Nirsevimab: Alleviating the burden of RSV morbidity in young children.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) and hospital admissions in early childhood. Recent advancements in novel preventive therapies, including extended half-life monoclonal antibodies and antenatal vaccination, have afforded new opportunities to significantly reduce the burden of this infection. Nirsevimab is a novel monoclonal antibody that provides sustained protection against RSV for at least 5 months among newborns and young children. It has received regulatory approval in numerous countries and is being implemented across various settings. Two pivotal Phase 3 trials (MELODY, HARMONIE) demonstrated significant reductions in RSV-associated LRTI hospitalisations following nirsevimab administration, with treatment efficacy of 62.1% and 83.2%. Emerging real-world data from early adopters of nirsevimab corroborates these findings. Studies from Spain, Luxembourg, France and the USA report effectiveness rates between 82% and 90% in preventing RSV-associated hospitalisations among infants entering their first RSV season. Current implementation strategies for nirsevimab have primarily focused on seasonal administration for all infants, aligned to local RSV seasons, and often include catch-up doses for those born before the season begins. Available cost-effectiveness analyses indicate that while nirsevimab offers significant potential public health benefits, its adoption must carefully consider economic factors such as treatment costs, implementation strategies tailored to local viral epidemiology, and logistics for vaccine delivery. Overall, nirsevimab presents a promising opportunity to alleviate the burden of severe RSV infections in young children. However, ongoing surveillance and refinements in implementation strategies are crucial to optimise its impact and ensure sustainability across diverse health-care settings.

PAs and NPs in liver transplantation: Perceptions, implementation, and effect.

OBJECTIVES: This study assessed the use and perceptions of physician associates/assistants (PAs) and NPs at liver transplant centers and sought to determine their financial effect. METHODS: Leaders of liver transplant programs performing 25 or more transplants in 2020 were contacted to complete an 11-question survey about the role and effect of PAs and NPs in liver transplant. A single-center retrospective analysis compared length of stay (LOS) and readmission rates for primary liver transplants and simultaneous liver-kidney transplants before and after a dedicated PA team was established. Chi-square and t -test analyses were performed. RESULTS: The survey achieved a 77% response rate, and 98% of institutions reported using PAs and NPs. The single-center study found the mean LOS post-transplant was significantly shorter in the post-PA cohort ( P = .0005). No significant difference was found in 30-day readmission rates. CONCLUSIONS: PAs and NPs are used broadly across the post-liver transplant care continuum. Using LOS as a surrogate financial marker suggests that a dedicated PA and NP team may contribute to cost savings.

Economic evaluation of population-based, expanded reproductive carrier screening for genetic diseases in Australia.

PURPOSE: This study aimed to evaluate the cost effectiveness of population-based, expanded reproductive carrier screening (RCS) for a 300 recessive gene panel from health service and societal perspectives. METHODS: A microsimulation model (PreConMod) was developed using 2016 Australian Census data as the base population. Epidemiologic, health, and indirect cost data were based on literature review. The study assessed the incremental cost effectiveness ratio of expanded RCS compared with (1) no population screening and (2) 3-condition screening for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome in a single birth cohort. Averted affected births and health service savings with expanded RCS were projected to year 2061. Both one-way and probability sensitivity analyses were conducted to assess the uncertainty of the parameter inputs. RESULTS: Expanded RCS was cost saving compared with no population screening and cost effective compared with the 3-condition screening (incremental cost effectiveness ratio of Australian dollar [AUD] 6287 per quality-adjusted life year gained) at an uptake rate of 50% for RCS, 59% for in vitro fertilization and preimplantation genetic testing, 90% for prenatal diagnosis testing, and 50% for elective termination of affected pregnancies and a cost of AUD595 per couple screened. Our model predicts that expanded RCS would avert one-third of affected births in a single birth cohort and reduce lifetime health service spending by AUD632.0 million. Expanded RCS was estimated to be cost saving from the societal perspective. CONCLUSION: Expanded RCS is cost effective from health service and societal perspectives. Expanded RCS is projected to avert significantly more affected births and result in health service saving beyond those expected from 3-condition screening or no population screening.

