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Abstract Background Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy. Methods We utilised data from two population-based cohorts: Scotland (2012–2018) and Sweden (2007–2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model. Results The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66–1.19]; Sweden aRR 1.08 [95% CI 0.86–1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66–1.60]; Sweden aRR 1.00 [95% CI 0.72–1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79–1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73–1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21–0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight

Summary: Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to American College of Medical Genetics/Association for Molecular Pathology criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes are poorly understood. We identified 168 rare CSSVs in blood-expressed genes in 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq). There was no evidence of a frameshift, nor of reduced expression consistent with nonsense-mediated decay, for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame insertions or deletions, 3.6% resulted in full exon skipping (in frame), and 0.6% resulted in full intron inclusion (in frame). Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion. The predicted impact on splicing using (1) SpliceAI, (2) MaxEntScan, and (3) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63%, and 61% of CSSVs, respectively. In summary, approximately one in four rare CSSVs did not show evidence for LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data.

Abstract The unexpected contamination of normal samples with tumour cells reduces variant detection sensitivity, compromising downstream analyses in canonical tumour-normal analyses. Leveraging whole-genome sequencing data available at Genomics England, we develop a tool for normal sample contamination assessment, which we validate in silico and against minimal residual disease testing. From a systematic review of $$771$$ 771 patients with haematological malignancies and sarcomas, we find contamination across a range of cancer clinical indications and DNA sources, with highest prevalence in saliva samples from acute myeloid leukaemia patients, and sorted CD3+ T-cells from myeloproliferative neoplasms. Further exploration reveals 108 hotspot mutations in genes associated with haematological cancers at risk of being subtracted by standard variant calling pipelines. Our work highlights the importance of contamination assessment for accurate somatic variants detection in research and clinical settings, especially with large-scale sequencing projects being utilised to deliver accurate data from which to make clinical decisions for patient care.

Aims Little is known about the use of the Mental Health Act (MHA) in children and young people (CYP). There is some evidence that having a diagnosis of psychosis or substance misuse disorder, having an intellectual disability, being older and being of black ethnicity are associated with involuntary admission. However, the existing literature is limited and relies on retrospective case note review or surveys based on a small number of sites over short periods of time. We investigated the social and clinical factors associated with MHA use in CYP using electronic health records. We hypothesised that older adolescence, psychosis, more severe illness, the presence of risk to others and Black ethnicity would be associated with involuntary admission under the MHA. Methods Using data from the Clinical Record Interactive Search (CRIS) system for South London and the Maudsley (SLaM) services we identified 2165 CYP under 18 years, with a first admission to inpatient units between 2007 and 2021 with complete data on variables of interest; 1638 (75.7%) were voluntary patients for the duration of the admission and 527 (25.3%) had been detained under a section 2 or 3 of the MHA during the admission. We conducted univariable logistic regression to investigate the association between clinical factors (diagnosis, severity of illness, risk) and social factors (gender, age, ethnicity, deprivation) with the outcome i.e. MHA admission. We then conducted multivariable logistic regression to investigate the association between the clinical and social factors and involuntary admission. Results In multivariable analyses we found evidence that a diagnosis of psychosis (OR 2.63, 95% CI 1.83–3.76, p < 0.001), being older (age 13–15 years: OR 5.88, 95% CI 3.46–10.03, p < 0.001; age 16–17 years: OR 6.72, 95% CI 3.97–11.41, p < 0.001), having a developmental disorder (OR 1.60, 95% CI 1.04–2.47, p = 0.033) and being of Black ethnicity (OR 2.14, 95% CI 1.60–2.89, p < 0.001) were associated with involuntary admission after accounting for other factors. Being less impaired (i.e. a higher CGAS score) was associated with a lower odds of involuntary admission (moderate impairment: OR 0.56, 95% CI 0.42–0.74, p < 0.001; lowest impairment: OR 0.41, 95% CI 0.30–0.54, p < 0.001). Conclusion In this large cohort of child and adolescent inpatients from South East London, we found that CYP of Black ethnicity are more likely than those from White groups to have an involuntary than voluntary psychiatric hospitalisation, after adjusting for social and clinical factors relating to admission. The finding that Black CYP are more than twice as likely to experience involuntary admission is in keeping with prior literature in CYP and the adult literature. This racial inequity requires further investigation to address disparities in access to mental health care and application of the MHA.

