Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study.

OBJECTIVE: To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia. DESIGN: Population based matched cohort study. SETTING: Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England. POPULATION: Adults (≥50 years) with a diagnosis of dementia between 1 January 1998 and 31 May 2018 (n=173 910, 63.0% women). Each new antipsychotic user (n=35 339, 62.5% women) was matched with up to 15 non-users using incidence density sampling. MAIN OUTCOME MEASURES: The main outcomes were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. An unrelated (negative control) outcome of appendicitis and cholecystitis combined was also investigated to detect potential unmeasured confounding. RESULTS: Compared with non-use, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio 2.19, 95% confidence interval (CI) 2.10 to 2.28), acute kidney injury (1.72, 1.61 to 1.84), venous thromboembolism (1.62, 1.46 to 1.80), stroke (1.61, 1.52 to 1.71), fracture (1.43, 1.35 to 1.52), myocardial infarction (1.28, 1.15 to 1.42), and heart failure (1.27, 1.18 to 1.37). No increased risks were observed for the negative control outcome (appendicitis and cholecystitis). In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%). CONCLUSIONS: Antipsychotic use compared with non-use in adults with dementia was associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury, but not ventricular arrhythmia. The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.

Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture.

BACKGROUND AND PURPOSE: There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis. EXPERIMENTAL APPROACH: The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested. Viral populations were monitored by ultra-deep sequencing, and the decrease of infectivity as a result of the treatment was measured. KEY RESULTS: Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments, virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi-species. CONCLUSION AND IMPLICATIONS: SARS-CoV-2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS-CoV-2 suppression.

Estimating the impact on patient safety of enabling the digital transfer of patients' prescription information in the English NHS.

OBJECTIVES: To estimate the number and burden of medication errors associated with prescription information transfer within the National Health Service (NHS) in England and the impact of implementing an interoperable prescription information system (a single digital prescribing record shared across NHS settings) in reducing these errors. METHODS: We constructed a probabilistic mathematical model. We estimated the number of transition medication errors that would be undetected by standard medicines reconciliation, based on published literature, and scaled this up based on the annual number of hospital admissions. We used published literature to estimate the proportion of errors that lead to harm and applied this to the number of errors to estimate the associated burden (healthcare resource use and deaths). Finally, we used reported effect sizes for electronic prescription information sharing interventions to estimate the impact of implementing an interoperable prescription information system on number of errors and resulting harm. RESULTS: Annually, around 1.8 million (95% credibility interval (CrI) 1.3 to 2.6 million) medication errors were estimated to occur at hospital transitions in England, affecting approximately 380 000 (95% CrI 260 397 to 539 876) patient episodes. Harm from these errors affects around 31 500 (95% CrI 22 407 to 42 906) patients, with 36 500 (95% CrI 25 093 to 52 019) additional bed days of inpatient care (costing around £17.8 million (95% CrI £12.4 to £24.9 million)) and >40 (95% CrI 9 to 146) deaths. Assuming the implementation of an interoperable prescription information system could reduce errors by 10% and 50%, there could be 180 000-913 000 fewer errors, 3000-15 800 fewer people who experience harm and 4-22 lives saved annually. CONCLUSIONS: An interoperable prescription information system could provide major benefits for patient safety. Likely additional benefits include healthcare professional time saved, improved patient experience and care quality, quicker discharge and enhanced cross-organisational medicines optimisation. Our findings provide vital safety and economic evidence for the case to adopt interoperable prescription information systems.

Measuring EQ-5D-5L utility values in parents who have experienced perinatal death.

