Prediction, screening and characterization of novel bioactive tetrapeptide matrikines for skin rejuvenation.

BACKGROUND: Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In skin, loss of dermal collagens and disorganization of elastic fibre components are key features of photoageing. Although the application of some small matrix-derived peptides to aged skin has been shown to beneficially affect in vitro cell behaviour and, in vivo, molecular architecture and clinical appearance, the discovery of new peptides has lacked a guiding hypothesis. OBJECTIVES: To identify, using protease cleavage site prediction, novel putative matrikines with beneficial activities for skin composition and structure. METHODS: Here, we present an in silico (peptide cleavage prediction) to in vitro (proteomic and transcriptomic activity testing in cultured human dermal fibroblasts) to in vivo (short-term patch test and longer-term split-face clinical study) discovery pipeline, which enables the identification and characterization of peptides with differential activities. RESULTS: Using this pipeline we showed that cultured fibroblasts were responsive to all applied peptides, but their associated bioactivity was sequence-dependent. Based on bioactivity, toxicity and protein source, we further characterized a combination of two novel peptides, GPKG (glycine-proline-lysine-glycine) and LSVD (leucine-serine-valine-aspartate), that acted in vitro to enhance the transcription of matrix -organization and cell proliferation genes and in vivo (in a short-term patch test) to promote processes associated with epithelial and dermal maintenance and remodelling. Prolonged use of a formulation containing these peptides in a split-face clinical study led to significantly improved measures of crow's feet and firmness in a mixed population. CONCLUSIONS: This approach to peptide discovery and testing can identify new synthetic matrikines, providing insights into biological mechanisms of tissue homeostasis and repair and new pathways to clinical intervention.

Like other organs and tissues, the skin is composed of both cells and a complex network of molecules and proteins called an extracellular matrix. This matrix contains proteins such as collagen and elastin and undergoes many changes when the skin is damaged by the sun. We know from previous studies that small parts of matrix proteins (called peptide 'matrikines') can help to treat the signs of sun-related skin ageing. In this UK study, we show that new beneficial peptides (with matrikine activity) can be identified using machine learning (artificial intelligence) techniques that predict where common matrix proteins might be 'cut' by skin enzymes. Candidate peptides were first made in the laboratory and then applied to skin cells in culture. These cell culture screens demonstrated that, while all the peptides showed some matrikine activity, two were particularly promising. These two peptides were then tested in a short-term study on the forearm skin of volunteers and, in a longer-term study, on the face. We found that the combination of these two peptides can prompt forearm skin cells to express genes that are involved in many different aspect of skin health and, over the longer 6-month period, produce visible benefits in the appearance of fine lines and wrinkles and firmness on the face. Our findings suggest that this approach may be able to identify beneficial peptide treatments for not only skin ageing and diseases, but also unwanted changes in the extracellular matrix of other tissues and organs.

The impact of providing care for physical health in severe mental illness on informal carers: a qualitative study.

BACKGROUND: People with severe mental illness (SMI) such as schizophrenia and bipolar disorder are at a substantially higher risk of premature death in that they die between 10 and 20 years earlier than the general population. Cardiovascular disease (CVD) and diabetes are the main potentially avoidable contributors to early death. Research that explores the experiences of people with SMI highlights their struggles in engaging with health professionals and accessing effective and timely interventions for physical health conditions. A consequence of such struggles to navigate and access physical healthcare results in many people with SMI relying heavily on support provided by informal carers (e.g., family members, close friends). Despite this, the experiences of informal carers, and the roles they undertake in relation to supporting the physical health and psychotropic medication use of people with SMI, remains under-researched. AIMS: To explore the impacts of providing care for physical health in severe mental illness on informal carers. METHOD: Thematic analysis of semi-structured interviews with eight informal carers of people with SMI in United Kingdom (UK) national health services. RESULTS: Informal carers played an active part in the management of the patient's conditions and shared their illness experience. Involvement of informal carers was both emotional and practical and informal carers' own lives were affected in ways that were sometimes deeply profound. Informal carers were involved in both 'looking after' the patient from the perspective of doing practical tasks such as collecting dispensed medication from a community pharmacy (caring for) and managing feelings and emotions (caring about). CONCLUSIONS: Providing care for the physical health of someone with SMI can be understood as having two dimensions - 'caring for' and 'caring about'. The findings suggest a bidirectional relationship between these two dimensions, and both have a cost for the informal carer. With appropriate support informal carers could be more actively involved at all stages of care without increasing their burden. This should be with an awareness that carers may minimise the information they share about their own needs and impacts of their role to spare the person they care and themselves any distress.

