Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites.

Acetamiprid is a pesticide active substance with insecticidal action whose approval was renewed by Commission Implementing Regulation (EU) 2018/113. In January 2022, the EFSA PPR Panel published a statement following a request from the European Commission to advise on human health or the environment based on new scientific evidence presented by France during the decision-making phase. In July 2022, by means of a further mandate received from the European Commission, EFSA was requested to provide advice if new information and any other scientific evidence that has become available since the assessment conducted for the renewal in 2018 warrant re-evaluation of (i) toxicological parameters used for the risk assessment of acetamiprid during the renewal process, including toxicological endpoints; (ii) the residue definition for acetamiprid in products of plant origin; and (iii) the safety of existing maximum residue levels (MRLs). Meanwhile, the applicant of acetamiprid in the EU submitted new toxicology studies regarding the toxicological profile of the metabolite IM-2-1. Furthermore, the European Commission was made aware that several recent publications in scientific literature were made available after the literature searches conducted by EFSA. As the new data could affect the advice that EFSA was expected to deliver through the 2022 mandate, EFSA was further requested to consider this information by means of a revised mandate received in September 2023. As regards re-evaluation of point (i) in this statement, this was addressed by an EFSA Working Group integrating all the available evidence. The results of the weight of evidence indicated that there are major uncertainties in the body of evidence for the developmental neurotoxicity (DNT) properties of acetamiprid and further data are therefore needed to come to a more robust mechanistic understanding to enable appropriate hazard and risk assessment. In view of these uncertainties, the EFSA WG proposed to lower the acceptable daily intake (ADI) and acute reference dose (ARfD) from 0.025 to 0.005 mg/kg body weight (per day). A revised residue definition for risk assessment was proposed for leafy and fruit crops as sum of acetamiprid and N-desmethyl-acetamiprid (IM-2-1), expressed as acetamiprid. Regarding pulses/oilseeds, root crops and cereals, the new data received did not indicate a need to modify the existing residue definition for risk assessment, which therefore remains as parent acetamiprid. Regarding the residue definition for enforcement, the available data did not indicate a need to modify the existing definition because acetamiprid is still a sufficient marker of the residues in all crop groups. Considering the new health-based guidance values derived in the present statement, a risk for consumer has been identified for 38 MRLs currently in place in the EU Regulation. Consequently, EFSA recommended to lower the existing MRLs for 38 commodities based on the assessment of fall-back Good Agricultural Practices received within an ad hoc data call. Some fall-back MRLs proposals require further risk management considerations.

Caregiver and Child Mental Health During 3 Years of the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) lockdowns (stay-at-home orders) had significant mental health consequences in 2020 to 2021 for caregivers and children. Little is known about "postlockdown" periods in 2022 to 2023. We investigated the mental health experiences of Australian families throughout the 3 years of the COVID-19 pandemic (2020-2023), by demographic characteristics and lockdown length. METHODS: A total N = 12 408 caregivers (N = 20 339 children, aged 0-17 years) completed Australia's only representative, repeated, cross-sectional, National Child Health Poll across 6 waves (June 2020-April 2023). Caregivers reported mental health for themselves (Kessler-6, poor versus not) and each child (self-rated mental health, poor/fair versus good/very good/excellent), and perceived impacts of the pandemic on own/child mental health (negative versus none/positive). Binary logistic models were fitted to predict marginal probabilities of each mental health measure by state/territory group (proxy for lockdown length), over time, adjusted for potential demographic confounders. RESULTS: Poor caregiver Kessler-6 was similar between genders but more common for sole caregivers, and those with a home language other than English and lower education. Poor/fair child self-rated mental health was similar between genders and increased with child age. Perceived negative impacts were more common for females and socially advantaged caregivers. Overall, negative mental health experiences increased with lockdown length, peaking with the height of lockdown in July 2021, before declining. CONCLUSIONS: Negative mental health experiences of Australian caregivers and children decreased during postlockdown periods of 2022-2023; however, social gradients persisted. These data can inform more precise mental health policies that enable better use of limited mental health infrastructure.

