Altered Osteoblast Metabolism with Aging Results in Lipid Accumulation and Oxidative Stress Mediated Bone Loss.

Cellular aging is associated with dysfunction of numerous tissues affecting multiple organ systems. A striking example of this is related to age-related bone loss, or osteoporosis, increasing fracture incidence. Interestingly, the two compartments of bone, cortical and cancellous or trabecular, rely on different mechanisms for development and maintenance during 'normal' aging. At a cellular level, the aging process disturbs a multitude of intracellular pathways. In particular, alterations in cellular metabolic functions thereby impacting cellular bioenergetics have been implicated in multiple tissues. Therefore, this study aimed to characterize how metabolic processes were altered in bone forming osteoblasts in aged mice compared to young mice. Metabolic flux analyses demonstrated both stromal cells and mature, matrix secreting osteoblasts from aged mice exhibited mitochondrial dysfunction. This was also accompanied by a lack of adaptability or metabolic flexibility to utilize exogenous substrates compared to osteoblasts cultured from young mice. Additionally, lipid droplets accumulated in both early stromal cells and mature osteoblasts from aged mice, which was further depicted as increased lipid content within the bone cortex of aged mice. Global transcriptomic analysis of the bone further supported these metabolic data as enhanced oxidative stress genes were up-regulated in aged mice, while osteoblast-related genes were down-regulated when compared to the young mice. Collectively, these data suggest that aging results in altered osteoblast metabolic handling of both exogenous and endogenous substrates which could contribute to age-related osteoporosis.

Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status.

Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders. Glucose has been considered the principal substrate for osteoblasts, although fatty acids are also important for osteoblast function. Here, we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation. As such, we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation. Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function. The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions. In vivo, conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism. Collectively, our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets, which are released via lipolysis to support cellular bioenergetic status when nutrients are limited. Perturbations in this process result in impairment of bone formation, specifically reducing ATP production and overall osteoblast function.

Advanced statistics identification of participant and treatment predictors associated with severe adverse effects induced by fluoropyrimidine-based chemotherapy.

PURPOSE: Adverse effects following fluoropyrimidine-based chemotherapy regimens are common. However, there are no current accepted diagnostic markers for prediction prior to treatment, and the underlying mechanisms remain unclear. This study aimed to determine genetic and non-genetic predictors of adverse effects. METHODS: Genomic DNA was analyzed for 25 single nucleotide polymorphisms (SNPs). Demographics, comorbidities, cancer and fluoropyrimidine-based chemotherapy regimen types, and adverse effect data were obtained from clinical records for 155 Australian White participants. Associations were determined by bivariate analysis, logistic regression modeling and Bayesian network analysis. RESULTS: Twelve different adverse effects were observed in the participants, the most common severe adverse effect was diarrhea (12.9%). Bivariate analysis revealed associations between all adverse effects except neutropenia, between genetic and non-genetic predictors, and between 8 genetic and 12 non-genetic predictors with more than 1 adverse effect. Logistic regression modeling of adverse effects revealed a greater/sole role for six genetic predictors in overall gastrointestinal toxicity, nausea and/or vomiting, constipation, and neutropenia, and for nine non-genetic predictors in diarrhea, mucositis, neuropathy, generalized pain, hand-foot syndrome, skin toxicity, cardiotoxicity and fatigue. The Bayesian network analysis revealed less directly associated predictors (one genetic and six non-genetic) with adverse effects and confirmed associations between six adverse effects, eight genetic predictors and nine non-genetic predictors. CONCLUSION: This study is the first to link both genetic and non-genetic predictors with adverse effects following fluoropyrimidine-based chemotherapy. Collectively, we report a wealth of information that warrants further investigation to elucidate the clinical significance, especially associations with genetic predictors and adverse effects.

Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma.

BACKGROUND: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER: NCT01176474 and NCT02970981.

Variations in policies for accessing elective musculoskeletal procedures in the English National Health Service: A documentary analysis.

