, and employing hot packs or gauze soaked in warm water for treatment (NNT 2, 2 to 4). Very few studies reported on secondary outcomes of pain, incidence of urinary tract infection or duration of hospital stay. Conclusion Promising interventions exist for PO-UR, but they need to be evaluated in randomized trials investigating comparative clinical and cost effectiveness, and acceptability to patients.

BackgroundAtrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of thromboembolic events. Anticoagulation therapy to prevent AF-related stroke has been shown to be cost-effective. A national screening programme for AF may prevent AF-related events, but would involve a substantial investment of NHS resources.ObjectivesTo conduct a systematic review of the diagnostic test accuracy (DTA) of screening tests for AF, update a systematic review of comparative studies evaluating screening strategies for AF, develop an economic model to compare the cost-effectiveness of different screening strategies and review observational studies of AF screening to provide inputs to the model.DesignSystematic review, meta-analysis and cost-effectiveness analysis.SettingPrimary care.ParticipantsAdults.InterventionScreening strategies, defined by screening test, age at initial and final screens, screening interval and format of screening {systematic opportunistic screening [individuals offered screening if they consult with their general practitioner (GP)] or systematic population screening (when all eligible individuals are invited to screening)}.Main outcome measuresSensitivity, specificity and diagnostic odds ratios; the odds ratio of detecting new AF cases compared with no screening; and the mean incremental net benefit compared with no screening.Review methodsTwo reviewers screened the search results, extracted data and assessed the risk of bias. A DTA meta-analysis was perfomed, and a decision tree and Markov model was used to evaluate the cost-effectiveness of the screening strategies.ResultsDiagnostic test accuracy depended on the screening test and how it was interpreted. In general, the screening tests identified in our review had high sensitivity (> 0.9). Systematic population and systematic opportunistic screening strategies were found to be similarly effective, with an estimated 170 individuals needed to be screened to detect one additional AF case compared with no screening. Systematic opportunistic screening was more likely to be cost-effective than systematic population screening, as long as the uptake of opportunistic screening observed in randomised controlled trials translates to practice. Modified blood pressure monitors, photoplethysmography or nurse pulse palpation were more likely to be cost-effective than other screening tests. A screening strategy with an initial screening age of 65 years and repeated screens every 5 years until age 80 years was likely to be cost-effective, provided that compliance with treatment does not decline with increasing age.ConclusionsA national screening programme for AF is likely to represent a cost-effective use of resources. Systematic opportunistic screening is more likely to be cost-effective than systematic population screening. Nurse pulse palpation or modified blood pressure monitors would be appropriate screening tests, with confirmation by diagnostic 12-lead electrocardiography interpreted by a trained GP, with referral to a specialist in the case of an unclear diagnosis. Implementation strategies to operationalise uptake of systematic opportunistic screening in primary care should accompany any screening recommendations.LimitationsMany inputs for the economic model relied on a single trial [the Screening for Atrial Fibrillation in the Elderly (SAFE) study] and DTA results were based on a few studies at high risk of bias/of low applicability.Future workComparative studies measuring long-term outcomes of screening strategies and DTA studies for new, emerging technologies and to replicate the results for photoplethysmography and GP interpretation of 12-lead electrocardiography in a screening population.Study registrationThis study is registered as PROSPERO CRD42014013739.FundingThe National Institute for Health Research Health Technology Assessment programme.

