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Abstract Background Premature birth and/or low birthweight have long-lasting effects on cognition. The purpose of the present systematic review is to examine whether the effects of prematurity and/or low birth weight on neurodevelopmental outcomes differ between males and females. Methods Web of Science, Scopus, and Ovid MEDLINE were searched for studies of humans born premature and/or of low birthweight, where neurodevelopmental phenotypes were measured at 1 year of age or older. Studies must have reported outcomes in such a way that it was possible to assess whether effects were greater in one sex than the other. Risk of bias was assessed using both the Newcastle–Ottawa scale and the National Institutes of Health Quality assessment tool for observational cohort and cross-sectional studies. Results Seventy-five studies were included for descriptive synthesis, although only 24 presented data in a way that could be extracted for meta-analyses. Meta-analyses found that severe and moderate prematurity/low birthweight impaired cognitive function, and severe prematurity/low birthweight also increased internalizing problem scores. Moderate, but not severe, prematurity/low birthweight significantly increased externalizing problem scores. In no case did effects of prematurity/low birthweight differ between males and females. Heterogeneity among studies was generally high and significant, although age at assessment was not a significant moderator of effect. Descriptive synthesis did not identify an obvious excess or deficiency of male-biased or female-biased effects for any trait category. Individual study quality was generally good, and we found no evidence of publication bias. Conclusions We found no evidence that the sexes differ in their susceptibility to the effects of severe or moderate prematurity/low birthweight on cognitive function, internalizing traits or externalizing traits. Result heterogeneity tended to be high, but this reflects that one sex is not consistently more affected than the other. Frequently stated generalizations that one sex is more susceptible to prenatal adversity should be re-evaluated.

Abstract SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.

ObjectivesThe interRAI Community Rehabilitation Assessment (CRA) is a comprehensive health assessment designed to collect essential health and function information for rehabilitation care planning, benchmarking, and evaluation of clinic and home-based programs. A portion of the CRA is completed through patient self-report. The objective of this study was to demonstrate how the CRA can be used to describe the baseline clinical characteristics of patients participating in ambulatory rehabilitation programs and measure change across numerous domains of function, health, and wellbeing over time.DesignCohort study.Setting and participantsIn total, 709 patients were assessed with the CRA across 25 ambulatory clinics in Ontario, Canada between January 1st, 2018, to December 31st, 2018. We examined sub-groups of patients receiving rehabilitation following stroke (n = 82) and hip or knee total joint replacement (n = 210).MethodsFrequency responses and means were compared between admission and discharge from the ambulatory rehabilitation programs. Measures of interest included self-reported difficulty in completing instrumental activities of daily living, locomotion, fear of falling, and pain.ResultsSignificant improvement relative to at admission was detected for the overall cohort and both sub-samples on individual instrumental activities of daily living, stair difficulty, use of mobility aides, distance walked, fear of falling, and pain.Conclusions and implicationsThe standardized and comparable information collected by the CRA is expected to provide clinicians, clinic, and health system administrators with essential health and function information that can be used for care planning, benchmarking, and evaluation.

Abstract Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT). Methods We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events. Results At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported. Conclusion Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018).

Abstract To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

Abstract Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.

Abstract Microbes are extensively present among various cancer tissues and play critical roles in carcinogenesis and treatment responses. However, the underlying relationships between intratumoral microbes and tumors remain poorly understood. Here, a MIcrobial Cancer‐association Analysis using a Heterogeneous graph transformer (MICAH) to identify intratumoral cancer‐associated microbial communities is presented. MICAH integrates metabolic and phylogenetic relationships among microbes into a heterogeneous graph representation. It uses a graph transformer to holistically capture relationships between intratumoral microbes and cancer tissues, which improves the explainability of the associations between identified microbial communities and cancers. MICAH is applied to intratumoral bacterial data across 5 cancer types and 5 fungi datasets, and its generalizability and reproducibility are demonstrated. After experimentally testing a representative observation using a mouse model of tumor‐microbe‐immune interactions, a result consistent with MICAH's identified relationship is observed. Source tracking analysis reveals that the primary known contributor to a cancer‐associated microbial community is the organs affected by the type of cancer. Overall, this graph neural network framework refines the number of microbes that can be used for follow‐up experimental validation from thousands to tens, thereby helping to accelerate the understanding of the relationship between tumors and intratumoral microbiomes.