Aims There is evidence that children and young people (CYP) of Black ethnicity are more likely to experience involuntary hospital admission. This is not explained by clinical and sociodemographic factors. One possible explanation are differences in pathways into, and/or use of mental health services (MHS). This study investigates the associations between ethnicity, pathways into MHS, MHS use and involuntary hospitalisation in CYP. Methods Using data from the Clinical Record Interactive Search (CRIS) system for (South London and the Maudsley) SLaM services we identified 652 CYP under 18 years admitted to inpatient units between 2008 and 2021 living within the SLaM catchment; 458 (70.2%) were admitted informally and 194 (29.7%) were detained. We conducted univariable logistic regression to investigate the association between pathways into MHS (referral source, S.136 presentation), MHS use (time known to services, recent appointment prior to admission, and presence of a care plan), clinical factors (diagnosis, severity, risk) and social factors (gender, age, ethnicity, deprivation) with the outcome i.e. involuntary admission. We then conducted multivariable logistic regression to investigate the association between the clinical and social factors and involuntary admission. Results In multivariable analyses we found evidence that adverse pathways into MHS such as S.136 presentation (OR 6.25, 95%CI 2.06-19.01, p = 0.001), and referrals from social services (OR 4.92, 95%CI 1.49-16.19, p = 0.009) and police/legal services (OR 4.22, 95%CI 1.03-17.31, p = 0.045) were associated with involuntary hospitalisation. There was no evidence that the duration of contact with MHS, having had an appointment in the 28 days prior to admission or a care plan in the 12 months prior to admission were associated with involuntary hospitalisation after adjusting for other factors. There was evidence that being of Black ethnicity (OR 2.04, 95%CI 1.19-3.50, p = 0.010), older age (13–15 years: OR 4.46, 95%CI 1.57-12.72, p = 0.005; age 16–17 years: OR 8.67, 95%CI 3.08-24.41, p < 0.001) and having a diagnosis of a psychotic disorder (OR 4.21, 95%CI 2.21-8.02, p < 0.001) were associated with involuntary admission after accounting for pathways into and use of MHS. Conclusion In this cohort of child and adolescent inpatients living in South East London, we found that CYP who experience adverse pathways into MHS are more likely to experience involuntary hospitalisation. Prior contact with MHS did not appear to influence involuntary admission. We found that Black CYP remained more than twice as likely to be admitted involuntarily after accounting for MHS use and pathways into MHS as well as social and clinical factors.

Abstract Background For decades, antenatal care in high-resource settings has involved 12–14 face-to-face visits across pregnancy. The COVID-19 pandemic forced many care providers to rapidly embrace telehealth to reduce face-to-face visits. Here we review recent advances in telehealth used to provide antenatal care. Main body We conducted a narrative review examining the impact of telehealth on obstetric care. Two broad types of telehealth are used in antenatal care. The first is real-time telehealth, where consultations are done virtually instead of face-to-face. The second is remote monitoring, where in-clinic physical examinations are replaced with at-home alternatives. These can include blood pressure monitoring, fetal heart rate monitoring, and emerging technologies such as tele-ultrasound. Large cohort studies conducted during the pandemic era have shown that telehealth appears not to have increased adverse clinical outcomes for mothers or babies. However, further studies may be required to confidently conclude rare outcomes are unchanged, such as maternal mortality, serious morbidity, or stillbirth. Health economic studies suggest telehealth has the potential to reduce the financial cost of care provision. Telehealth in antenatal care seems to be acceptable to both pregnant women and healthcare providers. Conclusion Adoption of telehealth technologies may improve the antenatal care experience for women and reduce healthcare expenditure without adversely impacting health outcomes for the mother or baby. More studies are warranted to confirm telehealth does not alter the risk of rare outcomes such as maternal or neonatal mortality.

