Risk factors and prediction of hypoglycaemia using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: The objective of the Hypoglycaemia REdefining SOLutions for better liVES (Hypo-RESOLVE) project is to use a dataset of pooled clinical trials across pharmaceutical and device companies in people with type 1 or type 2 diabetes to examine factors associated with incident hypoglycaemia events and to quantify the prediction of these events. METHODS: Data from 90 trials with 46,254 participants were pooled. Analyses were done for type 1 and type 2 diabetes separately. Poisson mixed models, adjusted for age, sex, diabetes duration and trial identifier were fitted to assess the association of clinical variables with hypoglycaemia event counts. Tree-based gradient-boosting algorithms (XGBoost) were fitted using training data and their predictive performance in terms of area under the receiver operating characteristic curve (AUC) evaluated on test data. Baseline models including age, sex and diabetes duration were compared with models that further included a score of hypoglycaemia in the first 6 weeks from study entry, and full models that included further clinical variables. The relative predictive importance of each covariate was assessed using XGBoost's importance procedure. Prediction across the entire trial duration for each trial (mean of 34.8 weeks for type 1 diabetes and 25.3 weeks for type 2 diabetes) was assessed. RESULTS: For both type 1 and type 2 diabetes, variables associated with more frequent hypoglycaemia included female sex, white ethnicity, longer diabetes duration, treatment with human as opposed to analogue-only insulin, higher glucose variability, higher score for hypoglycaemia across the 6 week baseline period, lower BP, lower lipid levels and treatment with psychoactive drugs. Prediction of any hypoglycaemia event of any severity was greater than prediction of hypoglycaemia requiring assistance (level 3 hypoglycaemia), for which events were sparser. For prediction of level 1 or worse hypoglycaemia during the whole follow-up period, the AUC was 0.835 (95% CI 0.826, 0.844) in type 1 diabetes and 0.840 (95% CI 0.831, 0.848) in type 2 diabetes. For level 3 hypoglycaemia, the AUC was lower at 0.689 (95% CI 0.667, 0.712) for type 1 diabetes and 0.705 (95% CI 0.662, 0.748) for type 2 diabetes. Compared with the baseline models, almost all the improvement in prediction could be captured by the individual's hypoglycaemia history, glucose variability and blood glucose over a 6 week baseline period. CONCLUSIONS/INTERPRETATION: Although hypoglycaemia rates show large variation according to sociodemographic and clinical characteristics and treatment history, looking at a 6 week period of hypoglycaemia events and glucose measurements predicts future hypoglycaemia risk.

Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review.

BACKGROUND: Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood. PURPOSE: To ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs. DATA SOURCES: MEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework. RESULTS: Fifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified. LIMITATIONS: Studies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors. CONCLUSIONS: Prognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring. PROSPERO REGISTRATION NUMBER: CRD42020208049.

The acceptability of primary care or community-based behavioural interventions for persistent physical symptoms: Qualitative systematic review.

PURPOSE: Persistent physical symptoms (PPS) are often associated with profound physical disability and psychological distress. Interventions for PPS that promote behavioural change aim to reduce levels of symptoms and improve overall functioning in patients. The evidence for these interventions is mixed, with effective relationships between patients and health practitioners (HPs) reported as the key to the success of primary care interventions. The objectives of this systematic review were to synthesize the qualitative evidence and to evaluate the acceptability of behavioural interventions for PPS in primary care, from the perspective of both patients and HPs. METHODS: A comprehensive literature search was conducted in seven major electronic bibliographic databases, to February 2019. The aim was to identify a broad range of literature including, qualitative research, mixed methods research, and qualitative data embedded in trial reports or process evaluations. Fifty-eight full papers were screened against the inclusion criteria. Nine studies were included and quality-assessed. A qualitative evidence synthesis was conducted using thematic synthesis. RESULTS: Some patients and HPs reported positive gains from taking part in or delivering interventions, with appropriate support and explanation of their symptoms important for patients. Barriers appeared to be underpinned by the relationship between the patients and HPs, and by beliefs and attitudes held by both parties. CONCLUSIONS: Patients should be provided with adequate information to make an informed decision about whether an intervention is appropriate for them, and interventions should not end suddenly or without adequate follow-up. HPs should receive training and supervision to address their lack of confidence, and improve their knowledge of PPS.

The suitability of patient-reported outcome measures used to assess the impact of hypoglycaemia on quality of life in people with diabetes: a systematic review using COSMIN methods.

