Exploring the impact of housing insecurity on the health and wellbeing of children and young people in the United Kingdom: a qualitative systematic review.

BACKGROUND: Housing insecurity can be understood as experiencing or being at risk of multiple house moves that are not through choice and related to poverty. Many aspects of housing have all been shown to impact children/young people's health and wellbeing. However, the pathways linking housing and childhood health and wellbeing are complex and poorly understood. METHODS: We undertook a systematic review synthesising qualitative data on the perspectives of children/young people and those close to them, from the United Kingdom (UK). We searched databases, reference lists, and UK grey literature. We extracted and tabulated key data from the included papers, and appraised study quality. We used best fit framework synthesis combined with thematic synthesis, and generated diagrams to illustrate hypothesised causal pathways. RESULTS: We included 59 studies and identified four populations: those experiencing housing insecurity in general (40 papers); associated with domestic violence (nine papers); associated with migration status (13 papers); and due to demolition-related forced relocation (two papers). Housing insecurity took many forms and resulted from several interrelated situations, including eviction or a forced move, temporary accommodation, exposure to problematic behaviour, overcrowded/poor-condition/unsuitable property, and making multiple moves. Impacts included school-related, psychological, financial and family wellbeing impacts, daily long-distance travel, and poor living conditions, all of which could further exacerbate housing insecurity. People perceived that these experiences led to mental and physical health problems, tiredness and delayed development. The impact of housing insecurity was lessened by friendship and support, staying at the same school, having hope for the future, and parenting practices. The negative impacts of housing insecurity on child/adolescent health and wellbeing may be compounded by specific life circumstances, such as escaping domestic violence, migration status, or demolition-related relocation. CONCLUSION: Housing insecurity has a profound impact on children and young people. Policies should focus on reducing housing insecurity among families, particularly in relation to reducing eviction; improving, and reducing the need for, temporary accommodation; minimum requirements for property condition; and support to reduce multiple and long-distance moves. Those working with children/young people and families experiencing housing insecurity should prioritise giving them optimal choice and control over situations that affect them.

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. METHODS: Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. RESULTS: Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. CONCLUSIONS: In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

Association between Transfusion Status and Overall Survival in Patients with Myelodysplastic Syndromes: A Systematic Literature Review and Meta-Analysis.

INTRODUCTION: Multiple studies show that transfusion independence (TI) in myelodysplastic syndrome (MDS) has a positive impact on overall survival (OS). To assess this, a systematic review and meta-analysis of the association between TI and OS in patients with MDS was conducted (PROSPERO ID: CRD42014007264). METHODS: Comprehensive searches of 5 key bibliographic databases were conducted and supplemented with additional search techniques. Included were studies that had recruited adults aged >18 years with MDS and had examined the impact of transfusion status on OS. RESULTS: Fifty-five studies (89 citations) were included. The vast majority reported a statistically significant hazard ratio (HR) for OS in favor of TI patients or in patients who acquired TI after treatment. A random-effects meta-analysis was conducted. Patients classed as TI at baseline showed a 59% decrease in the risk of death compared with transfusion-dependent (TD) patients [HR 0.41; 95% credible interval (CrI) 0.29-0.56], and this effect did not appear to interact significantly with illness severity (interaction coefficient HR 1.38; 95% CrI 0.62-3.41). A meta-analysis of studies where patients acquired TI was not possible, but those studies consistently reported a survival benefit for those who acquired TI. CONCLUSION: The findings revealed a 59% pooled reduction in mortality among TI patients when compared with TD patients.

Reducing the impact of physical inactivity: evidence to support the case for targeting people with chronic mental and physical conditions.

BACKGROUND: Recent evidence suggests that small increases in the physical activity of those considered least active can have a bigger health impact than raising levels of those already achieving or close to achieving recommendations. Profiling the characteristics of those who are least active allows for appropriate targeting of interventions. This study therefore examined the characteristics of people in the lowest physical activity bracket. METHODS: Data were taken from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) funded 'South Yorkshire Cohort', a longitudinal observational dataset of residents of South Yorkshire, England. Five separate outcomes based on a shortened version of the GPPAQ were used to represent the lowest levels of physical activity. Potential predictors examined were age, sex, body mass index, ethnicity, chronic conditions, current employment and deprivation. Descriptive statistics and logistic regression were conducted. RESULTS: Individuals with chronic mental and physical conditions (fatigue, insomnia, anxiety, depression, diabetes, breathing problems, high blood pressure, heart disease, stroke and cancer) were more likely to report the lowest levels of physical activity across all five outcomes. Demographic variations were also observed. CONCLUSIONS: Targeting people with chronic mental and physical conditions has the potential to reduce the impact of physical inactivity.