Abstract Introduction This systematic review sought predictors of unfavourable bleeding profiles in women using the etonogestrel contraceptive implant. Unfavourable bleeding is common and a leading cause of requests for removal. Methods We included randomised controlled trials (RCTs), and prospective and retrospective cohort studies from 1998 to October 2022. Inclusion criteria were healthy women using etonogestrel for contraception. Papers not in English were excluded as were ongoing or incomplete studies. We searched Pubmed, Pubmed Central, MEDLINE (Web of Science & Ovid), Cochrane library, CINAHL Plus, WHO (HINARI), Open Grey and Greynet.org. Risk of Bias was assessed using ROB2 IRPGv9 for RCTs and ROBINS‐I for non‐RCTs. We conducted a narrative analysis. Results We included 13 studies. Lower body mass index (BMI), younger age, parity and smoking status were statistically, significantly associated with unfavourable bleeding patterns in one or more studies. No studies reported post‐partum status having a significant association with unfavourable bleeding. The available data was too limited and too heterogeneous to perform a robust meta‐analysis. Discussion Heterogeneity in reported outcomes and timescales limited the accuracy of synthesis. Risk of bias was moderate to serious in non‐RCTs due to baseline differences and missing or imputed data. The protective effect of higher BMI for unfavourable bleeding is in keeping with previous reviews and studies and is a clinically important finding.

IntroductionSustainable implementation of early childhood programs requires resources, materials and methods that are adaptable, scalable and feasible for delivery through multiple sectors. Additional or modified program resources may be required to meet emerging needs, as programs go to scale. An active and effective monitoring, evaluation and learning (MEL) process may enable programs to be responsive to demands. The Reach Up: Early Childhood Parenting program, is designed primarily for disadvantaged children under 4 years of age in low- and middle-income countries (LMICs) to promote their development through playful caregiver interactions. The curriculum, training manuals and other materials and resources support implementers in the adaptation of the intervention, implementation, workforce training, monitoring and evaluation. This paper reports on how data collected from key informants drove modifications to program processes, materials and resources.MethodsWe conducted in-depth interviews with 14 key informants (including program managers, lead trainers, academics, consultants and workforce personnel) on their experiences with Reach Up across 15 LMICs where the program has been implemented. We also reviewed written records generated from (i) structured small group discussions at a Knowledge Exchange meeting of 31 Reach Up partners and (ii) notes from working groups formed at the meeting and tasked to continue working post-meeting to find solutions to support ongoing implementation. The transcripts from the in-depth interviews and the meeting records were analysed using thematic analysis with a mixture of pre-defined categories and data-driven sub-themes.ResultsThe main findings indicated that there was a need to: (i) develop advocacy and communication resources and materials to aid prospective implementers and other stakeholders, to make decisions for implementation, (ii) revise and/or add to the content and format of the curriculum and add content in the training and other supporting manuals and (iii) enhance the training process.Conclusion:The feedback from the key global partners informed the development of new knowledge materials, resources and processes and modifications to existing program materials and resources. These will help to support advocacy, ongoing implementations, and the process of transitioning the Reach Up early childhood intervention to scale.

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2–infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Abstract Background This paper enumerates and characterizes latent classes of adverse childhood experiences and investigates how they relate to prenatal substance use (i.e., smoking, alcohol, and other drugs) and poor infant outcomes (i.e., infant prematurity and low birthweight) across eight low- and middle-income countries (LMICs). Methods A total of 1189 mother-infant dyads from the Evidence for Better Lives Study cohort were recruited. Latent class analysis using the Bolck, Croon, and Hagenaars (BCH) 3-step method with auxiliary multilevel logistic regressions was performed. Results Three high-risk classes and one low-risk class emerged: (1) highly maltreated (7%, n = 89), (2) emotionally and physically abused with intra-familial violence exposure (13%, n = 152), (3), emotionally abused (40%, n = 474), and (4) low household dysfunction and abuse (40%, n = 474). Pairwise comparisons between classes indicate higher probabilities of prenatal drug use in the highly maltreated and emotionally abused classes compared with the low household dysfunction and abuse class. Additionally, the emotionally and physically abused with intra-familial violence exposure class had higher probability of low birthweight than the three remaining classes. Conclusion Our results highlight the multifaceted nature of ACEs and underline the potential importance of exposure to childhood adversities on behaviors and outcomes in the perinatal period. This can inform the design of antenatal support to better address these challenges.

