Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

The effect of maternal prenatal tobacco smoking on offspring academic achievement: A systematic review and meta-analysis.

BACKGROUND: Previous epidemiological studies examining the prospective association between maternal prenatal tobacco smoking and offspring academic achievement have reported conflicting results. Therefore, this systematic review and meta-analysis was conducted to examine the magnitude and consistency of association reported by those studies. METHODS: This systematic review and meta-analysis was guided by the PRISMA protocol. Relevant epidemiological studies on the topic were extracted from four main databases (PubMed/Medline, Embase, PsycINFO, and Scopus). The Newcastle-Ottawa Scale (NOS) was used to appraise the methodological quality of the included studies. We conducted a narrative assessment of the studies that did not report effect estimates. Inverse variance-weighted random effect meta-analysis was used to combine studies reporting effect sizes to estimate pooled adjusted odds ratio with 95% confidence intervals (95% CI). The review was prospectively registered in PROSPERO (CRD42022350901). RESULTS: Nineteen observational studies, published between 1973 and 2021 with a total of 1.25 million study participants were included in the final review. Of these, fifteen studies (79 %) reported reduced academic achievement in offspring exposed to maternal prenatal tobacco smoking. The eight primary studies (sample size = 723,877) included in the meta-analysis together suggested a 49 % higher risk of reduced academic achievement in offspring exposed to maternal prenatal tobacco smoking when compared to non-exposed offspring (Pooled odds ratio = 1.49, 95 % CI:1.17-1.91). CONCLUSION: Our review found a positive association between maternal prenatal tobacco smoking and offspring reduced academic achievement. However, variation in the adjustment of potential confounders and significant heterogeneity across included studies limited more conclusive inference. Mechanistic studies to identify causal pathways and specific academic impacts are needed to inform targeted developmental programs to assist child learning and academic performance.

The effects of pre-eclampsia on social and emotional developmental vulnerability in children at age five in Western Australia: A population data linkage study.

BACKGROUND: It is important to explore factors that may hinder early childhood development in AEDC Emotional Maturity and Social Competence domains as these underpin the foundation for health, well-being, and productivity over the life course. No previous study has examined whether, or to what extent, preeclampsia increases the risk of developmental vulnerability in social and emotional domains in early childhood. METHODS: We conducted a retrospective population-based cohort study on the association between preeclampsia and childhood developmental vulnerability in emotional maturity and social competence domains in children born in Western Australia in 2009, 2012 and 2015. We obtained records of births, developmental anomalies, midwives notifications and hospitalisations. These data were linked to the Australian Early Development Census (AEDC), from which developmental vulnerability in emotional maturity and social competence domains at a median age of 5 years was ascertained. Causal relative risks (RR) were estimated with doubly robust estimation. RESULTS: A total of 64,391 mother-offspring pairs were included in the final analysis. For the whole cohort, approximately 25 % and 23 % of children were classified as developmentally vulnerable or at-risk on AEDC emotional maturity and social competence domains, respectively. Approximately 2.8 % of children were exposed in utero to preeclampsia. Children exposed to preeclampsia were more likely to be classified as developmentally vulnerable or at-risk on the emotional maturity (RR = 1.19, 95%CI:1.11-1.28) and social competence domains (RR = 1.22, 95 % CI:1.13-1.31). CONCLUSION: Children exposed to pre-eclampsia in utero were more likely to be developmentally vulnerable in emotional maturity and social competence domains in this cohort. Our findings provide new insights into the harmful effect of preeclampsia on childhood developmental vulnerability.

The effectiveness of maternal pertussis vaccination for protecting Aboriginal and Torres Strait Islander infants against infection, 2012-2017: a retrospective cohort study.

