Sero-prevalence of syphilis and associated risk factors among pregnant women attending antenatal care at an urban-poor health centre in Kampala, Uganda: a cross-sectional study.

Introduction: syphilis and its outcomes remain a healthcare system burden with adverse consequences such as stillbirths, neonatal deaths and spontaneous abortions among others. The situation might have worsened because the COVID-19 pandemic has caused a major attention drift from other diseases. Additionally, much as testing for syphilis is a routine practice among pregnant mothers, its proportion is not known in urban health care setting. A study to determine the prevalence of syphilis among pregnant mothers in an urban poor setting is warranted. Methods: a cross-sectional study was conducted among pregnant women who attended antenatal care at Kawaala Health Centre IV in Kampala Capital City between December 2019 to March 2020. Informed consent was sought from study participants prior to data collection using structured questionnaires. Whole blood was collected and tested using SD Bioline HIV/syphilis duo rapid test kit (SD Standard Diagnostics, INC, Korea). Data analysis was done using STATA 14.2. Results: one thousand one hundred and sixty-nine pregnant women participated in the study, with a mean age of 25 years. About 27% of them had completed only primary-level education. Approximately 6% of the participants were HIV seropositive. The prevalence of syphilis was 5.9% (69/1169). HIV positivity (aOR: 4.13, 95%CI: 2.05-8.34), elevated blood pressure (aOR: 2.84, 95%CI: 1.42-5.69), and status of previous pregnancy (aOR: 0.21, 95%CI: 0.05-0.89) were significant predictors of the risk of syphilis among pregnant women in this setting. Conclusion: the prevalence of syphilis among pregnant women in urban poor settings is not low and so must not be underestimated. The potential drivers of syphilis among pregnant women are HIV, elevated blood pressure, and status of previous pregnancy. There should be increased awareness about routine syphilis testing among pregnant mothers attending antenatal care.

An evaluation of novel oncology approvals with a PMR/C for assessing data in racial and ethnic populations underrepresented in premarket clinical trials.

Clinical trials supporting oncology drug approvals frequently underrepresent diverse racial and ethnic populations. Recent policies have focused on ensuring premarket clinical trials are more inclusive and representative of racial and ethnic diversity in the general U.S. population or intended patient population; however, recent U.S. Food and Drug Administration (FDA) guidance on postmarketing approaches to collecting data in underrepresented populations demonstrates that, in certain circumstances, PMR/Cs may be issued to conduct more representative studies if there are remaining questions about safety or efficacy. This analysis demonstrates that prior to 2020 no drugs had a PMR/C to further characterize use in a more representative population, and in the last three years, more than half of novel oncology approvals have had such a PMR/C (21/40, 53%). In addition, this analysis helps to identify characteristics, such as single-arm pivotal trial design, U.S. enrollment, and results of safety subgroup analyses based on race and ethnicity, that may contribute to decisions to issue a PMR/C to conduct a study that is more representative of the racial and ethnic diversity of the U.S. or intended patient population. These results can inform efforts to improve premarket clinical trials to ensure they are representative and able to characterize use in any patient who may need the drug.

Designing a Library of Lived Experience for Mental Health: integrated realist synthesis and experience-based co-design study in UK mental health services.

OBJECTIVE: Living Library events involve people being trained as living 'Books', who then discuss aspects of their personal experiences in direct conversation with attendees, referred to as 'Readers'. This study sought to generate a realist programme theory and a theory-informed implementation guide for a Library of Lived Experience for Mental Health (LoLEM). DESIGN: Integrated realist synthesis and experience-based co-design. SETTING: Ten online workshops with participants based in the North of England. PARTICIPANTS: Thirty-one participants with a combination of personal experience of using mental health services, caring for someone with mental health difficulties and/or working in mental health support roles. RESULTS: Database searches identified 30 published and grey literature evidence sources which were integrated with data from 10 online co-design workshops conducted over 12 months. The analysis generated a programme theory comprising five context-mechanism-outcome (CMO) configurations. Findings highlight how establishing psychological safety is foundational to productive Living Library events (CMO 1). For Readers, direct conversations humanise others' experiences (CMO 2) and provide the opportunity to flexibly explore new ways of living (CMO 3). Through participation in a Living Library, Books may experience personal empowerment (CMO 4), while the process of self-authoring and co-editing their story (CMO 5) can contribute to personal development. This programme theory informed the co-design of an implementation guide highlighting the importance of tailoring event design and participant support to the contexts in which LoLEM events are held. CONCLUSIONS: The LoLEM has appeal across stakeholder groups and can be applied flexibly in a range of mental health-related settings. Implementation and evaluation are required to better understand the positive and negative impacts on Books and Readers. TRIAL REGISTRATION NUMBER: PROSPERO CRD42022312789.