BACKGROUND: Policymakers use clinical and cost-effectiveness evidence to support decisions about health service commissioning. In England, the National Institute for Health and Care Excellence (NICE) recommend that in cost-effectiveness analyses "effectiveness" is measured as quality-adjusted life years (QALYs), derived from health utility values. The impact of perinatal death (stillbirth/neonatal death) on parents' health utility is currently unknown. This knowledge would improve the robustness of cost-effectiveness evidence for policymakers. OBJECTIVE: This study aimed to estimate the impact of perinatal death on parents' health utility. METHODS: An online survey conducted with mothers and fathers in England who experienced a perinatal death. Participants reported how long ago their baby died and whether they/their partner subsequently became pregnant again. They were asked to rate their health on the EQ-5D-5L instrument (generic health measure). EQ-5D-5L responses were used to calculate health utility values. These were compared with age-matched values for the general population to estimate a utility shortfall (i.e. health loss) associated with perinatal death. RESULTS: There were 256 survey respondents with a median age of 40 years (IQR 26-40). Median time since death was 27 months (IQR 8-71). The mean utility value of the sample was 0.774 (95% CI 0.752-0.796). Utility values in the sample were 13% lower than general population values (p < 0.05). Over 10 years, this equated to a loss of 1.1 QALYs. This reduction in health utility was driven by anxiety and depression. CONCLUSIONS: Perinatal death has important and long-lasting health impacts on parents. Mental health support following perinatal bereavement is especially important.

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.

Generating EQ-5D-3L health utility scores from the Edinburgh Postnatal Depression Scale: a perinatal mapping study.

BACKGROUND: Perinatal depression (PND) describes depression experienced by parents during pregnancy or in the first year after a baby is born. The EQ-5D instrument (a generic measure of health status) is not often collected in perinatal research, however disease-specific measures, such as the Edinburgh Postnatal Depression Scale (EPDS) are widely used. Mapping can be used to estimate generic health utility index values from disease-specific measures like the EPDS. OBJECTIVE: To develop a mapping algorithm to estimate EQ-5D utility index values from the EPDS. METHODS: Patient-level data from the BaBY PaNDA study (English observational cohort study) provided 1068 observations with paired EPDS and EQ-5D (3-level version; EQ-5D-3L) responses. We compared the performance of six alternative regression model types, each with four specifications of covariates (EPDS score and age: base, squared, and cubed). Model performance (ability to predict utility values) was assessed by ranking mean error, mean absolute error, and root mean square error. Algorithm performance in 3 external datasets was also evaluated. RESULTS: There was moderate correlation between EPDS score and utility values (coefficient: - 0.42). The best performing model type was a two-part model, followed by ordinary least squared. Inclusion of squared and cubed covariates improved model performance. Based on graphs of observed and predicted utility values, the algorithm performed better when utility was above 0.6. CONCLUSIONS: This direct mapping algorithm allows the estimation of health utility values from EPDS scores. The algorithm has good external validity but is likely to perform better in samples with higher health status.

PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.

Myofibroblasts are responsible for scarring during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state and increasing profibrotic phenotype. Here, we show mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation. Integrating chromatin accessibility profiles with RNA expression provides insight into the transcription network underlying the switch in profibrotic myofibroblast states, emphasizing mechanoadaptive regulation of PAK1 as key drivers. Through genetic manipulation in liver and lung fibrosis, loss of PAK1-dependent signaling impairs the mechanoadaptive response in vitro and dramatically improves fibrosis in vivo. Moreover, we provide human validation for mechanisms underpinning PAK1-mediated mechanotransduction in liver and lung fibrosis. Collectively, these observations provide insight into the nuclear mechanics driving the profibrotic chromatin landscape in fibrosis, highlighting actomyosin-dependent mechanisms as potential therapeutic targets in fibrosis.

An economic evaluation of universal and targeted case-finding strategies for identifying antenatal depression: a model-based analysis comparing common case-finding instruments.

Half of women with depression in the perinatal period are not identified in routine care, and missed cases reflect inequalities in other areas of maternity care. Case finding (screening) for depression in pregnant women may be a cost-effective strategy to improve identification, and targeted case finding directs finite resources towards the greatest need. We compared the cost-effectiveness of three case-finding strategies: no case finding, universal (all pregnant women), and targeted (only pregnant women with risk factors for antenatal depression, i.e. history of anxiety/depression, age < 20 years, and adverse life events). A decision tree model was developed to represent case finding (at around 20 weeks gestation) and subsequent treatment for antenatal depression (up to 40 weeks gestation). Costs include case finding and treatment. Health benefits are measured as quality-adjusted life years (QALYs). The sensitivity and specificity of case-finding instruments and prevalence and severity of antenatal depression were estimated from a cohort study of pregnant women. Other model parameters were derived from published literature and expert consultation. The most cost-effective case-finding strategy was a two-stage strategy comprising the Whooley questions followed by the PHQ-9. The mean costs were £52 (universal), £61 (no case finding), and £62 (targeted case finding). Both case-finding strategies improve health compared with no case finding. Universal case finding is cost-saving. Costs associated with targeted case finding are similar to no case finding, with greater health gains, although targeted case finding is not cost-effective compared with universal case finding. Universal case finding for antenatal depression is cost-saving compared to no case finding and more cost-effective than targeted case finding.