OBJECTIVE: The overall aim of this study was to investigate how commissioning policies for accessing clinical procedures compare in the context of the English National Health Service. Our primary objective was to compare policy wording and categorise any variations identified. Our secondary objective was to explore how any points of variation relate to national guidance. METHODS: This study entailed documentary analysis of commissioning policies that stipulated criteria for accessing eight elective musculoskeletal procedures. For each procedure, we retrieved policies held by regions with higher and lower rates of clinical activity relative to the national average. Policies were subjected to content and thematic analysis, using constant comparison techniques. Matrices and descriptive reports were used to compare themes across policies for each procedure and derive categories of variation that arose across two or more procedures. National guidance relating to each procedure were identified and scrutinised, to explore whether these provided context for explaining the policy variations. RESULTS: Thirty-five policy documents held by 14 geographic regions were included in the analysis. Policies either focused on a single procedure/treatment or covered several procedures/treatments in an all-encompassing document. All policies stipulated criteria that needed to be fulfilled prior to accessing treatment, but there were inconsistences in the evidence cited. Policies varied in recurring ways, with respect to specification of non-surgical treatments and management, requirements around time spent using non-surgical approaches, diagnostic requirements, requirements around symptom severity and disease progression, and use of language, in the form of terms and phrases ('threshold modifiers') which could open up or restrict access to care. National guidance was identified for seven of the procedures, but this guidance did not specify criteria for accessing the procedures in question, making direct comparisons with regional policies difficult. CONCLUSIONS: This, to our knowledge, is the first study to identify recurring ways in which policies for accessing treatment can vary within a single-payer system with universal coverage. The findings raise questions around whether formulation of commissioning policies should receive more central support to promote greater consistency - especially where evidence is uncertain, variable or lacking.

Interventions in sexual and reproductive health services addressing violence against women in low-income and middle-income countries: a mixed-methods systematic review.

OBJECTIVES: To synthesise evidence on the effectiveness, cost-effectiveness and barriers to responding to violence against women (VAW) in sexual and reproductive health (SRH) services in low/middle-income countries (LMICs). DESIGN: Mixed-methods systematic review. DATA SOURCES: Medline, Embase, Psycinfo, Cochrane, Cinahl, IMEMR, Web of Science, Popline, Lilacs, WHO RHL, ClinicalTrials.gov, Google, Google Scholar, websites of key organisations through December 2019. ELIGIBILITY CRITERIA: Studies of any design that evaluated VAW interventions in SRH services in LMICs. DATA EXTRACTION AND SYNTHESIS: Concurrent narrative quantitative and thematic qualitative syntheses, integration through line of argument and mapping onto a logic model. Two reviewers extracted data and appraised quality. RESULTS: 26 studies of varied interventions using heterogeneous outcomes. Of ten interventions that strengthened health systems capacity to respond to VAW during routine SRH consultation, three reported no harm and reduction in some types of violence. Of nine interventions that strengthened health systems and communities' capacity to respond to VAW, three reported conflicting effects on re-exposure to some types of VAW and mixed effect on SRH. The interventions increased identification of VAW but had no effect on the provision (75%-100%) and uptake (0.6%-53%) of referrals to VAW services. Of seven psychosocial interventions in addition to SRH consultation that strengthened women's readiness to address VAW, four reduced re-exposure to some types of VAW and improved health. Factors that disrupted the pathway to better outcomes included accepting attitudes towards VAW, fear of consequences and limited readiness of the society, health systems and individuals. No study evaluated cost-effectiveness. CONCLUSIONS: Some VAW interventions in SRH services reduced re-exposure to some types of VAW and improved some health outcomes in single studies. Future interventions should strengthen capacity to address VAW across health systems, communities and individual women. First-line support should be better tailored to women's needs and expectations. PROSPERO REGISTRATION NUMBER: CRD42019137167.

Untargeted metabolomics in primary murine bone marrow stromal cells reveals distinct profile throughout osteoblast differentiation.

INTRODUCTION: Skeletal homeostasis is an exquisitely regulated process most directly influenced by bone resorbing osteoclasts, bone forming osteoblasts, and the mechano-sensing osteocytes. These cells work together to constantly remodel bone as a mechanism to prevent from skeletal fragility. As such, when an individual experiences a disconnect in these tightly coupled processes, fracture incidence increases, such as during ageing, gonadal hormone deficiency, weightlessness, and diabetes. While therapeutic options have significantly aided in the treatment of low bone mineral density (BMD) or osteoporosis, limited options remain for anabolic or bone forming agents. Therefore, it is of interest to continue to understand how osteoblasts regulate their metabolism to support the energy expensive process of bone formation. OBJECTIVE: The current project sought to rigorously characterize the distinct metabolic processes and intracellular metabolite profiles in stromal cells throughout osteoblast differentiation using untargeted metabolomics. METHODS: Primary, murine bone marrow stromal cells (BMSCs) were characterized throughout osteoblast differentiation using standard staining protocols, Seahorse XFe metabolic flux analyses, and untargeted metabolomics. RESULTS: We demonstrate here that the metabolic footprint of stromal cells undergoing osteoblast differentiation are distinct, and while oxidative phosphorylation drives adenosine triphosphate (ATP) generation early in the differentiation process, mature osteoblasts depend on glycolysis. Importantly, the intracellular metabolite profile supports these findings while also suggesting additional pathways critical for proper osteoblast function. CONCLUSION: These data are the first of their kind to characterize these metabolites in conjunction with the bioenergetic profile in primary, murine stromal cells throughout osteoblast differentiation and provide provocative targets for future investigation.