Which assisted reproductive technology (ART) treatment strategy is the most clinically and cost-effective for women of advanced maternal age: a Markov model.

OBJECTIVE: To evaluate the clinical and cost-effectiveness of preimplantation genetic testing for aneuploidy, social freezing, donor and autologous assisted reproductive technology (ART) treatment strategies for women aged 35-45 following 6-12 months of infertility. METHODS: Four Markov decision-analytic models comprising: (i) Preimplantation genetic testing for aneuploidy (PGT-A); (ii) autologous ART from age 40 using oocytes cryopreserved at age 32 (social freezing); (iii) ART using donated oocytes (donor ART); (iv) standard autologous ART treatment (standard care) were developed for a hypothetical cohort of 35 to 45 years old ART naïve women with 6-12 months of infertility. Input probabilities for key parameters including live birth rates were obtained from the available literature. Deterministic and probabilistic sensitivity analyses were conducted to address uncertainty in estimating the parameters and around the model's assumptions. Cost effectiveness was assessed from both societal and patient perspectives . RESULT(S): For infertile women at age 40 and above, social freezing is the most cost-saving strategy with the highest chance of a cumulative live birth at a lowest cost from a societal perspective. PGT-A and donor ART were associated with higher treatment costs and cumulative live-birth rates compared with the autologous ART. Among the four ART strategies, standard autologous ART has the lowest cumulative live birth rate of 45% at age 35 and decreasing to 1.6% by age 45 years. At a willingness-to-pay threshold of Australian dollars (A$)50,000, our model shows all alternative treatment strategies -PGT-A, social freezing and donor ART have a higher probability of being cost-effective compared to the standard autologous ART treatment. However, higher out-of-pocket expenditure may impede their access to these alternate strategies. CONCLUSION: Given current evidence, all alternate strategies have a higher probability of being cost-effective compared to the standard autologous ART treatment. Whether this represents value for money depends on societal and individual's willingness-to-pay for children conceived with ART treatment.

Effects of Power Training on Gait, Power, and Function in Children with Cerebral Palsy.

AIMS: This scoping review aims to: 1) examine available literature regarding the effects of power training on gait speed, power, and function in ambulatory children with CP and 2) identify the variations in exercise dosage and rehabilitation recommendations for power training and plyometrics in children with CP. METHODS: Four databases (PubMed, CINAHL, Embase, and Cochrane) were searched for papers including power or plyometric training with outcome measures for gait, power or functional performance. ES was calculated for RCTs. Cohorts and case series/studies were evaluated qualitatively. RESULTS: Ten articles fit search criteria: four RCTs, three cohort studies, one case series, and two case studies. Power training consistently demonstrated improvements in muscle power compared to its effects on gait and function. ES of mean MPST (W) ranged from 0.36-1.13. 1 MWT and SSGS ES were 1.31 and 1.15, respectively. TUG ES ranged from -0.33 to -2.42. ES for GMFM-66 was 0.13 and 1.11 for Dimension D and Dimension E, respectively. CONCLUSIONS: There is limited, but promising evidence to support that power training may improve gait speed, power, and function in children with CP. Future, more robust research is required to examine effects in a larger, diverse population, to determine long-term effects and exercise prescription.

Which Gay and Bisexual Men Attend Community-Based HIV Testing Services in Australia? An Analysis of Cross-Sectional National Behavioural Surveillance Data.