Evaluating the impact of the supporting the advancement of research skills (STARS) programme on research knowledge, engagement and capacity-building in a health and social care organisation in England.

OBJECTIVES: To evaluate the impact a novel education programme - to improve research engagement, awareness, understanding and confidence - had on a diverse health and social care workforce. Barriers and facilitators to engagement were explored together with research capacity-building opportunities and ways to embed a research culture. The programme is entitled 'Supporting The Advancement of Research Skills' (STARS programme); the paper reports findings from a health and social care setting in England, UK. METHODS: A four-level outcome framework guided the approach to evaluation and was further informed by key principles of research capacity development and relevant theory. Quantitative data were collected from learners before and after engagement; these were analysed descriptively. Semi-structured online interviews were conducted with learners and analysed thematically. A purposive sample was achieved to include a diversity in age, gender, health and social care profession, and level of attendance (regular attendees, moderate attendees and non-attenders). RESULTS: The evaluation spanned 18 half-day workshops and 11 seminars delivered by expert educators. 165 (2% of total staff at Midlands Partnership University NHS Foundation Trust (MPFT)) staffs booked one or more education sessions; 128 (77%) including Allied Health Professionals (AHPs), psychologists, nursing and midwifery, and social workers attended one or more session. Key themes of engagement with teaching sessions, relevance and impact of training and promoting a research active environment were identified with relevant sub-themes. Positive impacts of training were described in terms of research confidence, intentions, career planning and application of research skills as a direct result of training. Lack of dedicated time for research engagement, work pressures and time commitments required for the programme were key barriers. Facilitators that facilitated engagement are also described. CONCLUSIONS: Findings demonstrate the impact that a free, virtual and high-quality research education programme had at individual and organisational levels. The programme is the product of a successful collaboration between health and social care and academic organisations; this provides a useful framework for others to adapt and adopt. Key barriers to attendance and engagement spoke to system-wide challenges that an education programme could not address in the short-term. Potential solutions are discussed in relation to protecting staff time, achieving management buy-in, recognising research champions, and having a clear communication strategy.

Repression of the major immediate early promoter of human cytomegalovirus allows transcription from an alternate promoter.

Following infection, the human cytomegalovirus (HCMV) genome becomes rapidly associated with host histones which can contribute to the regulation of viral gene expression. This can be seen clearly during HCMV latency where silencing of the major immediate early promoter (MIEP), normally responsible for expression of the key lytic proteins IE72 and IE86, is mediated by histone methylation and recruitment of heterochromatin protein 1. Crucially, reversal of these histone modifications coupled with histone acetylation drives viral reactivation which can be blocked with specific histone acetyltransferase inhibitors (HATi). In lytic infection, a role for HATi is less clear despite the well-established enhancement of viral replication observed with histone deacetylase inhibitors. Here we report that a number of different broad-acting HATi have a minor impact on viral infection and replication during lytic infection with the more overt phenotypes observed at lower multiplicities of infection. However, specific analyses of the regulation of major immediate early (MIE) gene expression reveal that the HATi C646, which targets p300/CBP, transiently repressed MIE gene expression via inhibition of the MIEP but by 24 h post-infection MIE gene expression was rescued due to compensatory activation of an alternative IE promoter, ip2. This suggested that silencing of the MIEP promoted alternative ip2 promoter activity in lytic infection and, consistent with this, ip2 transcription is impaired in cells infected with a recombinant HCMV that does not auto-repress the MIEP at late times of infection. Furthermore, inhibition of the histone methyltransferases known to be responsible for auto-repression is similarly inhibitory to ip2 transcription in wild-type infected cells. We also observe that these discrete transcriptional activities of the MIEP and ip2 promoter are also reflected in reactivation; essentially in cells where the MIEP is silenced, ip2 activity is easier to detect at very early times post-reactivation whereas in cells where robust activation of the MIEP is observed ip2 transcription is reduced or delayed. Finally, we observe that inhibition of pathways demonstrated to be important for reactivation of HCMV in dendritic cells, e.g. in response to IL-6, are preferentially important for activation of the MIEP and not the ip2 promoter. Together, these data add to the hypothesis that the existence of multiple promoters within the MIE region of HCMV can drive reactivation in a cell type- and ligand-specific manner and also suggest that inter-dependent regulatory activity between the two promoters exists.

Multifaceted amelioration of cutaneous photoageing by (0.3%) retinol.