OBJECTIVES: To evaluate the effectiveness of maternal pertussis vaccination for preventing pertussis infections in Aboriginal and Torres Strait Islander infants under seven months of age. STUDY DESIGN: Retrospective cohort study; analysis of linked administrative health data. SETTING, PARTICIPANTS: Mother-infant cohort (Links2HealthierBubs) including all pregnant women who gave birth to live infants (gestational age ≥ 20 weeks, birthweight ≥ 400 g) in the Northern Territory, Queensland, and Western Australia during 1 January 2012 - 31 December 2017. MAIN OUTCOME MEASURES: Proportions of women vaccinated against pertussis during pregnancy, rates of pertussis infections among infants under seven months of age, and estimated effectiveness of maternal vaccination for protecting infants against pertussis infection, each by Indigenous status. RESULTS: Of the 19 892 Aboriginal and Torres Strait Islander women who gave birth to live infants during 2012-2017, 7398 (37.2%) received pertussis vaccine doses during their pregnancy, as had 137 034 of 259 526 non-Indigenous women (52.8%; Indigenous v non-Indigenous: adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.62-0.70). The annual incidence of notified pertussis infections in non-Indigenous infants declined from 16.8 (95% CI, 9.9-29) in 2012 to 1.4 (95% CI, 0.3-8.0) cases per 10 000 births in 2017; among Aboriginal and Torres Strait Islander infants, it declined from 47.6 (95% CI, 16.2-139) to 38.6 (95% CI, 10.6-140) cases per 10 000 births. The effectiveness of maternal vaccination for protecting non-Indigenous infants under seven months of age against pertussis infection during 2014-17 was 68.2% (95% CI, 51.8-79.0%); protection of Aboriginal and Torres Strait Islander infants was not statistically significant (36.1%; 95% CI, -41.3% to 71.1%). CONCLUSIONS: During 2015-17, maternal pertussis vaccination did not protect Aboriginal and Torres Strait Islander infants in the NT, Queensland, and WA against infection. Increasing the pertussis vaccination rate among pregnant Aboriginal and Torres Strait Islander women requires culturally appropriate, innovative strategies co-designed in partnership with Indigenous organisations and communities.

Mortality burden attributable to exceptional PM2.5 air pollution events in Australian cities: A health impact assessment.

Background: People living in Australian cities face increased mortality risks from exposure to extreme air pollution events due to bushfires and dust storms. However, the burden of mortality attributable to exceptional PM2.5 levels has not been well characterised. We assessed the burden of mortality due to PM2.5 pollution events in Australian capital cities between 2001 and 2020. Methods: For this health impact assessment, we obtained data on daily counts of deaths for all non-accidental causes and ages from the Australian National Vital Statistics Register. Daily concentrations of PM2.5 were estimated at a 5 km grid cell, using a Random Forest statistical model of data from air pollution monitoring sites combined with a range of satellite and land use-related data. We calculated the exceptional PM2.5 levels for each extreme pollution exposure day using the deviation from a seasonal and trend loess decomposition model. The burden of mortality was examined using a relative risk concentration-response function suggested in the literature. Findings: Over the 20-year study period, we estimated 1454 (95 % CI 987, 1920) deaths in the major Australian cities attributable to exceptional PM2.5 exposure levels. The mortality burden due to PM2.5 exposure on extreme pollution days was considerable. Variations were observed across Australia. Despite relatively low daily PM2.5 levels compared to global averages, all Australian cities have extreme pollution exposure days, with PM2.5 concentrations exceeding the World Health Organisation Air Quality Guideline standard for 24-h exposure. Our analysis results indicate that nearly one-third of deaths from extreme air pollution exposure can be prevented with a 5 % reduction in PM2.5 levels on days with exceptional pollution. Interpretation: Exposure to exceptional PM2.5 events was associated with an increased mortality burden in Australia's cities. Policies and coordinated action are needed to manage the health risks of extreme air pollution events due to bushfires and dust storms under climate change.

Economic burden of adverse perinatal outcomes from births to age 5 years in high-income settings: a protocol for a systematic review.

BACKGROUND: Adverse perinatal outcomes such as preterm, small for gestational age, low birth weight, congenital anomalies, stillbirth and neonatal death have devastating impacts on individuals, families and societies, with significant lifelong health implications. Despite extensive knowledge of the significant and lifelong health implications of adverse perinatal outcomes, information on the economic burden is limited. Estimating this burden will be crucial for designing cost-effective interventions to reduce perinatal morbidity and mortality. Thus, we will quantify the economic burden of adverse perinatal outcomes from births to age 5 years in high-income countries. METHODS AND ANALYSIS: A systematic review of all primary studies published in English in peer-reviewed journals on the economic burden for at least one of the adverse perinatal outcomes in high-income countries from 2010 will be searched in databases-MEDLINE (Ovid), EconLit, CINAHL (EBSCO), Embase (Ovid) and Global Health (Ovid). We will also search using Google Scholar and snowballing of the references list of included articles. The search terms will include three main concepts-costs, adverse perinatal outcome(s) and settings. We will use the Consolidated Health Economics Evaluation Reporting Standards 2022 and 17 criteria from the critical appraisal of cost-of-illness studies to assess the quality of each study. We will report the findings based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 statement. Costs will be converted into a common currency (US dollar), and we will estimate the pooled cost and subgroup analysis will be done. The reference lists of included papers will be reviewed. ETHICS AND DISSEMINATION: This systematic review will not involve human participants and requires no ethical approval. The results of this review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023400215.