In Australia, HIV testing services have become increasingly available in non-traditional settings such as peer-led, community-based services to expand access and increase uptake of HIV testing among gay and bisexual men (GBM). This study aimed to compare the socio-demographic and behavioural characteristics of GBM whose last HIV test was conducted at a community-based service to GBM whose last test was at a traditional clinical setting. We analysed behavioural surveillance data collected from 5988 participants in seven states and territories in the period 2016-2017. We found that non-HIV-positive GBM who attended community-based services were largely similar to men attending clinic-based settings, particularly in terms of sexual practice and risk of HIV. However, non-HIV-positive GBM who were younger, born in Asia, more socially engaged with other gay men but who had not recently used PrEP were more likely to attend community-based services for their last HIV test. This study points to the successful establishment of community-based HIV testing services in Australia as a way to attract subgroups of GBM at potentially higher risk of HIV.

Gay Men's Relationship Agreements in the Era of Pre-exposure Prophylaxis: An Analysis of Australian Behavioural Surveillance Data.

Using repeated, cross-sectional behavioural surveillance data from Australia, we assessed trends in relationship agreements and casual sex among HIV-negative and untested gay and bisexual men who had regular partners during 2013-2018. We conducted three analyses: (i) trends in relationship agreements and casual sex over time; (ii) bivariate comparisons of PrEP users and non-PrEP-users to identify factors associated with PrEP use; and (iii) multivariate logistic regression to identify factors independently associated with PrEP use. The analysis of trends over time included 21,593 men, from which a sub-sample (n = 3764) was used to compare PrEP users and non-PrEP-users. We found a large increase in agreements that allowed condomless sex with casual partners, particularly by PrEP users in relationships (nearly 40% of whom had such an agreement). A further 34% of PrEP users reported having casual condomless sex without an agreement that permitted that behaviour, while 13% of non-PrEP-users also reported condomless sex with casual partners without an agreement. PrEP use was independently associated with having agreements permitting condomless sex with casual partners, recent condomless sex with casual partners, having greater numbers of male partners, recent post-exposure prophylaxis use, having an HIV-positive regular male partner, and recent condomless sex with regular male partners. Our findings show a shift away from relationship agreements in which condomless sex was only sanctioned between regular partners.

A cost-effectiveness analysis of preimplantation genetic testing for aneuploidy (PGT-A) for up to three complete assisted reproductive technology cycles in women of advanced maternal age.

BACKGROUND: Current evidence suggests that preimplantation genetic testing for aneuploidy (PGT-A) used during assisted reproductive technology improves per-cycle live-birth rates but cumulative live-birth rate (CLBR) was similar to a strategy of morphological assessment (MA) of embryos. No study has assessed the cost-effectiveness of repeated cycles with PGT-A using longitudinal patient-level data. AIM: To assess the cost-effectiveness of repeated cycles with PGT-A compared to MA of embryos in older women. MATERIALS AND METHODS: Micro-costing methods were used to value direct resource consumption of 2093 assisted reproductive technology-naïve women aged ≥37 years undergoing up to three 'complete assisted reproductive technology cycles' (fresh plus cryopreserved embryos) with either PGT-A or MA in an Australian clinic between 2011 and 2014. Incremental cost-effective ratios were calculated from healthcare and patient perspectives with uncertainty assessed using non-parametric bootstrap methods. Cost-effectiveness acceptability curves were constructed to evaluate the probability of PGT-A being cost-effective over a range of willingness-to-pay thresholds. RESULTS: The CLBR and mean healthcare costs per patient were 30.90% and $22 962 for the PGT-A group, and 26.77% and $21 801 for the MA group, yielding an incremental cost-effective ratio of $28 103 for an additional live birth with PGT-A. At a willingness-to-pay threshold of $50 000 and above, there is more than an 80% probability of PGT-A being cost-effective from the healthcare perspective and a 50% likelihood from a patient perspective. CONCLUSION: This is the first study to use real-world patient-level data to assess the cost-effectiveness of PGT-A in older women from the healthcare and patient perspectives. The findings contribute to the ongoing debate on the role of PGT-A in clinical practice.

Assisted reproductive technology (ART) cumulative live birth rates following preimplantation genetic diagnosis for aneuploidy (PGD-A) or morphological assessment of embryos: A cohort analysis.

