Maternal and Neonatal Effects of Maternal Oral Exposure to Perfluoro-2-methoxyacetic Acid (PFMOAA) during Pregnancy and Early Lactation in the Sprague-Dawley Rat.

Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 µg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (µM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.

A collaboratively produced model of service design for children and young people with common mental health problems.

BACKGROUND: Little is known about the effectiveness of, and implementation complexities associated with, service delivery models for children and young people (CYP) experiencing 'common' mental health problems such as anxiety, depression, behavioural difficulties and self-harm. This paper outlines how a model for high-quality service design for this population group was developed by identifying available services, their effectiveness, cost-effectiveness and acceptability, and the barriers and enablers to access. METHODS: Sequential, mixed-methods design, combining evidence syntheses (scoping and integrative reviews of the international literature) with primary research (a collective case study in England and Wales). Data from these two elements were collaboratively synthesised in a subsequent model-building phase. RESULTS: The scoping review yielded a service model typology. The integrative review found effectiveness evidence only for four models: collaborative care (the only service model to also have cost-effectiveness evidence), outreach approaches, brief intervention services and an organisational framework called 'Availability, Responsiveness and Continuity'. No service model seemed more acceptable than others. Three case study themes were identified: pathways to support; service engagement; and learning and understanding. The model-building phase identified rapid access, learning self-care skills, individualised support, clear information, compassionate and competent staff and aftercare planning as core characteristics of high-quality services. These characteristics were underpinned by four organisational qualities: values that respect confidentiality; engagement and involvement; collaborative relationships; and a learning culture. CONCLUSIONS: A consistent organisational evidence-base for service design and delivery in CYP's mental health spanning many years appears to have had little impact on service provision in England and Wales. Rather than impose - often inflexible and untested - specific local or national models or frameworks, those commissioning, designing and delivering mental health services for CYP should (re)focus on already known, fundamental components necessary for high-quality services. These fundamental components have been integrated into a collaboratively produced general model of service design for CYP with common mental health problems. While this general model is primarily focused on British service provision, it is broad enough to have utility for international audiences.

Review: Crisis responses for children and young people - a systematic review of effectiveness, experiences and service organisation (CAMH-Crisis).

BACKGROUND: In England, one in six children aged 5-19 has a probable diagnosable mental health disorder. This is a major public health problem, with multiple agencies adopting varying approaches to care delivery for children and young people (CYP) in crisis. OBJECTIVES: To examine the organisation of crisis services across education, health, social care and voluntary sectors; the experiences and perceptions of CYP, families and staff; the effectiveness of current approaches to care and the goals of crisis intervention. METHODS: A systematic review of all relevant English language evidence regarding the provision and receipt of crisis support for CYP aged 5-25 (PROSPERO-CRD42019160134). Seventeen databases were searched from 1995 to 2021 and relevant UK-only grey literature was identified. Critical appraisal was conducted using appropriate design specific appraisal tools. A narrative approach to synthesis was conducted. RESULTS: In total, 138 reports (48 reports covering 42 primary research studies; 36 reports covering 39 descriptive accounts of the organisation services and 54 UK-only grey literature reports) were included. The evidence suggests that crisis services were organised as follows: triage/assessment-only, digitally mediated support approaches, and intervention approaches and models. When looking at experiences of crisis care, four themes were identified: (a) barriers and facilitators to seeking and accessing appropriate support; (b) what children and young people want from crisis services; (c) children's, young people's and families' experiences of crisis services; and (d) service provision. In determining effectiveness, the findings are summarised by type of service and were generated from single heterogenous studies. The goals of crisis services were identified. DISCUSSION: Despite a lack of high-quality international studies, findings suggest that support prior to reaching crisis point is important. From this work, various aspects of crisis care have been identified that can be incorporated into existing services across education, health, social care and the voluntary sector.

Molecular basis of USP7 inhibition by selective small-molecule inhibitors.

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

Perceptions of the key components of effective, acceptable and accessible services for children and young people experiencing common mental health problems: a qualitative study.

