Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.

Patient, supporter and primary healthcare professional perspectives on health risks in over 16s with attention deficit hyperactivity disorder (ADHD) in England: a national survey study.

BACKGROUND: Current research suggests that people with attention deficit hyperactivity disorder (ADHD) are at higher risk of physical and mental health disorders. This study aimed to explore these health risks in ADHD from the perspectives of multiple stakeholders. METHODS: This study forms part of the 'Managing young people with ADHD in Primary care (MAP) study'. A survey developed by the study team was distributed to over 16 year olds with ADHD, their supporters, primary healthcare professionals and health commissioners across England, via social media and through patient/clinical networks (September-October 2022). This survey contained two questions on health risks. Question one asked about views on health risks in ADHD (free text). Question two asked about advice given (options list and free text). Descriptive statistics summarised responses to questions one and two, and qualitative analysis (reflexive thematic analysis) was used to explore free text responses from question one. RESULTS: 782 participants responded to the MAP survey. Of these, 206 healthcare professionals, 157 people with ADHD and 88 supporters answered question one. The most mentioned perceived risks were substance misuse, sleep disorders, weight management and smoking. More people with ADHD reported disordered eating as a health risk (n = 32) than healthcare professionals (n = 5). Generated themes included perceived health risks, impact of living with ADHD, lack of adequate healthcare, and need for ADHD awareness. In respect to advice given (question two), based on responses from 258 professionals, 162 people with ADHD and 100 supporters, the most common advice discussed in consultation was mental health (n = 149, n = 50 and n = 17 respectively). High numbers of respondents reported not giving/receiving advice on wider health (n = 38, n = 88 and n = 61 respectively). CONCLUSIONS: Findings demonstrate that respondents perceived a range of physical and mental health risks posed by ADHD. These related to difficulties with activities of daily living, as well as healthcare interactions and the impact of core features of ADHD (e.g. impulsivity, emotional dysregulation). These risks are not currently explicitly addressed in United Kingdom national guidance on ADHD. More work is needed to examine and address the broader health outcomes of people with ADHD.

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.

"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.

LipidFinder 2.0: advanced informatics pipeline for lipidomics discovery applications.

SUMMARY: We present LipidFinder 2.0, incorporating four new modules that apply artefact filters, remove lipid and contaminant stacks, in-source fragments and salt clusters, and a new isotope deletion method which is significantly more sensitive than available open-access alternatives. We also incorporate a novel false discovery rate method, utilizing a target-decoy strategy, which allows users to assess data quality. A renewed lipid profiling method is introduced which searches three different databases from LIPID MAPS and returns bulk lipid structures only, and a lipid category scatter plot with color blind friendly pallet. An API interface with XCMS Online is made available on LipidFinder's online version. We show using real data that LipidFinder 2.0 provides a significant improvement over non-lipid metabolite filtering and lipid profiling, compared to available tools. AVAILABILITY AND IMPLEMENTATION: LipidFinder 2.0 is freely available at https://github.com/ODonnell-Lipidomics/LipidFinder and http://lipidmaps.org/resources/tools/lipidfinder. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

In transition with attention deficit hyperactivity disorder (ADHD): children's services clinicians' perspectives on the role of information in healthcare transitions for young people with ADHD.

BACKGROUND: National clinical guidelines emphasise the need for good communication of information by clinicians to young people and their parent/carers about what to expect during transition into adult services. Recent research indicates that of young people in need of transition for attention deficit hyperactivity disorder (ADHD), only a minority experience continuity of care into adulthood, with additional concerns about quality of transition. This qualitative analysis explored the role that information plays in the transition from child to adult mental health services for young people with ADHD, from the perspectives of clinicians working in children's services. METHODS: Participants were recruited from National Health Service (NHS) Trusts located across the United Kingdom (UK), with varying service configurations. Twenty-two qualitative interviews were conducted with 15 paediatricians and seven psychiatrists working in child services and supporting young people with ADHD. The Framework Method was used to complete a thematic analysis of data related to the role of information in transitional care. RESULTS: Two themes were identified in relation to the role of information in supporting transition and promoting continuity of care. Information for clinicians; about adult mental health services, the young person and their ADHD, and exchanged between services. Sharing information with young people; about transition processes, self-management, to support service engagement, and tailored to be accessible to young people with ADHD. Clinicians in children's services reported variable access to information. Clear protocols and being able to communicate about ADHD as a long-term condition, were described as having a positive impact on the transition process. CONCLUSIONS: These findings illustrate that clear information on the transition process, and communication of evidence based and up-to-date information on ADHD as a long-term condition are essential components for clinicians supporting transition into adult services. Information exchange can be supported through transition discussions with young people, and joint meetings between services Discussions should be accompanied by accessible resources for young people and parents/carers such as leaflets and websites. Further efforts should be focussed on enabling clinicians to provide timely and appropriate information to young people with ADHD to support transition.