Maternal exposure to ambient air temperature and adverse birth outcomes: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Multiple systematic reviews on prenatal ambient temperature and adverse birth outcomes exist, but the overall epidemiological evidence and the appropriate metric for thermal stress remain unclear. An umbrella review was performed to summarise and appraise the evidence with recommendations. METHODS: Systematic reviews and meta-analyses on the associations between ambient temperature and adverse birth outcomes (preterm birth, stillbirth, birth weight, low birth weight, and small for gestational age) up to December 20, 2023, were synthesised according to a published protocol. Databases PubMed, CINAHL, Scopus, MEDLINE/Ovid, EMBASE/Ovid, Web of Science Core Collection, systematic reviews repositories, electronic grey literature, and references were searched. Risk of bias was assessed using Joanna Briggs Institute's critical appraisal tool. RESULTS: Eleven systematic reviews, including two meta-analyses, were included. This comprised 90 distinct observational studies that employed multiple temperature assessment metrics with a very high overlap of primary studies. Primary studies were mostly from the United States while both Africa and South Asia contributed only three studies. A majority (7 out of 11) of the systematic reviews were rated as moderate risk of bias. All systematic reviews indicated that maternal exposures to both extremely high and low temperatures, particularly during late gestation are associated with increased risks of preterm birth, stillbirth, and reduced fetal growth. However, due to great differences in the exposure assessments, high heterogeneity, imprecision, and methodological limitations of the included systematic reviews, the overall epidemiological evidence was classified as probable evidence of causation. No study assessed biothermal metrics for thermal stress. CONCLUSIONS: Despite the notable methodological differences, prenatal exposure to extreme ambient temperatures, particularly during late pregnancy, was associated with adverse birth outcomes. Adhering to the appropriate systematic review guidelines for environmental health research, incorporating biothermal metrics into exposure assessment, evidence from broader geodemographic settings, and interventions are recommended in future studies.

The hidden impact of alcohol on young victims: an analysis of alcohol-related police offences resulting in hospitalisation.

BACKGROUND: Alcohol-related harm (ARH) is a significant public health concern affecting young individuals, particularly those involved in alcohol-related police incidents resulting in hospitalisation. However, the impact of alcohol on young victims remains under researched. This study aimed to identify the characteristics of offenders and victims involved in these incidents, analyse the types of offences, and understand the under-ascertainment of ARH in hospital records. METHODS: A retrospective longitudinal study of 12-24-year-olds born between 1980 and 2005 was conducted using linked data from hospital admissions, emergency department presentations, and police incident records. Alcohol-related incidents were identified based on the attending officers' opinions in the Western Australia Police's Incident Management System (IMS). Logistic and log-binomial regression were utilised to analyse the factors associated with victimisation and under-ascertainment of ARH. RESULTS: Our study included 22,747 individuals (11,433 victims and 11,314 offenders) involved in alcohol-related police incidents, with a small majority of victims being female (53%, n = 6,074) and a large majority of offenders being male (84.3%, n = 9,532). Most victims did not receive a diagnosis of ARH (71%, n = 760). Women were 10 times more likely to have been a victim in ARH police incidents and 2 times more likely to have an undiagnosed alcohol-related hospital admission than men. Victims and offenders predominantly came from disadvantaged areas and major cities. Aboriginal individuals were overrepresented as both offenders and victims. A significant proportion of individuals experienced emergency department presentations or hospital admissions, with head injuries being the most common. Assault causing bodily harm was the most prevalent offence resulting in hospitalisation (66%, n = 2,018). CONCLUSIONS: There is a noteworthy disparity between the quantity of hospital admissions attributed to alcohol-related incidents and the number of cases that are formally classified as ARH in the hospital system. This disparity highlights a more profound issue of substantial under-ascertainment or inadequate identification of ARH than previously acknowledged. Our findings justify the prioritisation of prevention strategies, beyond improvement in the documentation of alcohol-related hospitalisation. Considering the scale of the problem, and the underestimation of the burden of alcohol-related hospitalisation, a proportional increase in investment is necessary to achieve population-level reductions in ARH.