An Analysis of Dosing-Related Postmarketing Requirements for Novel Oncology Drugs Approved by the U.S. Food and Drug Administration, 2012-2022.

The FDA's Oncology Center of Excellence's (OCE) launch of Project Optimus signals increased focus on dose optimization approaches in oncology drug development, particularly toward optimization in the premarket setting. Although sponsors continue to adapt premarket study designs and approaches to align with FDA's expectations for dose optimization, including consideration of the optimal dosage(s), there are still instances where questions remain at the time of approval about whether the approved doses or schedules are optimal. In these cases, FDA can exercise regulatory flexibility by issuing postmarketing requirements (PMR) and avoid delaying patient access to promising therapies. This landscape analysis demonstrates that over the past decade (2012-2022), FDA frequently used PMRs to answer additional questions about dosing for novel oncology approvals. We found more than half of drugs (78/132, 59.1%) had a dosing PMR and observed a recent increase in PMRs intended to evaluate whether a lower dose could be more optimal. These results suggest there are opportunities to adapt premarket dose optimization strategies and leverage innovative development tools to ensure timely identification of the optimal dose.

Measuring quality of life in care homes when self-report is challenging: the construct validity, structural characteristics and internal consistency of the mixed-methods adult social care outcomes toolkit.

INTRODUCTION: The adult social care outcomes toolkit (ASCOT) measures social care-related quality of life (SCRQoL) using self-completion questionnaires and interviews. Many care home residents find such methods inaccessible, leading to a reliance on proxy-reporting. This study aimed to establish the psychometric properties of the mixed-methods toolkit [ASCOT-Care Homes, 4 outcome (CH4)] for measuring SCRQoL when residents cannot self-report. METHODS: Two cross-sectional, mixed-methods studies were undertaken in care homes for older people in England between 2015 and 2020. We used the ASCOT-CH4 (observation, and interviews with residents and proxies) to collect information about SCRQoL and collected additional data on residents' needs and characteristics, and variables hypothesised to be related to SCRQoL.Hypothesis testing was applied to establish construct validity, Cronbach's alpha for internal consistency and exploratory factor analysis for structural validity. RESULTS: The combined dataset included 475 residents from 54 care homes (34 nursing, 20 residential). Half had a diagnosis of dementia. Less than a third of residents were able to complete an ASCOT interview. Observations and proxy interviews informed researcher ratings, meaning there were no missing ASCOT-CH4 scores. ASCOT-CH4 was found to be a weak unidimensional scale, consistent with other ASCOT measures, with acceptable internal consistency (α = 0.77, 8 items). Construct validity was supported by the findings. CONCLUSIONS: The ASCOT-CH4 is an alternative to conventional proxy-questionnaires for measuring the SCRQoL of care home residents, with good psychometric properties. A limitation is that users need a range of data collection skills. Future research should explore whether findings are replicable when data are collected by other researchers.

Designing a library of lived experience for mental health (LoLEM): protocol for integrating a realist synthesis and experience based codesign approach.

INTRODUCTION: People with lived expertise in managing mental health challenges can be an important source of knowledge and support for other people facing similar challenges, and for carers to learn how best to help. However, opportunities for sharing lived expertise are limited. Living libraries support people with lived expertise to be 'living books', sharing their experiences in dialogue with 'readers' who can ask questions. Living libraries have been piloted worldwide in health-related contexts but without a clear model of how they work or rigorous evaluation of their impacts. We aim to develop a programme theory about how a living library could be used to improve mental health outcomes, using this theory to codesign an implementation guide that can be evaluated across different contexts. METHODS AND ANALYSIS: We will use a novel integration of realist synthesis and experience-based codesign (EBCD) to produce a programme theory about how living libraries work and a theory and experience informed guide to establishing a library of lived experience for mental health (LoLEM). Two workstreams will run concurrently: (1) a realist synthesis of literature on living libraries, combined with stakeholder interviews, will produce several programme theories; theories will be developed collaboratively with an expert advisory group of stakeholders who have hosted or taken part in a living library and will form our initial analysis framework; a systematic search will identify literature about living libraries; data will be coded into our analysis framework, and we will use retroductive reasoning to explain living libraries' impacts across multiple contexts. Individual stakeholder interviews will help refine and test theories; (2) data from workstream 1 will inform 10 EBCD workshops with people with experience of managing mental health difficulties and health professionals to produce a LoLEM implementation guide; data from this process will also inform the theory in workstream 1. ETHICS AND DISSEMINATION: Ethical approval was granted by Coventry and Warwick National Health Service Research Ethics Committee on 29 December 2021 (reference number 305975). The programme theory and implementation guide will be published as open access and shared widely through a knowledge exchange event, a study website, mental health provider and peer support networks, peer reviewed journals and a funders report. PROSPERO REGISTRATION DETAILS: CRD42022312789.

