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.

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.

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.

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-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). 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 for each patient. 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, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. Conclusions: Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevance: Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.

Prevalence and risk factors associated with under-five mortality in the Solomon Islands: an investigation from the 2015 Solomon Islands demographic and health survey data.

Background: Annually, over five million children die before their fifth birthday worldwide, with 98% of these deaths occurring in low-and middle-income countries. The prevalence and risks for under-five mortality are not well-established for the Solomon Islands. Methods: We used the Solomon Islands Demographic and Health Survey 2015 data (SIDHS 2015) to estimate the prevalence and risk factors associated with under-five mortality. Findings: Neonatal, infant, child and under-five mortality prevalence were 8/1000, 17/1000, 12/1000 and 21/1000 live births, respectively. After adjustment for potential confounders, neonatal mortality was associated with no breastfeeding [aRR 34.80 (13.60, 89.03)], no postnatal check [aRR 11.36 (1.22, 106.16)], and Roman Catholic [aRR 3.99 (1.34, 11.88)] and Anglican [aRR 2.78 (0.89, 8.65); infant mortality to no breastfeeding [aRR 11.85 (6.15, 22.83)], Micronesian [aRR 5.54 (1.67, 18.35)], and higher birth order [aRR 2.00 (1.03, 3.88)]; child mortality to multiple gestation [aRR 6.15 (2.08, 18.18)], Polynesian [aRR 5.80 (2.48, 13.53)], and Micronesian [aRR 3.65 (1.46, 9.10)], cigarette and tobacco [aRR 1.77 (0.79, 3.96)] and marijuana use [aRR 1.94 (0.43, 8.73)] and rural residence [aRR 1.85 (0.88, 3.92)]; under-five mortality to no breastfeeding [aRR 8.65 (4.97, 15.05)], Polynesian [aRR 3.23 (1.09, 9.54)], Micronesian [aRR 5.60 (2.52, 12.46)], and multiple gestation [aRR 3.34 (1.26, 8.88)]. Proportions of 9% for neonatal and 8% of under-five mortality were attributable to no maternal tetanus vaccination. Interpretation: Under-five mortality in the Solomon Islands from the SIDHS 2015 data was attributable to maternal health, behavioural, and sociodemographic risk factors. We recommended future studies to confirm these associations. Funding: No funding was declared to support this study directly.

Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer.

PURPOSE: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response. EXPERIMENTAL DESIGN: We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy. RESULTS: Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging. CONCLUSIONS: ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring. See related commentary by Pellini and Chaudhuri, p. 2176.

Prevalence and Factors Associated With Low Birth Weight in the Solomon Islands: Evidence From the 2015 Solomon Islands Demographic and Health Survey data.

Low birth weight (LBW) has contributed to more than 80% of under-5 deaths worldwide, most occurring in low- and middle-income countries. We used the 2015 Solomon Islands Demographic and Health Survey data to identify the prevalence and risks associated with LBW in the Solomon Islands. Low birth weight prevalence estimated was 10%. After adjustment for potential confounders, we found the risk of LBW for women with a history of marijuana and kava use was 2.6 times, adjusted relative risk (aRR) 2.64 and 2.5 times (aRR: 2.50) than among unexposed women, respectively. Polygamous relationship, no antenatal care, decision-making by another person were 84% (aRR: 1.84), 73% (aRR: 1.73), and 73% (aRR: 1.73) than among unexposed women, respectively. We also found that 10% and 4% of LBW cases in the Solomon Islands were attributable to a household of more than five members and tobacco and cigarette use history respectively. We concluded that LBW in the Solomon Islands relied more on behavioral risk factors, including substance use as well as health and social risk factors. We recommended further study on kava use and its impact on pregnancy and LBW.

Artificial intelligence (AI) for breast cancer screening: BreastScreen population-based cohort study of cancer detection.