Interpregnancy interval and adverse birth outcomes: a population-based cohort study of twins.

BACKGROUND: To investigate associations between interpregnancy intervals (IPIs) and adverse birth outcomes in twin pregnancies. METHODS: This retrospective cohort study of 9,867 twin pregnancies in Western Australia from 1980-2015. Relative Risks (RRs) were estimated for the interval prior to the pregnancy (IPI) as the exposure and after the pregnancy as a negative control exposure for preterm birth (< 37 weeks), early preterm birth (< 34 weeks), small for gestational age (SGA: < 10th percentile of birth weight by sex and gestational age) and low birth weight (LBW: birthweight < 2,500 g). RESULTS: Relative to IPIs of 18-23 months, IPIs of < 6 months were associated with a higher risk of early preterm birth (aRR 1.41, 95% CI 1.08-1.83) and LBW for at least one twin (aRR 1.16, 95% CI 1.06-1.28). IPIs of 6-11 months were associated with a higher risk of SGA (aRR 1.24, 95% CI 1.01-1.54) and LBW for at least one twin (aRR 1.09, 95% CI 1.01-1.19). IPIs of 60-119 months and ≥ 120 months were associated with an increased risk of preterm birth (RR 1.12, 95% CI 1.03-1.22; and (aRR 1.25, 95% CI 1.10-1.41, respectively), and LBW for at least one twin (aRR 1.17, 95% CI 1.08-1.28; and aRR 1.20, 95% CI 1.05-1.36, respectively). IPIs of ≥ 120 months were also associated with an increased risk of early preterm birth (aRR 1.42, 95% CI 1.01-2.00). After negative control analysis, IPIs ≥ 120 months remained associated with early preterm birth and LBW. CONCLUSION: Evidence for adverse associations with twin birth outcomes was strongest for long IPIs.

Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study.

PURPOSE: To examine the association between endometriosis and adverse pregnancy and perinatal outcomes (preeclampsia, placenta previa, and preterm birth). METHODS: A population-based retrospective cohort study was conducted among 468,778 eligible women who contributed 912,747 singleton livebirths between 1980 and 2015 in Western Australia (WA). We used probabilistically linked perinatal and hospital separation data from the WA data linkage system's Midwives Notification System and Hospital Morbidity Data Collection databases. We used a doubly robust estimator by combining the inverse probability weighting with the outcome regression model to estimate adjusted risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: There were 19,476 singleton livebirths among 8874 women diagnosed with endometriosis. Using a doubly robust estimator, we found pregnancies in women with endometriosis to be associated with an increased risk of preeclampsia with RR of 1.18, 95% CI 1.11-1.26, placenta previa (RR 1.59, 95% CI 1.42-1.79) and preterm birth (RR 1.45, 95% CI 1.37-1.54). The observed association persisted after stratified by the use of Medically Assisted Reproduction, with a slightly elevated risk among pregnancies conceived spontaneously. CONCLUSIONS: In this large population-based cohort, endometriosis is associated with an increased risk of preeclampsia, placenta previa, and preterm birth, independent of the use of Medically Assisted Reproduction. This may help to enhance future obstetric care among this population.

Influence of preterm birth on the association between gestational diabetes mellitus and childhood developmental vulnerability: a causal mediation analysis.

BACKGROUND: Epidemiological studies examining the direct and indirect effects of gestational diabetes mellitus (GDM) on offspring early childhood developmental vulnerability are lacking. Therefore, the aims of this study were to estimate the direct and indirect effects of GDM (through preterm birth) on early childhood developmental vulnerability. METHODS: We conducted a retrospective population-based cohort study on the association between gestational diabetes mellitus and early childhood developmental vulnerability in children born in Western Australia (WA) using maternal, infant and birth records from the Midwives Notification, Hospitalizations, Developmental Anomalies, and the Australian Early Development Census (AEDC) databases. We used two aggregated outcome measures: developmentally vulnerable on at least one AEDC domain (DV1) and developmentally vulnerable on at least two AEDC domains (DV2). Causal mediation analysis was applied to estimate the natural direct (NDE), indirect (NIE), and total (TE) effects as relative risks (RR). RESULTS: In the whole cohort (n = 64,356), approximately 22% were classified as DV1 and 11% as DV2 on AEDC domains. Estimates of the natural direct effect suggested that children exposed to GDM were more likely to be classified as DV1 (RR = 1.20, 95% CI: 1.10-1.31) and DV2 (RR = 1.34, 95% CI: 1.19-1.50) after adjusting for potential confounders. About 6% and 4% of the effect of GDM on early childhood developmental vulnerability was mediated by preterm birth for DV1 and DV2, respectively. CONCLUSION: Children exposed to gestational diabetes mellitus were more likely to be developmentally vulnerable in one or more AEDC domains. The biological mechanism for these associations is not well explained by mediation through preterm birth.