Breakthrough Therapy Designation Criteria Identify Drugs that Improve Clinical Outcomes for Patients: A Case for More Streamlined Coverage of Promising Therapies.

The breakthrough therapy designation (BTD) process was created to expedite clinical development timelines for drugs intended to treat serious conditions and preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies. This analysis demonstrates that BTD is a valuable tool for expediting approval of promising therapies in oncology. By comparing drugs indicated to treat non-small cell lung cancer (NSCLC) approved with BTD or without BTD between January 2013 and October 2021, BTD drugs reduced the risk of death by a median of 31% and progression by a median of 48%, while drugs never receiving BTD reduced the risk of death and progression by a median of 15% and 41.9%, respectively. These findings show that BTD criteria accurately identify drugs that improve long-term outcomes for patients with cancer and warrant coordinated efforts to ensure timely coverage decisions and access for patients.

Applying a dyadic outcomes approach to supporting older carers and care-recipients: A qualitative study of social care professionals in England.

There are an estimated 2 million older carers, aged 65 or over, in the UK. Older carers are more likely to care for a co-resident spouse/partner, provide high-intensity support and have their own health problems. The literature suggests that a 'dyadic outcomes approach' to social care (i.e. services and support that seek to understand and improve the quality of life of the older carer and the person they support, individually and together) may be especially beneficial for older carers. Such an approach may be applied in needs assessment and review, service evaluation, planning and delivery, or commissioning. However, there is a paucity of evidence of its effectiveness and feasibility in practice. In this qualitative study, we explored views of social care professionals in England on supporting older carers, as well as the feasibility, potential benefits and challenges of applying a dyadic outcomes approach into policy and practice. Overall, 25 professionals were interviewed between January and July 2021, including social workers, team leads, managers, commissioners and other representatives from local authorities, care providers and carer organisations. Findings indicate that there is limited focus on the specific needs of older carers in practice. Participants recognised the potential benefits of a dyadic approach, including the development of a holistic view that enables an effective response to supporting quality of life, for both carer and care-recipient, and building trust when working to support the caring dyad. Barriers to applying a dyadic approach included data protection and sharing, both within and between organisations; required workforce skills, experience and knowledge; and insufficient and competition-oriented adult social care funding that discourages collaborations between agencies. Despite the potential of the approach to improve the effectiveness of support for older caring dyads, these challenges need to be recognised and addressed if it is to be implemented.

The quality of life of older carers and the people they support: An international scoping review.

Older carers, aged 65 or over, may find it difficult to balance caring while maintaining their own health and quality of life (QoL). For older carers, especially, established approaches to separately identifying, assessing and addressing carers' and care-recipients' needs, may not fully consider the interwoven nature of caregiving relationships and the ways in which community-based social care services may impact the QoL of both parties. The purpose of this scoping review is to identify and synthesise what is already known about the QoL of older carers and care-recipients, considered together, which we refer to as 'dyadic QoL'; both in general, and with regard to the impact of community-based social care. We searched 16 electronic databases and grey literature in October and November 2020. A total 822 items were identified and reviewed based on the inclusion criteria: focusing on older carers and care-recipients from a dyadic perspective and their QoL or well-being, published since 2000 and in English. Fourteen papers were thematically analysed, and the findings were presented under two themes. First, the value of applying an overarching conceptual framework of 'interdependence theory' in understanding dyadic QoL, including two broad approaches: dyadic data analysis and the dynamics of caring relationships. Second, a number of papers highlighted the role of support from family, friends and neighbours and community-based social care services in promoting QoL outcomes of caring dyads. This review emphasised that considering the QoL of carers and care-recipients, together, would potentially improve the understanding of care needs, provision of care services and QoL outcomes. However, there is limited and fragmentary evidence about dyadic QoL or the impact of social care services on dyadic QoL outcomes. Future work is required to explore and evaluate the use of a dyadic approach in social care practice and research.

Homologous Recombination Deficiency: Concepts, Definitions, and Assays.

BACKGROUND: Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. METHODS: Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. RESULTS: This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. CONCLUSION: Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

Quadruple-negative RT-PCR assay for COVID-19, but clinically and radiologically COVID pneumonia with POTS: Case report and case-based review.