AIMS/HYPOTHESIS: It is generally accepted that hypoglycaemia can negatively impact the quality of life (QoL) of people living with diabetes. However, the suitability of patient-reported outcome measures (PROMs) used to assess this impact is unclear. The aim of this systematic review was to identify PROMs used to assess the impact of hypoglycaemia on QoL and examine their quality and psychometric properties. METHODS: Systematic searches (MEDLINE, EMBASE, PsycINFO, CINAHL and The Cochrane Library databases) were undertaken to identify published articles reporting on the development or validation of hypoglycaemia-specific PROMs used to assess the impact of hypoglycaemia on QoL (or domains of QoL) in adults with diabetes. A protocol was developed and registered with PROSPERO (registration no. CRD42019125153). Studies were assessed for inclusion at title/abstract stage by one reviewer. Full-text articles were scrutinised where considered relevant or potentially relevant or where doubt existed. Twenty per cent of articles were assessed by a second reviewer. PROMS were evaluated, according to COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines, and data were extracted independently by two reviewers against COSMIN criteria. Assessment of each PROM's content validity included reviewer ratings (N = 16) of relevance, comprehensiveness and comprehensibility: by researchers (n = 6); clinicians (n = 6); and adults with diabetes (n = 4). RESULTS: Of the 214 PROMs used to assess the impact of hypoglycaemia on QoL (or domains of QoL), seven hypoglycaemia-specific PROMS were identified and subjected to full evaluation: the Fear of Hypoglycemia 15-item scale; the Hypoglycemia Fear Survey; the Hypoglycemia Fear Survey version II; the Hypoglycemia Fear Survey-II short-form; the Hypoglycemic Attitudes and Behavior Scale; the Hypoglycemic Confidence Scale; and the QoLHYPO questionnaire. Content validity was rated as 'inconsistent', with most as '(very) low' quality, while structural validity was deemed 'unsatisfactory'. Other measurement properties (e.g. reliability) varied, and evidence gaps were apparent across all PROMs. None of the identified studies addressed cross-cultural validity or measurement error. Criterion validity and responsiveness were not assessed due to the lack of a 'gold standard' measure of the impact of hypoglycaemia on QoL against which to compare the PROMS. CONCLUSIONS/INTERPRETATION: None of the hypoglycaemia-specific PROMs identified had sufficient evidence to demonstrate satisfactory validity, reliability and responsiveness. All were limited in terms of content and structural validity, which restricts their utility for assessing the impact of hypoglycaemia on QoL in the clinic or research setting. Further research is needed to address the content validity of existing PROMs, or the development of new PROM(s), for the purpose of assessing the impact of hypoglycaemia on QoL. PROSPERO REGISTRATION: CRD42019125153.

What are the cost-savings and health benefits of improving detection and management for six high cardiovascular risk conditions in England? An economic evaluation.

OBJECTIVES: To estimate the cost savings and health benefits of improving detection of individuals at high risk of cardiovascular disease (CVD) in England, to determine to which patient subgroups these benefits arise, and to compare different strategies for subsequent management. DESIGN: An economic analysis using the School for Public Health Research CVD Prevention Model. SETTING: England 2018. PARTICIPANTS: Adults aged 16 and older with one or more high cardiovascular risk conditions, including hypertension, diabetes, non-diabetic hyperglycaemia, atrial fibrillation, chronic kidney disease and high cholesterol. INTERVENTIONS: Detection of 100% of individuals with CVD high risk conditions compared with current levels of detection in England. Detected individuals are assumed to be managed either according to current levels of care or National Institute of Health and Care Excellence (NICE) guidelines. MAIN OUTCOME MEASURES: Incremental and cumulative costs, savings, quality adjusted life years (QALYs), CVD cases, and net monetary benefit, from a UK NHS and Personal Social Services perspective. RESULTS: £68 billion could be saved, 4.9 million QALYs gained and 3.4 million cases of CVD prevented over 25 years if all individuals in England with the six CVD high risk conditions were diagnosed and subsequently managed at current levels. Additionally, if all detected individuals were managed according to NICE guidelines, total savings would be £61 billion, 8.1 million QALYs would be gained and 5.2 million CVD cases prevented. Most benefits come from detection of high cholesterol in the short term and diabetes in the long term. CONCLUSIONS: Substantial cost savings and health benefits would accrue if all individuals with conditions that increase CVD risk could be diagnosed, with detection of undiagnosed diabetes producing greatest benefits. Ensuring all conditions are managed according to NICE guidelines would further increase health benefits. Projected cost-savings could be invested in developing acceptable and cost-effective solutions for improving detection and management.

Behavioural modification interventions for medically unexplained symptoms in primary care: systematic reviews and economic evaluation.

