Adherence to exercise referral schemes by participants - what do providers and commissioners need to know? A systematic review of barriers and facilitators.

BACKGROUND: Physical inactivity levels are rising worldwide with major implications for the health of the population and the prevalence of non-communicable diseases. Exercise referral schemes (ERS) continue to be a popular intervention utilised by healthcare practitioners to increase physical activity. We undertook a systematic review of views studies in order to inform guidance from the UK National Institute of Health and Care Excellence (NICE) on exercise referral schemes to promote physical activity. This paper reports on the participant views identified, to inform those seeking to refine schemes to increase attendance and adherence. METHODS: Fifteen databases and a wide range of websites and grey literature sources were searched systematically for publications from 1995 to June 2013. In addition, a range of supplementary methods including, a call for evidence by NICE, contacting authors, reference list checking and citation tracking were utilised to identify additional research. Studies were included where they detailed schemes for adults aged 19 years or older who were 'inactive' (i.e. they are not currently meeting UK physical activity guidelines). Study selection was conducted independently in duplicate. Quality assessment was undertaken by one reviewer and checked by a second, with 20 % of papers being considered independently in duplicate. Papers were coded in qualitative data analysis software Atlas.ti. This review was reported in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement). RESULTS: Evidence from 33 UK-relevant studies identified that support from providers, other attendees and family was an important facilitator of adherence and 'making exercise a habit' post programme, as was the variety and personalised nature of sessions offered. Barriers to attendance included the inconvenient timing of sessions, their cost and location. An intimidating gym atmosphere, a dislike of the music and TV and a lack of confidence in operating gym equipment were frequently reported. CONCLUSIONS: These findings provide valuable insights that commissioners and providers should consider. The main themes were consistent across a large number of studies and further research should concentrate on programmes that reflect these findings.

Exploring the effect of case management in homelessness per components: A systematic review of effectiveness and implementation, with meta-analysis and thematic synthesis.

Background: Adequate housing is a basic human right. The many millions of people experiencing homelessness (PEH) have a lower life expectancy and more physical and mental health problems. Practical and effective interventions to provide appropriate housing are a public health priority. Objectives: To summarise the best available evidence relating to the components of case-management interventions for PEH via a mixed methods review that explored both the effectiveness of interventions and factors that may influence its impact. Search Methods: We searched 10 bibliographic databases from 1990 to March 2021. We also included studies from Campbell Collaboration Evidence and Gap Maps and searched 28 web sites. Reference lists of included papers and systematic reviews were examined and experts contacted for additional studies. Selection Criteria: We included all randomised and non-randomised study designs exploring case management interventions where a comparison group was used. The primary outcome of interest was homelessness. Secondary outcomes included health, wellbeing, employment and costs. We also included all studies where data were collected on views and experiences that may impact on implementation. Data Collection and Analysis: We assessed risk of bias using tools developed by the Campbell Collaboration. We conducted meta-analyses of the intervention studies where possible and carried out a framework synthesis of a set of implementation studies identified by purposive sampling to represent the most 'rich' and 'thick' data. Main Results: We included 64 intervention studies and 41 implementation studies. The evidence base was dominated by studies from the USA and Canada. Participants were largely (though not exclusively) people who were literally homeless, that is, living on the streets or in shelters, and who had additional support needs. Many studies were assessed as having a medium or high risk of bias. However, there was some consistency in outcomes across studies that improved confidence in the main findings. Case Management and Housing Outcomes: Case management of any description was superior to usual care for homelessness outcomes (standardised mean difference [SMD] = -0.51 [95% confidence interval [CI]: -0.71, -0.30]; p < 0.01). For studies included in the meta-analyses, Housing First had the largest observed impact, followed by Assertive Community Treatment, Critical Time Intervention and Intensive Case Management. The only statistically significant difference was between Housing First and Intensive Case Management (SMD = -0.6 [-1.1, -0.1]; p = 0.03) at ≥12 months. There was not enough evidence to compare the above approaches with standard case management within the meta-analyses. A narrative comparison across all studies was inconclusive, though suggestive of a trend in favour of more intensive approaches. Case Management and Mental Health Outcomes: The overall evidence suggested that case management of any description was not more or less effective compared to usual care for an individual's mental health (SMD = 0.02 [-0.15, 0.18]; p = 0.817). Case Management and Other Outcomes: Based on meta-analyses, case management was superior to usual care for capability and wellbeing outcomes up to 1 year (an improvement of around one-third of an SMD; p < 0.01) but was not statistically significantly different for substance use outcomes, physical health, and employment. Case Management Components: For homelessness outcomes, there was a non-significant trend for benefits to be greater in the medium term (≤3 years) compared to long term (>3 years) (SMD = -0.64 [-1.04, -0.24] vs. -0.27 [-0.53, 0]; p = 0.16) and for in-person meetings in comparison to mixed (in-person and remote) approaches (SMD = -0.73 [-1.25,-0.21]) versus -0.26 [-0.5,-0.02]; p = 0.13). There was no evidence from meta-analyses to suggest that an individual case manager led to better outcomes then a team, and interventions with no dedicated case manager may have better outcomes than those with a named case manager (SMD = -0.36 [-0.55, -0.18] vs. -1.00 [-2.00, 0.00]; p = 0.02). There was not enough evidence from meta-analysis to assess whether the case manager should have a professional qualification, or if frequency of contact, case manager availability or conditionality (barriers due to conditions attached to service provision) influenced outcomes. However, the main theme from implementation studies concerned barriers where conditions were attached to services. Characteristics of Persons Experiencing Homelessness: No conclusions could be drawn from meta-analysis other than a trend for greater reductions in homelessness for persons with high complexity of need (two or more support needs in addition to homelessness) as compared to those with medium complexity of need (one additional support need); effect sizes were SMD = -0.61 [-0.91, -0.31] versus -0.36 [-0.68, -0.05]; p = 0.3. The Broader Context of Delivery of Case Management Programmes: Other major themes from the implementation studies included the importance of interagency partnership; provision for non-housing support and training needs of PEH (such as independent living skills), intensive community support following the move to new housing; emotional support and training needs of case managers; and an emphasis on housing safety, security and choice. Cost Effectiveness: The 12 studies with cost data provided contrasting results and no clear conclusions. Some case management costs may be largely off-set by reductions in the use of other services. Cost estimates from three North American studies were $45-52 for each additional day housed. Authors' Conclusions: Case management interventions improve housing outcomes for PEH with one or more additional support needs, with more intense interventions leading to greater benefits. Those with greater support needs may gain greater benefit. There is also evidence for improvements to capabilities and wellbeing. Current approaches do not appear to lead to mental health benefits. In terms of case management components, there is evidence in support of a team approach and in-person meetings and, from the implementation evidence, that conditions associated with service provision should be minimised. The approach within Housing First could explain the finding that overall benefits may be greater than for other types of case management. Four of its principles were identified as key themes within the implementation studies: No conditionality, offer choice, provide an individualised approach and support community building. Recommendations for further research include an expansion of the research base outside North America and further exploration of case management components and intervention cost-effectiveness.