Assessing the utility of night-time presentations as a proxy for alcohol-related harm among young emergency department trauma patients.

OBJECTIVE: To assess the usefulness of night-time presentations to measure alcohol-related harm (ARH) in young trauma patients, aged 12-24 years, attending Western Australian EDs. METHODS: A retrospective longitudinal study examined alcohol-related ED presentations in Western Australia (WA; 2002-2016) among 12- to 24-year-olds. Data from the Emergency Department Data Collection, WA State Trauma Registry Database and Hospital Morbidity Data Collection were used to identify ARH through specific codes and text searches. These were compared to ARH estimates based on presentation time. Statistical analysis involved sensitivity and specificity calculations and Cox proportional hazards modelling. RESULTS: We identified 2644 (17.8%) night-time presentations as a proxy measure of ARH among the 14 887 presentations of patients aged 12-24 years. This closely matched the 3064 (20.6%) identified as ARH through coding methods. The highest risk for an ARH presentation occurred during the night hours between 00.00 and 04.59 hours. During these hours, the risk was 4.4-5.1 times higher compared to presentations at midday (between 12.00 and 12.59 hours). However, when looking at individual patients, we observed that night-time presentations were not a strong predictor of ARH (sensitivity: 0.39; positive predictive value: 0.46). CONCLUSIONS: Implementing targeted interventions during night hours could be beneficial in addressing ARH presentations. However, relying solely on the time of presentation as a proxy for ARH is unlikely to effectively identify ARH in young individuals. Instead, the present study emphasises the importance of implementing mandatory data collection strategies in EDs to ensure accurate measurement of ARH cases.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Determinants and geographic distribution of early newborn care in Ethiopia: evidence from the 2019 Ethiopian Mini Demographic Health Survey.

Early newborn care provided in the first 2 days of life is critical in reducing neonatal morbidity and mortality. This care can be used to monitor and evaluate the content and quality of neonatal postnatal care. This study aimed to identify determinants and geographic distributions of early newborn care uptake in Ethiopia. We used data from the 2019 Ethiopian Mini Demographic and Health Survey (EMDHS). We conducted a multilevel binary logistic regression model and geographic analysis to identify the determinants of receiving early newborn care. A total of 2105 children were included in the study. Of the included children, 39.6% (95% confidence interval (CI) 38%, 42%) received at least two components of early newborn care services in the first 2 days after birth. Greater odds of receiving early newborn care were experienced by infants to mothers with secondary or above education (adjusted odds ratio (AOR) = 1.72; 95% CI 1.44, 2.18), from households with highest wealth quantiles (AOR = 1.47; 95% CI 1.16, 1.79), with at least one antenatal care contact (AOR = 2.73; 95% CI 1.79, 4.16), with birth at health facility (AOR = 25.63; 95% CI 17.02, 38.60), and those births through cesarean section (AOR = 2.64; 95% CI 1.48, 4.71). Substantial geographic variation was observed in the uptake of early newborn care in Ethiopia. Several individual- and community-level factors were associated with newborn postnatal care. Policymakers should prioritise these areas and the enhancement of postnatal healthcare provisions for mothers with low socioeconomic status.

Critical Windows of Maternal Exposure to Biothermal Stress and Birth Weight for Gestational Age in Western Australia.