BACKGROUND: The term 'medically unexplained symptoms' is used to cover a wide range of persistent bodily complaints for which adequate examination and appropriate investigations do not reveal sufficiently explanatory structural or other specified pathologies. A wide range of interventions may be delivered to patients presenting with medically unexplained symptoms in primary care. Many of these therapies aim to change the behaviours of the individual who may have worsening symptoms. OBJECTIVES: An evidence synthesis to determine the clinical effectiveness and cost-effectiveness of behavioural modification interventions for medically unexplained symptoms delivered in primary care settings was undertaken. Barriers to and facilitators of the effectiveness and acceptability of these interventions from the perspective of patients and service providers were evaluated through qualitative review and realist synthesis. DATA SOURCES: Full search strategies were developed to identify relevant literature. Eleven electronic sources were searched. Eligibility criteria - for the review of clinical effectiveness, randomised controlled trials were sought. For the qualitative review, UK studies of any design were included. For the cost-effectiveness review, papers were restricted to UK studies reporting outcomes as quality-adjusted life-year gains. Clinical searches were conducted in November 2015 and December 2015, qualitative searches were conducted in July 2016 and economic searches were conducted in August 2016. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE. Updated searches were conducted in February 2019 and March 2019. PARTICIPANTS: Adult participants meeting the criteria for medically unexplained symptoms, including somatoform disorders, chronic unexplained pain and functional somatic syndromes. INTERVENTIONS: Behavioural interventions were categorised into types. These included psychotherapies, exercise-based interventions, multimodal therapies (consisting of more than one intervention type), relaxation/stretching/social support/emotional support, guided self-help and general practitioner interventions, such as reattribution. Evidence synthesis: a network meta-analysis was conducted to allow a simultaneous comparison of all evaluated interventions in a single coherent analysis. Separate network meta-analyses were performed at three time points: end of treatment, short-term follow-up (< 6 months since the end of treatment) and long-term follow-up (≥ 6 months after the end of treatment). Outcomes included physical and psychological symptoms, physical functioning and impact of the illness on daily activities. Economic evaluation: within-trial estimates of cost-effectiveness were generated for the subset of studies where utility values (or quality-adjusted life-years) were reported or where these could be estimated by mapping from Short Form questionnaire-36 items or Short Form questionnaire-12 items outcomes. RESULTS: Fifty-nine studies involving 9077 patients were included in the clinical effectiveness review. There was a large degree of heterogeneity both between and within intervention types, and the networks were sparse across all outcomes. At the end of treatment, behavioural interventions showed some beneficial effects when compared with usual care, in particular for improvement of specific physical symptoms [(1) pain: high-intensity cognitive-behavioural therapy (CBTHI) standardised mean difference (SMD) 0.54 [95% credible interval (CrI) 0.28 to 0.84], multimodal SMD 0.52 (95% CrI 0.19 to 0.89); and (2) fatigue: low-intensity cognitive-behavioural therapy (CBTLI) SMD 0.72 (95% CrI 0.27 to 1.21), relaxation/stretching/social support/emotional support SMD 0.87 (95% CrI 0.20 to 1.55), graded activity SMD 0.51 (95% CrI 0.14 to 0.93), multimodal SMD 0.52 (95% CrI 0.14 to 0.92)] and psychological outcomes [(1) anxiety CBTHI SMD 0.52 (95% CrI 0.06 to 0.96); (2) depression CBTHI SMD 0.80 (95% CrI 0.26 to 1.38); and (3) emotional distress other psychotherapy SMD 0.58 (95% CrI 0.05 to 1.13), relaxation/stretching/social support/emotional support SMD 0.66 (95% CrI 0.18 to 1.28) and sport/exercise SMD 0.49 (95% CrI 0.03 to 1.01)]. At short-term follow-up, behavioural interventions showed some beneficial effects for specific physical symptoms [(1) pain: CBTHI SMD 0.73 (95% CrI 0.10 to 1.39); (2) fatigue: CBTLI SMD 0.62 (95% CrI 0.11 to 1.14), relaxation/stretching/social support/emotional support SMD 0.51 (95% CrI 0.06 to 1.00)] and psychological outcomes [(1) anxiety: CBTHI SMD 0.74 (95% CrI 0.14 to 1.34); (2) depression: CBTHI SMD 0.93 (95% CrI 0.37 to 1.52); and (3) emotional distress: relaxation/stretching/social support/emotional support SMD 0.82 (95% CrI 0.02 to 1.65), multimodal SMD 0.43 (95% CrI 0.04 to 0.91)]. For physical functioning, only multimodal therapy showed beneficial effects: end-of-treatment SMD 0.33 (95% CrI 0.09 to 0.59); and short-term follow-up SMD 0.78 (95% CrI 0.23 to 1.40). For impact on daily activities, CBTHI was the only behavioural intervention to show beneficial effects [end-of-treatment SMD 1.30 (95% CrI 0.59 to 2.00); and short-term follow-up SMD 2.25 (95% CrI 1.34 to 3.16)]. Few effects remained at long-term follow-up. General practitioner interventions showed no significant beneficial effects for any outcome. No intervention group showed conclusive beneficial effects for measures of symptom load (somatisation). A large degree of heterogeneity was found across individual studies in the assessment of cost-effectiveness. Several studies suggested that the interventions produce fewer quality-adjusted life-years than usual care. For those interventions that generated quality-adjusted life-year gains, the mid-point incremental cost-effectiveness ratios (ICERs) ranged from £1397 to £129,267, but, where the mid-point ICER fell below £30,000, the exploratory assessment of uncertainty suggested that it may be above £30,000. LIMITATIONS: Sparse networks meant that it was not possible to conduct a metaregression to explain between-study differences in effects. Results were not consistent within intervention type, and there were considerable differences in characteristics between studies of the same type. There were moderate to high levels of statistical heterogeneity. Separate analyses were conducted for three time points and, therefore, analyses are not repeated-measures analyses and do not account for correlations between time points. CONCLUSIONS: Behavioural interventions showed some beneficial effects for specific medically unexplained symptoms, but no one behavioural intervention was effective across all medically unexplained symptoms. There was little evidence that these interventions are effective for measures of symptom load (somatisation). General practitioner-led interventions were not shown to be effective. Considerable heterogeneity in interventions, populations and sparse networks mean that results should be interpreted with caution. The relationship between patient and service provider is perceived to play a key role in facilitating a successful intervention. Future research should focus on testing the therapeutic effects of the general practitioner-patient relationship within trials of behavioural interventions, and explaining the observed between-study differences in effects within the same intervention type (e.g. with more detailed reporting of defined mechanisms of the interventions under study). STUDY REGISTRATION: This study is registered as PROSPERO CRD42015025520. 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. 46. See the NIHR Journals Library website for further project information.