BACKGROUND: Although retinol skin care products improve the appearance of photoaged skin, there is a need for an effective retinol concentration that provides skin benefits without irritation. OBJECTIVE: To compare the efficacy of topical 0.1%, 0.3% and 1% retinol in remodelling the cutaneous architecture in an in vivo experimental patch test study, and to determine tolerance of the most effective formulations when used in a daily in-use escalation study. METHODS: For the patch test study, retinol products were applied under occlusion, to the extensor forearm of photoaged volunteers (n = 5; age range 66-84 years), and 3 mm skin biopsies obtained after 12 days. Effects of different retinol concentrations, and a vehicle control, on key epidermal and dermal biomarkers of cellular proliferation and dermal remodelling were compared to untreated baseline. Separately, participants (n = 218) recorded their tolerance to 0.3% or 1% retinol over a six-week, approved regimen, which gradually increased the facial applications to once nightly. RESULTS: Retinol treatment induced a stepwise increase in epidermal thickness and induced the expression of stratum corneum proteins, filaggrin and KPRP. 0.3% retinol and 1% retinol were comparably effective at inducing keratinocyte proliferation in the epidermis, whilst reducing e-cadherin expression. Fibrillin-rich microfibril deposition was increased following treatment with 0.3% and 1% retinol (p < 0.01); other dermal components remained unaltered (e.g., fibronectin, collagen fibrils, elastin), and no evidence of local inflammation was detected. The in-use study found that 0.3% retinol was better tolerated than 1% retinol, with fewer and milder adverse events reported (χ2 (1) = 23.97; p < 0.001). CONCLUSIONS: This study suggests that 1% and 0.3% retinol concentrations were similarly effective at remodelling photodamaged skin in an in vivo model of long-term use. Use of 0.3% retinol in the escalation study was associated with fewer adverse reactions when applied daily. Hence, 0.3% retinol may be better tolerated than 1% retinol, thereby allowing longer-term topical application.

CONTEXTE: Même si les produits de soins pour la peau à base de rétinol améliorent l'apparence de la peau photovieillie, il est nécessaire d'obtenir une concentration efficace de rétinol procurant des bénéfices cutanés sans irritation. OBJECTIF: Comparer l'efficacité du rétinol à 0.1%, 0.3% et 1% en application locale dans le remodelage de l'architecture cutanée dans une étude d'irritation cutanée in vivo expérimental, et déterminer la tolérance des formulations les plus efficaces lorsqu'elles sont utilisées dans une étude à doses progressives quotidiennes en cours d'utilisation. MÉTHODES: Pour l'étude d'irritation cutanée, des produits à base de rétinol ont été appliqués sous occlusion, sur le muscle extenseur de l'avant-bras de volontaires présentant des signes de photovieillissement (n = 5; tranche d'âge: 66 à 84 ans), et des biopsies cutanées de 3 mm ont été obtenues après 12 jours. Les effets des différentes concentrations de rétinol, et d'un véhicule témoin sur les principaux biomarqueurs épidermiques et dermiques de la prolifération cellulaire et du remodelage dermique ont été comparés à ceux observés à une région non traitée. Séparément, les participants (n = 218) ont enregistré leur tolérance au rétinol à 0.3% ou 1% au cours d'un schéma posologique approuvé de six semaines, qui a progressivement augmenté les applications faciales à une fois par nuit. RÉSULTATS: Le traitement par rétinol a induit une augmentation progressive de l'épaisseur épidermique, et a induit l'expression des protéines de la couche cornée, la filaggrine et le KPRP. Le rétinol à 0.3% et le rétinol à 1% étaient aussi efficaces pour induire la prolifération des kératinocytes dans l'épiderme, tout en réduisant l'expression de la cadhérine E. Le dépôt de microfibrilles riches en fibrilline a augmenté après un traitement par rétinol à 0.3% et 1% (p < 0.001). CONCLUSIONS: Cette étude suggère que les concentrations de rétinol de 1% et 0.3% étaient aussi efficaces pour remodeler la peau photolésée dans un modèle in vivo lors d'une utilisation à long terme. L'utilisation de rétinol à 0.3% dans l'étude à doses progressives a été associée à moins d'effets indésirables lorsqu'il est appliqué quotidiennement. Par conséquent, le rétinol à 0.3% peut être mieux toléré que le rétinol à 1%, permettant ainsi une application topique à plus long terme.

The experiences of the caring dyad: (Un)articulated realities of living with cardiometabolic risk, metabolic syndrome and related diseases in severe mental illness.