Ameliorating Child poverty through Connecting Economic Services with child health Services (ACCESS): study protocol for a randomised controlled trial of the healthier wealthier families model in Sweden.

BACKGROUND: Sweden is often held up as an example of a country with low child deprivation; yet, rates of relative deprivation are rising. Every municipality in Sweden is required to provide free, timely and accessible budget and debt counselling under the Social Services Act. The services have been encouraged to perform preventative practice with families; however, this has not been realised. The Healthier Wealthier Families (HWF) model embeds universal screening for economic hardship into child health services and creates a referral pathway to economic support services. Given the universal child health system in Sweden, which is freely available and has excellent coverage of the child population, implementation of the HWF model has potential to support families to access the freely available municipal budget and debt counselling and ultimately improve rates of child deprivation in Sweden. METHODS/DESIGN: We will conduct a two-arm randomised waitlist-control superiority trial to examine the effectiveness and cost-effectiveness of the HWF model in the Sweden. A longitudinal follow-up with the cohort will explore whether any effects are maintained in the longer-term. DISCUSSION: HWF is a collaborative and sustainable model that could maximise the effectiveness of current services to address child deprivation in Sweden. The study outlined in this protocol is the first effectiveness evaluation of the HWF model in Sweden and is a crucial step before HWF can be recommended for national implementation within the child health services. TRIAL REGISTRATION: Clinicaltrials.gov; NCT05511961. Prospectively registered on 23 August 2022. https://clinicaltrials.gov/ct2/show/NCT05511961.

Why young people stop taking their attention deficit hyperactivity disorder medication: A thematic analysis of interviews with young people.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that can persist into adulthood. Young people often stop taking ADHD medication during adolescence despite evidence that continuation would be beneficial. Increasingly, young people are restarting medication in early adulthood suggesting that cessation was premature. In this paper we explore the reasons given by young people for discontinuing ADHD medication. METHODS: Qualitative data from the Children and Adolescents with ADHD in Transition between Children's and Adult Services (CATCh-uS) project was analysed to look for reasons for stopping medication. Semi-structured interviews with three groups of young people were analysed using thematic and framework analysis; this included young people prior to transition (n = 21); young people that had successfully transitioned to adult services (n = 22); and young people who left children's services prior to transition but re-entered adult services later (n = 21). RESULTS: Reasons given by young people for stopping ADHD medication included the following: the perceived balance between benefits and adverse effects of medication; perceptions of ADHD as a childhood or educational disorder; life circumstance of the young person and challenges young people faced in accessing services. CONCLUSIONS: A multidimensional approach is needed to address discontinuation of ADHD medication in order to improve the long-term prospects and quality of life for these young people. Possible approaches include access to non-pharmacological treatments and improved psychoeducation. As many reasons given by young people are not unique to ADHD, these findings are also of relevance to medication adherence in other chronic childhood conditions.

Associations between ongoing COVID-19 lockdown and the financial and mental health experiences of Australian families.

In 2020, Australia's successful COVID-19 public health restrictions comprised a national "initial lockdown" (March-May) and "ongoing lockdown" (July-November) for metropolitan Victorian residents only. We evaluated associations between ongoing lockdown and family finances and mental health. In the June and September 2020 Royal Children's Hospital National Child Health Polls, caregivers of children in Victoria and New South Wales (NSW) reported the following: job/income loss; material deprivation (inability to pay for essential items); income poverty; mental health (Kessler-6); perceived impact on caregiver/child mental health; and caregiver/child coping. Data from caregivers (N = 1207/902) in June/September were analysed using difference-in-difference modelling (NSW provided the comparator). During Victoria's ongoing lockdown, job/income loss increased by 11% (95%CI: 3%-18%); Kessler-6 poor mental health by 6% (95%CI: -0.3%-12%) and perceived negative mental health impacts by 14% for caregivers (95%CI: 6%-23%) and 12% for children (95%CI: 4%-20%). Female (vs. male) caregivers, metropolitan (vs. regional/rural) families, and families with elementary school-aged children (vs. pre-/high-school) were the most affected. The ongoing lockdown was associated with negative experiences of mental health, employment and income, but not deprivation or poverty, likely because of government income supplements introduced early in the pandemic. Future lockdowns require planned responses to outbreaks and evidence-informed financial and mental health supports.