BACKGROUND: Preimplantation genetic diagnosis for aneuploidy (PGD-A) for all 24 chromosomes improves implantation and clinical pregnancy rates per single assisted reproductive technology (ART) cycle. However, there is limited data on the live-birth rate of PGD-A over repeated cycles. AIM: To assess the cumulative live-birth rates (CLBR) of PGD-A compared with morphological assessment of embryos of up to three 'complete ART cycles' (fresh plus frozen/thaw cycles) in women aged 37 years or older. MATERIALS AND METHODS: A retrospective cohort study of ART treatments undertaken by ART-naïve women at a large Australian fertility clinic between 2011 and 2014. Cohorts were assigned based on the embryo selection method used in their first fresh cycle [PGD-A, n = 110 women (PGD-A group); morphological assessment of embryos, n = 1983 women (control group)]. CLBR, time to clinical pregnancy and cycles needed to achieve a live birth were measured over multiple cycles. RESULTS: Compared to the control group, the PGD-A group achieved a higher per cycle live-birth rate (14.47% vs 9.12%, P < 0.01), took a shorter mean time to reach a clinical pregnancy leading to a live-birth (104.8 days vs 140.6 days, P < 0.05) and required fewer cycles to achieve a live-birth (6.91 cycles vs 10.96 cycles, P < 0.01). However, after three 'complete ART cycles', the CLBR was comparable for the two groups (30.90% vs 26.77%, P = 0.34). CONCLUSION: This is the first study to assess the effectiveness of PGD-A over multiple ART cycles. These real-world findings suggest that PGD-A leads to better outcomes than using morphological assessment alone in women of advanced maternal age.

Social and Behavioural Correlates of HIV Testing Among Australian Gay and Bisexual Men in Regular Relationships.

In this study we sought to identify the social and behavioural characteristics of Australian gay and bisexual men who had and had not tested for HIV during their current relationship. The results were based on 2012 and 2013 data collected from ongoing cross-sectional and community-based surveys held in six Australian states and territories. One thousand five hundred and sixty-one non-HIV-positive men reported that they were in a primary relationship. The majority of gay and bisexual men in primary relationships had tested for HIV during the relationship (73.4 %). Among men who had not tested during the relationship, almost half of these men had never tested for HIV. As untested men within relationships are potentially at risk of acquiring and transmitting HIV to their partners unknowingly, it is important to promote HIV testing to these men.

The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review.

STUDY QUESTION: Is preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during assisted reproductive technology (ART) clinically and cost effective? SUMMARY ANSWER: The majority of published studies comparing a strategy of PGD-A with morphologically assessed embryos have reported a higher implantation rate per embryo using PGD-A, but insufficient data has been presented to evaluate the clinical and cost-effectiveness of PGD-A in the clinical setting. WHAT IS KNOWN ALREADY: Aneuploidy is a leading cause of implantation failure, miscarriage and congenital abnormalities in humans, and a significant cause of ART failure. Preclinical evidence of PGD-A indicates that the selection and transfer of euploid embryos during ART should improve clinical outcomes. STUDY DESIGN, SIZE AND DURATION: A systematic review of the literature was performed for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring checklist was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Nineteen articles meeting the inclusion criteria, comprising three RCTs in young and good prognosis patients and 16 observation studies were identified. Five of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). MAIN RESULTS AND ROLE OF CHANCE: Of the five studies that included a control group and reported implantation rates, four studies (including two RCTs) demonstrated improved implantation rates in the PGD-A group. Of the eight studies that included a control group, six studies (including two RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining two studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The three RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. LIMITATIONS, REASONS FOR CAUTION: Relevant studies may have been missed and findings from RCTs currently being undertaken could not be included. WIDER IMPLICATIONS OF THE FINDINGS: Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood.

Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.