BACKGROUND: Informal carers play an important role in the care of patients with mental illness. Little is known of the relationship experience of the patient and their informal carer (caring dyad) as the context for the intersection between physical and mental health. AIM: This study aimed to explore the impact of comorbid cardiometabolic risk (CMR), metabolic syndrome (MetS) and related diseases and severe mental illness (SMI) on the caring dyad. DESIGN: Between October 2018 and March 2020, we conducted 11 in-depth semi-structured interviews across 6 adult caring dyads, interviewing each individual separately. SETTING: Dyads were recruited within the United Kingdom; informal carers were nominated by the patient as a person who provided a significant amount of support. VARIABLE BEING STUDIED: Participants were asked about the impacts of illness and caring on daily life. DATA ANALYSIS: Data were analysed at the dyad level using thematic analysis, comparing and contrasting responses from each individual. RESULTS: Themes were identified: enhanced closeness, dissonance and balance within the caring dyad. DISCUSSION AND CONCLUSIONS: This study uses a particular population of patients with comorbid CMR factors, MetS and related diseases and SMI and their informal carers to explore the relevance and utility of caring dyads as an analytical framework to inform practice and policy. Future interventions should consider factors impacting on dyadic relationships to formulate effective and sustainable dyadic care and treatment to improve health outcomes for both patients with SMI and their informal carers. PATIENT/PUBLIC INVOLVEMENT: In this study, patients and informal carers were participants. Topic guides were piloted with a patient and informal carer.

Antidepressants for preventing postnatal depression.

BACKGROUND: Depression is common in the postnatal period and can lead to adverse effects on the infant and wider family, in addition to the morbidity for the mother. It is not clear whether antidepressants are effective for the prevention of postnatal depression and little is known about possible adverse effects for the mother and infant, particularly during breastfeeding. This is an update of a Cochrane Review last published in 2005. OBJECTIVES: To assess the effectiveness of antidepressant medication for the prevention of postnatal depression, in comparison with any other treatment, placebo or standard care. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR ‒ both Studies and References), CENTRAL (Wiley), MEDLINE (OVID), Embase (OVID), PsycINFO (OVID), on 13 February 2018. We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov on 13 February 2018 to identify any additional unpublished or ongoing studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of initiation of antidepressants (alone or in combination with another treatment), compared with any other treatment, placebo or standard care for the prevention of postnatal depression among women who were either pregnant or had given birth in the previous six weeks and were not currently depressed at baseline. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We requested missing information from investigators wherever possible and sought data to allow intention-to-treat analyses. MAIN RESULTS: Two trials including a total of 81 participants fulfilled the inclusion criteria for this review. All participants in both studies had a history of postnatal depression and were not taking antidepressant medication at baseline. Both trials were conducted by the same research group. Risk of bias was low or unclear in most domains for both studies. We were unable to perform a meta-analysis due to the small number of studies.One study compared nortriptyline with placebo and did not find any evidence that nortriptyline was effective in preventing postnatal depression. In this study, 23% (6/26) of women who took nortriptyline and 24% (6/25) of women who took placebo experienced postnatal depression (RR 0.96, 95% CI 0.36 to 2.59, very low quality evidence) in the first 17 weeks postpartum. One woman taking nortriptyline developed mania; and one side effect, constipation, was more common among women taking nortriptyline than those taking placebo.The second study compared sertraline with placebo. In this study, 7% (1/14) of women who took sertraline developed postnatal depression in the first 17 weeks postpartum compared with 50% (4/8) of women who took placebo. It is uncertain whether sertraline reduces the risk of postnatal depression (RR 0.14, 95% CI 0.02 to 1.07, very low quality evidence). One woman taking sertraline had a hypomanic episode. Two side effects (dizziness and drowsiness) were more common among women taking sertraline than women taking placebo.Conclusions are limited by the small number of studies, small sample sizes and incomplete outcome data due to study drop-out which may have led to bias in the results. We have assessed the certainty of the evidence as very low, based on the GRADE system. No data were available on secondary outcomes of interest including child development, the mother‒infant relationship, breastfeeding, maternal daily functioning, family relationships or maternal satisfaction. AUTHORS' CONCLUSIONS: Due to the limitations of the current evidence base, such as the low statistical power of the included studies, it is not possible to draw any clear conclusions about the effectiveness of antidepressants for the prevention of postnatal depression. It is striking that no new eligible trials have been completed in the period of over a decade since the last published version of this review. Larger trials are needed which include comparisons of antidepressant drugs with other prophylactic treatments (e.g. psychological interventions), and examine adverse effects for the fetus or infant. Future reviews in this area may benefit from broadening their focus to examine the effectiveness of antidepressants for the prevention of perinatal (i.e. antenatal or postnatal) depression, which could include studies comparing antidepressant discontinuation with continuation for the prevention of relapse of depression during pregnancy and the postnatal period.