Exploring the relationship between working from home, mental and physical health and wellbeing: a systematic review.

Background: Understanding the impact of working from home on health and wellbeing is of great interest to employers and employees alike, with a strong need for up-to-date guidance. The aim of this systematic review was to identify, appraise and synthesise existing research evidence that explores the impact of home working on health and wellbeing outcomes for working people and health inequalities in the population. Methods: We conducted a systematic review of qualitative, quantitative and observational studies. We searched databases, reference lists and UK grey literature and completed citation searching of included papers. We extracted and tabulated key data from the included papers and synthesised narratively. Factors associated with the health and wellbeing of people working at home reported in the literature were displayed by constructing mind maps of each individual factor which had been identified. The findings were combined with an a priori model to develop a final model, which was validated in consultation with stakeholders. Results: Of 96 studies which were found to meet the inclusion criteria for the review, 30 studies were published before the COVID-19 pandemic and a further 66 were published during the pandemic. The quality of evidence was limited by the study designs employed by the authors, with the majority of studies being cross-sectional surveys (n = 59). For the most part, for studies which collected quantitative data, measures were self-reported. The largest volume of evidence identified consisted of studies conducted during the COVID-19 pandemic which looked at factors which influence the relationship between working from home and measures relating to mental health and wellbeing. Fifteen studies which considered the potential for working at home to have different effects for different subgroups suggested that working at home may have more negative consequences during the COVID-19 pandemic for women and in particular, mothers. There was very little evidence on age (two studies), ethnicity (one study), education or income (two studies) in terms of moderating home working effects, and very limited evidence from before the COVID-19 pandemic. The concept of enforced working from home and having 'no choice' was reported in only one paper prior to the pandemic and two papers reporting on working from home as a result of COVID-19. However, the concept of lack of choice around working from home was implicit in much of the literature - even though it was not directly measured. There were no clear patterns of wellbeing measures which changed from positive to negative association (or vice versa) during the pandemic. Limitations: The quality of the evidence base was very much limited by study designs, particularly for studies published during the COVID-19 pandemic, with the majority of studies consisting of data collected by cross-sectional surveys (often online). Due to the rapidly expanding nature of the evidence on this topic, it is possible that new studies were published after the final citation searches were conducted. Discussion: The evidence base for the factors which influence the relationship between home working and health-related outcomes has expanded significantly as a result of the need for those whose work could be done from home to work at home during the COVID-19 pandemic. Our findings suggest that there are factors relating to the external context, the role of employers and the circumstances of the employee which contribute to determining whether someone works at home and what the associated impacts on health and wellbeing may be. Learning from the COVID-19 lockdown experience will be important to inform future policy on home and hybrid working. Future work: There is a need for better-quality studies of the health impact of home working, in particularly studies which recruit a range of participants who are representative of the working population and which are designed to minimise sampling/recruitment biases and response biases. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (project reference 18/93 PHR Public Health Review Team) and will be published in full in Public Health Research; Vol. 11, No. 4. See the NIHR Journals Library website for further project information. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Study registration: This study is registered as PROSPERO 2021 CRD42021253474.

INTRODUCTION: Working from home is becoming more common and has increased due to the COVID-19 pandemic. However, the impact of working at home on the health of home workers and the general population remains unclear. METHODS: We looked for research which had been undertaken to help to understand the impact of home working on people's health. One researcher summarised the findings of each paper in tables, and these were checked by a second researcher. These were then drawn together into a final diagram to summarise the findings of all the relevant studies. RESULTS: We found 96 papers and reports: 30 published before the COVID-19 pandemic and 66 published during the pandemic. This shows that the number of studies in this area has increased significantly as a result of home working due to COVID-19 lockdowns. The largest volume of studies we found were conducted during the pandemic and looked at measures of wellbeing and mental health. Lack of choice over whether to work from home was also considered in respect to wellbeing. Further measures linked to the home-work environment included feeling in control of time, lack of commuting to work, more time with the family, lower work/family conflict, and spaces shared with others. Openness to new ways of living was also included. Fifteen studies suggested overall that working at home may have more negative consequences during the COVID-19 pandemic for women and, in particular, mothers. There was very little evidence to tell us how a person's age, ethnicity, education or income might affect their health when working from home. CONCLUSIONS: Many factors determine whether someone works at home, and the effects on their health and wellbeing. These are related to what is happening in the world, the employer and type of job, and the circumstances of the employee.

Covariates of success in quitting smoking: a systematic review of studies from 2008 to 2021 conducted to inform the statistical analyses of quitting outcomes of a hospital-based tobacco dependence treatment service in the United Kingdom.