Background Opioids kill more people than any other drug. Naloxone is an opioid antagonist which can be distributed in take-home ‘kits’ for peer administration (take-home naloxone). Aim To determine the feasibility of carrying out a definitive randomised controlled trial of take-home naloxone in emergency settings. Design We used Welsh routine data (2015–21) to test the feasibility of developing a discriminant function to identify people at high risk of fatal opioid overdose. We carried out a cluster randomised controlled trial and qualitative study to examine experiences of service users and providers. We assessed feasibility of intervention and trial methods against predetermined progression criteria related to: site sign-up, staff trained, identification of eligible patients, proportion given kits, identification of people who died of opioid poisoning, data linkage and retrieval of outcomes. Setting This study was carried out in the emergency environment; sites comprised an emergency department and associated ambulance service catchment area. Participants At intervention sites, we invited emergency department clinicians and paramedics to participate. We recruited adult patients who arrived at the emergency department or were attended to by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the take-home naloxone and related training. Interventions Usual care comprised basic life support plus naloxone by paramedics or emergency department staff. The take-home naloxone intervention was offered in addition to usual care, with guidance for recipients on basic life support, the importance of calling the emergency services, duration of effect, safety and legality of naloxone administration. Results Discriminant function With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up. Randomised controlled trial Four sites participated in the trial and 299 of 687 (44%) eligible clinical staff were trained. Sixty take-home naloxone kits were supplied to patients during 1-year recruitment. Eligible patients were not offered take-home naloxone kits 164 times: ‘forgot’ (n = 136); ‘too busy’ (n = 15); suspected intentional overdose (n = 3). Qualitative interviews Service users had high levels of knowledge about take-home naloxone. They were supportive of the intervention but noted concerns about opioid withdrawal and resistance to attending hospital for an overdose. Service providers were positive about the intervention but reported barriers including difficulty with consenting and training high-risk opioid users. Health economics We were able to calculate costs to train staff at three sites (£40 per AS and £17 in Site 1 ED). No adverse events were reported. Progression criteria were not met – fewer than 50% of eligible staff were trained, fewer than 50% of eligible patients received the intervention and outcomes were not retrieved within reasonable timescales. Future work The take-home naloxone intervention needs to be developed and evaluated in emergency care settings, with appropriate methods. Limitations The Take-home naloxone Intervention Multicentre Emergency setting study was interrupted by coronavirus disease. Conclusions This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned. Trial registration This trial is registered as ISRCTN13232859. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information. Plain language summary Emergency ambulance staff and doctors in the emergency department regularly administer naloxone to people who have overdosed, reversing effects of the opioid – so-called ‘take-home naloxone’ – to administer to others in an emergency. We don’t know whether take-home naloxone saves lives. We carried out this feasibility study to see whether: we could identify a high-risk population to include in a trial to determine whether take-home naloxone reduces deaths from overdose ambulance paramedics and emergency department staff could be trained, and would then give out take-home naloxone kits to drug users they see. We included four areas in the study. We randomly selected two for distribution of take-home naloxone to patients at risk of or following an overdose by emergency department clinicians and local ambulance paramedics. We attempted to identify people at high risk of death from opioid overdose. We collected data about patients that were eligible and received take-home naloxone in the two intervention areas. We carried out interviews to find out about the views of patients and staff who gave out the kits. At the start, we agreed criteria that should be met for us to recommend that a full evaluation be carried out. We could not reliably identify people at high risk of death from opioid overdose, as deaths were rare in the population, and previous health service usage was variable. Less than half of eligible staff were trained to supply take-home naloxone (299/687, 44%), and less than half of eligible patients were given take-home naloxone (60/277, 21.7%) over 1 year. Patients were not offered take-home naloxone because staff forgot, were too busy or suspected an intentional overdose. Other patients left before receiving a kit. Service users liked the idea of take-home naloxone kits being provided in the emergency setting but reported resistance to attending hospital following an overdose. Service providers were supportive of providing take-home naloxone in the emergency setting but reported challenges in consent and training. Conclusion This study found that it was not feasible to deliver or evaluate this form of take-home naloxone, using this study design, in emergency care. Scientific summary Parts of this summary have been reproduced from Jones M, Bell F, Benger J, Black S, Buykx P, Dixon S, et al. Protocol for Take-home naloxone In Multicentre Emergency (TIME) settings: feasibility study. Pilot Feasib Stud 2020;6(1):1–10. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Background Opioids, such as heroin, kill more people worldwide by overdose than any other type of drug, and death rates associated with opioid poisoning in the United Kingdom (UK) are at record levels. Naloxone is an opioid antagonist which can be distributed in ‘kits’ for administration by witnesses in an overdose emergency. This intervention is known as take-home naloxone (THN). We know that THN can save lives on an individual level, but there is currently limited evidence about the effectiveness of THN distribution on an aggregate level, in specialist drug service settings or in emergency service (ES) settings. Notably, we do not know whether THN kits reduce deaths from opioid overdose in at-risk populations, if there are unforeseen harms associated with THN distribution or if THN is cost-effective. To address this research gap, we aimed to determine the feasibility of a fully powered cluster randomised controlled trial (RCT) of THN distribution in emergency settings. Aim To determine the feasibility of carrying out a definitive RCT of THN in emergency settings. Objectives To determine: the best form of THN kit, training and delivery whether a trial clustered by emergency department (ED) catchment area and the associated ambulance service (AS) is deliverable, as assessed against predefined progression criteria related to intervention, trial design and methods. Design We assessed feasibility of intervention and trial methods based upon the following predetermined progression criteria. Intervention feasibility Sign-up of four sites, including ≥ 50% eligible staff to complete training in delivering the intervention at each intervention site. Identification of ≥ 75% of people who have presented to ED or AS with opioid overdose or an opioid use-related problem over a 12-month period. THN kits issued to ≥ 50% eligible patients over a 12-month period at intervention sites. Serious adverse event rate [to be defined in agreement with Data Monitoring and Ethics Committee (DMEC)] of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment. Trial methods feasibility Identification and inclusion for follow-up of ≥ 75% of people who died of opioid poisoning in the following year in the study areas according to Office of National Statistics (ONS) mortality data (previous ONS data suggest between 140 and 180 such deaths across the 4 participating sites during the study period). Matching and data linkage in ≥ 90% of cases not dissented at the conclusion of quantitative data collection. Retrieval of primary and secondary outcomes from National Health Service (NHS) Digital and National Welsh Informatics Service within 6 months of projected timeline. As the intervention tested is for administration to recipients of the THN kits and peers who may suffer an overdose, we needed to find a way to identify cohorts to include in outcome comparisons. We therefore analysed Welsh routine data to test the feasibility of developing a discriminant function to identify a high-risk population for fatal opioid overdose. We scoped anonymised routine retrospective data from 1 January 2015 to 30 November 2021, sourced from the Welsh Demographic Service Dataset (WDSD) to define the study population. To categorise death associated with an opioid overdose, the annual district death extract (ADDE) dataset was used in conjunction with the WDSD to calculate an individual-level study end date. Finally, we considered critical care, ED and hospital admissions as well as substance misuse treatment for the 36 months up to the end of the study period. We carried out a RCT clustered by site in the emergency environment with a qualitative study to examine processes of implementation, patient safety, costs of training NHS staff and experiences of service users and providers. Two intervention sites (paired ED and local AS catchment area) were randomly selected from the four participating sites. Usual practice was continued in the other two sites, acting as controls. Alongside the RCT, we collected qualitative data via semistructured interviews with service users from substance use treatment centres and third-sector organisations. The interview questions were guided by literature around opioid overdose experience and emergency naloxone use, with the aim to explore how opioid users interact with the knowledge, behaviour and attitudes towards the use of THN kits and training to use the kits. Focus groups and interviews with service providers (paramedics and ED clinical staff) were conducted to discuss barriers in the provision of THN in the emergency setting as well as facilitators to this implementation. We assessed the feasibility of collecting costs associated with THN provision in the emergency setting by measuring the health service contacts and incorporating healthcare resource groups (HRGs) into the analysis to produce an overall cost. Setting This feasibility study was carried out in the emergency care environment, across study sites each centred on a receiving ED and defined geographically as the local AS catchment area for that receiving ED. Participants At intervention sites, we invited ED clinicians and paramedics to participate in the trial and recruited adult patients who arrived at the ED or were attended by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the THN and related training. Participants were to be identified for outcome comparison by application of the discriminant function, if completed, to the study site general populations. Interventions Usual care comprised administration of basic life support plus naloxone by paramedics or ED staff. The THN intervention was offered in addition to usual care and included a multi dose THN kit (Prenoxad) containing 2 mg naloxone hydrochloride 1 mg/1 ml solution for intramuscular (IM) injection, and instructions on the correct administration of the naloxone dose. Recipients also received guidance on: BLS; the importance of calling the ES; duration of effect; the safety of naloxone in terms of adverse events and overdose; and the legality of bystander administration of naloxone. Results TABLE S1Assessment against preset progression criteria Criteria Achieved Criteria met Sign-up of four sites, including ≥ 50% eligible staff to complete training in delivering the intervention at each intervention site Site 1: ED trained 81.1%, AS trained 54% of eligible staffSite 2: ED trained 8.1%, AS trained 33.8% of eligible staff No Identification of ≥ 75% of people who have presented to ED or AS with opioid overdose or an opioid use-related problem over a 12-month period Unable to assess Not known THN kits issued to ≥ 50% eligible patients over a 12-month period at intervention sites 21.7% of eligible patients were given kits No Serious adverse event rate (to be defined in agreement with the DMEC) of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment No serious adverse events were reported Yes Identification and inclusion for follow-up of ≥ 75% of people who died of opioid poisoning in the following year in the study areas according to ONS mortality data (previous ONS data suggest between 140 and 180 such deaths across the four participating sites during the study period) We were able to identify decedents from opioid poisoning in Wales but were unable to produce a discriminant function which included this group in a sufficiently small section of the general population, or to test these methods in a second population No Matching and data linkage in ≥ 90% of cases not dissented at the conclusion of quantitative data collection Due to significant delays in permissions processes for routine- linked data retrieval from NHS Digital, and low administration of THN kits, we did not attempt to match and link records for patients recruited to the trial No Retrieval of routinely recorded primary and secondary outcomes from national repositories within six-months of projected timeline Again, due to significant delays in permissions processes for routine- linked data retrieval, and low administration of THN kits, we did not attempt to retrieve routinely recorded primary and secondary outcomes No Discriminant function With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion of them having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up. RCT In total, 299 of 687 (43.5%) eligible staff were trained to supply THN kits to eligible patients at the two sites (Site 1: ED n = 107, AS n = 121; Site 2: ED n = 25, AS n = 46). Sixty THN kits were supplied to eligible patients during the recruitment period (Site 1: ED n = 36, AS n = 4; Site 2: ED n = 16, AS n = 4). Eligible patients were recorded as not being offered THN kits 164 times, with reasons reported for not offering eligible patients kits: staff forgot (n = 136); staff too busy (n = 15); and suspected intentional overdose (n = 3). Staff recorded 626 people as being considered for inclusion but found not to be eligible, with reasons listed as: uncooperative including being abusive towards staff (n = 55); lack of capacity (n = 35); reduced consciousness level (n = 41); patient in custody (n = 21); and patient absconded (n = 161). Qualitative interviews Service users had high levels of knowledge about THN, with variable previous access to kits. They generally supported the provision of THN kits and training in the emergency setting and felt that it should be expanded further to chemists and needle exchanges. They also noted the importance of including loved ones in training and felt that this gave them a sense of empowerment and motivation to help others in an overdose situation. They noted concerns with regards to opioid withdrawal and resistance to attending hospital for an overdose. The service users reported that the provision of THN kits and training to friends and family of opioid users would possibly be more beneficial and believed that incorporating THN provision into normal practice would help mitigate some of these barriers. Interviews and focus groups with service providers found that they were supportive about the provision of THN kits and training in the emergency setting. However, they also reported barriers including difficulties consenting and training opioid users, a high turnover of staff impacting the cascade of the intervention as well as negative attitudes towards the patient group and the coronavirus disease 2019 (COVID-19) pandemic. No adverse events were reported. Conclusion This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned. There does appear to be appetite for THN kit provision and training in the emergency setting. We conclude that the THN intervention as defined and administered in the Take-home naloxone Intervention Multicentre Emergency setting (TIME) study was not feasible and should not therefore go forward to full trial. However, there may be space for further development of this complex intervention in emergency care – for example, for protocols to allow administration to family and friends of opioid users; as well as methods for definition and identification of study cohorts for outcome comparisons. Trial registration This trial is registered as ISRCTN13232859. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information.