Involved, inputting or informing: "Shared" decision making in adult mental health care.

BACKGROUND: A diagnosis of serious mental illness can impact on the whole family. Families informally provide significant amounts of care but are disproportionately at risk of carer burden when compared to those supporting people with other long-term conditions. Shared decision making (SDM) is an ethical model of health communication associated with positive health outcomes; however, there has been little research to evaluate how routinely family is invited to participate in SDM, or what this looks like in practice. OBJECTIVE: This UK study aimed to better understand how the family caregivers of those diagnosed with SMI are currently involved in decision making, particularly decisions about treatment options including prescribed medication. Objectives were to Explore the extent to which family members wish to be involved in decisions about prescribed medication Determine how and when professionals engage family in these decisions Identify barriers and facilitators associated with the engagement of family in decisions about treatment. PARTICIPANTS: Open-ended questions were sent to professionals and family members to elicit written responses. Qualitative responses were analysed thematically. RESULTS: Themes included the definition of involvement and "rules of engagement." Staff members are gatekeepers for family involvement, and the process is not democratic. Family and staff ascribe practical, rather than recovery-oriented roles to family, with pre-occupation around notions of adherence. CONCLUSIONS: Staff members need support, training and education to apply SDM. Time to exchange information is vital but practically difficult. Negotiated teams, comprising of staff, service users, family, peers as applicable, with ascribed roles and responsibilities could support SDM.

Heart failure and chronic obstructive pulmonary disease multimorbidity at hospital discharge transition: a study of patient and carer experience.

BACKGROUND: Care for patients with multimorbidity represents a major challenge not only for patients and carers but to health-care systems. Hospital discharge transition is a critical point at which challenges for multimorbidity may amplify. OBJECTIVES: The main objective of the study was to explore the experiences of heart failure (HF) and chronic obstructive pulmonary disease (COPD) multimorbid patients and their carers on hospital discharge. Secondary objectives included identification of gaps in the health care of multimorbidity and optimal solutions from patients and carers' perspectives. DESIGN: Mixed methods were applied to collect data using patient self-completion questionnaire from an adapted version of the American Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey and in-depth interviews. SETTING: Participants were recruited from two cardiology and respiratory wards at a large regional hospital in England, and all had a multimorbidity diagnosis of COPD and HF. RESULTS AND CONCLUSIONS: Findings revealed that patients experienced difficulties in their communication with health-care professionals and there were specific challenges with information about medication. Qualitative descriptions revealed that experiences fell into two main categories: (i) information transfer to patients with multimorbidity in terms of issues with medication and clarity of information on diagnosis and (ii) communication and continuity of care after discharge. Respondents highlighted gaps in the management of patients with multimorbidity of HF and COPD at the critical time of care transition. They suggested the need for a comprehensive, coordinated and integrated approach to incorporate patients, carers and staff preferences for treatment on discharge from hospital.

The Triterpenoid MOMORDIN-Ic Inhibits HCMV by Preventing the Initiation of Gene Expression in Eukaryotic Cells.

Human cytomegalovirus (HCMV) primary infection, re-infection, and reactivation from latency cause morbidity in immune-compromised patients. Consequently, potential therapeutic strategies remain of interest for the treatment of infection. Naturally occurring triterpenoids derived from plants have been demonstrated to have anti-viral activity, although their precise mechanisms of action are not always fully understood. Here, we investigate the activity of Mormordin Ic (Mc) and demonstrate that it is potently anti-viral against HCMV. Through investigation of the mechanistic basis of this anti-viral activity, we identify that it is inhibitory to both viral and host gene expression, and to highly induced genes in particular. We go on to observe that Mc impacts on RNA Pol II activity and, specifically, reduces the occupancy of elongating RNA Pol II at a viral promoter. Next, we demonstrate that Mc is inhibitory to HCMV reactivation, and in doing so identify that it has greater activity against the canonical major immediate early promoter compared to the alternative ip2 promoter located downstream. Finally, we see evidence of RNA Pol II occupancy at the ip2 promoter in undifferentiated myeloid cells. Thus, Mc is potently anti-viral and a potential tool to probe the activity of multiple promoters considered important for controlling HCMV reactivation.

A national survey of adult safeguarding in NHS mental health services in England and Wales.