Support for primary care prescribing for adult ADHD in England: national survey.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with effective pharmacological treatments that improve symptoms and reduce complications. NICE guidelines recommend primary care practitioners prescribe medication for adult ADHD under shared care agreements with adult mental health services (AMHS). However, provision remains uneven, with some practitioners reporting a lack of support. AIM: This study aimed to describe supportive elements (prescribing, shared care, AMHS availability) of primary care prescribing for adult ADHD medication in England, to inform service improvement and improve access for this underserved population. DESIGN AND SETTING: Three interlinked cross-sectional surveys asked every integrated care board (ICB) in England (Commissioners), and convenience samples of healthcare professionals (HP) and people with lived experience (LE), about elements supporting pharmacological treatment of ADHD in primary care. METHOD: Descriptive analyses used percentages and confidence intervals to summarise responses by stakeholder group. Variations in reported provision and practice were explored and displayed visually using mapping software. RESULTS: Data from 782 respondents (42 Commissioners; 331 HP; 409 LE) revealed differences in reported provision by stakeholder group, including for prescribing (94.6% of HP vs 62.6% of LE). Over 40% of respondents reported extended AMHS waiting times of two years or more. There was some variability by NHS region, for example London had highest rates of HP reported prescribing (100%), and lowest reported extended waiting times (25.0%). CONCLUSION: Elements supporting appropriate shared care prescribing of ADHD medication via primary care are not universally available in England. Co-ordinated approaches are needed to address these gaps.

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps.

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying well-defined biological areas, as well as gaps within the AOP-Wiki for future research needs. It does not intend to provide a systematic and comprehensive summary of the available literature on AOPs but summarizes and maps biological knowledge and diseases represented by the already developed AOPs (with OECD endorsed status or under validation). Methods: Knowledge from the AOP-Wiki database were extracted and prepared for analysis using a multi-step procedure. An automatic mapping of the existing information on AOPs (i.e., genes/proteins and diseases) was performed using bioinformatics tools (i.e., overrepresentation analysis using Gene Ontology and DisGeNET), allowing both the classification of AOPs and the development of AOP networks (AOPN). Results: AOPs related to diseases of the genitourinary system, neoplasms and developmental anomalies are the most frequently investigated on the AOP-Wiki. An evaluation of the three priority cases (i.e., immunotoxicity and non-genotoxic carcinogenesis, endocrine and metabolic disruption, and developmental and adult neurotoxicity) of the EU-funded PARC project (Partnership for the Risk Assessment of Chemicals) are presented. These were used to highlight under- and over-represented adverse outcomes and to identify and prioritize gaps for further research. Discussion: These results contribute to a more comprehensive understanding of the adverse effects associated with the molecular events in AOPs, and aid in refining risk assessment for stressors and mitigation strategies. Moreover, the FAIRness (i.e., data which meets principles of findability, accessibility, interoperability, and reusability (FAIR)) of the AOPs appears to be an important consideration for further development.

The impact of maternal health on child's health outcomes during the first five years of child's life in countries with health systems similar to Australia: A systematic review.

INTRODUCTION: The first five years of life is an important developmental period that establishes the foundation for future health and well-being. Mothers play a primary role in providing emotional and physical nourishment during early childhood. This systematic review aims to explore the association between maternal health and child health in the first five years of the child's life. MATERIALS AND METHODS: As primary aims, we systematically synthesised published evidence relating to the first five years of life for associations between maternal health exposures (mental, physical and Health-Related Quality of Life (HRQoL) and child health outcomes (physical health, mental health, HRQoL and Health Service Use (HSU) /cost). As a secondary aim, we explored how the above associations vary between disadvantaged and non-disadvantaged populations. The search was limited to studies that published and collected data from 2010 to 2022. The systematic review was specific to countries with similar health systems to Australia. The search was conducted in MEDLINE, CINAHL, APA PsycINFO, GLOBAL HEALTH, and EMBASE databases. The quality of the included studies was assessed by The Effective Public Health Practice Project (EPHPP) tool. RESULTS: Thirteen articles were included in the final synthesis from the identified 9439 articles in the primary search. Six (46%) explored the association between maternal mental health and child's physical health, two (15%) explored maternal and child's physical health, one (8%) explored maternal and child's mental health, one (8%) explored maternal physical health and child's HRQoL, and three (23%) explored maternal mental health and child's HSU. We found an association between maternal health and child health (physical and mental) and HSU outcomes but no association between maternal health and child's overall HRQoL. The results for disadvantaged communities did not show any difference from the general population. DISCUSSION AND CONCLUSION: Our review findings show that maternal health influences the child's health in the first five years. However, the current evidence is limited, and the findings were primarily related to a specific maternal or child's health condition. There was no evidence of associations of child health outcomes in healthy mothers. There is an extensive research gap investigating maternal health exposures and child outcomes in quality of life and overall health.