Background: Smoking cessation interventions are being introduced into routine secondary care in the United Kingdom (UK), but there are person and setting-related factors that could moderate their success in quitting smoking. This review was conducted as part of an evaluation of the QUIT hospital-based tobacco dependence treatment service ( https://sybics-quit.co.uk). The aim of the review was to identify a comprehensive set of variables associated with quitting success among tobacco smokers contacting secondary healthcare services in the UK who are offered support to quit smoking and subsequently set a quit date. The results would then be used to inform the development of a statistical analysis plan to investigate quitting outcomes. Methods: Systematic literature review of five electronic databases. Studies eligible for inclusion investigated quitting success in one of three contexts: (a) the general population in the UK; (b) people with a mental health condition; (c) quit attempts initiated within a secondary care setting. The outcome measures were parameters from statistical analysis showing the effects of covariates on quitting success with a statistically significant (i.e., p-value <0.05) association. Results: The review identified 29 relevant studies and 14 covariates of quitting success, which we grouped into four categories: demographics (age; sex; ethnicity; socio-economic conditions; relationship status, cohabitation and social network), individual health status and healthcare setting (physical health, mental health), tobacco smoking variables (current tobacco consumption, smoking history, nicotine dependence; motivation to quit; quitting history), and intervention characteristics (reduction in amount smoked prior to quitting, the nature of behavioural support, tobacco dependence treatment duration, pharmacological aids). Conclusions: In total, 14 data fields were identified that should be considered for inclusion in datasets and statistical analysis plans for evaluating the quitting outcomes of smoking cessation interventions initiated in secondary care contexts in the UK. PROSPERO registration: CRD42021254551 (13/05/2021).

Stop smoking interventions are being incorporated as a systematic and opt-out component of secondary care services in the UK's National Health Service (NHS), driven by the NHS's Long Term Plan. This review was conducted as part of an evaluation of the QUIT hospital-based tobacco dependence treatment service ( https://sybics-quit.co.uk). To support the development of statistical analyses to find out what affects smokers' success in quitting smoking after contacting the service, research was needed to identify what characteristics of the individual smokers and the healthcare setting might be important for success in quitting. The main purpose of the review was to support the development of a statistical analysis plan of quitting outcomes. We looked at academic papers published between 2008 and 2021 that estimated the influence of different factors on success in quitting smoking. The results of the review summarise the list of factors that previous studies have found to have an influence on quitting outcomes. The list of factors was used to inform discussions with the service about what data fields it would be important for the service to collect because that data could be important for helping the service to understand variation in quitting outcomes.

The effectiveness of interventions to establish smoke-free homes in pregnancy and in the neonatal period: a systematic review.

This review considers the effectiveness of interventions to encourage the establishment of smoke-free homes during pregnancy and the neonatal period. A comprehensive search of the literature was undertaken to find relevant studies via electronic databases, citations and reference lists of included studies. The searches identified 17 papers that met the inclusion criteria. These were quality assessed and data extracted. Due to heterogeneity of the papers, a narrative synthesis was completed. Interventions were categorized in terms of those based on counselling, counselling plus additional elements, individually adapted programmes and motivational interviewing. The findings suggest inconclusive evidence relating to these intervention types, with a range of outcome measures reported. There were limitations throughout the papers in terms of study quality (especially sample size) and poor reporting of results in relation to effectiveness. The review was limited by its very specific population; however, it suggests that currently there is mixed evidence for the effectiveness of interventions to reduce parental environmental tobacco smoke in early infancy.

Factors relating to the uptake of interventions for smoking cessation among pregnant women: a systematic review and qualitative synthesis.

INTRODUCTION: The review had the aim of investigating factors enabling or discouraging the uptake of smoking cessation services by pregnant women smokers. METHODS: The literature was searched for papers relating to the delivery of services to pregnant or recently pregnant women who smoke. No restrictions were placed on study design. A qualitative synthesis strategy was adopted to analyze the included papers. RESULTS: Analysis and synthesis of the 23 included papers suggested 10 aspects of service delivery that may have an influence on the uptake of interventions. These were whether or not the subject of smoking is broached by a health professional, the content of advice and information provided, the manner of communication, having service protocols, follow-up discussion, staff confidence in their skills, the impact of time and resource constraints, staff perceptions of ineffectiveness, differences between professionals, and obstacles to accessing interventions. DISCUSSION: The findings suggest variation in practice between services and different professional groups, in particular regarding the recommendation of quitting smoking versus cutting down but also in regard to procedural aspects, such as recording status and repeat advice giving. These differences offer the potential for a pregnant woman to receive contradicting advice. The review suggests a need for greater training in this area and the greater use of protocols, with evidence of a perception of ineffectiveness/pessimism toward intervention among some service providers.

Integrating the promotion of physical activity within a smoking cessation programme: findings from collaborative action research in UK Stop Smoking Services.