BACKGROUND: Artificial intelligence (AI) has been proposed to reduce false-positive screens, increase cancer detection rates (CDRs), and address resourcing challenges faced by breast screening programs. We compared the accuracy of AI versus radiologists in real-world population breast cancer screening, and estimated potential impacts on CDR, recall and workload for simulated AI-radiologist reading. METHODS: External validation of a commercially-available AI algorithm in a retrospective cohort of 108,970 consecutive mammograms from a population-based screening program, with ascertained outcomes (including interval cancers by registry linkage). Area under the ROC curve (AUC), sensitivity and specificity for AI were compared with radiologists who interpreted the screens in practice. CDR and recall were estimated for simulated AI-radiologist reading (with arbitration) and compared with program metrics. FINDINGS: The AUC for AI was 0.83 compared with 0.93 for radiologists. At a prospective threshold, sensitivity for AI (0.67; 95% CI: 0.64-0.70) was comparable to radiologists (0.68; 95% CI: 0.66-0.71) with lower specificity (0.81 [95% CI: 0.81-0.81] versus 0.97 [95% CI: 0.97-0.97]). Recall rate for AI-radiologist reading (3.14%) was significantly lower than for the BSWA program (3.38%) (-0.25%; 95% CI: -0.31 to -0.18; P < 0.001). CDR was also lower (6.37 versus 6.97 per 1000) (-0.61; 95% CI: -0.77 to -0.44; P < 0.001); however, AI detected interval cancers that were not found by radiologists (0.72 per 1000; 95% CI: 0.57-0.90). AI-radiologist reading increased arbitration but decreased overall screen-reading volume by 41.4% (95% CI: 41.2-41.6). INTERPRETATION: Replacement of one radiologist by AI (with arbitration) resulted in lower recall and overall screen-reading volume. There was a small reduction in CDR for AI-radiologist reading. AI detected interval cases that were not identified by radiologists, suggesting potentially higher CDR if radiologists were unblinded to AI findings. These results indicate AI's potential role as a screen-reader of mammograms, but prospective trials are required to determine whether CDR could improve if AI detection was actioned in double-reading with arbitration. FUNDING: National Breast Cancer Foundation (NBCF), National Health and Medical Research Council (NHMRC).

Rates of reoperation after breast conserving cancer surgery in Western Australia before and after publication of the SSO-ASTRO margins guideline.

BACKGROUND: A 2014 SSO-ASTRO guideline on surgical margins aimed to reduce unnecessary reoperation after breast conserving surgery (BCS). We investigate whether publication of the guideline was associated with a reduction in reoperation in Western Australia (WA). METHODS: In this retrospective, population-based cohort study, cases of newly-diagnosed breast cancer were identified from the WA Cancer Registry. Linkage to the Hospital Morbidity Data Collection identified index BCS for invasive cancer between January 2009 and June 2018 (N = 8059) and reoperation within 90 days. Pre-guideline (2009-2013) and post-guideline (2014-2018) reoperation proportions were compared, and temporal trends were estimated with generalised linear regression. RESULTS: The pre-guideline reoperation proportion was 25.8% compared with 21.7% post-guideline (difference -4.0% [95% CI -5.9, -2.2, p < 0.001], odds ratio [OR] 0.80 [95% CI 0.72, 0.89, p < 0.001]). Absolute reductions were similar for repeat BCS (16.3% versus 14.6%; difference -1.8% [95% CI -3.4, -0.2, p = 0.03]) and conversion to mastectomy (9.4% versus 7.2%; difference -2.2% [95% CI -3.4, -1.0, p < 0.001]). Over the study period, there was an annual absolute change in reoperation of -0.8% (95% CI -1.2, -0.5, p < 0.001). Accounting for this linear trend, the difference in reoperation between time periods was -0.5% (95% CI -4.3, 3.3; p = 0.81), reflecting a non-significant reduction in conversion to mastectomy. CONCLUSIONS: Comparisons of pre- versus post-guideline time periods in WA showed reductions in reoperation that were similar to international estimates; however, an annual decline in reoperation predated the guideline. Analyses that do not account for temporal trends are likely to overestimate changes in reoperation associated with the guideline.

Average treatment effect of maternal prenatal tobacco smoking on offspring developmental vulnerability in early childhood.