The term 'medically unexplained symptoms' is used in relation to individuals who present to their general practitioner with persistent symptoms that cannot easily be explained, even after adequate physical examination and appropriate investigations. Common interventions delivered in primary care tend to be psychological interventions, behaviour therapies or physical exercise therapies. These therapies often aim to change the behaviours of the individual that may make symptoms worse. We conducted systematic reviews of existing evidence to evaluate the effectiveness and acceptability of behavioural interventions delivered in primary care, and a cost-effectiveness analysis to see whether or not they offer good value. Studies measured improvement in outcomes, such as physical or psychological symptoms, or health-related quality of life. There were large differences in the nature of the behavioural interventions delivered and so we grouped them into 'types'. These included intervention types involving exercise (e.g. aerobic or strengthening, or graded activity); different types of psychotherapy, for example cognitive­behavioural therapy; interventions focused on relaxation or social/emotional support; interventions offering education and information; and interventions by general practitioners, for example receiving training on how to implement a behavioural approach to treating medically unexplained symptoms. Statistical analyses were conducted to investigate which, if any, of the intervention types were effective when compared with usual care. Results indicated that some of the behavioural intervention types showed beneficial effects at the end of treatment and at short-term follow-up. In particular, cognitive­behavioural therapy at a higher intensity, and therapies consisting of components of more than one intervention type (i.e. multimodal therapies), showed beneficial effects for specific physical symptoms such as pain, fatigue or bowel symptoms. High-intensity cognitive­behavioural therapy, other types of psychotherapies and interventions focusing on relaxation and social/emotional support showed some beneficial effects on mood outcomes such as depression and anxiety. By long-term follow-up, effects had diminished. More complex measures of symptom load or 'somatisation' showed fewer beneficial effects. We found that no one intervention improved outcomes across all medically unexplained symptoms. However, the results of the statistical analyses should be interpreted with caution. Not only were there differences in the types of behavioural interventions trialled in the included studies, but there were also differences in the characteristics of interventions within the same type. Participants of the studies had a range of symptoms and syndromes, of varying severity and duration. Interventions of the same type varied in how they were delivered, for example the qualifications of the therapist and the contact time spent between therapist and patient. Owing to the limited number of studies in each intervention type, it has not been possible to identify how these differences influenced the results. Interventions delivered by general practitioners themselves did not generally show beneficial effects. However, the relationship between general practitioner and patient was perceived to be important. Patients valued receiving explanations for their symptoms and learning self-management techniques. This was facilitated by good relationships with their health-care practitioner. Health-care practitioners reported a need for training and supervision, but patients reported that the primary care setting was both appropriate and helpful. A successful behavioural intervention should allow a patient and their care provider to maintain a relationship where the patient feels supported. Analyses of the cost-effectiveness of the interventions showed a wide variation in costs. Costs varied between different intervention types, but also between interventions of the same type. Differences in the nature of interventions within the same intervention type, for example whether delivery is to groups or to individuals, make comparisons difficult. Future research should focus on identifying how the relationship between the general practitioner and their patient can influence the effectiveness of a behavioural intervention when it is conducted in the primary care setting. In addition, more research is needed to explore which aspects of the more promising interventions are influencing their effectiveness.