PROTOCOL: Exploring the effect of case management in homelessness per components: A systematic review of effectiveness and implementation, with meta-analysis and thematic synthesis.

This is the protocol for a Campbell review. The objectives are as follows: To carry out a mixed methods review to summarise current evidence relating to the components of case-management interventions for people experiencing homelessness.

A scoping review of system-level mechanisms to prevent children being in out-of-home care.

Identifying which approaches can effectively reduce the need for out-of-home care for children is critically important. Despite the proliferation of different interventions and approaches globally, evidence summaries on this topic are limited. This study is a scoping review using a realist framework to explore what research evidence exists about reducing the number of children and young people in care. Searches of databases and websites were used to identify studies evaluating intervention effect on at least one of the following outcomes: reduction in initial entry to care; increase in family reunification post care. Data extracted from papers included type of study, outcome, type and level of intervention, effect, mechanism and moderator, implementation issues and economic (EMMIE) considerations. Data were coded by: primary outcome; level of intervention (community, policy, organisation, family or child); and type of evidence, using the realist EMMIE framework. This is the first example of a scoping review on any topic using this framework. Evaluated interventions were grouped and analysed according to system-level mechanism. We present the spread of evidence across system-level mechanisms and an overview of how each system-level mechanism might reduce the number of children in care. Implications and gaps are identified.

Glutathione S-transferases as molecular markers of tumour progression and prognosis in renal cell carcinoma.

AIMS: Renal cell carcinoma (RCC) often recurs as distant metastasis; there is thus a need for new indicators to identify high-risk patients. Glutathione S-transferases (GST)-α and -π are involved in the renal bioactivation of toxic metabolites. The aim was to investigate whether their expression is of diagnostic and prognostic value. METHODS AND RESULTS: Western blotting of microdissected normal kidney and immunostaining of histological RCC microarrays shows expression of GST-α in proximal tubular cells, while GST-π was found in the distal nephron. Of the primary 174 RCC cases examined, GST-α immunoreactivity was restricted to conventional RCC (n=76, 68% positive) and was not seen in any other RCC subtypes. The cross-tabulation of the GST-α scores with other prognostic indices demonstrated that GST-α immunostaining was significantly more frequent in low-grade tumours (χ(2): P<0.004), and that conventional GST-α-positive RCC patients had a mean disease-free survival of 6.0 years (95% confidence interval 5.33-6.63), compared with 4.7 years (3.54-5.90) in GST-α-negative tumours (Kaplan-Meier survival analysis, P=0.011, log-rank test). CONCLUSIONS: GST-α is a highly specific diagnostic marker for primary conventional RCC, where it is a prognostic marker if grade is omitted from the multivariate analysis.

An exon 5-less splice variant of the extracellular calcium-sensing receptor rescues absence of the full-length receptor in the developing mouse lung.