BACKGROUND: Within the framework of collaborative action research, the aim was to explore the feasibility of developing and embedding physical activity promotion as a smoking cessation aid within UK 6/7-week National Health Service (NHS) Stop Smoking Services. METHODS: In Phase 1 three initial cycles of collaborative action research (observation, reflection, planning, implementation and re-evaluation), in an urban Stop Smoking Service, led to the development of an integrated intervention in which physical activity was promoted as a cessation aid, with the support of a theoretically based self-help guide, and self monitoring using pedometers. In Phase 2 advisors underwent training and offered the intervention, and changes in physical activity promoting behaviour and beliefs were monitored. Also, changes in clients' stage of readiness to use physical activity as a cessation aid, physical activity beliefs and behaviour and physical activity levels were assessed, among those who attended the clinic at 4-week post-quit. Qualitative data were collected, in the form of clinic observation, informal interviews with advisors and field notes. RESULTS: The integrated intervention emerged through cycles of collaboration as something quite different to previous practice. Based on field notes, there were many positive elements associated with the integrated intervention in Phase 2. Self-reported advisors' physical activity promoting behaviour increased as a result of training and adapting to the intervention. There was a significant advancement in clients' stage of readiness to use physical activity as a smoking cessation aid. CONCLUSIONS: Collaboration with advisors was key in ensuring that a feasible intervention was developed as an aid to smoking cessation. There is scope to further develop tailored support to increasing physical activity and smoking cessation, mediated through changes in perceptions about the benefits of, and confidence to do physical activity.

Understanding the experience of initiating community-based group physical activity by people with serious mental illness: A systematic review using a meta-ethnographic approach.

BACKGROUND: People living with serious mental illness (SMI) experience debilitating symptoms that worsen their physical health and quality of life. Regular physical activity (PA) may bring symptomatic improvements and enhance wellbeing. When undertaken in community-based group settings, PA may yield additional benefits such as reduced isolation. Initiating PA can be difficult for people with SMI, so PA engagement is commonly low. Designing acceptable and effective PA programs requires a better understanding of the lived experiences of PA initiation among people with SMI. METHODS: This systematic review of qualitative studies used the meta-ethnography approach by Noblit and Hare (1988). Electronic databases were searched from inception to November 2017. Eligible studies used qualitative methodology; involved adults (≥18 years) with schizophrenia, bipolar affective disorder, major depressive disorder, or psychosis; reported community-based group PA; and captured the experience of PA initiation, including key features of social support. Study selection and quality assessment were performed by four reviewers. RESULTS: Sixteen studies were included in the review. We identified a "journey" that depicted a long sequence of phases involved in initiating PA. The journey demonstrated the thought processes, expectations, barriers, and support needs of people with SMI. In particular, social support from a trusted source played an important role in getting people to the activity, both physically and emotionally. DISCUSSION: The journey illustrated that initiation of PA for people with SMI is a long complex transition. This complex process needs to be understood before ongoing participation in PA can be addressed. Registration-The review was registered on the International Prospective Register of Systematic Reviews (PROSPERO) on 22/03/2017 (registration number CRD42017059948).

Smartphone Apps to Support Self-Management of Hypertension: Review and Content Analysis.

BACKGROUND: Hypertension is a widespread chronic disease, and its effective treatment requires self-management by patients. Health-related apps provide an effective way of supporting hypertension self-management. However, the increasing range and variety of hypertension apps available on the market, owing to the global growth in apps, creates the need for patients and health care professionals to be informed about the effectiveness of these apps and the levels of privacy and security that they provide. OBJECTIVE: This study aimed to describe and assess all available apps supporting hypertension self-management in the most popular app stores and investigate their functionalities. METHODS: In January 2018, the UK Apple and Google Play stores were scanned for all free and paid apps supporting hypertension self-management. Apps were included if they were in English, had functionality supporting hypertension self-management, and targeted adult users with hypertension. The included apps were downloaded and their functionalities were investigated. Behavior change techniques (BCTs) linked with the theoretical domain framework (TDF) underpinning potentially effective apps were independently coded by two reviewers. The data privacy and security of the apps were also independently assessed. RESULTS: A total of 186 hypertension apps that met the inclusion criteria were included in this review. The majority of these apps had only one functionality (n=108), while the remainder offered different combinations of functionalities. A small number of apps had comprehensive functionalities (n=30) that are likely to be more effective in supporting hypertension self-management. Most apps lacked a clear theoretical basis, and 24 BCTs identified in these 30 apps were mapped to 10 TDF mechanisms of actions. On an average, 18.4 BCTs were mapped to 6 TDF mechanisms of actions that may support hypertension self-management behaviors. There was a concerning absence of evidence related to the effectiveness and usability of all 186 apps, and involvement of health care professionals in the app development process was minimal. Most apps did not meet the current standards of data security and privacy. CONCLUSIONS: Despite the widespread accessibility and availability of smartphone apps with a range of combinations of functionalities that can support the self-management of hypertension, only a small number of apps are likely to be effective. Many apps lack security measures as well as a clear theoretical basis and do not provide any evidence concerning their effectiveness and usability. This raises a serious issue, as health professionals and those with hypertension have insufficient information to make decisions on which apps are safe and effective.

Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company's health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG's probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.

Assessing prognosis and prediction of treatment response in early rheumatoid arthritis: systematic reviews.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, debilitating disease associated with reduced quality of life and substantial costs. It is unclear which tests and assessment tools allow the best assessment of prognosis in people with early RA and whether or not variables predict the response of patients to different drug treatments. OBJECTIVE: To systematically review evidence on the use of selected tests and assessment tools in patients with early RA (1) in the evaluation of a prognosis (review 1) and (2) as predictive markers of treatment response (review 2). DATA SOURCES: Electronic databases (e.g. MEDLINE, EMBASE, The Cochrane Library, Web of Science Conference Proceedings; searched to September 2016), registers, key websites, hand-searching of reference lists of included studies and key systematic reviews and contact with experts. STUDY SELECTION: Review 1 - primary studies on the development, external validation and impact of clinical prediction models for selected outcomes in adult early RA patients. Review 2 - primary studies on the interaction between selected baseline covariates and treatment (conventional and biological disease-modifying antirheumatic drugs) on salient outcomes in adult early RA patients. RESULTS: Review 1 - 22 model development studies and one combined model development/external validation study reporting 39 clinical prediction models were included. Five external validation studies evaluating eight clinical prediction models for radiographic joint damage were also included. c-statistics from internal validation ranged from 0.63 to 0.87 for radiographic progression (different definitions, six studies) and 0.78 to 0.82 for the Health Assessment Questionnaire (HAQ). Predictive performance in external validations varied considerably. Three models [(1) Active controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset (ASPIRE) C-reactive protein (ASPIRE CRP), (2) ASPIRE erythrocyte sedimentation rate (ASPIRE ESR) and (3) Behandelings Strategie (BeSt)] were externally validated using the same outcome definition in more than one population. Results of the random-effects meta-analysis suggested substantial uncertainty in the expected predictive performance of models in a new sample of patients. Review 2 - 12 studies were identified. Covariates examined included anti-citrullinated protein/peptide anti-body (ACPA) status, smoking status, erosions, rheumatoid factor status, C-reactive protein level, erythrocyte sedimentation rate, swollen joint count (SJC), body mass index and vascularity of synovium on power Doppler ultrasound (PDUS). Outcomes examined included erosions/radiographic progression, disease activity, physical function and Disease Activity Score-28 remission. There was statistical evidence to suggest that ACPA status, SJC and PDUS status at baseline may be treatment effect modifiers, but not necessarily that they are prognostic of response for all treatments. Most of the results were subject to considerable uncertainty and were not statistically significant. LIMITATIONS: The meta-analysis in review 1 was limited by the availability of only a small number of external validation studies. Studies rarely investigated the interaction between predictors and treatment. SUGGESTED RESEARCH PRIORITIES: Collaborative research (including the use of individual participant data) is needed to further develop and externally validate the clinical prediction models. The clinical prediction models should be validated with respect to individual treatments. Future assessments of treatment by covariate interactions should follow good statistical practice. CONCLUSIONS: Review 1 - uncertainty remains over the optimal prediction model(s) for use in clinical practice. Review 2 - in general, there was insufficient evidence that the effect of treatment depended on baseline characteristics. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016042402. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

What is the added value of ultrasound joint examination for monitoring synovitis in rheumatoid arthritis and can it be used to guide treatment decisions? A systematic review and cost-effectiveness analysis.