A 25-year-old woman with a background history of bronchial asthma and intellectual disability presented to hospital with progressively worsening dyspnoea. Despite testing negative four times for coronavirus disease infection by nasopharyngeal swab reverse-transcriptase polymerase chain reaction, her clinical symptoms of hypoxaemic respiratory failure and radiological findings on computed tomography pulmonary angiogram were consistent with coronavirus disease pneumonia. Although she made a quick recovery in the intensive care unit with a combination of empirical antibiotics, corticosteroids, high flow nasal oxygen, therapeutic anticoagulation and awake semi proning, her protracted hospital course due to persistent sinus tachycardia remained challenging. A diagnosis of potential postural orthostatic tachycardia syndrome was explored during the acute phase of illness following an active stand test and exclusion of other causes. She was treated with beta blockers as she failed to improve with non-pharmacological measures. We searched for similar cases by analysing the literature databases. Our case aims to stress the importance of recognising and treating patients with negative nasal reverse-transcriptase polymerase chain reaction swabs as coronavirus disease infection, especially if there is strong evidence of clinical and radiological findings where diagnosis is often under recognised in asthmatics with intellectual disability.

Exploring the views of being a proxy from the perspective of unpaid carers and paid carers: developing a proxy version of the Adult Social Care Outcomes Toolkit (ASCOT).

BACKGROUND: Outcomes-based policy and administration of public services present a compelling argument for the value of outcomes data. However, there are a number of challenges inherent in collecting these data from people who are unable to complete a paper-based survey or interview due to cognitive or communication impairments. In this paper, we explore the views of being a proxy from the perspective of unpaid carers and paid carers who may be asked to act as a proxy on behalf of the person(s) they care for. We consider the key issues that need to be addressed when adapting an instrument designed to measure social care outcomes, the Adult Social Care Outcomes Tool (ASCOT), into a proxy-report tool. METHODS: Participants took part in either a focus group (35 paid carers in eight focus groups), or a one-to-one interview (eight unpaid carers). All participants were recruited via carer organisations and care providers. Transcripts, field notes and audio data collected during focus groups and interviews were analysed using a thematic framework approach. RESULTS: Participants agreed that any person acting as a proxy would need to be very familiar with the care recipient, as well as their needs and care provision. A number of provisions for proxy respondents were proposed to improve face validity and acceptability of completing a questionnaire by proxy, and to ensure that any potential bias is reduced in the design of the questionnaire. These included: providing two sets of response options for each proxy perspective (the proxy themselves and the proxy view of how they think the care recipient would respond); a comments box to help people explain why they have selected a given response option (especially where these indicate unmet need); and providing clear guidance for the proxy respondent on how they should complete the questionnaire. CONCLUSIONS: This study has shown some of the challenges involved in assessing outcomes by proxy and explored some potential ways these can be mitigated. The findings highlight the benefits of developing and testing proxy measures in a robust way to widen participation in social care research.

A cross-sectional study exploring the relationship between regulator quality ratings and care home residents' quality of life in England.

BACKGROUND: The quality of life of people receiving health and social care is an important indicator of service quality, but the relationship between patient experience and outcomes and regulator quality ratings in England is unknown. In 2013, the health and social care regulator in England, the Care Quality Commission (CQC), introduced a new ratings system and by February 2017, all social care services were inspected and awarded new quality ratings (outstanding, good, requires improvement and inadequate). This study aimed to explore whether quality ratings were associated with residents' quality of life, controlling for confounding variables. METHODS: We conducted a nested, cross-sectional study, collecting social care-related quality of life (SCRQoL) data for 293 older care home residents in 34 care homes (20 nursing and 14 residential) in the South East of England. CQC ratings and other resident and home-level variables were also collected for the analysis. Multilevel modelling explored whether residents' social care-related quality of life (SCRQoL) was associated with regulator ratings, controlling for confounding variables. RESULTS: Outstanding and good homes were collapsed into one category and compared with homes requiring improvement. Nationally, only 2 % of care homes for older people are rated as inadequate and it was not possible to capture sufficient numbers for the analysis. We recruited one but it was re-inspected during the fieldwork period and its rating changed to requires improvement. The random intercept multilevel model, which accounted for 16.93% of the differences in SCRQoL within homes and 69.80% between, indicated that better SCRQoL was significantly associated with being female, better functioning, no dementia diagnosis, fewer communication difficulties, and living in a care home rated as outstanding/good by CQC. Size of home and registration category were not significant predictors. CONCLUSIONS: This study found evidence that quality ratings are associated with residents' SCRQoL. As well as aiming to improve quality and ensure minimum standards, quality ratings have the potential to inform user choice and help the public compare care homes based on quality. Future research to establish the generalisability and replicability of the results is required.