BackgroundFor many people with long COVID (LC), new-onset pain is a debilitating consequence. This study examined the nature of new-onset pain and concomitant symptoms in patients with LC to infer mechanisms of pain from the relationships between pain and health-related factors.MethodsPain and other symptoms were evaluated in 153 individuals with LC using the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs, EuroQoL Visual Analog Scale, and Quality of Life in Neurological Disorders. The relationships between pain and patient factors were analyzed using Chi Square and independent t-tests.Results20.3% of individuals who reported new-onset pain had neuropathic pain, which was associated with lower quality of life and higher rates of cognitive dysfunction compared to those with non-neuropathic pain. Other symptoms were similar between groups, however heart-related symptoms were more prevalent in individuals with neuropathic pain and mood swings were more prevalent for individuals with non-neuropathic pain.ConclusionsCharacterizing the relationships between NP and quality of life in individuals with LC can aid in developing better clinical management strategies. Understanding the associations between NP and cognitive dysfunction provides the imperative foundation for future studies further examining the pathophysiological mechanisms underlying pain development in LC.

Background Placenta accreta spectrum (PAS) disorder is a source of severe obstetric morbidity and mortality worldwide. The objective of this paper was to evaluate the potential relationship between social vulnerability and severe maternal morbidity in a cohort of patients delivering a pregnancy complicated by PAS.Methods A retrospective review of 323 deliveries at three academic medical institutions between January 2013 and June 2022 was included in the analyses. Patients were those with a histopathologically confirmed case of PAS. The composite morbidity outcome included such maternal complications as mechanical ventilation, injury to organs and transfusion of 4+units of red blood cells. Social vulnerability was measured by assigning subjects a value of the Childhood Opportunity Index based on their home zip code. Logistic regression models were employed and adjusted for potential confounders.Results 73% of our sample experienced composite severe maternal morbidity at the time of their delivery. There were no statistically significant associations between social vulnerability and severe surgical morbidity, either as a composite or individually, within the multivariate regression models.Conclusion Our results do not support the hypothesis that social vulnerability is associated with severe maternal morbidity in deliveries complicated by PAS. The present study suggests that the relationship between social vulnerability and obstetrical surgical morbidity is more complicated than can be assessed by the present linear regression models.