Primary care provision for young people with ADHD: a multi-perspective qualitative study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder. UK guidance states that primary care has a vital role in effective ADHD management, including referral, medication prescribing and monitoring, and providing broader mental health and wellbeing support. However, many GPs feel unsupported to provide health care for young people with ADHD. Inadequate health care is associated with rising costs for patients and society. AIM: To investigate the experiences of young people with ADHD accessing primary care in England, from the perspectives of people with lived experience of ADHD and healthcare professionals (HCPs). DESIGN AND SETTING: A qualitative study. Interviews were conducted with HCPs (GPs, practice managers, and a wellbeing worker) and people with lived experience of ADHD (young people aged 16-25 years and their supporters) located in integrated care systems across England. METHOD: Semi-structured interviews were conducted with participants at five purposively selected general practices (varying by deprivation, ethnicity, and setting). Questions focused on experiences of accessing/providing health care for ADHD. Reflexive thematic analysis was undertaken within a critical realist framework to understand how provision works in practice and to explore potential improvements. RESULTS: In total, 20 interviews were completed with 11 HCPs and nine people with lived experience. Three themes were generated: a system under stress, incompatibility between ADHD and the healthcare system, and strategies for change in ADHD primary care provision. CONCLUSION: Standardisation of ADHD management in primary care, providing better information and support for HCPs, and advising on reasonable adjustments for people with lived experience could help improve access to effective treatments for young people living with ADHD.

Feasibility of linking universal child and family healthcare and financial counselling: findings from the Australian Healthier Wealthier Families (HWF) mixed-methods study.

OBJECTIVES: 'Healthier Wealthier Families' (HWF) seeks to reduce financial hardship in the early years by embedding a referral pathway between Australia's universal child and family health (CFH) services and financial counselling. This pilot study investigated the feasibility and short-term impacts of HWF, adapted from a successful Scottish initiative. METHODS: Setting: CFH services in five sites across two states, coinciding with the COVID-19 pandemic. PARTICIPANTS: Caregivers of children aged 0-5 years experiencing financial hardship (study-designed screen). DESIGN: Mixed methods. With limited progress using a randomised trial (RCT) design in sites 1-3 (March 2020-November 2021), qualitative interviews with service providers identified implementation barriers including stigma, lack of knowledge of financial counselling, low financial literacy, research burden and pandemic disruption. This informed a simplified RCT protocol (site 4) and direct referral model (no randomisation, pre-post evaluation, site 5) (June 2021-May 2022). INTERVENTION: financial counselling; comparator: usual care (sites 1-4). Feasibility measures: proportions of caregivers screened, enrolled, followed up and who accessed financial counselling. Impact measures: finances (quantitative) and other (qualitative) to 6 months post-enrolment. RESULTS: 355/434 caregivers completed the screen (60%-100% across sites). In RCT sites (1-4), 79/365 (19%-41%) reported hardship but less than one-quarter enrolled. In site 5, n=66/69 (96%) caregivers reported hardship and 44/66 (67%) engaged with financial counselling; common issues were utility debts (73%), and obtaining entitlements (43%) or material aid/emergency relief (27%). Per family, financial counselling increased income from government entitlements by an average $A6504 annually plus $A784 from concessions, grants, brokerage and debt waivers. Caregivers described benefits (qualitative) including reduced stress, practical help, increased knowledge and empowerment. CONCLUSIONS: Financial hardship screening via CFH was acceptable to caregivers, direct referral was feasible, but individual randomisation was infeasible. Larger-scale implementation will require careful, staged adaptations where CFH populations and the intervention are well matched and low burden evaluation. TRIAL REGISTRATION NUMBER: ACTRN12620000154909.

Mothers' experiences of emotional abuse from an intimate partner and its associations with children's developmental outcomes at 5 years.