BACKGROUND: Early childhood developmental vulnerability has been closely related to the predictors of relatively good health, social and educational outcomes later in adulthood. However, the impacts of prenatal tobacco exposure on childhood developmental vulnerability have been rarely examined. Further, a few of the studies that have investigated maternal prenatal tobacco smoking and child developmental vulnerability have reported mixed results and there are currently no published estimates derived from causal epidemiological methods. METHODS: We conducted a retrospective population-based cohort study on the association between maternal prenatal tobacco smoking and developmental vulnerability in children born in Western Australia (WA). De-identified individual-level maternal, infant and birth records were obtained from the Midwives Notification System (MNS), a statutory record of all births in WA. WA register for Developmental Anomalies (WARDA) were also obtained from the WA Data Linkage. Records on early childhood developmental vulnerability at the median age of 5 years were obtained from the Australian Early Development Census (AEDC). We used a doubly robust estimator to estimate the causal effects. RESULTS: Complete data were available for 64,558 mothers-children's pairs. Approximately 16% of children were exposed to maternal prenatal tobacco smoking. Children exposed to maternal prenatal tobacco smoking were more likely to be classified as developmentally vulnerable/at-risk on the physical health and wellbeing (RR = 1.40, 95%CI:1.36-1.45), social competence (RR = 1.42, 95%CI: 1.38-1.47), emotional maturity (RR = 1.34, 95%CI:1.30-1.39), language and cognitive skills (RR = 1.50, 95%CI:1.45-1.54), and communication skills and general knowledge (RR = 1.37, 95%CI:1.33-1.42) domains. CONCLUSION: Maternal prenatal exposure to tobacco may influence early childhood developmental vulnerability. Early intervention to quit tobacco smoking before becoming pregnant could potentially reduce later childhood developmental vulnerability on multiple domains.

Interpregnancy interval and adverse pregnancy outcomes among pregnancies following miscarriages or induced abortions in Norway (2008-2016): A cohort study.

BACKGROUND: The World Health Organization recommends to wait at least 6 months after miscarriage and induced abortion before becoming pregnant again to avoid complications in the next pregnancy, although the evidence-based underlying this recommendation is scarce. We aimed to investigate the risk of adverse pregnancy outcomes-preterm birth (PTB), spontaneous PTB, small for gestational age (SGA) birth, large for gestational age (LGA) birth, preeclampsia, and gestational diabetes mellitus (GDM)-by interpregnancy interval (IPI) for births following a previous miscarriage or induced abortion. METHODS AND FINDINGS: We conducted a cohort study using a total of 49,058 births following a previous miscarriage and 23,707 births following a previous induced abortion in Norway between 2008 and 2016. We modeled the relationship between IPI and 6 adverse pregnancy outcomes separately for births after miscarriages and births after induced abortions. We used log-binomial regression to estimate unadjusted and adjusted relative risk (aRR) and 95% confidence intervals (CIs). In the adjusted model, we included maternal age, gravidity, and year of birth measured at the time of the index (after interval) births. In a sensitivity analysis, we further adjusted for smoking during pregnancy and prepregnancy body mass index. Compared to births with an IPI of 6 to 11 months after miscarriages (10.1%), there were lower risks of SGA births among births with an IPI of <3 months (8.6%) (aRR 0.85, 95% CI: 0.79, 0.92, p < 0.01) and 3 to 5 months (9.0%) (aRR 0.90, 95% CI: 0.83, 0.97, p = 0.01). An IPI of <3 months after a miscarriage (3.3%) was also associated with lower risk of GDM (aRR 0.84, 95% CI: 0.75, 0.96, p = 0.01) as compared to an IPI of 6 to 11 months (4.5%). For births following an induced abortion, an IPI <3 months (11.5%) was associated with a nonsignificant but increased risk of SGA (aRR 1.16, 95% CI: 0.99, 1.36, p = 0.07) as compared to an IPI of 6 to 11 months (10.0%), while the risk of LGA was lower among those with an IPI 3 to 5 months (8.0%) (aRR 0.84, 95% CI: 0.72, 0.98, p = 0.03) compared to an IPI of 6 to 11 months (9.4%). There was no observed association between adverse pregnancy outcomes with an IPI >12 months after either a miscarriage or induced abortion (p > 0.05), with the exception of an increased risk of GDM among women with an IPI of 12 to 17 months (5.8%) (aRR 1.20, 95% CI: 1.02, 1.40, p = 0.02), 18 to 23 months (6.2%) (aRR 1.24, 95% CI: 1.02, 1.50, p = 0.03), and ≥24 months (6.4%) (aRR 1.14, 95% CI: 0.97, 1.34, p = 0.10) compared to an IPI of 6 to 11 months (4.5%) after a miscarriage. Inherent to retrospective registry-based studies, we did not have information on potential confounders such as pregnancy intention and health-seeking bahaviour. Furthermore, we only had information on miscarriages that resulted in contact with the healthcare system. CONCLUSIONS: Our study suggests that conceiving within 3 months after a miscarriage or an induced abortion is not associated with increased risks of adverse pregnancy outcomes. In combination with previous research, these results suggest that women could attempt pregnancy soon after a previous miscarriage or induced abortion without increasing perinatal health risks.