BackgroundThere is a large number of research studies about the prevention of non-communicable diseases (NCD), with findings taking several years to be translated into practice. One reason for this lack of translation is a limited understanding of how to best disseminate NCD research findings to user-groups in a way that is salient and useful. An understanding of barriers and facilitators to dissemination is key to informing the development of strategies to increase dissemination. Therefore, this review aims to identify and synthesise the barriers and facilitators to dissemination of NCD research findings.MethodsA mixed studies systematic review was performed following JBI (formerly known as Joanna Briggs Institute) methodology. The search included articles from January 2000 until May 2021. We conducted a comprehensive search of bibliographic and grey literature of five databases to identify eligible studies. Studies were included if they involved end-users of public health research that were decision-makers in their setting and examined barriers/facilitators to disseminating research findings. Two pairs of reviewers mapped data from included studies against the Framework of Knowledge Translation (FKT) and used a convergent approach to synthesise the data.ResultsThe database search yielded 27,192 reports. Following screening and full text review, 15 studies (ten qualitative, one quantitative and four mixed methods) were included. Studies were conducted in 12 mostly high-income countries, with a total of 871 participants. We identified 12 barriers and 14 facilitators mapped to five elements of the FKT. Barriers related to: (i) the user-group (n = 3) such as not perceiving health as important and (ii) the dissemination strategies (n = 3) such as lack of understanding of content of guidelines. Several facilitators related to dissemination strategies (n = 5) such as using different channels of communication. Facilitators also related to the user-group (n = 4) such as the user-groups’ interest in health and research.ConclusionResearchers and government organisations should consider these factors when identifying ways to disseminate research findings to decision-maker audiences. Future research should aim to build the evidence base on different strategies to overcome these barriers.Systematic review registrationThe protocol of this review was deposited in Open Science Framework (https://doi.org/10.17605/OSF.IO/5QSGD).

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual’s genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.

IntroductionWoodchips as a source of particulate organic carbon (POC) are proposed as a nature-based solution to enhance nutrient uptake and retention in agricultural streams. However, the effective implementation of woodchips for nutrient removal in streams requires an advanced understanding of their potential and limits, considering their performance under various environmental conditions. This study tested the efficiency of woodchips on the uptake of soluble reactive phosphorus (SRP) and ammonium (N-NH4) across different experimental scales and complexity. We investigated whether the presence of woodchips can increase SRP and N-NH4 uptake in laboratory flumes under controlled conditions, outdoor flumes under semi-controlled conditions, and agricultural streams. Additionally, we examined how the effects of woodchips will change over time via a 6-week incubation in the outdoor flumes.MethodsThe woodchips were pre-colonized for four weeks to allow the growth of biofilms. We performed short-term nutrient additions without (control) and with (treatment) woodchips in all three experimental setups. Uptake parameters were determined via concentration changes over time in the laboratory flumes and concentration changes over travel distance in the outdoor flumes and the stream channels. The effects of woodchips on SRP and N-NH4 uptake rates were analyzed using an effect size model.ResultsWe found positive effects of woodchips on nutrient uptake only in the laboratory flumes but no or even negative effects in the outdoor flumes and the agricultural streams. Over the 6-week incubation in the outdoor flumes, we did not observe significant changes in the effects of woodchips on nutrient uptake.DiscussionThese findings highlight that considering experimental scales and influencing environmental conditions is crucial when testing the application of woodchips as nature-based solutions to mitigate nutrient loads in agricultural streams.

Objectives Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We aimed to explore how potential multiple early-life determinants of multimorbidity can be audited and characterised across three UK cohort studies. Approach We used the 1958 National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identify and categorise early-life variables that fit into 12 previously conceptualised domains of early-life determinants of multimorbidity. A data audit manually assigned variables into the domain they best represented. Principal component analysis (PCA) reduced the dimensionality of the data and structured variables into subgroups. Important PCA components defined as the component that contributed the greatest proportion of the overall variance were identified. Results Seven domains were characterised by 74 variables in ACONF, ten domains by 143 variables in the NCDS, and twelve domains by 289 variables in the BCS70. PCA analysis reduced the dimensionality of ACONF variables from 74 to 41, from 143 to 73 in the NCDS, and from 289 to 149 in the BCS70. Important PCA components included maternal fertility histories, long-term illnesses, educational ability, ethnicity, housing status and parental-child interactions. Conclusions and Implications Conceptualising the risk of future multimorbidity as lifecourse domains composed of multiple factors can help challenge the existing understanding of disease aetiology and inform strategies for the prevention of multimorbidity.

We present the case of a 75 year old transgender woman 18 months post gender-affirming vaginoplasty found to have unfavorable, intermediate risk prostate cancer. She elected a robotic radical prostatectomy with bilateral pelvic lymph node dissection. Postoperatively, the patient resumed neovaginal dilation without difficulty, and had improvements on International Prostate Symptom Score when compared to post-vaginoplasty, pre-prostatectomy. Incontinence measured by Revised Urinary Incontinence Scale remained mild. Robotic prostatectomy can, under appropriate circumstances, allow preservation of the neovaginal vault, but requires considerable experience and multidisciplinary intraoperative collaboration.

Coeliac Disease (CD) and Sjogren’s Syndrome (SS), both autoimmune disorders, are gaining attention for their complex interaction when occurring together. CD involves gluten intolerance and can present with gastrointestinal symptoms, while SS affects various organs, primarily causing dryness of the eyes and mouth. Diagnosis for each relies on specific criteria including serologic testing and histopathology. When these conditions overlap, they create unique clinical challenges, highlighting the need for a thorough understanding of their combined effects on health. This exploration aimed to uncover the intricacies of their relationship, including clinical manifestations and implications for diagnosis and management when dealing with both simultaneously. In both cases (58-year-old female and 47-year-old female), there was gastrointestinal villous atrophy as a manifestation of CD, which improved with simple dietary modification.