A Cost-Effectiveness Analysis of Newborn Screening for Severe Combined Immunodeficiency in the UK.

Severe combined immunodeficiency (SCID) can be detected through newborn bloodspot screening. In the UK, the National Screening Committee (NSC) requires screening programmes to be cost-effective at standard UK thresholds. To assess the cost-effectiveness of SCID screening for the NSC, a decision-tree model with lifetable estimates of outcomes was built. Model structure and parameterisation were informed by systematic review and expert clinical judgment. A public service perspective was used and lifetime costs and quality-adjusted life years (QALYs) were discounted at 3.5%. Probabilistic, one-way sensitivity analyses and an exploratory disbenefit analysis for the identification of non-SCID patients were conducted. Screening for SCID was estimated to result in an incremental cost-effectiveness ratio (ICER) of £18,222 with a reduction in SCID mortality from 8.1 (5-12) to 1.7 (0.6-4.0) cases per year of screening. Results were sensitive to a number of parameters, including the cost of the screening test, the incidence of SCID and the disbenefit to the healthy at birth and false-positive cases. Screening for SCID is likely to be cost-effective at £20,000 per QALY, key uncertainties relate to the impact on false positives and the impact on the identification of children with non-SCID T Cell lymphopenia.

Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme.

BACKGROUND: A decision tree model was built to estimate the economic impact of introducing screening for X-linked adrenoleukodystrophy (X-ALD) into an existing tandem mass spectrometry based newborn screening programme. The model was based upon the UK National Health Service (NHS) Newborn Blood Spot Screening Programme and a public service perspective was used with a lifetime horizon. The model structure and parameterisation were based upon literature reviews and expert clinical judgment. Outcomes included health, social care and education costs and quality adjusted life years (QALYs). The model assessed screening of boys only and evaluated the impact of improved outcomes from hematopoietic stem cell transplantation in patients with cerebral childhood X-ALD (CCALD). Threshold analyses were used to examine the potential impact of utility decrements for non-CCALD patients identified by screening. RESULTS: It is estimated that screening 780,000 newborns annually will identify 18 (95%CI 12, 27) boys with X-ALD, of whom 10 (95% CI 6, 15) will develop CCALD. It is estimated that screening may detect 7 (95% CI 3, 12) children with other peroxisomal disorders who may also have arisen symptomatically. If results for girls are returned an additional 17 (95% CI 12, 25) cases of X-ALD will be identified. The programme is estimated to cost an additional £402,000 (95% CI £399-407,000) with savings in lifetime health, social care and education costs leading to an overall discounted cost saving of £3.04 (95% CI £5.69, £1.19) million per year. Patients with CCALD are estimated to gain 8.5 discounted QALYs each giving an overall programme benefit of 82 (95% CI 43, 139) QALYs. CONCLUSION: Including screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non-CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs.

Searching for trial protocols: A comparison of methods.

INTRODUCTION: Registration and publication of trial protocols has become increasingly important and a requirement in some sources of funding and publication. Increased access to protocols yields many potential benefits, but there are issues regarding identification of published protocols. The aim of this investigation is to compare methods of retrieval for identifying trial protocols in a systematic review. METHODS: Six stages of searching (checking published trial reports, searching journal Web sites, Internet searching, trial registers, bibliographic databases, and contact with authors) were completed to identify 74 trial protocols. RESULTS: Fifty-seven percent of the trial protocols were identified upon completion of all 6 stages of searching. The most comprehensive method was searching trial registers that identified 51% of the protocols. Contact with authors was most effective at uniquely identifying protocols; 12% were retrieved via this single method. Contact with authors was the only effective method of identifying protocols for trials pre-2005. DISCUSSION: When attempting to identify trial protocols to include in systematic reviews, some methods are relatively quick to undertake but deliver a low yield. The most effective search strategy for most sources was retrieval by trial registration number where available. CONCLUSIONS: For protocols of trial results published pre-2005, review authors should contact authors as a priority. For protocols post-2005, they should check the trial publication for protocol details, search trial registers, and contact authors, ceasing searching once a predetermined point of diminishing returns has been reached.