The authors have recently demonstrated that, in the developing mouse lung, fetal plasma Ca(2+) suppresses branching morphogenesis and cell proliferation while promoting fluid secretion via activation of the extracellular Ca(2+)-sensing receptor (CaSR). The aim of the current study was to further elucidate the role of Ca(2+) in lung development by studying the effects of extracellular Ca(2+) on fetal lung development in mice lacking the CaSR. These mice were produced by exon 5 deletion in the CaSR gene. Since such a maneuver has been known to induce the expression of an exon 5-less splice variant of the CaSR in some tissues, the molecular and functional expression of this splice variant in the developing mouse lung was also investigated. Whereas there was a mild in vivo phenotype observed in these mice, in vitro sensitivity of Casr(-/-) lung explants to specific activators of the CaSR was unaffected. These results imply that compensatory expression of an exon 5-less splice variant rescues CaSR function in this mouse model and therefore a lung-specific, complete CaSR knockout model must be developed to fully appreciate the role for this receptor in lung development and the contribution of its ablation to postnatal respiratory disease.

Application of Dolichos biflorus in immunoassay detection of kidney collecting duct biomarkers.

Currently there are no biomarkers for detecting collecting duct damage in man. Antibodies to several collecting duct-specific antigens exist but sandwich assays have been difficult to establish due to the need for two different antibodies to the same protein. We hypothesized that a collecting duct-specific lectin could be used in combination with a collecting duct-specific antibody to negate the need for two different antibodies. The collecting duct specificity of selected antibodies (NiCa II 13C2, Pap XI 3C7, HuPaP VII 2B11 and aquaporin 2), was verified by immunohistochemistry. Aquaporin 2 and Pap XI 3C7 were used successfully in setting up assays with the lectin Dolichos biflorus, using the Meso Scale Discovery (MSD) platform. Antigen expression was highest in the papillae of rat and human kidney (corresponding to the greatest density of collecting ducts) and was also present in normal urine. We propose that further qualification and validation would lead to an assay for detecting collecting duct damage in man.

Mapping the evidence about what works to safely reduce the entry of children and young people into statutory care: a systematic scoping review protocol.

INTRODUCTION: The increasing number of children and young people entering statutory care in the UK is a significant social, health and educational priority. Development of effective approaches to safely reduce this number remains a complex but critical issue. Despite a proliferation in interventions, evidence summaries are limited. The present protocol outlines a scoping review of research evidence to identify what works in safely reducing the number of children and young people (aged ≤18 years) entering statutory social care. The mapping of evidence gaps, clusters and uncertainties will inform the research programme of the newly funded Department for Education's What Works Centre for Children's Social Care. METHODS AND ANALYSIS: The review uses Arksey and O'Malley's scoping review methodology. Electronic database and website searches will identify studies targeting reduction of care entry, reduction of care re-entry and increase in post-care reunification. Supplementary searching techniques will include international expert consultation. Abstracts and full-text studies will be independently screened by two reviewers. Ten per cent of data abstraction will be independently conducted by two reviewers, with the remainder being extracted and then verified by a second reviewer. Descriptive numerical summaries and a thematic qualitative synthesis will be generated. Evidence will be synthesised according to primary outcome, intervention point (mapped across socioecological domains) and the realist EMMIE categorisation of evidence type (Effectiveness; Mechanisms of change; Moderators; Implementation; Economic evaluation). ETHICS AND DISSEMINATION: Outputs will be a conceptual evidence map, a descriptive table quantitatively summarising evidence and a qualitative narrative summary. Results will be disseminated through a peer-reviewed publication, conference presentations, the What Works Centre website, and knowledge translation events with policy-makers and practitioners. Findings will inform the primary research programme of the What Works Centre for Children's Social Care and the subsequent suite of systematic reviews to be conducted by the Centre in this substantive area.

Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5.

The extracellular Ca(2+)-sensing receptor (CaR) is a key-player in plasma Ca(2+) homeostasis. It is essentially expressed in the parathyroid glands and along the kidney nephron. The distal convoluted tubules (DCT) and connecting tubules (CNT) in the kidney are involved in active Ca(2+) reabsorption, but the function of the CaR has remained unclear in these segments. Here, the Ca(2+)-selective Transient Receptor Potential Vanilloid-subtype 5 channel (TRPV5) determines active Ca(2+) reabsorption by forming the apical entry gate. In this study we show that the CaR and TRPV5 co-localize at the luminal membrane of DCT/CNT. Furthermore, by patch-clamp and Fura-2-ratiometric measurements we demonstrate that activation of the CaR leads to elevated TRPV5-mediated currents and increases intracellular Ca(2+) concentrations in cells co-expressing TRPV5 and CaR. Activation of CaR initiated a signaling cascade that activated phorbol-12-myristate-13-acetate (PMA)-insensitive protein kinase C (PKC) isoforms. Importantly, mutation of two putative PKC phosphorylation sites, S299 and S654, in TRPV5 prevented the stimulatory effect of CaR activation on channel activity, as did a dominant negative CaR construct, CaR(R185Q). Interestingly, the activity of TRPV6, TRPV5' closest homologue, was not affected by the activated CaR. We conclude that activation of the CaR stimulates TRPV5-mediated Ca(2+) influx via a PMA-insensitive PKC isoform pathway.