BACKGROUND: Intimate partner violence (IPV) is associated with an increased risk of poorer child development. Existing research has focused on physical abuse with less known about the associations with emotional IPV. OBJECTIVE: To describe the period prevalence of mother's experiences of emotional IPV during children's preschool years and associations with child mental, physical, social, and cognitive development. METHODS: Secondary analysis of control group data (n = 194) from an Australian randomised trial (right@home), which recruited pregnant women experiencing social adversity from antenatal clinics in 2013-14. Women reported emotional abuse (Composite Abuse Scale) at child ages 3-5 years. Measures of child development at 5 years included: Strengths and Difficulties Questionnaire, Social Skills Improvement System, Pediatric Quality of Life Inventory, Clinical Evaluation of Language Fundamentals, School Entry Alphabetic and Phonological Awareness Readiness Test, NIH executive function subtests, sleep and health. The prevalence of emotional IPV from 3 to 5 years was estimated. Regression models compared developmental outcomes according to emotional IPV exposure, adjusted for child age, child gender, and maternal education. Missing data were accounted for using multiple imputation. RESULTS: From 3-5 years, emotional IPV was experienced by 57% of women. Emotional IPV exposure was consistently associated with poorer child developmental outcomes. Differences were most apparent for SDQ internalising (mean difference 1.2, 95% CI 0.2 to 2.1) and externalising difficulties (1.2, 95% CI -0.1 to 2.4). CONCLUSIONS: Emotional IPV was highly prevalent amongst families experiencing social adversity. Developing acceptable and effective identification processes and interventions that prioritise families experiencing co-occurring social adversities should be a public health priority.

Embedding nurse home visiting in universal healthcare: 6-year follow-up of a randomised trial.

OBJECTIVE: Nurse home visiting (NHV) is designed to redress child and maternal health inequities. Of the previous trials to investigate NHV benefits beyond preschool, none were designed for populations with universal healthcare. To address this evidence gap, we investigated whether the Australian 'right@home' NHV programme improved child and maternal outcomes when children turned 6 and started school. METHODS: A screening survey identified pregnant women experiencing adversity from antenatal clinics across two states (Victoria, Tasmania). 722 were randomised: 363 to the right@home programme (25 visits promoting parenting and home learning environment) and 359 to usual care. Child measures at 6 years (first school year): Strengths and Difficulties Questionnaire (SDQ), Social Skills Improvement System (SSIS), Childhood Executive Functioning Inventory (CHEXI) (maternal/teacher-reported); general health and paediatric quality of life (maternal-reported) and reading/school adaptation items (teacher-reported). Maternal measures: Personal Well-being Index (PWI), Depression Anxiety Stress Scales, warm/hostile parenting, Child-Parent Relationship Scale (CPRS), emotional abuse and health/efficacy items. Following best-practice methods for managing missing data, outcomes were compared between groups (intention-to-treat) using regression models adjusted for stratification factors, baseline variables and clustering (nurse/site level). RESULTS: Mothers reported on 338 (47%) children, and teachers on 327 (45%). Patterns of group differences favoured the programme arm, with small benefits (effect sizes ranging 0.15-0.26) evident for SDQ, SSIS, CHEXI, PWI, warm parenting and CPRS. CONCLUSIONS: Four years after completing the right@home programme, benefits were evident across home and school contexts. Embedding NHV in universal healthcare systems from pregnancy can offer long-term benefits for families experiencing adversity. TRIAL REGISTRATION NUMBER: ISRCTN89962120.

Protocol for the mixed methods, Managing young people (aged 16-25) with Attention deficit hyperactivity disorder in Primary care (MAP) study: mapping current practice and co-producing guidance to improve healthcare in an underserved population.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children and adolescents, with an average worldwide prevalence of 5%. Up to 40% of young people continue to experience symptoms into adulthood. Young people with ADHD experience poorer outcomes than their peers across multiple domains, with treatment shown to reduce these risks. Primary care practitioners play an important role in healthcare provision for this group in the UK. However, many feel unsure about how best to provide support, reporting prescribing concerns and need for more evidence-based guidance. A lack of national data on primary care provision hinders efforts to improve access to care and optimise outcomes. This mixed-methods study aims to provide evidence that may be used to improve primary care services for young people aged 16-25 years with ADHD. METHODS AND ANALYSIS: There are three interlinked work packages: (a) a mapping study including a survey of stakeholders (healthcare professionals, people with ADHD and commissioners) will map ADHD prescribing practice, shared-care arrangements, available support and practitioner roles by geographic locations across England for different respondent groups; (b) a qualitative study involving semi-structured interviews with stakeholders (10-15 healthcare professionals and 10-15 people with ADHD) will explore experiences of 'what works' and 'what is needed' in terms of service provision and synthesise findings; (c) workshops will integrate findings from (a) and (b) and work with stakeholders to use this evidence to codevelop key messages and guidance to improve care. ETHICS AND DISSEMINATION: The protocol has been approved by Yorkshire and the Humber-Bradford Leeds Research Ethics Committee. Recruitment commenced in September 2022. Findings will be disseminated via research articles in peer-reviewed journals, conference presentations, public involvement events, patient groups and media releases. A summary of study findings will be shared with participants at the end of the study. TRIAL REGISTRATION NUMBER: NCT05518435.