BACKGROUND: Following the introduction of the No Secrets (Department of Helath, (2000). No Secrets: Guidance on Developing and Implementing Multi-agency Policies and Procedures to Protect Vulnerable Adults from Abuse. London: HMSO) guidance, the implementation and development of adult safeguarding practices and procedures across national services has become an ongoing endeavour. Despite existing research highlighting practice improvements in many services, NHS mental health services are persistently criticised for their lack of engagement with the national adult safeguarding agenda ( Department of Health (2009) . Safeguarding Adults: Report on the Consultation on the Review of 'No Secrets'. London: HMSO). AIM: To investigate the organisational structure, implementation and development of adult safeguarding in NHS mental health services. METHOD: A cross-sectional survey was distributed on-line to 79 (72 NHS Mental Health Trusts in England and seven Health Boards in Wales) NHS mental health services. Results Thirty-three completed surveys were returned, yielding a response rate of 41%. The results highlight adequate arrangements for adult safeguarding in many services; however, it appears implementation is in its initial stages. Responses suggest that staff attitudes and uptake of training are the greatest barrier to practice; however, barriers are also indicated at a strategic and operational level. CONCLUSION: The importance of adult safeguarding must be recognised at all levels and there is an immediate need for improvement to staff training and engagement to ensure future effective practice in this area.

A mixed methods study to understand perinatal mental healthcare referral decisions among midwives and health visitors in the UK.

Background: In the UK approximately half of women requiring perinatal mental health (PNMH) care do not receive treatment despite having routine contact with midwives (MWs) and health visitors (HVs). Limited research has been undertaken regarding MWs'/HVs' decision-making around referring women for secondary PNMH care. In particular, the impact that the level of local secondary PNMH services may have on MWs'/HVs' referral decisions is unexplored. Aim: To understand MWs'/HVs' decision-making in relation to referring women with identified PNMH problems, to identify barriers and facilitators to effective and timely referrals including any impact of the local secondary PNMH service provision. Methods: Participants were recruited from four National Health Service (NHS) Trusts in England, located across two geographical areas, that provided different types of PNMH services. One area had PNMH services that met National Institute for Health and Care Excellence (NICE) guidelines; the other area had no secondary PNMH services. A sequential mixed methods design was used: In-depth semi-structured interviews with practising MWs/HVs (n = 24) to explore their approach to PNMH referral decision-making, analysed using thematic analysis; Questionnaire offered to all practising MWs/HVs in the two geographical areas to measure factors that may impact on PNMH referral decision-making allowing for statistical comparisons to be made between the professional groups/geographical areas. Findings: Three themes were identified from the interviews that impacted on MWs'/HVs' PNMH referral decision-making: identifying need; education, skills and experience; and referral pathways.Questionnaire response rate 13.1% (n = 99). The most reported facilitators to referral decision-making were a trusted relationship between MWs/HVs and women and routine enquiry about women's mental health; the most reported barriers were stigma associated with mental ill-health and women's perceived fear of child removal. Conclusion: Fundamental to MWs'/HVs' decision-making was their perceived relationship between themselves and women. Although PNMH service provision is important for women to ensure they receive appropriate PNMH care, service provision appeared less important to MWs'/HVs' referral decision-making than how maternity/health visiting services were delivered. Further important factors to MWs/HVs were to the ability to provide continuity of carer with women allowing MWs/HVs to identify women who would benefit from referral for secondary PNMH care.

Self-injury and harm minimisation on acute wards.

Practitioners' attitudes to self-injury vary widely. While some healthcare professionals are comfortable providing advice about safe self-injury in the inpatient setting, others believe they have a duty of care to protect patients from harming themselves, including removing all potentially sharp implements and increasing observation levels. This article describes work undertaken at South Staffordshire and Shropshire Healthcare NHS Foundation Trust to explore self-injurious behaviour in inpatient settings, including staff knowledge and perceptions and service users' experiences. Development of clinical guidelines for safe self-injury is also discussed.

Matrikines as mediators of tissue remodelling.

Extracellular matrix (ECM) proteins confer biomechanical properties, maintain cell phenotype and mediate tissue repair (via release of sequestered cytokines and proteases). In contrast to intracellular proteomes, where proteins are monitored and replaced over short time periods, many ECM proteins function for years (decades in humans) without replacement. The longevity of abundant ECM proteins, such as collagen I and elastin, leaves them vulnerable to damage accumulation and their host organs prone to chronic, age-related diseases. However, ECM protein fragmentation can potentially produce peptide cytokines (matrikines) which may exacerbate and/or ameliorate age- and disease-related ECM remodelling. In this review, we discuss ECM composition, function and degradation and highlight examples of endogenous matrikines. We then critically and comprehensively analyse published studies of matrix-derived peptides used as topical skin treatments, before considering the potential for improvements in the discovery and delivery of novel matrix-derived peptides to skin and internal organs. From this, we conclude that while the translational impact of matrix-derived peptide therapeutics is evident, the mechanisms of action of these peptides are poorly defined. Further, well-designed, multimodal studies are required.