Sex-specific differences in immunogenomic features of response to immune checkpoint blockade.

Introduction: The magnitude of response to immune checkpoint inhibitor (ICI) therapy may be sex-dependent, as females have lower response rates and decreased survival after ICI monotherapy. The mechanisms underlying this sex dimorphism in ICI response are unknown, and may be related to sex-driven differences in the immunogenomic landscape of tumors that shape anti-tumor immune responses in the context of therapy. Methods: To investigate the association of immunogenic mutations with HLA haplotypes, we leveraged whole exome sequence data and HLA genotypes from 482 non-small cell lung cancer (NSCLC) tumors from The Cancer Genome Atlas (TCGA). To explore sex-specific genomic features linked with ICI response, we analyzed whole exome sequence data from patients with NSCLC treated with ICI. Tumor mutational burden (TMB), HLA class I and II restricted immunogenic missense mutation (IMM) load, and mutational smoking signature were defined for each tumor. IMM load was combined with HLA class I and II haplotypes and correlated with therapeutic response and survival following ICI treatment. We examined rates of durable clinical benefit (DCB) for at least six months from ICI treatment initiation. Findings were validated utilizing whole exome sequence data from an independent cohort of ICI treated NSCLC. Results: Analysis of whole exome sequence data from NSCLC tumors of females and males revealed that germline HLA class II diversity (≥9 unique HLA alleles) was associated with higher tumor class II IMM load in females (p=0.01) and not in males (p=0.64). Similarly, in tumors of female patients, somatic HLA class II loss of heterozygosity was associated with increased IMM load (p=0.01) while this association was not observed in tumors in males (p=0.20). In females, TMB (p=0.005), class I IMM load (p=0.005), class II IMM load (p=0.004), and mutational smoking signature (p<0.001) were significantly higher in tumors responding to ICI as compared to non-responding tumors. In contrast, among males, there was no significant association between DCB and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017). Conclusions: Inherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICI and likely mediate the dimorphic outcomes with ICI therapy. Deeper understanding of the selective pressures and mechanisms of immune escape in tumors in males and females can inform patient selection strategies and can be utilized to further hone immunotherapy approaches in cancer.

Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy.

BACKGROUND: Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor-immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade. METHODS: Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance. RESULTS: Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts. CONCLUSIONS: Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.

Maternal acute thermophysiological stress and stillbirth in Western Australia, 2000-2015: A space-time-stratified case-crossover analysis.

BACKGROUND: The extreme thermal environment driven by climate change disrupts thermoregulation in pregnant women and may threaten the survival of the developing fetus. OBJECTIVES: To investigate the acute effect of maternal exposure to thermophysiological stress (measured with Universal Thermal Climate Index, UTCI) on the risk of stillbirth and modification of this effect by sociodemographic disparities. METHODS: We conducted a space-time-stratified case-crossover analysis of daily UTCI and 2835 singleton stillbirths between 1st January 2000 and 31st December 2015 across multiple small areas in Western Australia. Distributed lag non-linear models were combined with conditional quasi-Poisson regression to investigate the effects of the UTCI exposure from the preceding 6 days to the day of stillbirth. We also explored effect modification by fetal and maternal sociodemographic factors. RESULTS: The median UTCI was 13.9 °C (representing no thermal stress) while the 1st and 99th percentiles were 0.7 °C (slight cold stress) and 31.7 °C (moderate heat stress), respectively. Relative to median UTCI, we found positive associations between acute maternal cold and heat stresses and higher risks of stillbirth, increasing with the intensity and duration of the thermal stress episodes. The cumulative risk from the preceding 6 days to the day of stillbirth was stronger in the 99th percentile (RR = 1.19, 95% CI: 1.17, 1.21) than the 1st percentile (RR = 1.14, 95% CI: 1.12, 1.15), relative to the median UTCI. The risks were disproportionately higher in term and male stillborn fetuses, smoking, unmarried, ≤19 years old, non-Caucasian, and low socioeconomic status mothers. DISCUSSION: Acute maternal exposure to both cold and heat stresses may contribute to the risk of stillbirth and be exacerbated by sociodemographic disparities. The findings suggest public health attention, especially for the identified higher-risk groups. Future studies should consider the use of a human thermophysiological index, rather than surrogates such as ambient temperature.