Factors affecting mortality in older trauma patients-A systematic review and meta-analysis.

INTRODUCTION: Major trauma in older people is a significant health burden in the developed world. The aging of the population has resulted in larger numbers of older patients suffering serious injury. Older trauma patients are at greater risk of death from major trauma, but the reasons for this are less well understood. The aim of this review was to identify the factors affecting mortality in older patients suffering major injury. MATERIALS AND METHODS: A systematic review of Medline, Cinhal and the Cochrane database, supplemented by a manual search of relevant papers was undertaken, with meta-analysis. Multi-centre cohort studies of existing trauma registries that reported risk-adjusted mortality (adjusted odds ratios, AOR) in their outcomes and which analysed patients aged 65 and older as a separate cohort were included in the review. RESULTS: 3609 papers were identified from the electronic databases, and 28 from manual searches. Of these, 15 papers fulfilled the inclusion criteria. Demographic variables (age and gender), pre-existing conditions (comorbidities and medication), and injury-related factors (injury severity, pattern and mechanism) were found to affect mortality. The 'oldest old', aged 75 and older, had higher mortality rates than younger patients, aged 65-74 years. Older men had a significantly higher mortality rate than women (cumulative odds ratio 1.51, 95% CI 1.37-1.66). Three papers reported a higher risk of death in patients with pre-existing conditions. Two studies reported increased mortality in patients on warfarin (cumulative odds ratio 1.32, 95% CI 1.05-1.66). Higher mortality was seen in patients with lower Glasgow coma scores and systolic blood pressures. Mortality increased with increased injury severity and number of injuries sustained. Low level falls were associated with higher mortality than motor vehicle collisions (cumulative odds ratio 2.88, 95% CI 1.26-6.60). CONCLUSIONS: Multiple factors contribute to mortality risk in older trauma patients. The relation between these factors and mortality is complex, and a fuller understanding of the contribution of each factor is needed to develop a better predictive model for trauma outcomes in older people. More research is required to identify patient and process factors affecting mortality in older patients.

What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation.

BACKGROUND: Tobacco smoking is one of the leading causes of deaths worldwide. Nearly one-fifth of adults in the UK regularly smoke cigarettes. The ill-health associated with smoking costs the NHS over £3B every year. A number of pharmacological interventions are available that can help people to quit smoking. These include nicotinic receptor partial agonists such as varenicline or cytisine. Varenicline is a synthetic product licensed for use in the UK, while cytisine is derived naturally from the seeds of the plant Cytisus laborinum L. (golden rain acacia). OBJECTIVES: To review the evidence on the clinical effectiveness and safety of cytisine from smoking cessation compared with varenicline; to develop an economic model to estimate the cost-effectiveness of cytisine and varenicline; and to provide recommendations based on value of information analyses as to whether or not a head-to-head trial of cytisine and varenicline would represent effective use of resources. DATA SOURCES: Efficacy and adverse events data were sourced from a recent Cochrane review. These data were supplemented with an updated search of twelve electronic databases, including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature and The Cochrane Library, for the period from December 2011 to January 2013. The review included randomised controlled trials (RCTs) of adult smokers attempting to quit using varenicline or cytisine. Further interventions were considered (placebo, nicotine replacement therapy, bupropion) to allow an indirect comparison between varenicline and cytisine. The primary outcome was abstinence at a minimum of 6 months' follow-up. Secondary outcomes were common adverse events such as abnormal dreams, headache, nausea, insomnia and serious adverse events. REVIEW METHODS: A systematic review and network meta-analysis of the clinical evidence was undertaken. A random-effects model was used to allow for heterogeneity between studies. The economic model structure was based on a published model. Probabilistic sensitivity analyses were undertaken to estimate the treatment expected to be most cost-effective given current information. Formal expected value of perfect information, perfect partial information and of sample information were performed. RESULTS: Twenty-three (RCTs) were included in the systematic review, comprising a total of 10,610 participants. Twenty-one trials of varenicline of differing dosing schedules and two trials of cytisine at standard dose met the inclusion criteria. No head-to-head trials comparing varenicline with cytisine were identified. The methodological quality of the studies was judged to be moderate to good. Cytisine was more efficacious than placebo [hazard ratio (HR) 4.27, 95% credible interval (CrI) 2.05 to 10.05], as was standard-dose varenicline (HR 2.58, 95% Crl 2.16 to 3.15). Standard-dose varenicline treatment was associated with significantly higher rates of headache, insomnia and nausea than placebo; there was no significant difference in the rates of abnormal dreams. There were no significant differences in the rates of headache or nausea between cytisine and placebo; data were identified for neither abnormal dreams nor insomnia. Using expected values, cytisine is anticipated to dominate varenicline, in that it produces more quality-adjusted life-years at a lower associated cost. This occurred in approximately 90% of the scenarios performed. However, owing to the large number of people who wish to quit smoking (estimated to be 3 million over a 10-year period), the implications of making an incorrect decision is large. The expected value of sample information indicated that conducting a head-to-head trial of cytisine and varenicline was worthwhile, and that 1000 smokers per arm was an appropriate number to recruit. CONCLUSIONS: On the basis of the evidence included in this review, varenicline and cytisine are both effective interventions to aid smoking cessation when compared with placebo. Cytisine is estimated to be both more clinically effective and cost-effective than varenicline. However, there is uncertainty in the decision, and a head-to-head trial of cytisine and varenicline would appear to be an effective use of resources. STUDY REGISTRATION: The study was registered as PROSPERO CRD42012003455. FUNDING DETAILS: The National Institute for Health Research Health Technology Assessment programme.