Retinal arteriolar tortuosity and fractal dimension are associated with long-term cardiovascular outcomes in people with type 2 diabetes.

AIMS/HYPOTHESIS: Our aim was to determine whether quantitative retinal traits in people with type 2 diabetes are independently associated with incident major cardiovascular events including CHD and stroke. METHODS: A total of 1066 men and women with type 2 diabetes, aged 65-74 years, were followed up over 8 years in the population-based Edinburgh Type 2 Diabetes Study. Using retinal photographs taken at baseline and specialist software, a number of quantitative retinal traits were measured, including arteriolar and venular widths and tortuosity as well as fractal dimension (a measure of the branching pattern complexity of the retinal vasculature network). Incident CHD events occurring during follow-up included fatal and non-fatal myocardial infarction, first episodes of angina and coronary interventions for CHD. Incident cerebrovascular events included fatal and non-fatal stroke or transient ischaemic attack. Cox proportional hazard regression analyses were performed to identify the association of the retinal traits with cardiovascular events in the population with retinal data available (n = 1028). RESULTS: A total of 200 participants had an incident cardiovascular event (139 CHD and 61 cerebrovascular events). Following adjustment for age and sex, arteriolar tortuosity and fractal dimension were associated with cerebrovascular events (HR 1.27 [95% CI 1.02, 1.58] and HR 0.74 [95% CI 0.57, 0.95], respectively), including with stroke alone (HR 1.30 [95% CI 1.01, 1.66] and HR 0.73 [95% CI 0.56, 0.97], respectively). These associations persisted after further adjustment for established cardiovascular risk factors (HR 1.26 [95% CI 1.01, 1.58] and HR 0.73 [95% CI 0.56, 0.94], respectively). Associations generally reduced in strength after a final adjustment for the presence of diabetic retinopathy, but the association of fractal dimension with incident cerebrovascular events and stroke retained statistical significance (HR 0.73 [95% CI 0.57, 0.95] and HR 0.72 [95% CI 0.54, 0.97], respectively). Associations of retinal traits with CHD were generally weak and showed no evidence of statistical significance. CONCLUSIONS/INTERPRETATION: Arteriolar tortuosity and fractal dimension were associated with incident cerebrovascular events, independent of a wide range of traditional cardiovascular risk factors including diabetic retinopathy. These findings suggest potential for measurements of early retinal vasculature change to aid in the identification of people with type 2 diabetes who are at increased risk from stroke.

Coronary microvascular dysfunction is associated with degree of anaemia in end-stage renal disease.

BACKGROUND: Coronary microvascular dysfunction (CMD) is common in end-stage renal disease (ESRD) and is an adverse prognostic marker. Coronary flow velocity reserve (CFVR) is a measure of coronary microvascular function and can be assessed using Doppler echocardiography. Reduced CFVR in ESRD has been attributed to factors such as diabetes, hypertension and left ventricular hypertrophy. The contributory role of other mediators important in the development of cardiovascular disease in ESRD has not been studied. The aim of this study was to examine the prevalence of CMD in a cohort of kidney transplant candidates and to look for associations of CMD with markers of anaemia, bone mineral metabolism and chronic inflammation. METHODS: Twenty-two kidney transplant candidates with ESRD were studied with myocardial contrast echocardiography, Doppler CFVR assessment and serum multiplex immunoassay analysis. Individuals with diabetes, uncontrolled hypertension or ischaemic heart disease were excluded. RESULTS: 7/22 subjects had CMD (defined as CFVR < 2). Demographic, laboratory and echocardiographic parameters and serum biomarkers were similar between subjects with and without CMD. Subjects with CMD had significantly lower haemoglobin than subjects without CMD (102 g/L ± 12 vs. 117 g/L ± 11, p = 0.008). There was a positive correlation between haemoglobin and CFVR (r = 0.7, p = 0.001). Similar results were seen for haematocrit. In regression analyses, haemoglobin was an independent predictor of CFVR (ß = 0.041 95% confidence interval 0.012-0.071, p = 0.009) and of CFVR < 2 (odds ratio 0.85 95% confidence interval 0.74-0.98, p = 0.022). CONCLUSIONS: Among kidney transplant candidates with ESRD, there is a high prevalence of CMD, despite the absence of traditional risk factors. Anaemia may be a potential driver of microvascular dysfunction in this population and requires further investigation.