BACKGROUND: Central nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI). METHODS: Antiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF. RESULTS: A total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P <0.001), whereas it decreased by 6.7% in subjects with baseline levels of more than 21 nmol/L (n = 11; P = 0.001). In a subset with available flow cytometry data (n = 42), the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P <0.001) and 0.73 (P = 0.02) per 10 weeks, respectively. CONCLUSIONS: Neopterin levels and the percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1 infection, suggesting an accrual of intrathecal inflammation, a major contributor to neuropathology in HIV infection.

Longitudinal characterization of depression and mood states beginning in primary HIV infection.

Though depression is known to frequently afflict those with chronic HIV, mood during the early course of HIV is not well characterized. In a prospective study we assessed mood during primary HIV infection [primary HIV infection (PHI), <1 year duration], its association with neuropsychological performance and markers of neurological disease, and its longitudinal course including effects of antiretroviral therapy (ART). The Beck Depression Inventory (BDI) and Profile of Mood States (POMS) subscales were longitudinally administered prior to and after ART in PHI subjects. This evaluation of mood was done concurrently with blood, cerebrospinal fluid (CSF) and neuropsychological [total z and global deficit score (GDS)] evaluation at each visit. Analysis employed Spearman's rho, logistic regression, and linear mixed models. 47.7 % of the 65 men recruited at a median 3.5 months HIV duration met BDI criteria for clinical depression at baseline, classified as 'mild' (n = 11), 'moderate' (n = 11), or 'severe' (n = 9). Drug, alcohol, and depression history did not associate with BDI score. Proportional somatic-performance scores were worse than cognitive-affective scores (p = .0045). Vigor subscore of POMS was reduced compared to norms and correlated with total z (r = 0.33, p = 0.013) and GDS (r = -0.32, p = 0.016). BDI and POMS correlated with one another (r = 0.85, p < .0001), but not with CSF or plasma HIV RNA, WBC, albumin ratio or neopterin. Improvement was not observed in BDI and POMS over 330 total follow-up visits, even after initiation of ART. Depression was prevalent during PHI in our subjects, associated with abnormal somatic-performance and vigor scores. Neither neuropsychological performance nor disease biomarkers correlated with depressed mood. Mood indices did not improve over time in the presence of ART.

Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection.

BACKGROUND: Cerebrospinal fluid (CSF) and neuroimaging abnormalities demonstrate neuronal injury during chronic AIDS, but data on these biomarkers during primary human immunodeficiency virus (HIV) infection is limited. METHODS: We compared CSF concentrations of neurofilament light chain, t-tau, p-tau, amyloid precursor proteins, and amyloid-beta 42 in 92 subjects with primary HIV infection and 25 controls. We examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS)-based metabolites. RESULTS: Neurofilament light chain was elevated in primary HIV infection compared with controls (P = .0004) and correlated with CSF neopterin (r = 0.38; P = .0005), interferon gamma-induced protein 10 (r = 0.39; P = .002), white blood cells (r = 0.32; P = .004), protein (r = 0.59; P < .0001), and CSF/plasma albumin ratio (r = 0.60; P < .0001). Neurofilament light chain correlated with decreased N-acteylaspartate/creatine and glutamate/creatine in the anterior cingulate (r = -0.35, P = .02; r = -0.40, P = .009, respectively), frontal white matter (r = -0.43, P = .003; r = -0.30, P = .048, respectively), and parietal gray matter (r = -0.43, P = .003; r = -0.47, P = .001, respectively). Beta-amyloid was elevated in the primary infection group (P = .0005) and correlated with time infected (r = 0.34; P = .003). Neither marker correlated with neuropsychological abnormalities. T-tau and soluble amyloid precursor proteins did not differ between groups. CONCLUSIONS: Elevated neurofilament light chain and its correlation with MRS-based metabolites suggest early neuronal injury in a subset of participants with primary HIV infection through mechanisms involving central nervous system inflammation.

'Joining the Dots: Linking Prenatal Drug Exposure to Childhood and Adolescence' - research protocol of a population cohort study.