BackgroundAlthough antidepressants are often a first‐line treatment for adults with moderate to severe depression, many people do not respond adequately to medication, and are said to have treatment‐resistant depression (TRD). Little evidence exists to inform the most appropriate 'next step' treatment for these people. ObjectivesTo assess the effectiveness of standard pharmacological treatments for adults with TRD. Search methodsWe searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (March 2016), CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science (31 December 2018), the World Health Organization trials portal and ClinicalTrials.gov for unpublished and ongoing studies, and screened bibliographies of included studies and relevant systematic reviews without date or language restrictions. Selection criteriaRandomised controlled trials (RCTs) with participants aged 18 to 74 years with unipolar depression (based on criteria from DSM‐IV‐TR or earlier versions, International Classification of Diseases (ICD)‐10, Feighner criteria or Research Diagnostic Criteria) who had not responded to a minimum of four weeks of antidepressant treatment at a recommended dose. Interventions were: (1) increasing the dose of antidepressant monotherapy;(2) switching to a different antidepressant monotherapy;(3) augmenting treatment with another antidepressant;(4) augmenting treatment with a non‐antidepressant.All were compared with continuing antidepressant monotherapy. We excluded studies of non‐standard pharmacological treatments (e.g. sex hormones, vitamins, herbal medicines and food supplements). Data collection and analysisTwo reviewers used standard Cochrane methods to extract data, assess risk of bias, and resolve disagreements. We analysed continuous outcomes with mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (CI). For dichotomous outcomes, we calculated a relative risk (RR) and 95% CI. Where sufficient data existed, we conducted meta‐analyses using random‐effects models. Main resultsWe included 10 RCTs (2731 participants). Nine were conducted in outpatient settings and one in both in‐ and outpatients. Mean age of participants ranged from 42 ‐ 50.2 years, and most were female. One study investigated switching to, or augmenting current antidepressant treatment with, another antidepressant (mianserin). Another augmented current antidepressant treatment with the antidepressant mirtazapine. Eight studies augmented current antidepressant treatment with a non‐antidepressant (either an anxiolytic (buspirone) or an antipsychotic (cariprazine; olanzapine; quetiapine (3 studies); or ziprasidone (2 studies)). We judged most studies to be at a low or unclear risk of bias. Only one of the included studies was not industry‐sponsored. There was no evidence of a difference in depression severity when current treatment was switched to mianserin (MD on Hamilton Rating Scale for Depression (HAM‐D) = ‐1.8, 95% CI ‐5.22 to 1.62, low‐quality evidence)) compared with continuing on antidepressant monotherapy. Nor was there evidence of a difference in numbers dropping out of treatment (RR 2.08, 95% CI 0.94 to 4.59, low‐quality evidence; dropouts 38% in the mianserin switch group; 18% in the control). Augmenting current antidepressant treatment with mianserin was associated with an improvement in depression symptoms severity scores from baseline (MD on HAM‐D ‐4.8, 95% CI ‐8.18 to ‐1.42; moderate‐quality evidence). There was no evidence of a difference in numbers dropping out (RR 1.02, 95% CI 0.38 to 2.72; low‐quality evidence; 19% dropouts in the mianserin‐augmented group; 38% in the control). When current antidepressant treatment was augmented with mirtazapine, there was little difference in depressive symptoms (MD on Beck Depression Inventory (BDI‐II) ‐1.7, 95% CI ‐4.03 to 0.63; high‐quality evidence) and no evidence of a difference in dropout numbers (RR 0.50, 95% CI 0.15 to 1.62; dropouts 2% in mirtazapine‐augmented group; 3% in the control). Augmentation with buspirone provided no evidence of a benefit in terms of a reduction in depressive symptoms (MD on Montgomery and Asberg Depression Rating Scale (MADRS) ‐0.30, 95% CI ‐9.48 to 8.88; low‐quality evidence) or numbers of drop‐outs (RR 0.60, 95% CI 0.23 to 1.53; low‐quality evidence; dropouts 11% in buspirone‐augmented group; 19% in the control). Severity of depressive symptoms reduced when current treatment was augmented with cariprazine (MD on MADRS ‐1.50, 95% CI ‐2.74 to ‐0.25; high‐quality evidence), olanzapine (MD on HAM‐D ‐7.9, 95% CI ‐16.76 to 0.96; low‐quality evidence; MD on MADRS ‐12.4, 95% CI ‐22.44 to ‐2.36; low‐quality evidence), quetiapine (SMD ‐0.32, 95% CI ‐0.46 to ‐0.18; I2 = 6%, high‐quality evidence), or ziprasidone (MD on HAM‐D ‐2.73, 95% CI ‐4.53 to ‐0.93; I2 = 0, moderate‐quality evidence) compared with continuing on antidepressant monotherapy. However, a greater number of participants dropped out when antidepressant monotherapy was augmented with an antipsychotic (cariprazine RR 1.68, 95% CI 1.16 to 2.41; quetiapine RR 1.57, 95% CI: 1.14 to 2.17; ziprasidone RR 1.60, 95% CI 1.01 to 2.55) compared with antidepressant monotherapy, although estimates for olanzapine augmentation were imprecise (RR 0.33, 95% CI 0.04 to 2.69). Dropout rates ranged from 10% to 39% in the groups augmented with an antipsychotic, and from 12% to 23% in the comparison groups. The most common reasons for dropping out were side effects or adverse events. We also summarised data about response and remission rates (based on changes in depressive symptoms) for included studies, along with data on social adjustment and social functioning, quality of life, economic outcomes and adverse events. Authors' conclusionsA small body of evidence shows that augmenting current antidepressant therapy with mianserin or with an antipsychotic (cariprazine, olanzapine, quetiapine or ziprasidone) improves depressive symptoms over the short‐term (8 to 12 weeks). However, this evidence is mostly of low or moderate quality due to imprecision of the estimates of effects. Improvements with antipsychotics need to be balanced against the increased likelihood of dropping out of treatment or experiencing an adverse event. Augmentation of current antidepressant therapy with a second antidepressant, mirtazapine, does not produce a clinically important benefit in reduction of depressive symptoms (high‐quality evidence). The evidence regarding the effects of augmenting current antidepressant therapy with buspirone or switching current antidepressant treatment to mianserin is currently insufficient. Further trials are needed to increase the certainty of these findings and to examine long‐term effects of treatment, as well as the effectiveness of other pharmacological treatment strategies.

Cardiac rehabilitation (CR) is an outpatient chronic disease management programme to optimise patient recovery and prevent further cardiac events. Programmes offer core components to optimise cardiovascular risk reduction, foster healthy behaviours (eg, exercise, healthy eating, tobacco cessation), increase patients’ understanding of their disease and improve psychosocial well-being. CR has been shown to improve health-related quality of life, as well as decrease subsequent morbidity and cardiovascular mortality by approximately 20%.1 As a result, CR is an integral recommendation in many clinical guidelines for secondary prevention in cardiac patients.2 However, CR utilisation remains suboptimal. Such underutilisation can be attributed in part to low referral by healthcare providers. However, even among patients referred, few enrol in CR, and many of those who do drop out.3 Factors impacting utilisation of CR include distance, financial resources, work and other time constraints, gender, age, social support, illness perceptions, and depression.4 Here we highlight the updated systematic review and meta-analysis of interventions to increase patient utilisation of CR.5 Utilisation was operationalised as enrolment (ie, patient attendance at a first visit), adherence (ie, percentage of prescribed sessions completed) and completion (ie, patients attended at least some of the programme and had a formal reassessment by staff at the end of the programme) of CR.6 Harms, costs and equity were also considered (secondary outcomes). A search was performed through July 2018 to identify trials published since the previous systematic review. The Cochrane Library, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, EBSCOhost and Conference Proceedings Citation Index, among other databases, were searched. The reference lists of relevant systematic reviews were hand-searched for additional trials, and two clinical trial registers were also searched. Randomised controlled trials in adults with myocardial infarction, angina, undergoing coronary artery bypass graft surgery or percutaneous coronary intervention, …

Objectives. Determine the optimal, licensed, first-line anticoagulant for prevention of ischemic stroke in patients with non-valvular atrial fibrillation (AF) in England and Wales from the UK National Health Service (NHS) perspective and estimate value to decision making of further research. Methods. We developed a cost-effectiveness model to compare warfarin (international normalized ratio target range 2–3) with directly acting (or non–vitamin K antagonist) oral anticoagulants (DOACs) apixaban 5 mg, dabigatran 150 mg, edoxaban 60 mg, and rivaroxaban 20 mg, over 30 years post treatment initiation. In addition to death, the 17-state Markov model included the events stroke, bleed, myocardial infarction, and intracranial hemorrhage. Input parameters were informed by systematic literature reviews and network meta-analysis. Expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) were estimated to provide an upper bound on value of further research. Results. At willingness-to-pay threshold £20,000, all DOACs have positive expected incremental net benefit compared to warfarin, suggesting they are likely cost-effective. Apixaban has highest expected incremental net benefit (£7533), followed by dabigatran (£6365), rivaroxaban (£5279), and edoxaban (£5212). There was considerable uncertainty as to the optimal DOAC, with the probability apixaban has highest net benefit only 60%. Total estimated population EVPI was £17.94 million (17.85 million, 18.03 million), with relative effect between apixaban versus dabigatran making the largest contribution with EVPPI of £7.95 million (7.66 million, 8.24 million). Conclusions. At willingness-to-pay threshold £20,000, all DOACs have higher expected net benefit than warfarin but there is considerable uncertainty between the DOACs. Apixaban had the highest expected net benefit and greatest probability of having highest net benefit, but there is considerable uncertainty between DOACs. A head-to-head apixaban versus dabigatran trial may be of value.