Educational experiences of young people with ADHD in the UK: Secondary analysis of qualitative data from the CATCh-uS mixed-methods study.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and/or impulsivity. Young people with ADHD have poorer educational and social outcomes than their peers. We aimed to better understand educational experiences of young people with ADHD in the UK, and make actionable recommendations for schools. METHODS: In this secondary analysis of qualitative data, we used Thematic Analysis to analyse information relating to experiences of education from 64 young people with ADHD and 28 parents who participated in the Children and adolescents with ADHD in Transition between Children's services and adult Services (CATCh-uS) study. Emerging patterns within and across codes led to organization of the data into themes and subthemes through an iterative process. RESULTS: Two main themes were generated. The first described young people's early experiences of education, often within a mainstream setting; we labelled this the problematic provision loop, as this was a negative cycle that was repeated several times for some participants. The second theme described young people's more positive progression through education once they progressed out of the problematic loop. CONCLUSIONS: Educational experiences for young people with ADHD are often negative and fraught with complication. Young people with ADHD often found themselves on a more positive trajectory after they were placed in an alternative form of education provision (mainstream or otherwise), or where they were able to study topics that interest them and play to their strengths. We make recommendations that commissioners, local authorities and schools could consider in order to better support those with ADHD.

"You do need to do the interaction": Mothers' perceptions of responsive parenting following a home-based parenting intervention.

Responsive parenting (also known as responsivity) is a dynamic and bidirectional exchange between the parent-child dyad and associated with a child's social and cognitive development. Optimal interactions require a sensitivity and understanding of a child's cues, responsiveness to the child's need, and a modification of the parent's behavior to meet this need. This qualitative study explored the impact of a home visiting program on mothers' perceptions of their responsivity to their children. This study is part of a larger body of research known as right@home, an Australian nurse home visiting program promoting children's learning and development. Preventative programs such as right@home prioritize population groups experiencing socioeconomic and psychosocial adversity. They provide opportunities to promote children's development through the enhancement of parenting skills and an increase in responsive parenting. Semi-structured interviews were conducted with 12 mothers, providing insight into their perceptions of responsive parenting. Four themes were extracted from the data using inductive thematic analysis. These indicated that: (1) mothers' perceived preparation for parenting, (2) recognition of mother and child needs, (3) response to mother and child needs, and (4) motivation to parent with responsiveness, were considered important. This research highlights the importance of interventions that focus on the parent-child relationship in increasing mother's parenting capabilities and promoting responsive parenting.

La crianza con sensibilidad (también conocida como crianza con capacidad de respuesta) es un dinámico intercambio en ambas direcciones entre la díada progenitor-niño, asociada con el desarrollo social y cognitivo del niño. Las interacciones óptimas requieren de una sensibilidad y comprensión de las señales del niño, capacidad de respuesta a la necesidad del niño, y de una modificación del comportamiento del progenitor para cumplir con esta necesidad. Este estudio cualitativo exploró el impacto de un programa de visita a casa sobre las percepciones de las madres acerca de su capacidad de respuesta a sus niños. Este estudio es parte de un mayor cuerpo investigativo conocido como right@home (justo en casa), un programa australiano de visita a casa por parte de enfermeras que promueve el aprendizaje y desarrollo de los niños. Los programas preventivos tales como right@home dan prioridad a grupos de población que experimentan adversidad socioeconómica y sicosocial. Ellos ofrecen oportunidades para promover el desarrollo de los niños por medio del mejoramiento de las habilidades de crianza y un incremento de la sensibilidad en la crianza. Se llevaron a cabo entrevistas semiestructuradas con 12 madres, lo cual aportó ideas sobre sus percepciones de la crianza con sensibilidad. Se extrajeron cuatro temas de la información usando análisis temáticos inductivos. Estos indicaron que se consideraban importantes (1) el cómo las madres percibían su preparación para la crianza, (2) el reconocimiento de las necesidades de la madre y del niño, (3) la respuesta a las necesidades de la madre y del niño, y (4) la motivación a criar con sensibilidad. Esta investigación subraya la importancia de intervenciones que se enfoquen en la relación progenitor-niño para aumentar las capacidades de crianza de la madre y promover una crianza con sensibilidad.