INTRODUCTION: Prenatal drug exposure (PDE) is one of the most important causes of child harm, but comprehensive information about the long-term outcomes of the families is difficult to ascertain. The Joining the Dots cohort study uses linked population data to understand the relationship between services, therapeutic interventions and outcomes of children with PDE. METHODS AND ANALYSIS: Information from routinely collected administrative databases was linked for all births registered in New South Wales (NSW), Australia between 1 July 2001 and 31 December 2020 (n=1 834 550). Outcomes for seven mutually exclusive groups of children with varying prenatal exposure to maternal substances of addiction, including smoking, alcohol, prescription/illicit drugs and neonatal abstinence syndrome will be assessed. Key exposure measures include maternal drug use type, maternal social demographics or social determinants of health, and maternal physical and mental health comorbidities. Key outcome measures will include child mortality, academic standardised testing results, rehospitalisation and maternal survival. Data analysis will be conducted using Stata V.18.0. ETHICS AND DISSEMINATION: Approvals were obtained from the NSW Population and Health Services Research Ethics Committee (29 June 2020; 2019/ETH12716) and the Australian Capital Territory Health Human Research Ethics Committee (11 October 2021; 2021-1231, 2021-1232, 2021-1233); and the Aboriginal Health and Medical Research Council (5 July 2022; 1824/21), and all Australian educational sectors: Board of Studies (government schools), Australian Independent Schools and Catholic Education Commission (D2014/120797). Data were released to researchers in September 2022. Results will be presented in peer-reviewed academic journals and at international conferences. Collaborative efforts from similar datasets in other countries are welcome.

School performance in children with prenatal drug exposure and out-of-home care in NSW, Australia: a retrospective population-based cohort study.

BACKGROUND: Prenatal drug exposure (PDE) is a global public health problem that is strongly associated with the need for child protection services, including placement into out-of-home care (OOHC). We aimed to assess school outcomes for children with PDE (both with and without neonatal abstinence syndrome [NAS]) and the association of school performance with OOHC. METHODS: Using linked population health, OOHC, and school test data, we compared results on the Australian standardised curriculum-based test, the National Assessment Program-Literacy and Numeracy (NAPLAN), for children with PDE who were born in New South Wales (NSW) between 2001 and 2020 and had completed at least one NAPLAN test between Jan 1, 2008, and June 30, 2021, administered in Year 3 (age 8-9 years), Year 5 (age 10-11 years), Year 7 (age 12-13 years), or Year 9 (age 14-15 years). Linked datasets included NSW Perinatal Data Collection (birth data), NSW Admitted Patient Data Collection (hospital diagnoses), NSW Education Standards Authority (NAPLAN scores), NSW Family and Community Services Dataset-KiDS Data Collection (OOHC information), NSW Mental Health Ambulatory Data Collection, and NSW Registry for Births, Deaths, and Marriages. The primary outcome was scoring above or below the National Minimum Standard (NMS) in any test domain (mathematics, language, writing, and spelling) at each year level, comparing the relative risk of scoring below NMS between children with and without PDE (and with or without NAS within the PDE group), and with and without OOHC contact. The association between OOHC on the likelihood of scoring above NMS was also investigated for PDE and non-PDE cohorts. FINDINGS: The PDE cohort included 3836 children, and the non-PDE cohort included 897 487 children. Within the PDE cohort, 3192 children had a NAS diagnosis and 644 children had no NAS diagnosis. 1755 (45·8%) children with PDE required OOHC compared with 12 880 (1·4%) of 897 487 children without PDE. Children with PDE were more likely than children without PDE to score below NMS in any domain from Year 3 (risk ratio 2·72 [95% CI 2·58-2·76]) to Year 9 (2·36 [2·22-2·50]). Performance was similar regardless of a NAS diagnosis (Year 3: 0·96 [0·84-1·10]; Year 9: 0·98 [0·84-1·15]). The likelihood of scoring above NMS in Year 9 was reduced for children with PDE and without NAS (0·57 [0·45-0·73]) and NAS (0·58 [0·52-0·64]) compared with those without PDE, and also for children who received OOHC (0·60 [0·57-0·64]) compared with those without OOHC, when adjusted for confounders. Among children with PDE, those receiving OOHC had a similar likelihood of scoring above NMS compared with children who did not receive OOHC, from Year 3 (1·01 [0·92-1·11]) to Year 9 (0·90 [0·73-1·10]), when adjusted for confounding factors. By contrast, among children without PDE, those receiving OOHC were less likely to score above NMS than those who did not receive OOHC, from Year 3 (0·78 [0·76-0·80]) to Year 9 (0·58 [0·54-0·61]). INTERPRETATION: Compared with children without PDE, school performance in children with PDE-regardless of whether they were diagnosed with NAS-is poor, and the gap widens with age. The risk of poor performance persists regardless of OOHC status. This finding underscores the need for all children with PDE to receive long-term, culturally sensitive, and proactive support to improve life success. FUNDING: SPHERE Mindgardens Neuroscience Network, Australian Red Cross, Alpha Maxx Healthcare, Centre for Research Excellence for Integrated Health and Social Care, National Health and Medical Research Council, and University of Sydney.