BACKGROUND: Children and young people's (CYP) mental health is a major public health concern internationally and the recent Covid-19 pandemic has amplified these concerns. However, only a minority of CYP receive support from mental health services due to the attitudinal and structural barriers they and their families encounter. For over 20 years, report after report has consistently highlighted the shortcomings of mental health services for CYP in the United Kingdom and attempts to improve services have been largely unsuccessful. The findings reported in this paper are from a multi-stage study that aimed to develop a model of effective, high-quality service design for CYP experiencing common mental health problems. The aim of the stage reported here was to identify CYP's, parents' and service providers' perceptions of the effectiveness, acceptability and accessibility of services. METHODS: Case studies were conducted of nine different services for CYP with common mental health problems in England and Wales. Data were collected using semi-structured interviews with 41 young people, 26 parents and 41 practitioners and were analysed using the Framework approach. Patient and Public Involvement was integrated throughout the study with a group of young co-researchers participating in data collection and analysis. RESULTS: Four key themes defined participants' perceptions of service effectiveness, acceptability and accessibility. Firstly, open access to support with participants highlighting the importance of self-referral, support at the point of need and service availability to CYP/parents. Secondly, the development of therapeutic relationships to promote service engagement which was based on assessment of practitioner's personal qualities, interpersonal skills and mental health expertise and underpinned by relational continuity. Thirdly, personalisation was viewed as promoting service appropriateness and effectiveness by ensuring support was tailored to the individual. Fourthly, the development of self-care skills and mental health literacy helped CYP/parents manage and improve their/their child's mental health problems. CONCLUSIONS: This study contributes to knowledge by identifying four components that are perceived to be central to providing effective, acceptable and accessible mental health services for CYP with common mental health problems irrespective of service model or provider. These components could be used as the foundations for designing and improving services.

In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays.

Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chemicals for human estrogen receptor (hER) transcriptional activation. Nearly all compounds activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compounds and PFOSA. Receptor activation and relative potencies were evaluated based on effect concentration 20% (EC20), top percent of max fold induction (pmaxtop), and area under the curve (AUC). HFPO-DA and HFPO-DA-AS were the most potent (lowest EC20, highest pmaxtop and AUC) of all PFAS in rat and human PPARα assays, being slightly less potent than oleic and linoleic acid, while NBP2 was the most potent in rat and human PPARγ assays. Only PFHxS, 8:2 and 6:2 FTOH exhibited hER agonism >20% pmax. In vitro measures of human and rat PPARα and PPARγ activity did not correlate with oral doses or serum concentrations of PFAS that induced increases in male rat liver weight from the National Toxicology Program 28-d toxicity studies. Data indicate that both PPARα and PPARγ activation may be molecular initiating events that contribute to the in vivo effects observed for many PFAS.

Prevalence of frailty and cognitive impairment in older transplant candidates - a preview to the Kidney Transplantation in Older People (KTOP): impact of frailty on outcomes study.

BACKGROUND: Kidney transplantation in older people has increased, however older transplant recipients experience mixed outcomes that invariably impacts on their quality of life. The increased vulnerability of older end stage kidney disease patients to frailty and cognitive impairment, may partially explain the differences in outcomes observed. The Kidney Transplantation in Older People (KTOP): impact of frailty on clinical outcomes study is an active clinical study aiming to explore the experience of older people waiting for and undergoing transplantation. In this manuscript we present the study protocol, the study cohort, and the prevalence of frailty and cognitive impairment identified at recruitment. METHODS: The KTOP study is a single centre, prospective, mixed methods, observational study. Recruitment began in October 2019. All patients aged 60 or above either active on the deceased donor waitlist or undergoing live donor transplantation were eligible for recruitment. Recruited participants completed a series of questionnaires assessing frailty, cognition, and quality of life, which are repeated at defined time points whilst on the waitlist and post-transplant. Clinical data was concurrently collected. Any participants identified as frail or vulnerable were also eligible for enrolment into the qualitative sub-study. RESULTS: Two hundred eight participants have been recruited (age 60-78). Baseline Montreal Cognitive Assessments were available for 173 participants, with 63 (36.4%) participants identified as having scores below normal (score < 26). Edmonton Frail Scale assessments were available for 184 participants, with 29 participants (15.8%) identified as frail (score ≥ 8), and a further 37 participants (20.1%) identified as being vulnerable (score 6-7). CONCLUSION: In the KTOP study cohort we have identified a prevalence of 36.4% of participants with MoCA scores suggestive of cognitive impairment, and a prevalence of frailty of 15.8% at recruitment. A further 20.1% were vulnerable. As formal testing for cognition and frailty is not routinely incorporated into the work up of older people across many units, the presence and significance of these conditions is likely not known. Ultimately the KTOP study will report on how these parameters evolve over time and following a transplant, and describe their impact on quality of life and clinical outcomes.