Objective The lifelong risks of cardiovascular disease following hypertensive disorders of pregnancy are well described. Awareness of these risks and associated health-seeking behaviours among affected individuals remains unclear. We aimed to assess participants’ knowledge of their cardiovascular disease risk and relevant health-seeking behaviours following a pregnancy affected by preeclampsia or gestational hypertension.Methods We undertook a single-site, cross-sectional cohort study. The target population included individuals who birthed at a large tertiary referral centre in Melbourne, Australia, between 2016 and 2020, and were diagnosed with gestational hypertension or pre-eclampsia. Participants completed a survey assessing pregnancy details, medical comorbidities, knowledge of future risks and health-seeking behaviours post-pregnancy.Results 1526 individuals met inclusion criteria and 438 (28.6%) completed the survey. Of these, 62.6% (n=237) were unaware of their increased risk of cardiovascular disease following a hypertensive disorder of pregnancy. Participants who reported awareness of their increased risk were more likely to have annual blood pressure monitoring (54.6% vs 38.1%, p

Abstract Background Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. Methods We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. Discussion Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing “standard” UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. Trial identifiers Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018–004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Abstract Background A growing body of evidence suggests that early life health and developmental outcomes can be improved through parental support programs. The objective of this project was to test the feasibility, impact, and relative cost-effectiveness of an adapted “Reach Up and Learn” program delivered through home-visiting programs as well as through center-based parenting groups on child health and development in the municipality of Boa Vista, Brazil. Methods A randomized, stepped-wedge design was used to roll out and evaluate the two parenting platforms in Boa Vista municipality. A total of 39 neighborhoods with a high Neighborhood Vulnerability Index were selected for the study. For the first phase of the program, nine neighborhoods were randomly selected for home visits, and two were randomly selected for the center-based parenting groups. In the second phase of the program, 10 neighborhoods were added to the home-visiting program, and eight were added to the center-based program. In the final phase of the program, the remaining 10 control areas will also be assigned to treatment. Study eligibility will be assessed through a baseline survey completed by all pregnant women in the 39 study areas. Pregnant women will be eligible to participate in the study if they are either classified as poor, were under age 20 years when they became pregnant, or if they indicate to have been exposed to domestic or sexual violence. To assess program impact, an endline survey will be conducted when children reach age 2 years. The primary study outcome is child development at age 2 years as measured by the PRIDI instrument. Secondary outcome will be infant mortality, which will be assessed linking municipal vital registration systems to the program rollout. Discussion This trial will assess the feasibility and impact of parenting programs rolled out at medium scale. The results from the trial should create evidence urgently needed for guiding Brazil’s national Criança Feliz program as well as similar efforts in other countries. Trial registration ClinicalTrials.gov, ID: NCT03386747 . Registered on 13 December 2017. All items of the World Health Organization Trial Registration Data Set are available in this record.

Background: Monitoring rates of severe maternal morbidity (such as eclampsia and uterine rupture) is useful to assess the quality of obstetric care, particularly in low and lower-middle-income countries (LMICs). Methods: We undertook a systematic review characterising the proportion and causes of severe maternal morbidity in the Asia Pacific region. We searched Medline, Embase, Cochrane CENTRAL library and the World Health Organization Western Pacific Index database for studies in the Asia-Pacific reporting maternal morbidity/near miss using a predefined search strategy. We included cohort, case-control and cross-sectional studies published in English before September 2020. A meta-analysis was performed calculating the overall proportion of near miss events by sub-region, country, near miss definition, economic status, setting and cause using a random-effects model. Findings: We identified 26,232 articles, screened 24,306 and retrieved 454 full text articles. Of these, 197 studies spanning 27 countries were included. 13 countries in the region were not represented. There were 30,183,608 pregnancies and 100,011 near misses included. The total proportion of near miss events was 4•4 (95% CI 4•3-4•5) per 1000 total births. The greatest proportion of near misses were found in the Western Pacific region (around Papua New Guinea) at 11•8 per 1000 births (95% CI 6•6-17•1; I2 96.05%). Low-income countries displayed the greatest proportion of near misses (13•4, 95% CI 6•0-20•7), followed by lower-middle income countries (11•1; 95% CI 10•4 - 11•9). High-income countries had the lowest proportion (2•2, 95% CI 2•1-2•3). Postpartum haemorrhage was the most common near miss event (5•9, 95% CI 4•5-7•2), followed by eclampsia (2•7, 95% CI 2•4 – 2•9). Interpretation: There is a high burden of severe maternal morbidity in the Asia-Pacific. LMICs are disproportionately affected. Most of the common causes are preventable. This provides an opportunity to implement targeted interventions which could have major clinical impact.