Health Care Needs and Costs for Children Exposed to Prenatal Substance Use to Adulthood.

Importance: Children exposed to substance use during pregnancy have increased health needs but whether these are influenced by engagement in out-of-home care is uncertain. Objective: To evaluate the association between substance use during pregnancy, out-of-home care and hospitalization utilization, and costs from birth up to age 20 years. Design, Setting, and Participants: This was a retrospective cohort study using individual-linked population birth, hospital, and out-of-home care information of all liveborn infants from New South Wales, Australia, between 2001 and 2020 using longitudinal population-based linkage records from administrative databases. Substance use during pregnancy included newborns with neonatal abstinence syndrome (n = 5946) and intrauterine exposure to drugs of addiction (n = 1260) and other substances (eg, tobacco, alcohol, and illicit drugs or misused prescription drugs; n = 202 098). Children not exposed to substance use during pregnancy were those without known exposure to substance use during pregnancy (n = 1 611 351). Data were analyzed from July 2001 to December 2021. Main Outcomes: Main outcomes were hospital readmission, length of stay, and cost burden associated with substance use during pregnancy from birth up to age 20 years. Outcomes were investigated using 2-part and Poisson regression models adjusted for sociodemographic characteristics. Mediation analysis was used to evaluate whether the association of substance use during pregnancy with risk of readmission was mediated through engagement with out-of-home care. Results: Of the 1 820 655 live births, 935 807 (51.4%) were male. The mean (SD) age of mothers was 30.8 (5.5) years. Compared with children who were not exposed to substance use during pregnancy, those who were exposed incurred significantly higher birth hospital costs (adjusted mean difference, A$1585 per child [US$1 = A$1.51]; 95% CI, 1585-1586). If discharged alive, more children with exposure to substance use during pregnancy had at least 1 readmission (90 433/209 304 [43.4%] vs 616 425/1 611 351[38.3%]; adjusted relative risk [RR], 1.06; 95% CI, 1.06-1.07), most commonly for respiratory conditions (RR, 1.11; 95% CI, 1.09-1.12) and mental health/behavioral disorders (RR, 1.36; 95% CI, 1.33-1.41). Excess hospital costs associated with substance use during pregnancy were A$129.0 million in 2019 to 2020. Mediation analyses showed that any out-of-home care contact mediated the association between substance use during pregnancy and risk of inpatient readmission and lower health care cost (decreased by A$25.4 million). For children with neonatal abstinence syndrome, any out-of-home care contact mediated readmission risk by approximately 30%, from adjusted RR, 1.28; 95% CI, 1.19-1.35, to RR, 1.01; 95% CI, 0.98-1.02. Conclusion and Relevance: Children who were exposed to substance use during pregnancy incurred more hospital costs than children who were not exposed up to 20 years of age, but this was reduced in association with any contact with out-of-home care. This provides insights into possible strategies for reducing health and financial burdens associated with exposure to substance use during pregnancy for children.