First Contact Practitioners' (FCPs) and General Practitioners' Perceptions Towards FCPs Delivering Vocational Advice to Patients with Musculoskeletal Conditions: A Qualitative Investigation of the Implementation Potential of the I-SWAP Initiative.

Purpose Musculoskeletal (MSK) pain is a common cause of work absence. The recent SWAP (Study of Work And Pain) randomised controlled trial (RCT) found that a brief vocational advice service for primary care patients with MSK pain led to fewer days' work absence and provided good return-on-investment. The I-SWAP (Implementation of the Study of Work And Pain) initiative aimed to deliver an implementation test-bed of the SWAP vocational advice intervention with First Contact Practitioners (FCP). This entailed adapting the SWAP vocational advice training to fit the FCP role. This qualitative investigation explored the implementation potential of FCPs delivering vocational advice for patients with MSK pain. Methods Semi-structured interviews and focus groups were conducted with 10 FCPs and 5 GPs. Data were analysed thematically and findings explored using Normalisation Process Theory (NPT). Results I-SWAP achieved a degree of 'coherence' (i.e. made sense), with both FCPs and GPs feeling FCPs were well-placed to discuss work issues with these patients. However, for many of the FCPs, addressing or modifying psychosocial and occupational barriers to return-to-work was not considered feasible within FCP consultations, and improving physical function was prioritised. Concerns were also raised that employers would not act on FCPs' recommendations regarding return-to-work. Conclusion FCPs appear well-placed to discuss work issues with MSK patients, and signpost/refer to other services; however, because they often only see patients once they are less suited to deliver other aspects of vocational advice. Future research is needed to explore how best to provide vocational advice in primary care settings.

Reconnaissance of Mixed Organic and Inorganic Chemicals in Private and Public Supply Tapwaters at Selected Residential and Workplace Sites in the United States.

Safe drinking water at the point-of-use (tapwater, TW) is a United States public health priority. Multiple lines of evidence were used to evaluate potential human health concerns of 482 organics and 19 inorganics in TW from 13 (7 public supply, 6 private well self-supply) home and 12 (public supply) workplace locations in 11 states. Only uranium (61.9 µg L-1, private well) exceeded a National Primary Drinking Water Regulation maximum contaminant level (MCL: 30 µg L-1). Lead was detected in 23 samples (MCL goal: zero). Seventy-five organics were detected at least once, with median detections of 5 and 17 compounds in self-supply and public supply samples, respectively (corresponding maxima: 12 and 29). Disinfection byproducts predominated in public supply samples, comprising 21% of all detected and 6 of the 10 most frequently detected. Chemicals designed to be bioactive (26 pesticides, 10 pharmaceuticals) comprised 48% of detected organics. Site-specific cumulative exposure-activity ratios (∑EAR) were calculated for the 36 detected organics with ToxCast data. Because these detections are fractional indicators of a largely uncharacterized contaminant space, ∑EAR in excess of 0.001 and 0.01 in 74 and 26% of public supply samples, respectively, provide an argument for prioritized assessment of cumulative effects to vulnerable populations from trace-level TW exposures.

Understanding the impact of eating disorders: using the reflecting team as a learning strategy for students.