BACKGROUND: There is limited and inconsistent evidence on the risk of ambient temperature on small for gestational age (SGA) and there are no known related studies for large for gestational age (LGA). In addition, previous studies used temperature rather than a biothermal metric. OBJECTIVES: Our aim was to examine the associations and critical susceptible windows of maternal exposure to a biothermal metric [Universal Thermal Climate Index (UTCI)] and the hazards of SGA and LGA. METHODS: We linked 385,337 singleton term births between 1 January 2000 and 31 December 2015 in Western Australia to daily spatiotemporal UTCI. Distributed lag nonlinear models with Cox regression and multiple models were used to investigate maternal exposure to UTCI from 12 weeks preconception to birth and the adjusted hazard ratios (HRs) of SGA and LGA. RESULTS: Relative to the median exposure, weekly and monthly specific exposures showed potential critical windows of susceptibility for SGA and LGA at extreme exposures, especially during late gestational periods. Monthly exposure showed strong positive associations from the 6th to the 10th gestational months with the highest hazard of 13% for SGA (HR=1.13; 95% CI: 1.10, 1.14) and 7% for LGA (HR=1.07; 95% CI: 1.03, 1.11) at the 10th month for the 1st UTCI centile. Entire pregnancy exposures showed the strongest hazards of 11% for SGA (HR=1.11; 95% CI: 1.04, 1.18) and 3% for LGA (HR=1.03; 95% CI: 0.95, 1.11) at the 99th UTCI centile. By trimesters, the highest hazards were found during the second and first trimesters for SGA and LGA, respectively, at the 99th UTCI centile. Based on estimated interaction effects, male births, mothers who were non-Caucasian, smokers, ≥35 years of age, and rural residents were most vulnerable. CONCLUSIONS: Both weekly and monthly specific extreme biothermal stress exposures showed potential critical susceptible windows of SGA and LGA during late gestational periods with disproportionate sociodemographic vulnerabilities. https://doi.org/10.1289/EHP12660.

Prediction Models for Adverse Pregnancy Outcomes in India: Methodological Considerations for an Emerging Topic.

Stillbirth is over-represented in lower and lower-middle-income countries and understandably this has motivated greater research investment in the development of prediction models. Prediction is particularly challenging for pregnancy outcomes because only part of the population is represented in observational research. Notably, unrecognised pregnancies and miscarriages are typically excluded from the development of prediction models and the consequences of such selection are not well understood. Other methodological challenges in developing stillbirth prediction models are within the control of the researcher. Identifying whether the intended model is for aetiological explanation versus prediction, attainment of a sufficiently large representative sample, and internal and external validation are among such methodological considerations. These considerations are discussed in relation to a recently published study on prediction of stillbirth after 28 weeks of pregnancy for women with hypertensive disorders of pregnancy in India. The predictive ability of this model amounts to the flip of a coin. Future screening based on such a model may be expensive, increase psychological distress among patients and introduce additional iatrogenic perinatal morbidities from over-treatment. Future research should address the methodological considerations described in this article.

Overweight/obesity and other predictors of gestational diabetes among Aboriginal and non-Aboriginal women in Western Australia.

This population-based study investigated the association of BMI and other predictors with gestational diabetes mellitus (GDM) among Australian Aboriginal and non-Aboriginal mothers. We conducted a state-wide retrospective cohort study that included all singleton births in Western Australia (n = 134,552) between 2012 and 2015 using population health datasets linked by the Western Australian Data Linkage Branch. Associations between GDM and its predictors were estimated as adjusted relative risks (aRRs) from multivariable generalised linear models. Adjusted ratio of relative risks (aRRRs) compared RRs in Aboriginal and non-Aboriginal mothers. Adjusted population attributable fractions estimated the contribution of overweight/obesity to GDM burden, and adjusted predicted probabilities for GDM were plotted against BMI levels. The following predictors had stronger associations with GDM in Aboriginal, compared to non-Aboriginal, mothers: maternal obesity (aRR [95% CI] 3.16 [2.54-3.93]; aRRR 1.57 [1.26-1.94]), previous LGA (aRR 1.70 [1.37-2.12]; aRRR 1.41 [1.13-1.76]) and previous macrosomia (birthweight ≥ 4 kg) (aRR 1.55 [1.24-1.94]; aRRR 1.53 [1.22-1.91]). 46.1% (95% CI: 36.6-54.1) of GDM cases in Aboriginal women (23.3% in non-Aboriginal mothers, 95% CI: 21.6-25.1) were attributed to overweight/obesity. Compared to non-Aboriginal mothers, adjusted GDM probabilities were higher at all BMI levels and showed greater increase with BMI. Overweight/obesity is a key driver of GDM among Aboriginal women. Association between BMI and GDM is stronger in Aboriginal, compared to non-Aboriginal, women especially at higher BMI.