Le parentage réactif (aussi connu comme réactivité) est un échange dynamique et bidirectionnel entre la dyade parent-enfant, et lié au développement social et cognitive d'un enfant. Les interactions optimales demandent une sensibilité et une compréhension des signaux de l'enfant, la réactivité au besoin de l'enfant, et une modification du comportement du parent pour répondre à ce besoin. Cette étude qualitative a exploré l'impact d'un programme de visite à domicile sur les perceptions des mères de leur réactivité à leurs enfants. Cette étude fait partie de recherches plus étendues connues sous le nom de de right@home, un programme de visite infirmières à domicile australien promouvant l'apprentissage et le développement des enfants. Les programmes de prévention tels que right@home privilégient les groupes de population marqués par l'adversité socioéconomique et psychosociale. Ils offrent des opportunités de promouvoir le développement des enfants au travers du renforcement des capacités de parentage et une augmentation du parentage réactif. Des entretiens semi-structurés ont été faits avec 12 mères, offrant un aperçu de leurs perceptions du parentage réactif. Quatre thèmes ont été extraits des données en utilisant une analyse thématique inductive. Ces dernières ont indiqué que (1) la préparation perçue des mères pour le parentage, (2) la reconnaissance des besoins de la mère et de l'enfant, (3) la réponse aux besoins de la mère et de l'enfant, et (4) la motivation du parent avec la réaction ont toutes été considérées comme importantes. Ces recherches mettent en lumière l'importance d'interventions qui se concentrent sur la relation parent-enfant en augmentant les capacités de parentage des mères et en promouvant le parentage réactif.

Assessment of neurotransmitter release in human iPSC-derived neuronal/glial cells: a missing in vitro assay for regulatory developmental neurotoxicity testing.

Human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) and their differentiated neuronal/glial derivatives have been recently considered suitable to assess in vitro developmental neurotoxicity (DNT) triggered by exposure to environmental chemicals. The use of human-relevant test systems combined with in vitro assays specific for different neurodevelopmental events, enables a mechanistic understanding of the possible impact of environmental chemicals on the developing brain, avoiding extrapolation uncertainties associated with in vivo studies. Currently proposed in vitro battery for regulatory DNT testing accounts for several assays suitable to study key neurodevelopmental processes, including NSC proliferation and apoptosis, differentiation into neurons and glia, neuronal migration, synaptogenesis, and neuronal network formation. However, assays suitable to measure interference of compounds with neurotransmitter release or clearance are at present not included, which represents a clear gap of the biological applicability domain of such a testing battery. Here we applied a HPLC-based methodology to measure the release of neurotransmitters in a previously characterized hiPSC-derived NSC model undergoing differentiation towards neurons and glia. Glutamate release was assessed in control cultures and upon depolarization, as well as in cultures repeatedly exposed to some known neurotoxicants (BDE47 and lead) and chemical mixtures. Obtained data indicate that these cells have the ability to release glutamate in a vesicular manner, and that both glutamate clearance and vesicular release concur in the maintenance of extracellular glutamate levels. In conclusion, analysis of neurotransmitter release is a sensitive readout that should be included in the envisioned battery of in vitro assays for DNT testing.

Prediction of in vivo prenatal chlorpyrifos exposure leading to developmental neurotoxicity in humans based on in vitro toxicity data by quantitative in vitro-in vivo extrapolation.