Too few patients utilize cardiac rehabilitation (CR), despite its benefits. The Cochrane review assessing the effectiveness of interventions to increase CR utilization (enrolment, adherence, and completion) was updated. A search was performed through July 2018 of the Cochrane and MEDLINE (Medical Literature Analysis and Retrieval System Online) databases, among other sources. Randomized controlled trials in adults with myocardial infarction, angina, revascularization, or heart failure were included. Interventions had to aim to increase utilization of comprehensive phase II CR. Two authors independently performed all stages of citation processing. Following the random-effects meta-analysis, meta-regression was undertaken to explore the impact of pre-specified factors. Twenty-six trials with 5299 participants were included (35.8% women). Low-quality evidence showed an effect of interventions in increasing enrolment (risk ratio (RR) = 1.27, 95% confidence interval (CI) = 1.13⁻1.42). Meta-regression analyses suggested that the intervention deliverer (nurse or allied healthcare provider, p = 0.02) and delivery format (face-to-face, p = 0.01) were influential in increasing enrolment. There was low-quality evidence that interventions to increase adherence were effective (standardized mean difference (SMD) = 0.38, 95% CI = 0.20⁻0.55), particularly where remotely-offered (SMD = 0.56, 95% CI = 0.36⁻0.76). There was moderate-quality evidence that interventions to increase program completion were effective (RR = 1.13, 95% CI = 1.02⁻1.25). There are effective interventions to increase CR utilization, but more research is needed to establish specific, implementable materials and protocols, particularly for completion.

Background:\ud International clinical practice guidelines routinely recommend that cardiac patients participate in rehabilitation programmes for comprehensive secondary prevention. However, data show that only a small proportion of these patients utilise rehabilitation.\ud \ud Objectives:\ud First, to assess interventions provided to increase patient enrolment in, adherence to, and completion of cardiac rehabilitation. Second, to assess intervention costs and associated harms, as well as interventions intended to promote equitable CR utilisation in vulnerable patient subpopulations.\ud \ud Search methods:\ud Review authors performed a search on 10 July 2018, to identify studies published since publication of the previous systematic review. We searched the Cochrane Central Register of Controlled Trials (CENTRAL); the National Health Service (NHS) Centre for Reviews and Dissemination (CRD) databases (Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effects (DARE)), in the Cochrane Library (Wiley); MEDLINE (Ovid); Embase (Elsevier); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost); and Conference Proceedings Citation Index ‐ Science (CPCI‐S) on Web of Science (Clarivate Analytics). We checked the reference lists of relevant systematic reviews for additional studies and also searched two clinical trial registers. We applied no language restrictions.\ud \ud Selection criteria:\ud We included randomised controlled trials (RCTs) in adults with myocardial infarction, with angina, undergoing coronary artery bypass graft surgery or percutaneous coronary intervention, or with heart failure who were eligible for cardiac rehabilitation. Interventions had to aim to increase utilisation of comprehensive phase II cardiac rehabilitation. We included only studies that measured one or more of our primary outcomes. Secondary outcomes were harms and costs, and we focused on equity.\ud \ud Data collection and analysis:\ud Two review authors independently screened the titles and abstracts of all identified references for eligibility, and we obtained full papers of potentially relevant trials. Two review authors independently considered these trials for inclusion, assessed included studies for risk of bias, and extracted trial data independently. We resolved disagreements through consultation with a third review author. We performed random‐effects meta‐regression for each outcome and explored prespecified study characteristics.\ud \ud Main results:\ud Overall, we included 26 studies with 5299 participants (29 comparisons). Participants were primarily male (64.2%). Ten (38.5%) studies included patients with heart failure. We assessed most studies as having low or unclear risk of bias. Sixteen studies (3164 participants) reported interventions to improve enrolment in cardiac rehabilitation, 11 studies (2319 participants) reported interventions to improve adherence to cardiac rehabilitation, and seven studies (1567 participants) reported interventions to increase programme completion. Researchers tested a variety of interventions to increase utilisation of cardiac rehabilitation. In many studies, this consisted of contacts made by a healthcare provider during or shortly after an acute care hospitalisation.\ud \ud Low‐quality evidence shows an effect of interventions on increasing programme enrolment (19 comparisons; risk ratio (RR) 1.27, 95% confidence interval (CI) 1.13 to 1.42). Meta‐regression revealed that the intervention deliverer (nurse or allied healthcare provider; P = 0.02) and the delivery format (face‐to‐face; P = 0.01) were influential in increasing enrolment. Low‐quality evidence shows interventions to increase adherence were effective (nine comparisons; standardised mean difference (SMD) 0.38, 95% CI 0.20 to 0.55), particularly when they were delivered remotely, such as in home‐based programs (SMD 0.56, 95% CI 0.37 to 0.76). Moderate‐quality evidence shows interventions to increase programme completion were also effective (eight comparisons; RR 1.13, 95% CI 1.02 to 1.25), but those applied in multi‐centre studies were less effective than those given in single‐centre studies, leading to questions regarding generalisability. A moderate level of statistical heterogeneity across intervention studies reflects heterogeneity in intervention approaches. There was no evidence of small‐study bias for enrolment (insufficient studies to test for this in the other outcomes).\ud \ud With regard to secondary outcomes, no studies reported on harms associated with the interventions. Only two studies reported costs. In terms of equity, trialists tested interventions designed to improve utilisation among women and older patients. Evidence is insufficient for quantitative assessment of whether women‐tailored programmes were associated with increased utilisation, and studies that assess motivating women are needed. For older participants, again while quantitative assessment could not be undertaken, peer navigation may improve enrolment.\ud \ud Authors' conclusions:\ud Interventions may increase cardiac rehabilitation enrolment, adherence and completion; however the quality of evidence was low to moderate due to heterogeneity of the interventions used, among other factors. Effects on enrolment were larger in studies targeting healthcare providers, training nurses, or allied healthcare providers to intervene face‐to‐face; effects on adherence were larger in studies that tested remote interventions. More research is needed, particularly to discover the best ways to increase programme completion.

Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs.

BACKGROUND Healthcare professionals have a duty to maintain basic life support (BLS) skills. This study aims to evaluate medical students' factual knowledge of BLS and the training they receive. METHODS A cross-sectional, closed-response questionnaire was distributed to the first- and fourth-year students studying at institutions in the United Kingdom. The paper questionnaire sought to quantify respondent's previous BLS training, factual knowledge of the BLS algorithm using five multiple choice questions (MCQs), and valuate their desire for further BLS training. Students received 1 point for each correctly identified answer to the 5 MCQ's. RESULTS A total of 3,732 complete responses were received from 21 medical schools. Eighty percent (n=2,999) of students completed a BLS course as part of their undergraduate medical studies. There was a significant difference (P

BACKGROUND: Procalcitonin levels may be raised in bacterial infections and have been used to guide antibiotic therapy. There is little data on procalcitonin and limb cellulitis. OBJECTIVES: Within a clinical trial of antibiotic therapy, we examined the correlation between clinical observations, blood tests and local measurements of skin damage, with serum procalcitonin levels. METHODS: The data is from a subset of the patients recruited into a clinical trial of antibiotic therapy for cellulitis (clindamycin for cellulitis, NCT01876628) whose procalcitonin levels were correlated with clinical and laboratory measurements. We selected the variables strongly correlated with procalcitonin and evaluated the predictive value of the baseline procalcitonin on the primary trial outcome. RESULTS: 136 patients provided 307 procalcitonin levels which were correlated with 8 variables. The strongest correlations (correlation coefficient of >0.5) with procalcitonin were the affected skin area (0.537), C-reactive protein (0.574) and neutrophil:lymphocyte ratio (0.567). Receiver operator characteristic curves demonstrated poor sensitivity and specificity of procalcitonin in predicting primary outcome. Procalcitonin baseline levels were low but decreased as patients recovered. CONCLUSIONS: Procalcitonin levels are generally low in limb cellulitis and cannot be used to confirm the diagnosis or the need for antibiotic therapy. Procalcitonin is a poor predictor of early improvement.

Background Antidepressants continue to be a first-line treatment for adults with moderate to severe major depression. However, many people prescribed antidepressants for depression will not respond fully to such medication, and little evidence is available to inform the most appropriate 'next step' treatment for such patients, who may be referred to as having treatment-resistant depression (TRD). National Institute for Health and Care Excellence (NICE) guidance suggests that the 'next step' for those who do not respond to antidepressants may include a change in the dose or type of antidepressant medication, the addition of another medication, or the start of psychotherapy. Different types of psychotherapies may be used for TRD; evidence on these treatments is available but has not been collated to date.Along with the sister review of pharmacological therapies for TRD, this review summarises available evidence for the effectiveness of psychotherapies for adults (18 to 74 years) with TRD with the goal of establishing the best 'next step' for this group.Objectives To assess the effectiveness of psychotherapies for adults with TRD.Search methods We searched the Cochrane Common Mental Disorders Controlled Trials Register (until May 2016), along with CENTRAL, MEDLINE, Embase, and PsycINFO via OVID (until 16 May 2017). We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished and ongoing studies. We did not apply date or language restrictions.Selection criteria We included randomised controlled trials (RCTs) that enrolled participants 18 to 74 years of age who had received a diagnosis of unipolar depression that had not responded to antidepressant treatment of at least four weeks' duration at a recommended dose. We excluded studies of people with drug intolerance. Acceptable diagnoses of unipolar depression were based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) or earlier versions of this publication, International Classification of Diseases (ICD)-10, Feighner criteria, or Research Diagnostic Criteria. We included studies conducted to perform either of the following comparisons in patients with TRD.1. Any psychological therapy versus antidepressant treatment alone, or another psychological therapy.2. Any psychological therapy given in addition to antidepressant medication versus antidepressant treatment alone, or a psychological therapy alone.Primary outcomes required were change in depressive symptoms and number of dropouts from study or treatment (as a measure of acceptability).Data collection and analysis Review authors extracted data, assessed risk of bias in duplicate, and resolved disagreements through discussion or consultation with a third person. We conducted random-effects meta-analyses when appropriate. We summarised continuous outcomes using mean differences (MDs) or standardised mean differences (SMDs), and we summarised dichotomous outcomes using risk ratios (RRs).Main results We included six trials (n = 698; most participants were women approximately 40 years of age). All studies evaluated psychotherapy plus usual care (with antidepressants) versus usual care (with antidepressants). Three studies addressed the addition of cognitive-behavioural therapy (CBT) to usual care (n = 522), and one study each evaluated intensive short-term dynamic psychotherapy (ISTDP) (n = 60), interpersonal therapy (IPT) (n = 34), or group dialectical behavioural therapy (DBT) (n = 19) as the intervention. Most studies were small (except one trial of CBT was large), and all studies were at high risk of detection bias for the main outcome of self-reported depressive symptoms.A random-effects meta-analysis of five trials (n = 575) showed that psychotherapy given in addition to usual care (vs usual care alone) produced improvement in self-reported depressive symptoms (MD -4.07 points, 95% confidence interval (CI) -7.07 to -1.07 on the Beck Depression Inventory (BDI) scale) over the short term (up to six months). Effects were similar when data from all six studies were combined for self-reported depressive symptoms (SMD -0.40, 95% CI -0.65 to -0.14; n = 635). The quality of this evidence was moderate. Similar moderate-quality evidence of benefit was seen on the Patient Health Questionnaire-9 Scale (PHQ-9) from two studies (MD -4.66, 95% CI 8.72 to -0.59; n = 482) and on the Hamilton Depression Rating Scale (HAMD) from four studies (MD -3.28, 95% CI -5.71 to -0.85; n = 193).High-quality evidence shows no differential dropout (a measure of acceptability) between intervention and comparator groups over the short term (RR 0.85, 95% CI 0.58 to 1.24; six studies; n = 698).Moderate-quality evidence for remission from six studies (RR 1.92, 95% CI 1.46 to 2.52; n = 635) and low-quality evidence for response from four studies (RR 1.80, 95% CI 1.2 to 2.7; n = 556) indicate that psychotherapy was beneficial as an adjunct to usual care over the short term.With the addition of CBT, low-quality evidence suggests favourable effects on depression scores on the BDI scale over the medium term (12 months) (RR -3.40, 95% CI -7.21 to 0.40; two studies; n = 475) and over the long term (46 months) (RR -1.90, 95% CI -3.22 to -0.58; one study; n = 248). Moderate-quality evidence for adjunctive CBT suggests no difference in acceptability (dropout) over the medium term (RR 0.98, 95% CI 0.66 to 1.47; two studies; n = 549) and favourable results with added CBT over the long term (RR 0.80, 95% CI 0.66 to 0.97; one study; n = 248) versus usual care alone.Two studies reported serious adverse events (one suicide, two hospitalisations, and two exacerbations of depression) in 4.2% of the total sample, which occurred only in the usual care group (no events in the intervention group).An economic analysis (conducted as part of an included study) from the UK healthcare perspective (National Health Service (NHS)) revealed that adjunctive CBT was cost-effective over nearly four years.Authors' conclusions Moderate-quality evidence shows that psychotherapy added to usual care (with antidepressants) is beneficial for depressive symptoms and for response and remission rates over the short term for patients with TRD. Medium- and long-term effects seem similarly beneficial, although most evidence was derived from a single large randomised controlled trial. Psychotherapy added to usual care seems as acceptable as usual care alone.Further evidence is needed on the effectiveness of different types of psychotherapies for patients with TRD. No evidence currently shows whether switching to a psychotherapy is more beneficial for this patient group than continuing an antidepressant medication regimen. Addressing this evidence gap is an important goal for researchers.