Circulating Plasma Proteins in Aortic Stenosis: Associations With Severity, Myocardial Response, and Clinical Outcomes.

BACKGROUND: Echocardiographic indexes of aortic stenosis may not comprehensively reflect disease morbidity. Plasma proteomic profiling may add prognostic value in these patients. METHODS AND RESULTS: Proximity extension assays (Olink) of 183 circulating cardiovascular and inflammatory proteins were performed in a prospective follow-up study of 122 asymptomatic/minimally symptomatic patients (mean±SD age, 69.1±10.9 years; 61% men) with moderate to severe aortic stenosis and preserved left ventricular ejection fraction. Protein signatures of higher-risk echocardiographic subgroups were determined. Associations of proteins with the primary composite outcome (heart failure hospitalization, progression to New York Heart Association class III-IV, or all-cause mortality) were evaluated using competing risk analyses, with aortic valve replacement being the competing risk. Network analysis unveiled mutually exclusive communities of proteins and echocardiographic parameters, connected only through NT-proBNP (N-terminal pro-B-type natriuretic peptide). Members of the tumor necrosis factor receptor superfamily (TNFRSF1A, TNFRSF1B, and TNFRSF14), and trefoil factor-3 were major hub proteins among the circulating biomarkers. Left ventricular global longitudinal strain >-15% was associated with higher levels of proteins, primarily of inflammation and immune regulation, whereas aortic valve area <1 cm2, E/e' >15, and left atrial reservoir strain <20% were associated with higher levels of NT-proBNP. Of 14 proteins associated with the primary end point, phospholipase-C, C-X-C motif chemokine-9, and interleukin-10 receptor subunit ß demonstrated the highest hazard ratios after adjusting for clinical factors (q<0.05). CONCLUSIONS: Plasma proteins involved in inflammation and immune regulation were differentially expressed in patients with aortic stenosis with reduced left ventricular global longitudinal strain, and associated with adverse clinical outcomes. Their incorporation into aortic stenosis risk stratification warrants further assessment.

The converging and diverging characteristics of HIV-positive and HIV-negative gay men in the Australian Gay Community Periodic Surveys, 2000-2009.

To assess the changing health promotion needs of human immunodeficiency virus (HIV)-positive gay men in Australia, we analysed the social and behavioural characteristics of HIV-positive men in the Australian Gay Community Periodic Surveys. We looked at change over time in the characteristics of HIV-positive men (from 2000-2001 to 2008-2009) and compared HIV-positive men with their HIV-negative peers within each time period. Multivariate logistic regression analysis was used to assess independent changes over time within each HIV status group. A total of 21,620 responses were included in the analyses; 10,537 in 2000-2001 and 11,083 in 2008-2009. Between the two time periods, HIV-positive and HIV-negative men became more similar in the following areas: paid employment, sexual identity, number of male sex partners, the likelihood of having a regular male partner and having a seroconcordant regular male partner. The two groups diverged in these areas: age, ethnicity, educational level, social engagement with gay men, types of relationship with regular male partners, likelihood of unprotected anal intercourse with casual male partners and likelihood of HIV disclosure to casual male partners. Workforce participation and educational attainment have improved among HIV-positive gay men since 2000, but they still lag behind their HIV-negative peers in these areas. Because HIV-positive men are an ageing cohort, support services will need to increasingly address issues of HIV, sexuality and ageing with HIV-positive men. The increase in unprotected anal intercourse and HIV disclosure with casual partners means that education and support services will increasingly need to address effective HIV disclosure and non-condom-based risk reduction strategies with both HIV-positive and HIV-negative gay men.