This article outlines how the application of a reflecting team from systemic family therapy practice was used as a learning strategy for a postgraduate programme for healthcare students. The programme was designed to increase the students' skills, knowledge and awareness of the needs of people with eating disorders, and their families. There were some benefits to this learning strategy. Students reported that the use of a reflecting team enabled them to gain a deep understanding of the emotional impact of eating disorders on individuals and their carers. However, as this method of learning was new to the students, they needed some initial instruction on the approach. During the programme of study, it became evident that the health professionals were deeply affected by the experiences of people with eating disorders. This would suggest that possibly it was the presence of the sufferers themselves as part of the reflecting team that provided the pivotal learning opportunity, rather than the reflecting team per se.

Occurrence and In Vitro Bioactivity of Estrogen, Androgen, and Glucocorticoid Compounds in a Nationwide Screen of United States Stream Waters.

In vitro bioassays are sensitive, effect-based tools used to quantitatively screen for chemicals with nuclear receptor activity in environmental samples. We measured in vitro estrogen (ER), androgen (AR), and glucocorticoid receptor (GR) activity, along with a broad suite of chemical analytes, in streamwater from 35 well-characterized sites (3 reference and 32 impacted) across 24 states and Puerto Rico. ER agonism was the most frequently detected with nearly all sites (34/35) displaying activity (range, 0.054-116 ng E2Eq L-1). There was a strong linear relationship (r2 = 0.917) between in vitro ER activity and concentrations of steroidal estrogens after correcting for the in vitro potency of each compound. AR agonism was detected in 5/35 samples (range, 1.6-4.8 ng DHTEq L-1) but concentrations of androgenic compounds were largely unable to account for the in vitro activity. Similarly, GR agonism was detected in 9/35 samples (range, 6.0-43 ng DexEq L-1); however, none of the recognized GR-active compounds on the target-chemical analyte list were detected. The utility of in vitro assays in water quality monitoring was evident from both the quantitative agreement between ER activity and estrogen concentrations, as well as the detection of AR and GR activity for which there were limited or no corresponding target-chemical detections to explain the bioactivity. Incorporation of in vitro bioassays as complements to chemical analyses in standard water quality monitoring efforts would allow for more complete assessment of the chemical mixtures present in many surface waters.

How action researchers use anxiety to facilitate change in health care.

AIM: The aim of this paper is to report on the role of an action researcher in a study investigating the change process in a health service context where a new assessment clinic was developed to manage the excessive waiting list for that service. BACKGROUND: For effective organisational change in health, there is a suggestion that change agents need to be emotionally intelligent; recognising the emotional state of individuals, reconciling that with the organisational drivers and making an assessment of readiness for organisational change. Anxiety features throughout this literature and there is a suggestion that being aware of anxiety and managing anxiety is within the emotionally intelligent change agent's repertoire, but there is a gap in the literature that explains this relationship in detail. METHODS: Data were generated to investigate the discrete nature of the role of the action researcher during this organisational change that spanned two years, through three methods: participant observations in the field captured in field notes (n = 72); observations of team meetings that had been recorded and transcribed (n = 13); interviews with key informants pre- and postintervention (n = 14); a reflexive diary one document of 8920 words (n = 1). FINDINGS: The data illuminating the interaction between the action researcher and participants were synthesised into two broad themes: how the action researcher introduced anxiety into the system; how the action researcher facilitated the participants to tolerate change anxiety. DISCUSSION/RELEVANCE TO CLINICAL PRACTICE: The findings from this study can be applied in clinical practice where change in practice is planned. Part of the requirement of a change agent in the NHS might be to be sufficiently emotionally literate to understand anxiety in the participant system and manage it to effect change.

Using circular questions as a tool in qualitative research.