High cholesterol is an important risk factor contributing to the global burden of disease. A WHO report estimated that it accounts for more than one-third of all deaths worldwide, and causes 18% of cerebrovascular disease (CVD) and 56% of ischaemic heart disease.1 The evidence that lipid-lowering drugs can reduce both lipid levels and the risk of heart attacks and strokes is well established. Lipid-lowering medications include statins, fibrates, niacin and bile acid resins. The effectiveness of statins is supported by large randomised trials and meta-analyses2 3 showing that the absolute reduction in LDL-cholesterol is linearly related to a reduction in the incidence of coronary and major vascular events.2 Statins are recommended as first-line therapy, whereas fibrates, niacin and bile acid resins are generally second-line therapy, alone or in combination with statins.4 5 Despite this evidence and the availability of guidelines, lipid-lowering therapy is still underused. Although recommendations about drug treatments vary between countries, most generally recommend statin treatment in people with clinical evidence of CVD to reduce further ischaemic events. In adults who have no history of a cardiovascular event, lipid-lowering medication is recommended if there is a 20% or greater risk of developing CVD in the next 10 years.4 Recommendations by the American College of Cardiology/American Heart Association have recently broadened the indications for lipid-lowering therapy, adding to the challenge of ensuring adequate treatment coverage.5 Adherence to treatment is important for optimal effectiveness. Adherence is defined as the extent to which people take medication as prescribed. A number of factors have been linked to poor adherence, such as lack of knowledge, denial, adverse effects, impaired memory and non-acceptance of treatment. Interventions to improve adherence to medication can focus on the person (patient education), the drug regimen (simplification of regimens), the physician (decision-making aids) …

Background Although psychological interventions are recommended for the management of coronary heart disease (CHD), there remains considerable uncertainty regarding their effectiveness. Design Systematic review and meta-analysis of randomised controlled trials (RCTs) of psychological interventions for CHD. Methods The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL and PsycINFO were searched to April 2016. Retrieved papers, systematic reviews and trial registries were hand-searched. We included RCTs with at least 6 months of follow-up, comparing the direct effects of psychological interventions to usual care for patients following myocardial infarction or revascularisation or with a diagnosis of angina pectoris or CHD defined by angiography. Two authors screened titles for inclusion, extracted data and assessed risk of bias. Studies were pooled using random effects meta-analysis and meta-regression was used to explore study-level predictors. Results Thirty-five studies with 10,703 participants (median follow-up 12 months) were included. Psychological interventions led to a reduction in cardiovascular mortality (rfcelative risk 0.79, 95% confidence interval [CI] 0.63 to 0.98), although no effects were observed for total mortality, myocardial infarction or revascularisation. Psychological interventions improved depressive symptoms (standardised mean difference [SMD] –0.27, 95% CI –0.39 to –0.15), anxiety (SMD –0.24, 95% CI –0.38 to –0.09) and stress (SMD –0.56, 95% CI –0.88 to –0.24) compared with controls. Conclusions We found that psychological intervention improved psychological symptoms and reduced cardiac mortality for people with CHD. However, there remains considerable uncertainty regarding the magnitude of these effects and the specific techniques most likely to benefit people with different presentations of CHD.

Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation. Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library. Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation. Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin. Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis. Systematic review registration PROSPERO CRD 42013005324.