Estimating the impact of implementing an integrated care management approach with Atrial fibrillation Better Care (ABC) pathway for patients with atrial fibrillation in England from 2020-2040.

BACKGROUND: Stroke prevention is central to the management of atrial fibrillation (AF), but there remains a residual risk of adverse outcomes in anticoagulated AF patients. Hence, current guidelines have proposed a more holistic or integrated approach to AF management, based on the Atrial fibrillation Better Care (ABC) pathway, as follows: A: Avoid stroke with Anticoagulation; B: Better symptom control with patient-centred symptom directed decisions on rate or rhythm control; C: Cardiovascular and comorbidity management, including lifestyle factors. There has been no formal healthcare cost analysis from the UK NHS perspective, of ABC pathway implementation to optimise the management of AF. Our aim was to estimate the number of patients with AF in the UK each year up to 2040, their morbidity and mortality, and the associated healthcare costs. Secondly, to estimate improvements in morbidity and mortality of implementing an ABC pathway, and the impact on costs. RESULTS: In 2020 there were an estimated 1 463 538 AF patients, resulting in £286 m of stroke care and £191 m of care related to bleeds annually. By 2030 it is expected that there will be 2 115 332 AF patients, resulting in £666 m of stroke healthcare and £444 m of healthcare related to bleeds. By 2040 this is expected to rise to 2 856 489 AF patients, with £1 096 m of stroke healthcare and £731 m of healthcare related to bleeds for that year. If in 2040, patients are managed on an ABC pathway this could prevent between 3 724 and 18 622 strokes, between 5 378 and 26 890 bleeds and save between 16 131 and 80 653 lives depending on the proportion of patients managed on the pathway. This would equate to cost reductions of between £143.9 m and £719.6 m for the year. CONCLUSION: We estimate there will be a substantial healthcare burden in the UK NHS associated with AF, from strokes, bleeds and mortality over the next decades. If patients are managed with a holistic or integrated care approach based on the ABC pathway, this could prevent strokes and bleeds that equate to substantial NHS healthcare cost reductions, and save lives.

Organisational and student characteristics, fidelity, funding models, and unit costs of recovery colleges in 28 countries: a cross-sectional survey.

BACKGROUND: Recovery colleges were developed in England to support the recovery of individuals who have mental health symptoms or mental illness. They have been founded in many countries but there has been little international research on recovery colleges and no studies investigating their staffing, fidelity, or costs. We aimed to characterise recovery colleges internationally, to understand organisational and student characteristics, fidelity, and budget. METHODS: In this cross-sectional study, we identified all countries in which recovery colleges exist. We repeated a cross-sectional survey done in England for recovery colleges in 28 countries. In both surveys, recovery colleges were defined as services that supported personal recovery, that were coproduced with students and staff, and where students learned collaboratively with trainers. Recovery college managers completed the survey. The survey included questions about organisational and student characteristics, fidelity to the RECOLLECT Fidelity Measure, funding models, and unit costs. Recovery colleges were grouped by country and continent and presented descriptively. We used regression models to explore continental differences in fidelity, using England as the reference group. FINDINGS: We identified 221 recovery colleges operating across 28 countries, in five continents. Overall, 174 (79%) of 221 recovery colleges participated. Most recovery colleges scored highly on fidelity. Overall scores for fidelity (ß=-2·88, 95% CI 4·44 to -1·32; p=0·0001), coproduction (odds ratio [OR] 0·10, 95% CI 0·03 to 0·33; p<0·0001), and being tailored to the student (OR 0·10, 0·02 to 0·39; p=0·0010), were lower for recovery colleges in Asia than in England. No other significant differences were identified between recovery colleges in England, and those in other continents where recovery colleges were present. 133 recovery colleges provided data on annual budgets, which ranged from €0 to €2 550 000, varying extensively within and between continents. From included data, all annual budgets reported by the college added up to €30 million, providing 19 864 courses for 55 161 students. INTERPRETATION: Recovery colleges exist in many countries. There is an international consensus on key operating principles, especially equality and a commitment to recovery, and most recovery colleges achieve moderate to high fidelity to the original model, irrespective of the income band of their country. Cultural differences need to be considered in assessing coproduction and approaches to individualising support. FUNDING: National Institute for Health and Care Research.