BACKGROUND: Synovitis (inflamed joint synovial lining) in rheumatoid arthritis (RA) can be assessed by clinical examination (CE) or ultrasound (US). OBJECTIVE: To investigate the added value of US, compared with CE alone, in RA synovitis in terms of clinical effectiveness and cost-effectiveness. DATA SOURCES: Electronic databases including MEDLINE, EMBASE and the Cochrane databases were searched from inception to October 2015. REVIEW METHODS: A systematic review sought RA studies that compared additional US with CE. Heterogeneity of the studies with regard to interventions, comparators and outcomes precluded meta-analyses. Systematic searches for studies of cost-effectiveness and US and treatment-tapering studies (not necessarily including US) were undertaken. MATHEMATICAL MODEL: A model was constructed that estimated, for patients in whom drug tapering was considered, the reduction in costs of disease-modifying anti-rheumatic drugs (DMARDs) and serious infections at which the addition of US had a cost per quality-adjusted life-year (QALY) gained of £20,000 and £30,000. Furthermore, the reduction in the costs of DMARDs at which US becomes cost neutral was also estimated. For patients in whom dose escalation was being considered, the reduction in number of patients escalating treatment and in serious infections at which the addition of US had a cost per QALY gained of £20,000 and £30,000 was estimated. The reduction in number of patients escalating treatment for US to become cost neutral was also estimated. RESULTS: Fifty-eight studies were included. Two randomised controlled trials compared adding US to a Disease Activity Score (DAS)-based treat-to-target strategy for early RA patients. The addition of power Doppler ultrasound (PDUS) to a Disease Activity Score 28 joints-based treat-to-target strategy in the Targeting Synovitis in Early Rheumatoid Arthritis (TaSER) trial resulted in no significant between-group difference for change in Disease Activity Score 44 joints (DAS44). This study found that significantly more patients in the PDUS group attained DAS44 remission (p = 0.03). The Aiming for Remission in Rheumatoid Arthritis (ARCTIC) trial found that the addition of PDUS and grey-scale ultrasound (GSUS) to a DAS-based strategy did not produce a significant between-group difference in the primary end point: composite DAS of < 1.6, no swollen joints and no progression in van der Heijde-modified total Sharp score (vdHSS). The ARCTIC trial did find that the erosion score of the vdHS had a significant advantage for the US group (p = 0.04). In the TaSER trial there was no significant group difference for erosion. Other studies suggested that PDUS was significantly associated with radiographic progression and that US had added value for wrist and hand joints rather than foot and ankle joints. Heterogeneity between trials made conclusions uncertain. No studies were identified that reported the cost-effectiveness of US in monitoring synovitis. The model estimated that an average reduction of 2.5% in the costs of biological DMARDs would be sufficient to offset the costs of 3-monthly US. The money could not be recouped if oral methotrexate was the only drug used. LIMITATIONS: Heterogeneity of the trials precluded meta-analysis. Therefore, no summary estimates of effect were available. Additional costs and health-related quality of life decrements, relating to a flare following tapering or disease progression, have not been included. The feasibility of increased US monitoring has not been assessed. CONCLUSION: Limited evidence suggests that US monitoring of synovitis could provide a cost-effective approach to selecting RA patients for treatment tapering or escalation avoidance. Considerable uncertainty exists for all conclusions. Future research priorities include evaluating US monitoring of RA synovitis in longitudinal clinical studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015017216. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Understanding the experience of initiating community-based physical activity and social support by people with serious mental illness: a systematic review using a meta-ethnographic approach.

BACKGROUND: People with long-term serious mental illness live with severe and debilitating symptoms that can negatively influence their health and quality of life, leading to outcomes such as premature mortality, morbidity and obesity. An interplay of social, behavioural, biological and psychological factors is likely to contribute to their poor physical health. Participating in regular physical activity could bring symptomatic improvements, weight loss benefits, enhanced wellbeing and when undertaken in a community-based group setting can yield additional, important social support benefits. Yet poor uptake of physical activity by people with serious mental illness is a problem. This review will systematically search, appraise and synthesise the existing evidence that has explored the experience of community-based physical activity initiation and key features of social support within these contexts by adults with schizophrenia, bipolar affective disorder, major depressive disorder or psychosis using the meta-ethnography approach. This new understanding may be key in designing more acceptable and effective community-based group PA programmes that meet patients' need and expectations. METHODS: This will be a systematic review of qualitative studies using the meta-ethnography approach. The following databases will be searched: ASSIA, CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, Health Technology Assessment Database, MEDLINE, PsycINFO, Sociological Abstracts, SPORTDiscus and Web of Science. Grey literature will also be sought. Eligible studies will use qualitative methodology; involve adults (≥18 years) with schizophrenia, bipolar affective disorder, major depressive disorder or psychosis; will report community-based group physical activity; and capture the experience of physical activity initiation and key features of social support from the perspective of the participant. Study selection and assessment of quality will be performed by two reviewers. Data will be extracted by one reviewer, tabled, and checked for accuracy by the second reviewer. The meta-ethnography approach by Noblit and Hare (Meta-ethnography: synthesizing qualitative studies 11, 1988) will be used to synthesise the data. DISCUSSION: This systematic review is expected to provide new insights into the experience of community-based group physical activity initiation for adults who have a serious mental illness to inform person-centred improvements to the management of serious mental illness through physical activity. SYSTEMATIC REVIEW REGISTRATION: The protocol has been registered on the International Prospective Register of Systematic Reviews (PROSPERO) on 22/03/2017; (registration number CRD42017059948 ).