Background:\ud Coronary heart disease (CHD) is the most common cause of death globally, although mortality rates are falling. Psychological symptoms are prevalent for people with CHD, and many psychological treatments are offered following cardiac events or procedures with the aim of improving health and outcomes. This is an update of a Cochrane systematic review previously published in 2011.\ud \ud Objectives:\ud To assess the effectiveness of psychological interventions (alone or with cardiac rehabilitation) compared with usual care (including cardiac rehabilitation where available) for people with CHD on total mortality and cardiac mortality; cardiac morbidity; and participant-reported psychological outcomes of levels of depression, anxiety, and stress; and to explore potential study-level predictors of the effectiveness of psychological interventions in this population.\ud \ud Search methods:\ud We updated the previous Cochrane Review searches by searching the following databases on 27 April 2016: CENTRAL in the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid), and CINAHL (EBSCO).\ud \ud Selection criteria:\ud We included randomised controlled trials (RCTs) of psychological interventions compared to usual care, administered by trained staff, and delivered to adults with a specific diagnosis of CHD. We selected only studies estimating the independent effect of the psychological component, and with a minimum follow-up of six months. The study population comprised of adults after: a myocardial infarction (MI), a revascularisation procedure (coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI)), and adults with angina or angiographically defined coronary artery disease (CAD). RCTs had to report at least one of the following outcomes: mortality (total- or cardiac-related); cardiac morbidity (MI, revascularisation procedures); or participant-reported levels of depression, anxiety, or stress.\ud \ud Data collection and analysis:\ud Two review authors independently screened titles and abstracts of all references for eligibility. A lead review author extracted study data, which a second review author checked. We contacted study authors to obtain missing information.\ud \ud Main results:\ud This review included 35 studies which randomised 10,703 people with CHD (14 trials and 2577 participants added to this update). The population included mainly men (median 77.0%) and people post-MI (mean 65.7%) or after undergoing a revascularisation procedure (mean 27.4%). The mean age of participants within trials ranged from 53 to 67 years. Overall trial reporting was poor, with around a half omitting descriptions of randomisation sequence generation, allocation concealment procedures, or the blinding of outcome assessments. The length of follow-up ranged from six months to 10.7 years (median 12 months). Most studies (23/35) evaluated multifactorial interventions, which included therapies with multiple therapeutic components. Ten studies examined psychological interventions targeted at people with a confirmed psychopathology at baseline and two trials recruited people with a psychopathology or another selecting criterion (or both). Of the remaining 23 trials, nine studies recruited unselected participants from cardiac populations reporting some level of psychopathology (3.8% to 53% with depressive symptoms, 32% to 53% with anxiety), 10 studies did not report these characteristics, and only three studies excluded people with psychopathology.\ud \ud Moderate quality evidence showed no risk reduction for total mortality (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.77 to 1.05; participants = 7776; studies = 23) or revascularisation procedures (RR 0.94, 95% CI 0.81 to 1.11) with psychological therapies compared to usual care. Low quality evidence found no risk reduction for non-fatal MI (RR 0.82, 95% CI 0.64 to 1.05), although there was a 21% reduction in cardiac mortality (RR 0.79, 95% CI 0.63 to 0.98). There was also low or very low quality evidence that psychological interventions improved participant-reported levels of depressive symptoms (standardised mean difference (SMD) -0.27, 95% CI -0.39 to -0.15; GRADE = low), anxiety (SMD -0.24, 95% CI -0.38 to -0.09; GRADE = low), and stress (SMD -0.56, 95% CI -0.88 to -0.24; GRADE = very low).\ud \ud There was substantial statistical heterogeneity for all psychological outcomes but not clinical outcomes, and there was evidence of small-study bias for one clinical outcome (cardiac mortality: Egger test P = 0.04) and one psychological outcome (anxiety: Egger test P = 0.012). Meta-regression exploring a limited number of intervention characteristics found no significant predictors of intervention effects for total mortality and cardiac mortality. For depression, psychological interventions combined with adjunct pharmacology (where deemed appropriate) for an underlying psychological disorder appeared to be more effective than interventions that did not (β = -0.51, P = 0.003). For anxiety, interventions recruiting participants with an underlying psychological disorder appeared more effective than those delivered to unselected populations (β = -0.28, P = 0.03).\ud \ud Authors' conclusions:\ud This updated Cochrane Review found that for people with CHD, there was no evidence that psychological treatments had an effect on total mortality, the risk of revascularisation procedures, or on the rate of non-fatal MI, although the rate of cardiac mortality was reduced and psychological symptoms (depression, anxiety, or stress) were alleviated; however, the GRADE assessments suggest considerable uncertainty surrounding these effects. Considerable uncertainty also remains regarding the people who would benefit most from treatment (i.e. people with or without psychological disorders at baseline) and the specific components of successful interventions. Future large-scale trials testing the effectiveness of psychological therapies are required due to the uncertainty within the evidence. Future trials would benefit from testing the impact of specific (rather than multifactorial) psychological interventions for participants with CHD, and testing the targeting of interventions on different populations (i.e. people with CHD, with or without psychopathologies).

BackgroundFibromyalgia (FM) is a chronic, debilitating pain disorder. Dissatisfaction with conventional medicine can lead people with FM to turn to complementary and alternative medicine (CAM). Two previous overviews of systematic reviews of CAM for FM have been published, but they did not assessed for risk of bias in the review process.MethodsFive databases Medline, Embase, AMED (via OVID), Web of Science and Central were searched from their inception to December 2015. Reference lists were hand-searched. We had two aims: the first was to provide an up-to-date and rigorously conducted synthesis of systematic reviews of CAM literature on FM; the second was to evaluate the quality of the available systematic review evidence using two different tools: AMSTAR (Shea et al. BMC Med Res Methodol 15; 7:10, 2007) and a more recently developed tool ROBIS (Whiting et al. J Clin Epidemiol 69:225-34, 2016) specifically designed to assess risk of bias in systematic reviews. Any review that assessed one of eight CAM therapies for participants diagnosed with FM was considered. The individual studies had to be randomised controlled trials where the intervention was compared to placebo, treatment as usual or waitlist controls to be included. The primary outcome measure was pain, and the secondary outcome measure was adverse events.ResultsWe identified 15 reviews that met inclusion criteria. There was low-quality evidence that acupuncture improves pain compared to no treatment or standard treatment, but good evidence that it is no better than sham acupuncture. The evidence for homoeopathy, spinal manipulation and herbal medicine was limited.ConclusionsOverall, five reviews scored 6 or above using the AMSTAR scale and the inter-rater agreement was good (83.6%), whereas seven reviews achieved a low risk of bias rating using ROBIS and the inter-rater agreement was fair (60.0%). No firm conclusions were drawn for efficacy of either spinal manipulation or homoeopathy for FM. There is limited evidence for topical Capsicum, but further research is required. There is some evidence to support the effectiveness of acupuncture for FM, but further high-quality trials are needed to investigate its benefits, harms and mechanisms of action, compared with no or standard treatment.Systematic review registrationPROSPERO CRD42016035846.

BackgroundWarfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements.ObjectiveTo determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.DesignFour systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.SettingHospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).ParticipantsPatients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).InterventionsNOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.Main outcome measuresEfficacy Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism.Safety Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.Data sourcesMEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014.Review methodsTwo reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models.ResultsApixaban (Eliquis®, Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana®, Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication.ConclusionsNOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE.LimitationsThese relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.Future workCalculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials.Study registrationThis study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.FundingThe National Institute for Health Research Health Technology Assessment programme.

Undergoing general anaesthesia is distressing for children, with up to two-thirds demonstrating abnormal behaviours after their procedure, such as emergence delirium (ED) and post-hospitalization behaviour change. The aim of this systematic review was to determine the effect of intraoperative i.v. α2-adrenergic agonists on postoperative behaviour in children. We included published full-text reports of randomized controlled trials involving children who received i.v. clonidine or dexmedetomidine after induction of general anaesthesia, who were assessed for postoperative behavioural disturbance. After screening of references identified by the search strategy, a data collection form was developed and piloted. Data extraction was performed by one reviewer and checked by a second. Twelve randomized trials met the inclusion criteria. Ten studies (n=669) reported dichotomous data that were included in the pooled analysis of α2-adrenergic agonists vs placebo. There was strong evidence that i.v. α2-adrenergic agonists reduced postoperative ED (overall summary odds ratio 0.28, 95% confidence interval 0.19–0.40, P

e13524 Background: The aim of this global patient survey was to better understand the needs and expectations of patients with NETs regarding access to diagnostic tools and treatment. Methods: In 2017, an online, questionnaire survey of NET patients/family members, patient advocates and healthcare professionals (HCPs) was conducted. Results: In total, 443 participants from 26 countries responded: 338 patients/families; 35 advocates; 70 HCPs. Following NET diagnosis, many patients use patient association (69%) and HCP (48%) websites to fulfill their informational needs. Patients overestimated the availability of key diagnostic tools and treatments compared to HCPs: Gallium-68-Dotatate PET/CT scan was believed available by 28% of patients vs. 14% of HCPs; fluorodeoxyglucose PET by 77% of patients vs. 64% of HCPs; peptide receptor radionuclide therapy by 58% of patients vs. 23% of HCPs; genetic test/precision medicine by 75% of patients vs. 71% of HCPs; and transplantation by 86% of patients vs. 55% of HCPs. Reasons reported by patients and advocates for unavailability of treatment were: not provided by healthcare system (28% & 67%, respectively); non-referral (19% & 33%, respectively), unable to afford treatment (18% & 57%, respectively); treatment not covered by insurance (17% & 24%, respectively); distance to treatment centre (15% & 48%, respectively). Almost a third (30%) of patients had to travel more than 300 km/186 miles for treatment or consultation with a NET specialist, while 34% of patients did not have access to an MDT and those that did may be in contact with them less than once per year (14%). In contrast, advocates and HCPs believe there is wider availability of MDTs (94% and 70%, respectively). Conclusions: Patients are increasingly well-educated about NETs and often travel considerable distances to obtain specialist treatment. However, there remains considerable disparity in what patients feel is available to them in terms of the latest tools and treatments, compared to what is there in reality. This significant difference in perception needs to be managed delicately by both advocates and healthcare professionals.

Neuroendocrine tumors of the small intestine are the most common causes of the carcinoid syndrome. Carcinoid heart disease occurs in more than half of the patients with the carcinoid syndrome. Patients with carcinoid heart disease who need to undergo surgery should also undergo preoperative evaluation by an expert cardiologist. Treatment with long-acting somatostatin analogs aims at controlling the excessive hormonal output and symptoms related to the carcinoid syndrome and at preventing a carcinoid crisis during interventions. Patients with a gastrinoma require pre- and postoperative treatment with high doses of proton pump inhibitors. Patients with a glucagonoma require somatostatin analog treatment and nutritional supplementation. Patients with a VIPoma also require somatostatin analog treatment and intravenous fluid and electrolyte therapy. Insulinoma patients generally require intravenous glucose infusion prior to operation. In patients with localized operable insulinoma, somatostatin analog infusion should only be considered after the effect of this therapy has been electively studied.

Background Lipid-lowering drugs are widely underused, despite strong evidence indicating they improve cardiovascular end points. Poor patient adherence to a medication regimen can affect the success of lipid-lowering treatment. Objectives To assess the effects of interventions aimed at improving adherence to lipid-lowering drugs, focusing on measures of adherence and clinical outcomes. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and CINAHL up to 3 February 2016, and clinical trials registers (ANZCTR and ClinicalTrials.gov) up to 27 July 2016. We applied no language restrictions. Selection criteria We evaluated randomised controlled trials of adherence-enhancing interventions for lipid-lowering medication in adults in an ambulatory setting with a variety of measurable outcomes, such as adherence to treatment and changes to serum lipid levels. Two teams of review authors independently selected the studies. Data collection and analysis Three review authors extracted and assessed data, following criteria outlined by the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the quality of the evidence using GRADEPro. Main results For this updated review, we added 24 new studies meeting the eligibility criteria to the 11 studies from prior updates. We have therefore included 35 studies, randomising 925,171 participants. Seven studies including 11,204 individuals compared adherence rates of those in an intensification of a patient care intervention (e.g. electronic reminders, pharmacist-led interventions, healthcare professional education of patients) versus usual care over the short term (six months or less), and were pooled in a meta-analysis. Participants in the intervention group had better adherence than those receiving usual care (odds ratio (OR) 1.93, 95% confidence interval (CI) 1.29 to 2.88; 7 studies; 11,204 participants; moderate-quality evidence). A separate analysis also showed improvements in long-term adherence rates (more than six months) using intensification of care (OR 2.87, 95% CI 1.91 to 4.29; 3 studies; 663 participants; high-quality evidence). Analyses of the effect on total cholesterol and LDL-cholesterol levels also showed a positive effect of intensified interventions over both short- and long-term follow-up. Over the short term, total cholesterol decreased by a mean of 17.15 mg/dL (95% CI 1.17 to 33.14; 4 studies; 430 participants; low-quality evidence) and LDL-cholesterol decreased by a mean of 19.51 mg/dL (95% CI 8.51 to 30.51; 3 studies; 333 participants; moderate-quality evidence). Over the long term (more than six months) total cholesterol decreased by a mean of 17.57 mg/dL (95% CI 14.95 to 20.19; 2 studies; 127 participants; high-quality evidence). Included studies did not report usable data for health outcome indications, adverse effects or costs/resource use, so we could not pool these outcomes. We assessed each included study for bias using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. In general, the risk of bias assessment revealed a low risk of selection bias, attrition bias, and reporting bias. There was unclear risk of bias relating to blinding for most studies. Authors' conclusions The evidence in our review demonstrates that intensification of patient care interventions improves short- and long-term medication adherence, as well as total cholesterol and LDL-cholesterol levels. Healthcare systems which can implement team-based intensification of patient care interventions may be successful in improving patient adherence rates to lipid-lowering medicines.