Abstract Background A key role of public health policy-makers and practitioners is to ensure beneficial interventions are implemented effectively enough to yield improvements in public health. The use of evidence to guide public health decision-making to achieve this is recommended. However, few studies have examined the relative value, as reported by policy-makers and practitioners, of different broad research outcomes (that is, measures of cost, acceptability, and effectiveness). To guide the conduct of research and better inform public health policy and practice, this study aimed at describing the research outcomes that Australian policy-makers and practitioners consider important for their decision-making when selecting: (a) public health interventions; (b) strategies to support their implementation; and (c) to assess the differences in research outcome preferences between policy-makers and practitioners. Method An online value-weighting survey was conducted with Australian public health policy-makers and practitioners working in the field of non-communicable disease prevention. Participants were presented with a list of research outcomes and were asked to select up to five they considered most critical to their decision-making. They then allocated 100 points across these – allocating more points to outcomes perceived as more important. Outcome lists were derived from a review and consolidation of evaluation and outcome frameworks in the fields of public health knowledge translation and implementation. We used descriptive statistics to report relative preferences overall and for policy-makers and practitioners separately. Results Of the 186 participants; 90 primarily identified as policy-makers and 96 as public health prevention practitioners. Overall, research outcomes of effectiveness, equity, feasibility, and sustainability were identified as the four most important outcomes when considering either interventions or strategies to implement them. Scores were similar for most outcomes between policy-makers and practitioners. Conclusion For Australian policy-makers and practitioners working in the field of non-communicable disease prevention, outcomes related to effectiveness, equity, feasibility, and sustainability appear particularly important to their decisions about the interventions they select and the strategies they employ to implement them. The findings suggest researchers should seek to meet these information needs and prioritize the inclusion of such outcomes in their research and dissemination activities. The extent to which these outcomes are critical to informing the decision of policy-makers and practitioners working in other jurisdictions or contexts warrants further investigation.

Abstract Background Pedestrians and cyclists are often referred to as “vulnerable road users,” yet most research is focused on fatal crashes. We used fatal and nonfatal crash data to examine risk factors (i.e., relationship to an intersection, urbanicity, crash circumstances, and vehicle type) for police-reported pedestrian and cyclist injuries on public roads among children aged 0–9 and aged 10–19. We also compared risk factors among these two age groups with adults aged 20–29 and aged 30–39. Methods Crash data were obtained for 2016–2020 from the National Highway Traffic Safety Administration’s Fatality Analysis Reporting System for fatal crash injuries and Crash Report Sampling System for nonfatal crash injuries. We collected data on victim demographics, roadway, and vehicle- and driver-related factors. Descriptive analyses were conducted between and within pedestrian and cyclist victims. Results We analyzed 206,429 pedestrian injuries (36% in children aged 0–19) and 148,828 cyclist injuries (41% in children aged 0–19) from 2016 to 2020. Overall, child pedestrians had lower injury rates than adults, but children aged 10–19 had greater cycling crash rates than adults. Almost half of the pedestrian injuries in children aged 0–9 were “dart-out” injuries (43%). In the majority of the cyclist injuries, children in both age groups failed to yield to vehicles (aged 0–9 = 40% and aged 10–19 = 24%). For children and all ages included in the study, the fatality risk ratio was highest when pedestrians and cyclists were struck by larger vehicles, such as trucks and buses. Further exploration of roadway factors is presented across ages and transportation mode. Conclusion Our findings on child, driver, vehicle, and roadway factors related to fatal and nonfatal pedestrian and cyclist injuries may help to tailor prevention efforts for younger and older children.

Purpose: Due to limited data on treatment-related risk factors associated with esophageal stricture in childhood cancer survivors, this study aimed to assess such factors in long-term survivors. Methods: A case-cohort study was conducted involving 36 cases of five-year childhood cancer survivors with esophageal stricture and a sub-cohort of 540 survivors diagnosed with cancer in 1970–2007 as identified within the Nordic ‘Adult Life after Childhood Cancer in Scandinavia’ program. Individualized treatment details were retrieved from medical records. Radiation doses to each body region and average dose to the esophagus were reconstructed for patients that received radiotherapy. We used a modified Cox proportional hazard model to evaluate associations between esophageal stricture and risk factors by calculating incidence rate ratio (IRR), with 95 % confidence intervals (CIs). Results: An increased rate of esophageal stricture was found in survivors who received total body irradiation (IRR=13.7, 95 %CI 4.6–41.1), chest- and neck-directed radiotherapy (IRR=23.5, 95 %CI 8.5−64.7) and doses of ≥12 Gy to the esophagus (IRR=26.8, 95 % CI=9.0–80.3) compared to non-irradiated survivors. Treatment with chemotherapy was also associated with esophageal stricture (IRR=8.4, 95 % CI=2.9–24.4). Notably, leukemia survivors faced an elevated rate (IRR=3.8, 95 % CI 1.8–8.1) compared with survivors of CNS and other solid tumors. Conclusions: Our findings indicate an increased risk of esophageal stricture among childhood cancer survivors, with both neck- and chest-directed radiotherapy and chemotherapy as important risk factors.

ABSTRACTHead and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS [HR = 0.60 (95%CI: 0.40–0.89, p = .01)]. Among other microbes, Yersinia pseudotuberculosis was associated with the worst survival (HR = 3.88; p = .008), while Pseudomonas viridiflava had the best survival (HR = 0.05; p = .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 (p

AbstractTranscription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical “MF-like” morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets.

The avian vampire fly is an invasive species on the Galapagos Islands, where its hematophagous larvae utilize nestling birds as hosts. It poses a serious threat to populations and species of Darwin finches and other avian species. Prior studies suggest that the avian vampire fly larvae develop more rapidly in nests of small tree finches compared to sympatric green warbler finch nests. Here we investigate factors that may differentially influence larval growth in the two host species, including nest microclimate and nestling diet. We collected nest base temperature and humidity data as proxies for nest microclimate. As indicators of dietary composition and quality, we measured stable isotope δ13C and δ15N composition of nestling blood, used the C:N ratios as an indicator of relative protein content, and assessed the amino acid composition of the blood. The hematophagous larvae living off nestling blood were analyzed for the same parameters except amino acid composition. The effect of nest base humidity on nest base temperature significantly depended on bird species: at low humidity levels nest base temperature was higher in the small tree finch, and declined in both species as nest base humidity increased, which suggests higher stable heat capacity of small tree finch nests. The effect of age group based on the predicted onset of thermoregulation was marginally significant. Nest base temperatures were significantly higher in small tree finch nests during the predicted female brooding period before fully effective thermoregulation. Stable isotope δ13C levels were significantly higher in the blood of small tree finch nestlings compared to warbler finch nestlings, suggesting a difference in nestling food composition and source, while. δ15N levels were similar. The C:N ratios and amino acid composition of nestling blood were not significantly different between the two species, suggesting similar dietary quality. Thus, the faster development of larvae in small tree finch nests may be due to higher nest base temperatures during the early nestling phase rather than host blood quality parameters.