Is group cognitive behaviour therapy for postnatal depression evidence-based practice? A systematic review.

BACKGROUND: There is evidence that psychological therapies including cognitive behaviour therapy (CBT) may be effective in reducing postnatal depression (PND) when offered to individuals. In clinical practice, this is also implemented in a group therapy format, which, although not recommended in guidelines, is seen as a cost-effective alternative. To consider the extent to which group methods can be seen as evidence-based, we systematically review and synthesise the evidence for the efficacy of group CBT compared to currently used packages of care for women with PND, and we discuss further factors which may contribute to clinician confidence in implementing an intervention. METHODS: Seventeen electronic databases were searched. All full papers were read by two reviewers and a third reviewer was consulted in the event of a disagreement on inclusion. Selected studies were quality assessed, using the Cochrane Risk of Bias Tool, were data extracted by two reviewers using a standardised data extraction form and statistically synthesised where appropriate using the fixed-effect inverse-variance method. RESULTS: Seven studies met the inclusion criteria. Meta-analyses showed group CBT to be effective in reducing depression compared to routine primary care, usual care or waiting list groups. A pooled effect size of d = 0.57 (95% CI 0.34 to 0.80, p < 0.001) was observed at 10-13 weeks post-randomisation, reducing to d = 0.28 (95% CI 0.03 to 0.53, p = 0.025) at 6 months. The non-randomised comparisons against waiting list controls at 10-13 weeks was associated with a larger effect size of d = 0.94 (95% CI 0.42 to 1.47, p < 0.001). However due to the limitations of the available data, such as ill-specified definitions of the CBT component of the group programmes, these results should be interpreted with caution. CONCLUSIONS: Although the evidence available is limited, group CBT was shown to be effective. We argue, therefore, that there is sufficient evidence to implement group CBT, conditional upon routinely collected outcomes being benchmarked against those obtained in trials of individual CBT, and with other important factors such as patient preference, clinical experience, and information from the local context taken into account when making the treatment decision.

A qualitative evidence synthesis of employees' views of workplace smoking reduction or cessation interventions.

BACKGROUND: The need to reduce smoking rates is a recognised public health policy issue in many countries. The workplace offers a potential context for offering smokers' programmes and interventions to assist smoking cessation or reduction. A qualitative evidence synthesis of employees' views about such programmes might explain why some interventions appear effective and others not, and can be used to develop evidence-based interventions for this population and setting. METHODS: A qualitative evidence synthesis of primary research exploring employees' views about workplace interventions to encourage smoking cessation, including both voluntary programmes and passive interventions, such as restrictions or bans. The method used was theory-based "best fit" framework synthesis. RESULTS: Five relevant theories on workplace smoking cessation were identified and used as the basis for an a priori framework. A comprehensive literature search, including interrogation of eight databases, retrieved 747 unique citations for the review. Fifteen primary research studies of qualitative evidence were found to satisfy the inclusion criteria. The synthesis produced an evidence-based conceptual model explaining employees' experiences of, and preferences regarding, workplace smoking interventions. CONCLUSION: The synthesis suggests that workplace interventions should employ a range of different elements if they are to prove effective in reducing smoking among employees. This is because an employee who feels ready and able to change their behaviour has different needs and preferences from an employee who is not at that stage. Only a multi-faceted intervention can satisfy the requirements of all employees.