Introduction: Epidemiological studies in children suggested that in utero exposure to chlorpyrifos (CPF), an organophosphate insecticide, may cause developmental neurotoxicity (DNT). We applied quantitative in vitro-in vivo extrapolation (QIVIVE) based on in vitro concentration and non-choline esterase-dependent effects data combined with Benchmark dose (BMD) modelling to predict oral maternal CPF exposure during pregnancy leading to fetal brain effect concentration. By comparing the results with data from epidemiological studies, we evaluated the contribution of the in vitro endpoints to the mode of action (MoA) for CPF-induced DNT. Methods: A maternal-fetal PBK model built in PK-Sim® was used to perform QIVIVE predicting CPF concentrations in a pregnant women population at 15 weeks of gestation from cell lysate concentrations obtained in human induced pluripotent stem cell-derived neural stem cells undergoing differentiation towards neurons and glia exposed to CPF for 14 days. The in vitro concentration and effect data were used to perform BMD modelling. Results: The upper BMD was converted into maternal doses which ranged from 3.21 to 271 mg/kg bw/day. Maternal CPF blood levels from epidemiological studies reporting DNT findings in their children were used to estimate oral CPF exposure during pregnancy using the PBK model. It ranged from 0.11 to 140 µg/kg bw/day. Discussion: The effective daily intake doses predicted from the in vitro model were several orders of magnitude higher than exposures estimated from epidemiological studies to induce developmental non-cholinergic neurotoxic responses, which were captured by the analyzed in vitro test battery. These were also higher than the in vivo LOEC for cholinergic effects. Therefore, the quantitative predictive value of the investigated non-choline esterase-dependent effects, although possibly relevant for other chemicals, may not adequately represent potential key events in the MoA for CPF-associated DNT.

Management of heart failure in patients with kidney disease-updates from the 2021 ESC guidelines.

The wide overlap between the syndromes of chronic kidney disease (CKD) and chronic heart failure (HF) means that familiarity with the 2021 European Society of Cardiology guidelines is of importance to nephrologists. The common risk factors for the two syndromes together with the adverse cardiac structural remodelling associated with CKD means that many kidney disease patients experience breathlessness and fall within the HF phenotypes categorized in the guidelines. The management of HF is evolving rapidly leading to significant changes in the latest guideline iteration. The 2021 guidelines have changed from the 2016 version firstly by an increased focus on identifying the three phenotypes of HF to guide appropriate evidence-based management. Secondly, a new and simplified treatment algorithm for HF with reduced ejection fraction involving the rapid sequential initiation and up-titration of four 'pillars' of drug treatment-angiotensin-converting enzyme inhibitors or angiotensin-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and now, thanks to convincing trial data, sodium-glucose co-transporter 2 inhibitors. Thirdly, guidelines for device therapy have been changed with down-graded advice on indications for primary prevention implantable cardioverter defibrillator therapy for patients with non-ischaemic HF and for cardiac resynchronization therapy with left bundle branch block (LBBB) and a QRS duration <150 ms. There are updated treatment plans for HF associated with non-cardiovascular comorbidities including CKD.

Parenting roles for young people with attention-deficit/hyperactivity disorder transitioning to adult services.

AIM: To inform transitions from child to adult health services, we explored the work and roles parents take in the care of young people with attention-deficit/hyperactivity disorder (ADHD) aged 14 to 25 years old. METHOD: Using framework thematic analysis, we analysed data collected from 28 semi-structured interviews with parents of young people with ADHD to generate a typology and triangulated it against findings from 64 interviews with young people with ADHD. The interviews were carried out as part of a three-strand, interactive mixed-method study. RESULTS: An entourage typology of three parent roles was identified. Parents moved between 'manager' and 'roadie' roles as their child gradually matured. A 'superfan' role was identified which supported young people's positive self-image but may impede withdrawal from the 'manager' role. Continued parental involvement into adulthood reflected a need to maintain the balance of resources required to maintain quality of life for the whole family. INTERPRETATION: This is the first study to explore parental roles in the health care of young people with ADHD. Parents will vary in their capacity to fulfil the identified roles and step back their care as their children reach adulthood. The findings can inform intervention development to support families and transition between services. WHAT THIS PAPER ADDS: Parents move from a 'manager' to 'roadie' role as young people mature. A 'superfan' role supports positive self-image and directed health care work. Continued involvement reflects parental responsibility to juggle wider family needs and resources. Parents differ in capacity to fulfil and move between these roles.

Variation in general practice referral rate to acute medicine services and association with hospital admission. A retrospective observational study.