An economic evaluation of targeted case-finding strategies for identifying postnatal depression: A model-based analysis comparing common case-finding instruments.

BACKGROUND: Half of women with postnatal depression (PND) are not identified in routine care. We aimed to estimate the cost-effectiveness of PND case-finding in women with risk factors for PND. METHODS: A decision tree was developed to represent the one-year costs and health outcomes associated with case-finding and treatment for PND. The sensitivity and specificity of case-finding instruments, and prevalence and severity of PND, for women with ≥1 PND risk factor were estimated from a cohort of postnatal women. Risk factors were history of anxiety/depression, age < 20 years, and adverse life events. Other model parameters were derived from published literature and expert consultation. Case-finding for high-risk women only was compared with no case-finding and universal case-finding. RESULTS: More than half of the cohort had one or more PND risk factor (57.8 %; 95 % CI 52.7 %-62.7 %). The most cost-effective case-finding strategy was the Edinburgh Postnatal Depression Scale with a cut-off of ≥10 (EPDS-10). Among high-risk women, there is a high probability that EPDS-10 case-finding for PND is cost-effective compared to no case-finding (78.5 % at a threshold of £20,000/QALY), with an ICER of £8146/QALY gained. Universal case-finding is even more cost-effective at £2945/QALY gained (versus no case-finding). There is a greater health improvement with universal rather than targeted case-finding. LIMITATIONS: The model includes costs and health benefits for mothers in the first year postpartum, the broader (e.g. families, societal) and long-term impacts are also important. CONCLUSIONS: Universal PND case-finding is more cost-effective than targeted case-finding which itself is more cost-effective than not case-finding.

Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study.

PURPOSE: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. METHODS: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb-July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. RESULTS: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32-81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7-8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months' treatment duration; median of 4 mm [IQR - 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month's duration of BrET. DISCUSSION: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.

Evidence-based Recovery Colleges: developing a typology based on organisational characteristics, fidelity and funding.

PURPOSE: Recovery Colleges (RCs) have been implemented across England with wide variation in organisational characteristics. The purpose of this study is to describe RCs across England in terms of organisational and student characteristics, fidelity and annual spending, to generate a RC typology based on characteristics and to explore the relationship between characteristics and fidelity. METHODS: All RC in England meeting criteria on recovery orientation, coproduction and adult learning were included. Managers completed a survey capturing characteristics, fidelity and budget. Hierarchical cluster analysis was conducted to identify common groupings and generate an RC typology. RESULTS: Participants comprised 63 (72%) of 88 RC in England. Fidelity scores were high (median 11, IQR 9-13). Both NHS and strengths-focussed RCs were associated with higher fidelity. The median annual budget was £200,000 (IQR £127,000-£300,000) per RC. The median cost per student was £518 (IQR £275-£840), cost per course designed was £5,556 (IQR £3,000-£9,416) and per course run was £1,510 (IQR £682-£3,030). The total annual budget across England for RCs is an estimated £17.6 m including £13.4 m from NHS budgets, with 11,000 courses delivered to 45,500 students. CONCLUSION: Although the majority of RCs had high levels of fidelity, there were sufficiently pronounced differences in other key characteristics to generate a typology of RCs. This typology might prove important for understanding student outcomes and how they are achieved and for commissioning decisions. Staffing and co-producing new courses are key drivers of spending. The estimated budget for RCs was less than 1% of NHS mental health spending.