BACKGROUND: Circular questions are used within systematic family therapy as a tool to generate multiple explanations and stories from a family situation and as a means to stimulate the curiosity of the therapist while avoiding their temptation to seek a one definitive explanation. AIM: To consider the potential for using this approach in qualitative research, with researchers using carefully crafted questions to invite respondents to provide information about the meanings behind a phenomenon or consider how relationships between people contribute to it. DISCUSSION: Drawing on examples from a study into children's mental health services, this paper discusses the application of the technique of circular questioning from systemic family therapy to qualitative research. CONCLUSION: The use of circular questions is a technique that qualitative researchers could employ in the field when conducting interviews with individuals or groups, or when engaged in participant observation as a means to obtain rich sources of data. IMPLICATIONS FOR PRACTICE: Circular questioning can help to promote curiosity in the researcher and invite responses that illuminate relational issues between participants in a study.

Service design for children and young people with common mental health problems: literature review, service mapping and collective case study.

Background: The mental health of children/young people is a growing concern internationally. Numerous reports and reviews have consistently described United Kingdom children's mental health services as fragmented, variable, inaccessible and lacking an evidence base. Little is known about the effectiveness of, and implementation complexities associated with, service models for children/young people experiencing 'common' mental health problems like anxiety, depression, attention deficit hyperactivity disorder and self-harm. Aim: To develop a model for high-quality service design for children/young people experiencing common mental health problems by identifying available services, barriers and enablers to access, and the effectiveness, cost effectiveness and acceptability of such services. Design: Evidence syntheses with primary research, using a sequential, mixed-methods design. Inter-related scoping and integrative reviews were conducted alongside a map of relevant services across England and Wales, followed by a collective case study of English and Welsh services. Setting: Global (systematic reviews); England and Wales (service map; case study). Data sources: Literature reviews: relevant bibliographic databases and grey literature. Service map: online survey and offline desk research. Case study: 108 participants (41 children/young people, 26 parents, 41 staff) across nine case study sites. Methods: A single literature search informed both reviews. The service map was obtained from an online survey and internet searches. Case study sites were sampled from the service map; because of coronavirus disease 2019, case study data were collected remotely. 'Young co-researchers' assisted with case study data collection. The integrative review and case study data were synthesised using the 'weaving' approach of 'integration through narrative'. Results: A service model typology was derived from the scoping review. The integrative review found effectiveness evidence for collaborative care, outreach approaches, brief intervention services and the 'availability, responsiveness and continuity' framework. There was cost-effectiveness evidence only for collaborative care. No service model appeared to be more acceptable than others. The service map identified 154 English and Welsh services. Three themes emerged from the case study data: 'pathways to support'; 'service engagement'; and 'learning and understanding'. The integrative review and case study data were synthesised into a coproduced model of high-quality service provision for children/young people experiencing common mental health problems. Limitations: Defining 'service model' was a challenge. Some service initiatives were too new to have filtered through into the literature or service map. Coronavirus disease 2019 brought about a surge in remote/digital services which were under-represented in the literature. A dearth of relevant studies meant few cost-effectiveness conclusions could be drawn. Conclusions: There was no strong evidence to suggest any existing service model was better than another. Instead, we developed a coproduced, evidence-based model that incorporates the fundamental components necessary for high-quality children's mental health services and which has utility for policy, practice and research. Future work: Future work should focus on: the potential of our model to assist in designing, delivering and auditing children's mental health services; reasons for non-engagement in services; the cost effectiveness of different approaches in children's mental health; the advantages/disadvantages of digital/remote platforms in delivering services; understanding how and what the statutory sector might learn from the non-statutory sector regarding choice, personalisation and flexibility. Study registration: This study is registered as PROSPERO CRD42018106219. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/09/08) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 13. See the NIHR Funding and Awards website for further award information.

In this research study, we explored services for children and young people with 'common' mental health problems like depression, anxiety and self-harm. We aimed to find out what services exist, how children/young people and families find out about and access these services, what the services actually do, whether they are helpful and whether they offer value for money. We looked at the international literature (reports and research papers) to identify different approaches to providing support, and to find out whether certain approaches worked better than others and whether children/young people and families preferred some approaches over others. The literature provided very little information about the value for money of services. We also carried out a survey and used the internet to identify 154 relevant services in England and Wales. To explore services in more detail, and hear directly from those using them, we planned to visit 9 of the 154 services to interview children/young people, parents and staff. Unfortunately, coronavirus disease 2019 stopped us directly visiting the nine services and so we conducted phone and video interviews instead. We still managed to speak to, and hear the experiences of, more than 100 people (including children/young people and parents). We combined information from the literature with information from the interviews to create an evidence-based 'model' of what services should look like. This model considers some basic things like how quickly children/young people could access a service, what information was available, the importance of confidentiality and whether staff make the service fit with the child/young person's needs and interests. It also considers whether the service helps children/young people learn skills to manage their mental health and whether staff at a service work well together. We hope our model will help existing and new services improve what they offer to children/young people and families.