The clinical effectiveness and cost-effectiveness of treat-to-target strategies in rheumatoid arthritis: a systematic review and cost-effectiveness analysis.

BACKGROUND: Treat to target (TTT) is a broad concept for treating patients with rheumatoid arthritis (RA). It involves setting a treatment target, usually remission or low disease activity (LDA). This is often combined with frequent patient assessment and intensive and rapidly adjusted drug treatment, sometimes based on a formal protocol. OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of TTT compared with routine care. DATA SOURCES: Databases including EMBASE and MEDLINE were searched from 2008 to August 2016. REVIEW METHODS: A systematic review of clinical effectiveness was conducted. Studies were grouped according to comparisons made: (1) TTT compared with usual care, (2) different targets and (3) different treatment protocols. Trials were subgrouped by early or established disease populations. Study heterogeneity precluded meta-analyses. Narrative synthesis was undertaken for the first two comparisons, but was not feasible for the third. A systematic review of cost-effectiveness was also undertaken. No model was constructed as a result of the heterogeneity among studies identified in the clinical effectiveness review. Instead, conclusions were drawn on the cost-effectiveness of TTT from papers relating to these studies. RESULTS: Sixteen clinical effectiveness studies were included. They differed in terms of treatment target, treatment protocol (where one existed) and patient visit frequency. For several outcomes, mixed results or evidence of no difference between TTT and conventional care was found. In early disease, two studies found that TTT resulted in favourable remission rates, although the findings of one study were not statistically significant. In established disease, two studies showed that TTT may be beneficial in terms of LDA at 6 months, although, again, in one case the finding was not statistically significant. The TICORA (TIght COntrol for RA) trial found evidence of lower remission rates for TTT in a mixed population. Two studies reported cost-effectiveness: in one, TTT dominated usual care; in the other, step-up combination treatments were shown to be cost-effective. In 5 of the 16 studies included the clinical effectiveness review, no cost-effectiveness conclusion could be reached, and in one study no conclusion could be drawn in the case of patients denoted low risk. In the remaining 10 studies, and among patients denoted high risk in one study, cost-effectiveness was inferred. In most cases TTT is likely to be cost-effective, except where biological treatment in early disease is used initially. No conclusions could be drawn for established disease. LIMITATIONS: TTT refers not to a single concept, but to a range of broad approaches. Evidence reflects this. Studies exhibit substantial heterogeneity, which hinders evidence synthesis. Many included studies are at risk of bias. FUTURE WORK: Future studies comparing TTT with usual care must link to existing evidence. A consistent definition of remission in studies is required. There may be value in studies to establish the importance of different elements of TTT (the setting of a target, the intensive use of drug treatments and protocols pertaining to those drugs and the frequent assessment of patients). CONCLUSION: In early RA and studies of mixed early and established RA populations, evidence suggests that TTT improves remission rates. In established disease, TTT may lead to improved rates of LDA. It remains unclear which element(s) of TTT (the target, treatment protocols or increased frequency of patient visits) drive these outcomes. Future trials comparing TTT with usual care and/or different TTT targets should use outcomes comparable with existing literature. Remission, defined in a consistent manner, should be the target of choice of future studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015017336. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The Cost-effectiveness of Sequences of Biological Disease-modifying Antirheumatic Drug Treatment in England for Patients with Rheumatoid Arthritis Who Can Tolerate Methotrexate.

OBJECTIVE: To ascertain whether strategies of treatment with a biological disease-modifying antirheumatic drug (bDMARD) are cost-effective in an English setting. Results are presented for those patients with moderate to severe rheumatoid arthritis (RA) and those with severe RA. METHODS: An economic model to assess the cost-effectiveness of 7 bDMARD was developed. A systematic literature review and network metaanalysis was undertaken to establish relative clinical effectiveness. The results were used to populate the model, together with estimates of Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients taking bDMARD; and trajectory of HAQ for patients using nonbiologic therapy (NBT). Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness when only patients with the most severe prognoses taking NBT were provided with bDMARD treatment. The costs per quality-adjusted life-year (QALY) values were compared with reported thresholds from the UK National Institute for Health and Care Excellence of £20,000 to £30,000 (US$24,700 to US$37,000). RESULTS: In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate to severe RA. Under the supplementary analyses, the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate to severe RA. CONCLUSION: The cost-effectiveness of bDMARD in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses.

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES: The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS: Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS: Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS: bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003386. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review and economic evaluation of exercise referral schemes in primary care: a short report.