Developing a proxy version of the Adult social care outcome toolkit (ASCOT).

BACKGROUND: Social care-related quality of life is a key outcome indicator used in the evaluation of social care interventions and policy. It is not, however, always possible to collect quality of life data by self-report even with adaptations for people with cognitive or communication impairments. A new proxy-report version of the Adult Social Care Outcomes Toolkit (ASCOT) measure of social care-related quality of life was developed to address the issues of wider inclusion of people with cognitive or communication difficulties who may otherwise be systematically excluded. The development of the proxy-report ASCOT questionnaire was informed by literature review and earlier work that identified the key issues and challenges associated with proxy-reported outcomes. METHODS: To evaluate the acceptability and content validity of the ASCOT-Proxy, qualitative cognitive interviews were conducted with unpaid carers or care workers of people with cognitive or communication impairments. The proxy respondents were invited to 'think aloud' while completing the questionnaire. Follow-up probes were asked to elicit further detail of the respondent's comprehension of the format, layout and content of each item and also how they weighed up the options to formulate a response. RESULTS: A total of 25 unpaid carers and care workers participated in three iterative rounds of cognitive interviews. The findings indicate that the items were well-understood and the concepts were consistent with the item definitions for the standard self-completion version of ASCOT with minor modifications to the draft ASCOT-Proxy. The ASCOT-Proxy allows respondents to rate the proxy-proxy and proxy-patient perspectives, which improved the acceptability of proxy report. CONCLUSIONS: A new proxy-report version of ASCOT was developed with evidence of its qualitative content validity and acceptability. The ASCOT-Proxy is ready for empirical testing of its suitability for data collection as a self-completion and/or interview questionnaire, and also evaluation of its psychometric properties.

Adapting the adult social care outcomes toolkit (ASCOT) for use in care home quality monitoring: conceptual development and testing.

BACKGROUND: Alongside an increased policy and practice emphasis on outcomes in social care, English local authorities are now obliged to review quality at a service level to help in their new role of ensuring the development of diverse and high-quality care markets to meet the needs of all local people, including self-funders. The Adult Social Care Outcomes Toolkit (ASCOT) has been developed to measure the outcomes of social care for individuals in a variety of care settings. Local authorities have expressed an interest in exploring how the toolkit might be used for their own purposes, including quality monitoring. This study aimed to explore how the care homes version of the ASCOT toolkit might be adapted for use as a care home quality indicator and carry out some preliminary testing in two care homes for older adults. METHODS: Consultations were carried out with professional and lay stakeholders, with an interest in using the tool or the ratings it would produce. These explored demand and potential uses for the measure and fed into the conceptual development. A draft toolkit and method for collecting the data was developed and the feasibility of using it for quality monitoring was tested with one local authority quality monitoring team in two homes for older adults. RESULTS: Stakeholders expressed an interest in care home quality ratings based on residents' outcomes but there were tensions around who might collect the data and how it might be shared. Feasibility testing suggested the measure had potential for use in quality monitoring but highlighted the importance of training in observational techniques and interviewing skills. The quality monitoring officers involved in the piloting recommended that relatives' views be collected in advance of visits, through surveys not interviews. CONCLUSIONS: Following interest from another local authority, a larger evaluation of the measure for use in routine quality monitoring is planned. As part of this, the ratings made using this measure will be validated against the outcomes of individual residents and compared with the quality ratings of the regulator, the Care Quality Commission.

Neurotrophic effects of growth/differentiation factor 5 in a neuronal cell line.

The neurotrophin growth/differentiation factor 5 (GDF5) is studied as a potential therapeutic agent for Parkinson's disease as it is believed to play a role in the development and maintenance of the nigrostriatal system. Progress in understanding the effects of GDF5 on dopaminergic neurones has been hindered by the use of mixed cell populations derived from primary cultures or in vivo experiments, making it difficult to differentiate between direct and indirect effects of GDF5 treatment on neurones. In an attempt to establish an useful model to study the direct neuronal influence of GDF5, we have characterised the effects of GDF5 on a human neuronal cell line, SH-SY5Y. Our results show that GDF5 has the capability to promote neuronal but not dopaminergic differentiation. We also show that it promotes neuronal survival in vitro following a 6-hydroxydopamine insult. Our results show that application of GDF5 to SH-SY5Y cultures induces the SMAD pathway which could potentially be implicated in the intracellular transmission of GDF5's neurotrophic effects. Overall, our study shows that the SH-SY5Y neuroblastoma cell line provides an excellent neuronal model to study the neurotrophic effects of GDF5.