"Best fit" framework synthesis: refining the method.

BACKGROUND: Following publication of the first worked example of the "best fit" method of evidence synthesis for the systematic review of qualitative evidence in this journal, the originators of the method identified a need to specify more fully some aspects of this particular derivative of framework synthesis. METHODS AND RESULTS: We therefore present a second such worked example in which all techniques are defined and explained, and their appropriateness is assessed. Specified features of the method include the development of new techniques to identify theories in a systematic manner; the creation of an a priori framework for the synthesis; and the "testing" of the synthesis. An innovative combination of existing methods of quality assessment, analysis and synthesis is used to complete the process. This second worked example was a qualitative evidence synthesis of employees' views of workplace smoking cessation interventions, in which the "best fit" method was found to be practical and fit for purpose. CONCLUSIONS: The method is suited to producing context-specific conceptual models for describing or explaining the decision-making and health behaviours of patients and other groups. It offers a pragmatic means of conducting rapid qualitative evidence synthesis and generating programme theories relating to intervention effectiveness, which might be of relevance both to researchers and policy-makers.

Heart-type fatty acid binding protein as an early marker for myocardial infarction: systematic review and meta-analysis.

BACKGROUND: Heart-type fatty acid binding protein (H-FABP) has been proposed as an early biomarker of myocardial infarction (MI). The authors aimed to undertake a systematic review and meta-analysis to estimate the early sensitivity and specificity of quantitative and qualitative H-FABP assays. METHODS: The authors undertook a systematic search using electronic databases, citation lists and expert contacts to identify all diagnostic cohort studies of patients presenting with suspected acute coronary syndrome that compared H-FABP at presentation to a reference standard based on the Universal definition of MI. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Meta-analysis was conducted using Bayesian Markov chain Monte Carlo simulation. RESULTS: The authors included eight studies of quantitative H-FABP and nine studies of qualitative H-FABP. The summary estimates of sensitivity and specificity were 81% (95% prediction interval 50% to 95%) and 80% (26% to 98%) respectively for the quantitative assays and 68% (11% to 97%) and 92% (20% to 100%) respectively for the qualitative assays. Four studies reported the sensitivity of troponin and H-FABP at presentation in which the combination was considered positive if either test was positive. The addition of H-FABP to troponin increased sensitivity from 42-75% to 76-97% but decreased specificity from 94-100% to 65-93%. CONCLUSION: H-FABP has modest sensitivity and specificity for MI at presentation but estimates are subject to substantial uncertainty and primary data are subject to substantial heterogeneity. H-FABP may have a role alongside troponin in improving early sensitivity but comparison with high sensitivity troponin assays is required.

Unhappiness and dissatisfaction in doctors cannot be predicted by selectors from medical school application forms: a prospective, longitudinal study.

BACKGROUND: Personal statements and referees' reports are widely used on medical school application forms, particularly in the UK, to assess the suitability of candidates for a career in medicine. However there are few studies which assess the validity of such information for predicting unhappiness or dissatisfaction with a career in medicine. Here we combine data from a long-term prospective study of medical student selection and training, with an experimental approach in which a large number of assessors used a paired comparison technique to predict outcome. METHODS: Data from a large-scale prospective study of students applying to UK medical schools in 1990 were used to identify 40 pairs of doctors, matched by sex, for whom personal statements and referees' reports were available, and who in a 2002/3 follow-up study, one pair member was very satisfied and the other very dissatisfied with medicine as a career. In 2005, 96 assessors, who were experienced medical school selectors, doctors, medical students or psychology students, used information from the doctors' original applications to judge which member of each pair of doctors was the happier, more satisfied doctor. RESULTS: None of the groups of assessors were significantly different from chance expectations in using applicants' personal statements and the referees' reports to predict actual future satisfaction or dissatisfaction, the distribution being similar to binomial expectations. However judgements of pairs of application forms from pairs of doctors showed a non-binomial distribution, indicating consensus among assessors as to which doctor would be the happy doctor (although the consensus was wrong in half the cases). Assessors taking longer to do the task concurred more. Consensus judgements seem mainly to be based on referees' predictions of academic achievement (even though academic achievement is not actually a valid predictor of happiness or satisfaction). CONCLUSION: Although widely used in medical student selection to assess motivation, interest and commitment to a medical career, the personal statement and the referee's report cannot validly be used by assessors, including experienced medical school selectors, to identify doctors who will subsequently be dissatisfied with a medical career.