Solution-focused approach therapy for mental health nursing students.

Solution-focused therapy is a model of therapy that builds on the client's strengths, is future-focused and can be generally offered as a brief intervention. It can be used across multiple clinical settings and is not limited to being useful for clients accessing mental health services. Learning the underlying principles and developing a foundation level of skill in the approach was found to be achievable in an undergraduate nursing course, with students reporting an increase in their knowledge of the model and confidence in basic therapeutic skills in just one day of training. In this paper, we introduce the solution-focused approach in relation to nursing practice. We describe the template used for the training day offered to undergraduate mental health nurses. Students reported that this method of learning a therapeutic approach was helpful and increased both their knowledge and skill base.

Structural Analysis of Bacillus subtilis Sigma Factors.

Bacteria use an array of sigma factors to regulate gene expression during different stages of their life cycles. Full-length, atomic-level structures of sigma factors have been challenging to obtain experimentally as a result of their many regions of intrinsic disorder. AlphaFold has now supplied plausible full-length models for most sigma factors. Here we discuss the current understanding of the structures and functions of sigma factors in the model organism, Bacillus subtilis, and present an X-ray crystal structure of a region of B. subtilis SigE, a sigma factor that plays a critical role in the developmental process of spore formation.

A proposal to embed patient and public involvement within qualitative data collection and analysis phases of a primary care based implementation study.

BACKGROUND: Patient and public involvement (PPI) is increasingly seen as essential to health service research. There are strong moral and ethical arguments for good quality PPI. Despite the development of guidance aimed at addressing the inconsistent reporting of PPI activities within research, little progress has been made in documenting the steps taken to undertake PPI and how it influences the direction of a study. Without this information, there are minimal opportunities to share learnings across projects and strengthen future PPI practices. The aim of this paper is to present details on the processes and activities planned to integrate PPI into the qualitative research component of a mixed-methods, multi-site study evaluating the implementation of a smart template to promote personalised primary care for patients with multiple long-term conditions. METHODS: This proposal describes the processes and activities planned to integrate PPI into the development and piloting of qualitative data collection tools (topic guides for both practice staff and patients) and a tailored data analysis package developed for PPI members incorporating broad concepts and specific methods of qualitative data analysis. DISCUSSION: Outputs relating to PPI activity may include clear, concise and suitably worded topic guides for qualitative interviews. Piloting of the topic guides via mock interviews will further develop researchers' skills including sensitisation to the experiences of participants being interviewed. Working with PPI members when analysing the qualitative data aims to provide reciprocal learning opportunities and may contribute to improving the overall rigour of the data analysis. The intent of publishing proposed PPI activities within this project is to inform the future delivery of high quality PPI.

Patient and public involvement (PPI) improves healthcare research, however, there is little published evidence of proposed PPI activities within a research study. The aim of this article is to describe the proposed PPI activities which are to be integrated into a study implementing a smart template to promote personalised care for people with multiple long-term conditions within primary care in the United Kingdom. The proposal describes the ways in which PPI members will be included within the data collection and analysis phases of a research study which includes interviews with primary care staff and patients. PPI members will be asked to develop questions for these interviews and to take part in a mock interview whereby a researcher interviews a PPI member. The proposal also provides details on qualitative data analysis workshops which will be specifically developed for PPI members. The impact of PPI activities could include clear, concise and suitably worded questions used within the interviews. Piloting of these questions via mock interviews may enable researchers to further develop their interviewing skills. It is anticipated that involving PPI members when analysing qualitative data will provide opportunities for reciprocal learning and lead to rich interpretations of the data, inclusive of the PPI members' perspectives. Publishing a record of planned PPI activities and potential impacts demonstrates the rationale and considerations made by the team to ensure that involvement in this study is meaningful and has potential benefits for all involved. The team hopes this proposal will support others with the planning and delivery of PPI activities. In future publications, we will reflect on the learnings, challenges, and outcomes from the PPI activities detailed in this proposal.