BACKGROUND: Variation in general practice (GP) referral rates to outpatient services is well described however variance in rates of referral to acute medical units is lacking. OBJECTIVE: To investigate variance in GP referral rate for acute medical assessment and subsequent need for hospital admission. METHODS: A retrospective cohort study of acute medical referrals from 88 GPs in Lothian, Scotland between 2017 and 2020 was performed using practice population size, age, deprivation, care home residence, and distance from hospital as explanatory variables. Patient-level analysis of demography, deprivation, comorbidity, and acuity markers was subsequently performed on referred and clinically assessed acute medical patients (n = 42,424) to examine how practice referral behaviour reflects clinical need for inpatient hospital care. RESULTS: Variance in GP referral rates for acute medical assessment was high (2.53-fold variation 1st vs. 4th quartile) and incompletely explained by increasing age and deprivation (adjusted R2 0.67, P < 0.001) such that significant variance remained after correction for confounders (2.15-fold). Patients from the highest referring quartile were significantly less likely to require hospital admission than those from the third, second, or lowest referring quartiles (adjusted odds ratio 1.28 [1.21-1.36, P < 0.001]; 1.30 [1.23-1.37, P < 0.001]; 1.53 [1.42-1.65, P < 0.001]). CONCLUSIONS: High variation in GP practice referral rate for acute medical assessment is incompletely explained by practice population socioeconomic factors and negatively associates with need for urgent inpatient care. Identifying modifiable factors influencing referral rate may provide opportunities to facilitate community-based care and reduce congestion on acute unscheduled care pathways.

Managing the populations need for urgent medical care is challenge in many healthcare systems and overcrowding of urgent medical services negatively affects patient experience and can affect timely treatment. In the United Kingdom, the primary sources of patients attending for acute medical care are self-attendance to the hospital or by way of referral by a primary care physician (general practitioner). These data for the first time demonstrate high variation in referral rates for acute medical assessment between general practices which is incompletely explained by factors such as the age, deprivation, distance to the hospital or care home residence status of the care home population. Analysis of over 40,000 of these referrals for urgent medical care was subsequently undertaken to further investigate this variation. After adjusting for important clinical factors, patients referred from "high referring" practices were over 50% less likely to require inpatient hospital care than patients from lower referring practices. This suggests that the threshold for referral varies greatly between individual primary care clinicians, practices, or practice populations and many of these patients may have been suitable for less urgent community-based care. Identification of modifiable factors that account for this unexplained variation may facilitate community-based care and improve patient experience by reducing unnecessary attendance and congestion in already busy emergency care services.

The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK.

The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organization as Alpha. Originating in early autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK and the imposition of new restrictions, in particular, the English national lockdown in November 2020. While these interventions succeeded in reducing the absolute number of cases, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of the SARS-CoV-2 lineages that preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically infected individual. We conclude that the latter provides the best explanation of the observed behaviour and dynamics of the variant, although the individual need not be immunocompromised, as persistently infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs and find that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations and a lack of the rapid evolutionary rate on its ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms), it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence.

Nurse home visiting to improve child and maternal outcomes: 5-year follow-up of an Australian randomised controlled trial.

OBJECTIVES: Nurse home visiting (NHV) is widely implemented to address inequities in child and maternal health. However, few studies have examined longer-term effectiveness or delivery within universal healthcare systems. We evaluated the benefits of an Australian NHV program ("right@home") in promoting children's language and learning, general and mental health, maternal mental health and wellbeing, parenting and family relationships, at child ages 4 and 5 years. SETTING AND PARTICIPANTS: Randomised controlled trial of NHV delivered via universal, child and family health services (the comparator). Pregnant women experiencing adversity (≥2 of 10 risk factors) were recruited from 10 antenatal clinics across 2 states (Victoria, Tasmania) in Australia. INTERVENTION: Mothers in the intervention arm were offered 25 nurse home visits (mean 23·2 home visits [SD 7·4, range 1-43] received) of 60-90 minutes, commencing antenatally and continuing until children's second birthdays. PRIMARY AND SECONDARY OUTCOMES MEASURED: At 4 and 5 years, outcomes were assessed via parent interview and direct assessment of children's language and learning (receptive and expressive language, phonological awareness, attention, and executive function). Outcomes were compared between intervention and usual care arms (intention to treat) using adjusted regression with robust estimation to account for nurse/site. Missing data were addressed using multiple imputation and inverse probability weighting. RESULTS: Of 722 women enrolled in the trial, 225 of 363 (62%) intervention and 201 of 359 (56%) usual care women provided data at 5 years. Estimated group differences showed an overall pattern favouring the intervention. Statistical evidence of benefits was found across child and maternal mental health and wellbeing, parenting and family relationships with effect sizes ranging 0·01-0·27. CONCLUSION: An Australian NHV program promoted longer-term family functioning and wellbeing for women experiencing adversity. NHV can offer an important component of a proportionate universal system that delivers support and intervention relative to need. TRIAL REGISTRATION: 2013-2016, registration ISRCTN89962120.