What empirical research has been undertaken on the ethics of clinical research in India? A systematic scoping review and narrative synthesis.

INTRODUCTION: The 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. METHODS: Our 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. RESULTS: Titles/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. CONCLUSION: The 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.

Recovery from chronic fatigue syndrome: a systematic review-heterogeneity of definition limits study comparison.

BACKGROUND: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a common illness with a major impact on quality of life. Recovery is poorly understood. Our aim was to describe definitions of recovery in paediatric CFS/ME, the rate of recovery and the time to recovery. METHODS: This systematic review included a detailed search of MEDLINE, EMBASE, PsycInfo and Cochrane Library between 1994 and July 2018. Inclusion criteria were (1) clinical trials and observational studies, (2) participants aged <19 years with CFS/ME, (3) conducted in Western Healthcare systems and (4) studies including a measure of recovery and time taken to recover. RESULTS: Twelve papers (10 studies) were identified, involving 826 patients (range 23-135). Recovery rates were highly varied, ranging between 4.5% and 83%.Eleven distinct definitions of recovery were used; six were composite outcomes while five used unidimensional outcomes. Outcome measures used to define recovery were highly heterogeneous. School attendance (n=8), fatigue (n=6) and physical functioning (n=4) were the most common outcomes included in definition of recovery. Only five definitions included a personal measure of recovery. IMPLICATIONS: Definitions of recovery are highly variable, likely secondary to differences in study design, outcomes used, follow-up and study populations. Heterogeneous definitions of recovery limit meaningful comparison between studies, highlighting the need for a consensus definition going forward. Recovery is probably best defined from the child's own perspective with a single self-reported measure. If composite measures are used for research, there should be agreement on the core outcome set used.

Antipsychotic Polypharmacy and Metabolic Syndrome in Schizophrenia: A Review of Systematic Reviews.

(Reprinted with permission from BMC Psychiatry (2018) 18:275).

Survival and late toxicities following concurrent chemo-radiotherapy for locally advanced stage III non-small cell lung cancer: findings of a 10-year Australian single centre experience with long term clinical follow up.

BACKGROUND: The preferred management of patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemo-radiotherapy (CRT). Acute CRT-related toxicities are well defined, however, less is known about late toxicities. The aim of the study was to examine the outcomes and late toxicities in Stage III NSCLC treated with CRT. METHODS: A retrospective review of the data from patients with stage III NSCLC treated with CRT was performed between May 2000 and June 2010. Demographics, tumour and treatment characteristics, toxicities and survival data were examined from hospital records of the patients. Progression free survival (PFS) and overall survival (OS) were evaluated by standard Kaplan-Meier survival curves. The censor date was set on 31 October 2016. RESULTS: Sixty-three patients were identified with a median age of 66.6 years [interquartile range (IQR) 57.2-72.1], two-third (n=41, 65.1%) were male, majority were current or ex-smokers (n=52, 82.5%), 42 (66.7%) patients had stage IIIB disease and 21 (33.3%) had stage IIIA disease. The most common histologic subtype was adenocarcinoma 30 (47.6%). The median PFS and OS of the whole population was 10.6 months (95% CI, 4.1-17.3 months) and 21 months (95% CI, 12.7-29.3 months) respectively. The 5-year OS rates for stage IIIA and IIIB were 24% and 16% respectively. The 1-, 3- and 5-year OS rates for all patients were 63.5%, 46% and 18.7% respectively. Acute grade 3 and 4 toxicities included 28 haematological and 17 non-haematological events. The incidence of late toxicities was 58.9%. Thirty-three events of late grade 3 and 4 toxicities were recorded. The most common late toxicity was symptomatic radiation-induced pulmonary fibrosis (39.3%), others include ototoxicity (7.1%), persistent dysphagia (7.1%) and one case of acute myeloid leukaemia. All patients that were alive at the censor date had developed radiation-induced fibrosis with associated symptoms of respiratory insufficiency. CONCLUSIONS: The 5-year OS of patients with stage III NSCLC treated with CRT was in keeping with survival figures reported from prospective clinical trials. There is, however, significant morbidity associated with long-term survival and this should be taken into account when making informed treatment decisions.