Bearing witness: A grounded theory of the experiences of staff at two United Kingdom Higher Education Institutions following a student death by suicide.

Wider networks of people are affected by a suicide death than originally thought, including those whose job-role brings them into contact with a death by suicide of another person. The impact of student suicide within United Kingdom (UK) Higher Education Institutions (HEIs) is unexplored and the experiences of staff members remain unknown. It is not known whether staff members have specific postvention needs following a student death by suicide. Any postvention support currently offered to staff members within UK HEIs lacks a context-specific evidence base. This study asked 'How is a student suicide experienced by staff members within a UK HEI and what are the features of that experience?' Staff members from diverse job-roles in two UK HEIs responded to a qualitative survey (n = 19) and participated in semi-structured interviews (n = 10). Data were transcribed and subjected to a constructivist grounded theory analysis. Participants' experiences informed the development of a core category: 'Bearing witness', which encompassed six further categories: 'Responding to a student suicide'; 'Experiencing a student suicide'; 'Needs and fears'; 'Experiences of support'; 'Human stories'; and 'Cultural stories'. The resulting grounded theory demonstrates how participants' perceptions of impact are informed by their experiences of undertaking tasks following a student suicide within the community of their HEI. Processes of constructing perceptions of closeness to the student who died are evident amongst participants who did not know the student prior to their death. Tailored postvention support is required to respond to the range and complexity of HEI staff needs following a student death by suicide.

'Lost time'. Patients with early inflammatory/rheumatoid arthritis and their experiences of delays in Primary Care.

BACKGROUND: Early referral forms a crucial part in early inflammatory/rheumatoid arthritis (EI/RA) recovery. Delayed decisions to refer can lead to severe incapacity and emotional distress for individuals and family and feelings of lost time. How patients with EI/RA experience early referral decisions in Primary Care is an under explored area and warrants further investigation. AIM: To explore how patients newly diagnosed with EI/RA experienced their early contacts with Primary Care as they negotiated their journey through the referral process into secondary care. DESIGN AND SETTING: Qualitative face-to-face interviews with newly diagnosed EI/RA patients. METHODS: In-depth semi-structured interviews were conducted to explore patients' experiences of referral from first symptoms to General Practitioner referral. All participants were interviewed within 2 weeks of being diagnosed in Secondary Care. Data analysis was conducted using interpretative phenomenological analysis. FINDINGS: All participants in this study described having experienced struggles with their navigation through Primary Care towards diagnosis and specialist EI/RA services. This struggle comprised five key elements: 'family persuasion', 'lack of continuity in care', 'pushing for referral', 'strained relations' and 'lost time'. CONCLUSION: The delays experienced by patients when attempting to reach an early referral decision in Primary Care cause frustration for those presenting with EI/RA, partly because they do not feel heard. There is a significant impact on patients and their families when referral to specialist care is delayed.

The role of pharmacy in the management of cardiometabolic risk, metabolic syndrome and related diseases in severe mental illness: a mixed-methods systematic literature review.

BACKGROUND: Individuals with severe mental illness, e.g. schizophrenia have up to a 20% shortened life expectancy compared to the general population. Cardiovascular disease, due to cardiometabolic risk and metabolic syndrome, accounts for most of this excess mortality. A scoping search revealed that there has not been a review of published studies on the role of pharmacy in relation to cardiometabolic risk, metabolic syndrome and related diseases (e.g. type 2 diabetes) in individuals with severe mental illness. METHODS: A mixed-methods systematic review was performed. Eleven databases were searched using a comprehensive search strategy to identify English-language studies where pharmacy was involved in an intervention for cardiometabolic risk, metabolic syndrome or related diseases in severe mental illness in any study setting from any country of origin. First, a mapping review was conducted. Then, implementation strategies used to implement the study intervention were classified using the Cochrane Effective Practice and Organisation of Care Taxonomy. Impact of the study intervention on the process (e.g. rate of diagnosis of metabolic syndrome) and clinical (e.g. diabetic control) outcomes were analysed where possible (statistical tests of significance obtained for quantitative outcome parameters reported). Quality assessment was undertaken using a modified Mixed Methods Appraisal Tool. RESULTS: A total of 33 studies were identified. Studies were heterogeneous for all characteristics. A total of 20 studies reported quantitative outcome data that allowed for detailed analysis of the impact of the study intervention. The relationship between the total number of implementation strategies used and impact on outcomes measured is unclear. Inclusion of face-to-face interaction in implementation of interventions appears to be important in having a statistically significantly positive impact on measured outcomes even when used on its own. Few studies included pharmacy staff in community or general practitioner practices (n = 2), clinical outcomes, follow up of individuals after implementation of interventions (n = 3). No studies included synthesis of qualitative data. CONCLUSIONS: Our findings indicate that implementation strategies involving face-to-face interaction of pharmacists with other members of the multidisciplinary team can improve process outcomes when used as the sole strategy. Further work is needed on clinical outcomes (e.g. cardiovascular risk reduction), role of community pharmacy and qualitative studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018086411.