Inadequate patient adherence to a medication regimen is a major factor in the lack of success in treating hyperlipidemia. Improved adherence rates may result in significantly improved cardiovascular outcomes in populations treated with lipid-lowering therapy. The purpose of this metaanalysis was to evaluate the effectiveness of interventions aimed at improving adherence to lipid-lowering drugs, focusing on measures of adherence and clinical outcomes.We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases through January 14, 2015, and also used the results from previous Cochrane reviews of this title. Randomized controlled trials of adherence-enhancing interventions for lipid-lowering medication in adults in an ambulatory setting with measurable outcomes were evaluated with criteria outlined by the Cochrane Handbook for Systematic Reviews of Interventions.Twenty-seven studies randomly assigning 899,068 participants to a variety of interventions were analyzed. One group of interventions categorized as intensified patient care showed significant improvement in adherence rates when compared to usual care (odds ratio 1.93; 95% confidence interval [CI] 1.29-2.88). Additionally, after6 months of follow-up, total cholesterol decreased by a mean of 17.15 mg/dL (95% CI 1.17-33.14), while after6 months total cholesterol decreased by a mean of 17.57 mg/dL (95% CI 14.95-20.19).Healthcare systems that can implement team-based intensified patient care interventions, such as electronic reminders, pharmacist-led interventions, and healthcare professional education of patients, may be successful in improving adherence rates to lipid-lowering medicines.

ObjectivesTo conduct a systematic review of the risks of short-term outcomes following major treatments for clinically localized prostate cancer.Materials and methodsMEDLINE, EMBASE and the Cochrane Library from 2004 to January 2013. Study arms that included at least 100 men with localized prostate cancer in receipt of surgery, radiotherapy or active surveillance and reported symptomatic and quality of life (QoL) data from 6 months to five years after treatment were eligible. Data were extracted by one reviewer and checked by another.Results64 studies (80 treatment cohorts) were included. Most were single treatment cohorts from the US or Europe. Prostatectomy was the most common treatment (39 cohorts), followed by radiotherapy (external beam and brachytherapy; 31 cohorts), with only one active surveillance cohort. Most frequently measured symptoms were urinary, followed by sexual and bowel; QoL was assessed in only 17 cohorts. Most studies used validated measures, although poor data reporting and differences between studies meant that it was not possible to pool data. ConclusionData on the precise impact of short-term symptomatic and QoL outcomes following treatment for localized prostate cancer is of insufficient quality for clear guidance to men about the risks to these aspects of their lives. It is important that future studies focus on collecting core outcomes through validated measures and comply with reporting guidelines so that clear and accurate information can be derived for men considering screening or treatment for prostate cancer.

Aliment Pharmacol Ther 2011; 34: 235–242 Summary Background Somatostatin analogues are the mainstay of therapy for malignant carcinoid syndrome. There is clear evidence that the once monthly intramuscular formulation, Octreotide LAR, controls symptoms of carcinoid syndrome, and recent data also suggests an antitumour effect. There is limited data on prolonged release Lanreotide (Somatuline Autogel, Ipsen Pharma Biotech, Signes, France) and no long-term data to date. Aim To present long-term results of prolonged release Lanreotide in a large cohort of patients with malignant carcinoid syndrome, assessing clinical and objective response and tolerance. Methods Seventy six patients with metastatic midgut neuroendocrine tumours and carcinoid syndrome were included in this 9-year retrospective study. Clinical response was based on symptom score with radiological assessment based on RECIST (Response Evaluation Criteria In Solid Tumours). Results Data were available in 69 patients. Ninety four percent achieved symptomatic response at first follow-up visit. Forty six percent had loss of symptomatic response, but 44% of these achieved control with an increase in dose of prolonged release Lanreotide. Overall, symptoms were well controlled throughout the study period with prolonged release Lanreotide alone in 74% of patients. Twenty six percent required additional treatment despite good initial response. Only 30% demonstrated radiological progression. Eleven patients who were switched from Octreotide LAR had return of symptomatic control. No significant adverse effects were experienced. Conclusions Prolonged release Lanreotide provides good symptomatic control of diarrhoea and flushing as well as tumour stability in patients with malignant carcinoid syndrome.

SUMMARYBackgroundOctreotide LAR is an established treatment for malignant carcinoid syn-drome. However, studies with large number of patients and long follow-up are lacking.AimTo present long-terms results with octreotide LAR, assessing duration ofclinical and objective response and treatment tolerance, in a large,homogeneous cohort of patients with malignant carcinoid syndrome.MethodsA total of 108 patients with metastatic midgut neuroendocrine tumourswere included in this 8-year study. Clinical evaluation was based on asymptom score. Radiological assessment was based on RECIST(Response Evaluation Criteria In Solid Tumours) criteria.ResultsOf the 108 patients, 24% had a sustained symptomatic response. In theremaining patients, loss of symptomatic response with the initial dosewas noted within 3-60 months. In 17% of them, symptoms were con-trolled by just an increase of octreotide LAR dose, whilst the otherpatients required additional treatment. Overall, in 45.3% of patients,symptoms were well controlled during the study period with onlyoctreotide LAR, and no additional treatment was required. No signifi-cant adverse effects were noted.ConclusionsOctreotide LAR treatment provides a sustained symptomatic response inabout half of the patients with malignant carcinoid syndrome and con-tributes to disease stabilization for a longer period than previouslydescribed.