Antioxidant activities, phenolic compounds, and mineral composition of seed from Acacia retinodes, A. Provincialis and A. Tenuissima.

Seeds of the species Acacia retinodes, A. provincialis, and A. tenuissima) from different growing locations were analysed for their mineral composition, free and bound polyphenols, and flavonoids. Previous research has studied these compounds in only a limited number of Acacia species, and only one study reports significant differences between three species. All species were rich in potassium (353 - 427 mg/100 g), sodium (14 - 240 mg/100 g) and iron (7 - 8 mg/100 g). The free polyphenol extracts of all species had higher total phenolic content, total flavonoid content and antioxidant activities than their bound counterparts, indicating the possibility of higher bioavailability than the bound polyphenol extracts. The predominant phenolic compounds found in the Acacia polyphenol seed extracts were 6-Hydroxy-2-methylindole and 2,2'-Methylenebis(6-tert-butyl-methylphenol), though no phenolic compounds were identified in the bound extracts of A. retinodes Grampians and A. provincialis Tarrington. Other compounds identified in the seed extracts include sucrose, d-fructofuranose and d-pinitol.

Maternal Pertussis Vaccination, Infant Immunization, and Risk of Pertussis.

OBJECTIVES: Following the introduction of jurisdictional maternal pertussis vaccination programs in Australia, we estimated maternal vaccine effectiveness (VE) and whether maternal pertussis vaccination modified the effectiveness of the first 3 primary doses of pertussis-containing vaccines. METHODS: We conducted a population-based cohort study of 279 418 mother-infant pairs using probabilistic linkage of administrative health records in 3 Australian jurisdictions. Infants were maternally vaccinated if their mother had a documented pertussis vaccination ≥14 days before birth. Jurisdictional immunization records were used to identify receipt of the first 3 infant doses of pertussis-containing vaccines. Infant pertussis infections were identified using notifiable disease records. VE was estimated using Cox proportional hazard models. RESULTS: Pertussis was administered during 51.7% (n = 144 429/279 418) of pregnancies, predominantly at 28-31 weeks' gestation. VE of maternal pertussis vaccination declined from 70.4% (95% confidence interval [CI], 50.5-82.3) among infants <2 months old to 43.3% (95% CI, 6.8-65.6) among infants 7-8 months old and was not significant after 8 months of age. Although we observed slightly lower VE point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% CI, 0.61-3.39). CONCLUSIONS: Pertussis vaccination near 28 weeks' gestation was associated with lower risk of infection among infants through 8 months of age. Although there was some evidence of lower effectiveness of infant vaccination among maternally vaccinated infants, this did not appear to translate to greater risk of disease.

Fluoride-induced apoptosis in non-skeletal tissues of experimental animals: A systematic review and meta-analysis.

Different studies have suggested that fluoride can induce apoptosis in non-skeletal tissues, however, evidence from these experimental studies is still controversial. This meta-analysis aims to clarify the mechanism of fluoride-induced apoptosis in non-skeletal tissues of experimental animals. Primary studies which measured apoptosis were identified through exhaustive database searching in PubMed, Embase, Web of Science Core Collection, Scopus, and references of included studies. A random effects model with standardized mean difference (SMD) was used for meta-analyses. The heterogeneity of the studies was evaluated using Higgin's I2 statistics. The risk of bias and publication bias were assessed using the SYRCLE's risk of bias tool and Egger's test, respectively. There was an increase in total apoptotic cells, and the expression of Bax, Bax/Bcl-2 ratio, caspase-3, caspase-8, caspase-9, Cyt c, and p53, and a decrease in the expression of Bcl-2 in the fluoride-treated groups as compared to the control groups. However, there was no evidence of a difference in the expression of APAF-1 in the two groups. The subgroup analysis highlighted the role of the intervention period in modification of the apoptotic effect of fluoride and that the susceptibility and tolerance of different animal species and tissues vary. Meta-regression analysis indicated that the studies' effect size for total apoptotic cells was influenced by animal species and that of Bax by the sample source. The results of this meta-analysis revealed that fluoride causes apoptosis by up-regulating caspase-3, -8, and -9, Cyt c, p53, Bax, and down-regulating Bcl-2 with a concomitant up-regulation of the Bax/Bcl-2 ratio.