The INSIGHT project: reflections on the co-production of a quality recognition programme to showcase excellence in public involvement in health and care research.

BACKGROUND: The quality of Patient and Public Involvement (PPI) in healthcare research varies considerably and is frequently tokenistic. We aimed to co-produce the Insight | Public Involvement Quality Recognition and Awards programme, based on the UK Standards for Public Involvement (UKSPI) alongside an incremental scale designed by Expert Citizens (a lived experience-led community group), to incentivise and celebrate continuous improvement in PPI. METHODS: We used Task and Finish Groups (19/44 [43%] public contributor membership) to co-produce the programme which we piloted in three organisations with different healthcare research models. We used surveys and review sessions to capture learning and reflections. RESULTS: We co-created: (1) A Quality descriptor matrix comprising four incremental quality levels (Welcoming, Listening, Learning, Leading) for each UKSPI standard. (2) An assessment framework including guidance materials, self-assessment form and final report template. (3) An assessor training package. (4) The quality awards event format and nomination form. These materials were modified based on pilot-site feedback. Of survey respondents: 94.4% felt they had made at least 'Some' personal contribution (half said 'Quite a lot'/'A great deal'), 88.9% said they were 'Always'/'Often' able to express their views freely and, 100% stated the programme would have 'A lot of impact'/'Quite a bit of impact'. During the project, we identified the importance of taking time to explain project aims and contributor roles, adapting to the needs of individual contributors and, using smaller bespoke sessions outside the main Task and Finish Groups. CONCLUSIONS: We co-produced and piloted a quality recognition programme to incentivise and celebrate continuous quality improvement in PPI. One public contributor stated, "I feel strongly that the Insight framework and awards will raise awareness of the [public involvement] work going on in many community settings. [It] is likely to result in better sharing of positive practice, incentivising research groups of any size to start work or to improve the quality of [PPI] could be one of the main benefits. I'm excited that if this initiative takes off, regionally and then in the longer term nationally, it could be a significant step in advancing the [public] voice."

How researchers involve members of the public in health research varies widely. We developed a scheme that encourages researchers from any health research organisation to improve the quality of public involvement. We used joint workshops with researchers, health workers and members of the public to design the scheme. We then tested it in three research organisations. We recorded the experience of people taking part in the project to learn what went well and what could be improved. We looked at the six areas covered in the UK Standards for Public Involvement. For each area, we worked together to define four levels (Welcoming, Listening, Learning, Leading) of increasing quality. We designed the materials needed for organisations to take part in the scheme. We also created a training pack for assessors and the format of a celebration event. We modified the materials after testing them. We asked those who took part in the project, half of whom were lay members, what they thought. 94% felt they had made at least some personal contribution. 89% said they were often or always able to express their views freely. Everyone thought the project would have some degree of impact. Overall, those members of the public who took part said they enjoyed the process and felt that their views were listened to. Along the way, we learned that it was important to carefully explain the project's aims, be clear about roles and have 1to1 discussions outside the main workshops.

Crisis care for children and young people with mental health problems: national mapping, models of delivery, sustainability and experience (CAMH-Crisis2). A study protocol.