Directly Acting Oral Anticoagulants for the Prevention of Stroke in Atrial Fibrillation in England and Wales: Cost-Effectiveness Model and Value of Information Analysis.

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.

Antipsychotic polypharmacy and metabolic syndrome in schizophrenia: a review of systematic reviews.

BACKGROUND: There is conflicting evidence on the association between antipsychotic polypharmacy and metabolic syndrome in schizophrenia. We conducted a review of published systematic reviews to evaluate evidence on the association between metabolic syndrome (diabetes, hypertension, and hyperlipidaemia) and exposure to antipsychotic polypharmacy in schizophrenia. METHODS: We searched five electronic databases, complemented by reference screening, to find systematic reviews that investigated the association of antipsychotic polypharmacy in schizophrenia with hypertension, diabetes, or hyperlipidaemia. Selection of reviews, data extraction and review quality were conducted independently by two people and disagreements resolved by discussion. Results were synthesised narratively. RESULTS: We included 12 systematic reviews, which reported heterogeneous results, mostly with narrative syntheses and without pooled data. The evidence was rated as low quality. There was some indication of a possible protective effect of drug combinations including aripiprazole for diabetes and hyperlipidaemias, compared to other combinations and/or monotherapy. Only one review reported the association between APP and hypertension. The most frequently reported combinations of medication included clozapine, possibly representing a sample of patients with treatment resistant illness. No included review reported results separately by setting (primary or secondary care). CONCLUSIONS: Further robust studies are needed to elucidate the possible protective effect of aripiprazole. Long-term prospective studies are required for accurate appraisal of diabetes risk, hypertension and hyperlipidaemia in patients exposed to antipsychotic polypharmacy.

Can early warning scores identify deteriorating patients in pre-hospital settings? A systematic review.

OBJECTIVE: To evaluate the effectiveness and predictive accuracy of early warning scores (EWS) to predict deteriorating patients in pre-hospital settings. METHODS: Systematic review. Seven databases searched to August 2017. Study quality was assessed using QUADAS-2. A narrative synthesis is presented. ELIGIBILITY: Studies that evaluated EWS predictive accuracy or that compared outcomes in populations that did or did not use EWS, in any pre-hospital setting were eligible for inclusion. EWS were included if they aggregated three or more physiological parameters. RESULTS: Seventeen studies (157,878 participants) of predictive accuracy were included (16 in ambulance service and 1 in nursing home). AUCs ranged from 0.50 (CI not reported) to 0.89 (95%CI 0.82, 0.96). AUCs were generally higher (>0.80) for prediction of mortality within short time frames or for combination outcomes that included mortality and ICU admission. Few patients with low scores died at any time point. Patients with high scores were at risk of deterioration. Results were less clear for intermediate thresholds (≥4 or 5). Five studies were judged at low or unclear risk of bias, all others were judged at high risk of bias. CONCLUSIONS: Very low and high EWS are able to discriminate between patients who are not likely and those who are likely to deteriorate in the pre-hospital setting. No study compared outcomes pre- and post-implementation of EWS so there is no evidence on whether patient outcomes differ between pre-hospital settings that do and do not use EWS. Further studies are required to address this question and to evaluate EWS in pre-hospital settings.

Application of causal inference methods in the analyses of randomised controlled trials: a systematic review.