BACKGROUND: It is estimated that only 39% of men and 29% of women in England achieve the levels of physical activity that are recommended to protect health and prevent disease. One approach to addressing this problem has been the development of exercise referral schemes (ERSs), in which health professionals refer patients to external exercise providers. These schemes have been widely rolled out across the UK despite concerns that they may not produce sustained changes in levels of physical activity and, therefore, may not be cost-effective interventions. The evidence to determine clinical effectiveness and cost-effectiveness was evaluated in 2009. This review seeks to update this earlier work by incorporating new evidence and re-examining the cost-effectiveness. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of ERSs compared with usual care. DESIGN: Exhaustive searches of relevant electronic databases and journals were undertaken to identify new studies evaluating ERSs using a randomised controlled trial (RCT) design. RCTs that incorporated a qualitative evaluation of the intervention were identified in order to explore the barriers and facilitators to the uptake of and adherence to ERSs. Data were extracted using a previously designed tool and study quality assessed for potential bias. Where data could be pooled, meta-analyses were carried out. Qualitative analysis was also undertaken using a thematic approach. The cost-effectiveness was evaluated using a Markov structure which estimated the likelihood of becoming physically active and the subsequent risk reduction on coronary heart disease (CHD), stroke and type 2 diabetes mellitus. The model adopts a lifetime horizon, and a NHS and Personal Social Services perspective was taken with discounting at 1.5% for both costs and benefits. RESULTS: The search identified one new RCT and one new qualitative study. The new data were pooled with existing data from the 2011 review by Pavey et al. [Pavey TG, Anokye N, Taylor AH, Trueman P, Moxham T, Fox KR, et al. The clinical effectiveness and cost-effectiveness of exercise referral schemes: a systematic review and economic evaluation. Health Technol Assess 2011;15(44)] to give a total of eight studies with 5190 participants. The proportion of individuals achieving 90-150 minutes of at least moderate-intensity activity per week at 6-12 months' follow-up was greater for ERSs than usual care (relative risk 1.12; 95% confidence interval 1.04 to 1.20). Older patients and those referred for CHD risk factors appeared to be more likely than others to increase their levels of physical activity. Qualitative evidence suggests that interventions enabling the development of social support networks are beneficial in promoting uptake and adherence. Exercise referral gained 0.003 quality-adjusted life-years (QALYs) at an additional cost of £225 per person. The estimated mean incremental cost-effectiveness ratio (ICER) in the probabilistic sensitivity analysis was £76,276. In the univariate sensitivity analysis the results were very sensitive (ICERs ranged from < £30,000 to > £100,000) to changes in the effect of ERSs on physical activity uptake and the duration of the protective effects and the direct health-related quality-of-life gains attributable to physical activity. CONCLUSIONS: Exercise referral schemes result in a small improvement in the number of people who increase their levels of physical activity. The cost-effectiveness analysis indicates that the ICER for ERSs compared with usual care is around £76,000 per QALY, although the cost-effectiveness of ERSs is subject to considerable uncertainty. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005200. FUNDING: National Institute for Health Research Health Technology Assessment programme.

The safety of intravitreal bevacizumab monotherapy in adult ophthalmic conditions: systematic review.

OBJECTIVES: To assess the safety of intravitreal bevacizumab (IVB) as a monotherapy and to evaluate the relationship between quality of treatment and adverse events. DATA SOURCES: Cochrane Library, Ovid MEDLINE, MEDLINE in-process, Ovid EMBASE and Toxicology Literature Online (TOXLINE) from January 2009 to May 2012. Studies included in an earlier systematic review were also assessed for inclusion. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Randomised controlled trials (RCTs), controlled trials or observational studies including ≥10 participants reporting adverse events data following IVB monotherapy as a primary treatment in patients (aged 18 years or more) with any eye condition were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Study selection was undertaken independently by a minimum of two reviewers using pre-defined criteria. Data abstraction and quality assessment were performed by one reviewer, and then checked by a second reviewer. Study quality was assessed for only RCTs in accordance to the Cochrane Risk of Bias Tool. Additional items relating to safety data were also assessed. Results were tabulated or meta-analysed as appropriate. RESULTS: 22 RCTs and 67 observational studies were included. Only two RCTs reported valid safety data. Rates of serious adverse events following treatment were low. There was insufficient data to explore the relationship between the incidence of adverse events and quality of IVB injection. LIMITATIONS: A majority of relevant existing studies were characterised by small sample sizes, unclear diagnostic criteria and reporting of safety outcomes. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Available evidence demonstrates low rates of serious local and systemic adverse events following treatment. However, the role of IVB quality in the incidence of adverse events remains unclear. Robust evidence is needed to examine the relationship between the incidence of adverse events and variables such as injection techniques, pre-existing risk factors (eg, immunosuppression, cross-contamination) and quality of IVB treatment.