Introduction Adolescent e-cigarette use, globally and within Australia, has increased in recent years. In response, public health agencies have called for the development of education and communication programmes targeting adolescents. Despite such recommendations, few rigorous evaluations of such interventions currently exist. The main objective of this study is to examine the potential effect of a text message intervention targeting parents and adolescents on adolescent susceptibility to e-cigarette use (eg, intentions towards using e-cigarettes). Secondary objectives are to (1): examine the effect of the intervention on adolescent e-cigarette and combustible tobacco use and (2) examine the acceptability of the intervention.Methods and analysis A randomised controlled trial employing a 2×2 factorial design will be conducted with parent–adolescent dyads (aged 12–15 years). Dyads will be randomly allocated to one of four arms: arm 1—a text message intervention delivered to adolescents only; arm 2—a text message intervention delivered to the parents of adolescents only; arm 3—a text message intervention delivered to both the parents and adolescents; and arm 4—an information only control, consisting of an e-cigarette factsheet provided to parents only. Participant recruitment commenced in March 2023 with the aim to recruit 120 parent–adolescent dyads. Data collection to assess study outcomes will occur at baseline, 6, 12 and 24 months post the commencement of the intervention. The primary endpoint will be 6-month follow-up. The primary outcome will be adolescent susceptibility to e-cigarette use, assessed using validated items. Analyses of trial outcomes will be undertaken under an intention-to-treat framework, with all participants included in the analysis in the group they were allocated.Ethics and dissemination Ethics approval has been obtained from the human research ethics committee of the University of Newcastle (H-2022-0340). Findings will be disseminated in peer-reviewed journals and at conferences.Trial registration number The trial was registered prospectively with Australian New Zealand Clinical Trials Registry (ACTRN12623000079640).

Across social structures within society, including healthcare, power relations manifest according to gender, socioeconomic status, race, ethnicity, and class influencing infection related healthcare access and health providing-behaviours. Therefore, accounting for sociocultural drivers, including gender, race, and class, and their influence on economic status can improve healthcare access and health-providing behaviours in infection prevention and control (IPC) as well as antibiotic use, which in turn helps mitigate the spread of antimicrobial resistance (AMR). This Wellcome funded research will investigate how and why the social determinants of health and economic status influence how people seek, experience, and provide healthcare for suspected or proven (bacterial) infections and how these factors influence antibiotic prescribing and use in South Africa (upper middle-income country) and India (lower middle-income country). The aim of this body of work is to, (1) define and estimate the sociocultural and economic drivers for AMR in different resource settings, (2) design, implement and evaluate context-sensitive IPC and antimicrobial stewardship (AMS) interventions, and (3) inform policy and strategy for AMR mitigation. The population will be healthcare workers (HCWs), patients, and their carers across acute medical and surgical pathways where IPC and antibiotic-related healthcare access and health-providing behaviours will be studied. Qualitative methods will include ethnographic research, semi-structured in-depth interviews, and focus groups with healthcare providers, patients and carers. Quantitative analysis of bedside observational data from hospitals and population level data on antibiotic use will study the various predictors of AMR using bivariable and multivariable regression analyses. The research will provide high-quality evidence on how social determinants intersect with health, social well-being, and vulnerability in IPC practices and antibiotic use. Using this knowledge we will: 1) design, implement, and measure effects of interventions accounting for these factors; 2) provide a toolkit for advocacy for actors in AMR, and healthcare to assist them to promote dialogue, including policy dialogue on this issue. This work directly benefits the target population and informs healthcare services and practice across the participating countries with potential for wider translation. The setting will be hospitals in South Africa (middle-income country) and India (lower middle-income country). The population will be healthcare workers (HCWs), patients, and their carers across acute medical and surgical pathways where IPC and antibiotic-related health-seeking and health-providing behaviours will be studied. These populations represent communities most affected by infections and AMR because existing interventions do not address a) differences in how surgical versus medical teams manage infections; b) the role of the wider social network of individuals on their decision-making, c) intersection of the social determinants of health including race, gender, socioeconomic deprivation with AMR.

Objective Pragmatic methodologies, often termed rapid-learning, are being pursued that can match the pace of innovation in radiotherapy and generate evidence from the real-world treatment setting. It is important to understand the feasibility of implementing such pragmatic approaches before their application in practice. This study investigated key professional stakeholders’ perceptions and opinions of rapid-learning and real-world data (RWD).Methods and analysis Twenty-three interviews were conducted with key professional stakeholders based across five UK radiotherapy cancer centres. Centres varied in size and reflected different healthcare environments. Data were collected between December 2022 and May 2023, and analysed using inductive thematic analysis.Results Four themes were generated: (1) the alignment of rapid-learning methodologies with the reality of practice, (2) concerns related to the variability of RWD, (3) the maturity of data infrastructures and capacity for rapid-learning and (4) further support, education and evidence needed to convince stakeholders to adopt rapid-learning approaches.Conclusion The potential of rapid-learning to help address evidence gaps in radiotherapy development was positively received by different professional stakeholders. However, the effectiveness of rapid-learning was viewed as being highly dependent on the collection of quality data in the routine setting, while the variable set-up at different cancer centres is also likely to be a key challenge for potential implementation. Developing data infrastructures to improve data interoperability was considered crucial for rapid-learning implementation, along with method clarity, educational support and training for radiotherapy teams.