BACKGROUND: Applications of causal inference methods to randomised controlled trial (RCT) data have usually focused on adjusting for compliance with the randomised intervention rather than on using RCT data to address other, non-randomised questions. In this paper we review use of causal inference methods to assess the impact of aspects of patient management other than the randomised intervention in RCTs. METHODS: We identified papers that used causal inference methodology in RCT data from Medline, Premedline, Embase, Cochrane Library, and Web of Science from 1986 to September 2014, using a forward citation search of five seminal papers, and a keyword search. We did not include studies where inverse probability weighting was used solely to balance baseline characteristics, adjust for loss to follow-up or adjust for non-compliance to randomised treatment. Studies where the exposure could not be assigned were also excluded. RESULTS: There were 25 papers identified. Nearly half the papers (11/25) estimated the causal effect of concomitant medication on outcome. The remainder were concerned with post-randomisation treatment regimens (sequential treatments, n =5 ), effects of treatment timing (n = 2) and treatment dosing or duration (n = 7). Examples were found in cardiovascular disease (n = 5), HIV (n = 7), cancer (n = 6), mental health (n = 4), paediatrics (n = 2) and transfusion medicine (n = 1). The most common method implemented was a marginal structural model with inverse probability of treatment weighting. CONCLUSIONS: Examples of studies which exploit RCT data to address non-randomised questions using causal inference methodology remain relatively limited, despite the growth in methodological development and increasing utilisation in observational studies. Further efforts may be needed to promote use of causal methods to address additional clinical questions within RCTs to maximise their value.

Interventions for preventing or treating malnutrition in homeless problem-drinkers: a systematic review.

BACKGROUND: Excessive drinking leads to poor absorption of nutrients and homeless problem-drinkers often have nutritionally inadequate diets. Depletion of nutrients such as vitamin B1 can lead to cognitive impairment, which can hinder efforts to reduce drinking or engage with services. This review aimed to assess effectiveness of interventions designed to prevent or treat malnutrition in homeless problem-drinkers. METHODS: We systematically searched nine electronic databases and 13 grey literature sources for studies evaluating interventions to improve nutrition in homeless populations, without regional or language restrictions. Screening for inclusion was done in duplicate. One reviewer extracted data and assessed risk of bias, and another checked the extractions. Primary outcomes were nutrition status/deficiency, liver damage, and cognitive function. Secondary outcomes included abstinence, comorbidities, resource use, acceptability and engagement with intervention. Results were synthesised narratively. RESULTS: We included 25 studies (2 Randomised Controlled Trials; 15 uncontrolled before and after; 7 surveys; 1 case-control). Nine studies evaluated educational and support interventions, five food provision, and three supplement provision. Eight studies evaluated a combination of these interventions. No two interventions were the same, and all studies were at high risk of bias. Nutritional status (intake/ deficiency) were reported in 11 studies and liver function in one. Fruit and vegetable intake improved with some education and support interventions (n = 4 studies) but not others (n = 2). Vitamin supplements appeared to improve vitamin deficiency levels in the blood (n = 2). Free or subsidised meals (n = 4) and food packs (n = 1) did not always fulfil dietary needs, but were usually considered acceptable by users. Some multicomponent interventions improved nutrition (n = 3) but acceptability varied (n = 3). No study reported cost effectiveness. CONCLUSIONS: The evidence for any one intervention for improving malnutrition in homeless problem-drinkers was based on single studies at high risk of bias. Various food and supplement provision interventions appear effective in changing nutritional status in single studies. Educational and multicomponent interventions show improved nutritional behaviour in some studies but not others. Further better quality evidence is required before these interventions can be recommended for implementation. Any future studies should seek the end user input in their design and conduct. TRIAL REGISTRATION: Registered with PROSPERO: CRD42015024247 .

Quality of family relationships and outcomes of dementia: a systematic review.

OBJECTIVES: To evaluate the association between the quality of relationship between a person with dementia and their family carer and outcomes for the person with dementia. DESIGN: Systematic review. ELIGIBILITY CRITERIA: Cohort studies of people with clinically diagnosed dementia and their main carers. Exposures of interest were any elements of relationship quality, for example, attachment style, expressed emotion and coping style. Our primary outcome was institutionalisation, and secondary outcomes were hospitalisation, death, quality of life and behavioural and psychiatric symptoms of dementia ('challenging behaviour'). DATA SOURCES: MEDLINE, Embase, Web of Science, PsycInfo, the Cochrane Library and Opengrey were searched from inception to May 2017. STUDY APPRAISAL AND SYNTHESIS METHODS: The Newcastle-Ottawa Scale was used to assess risk of bias. A narrative synthesis of results was performed due to differences between studies. RESULTS: Twenty studies were included. None of the studies controlled for all prespecified confounding factors (age, gender, socioeconomic status and severity of dementia). Reporting of results was inadequate with many studies simply reporting whether associations were 'statistically significant' without providing effect size estimates or CIs. There was a suggestion of an association between relationship factors and global challenging behaviour. All studies evaluating global challenging behaviour provided statistical evidence of an association (most P values below 0.02). There was no consistent evidence for an association for any other outcome assessed. CONCLUSIONS: There is currently no strong or consistent evidence on the effects of relationship factors on institutionalisation, hospitalisation, death or quality of life for people with dementia. There was a suggestion of an association between relationship factors and challenging behaviour, although the evidence for this was weak. To improve our ability to support those with dementia and their families, further robust studies are needed. PROSPERO REGISTRATION NUMBER: CRD42015020518.