An integrated ecological approach to countering targeted violence on the U.S.-Mexico border: Insights and lessons learned.

Well-integrated and productive communities are an asset to the development and advancement of our nation, and they have an important role to play in planning, learning, and enforcing safety to enhance national and border security. REACH (Resilience, Education, Action, Commitment, and Humanity) is a community-based project housed at The University of Texas at El Paso that aims to prevent targeted violence and domestic terrorism in El Paso County. We integrated three frameworks (i.e., Whole Community Preparedness, Socio-Ecological Model, and Global Citizen Education) to involve local residents in efforts to combat and mitigate targeted violence. REACH had two goals: to (1) prevent targeted violence and domestic terrorism through education, outreach, and community capacity-building aimed at identifying and deterring radicalization (primary prevention) and (2) reduce the short-term and long-term impact and prevent re-occurrence of targeted violence and domestic terrorism (secondary and tertiary prevention). Overall, our project served 8,934 participants directly and reached many more through our media cavmpaigns and outreach efforts during our 2 years of project implementation (2021-2023). Our project design may serve as an implementation model for other community-based projects on the U.S.-Mexico border and can be replicated with other target populations in the U.S. Insights and lessons learned from this project are discussed.

Better maternity care pathways in pregnancies after stillbirth or neonatal death: a feasibility study.

BACKGROUND: Around 1 in 150 babies are stillborn or die in the first month of life in the UK. Most women conceive again, and subsequent pregnancies are often characterised by feelings of stress and anxiety, persisting beyond the birth. Psychological distress increases the risk of poor pregnancy outcomes and longer-term parenting difficulties. Appropriate emotional support in subsequent pregnancies is key to ensure the wellbeing of women and families. Substantial variability in existing care has been reported, including fragmentation and poor communication. A new care package improving midwifery continuity and access to emotional support during subsequent pregnancy could improve outcomes. However, no study has assessed the feasibility of a full-scale trial to test effectiveness in improving outcomes and cost-effectiveness for the National Health Service (NHS). METHODS: A prospective, mixed-methods pre-and post-cohort study, in two Northwest England Maternity Units. Thirty-eight women, (≤ 20 weeks' gestation, with a previous stillbirth, or neonatal death) were offered the study intervention (allocation of a named midwife care coordinator and access to group and online support). Sixteen women receiving usual care were recruited in the 6 months preceding implementation of the intervention. Outcome data were collected at 2 antenatal and 1 postnatal visit(s). Qualitative interviews captured experiences of care and research processes with women (n = 20), partners (n = 5), and midwives (n = 8). RESULTS: Overall recruitment was 90% of target, and 77% of women completed the study. A diverse sample reflected the local population, but non-English speaking was a barrier to participation. Study processes and data collection methods were acceptable. Those who received increased midwifery continuity valued the relationship with the care coordinator and perceived positive impacts on pregnancy experiences. However, the anticipated increase in antenatal continuity for direct midwife contacts was not observed for the intervention group. Take-up of in-person support groups was also limited. CONCLUSIONS: Women and partners welcomed the opportunity to participate in research. Continuity of midwifery care was supported as a beneficial strategy to improve care and support in pregnancy after the death of a baby by both parents and professionals. Important barriers to implementation included changes in leadership, service pressures and competing priorities. TRIAL REGISTRATION: ISRCTN17447733 first registration 13/02/2018.

A Feasibility Randomized Controlled Trial of a Parenting Intervention Offered to Women With Severe Mental Health Problems and Delivered in a Mother and Baby Unit Setting: The IMAgINE Study Outcomes.