This essay examines how fashion was complexly constructed and experienced at the Louisiana Purchase Exposition of 1904, better known as the St. Louis World’s Fair. It takes as its point of departure a striking poster illustrated by the Czech artist Alphonse Mucha to advertise the event for a European audience. The image depicts an elegantly clad woman and traditionally dressed Native American joined by the hand – allegorical symbols of the old and new. Ideas about the progressive 'new woman' and the mythical 'vanishing Indian' were evident throughout the fairgrounds in exhibits that showcased art, industry, cultural heritage, entertainment, and American political power. An analysis of photographs taken there by Jessie Tarbox Beals, Frances Benjamin Johnston, and Emme and Mayme Gerhard reveals that sartorial encounters between fairgoers and participants played a key role in articulating the exhibition’s narrative of progress, while also problematizing contemporaneous attitudes towards race and gender.

Aims The aim of this project is to improve the monitoring of patients on lithium under the South Gloucestershire Later Life Community Mental Health Team and to clarify the process for this monitoring with the aim of improving patient care and safety. We aim to try to achieve 100% compliance with agreed standards based on NICE and Trust guidelines. Methods Following a meeting with team medics we agreed a series of nine standards derived from local and national guidelines. We then used a locally held database of patients on the later life CMHT caseload on lithium therapy to identify our sample and devised a simple audit tool to collate the information. We used Rio electronic health records and ICE blood results to obtain baseline data from June 2022 to December 2022. We used the plan-do-study-act (PDSA) cycle model for quality improvement. Following analysis of the baseline data, we planned and implemented key changes of the physical health nursing team taking over investigations from primary care and utilising a bespoke database. We also completed an education session for staff. Following these changes, data was collected and analysed from June until November 2023. From the analysis of these results, a further change was planned for PDSA cycle 2 and further data collection is planned. Results Results from baseline data showed that six out of eight standards had compliance of < 60%, which included the time-sensitive investigations such as lithium levels every 3 months; kidney function tests every 3–6 months; calcium level every 6 months. Weight/BMI monitoring and documentation of side effects also had poor results. Average compliance across all standards was 57%. Following the agreed steps to improve compliance, PDSA cycle 1 results showed improvement across the board, with average compliance increasing to 94%. Time-sensitive investigations now had 100% compliance (lithium level, kidney function, calcium level). Areas for improvement remain, namely in weight/BMI monitoring every 6 months and clear action plans for results falling out of range being clearly documented in patient notes. Conclusion By working closely with the physical health nursing team to devise a bespoke local database of information and taking over the investigations from primary care, we have shown an improvement across all standards, therefore improving the quality of care and patient safety.

Aims There remains stigma surrounding electroconvulsive therapy (ECT) amongst junior doctors, as well as gaps in knowledge, recent studies have shown. The aim of this study is to reduce stigma and negative biases towards ECT among junior doctors in Hertfordshire. This research strives to improve clinical knowledge regarding ECT amongst the same population of junior doctors. After highlighting stigma and gaps in clinical knowledge amongst junior doctors, we aimed to implement an educational intervention to reduce these and assess the impact it made. Methods Over 80 doctors ranging from foundation year 1 doctors to consultants attended a weekly academic teaching for doctors working in Psychiatry. A 50-minute slot was set aside for a teaching session on ECT. This included a pre- and post-teaching anonymous questionnaire, with open and closed questions, asking junior doctors about their previous exposure to ECT, and asking them to list three words they associated with ECT. The teaching session included: what ECT is, indications, side effects, a short video explaining the procedure, an open discussion about stigma and ECT, a brief overview about the future of neuromodulation, and a consultant psychiatrist who is part of the ECT team talking through the before, during, after, and answering questions from the participants. Results 31 participants answered the pre-intervention questionnaire. Of the 31 respondents, 70% reported learning about ECT during medical school. However, 40% reported little teaching and only 13% had observed ECT. From thematic analysis of free text responses, 54% of respondents expressed detailed understanding of ECT, with 71% agreeing that ECT is a humane treatment. 80% expressed that ECT should be part of NICE guidelines. 50% of respondents conveyed that stigmatised portrayals of ECT in popular culture have influenced their negative opinion of ECT. Of the 10 responses to the post-teaching questionnaire, 100% agreed that ECT is a humane treatment and that ECT should be part of NICE guidelines for treatment of severe/treatment-resistant depression. From thematic analysis, when asked to name 3 words they associated with ECT, 60% of participants described ECT as effective or successful and 40% described ECT as safe. 72% of the words used were positive descriptors. Conclusion ECT is not covered thoroughly during medical school. Before this teaching, about half of the trainees expressed a negative opinion of ECT due to popular culture. Post-teaching, positive opinions had increased, and more trainees (100%) agreed that ECT is a humane treatment and should be part of NICE guidelines.

Background Data sharing in developmental science is increasingly encouraged, supported by funder and publisher mandates for open data access. Data sharing can accelerate discovery, link researchers with high quality analytic expertise to researchers with large datasets and democratise the research landscape to enable researchers with limited funding to access large sample sizes. However, there are also significant privacy and security concerns, in addition to conceptual and ethical considerations. These are particularly acute for developmental science, where child participants cannot consent themselves. As we move forward into a new era of data openness, it is essential that we adequately represent the views of stakeholder communities in designing data sharing efforts. Methods We conducted a comprehensive survey of the opinions of 195 parents on data sharing in developmental science. Survey themes included how widely parents are willing to share their child’s data, which type of organisations they would share the data with and the type of consent they would be comfortable providing. Results Results showed that parents were generally supportive of curated, but not open, data sharing. In addition to individual privacy and security concerns, more altruistic considerations around the purpose of research were important. Parents overwhelmingly supported nuanced consenting models in which preferences for particular types of data sharing could be changed over time. This model is different to that implemented in the vast majority of developmental science research and is contrary to many funder or publisher mandates. Conclusions The field should look to create shared repositories that implement features such as dynamic consent and mechanisms for curated sharing that allow consideration of the scientific questions addressed. Better communication and outreach are required to build trust in data sharing, and advanced analytic methods will be required to understand the impact of selective sharing on reproducibility and representativeness of research datasets.

Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the ex vivo introduction of a missing gene into patients’ own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.