Predictive values of referrals for transient ischaemic attack from first-contact health care: a systematic review.

BACKGROUND: Over 150 000 cases of suspected transient ischaemic attack (TIA) are referred to outpatient clinics in England each year. The majority of referrals are made by GPs. AIM: This study aimed to identify how many patients referred to a TIA clinic actually have TIA (that is, calculate the positive predictive value [PPV] of first-contact healthcare referral) and to record the alternative diagnoses in patients without TIA, in order to determine the optimal service model for patients with suspected TIA. DESIGN AND SETTING: A systematic review of TIA clinic referrals from first-contact health professionals (GPs and emergency department [ED] doctors) was undertaken. METHOD: Four databases were searched using terms for TIA and diagnostic accuracy. Data on the number of patients referred to a TIA clinic who actually had a TIA (PPVs) were extracted. Frequencies of differential diagnoses were recorded, where reported. Study quality was assessed using the QUADAS-2 tool. RESULTS: Nineteen studies were included and reported sufficient information on referrals from GPs and ED doctors to derive PPVs (n = 15 935 referrals). PPVs for TIA ranged from 12.9% to 72.5%. A formal meta-analysis was not conducted due to heterogeneity across studies. Of those not diagnosed with TIA, approximately half of the final diagnoses were of neurological or cardiovascular conditions. CONCLUSION: This study highlights the variation in prevalence of true vascular events in patients referred to TIA clinics. For patients without a cerebrovascular diagnosis, the high prevalence of conditions that also require specialist investigations and management are an additional burden on a care pathway that is primarily designed to prevent recurrent stroke. Service commissioners need to assess whether the existing outpatient provision is optimal for people with pathologies other than cerebrovascular disease.

Models to predict relapse in psychosis: A systematic review.

BACKGROUND: There is little evidence on the accuracy of psychosis relapse prediction models. Our objective was to undertake a systematic review of relapse prediction models in psychosis. METHOD: We conducted a literature search including studies that developed and/or validated psychosis relapse prediction models, with or without external model validation. Models had to target people with psychosis and predict relapse. The key databases searched were; Embase, Medline, Medline In-Process Citations & Daily Update, PsychINFO, BIOSIS Citation Index, CINAHL, and Science Citation Index, from inception to September 2016. Prediction modelling studies were assessed for risk of bias and applicability using the PROBAST tool. RESULTS: There were two eligible studies, which included 33,088 participants. One developed a model using prodromal symptoms and illness-related variables, which explained 14% of relapse variance but was at high risk of bias. The second developed a model using administrative data which was moderately discriminative (C = 0.631) and associated with relapse (OR 1.11 95% CI 1.10, 1.12) and achieved moderately discriminative capacity when validated (C = 0.630). The risk of bias was low. CONCLUSIONS: Due to a lack of high quality evidence it is not possible to make any specific recommendations about the predictors that should be included in a prognostic model for relapse. For instance, it is unclear whether prodromal symptoms are useful for predicting relapse. The use of routine data to develop prediction models may be a more promising approach, although we could not empirically compare the two included studies.

Screening strategies for atrial fibrillation: a systematic review and cost-effectiveness analysis.

BACKGROUND: Atrial 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. OBJECTIVES: To 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. DESIGN: Systematic review, meta-analysis and cost-effectiveness analysis. SETTING: Primary care. PARTICIPANTS: Adults. INTERVENTION: Screening 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 MEASURES: Sensitivity, 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 METHODS: Two 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. RESULTS: Diagnostic 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. CONCLUSIONS: A 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. LIMITATIONS: Many 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 WORK: Comparative 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 REGISTRATION: This study is registered as PROSPERO CRD42014013739. FUNDING: The National Institute for Health Research Health Technology Assessment programme.