Objectives This study aimed to explore the experiences of parents caring for children with intellectual and developmental disabilities (IDD) during the UK national lockdown in spring 2020, resulting from the COVID-19 pandemic.Design Participants were identified using opportunity sampling from the IMAGINE-ID national (UK) cohort and completed an online survey followed by a semistructured interview. Interviews were analysed using thematic analysis.Setting Interviews were conducted over the telephone in July 2020 as the first UK lockdown was ending.Participants 23 mothers of children with intellectual and developmental disabilities aged 5–15 years were recruited.Results Themes reported by parents included: managing pre-existing challenges during a time of extreme change, having mixed emotions about the benefits and difficulties that arose during the lockdown and the need for appropriate, individualised support.Conclusions Our findings confirm observations previously found in UK parents of children with IDD and provide new insights on the use of technology during the pandemic for schooling and healthcare, as well as the need for regular check-ins.

Abstract Background Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. Methods We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. Results We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. Conclusions Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

Background: There has been increasing interest in assessing longer term developmental and health outcomes in IVF-conceived offspring compared with those born after natural conception. So far, the findings have been conflicting. The Australian Early Developmental Consensus (AEDC) assesses children in their first year of primary school across five domains; physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, and communication skills and general knowledge. Aim: To compare school entry (5-7 years of age) outcomes in IVF-conceived children in Victoria with naturally conceived controls. Method: We undertook a statewide data linkage study, with perinatal data (births 2005-2014) linked to data from major IVF providers in Victoria and the AEDC. Our approach to analysis included: complete case analysis, multiple imputation of missing data, consideration of clustering (siblings) and inverse probability weighted modeling to adjust for covariates. Our primary outcome was an AEDC score indicative of developmental vulnerability in two or more domains. We adjusted for the child’s age at assessment, sex, highest level of maternal education, maternal age, parity, SEIFA (Socio-Economic Indexes for Areas) quintile, language background other than English, and Aboriginal and Torres Strait Islander (ATSI) status. Results: The linked dataset comprised 163,418 children, including 4,441 IVF-conceived children. The IVF conceived population had older, more highly educated mothers who lived in more affluent areas and were less likely to be from non-English speaking backgrounds or identify as ATSI. IVF-conceived children were less likely to be developmentally vulnerable, in both unadjusted (RR 0.59, 95%CI: 0.52-0.67, p

Summary: The failure to mount an antibody response following viral infection or seroconversion failure is a largely underappreciated and poorly understood phenomenon. Here, we identified immunologic markers associated with robust antibody responses after influenza virus infection in two independent human cohorts, SHIVERS and FLU09, based in Auckland, New Zealand and Memphis, Tennessee, USA, respectively. In the SHIVERS cohort, seroconversion significantly associates with (1) hospitalization, (2) greater numbers of proliferating, activated CD4+ T cells, but not CD8+ T cells, in the periphery during the acute phase of illness, and (3) fewer inflammatory monocytes (CD14hiCD16+) by convalescence. In the FLU09 cohort, fewer CD14hiCD16+ monocytes during early illness in the nasal mucosa were also associated with the generation of influenza-specific mucosal immunoglobulin A (IgA) and IgG antibodies. Our study demonstrates that seroconversion failure after infection is a definable immunological phenomenon, associated with quantifiable cellular markers that can be used to improve diagnostics, vaccine efficacy, and epidemiologic efforts.

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.

ObjectiveTo assess the feasibility of a problem-solving skills training intervention in improving psychological outcomes in mothers of infants with sickle cell disease (SCD).Design and methodsThis parallel randomized controlled trial recruited 64 babies with SCD, 6 to 12 months of age, and their mothers. Baseline measurements assessed mothers' coping and problem-solving skills, depression, and parental stress before random assignment to intervention or control groups (n = 32 each). Problem-solving skills intervention was delivered through 6 monthly sessions, when babies attended for routine penicillin prophylaxis. All measurements were repeated for both groups at the end of the intervention period. Intention to treat analysis used repeated measures mixed models with the restricted estimation maximum likelihood approach.ResultsThe problem-solving intervention had no significant effect on mothers' problem-solving skills (adjusted treatment effect: -1.69 points (95% CI:-5.62 to 2.25)), coping behaviours (adjusted treatment effect: 0.65 points (95% CI:- -7.13 to 8.41)) or depressive symptoms (adjusted treatment effect: -0.41 (95% CI: -6.00 to 5.19)). It reduced mothers' level of difficulty in managing stressful events by 9.5 points (95% CI (-16.86 to -2.16); effect size: 0.21 SD). In the subgroup of mothers at risk of depression (n = 31 at baseline), the intervention reduced depression scores with treatment effect of 10.4 points (95%CI: -18.83 to -1.88; effect size: 0.67 SD).ConclusionThis problem-solving skills intervention study suggests feasibility and possible efficacy in improving some maternal outcomes. Further refinement and culturally appropriate adaptations of the intervention could lead to stronger effects.