Background: Approximately 1-2% of mothers may experience severe mental illness (SMI) requiring admission to an inpatient Mother and Baby Unit (MBU). MBUs aim to provide mental health assessment and treatment and strengthen the mother-infant relationship, essential for infant development. Whilst MBUs offer various interventions, they do not routinely offer structured parenting interventions. The Baby Triple P Positive Parenting Program (BTP) was developed to enhance parenting competence, psychological coping and the quality of partner and other social support. Guided by lived experience consultation, we aimed to determine the feasibility and acceptability of delivering BTP plus Treatment as Usual (TAU) in this setting. Method: A multi-site, parallel-group, single-blind pilot randomized controlled trial (registration: ISRCTN12765736) comparing BTP+TAU to TAU in participants, recruited from two MBUs in England. The Baby Triple P intervention consisted of eight parenting sessions, with the final four being delivered over the telephone following MBU discharge. Feasibility outcomes were participant intervention engagement and study retention. Clinical outcomes including maternal parenting competence, bonding and mental health outcomes were assessed at baseline, post-baseline/intervention (10 weeks) and six-month follow-up. Data were analyzed using descriptive statistics and linear regression models. An economic feasibility analysis was also conducted. Results: Thirty-seven of the 67 eligible participants consented; 34 were randomized (16 to BTP+TAU and 18 to TAU), of whom 20 were retained at post-intervention data collection and 21 at six-month follow-up. Twelve participants (75%) completed the intervention, which was rated as highly acceptable. Clinical outcomes signaled potential improvements in maternal parenting competence, bonding, mood and mental health symptomatology in participants who received the intervention. Healthcare resource use and EQ-5D-5L questionnaires were well-completed by participants. Delivering BTP in this setting is estimated to cost £443-822 per participant. Conclusions: This is the first trial of a parenting intervention in a MBU setting. BTP is feasible and acceptable to mothers with SMI, with a promising signal for treatment efficacy. Although minor modifications may be required for the collection of observer-rated measures post-MBU discharge, the findings indicate that a larger, definitive trial could be conducted, especially if the setting is extended to include perinatal mental health community settings.

Women's preferences for antenatal care in Tanzania: a discrete choice experiment.

BACKGROUND: The stillbirth rate in Tanzania remains high. Greater engagement with antenatal care may help to reduce stillbirths. We investigated which characteristics of antenatal care clinics are preferred by pregnant women in Tanzania. METHODS: We conducted an unlabelled discrete choice experiment (DCE) with think-aloud interviews. Participants were pregnant women, regardless of parity/gestation, from the Mwanza and Manyara regions of Tanzania. We asked participants to choose which of two hypothetical antenatal clinics they would rather attend. Clinics were described in terms of transport mode, cleanliness, comfort, visit content, and staff attitude. Each participant made 12 choices during the experiment, and a purposively selected sub-set simultaneously verbalised the rationale for their choices. We analysed DCE responses using a multinomial logit model adjusted for study region, and think-aloud data using the Framework approach. RESULTS: We recruited 251 participants split evenly between the 2 geographical regions. Staff attitude was the most important attribute in clinic choice and dominated the think-aloud narratives. Other significant attributes were mode of transport (walking was preferred) and content of clinic visit (preference was stronger with each additional element of care provided). Cleanliness of the clinic was not a significant attribute overall and the think-aloud exercise identified a willingness to trade-off cleanliness and comfort for respectful care. CONCLUSION: Women would prefer to attend a clinic with kind staff which they can access easily. This study suggests that exploration of barriers to providing respectful care, and enabling staff to deliver it, are important areas for future investment. The DCE shows us what average preferences are; antenatal care that is aligned with identified preferences should increase uptake and engagement versus care which does not acknowledge them.

Ultrastructural view of astrocyte arborization, astrocyte-astrocyte and astrocyte-synapse contacts, intracellular vesicle-like structures, and mitochondrial network.