IntroductionOlder adults with chronic disease prioritize functional independence. We aimed to describe the feasibility of capturing functional disability and treatment toxicity among older adults with lung cancer using a longitudinal comprehensive geriatric assessment (CGA) and molecular biomarkers of aging.MethodsThis prospective study included adults ≥60 years with any newly diagnosed non-small-cell lung cancer. Participants were recruited from central Ohio (2018–2020). Study assessments included the Cancer and Aging Research Group CGA (CARG-CGA), short physical performance battery (SPPB), and the blessed orientation-memory concentration (BOMC) test at baseline, 3, 6, and 12 months. Activities of daily living (ADLs) and instrumental ADLs (IADLs), quality of life (QoL, PROMIS 10), and treatment toxicity were captured monthly. Stool and blood were collected to characterize the gut microbiome and age-related blood biomarkers.ResultsThis study enrolled 50 participants with an average age of 71.7 years. Ninety-two percent of participants were Caucasian, 58% were male, and all were non-Hispanic. Most had advanced stage (stage III/IV: 90%; stage I/II: 10%), with adenocarcinoma the predominant histologic subtype (68% vs. 24% squamous). First-line treatments included chemotherapy (44%), immune checkpoint inhibitors (ICIs, 22%), chemotherapy and ICIs (30%), or tyrosine kinase inhibitors (4%). The median baseline CARG toxicity score was 8 (range 2–12). Among patients with treatment-related toxicity (n = 49), 39 (79.6%) cases were mild (grade 1–2), and 10 (20.4%) were moderate to severe (≥ grade 3). Treatment toxicity was greater among those with a CARG score ≥8 (28.0% vs. 13.6%). Higher IADL independence, QoL, and SPPB scores at baseline were positively associated with Candidatus Gastranaerophilales bacterium, Lactobacillus rogosae, and Enterobacteria phage P4. Romboutsia ilealis, Streptococcus, and Lachnoclostridium sp An138 and T cell lag3 and cd8a were associated with worse IADLs, QoL, and SPPB scores at baseline.DiscussionA longitudinal CGA and biomarker collection is feasible among older adults undergoing lung cancer treatment. Gut microbe and T cell gene expression changes correlated with subjective and objective functional status assessments. Future research will test causality in these associations to improve outcomes through novel supportive care interventions to prevent functional disability.

Background and Aims: Inflammatory Bowel Disease (IBD) affects many women of childbearing age. High levels of voluntary childlessness and high levels of pregnancy-related fears have been reported amongst these patients in several quantitative studies. We investigated the lived experiences of pregnant patients to better understand decision-making processes around family planning. Methods: Nine participants between 7 and 34 weeks pregnant (6 Crohn's Disease/3 Ulcerative Colitis), with an age range of 22–39 were recruited prospectively from three United Kingdom hospitals. Semi-structured interviews were conducted, and audio recorded. Interpretative phenomenological analysis was used to interpret the data. Results: Two main themes emerged: 1) IBD is perceived as a threat to family planning; and 2) healthcare professional advice, support, and reassurance was important. IBD was viewed as a potential threat to fertility and reproductive health. Consequently, women's lived experience of pregnancy is shaped by anxiety and pregnancy-related worries for mother and baby. Mothers actively sought out expert medical assurances to alleviate some of the perceived fears. Conclusion: Previous research has repeatedly found that women with IBD exhibit high levels of pregnancy-related worries and anxieties. Our findings find that high levels of anxiety are due to patients’ perceptions that IBD is a threat to their reproductive health and their offspring. Women relied on a medicalized discourse to understand their IBD experiences during pregnancy and actively sought biomedical resources for assistance before and during pregnancy. Consultants should be aware that when dealing with pregnant patients, some women may experience anxiety and require extra support.

Efficient degradation of phagocytic cargo in lysosomes is crucial to maintain cellular homeostasis and defending cells against pathogens. However, the mechanisms underlying the degradation and recycling of macromolecular cargo within the phagolysosome remain incompletely understood. We previously reported that the phagolysosome containing the corpse of the polar body in C. elegans tubulates into small vesicles to facilitate corpse clearance, a process that requires cargo protein degradation and amino acid export. Here we show that degradation of hexosylceramides by the prosaposin ortholog SPP-10 and glucosylceramidases is required for timely corpse clearance. We observed accumulation of membranous structures inside endolysosomes of spp-10-deficient worms, which are likely caused by increased hexosylceramide species. spp-10 deficiency also caused alteration of additional sphingolipid subclasses, like dihydroceramides, 2-OH-ceramides, and dihydrosphingomyelins. While corpse engulfment, initial breakdown of corpse membrane inside the phagolysosome and lumen acidification proceeded normally in spp-10-deficient worms, formation of the cargo-containing vesicles from the corpse phagolysosome was reduced, resulting in delayed cargo degradation and phagolysosome resolution. Thus, by combining ultrastructural studies and sphingolipidomic analysis with observing single phagolysosomes over time, we identified a role of prosaposin/SPP-10 in maintaining phagolysosomal structure, which promotes efficient resolution of phagocytic cargos.

Abstract Background In Scotland, and in several other countries, most second-hand smoke exposure now occurs in low-income households, where housing constraints and sole parenting often make it harder to create a smoke-free home. This pilot study provided people who smoke with a free 12-week supply of nicotine replacement therapy through local community pharmacies to reduce smoking indoors. Methods Twenty-five parents/caregivers who smoked in the home and cared for children at least weekly were recruited via Facebook during the COVID-19 pandemic. Air quality (PM2.5) was monitored in participant homes for seven days before their first pharmacy visit and 12 weeks later. Qualitative interviews (N = 14) were conducted with 13 participants who completed the study and one who withdrew part-way through. The interviews explored views/experiences of using nicotine replacement therapy to help create a smoke-free home. Another participant took part in a shorter telephone discussion at their request, with detailed notes taken by the interviewer, because of their speech disorder. Results Three participants reported smoking outdoors only, one of whom subsequently quit smoking. Six participants reported reduced cigarette consumption by 50% in the home, four reported no (sustained) reduction and one reported increased smoking indoors. Self-reported outcomes were not always consistent with PM2.5 readings. Participants’ experiences of accessing nicotine replacement therapy through community pharmacies varied. Some suggested ongoing support to use nicotine replacement products could better assist behavioural change, and that access could be streamlined by posting products to the home. Several suggested that focusing on changing home smoking behaviours using nicotine replacement therapy might facilitate a future quit attempt. Conclusion Access to free nicotine replacement therapy for temporary use indoors may support some people who smoke to reduce children’s exposure to second-hand smoke. Our findings confirm the need to modify the intervention before undertaking a definitive trial to assess the effectiveness of this approach. This work is now underway.