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies.

The EU Directive 2010/63/EU   on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.

Patterns of maternal depression, anxiety, and stress symptoms from pregnancy to 5 years postpartum in an Australian cohort experiencing adversity.

The objective of this study is to describe the longitudinal patterns of depression, anxiety, and stress symptoms from pregnancy to 5 years postpartum, in a cohort of Australian mothers experiencing adversity. Longitudinal data were drawn from the control group of a trial of nurse home visiting. Pregnant women experiencing adversity (≥ 2 of 10 adversity risk factors) were recruited from antenatal clinics across 2 Australian states (30 April 2013-29 August 2014). Women completed the Depression Anxiety and Stress Scales short-form (DASS-21) at 11 time-points from pregnancy to 5 years postpartum. DASS-21 scores were summarized at each time-point for all women and by level of adversity risk. Three hundred fifty-nine women (100%) completed the DASS-21 in pregnancy and 343 (96%) provided subsequent data. Mental health symptoms were highest in pregnancy and at 4 and 5 years postpartum. While this pattern was comparable across levels of antenatal adversity risk, women with greatest adversity risk had consistently higher mental health symptoms. In a cohort of mothers experiencing adversity, depression, anxiety, and stress symptoms were highest in pregnancy and at 4 to 5 years postpartum. The striking patterns of persistent, high, mental health symptoms, beyond the first year postpartum, can inform a more equitable and responsive health system.

Hair cortisol in mother-child dyads: examining the roles of maternal parenting and stress in the context of early childhood adversity.

Physiological stress is thought to be one way that early adversity may impact children's health. How this occurs may be related to parental factors such as mothers' own stress and parenting behaviour. Hair cortisol offers a novel method for examining long-term physiological stress in mother-child dyads. The current study used hair cortisol to examine the role that maternal physiological stress and parenting behaviours play in explaining any effects of adversity on young children's physiological stress. This cross-sectional study comprised 603 mother-child dyads at child age 2 years, recruited during pregnancy for their experience of adversity through an Australian nurse home visiting trial. Hair cortisol data were available for 438 participating mothers (73%) and 319 (53%) children. Confirmatory factor analysis was used to define composite exposures of economic (e.g. unemployment, financial hardship) and psychosocial (e.g. poor mental health, family violence) adversity, and positive maternal parenting behaviour (e.g. warm, responsive). Structural equation modelling examined maternal mediating pathways through which adversity was associated with children's physiological stress. Results of the structural model showed that higher maternal and child physiological stress (hair cortisol) were positively associated with one another. Parenting behaviour was not associated with children's physiological stress. There was no evidence of any mediating pathways by which economic or psychosocial adversity were associated with children's physiological stress. The independent association identified between maternal and child hair cortisol suggests that young children's physiological stress may not be determined by exogenous environmental exposures; endogenous genetic factors may play a greater role.

Transition between child and adult services for young people with attention-deficit hyperactivity disorder (ADHD): findings from a British national surveillance study.

BACKGROUND: Optimal transition from child to adult services involves continuity, joint care, planning meetings and information transfer; commissioners and service providers therefore need data on how many people require that service. Although attention-deficit hyperactivity disorder (ADHD) frequently persists into adulthood, evidence is limited on these transitions. AIMS: To estimate the national incidence of young people taking medication for ADHD that require and complete transition, and to describe the proportion that experienced optimal transition. METHOD: Surveillance over 12 months using the British Paediatric Surveillance Unit and Child and Adolescent Psychiatry Surveillance System, including baseline notification and follow-up questionnaires. RESULTS: Questionnaire response was 79% at baseline and 82% at follow-up. For those aged 17-19, incident rate (range adjusted for non-response) of transition need was 202-511 per 100 000 people aged 17-19 per year, with successful transition of 38-96 per 100 000 people aged 17-19 per year. Eligible young people with ADHD were mostly male (77%) with a comorbid condition (62%). Half were referred to specialist adult ADHD and 25% to general adult mental health services; 64% had referral accepted but only 22% attended a first appointment. Only 6% met optimal transition criteria. CONCLUSIONS: As inclusion criteria required participants to be on medication, these estimates represent the lower limit of the transition need. Two critical points were apparent: referral acceptance and first appointment attendance. The low rate of successful transition and limited guideline adherence indicates significant need for commissioners and service providers to improve service transition experiences.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD: Prospective observational cohort study. SETTING AND PARTICIPANTS: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept.