The complexity of astrocyte morphology and syncytial coupling through gap junctions are crucial for astrocyte function in the brain. However, the ultrastructural details of astrocyte arborization and interactions between neighboring astrocytes remain unknown. While a prevailing view is that synapses selectively contact peripheral astrocyte processes, the precise spatial-location selectivity of synapses abutting astrocytes is unresolved. Additionally, knowing the location and quantity of vesicles and mitochondria are prerequisites to answer two emerging questions - whether astrocytes have a signaling role within the brain and whether astrocytes are highly metabolically active. Here, we provided structural context for these questions by tracing and 3D reconstructing three neighboring astrocytes using serial block-face scanning electron microscopy. Our reconstructions reveal a spongiform astrocytic morphology resulting from the abundance of reflexive and leaflet processes. At the interfaces, varying sizes of astrocyte-astrocyte contacts were identified. Inside an astrocyte domain, synapses contact the entire astrocyte, and synapse-astrocyte contacts increase from soma to terminal leaflets. In contrast to densely packed vesicles at synaptic boutons, vesicle-like structures were scant within astrocytes. Lastly, astrocytes contain dense mitochondrial networks with a mitochondrial volume ratio similar to that of neurites. Together, these ultrastructural details should expand our understanding of functional astrocyte-astrocyte and astrocyte-neuron interactions.

Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM): a trial-based and model-based cost-effectiveness analysis from a stepped wedge, cluster-randomised trial.

BACKGROUND: The AFFIRM intervention aimed to reduce stillbirth and neonatal deaths by increasing awareness of reduced fetal movements (RFM) and implementing a care pathway when women present with RFM. Although there is uncertainty regarding the clinical effectiveness of the intervention, the aim of this analysis was to evaluate the cost-effectiveness. METHODS: A stepped-wedge, cluster-randomised trial was conducted in thirty-three hospitals in the United Kingdom (UK) and Ireland. All women giving birth at the study sites during the analysis period were included in the study. The costs associated with implementing the intervention were estimated from audits of RFM attendances and electronic healthcare records. Trial data were used to estimate a cost per stillbirth prevented was for AFFIRM versus standard care. A decision analytic model was used to estimate the costs and number of perinatal deaths (stillbirths + early neonatal deaths) prevented if AFFIRM were rolled out across Great Britain for one year. Key assumptions were explored in sensitivity analyses. RESULTS: Direct costs to implement AFFIRM were an estimated £95,126 per 1,000 births. Compared to standard care, the cost per stillbirth prevented was estimated to be between £86,478 and being dominated (higher costs, no benefit). The estimated healthcare budget impact of implementing AFFIRM across Great Britain was a cost increase of £61,851,400/year. CONCLUSIONS: Perinatal deaths are relatively rare events in the UK which can increase uncertainty in economic evaluations. This evaluation estimated a plausible range of costs to prevent baby deaths which can inform policy decisions in maternity services. TRIAL REGISTRATION: The trial was registered with www. CLINICALTRIALS: gov , number NCT01777022 .

No association between breast pain and breast cancer: a prospective cohort study of 10 830 symptomatic women presenting to a breast cancer diagnostic clinic.

BACKGROUND: Women with breast pain constitute >20% of breast clinic attendees. AIM: To investigate breast cancer incidence in women presenting with breast pain and establish the health economics of referring women with breast pain to secondary care. DESIGN AND SETTING: A prospective cohort study of all consecutive women referred to a breast diagnostic clinic over 12 months. METHOD: Women were categorised by presentation into four distinct clinical groups and cancer incidence investigated. RESULTS: Of 10 830 women, 1972 (18%) were referred with breast pain, 6708 (62%) with lumps, 480 (4%) with nipple symptoms, 1670 (15%) with 'other' symptoms. Mammography, performed in 1112 women with breast pain, identified cancer in eight (0.7%). Of the 1972 women with breast pain, breast cancer incidence was 0.4% compared with ∼5% in each of the three other clinical groups. Using 'breast lump' as reference, the odds ratio (OR) of women referred with breast pain having breast cancer was 0.05 (95% confidence interval = 0.02 to 0.09, P<0.001). Compared with reassurance in primary care, referral was more costly (net cost £262) without additional health benefits (net quality-adjusted life-year [QALY] loss -0.012). The greatest impact on the incremental cost-effectiveness ratio (ICER) was when QALY loss because of referral-associated anxiety was excluded. Primary care reassurance no longer dominated, but the ICER remained greater (£45 528/QALY) than typical UK National Health Service cost-effectiveness thresholds. CONCLUSION: This study shows that referring women with breast pain to a breast diagnostic clinic is an inefficient use of limited resources. Alternative management pathways could improve capacity and reduce financial burden.