Pain during cardiac implantable electronic device implantation.

In order to evaluate the extent and causes of pain during cardiac implantable electronic device (CIED) implantation in our hospital, a prospective audit over a 23-month period using a patient selfreporting questionnaire was undertaken. In total, 599 procedures were reported, 52.9% for de novo pacemaker implantation and 23.4% for high-energy devices (cardiac resynchronisation therapy defibrillator [CRT-D], implantable cardiac defibrillator [ICD], subcutaneous ICD). Overall, the median pain score was 2/10 (interquartile range 2-4). In total, 61.6% (367/599) reported no pain or mild pain (pain scores 0-3/10), 27.7% (165/599) reported moderate pain (pain score of 4-6/10) and 10.7% (64/599) reported severe pain (pain score of 7-10/10) during the procedure. Significant preimplant worry (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.22 to 3.73) and higher lidocaine doses (OR 1.06, 95%CI 1.00 to 1.11) were associated with severe patient-reported pain. In conclusion, most patients underwent CIED implantation with minimum stress and maximum comfort. An important minority reported severe pain during the procedure. Optimising surgical technique and interventions targeted at reducing pre- and peri-implant worry, particularly in women, and especially in those receiving ICDs, warrants further investigation to reduce patient-reported pain during CIED implantation.

Disseminating research: how joint NHS and university posts can support this process.

This article outlines the key challenges inherent in sharing and disseminating research findings within NHS organisations. Staff working in joint posts between universities and clinical settings are in a unique position to address these challenges. They should encourage article publication, presentations, and the implementation of recommendations that are locally relevant. An action research approach is key to boosting the likelihood of findings being implemented. Such steps would also enable clinical staff to become more research aware.

Early Intervention in Psychosis: Effectiveness and Implementation of a Combined Exercise and Health Behavior Intervention Within Routine Care.

Aim: Young people with psychosis have higher rates of obesity, premature cardiovascular disease, and death compared to non-psychotic peers in the general population due to changes in metabolic regulation linked to antipsychotic medication and adverse health risk behaviors. The aim of this paper is to outline the development, implementation, and evaluation of a combined 12-week exercise and health behavior intervention delivered as part of an Early Intervention in Psychosis (EIP) routine service, within the UK. Methods: Participants (n = 27) completed a 12-week combined intervention program, engaging in weekly, 90-min sessions comprising a healthy behavior education session (45 min), followed by a facilitated exercise session (45 min). Anthropometric data from participants (n = 26) were collected at baseline, 12 weeks, and 12 months post-intervention. Health behaviors and clinical measurements were assessed at baseline and 12 months. Results: Mean baseline data suggests participants were at an increased health risk on entry to the program, with elevated values in mean body mass index (BMI; 70% overweight/obese), waist circumference, resting heart rate, and triglycerides. Fifty percent reported smoking daily, 64% ate < 5 fruits/vegetables per day, and 52% of participants were prescribed highly obesogenic antipsychotic medications (i.e., Olanzapine). At 12 weeks and 12 months, no changes were observed in mean BMI, waist circumference or any other clinical variable (p > 0.05). At 12 months, participants reported a positive impact on health behaviors including improved diet, increased physical activity levels, and cessation of substance use (n = 2), alcohol use (n = 2), and smoking (n = 4). Focus groups captured participant experiences, engagement with and satisfaction with the program, including challenges/barriers to program adherence. Conclusions: The 12-week exercise and health behaviors program supported participants to attenuate their physical health risk which was sustained at 12-month follow-up. Self-reported positive health behavior changes are likely to have contributed to the prevention of excessive weight gain in this high-risk period. The evaluation was designed to have validity for a "real world EIP setting" and reflect the complexity of delivery to this participant group. Evaluation findings influenced subsequent commissioning of the physical health intervention as an ongoing element of routine EIP care within the participant site.