Defects in PEX3 are associated with a severe neonatal-lethal form of Zellweger spectrum disorder. We report two moderately affected siblings whose clinical and biochemical phenotypes expand the reported spectrum of PEX3-related disease. Genome sequencing of an adolescent male with progressive movement disorder, spasticity and neurodegeneration, and previous non-diagnostic plasma very-long chain fatty acid analysis, revealed a homozygous likely pathogenic missense variant in PEX3 [c.991G > A; p.(Gly331Arg)]. A younger sibling with significant motor decline since the age of three years was also subsequently found to be homozygous for the familial PEX3 variant. A comprehensive review of the scientific literature identified three additional families with non-lethal infantile- or childhood-onset PEX3-related disease, which together with this clinical report illustrate the potential for highly variable disease severity. Our findings demonstrate the diagnostic utility of genome-wide sequencing for identifying clinically and biochemically heterogeneous inherited metabolic disorders such as the peroxisome biogenesis disorders.

Summary: Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity. : In this article, Scherer and colleagues present a human induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten genes associated with autism spectrum disorder. They also show that some of these genes, pertaining to diverse functional categories, can underlie common phenotypes in CRISPR-isogenic iPSC-derived glutamatergic neurons. Keywords: iPSC, CRISPR, isogenic, knockout, StopTag, NGN2, autism, convergence, sEPSC

Abstract Background Twin-to-twin transfusion syndrome (TTTS) is a serious complication of 10–15% of twin or triplet pregnancies in which multiple fetuses share a single placenta. Communicating placental vessels allow one fetus (the donor) to pump blood to the other (the recipient). Mortality rates without intervention are high, approaching 100% in some series, with fetal deaths usually due to cardiac failure. Surgical correction using laser photocoagulation of communicating placental vessels was developed in the 1980s and refined in the 1990s. Since it was introduced in Victoria in 2006, laser surgery has been performed in approximately 120 pregnancies. Survival of one or more fetuses following laser surgery is currently > 90%, however the neurodevelopmental outcomes for survivors remain incompletely understood. Prior to laser therapy, at least one in five survivors of TTTS had serious adverse neurodevelopmental outcomes (usually cerebral palsy). Current estimates of neurological impairment among survivors following laser surgery vary from 4 to 31% and long-term follow-up data are limited. Methods This paper describes the methodology for a retrospective cohort study in which children aged 24 months and over (corrected for prematurity), who were treated with laser placental photocoagulation for TTTS at Monash Health in Victoria, Australia, will undergo comprehensive neurodevelopmental assessment by a multidisciplinary team. Evaluation will include parental completion of pre-assessment questionnaires of social and behavioural development, a standardised medical assessment by a developmental paediatrician or paediatric neurologist, and age-appropriate cognitive and academic, speech and fine and gross motor assessments by psychologists, speech and occupational therapists or physiotherapists. Assessments will be undertaken at the Murdoch Children’s Research Institute/Royal Children’s Hospital, at Monash Health or at another mutually agreed location. Results will be recorded in a secure online database which will facilitate future related research. Discussion This will be the first study to report and evaluate neurodevelopmental outcomes following laser surgery for twin-to-twin transfusion syndrome in Victoria, and will inform clinical practice regarding follow-up of children at risk of adverse outcomes.

Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood–brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and eclampsia. We included women recruited to the South African Preeclampsia Obstetric Adverse Events (PROVE) biobank. Blood and cerebrospinal fluid (CSF) were collected around delivery. CSF was analyzed for neuroinflammatory markers interleukin 1β, interleukin 6, interleukin-8 and tumor necrosis factor alpha (TNF-alpha). The CSF to plasma albumin ratio was measured to assess blood–brain barrier function. Women with eclampsia (n = 4) showed increased CSF concentrations of all pro-inflammatory cytokines and TNF-alpha compared to women with normotensive pregnancies (n = 7) and also for interleukin-6 and TNF-alpha compared to women with preeclampsia (n = 4). Women with preeclampsia also showed increases in pro-inflammatory cytokines IL-6 and IL-8 but not TNF-alpha in the CSF compared to women with normotensive pregnancies. In particular, women with eclampsia but also women with preeclampsia showed an increase in the CSF to plasma albumin ratio compared to normotensive women. In conclusion, women with preeclampsia and eclampsia show evidence of neuroinflammation and an injured blood–brain barrier. These findings are seen in particular among women with eclampsia.

Abstract Background Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.

Chronic lung disease: Giving importance to patients’ emotions An exploration of patient perceptions of living with chronic lung disease will help develop a new patient reported experience scale. Healthcare services are aiming to provide effective patient-centered care for those with chronic obstructive pulmonary disease (COPD). Such care strategies require structured, validated patient feedback scales to facilitate accurate communication between patients, carers and healthcare professionals. Susan Walker at Anglia Ruskin University in Chelmsford, UK, and co-workers analyzed qualitative data from interviews with 64 COPD patients in London and Essex regarding their emotions and perceptions of living with COPD, with the aim of creating a patient reported experience measure, or PREM. Initial results identified five themes—including ‘journey to diagnosis’ and ‘everyday life’—and twenty-one affective responses, ranging from negative to positive. The team will take these results forward for further validation.

Objective: To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. Participants and Methods: We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. Results: Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; P

Abstract Autism spectrum disorder is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to autism spectrum disorder, showing de novo and inherited unbalanced copy number variants and smaller insertions and deletions (indels), more complex structural variants, as well as single-nucleotide variants deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two copy number variant microdeletions, which affect regions of NRXN1 and MBD5—each well-established in association with risk of autism spectrum disorder and other neurodevelopmental disorders. Although each copy number variant would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.

The Canadian beaver (Castor canadensis) is the largest indigenous rodent in North America. We report a draft annotated assembly of the beaver genome, the first for a large rodent and the first mammalian genome assembled directly from uncorrected and moderate coverage (< 30 ×) long reads generated by single-molecule sequencing. The genome size is 2.7 Gb estimated by k-mer analysis. We assembled the beaver genome using the new Canu assembler optimized for noisy reads. The resulting assembly was refined using Pilon supported by short reads (80 ×) and checked for accuracy by congruency against an independent short read assembly. We scaffolded the assembly using the exon–gene models derived from 9805 full-length open reading frames (FL-ORFs) constructed from the beaver leukocyte and muscle transcriptomes. The final assembly comprised 22,515 contigs with an N50 of 278,680 bp and an N50-scaffold of 317,558 bp. Maximum contig and scaffold lengths were 3.3 and 4.2 Mb, respectively, with a combined scaffold length representing 92% of the estimated genome size. The completeness and accuracy of the scaffold assembly was demonstrated by the precise exon placement for 91.1% of the 9805 assembled FL-ORFs and 83.1% of the BUSCO (Benchmarking Universal Single-Copy Orthologs) gene set used to assess the quality of genome assemblies. Well-represented were genes involved in dentition and enamel deposition, defining characteristics of rodents with which the beaver is well-endowed. The study provides insights for genome assembly and an important genomics resource for Castoridae and rodent evolutionary biology.

Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, ‘isogenic’ iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery.

The development of neural connectivity is essential for brain function, and disruption of this process is associated with autism spectrum disorders (ASDs). DIX domain containing 1 (DIXDC1) has previously been implicated in neurodevelopmental disorders, but its role in postnatal brain function remains unknown. Using a knockout mouse model, we determined that DIXDC1 is a regulator of excitatory neuron dendrite development and synapse function in the cortex. We discovered that MARK1, previously linked to ASDs, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner. Finally, rare missense variants in DIXDC1 were identified in ASD patient cohorts via genetic sequencing. Interestingly, the variants inhibit DIXDC1 isoform 1 phosphorylation, causing impairment to dendrite and spine growth. These data reveal that DIXDC1 is a regulator of cortical dendrite and synaptic development and provide mechanistic insight into morphological defects associated with neurodevelopmental disorders.