Background: One in six five 16-year-olds have a probable mental health difficulty. Of these, almost half of older teenagers and a quarter of 11-16-year-olds report having self-harmed or attempted suicide. Currently, there is little research into mental health crisis services for young people, with little understanding of what services exist, who uses them, or what works best. Question: 'How are mental health crisis responses for children and young people up to the age of 25 sustained, experienced and integrated within their local systems of services'? Objectives:     1.    To describe National Health Service (NHS), local authority, education and third sector approaches to the implementation and organisation of crisis care for children and young people across England and Wales.    2.   To identify eight contrasting case studies in which to evaluate how crisis services have developed and are currently organised, sustained, experienced and integrated within the context of their local systems of services.    3.   To compare and contrast these services in the context of the available international evidence, drawing out and disseminating clear implications for the design and delivery of future crisis responses for children and young people and their families. Methods: A sequential mixed methods approach, underpinned by normalisation process theory will be employed. A survey will create a detailed record of how crisis responses across England and Wales are organised, implemented and used. Subsequently, eight contrasting services in relation to geographic and socioeconomic setting, populations served, and service configuration will be identified as case studies. Interviews will be conducted with children, young people and parents/carers who have used the service, as well as commissioners, managers and practitioners. Operational policies and service usage data will also be examined. Analysis of how each service is provided, experienced, implemented and sustained will be conducted both inductively and deductively, reflecting normalisation process theory constructs.

BACKGROUND: There has been a sharp increase in children and young people experiencing extreme emotional distress and/or self-harm, which is also known as 'crisis'. Services for young people in crisis are a priority in the UK but little is currently known about what crisis services exist, who uses them, or what type of service works best. AIM AND OBJECTIVES: This project aims to explore the types of mental health crisis services currently available to children and young people up to the age of 25 in England and Wales, and to examine how they are organised, perceived and integrated within other local care systems. The objectives are to: 1. Find out what NHS, local authority, education and charity sector crisis services exist for children and young people across England and Wales, to describe the services and to create a database of them. 2. Identify eight contrasting services from the database and evaluate how these services are organised, perceived and integrated within local care systems. 3. Compare and contrast these services with the available international evidence, drawing out clear implications for the design and delivery of future crisis responses for children and young people and their families. METHODS: We will use a survey to create a database of crisis response services across England and Wales. From the database we will identify eight contrasting services and we will conduct interviews with children, young people and parents/carers who have used the service as well as managers and staff. We will look at how the services work and explore how they are used and by whom. We will compare and contrast each case study and consider findings of other research studies from around the world to draw clear, actionable, lessons for the future provision of high-quality crisis services for children and young people.

Dose additive maternal and offspring effects of oral maternal exposure to a mixture of three PFAS (HFPO-DA, NBP2, PFOS) during pregnancy in the Sprague-Dawley rat.

Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains unclear. Previously we reported that oral administration of hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), or perfluorooctane sulfonate (PFOS) individually during pregnancy produced maternal and F1 effects. Here, we hypothesized that responses to the combined exposure to these three PFAS would be dose additive. Pregnant Sprague-Dawley rats were exposed to a fixed-ratio equipotent mixture where the top dose contained each PFAS at their ED50 for neonatal mortality (100 % dose = PFOS 3 mg/kg; NBP2 10 mg/kg; HFPO-DA 110 mg/kg), followed by a dilution series (33.3, 10, 3.3, and 1 %) and vehicle controls (0 % dose). Consistent with the single chemical studies, dams were exposed from gestation day (GD)14-18 or from GD8-postnatal day (PND2). Fetal and maternal livers on GD18 displayed multiple significantly upregulated genes associated with lipid and carbohydrate metabolism at all dose levels, while dams displayed significantly increased liver weight (≥3.3 % dose) and reduced serum thyroid hormones (≥33.3 % dose). Maternal exposure from GD8-PND2 significantly reduced pup bodyweights at birth (≥33.3 % dose) and PND2 (all doses), increased neonatal liver weights (≥3.3 % dose), increased pup mortality (≥3.3 % dose), and reduced maternal bodyweights and weight gain at the top dose. Echocardiography of adult F1 males and females identified significantly increased left ventricular anterior wall thickness (~10 % increase), whereas other cardiac morphological, functional, and transcriptomic measures were unaffected. Mixture effects in maternal and neonatal animals conformed to dose addition using a relative potency factor (RPF) analysis. Results support dose addition-based cumulative assessment approaches for estimating combined effects of PFAS co-exposure.