BACKGROUND: In light of the vulnerability of the developing brain, mixture risk assessment (MRA) for the evaluation of developmental neurotoxicity (DNT) should be implemented, since infants and children are co-exposed to more than one chemical at a time. One possible approach to tackle MRA could be to cluster DNT chemicals in a mixture on the basis of their mode of action (MoA) into 'similar' and 'dissimilar', but still contributing to the same adverse outcome, and anchor DNT assays to common key events (CKEs) identified in DNT-specific adverse outcome pathways (AOPs). Moreover, the use of human in vitro models, such as induced pluripotent stem cell (hiPSC)-derived neuronal and glial cultures would enable mechanistic understanding of chemically-induced adverse effects, avoiding species extrapolation. METHODS: HiPSC-derived neural progenitors differentiated into mixed cultures of neurons and astrocytes were used to assess the effects of acute (3 days) and repeated dose (14 days) treatments with single chemicals and in mixtures belonging to different classes (i.e., lead(II) chloride and methylmercury chloride (heavy metals), chlorpyrifos (pesticide), bisphenol A (organic compound and endocrine disrupter), valproic acid (drug), and PCB138 (persistent organic pollutant and endocrine disrupter), which are associated with cognitive deficits, including learning and memory impairment in children. Selected chemicals were grouped based on their mode of action (MoA) into 'similar' and 'dissimilar' MoA compounds and their effects on synaptogenesis, neurite outgrowth, and brain derived neurotrophic factor (BDNF) protein levels, identified as CKEs in currently available AOPs relevant to DNT, were evaluated by immunocytochemistry and high content imaging analysis. RESULTS: Chemicals working through similar MoA (i.e., alterations of BDNF levels), at non-cytotoxic (IC20/100), very low toxic (IC5), or moderately toxic (IC20) concentrations, induce DNT effects in mixtures, as shown by increased number of neurons, impairment of neurite outgrowth and synaptogenesis (the most sensitive endpoint as confirmed by mathematical modelling) and increase of BDNF levels, to a certain extent reproducing autism-like cellular changes observed in the brain of autistic children. CONCLUSIONS: Our findings suggest that the use of human iPSC-derived mixed neuronal/glial cultures applied to a battery of assays anchored to key events of an AOP network represents a valuable approach to identify mixtures of chemicals with potential to cause learning and memory impairment in children.

Clinician perspectives on the use of National Institute for Health and Care Excellence guidelines for the process of transition in Attention Deficit Hyperactivity Disorder.

BACKGROUND: The UK National Institute for Health and Care Excellence (NICE) clinical guidelines recommends the following steps in the transition from child to adult services for young people with attention deficit hyperactivity disorder (ADHD): reassessment before and after transition, transition planning, formal meeting between services, and involvement from young person and carer, completed by age 18. METHODS: A UK surveillance study asked clinicians to report young people on their caseloads with ADHD in need of transition to adult services in 2016 to support their continued access to medication need. Clinicians reported young people as they aged to within 6 months of the transition boundary, a prospective questionnaire prior to transition asked about intended transition and the use of local transition protocols. A retrospective questionnaire sent 9 months later established which steps recommended by NICE were followed during transition. Clinicians (38) working in child or adult services were interviewed about their experiences of transition and the use of NICE guidelines during transition and were analysed using a framework approach. RESULTS: Information was shared between services in 85% of the 315 identified transition cases. A joint meeting was planned in 16% of cases; joint working before transfer occurred in 10% of cases. Clinicians were aware of NICE guidelines; they had mixed views on whether (local) guidelines or protocols were helpful. The main reason for not following guidelines was workload and resources: "NICE recommends stuff that is miles above what we will ever be able to provide". CONCLUSIONS: Clinicians involved in the transition process of young people with ADHD judged NICE guidelines to be unrealistic given the current limited resources and service organization. More open dialogue is needed for recommendations on service models to bridge the gap between guideline recommendations and what is viewed as feasible and how implementation of guidance is funded, monitored, and prioritized. This may lead to valuable changes in the consultation process, for example, consideration of a layered (gold, standard, and minimal) system for some NICE guidelines.