Prenatal influenza vaccination and allergic and autoimmune diseases in childhood: A longitudinal, population-based linked cohort study.

BACKGROUND: Few studies have evaluated the effect of maternal influenza vaccination on the development of allergic and autoimmune diseases in children beyond 6 months of age. We aimed to investigate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and subsequent diagnosis of allergic and autoimmune diseases. METHODS AND FINDINGS: This longitudinal, population-based linked cohort study included 124,760 singleton, live-born children from 106,206 mothers in Western Australia (WA) born between April 2012 and July 2016, with up to 5 years of follow-up from birth. In our study cohort, 64,169 (51.4%) were male, 6,566 (5.3%) were Aboriginal and/or Torres Strait Islander children, and the mean age at the end of follow-up was 3.0 (standard deviation, 1.3) years. The exposure was receipt of seasonal IIV during pregnancy. The outcomes were diagnosis of an allergic or autoimmune disease, including asthma and anaphylaxis, identified from hospital and/or emergency department (ED) records. Inverse probability of treatment weights (IPTWs) accounted for baseline probability of vaccination by maternal age, Aboriginal and/or Torres Strait Islander status, socioeconomic status, body mass index, parity, medical conditions, pregnancy complications, prenatal smoking, and prenatal care. The models additionally adjusted for the Aboriginal and/or Torres Strait Islander status of the child. There were 14,396 (11.5%) maternally vaccinated children; 913 (6.3%) maternally vaccinated and 7,655 (6.9%) maternally unvaccinated children had a diagnosis of allergic or autoimmune disease, respectively. Overall, maternal influenza vaccination was not associated with diagnosis of an allergic or autoimmune disease (adjusted hazard ratio [aHR], 1.02; 95% confidence interval [CI], 0.95 to 1.09). In trimester-specific analyses, we identified a negative association between third trimester influenza vaccination and the diagnosis of asthma (n = 40; aHR, 0.70; 95% CI, 0.50 to 0.97) and anaphylaxis (n = 36; aHR, 0.67; 95% CI, 0.47 to 0.95).We did not capture outcomes diagnosed in a primary care setting; therefore, our findings are only generalizable to more severe events requiring hospitalization or presentation to the ED. Due to small cell sizes (i.e., <5), estimates could not be determined for all outcomes after stratification. CONCLUSIONS: In this study, we observed no association between in utero exposure to influenza vaccine and diagnosis of allergic or autoimmune diseases. Although we identified a negative association of asthma and anaphylaxis diagnosis when seasonal IIV was administered later in pregnancy, additional studies are needed to confirm this. Overall, our findings support the safety of seasonal inactivated influenza vaccine during pregnancy in relation to allergic and autoimmune diseases in early childhood and support the continuation of current global maternal vaccine programs and policies.

Prevalence and risk factors of adverse birth outcomes in the Pacific Island region: A scoping review.

BACKGROUND: Prevalence and exposures of adverse birth outcomes is well studied in low-and-middle-income countries but not well-established for the Pacific Island region. Our study mapped the available evidence on low birth weight (LBW), preterm birth, and small for gestational age (SGA)'s prevalence and their corresponding risks in the region. METHODS: We followed the five-staged Arksey and O'Malley's framework with clinicians' consultation in the region. Five scholarly databases and non-indexed studies were searched and extracted data were analysed as numerical and thematic summaries mapping the outcomes and exposures. FINDINGS: We included 20 studies representing 11 Pacific Island countries with the following mean prevalence and associations at 95% confidence interval. Estimated mean prevalence for LBW and preterm births were 12% and 13%, respectively. LBW were associated with malaria in pregnancy [aOR 3.3 (1.00, 10.60)], and betel nut and tobacco [aOR 2.4 (1.00, 6.00)]. Preterm births were associated with malaria in pregnancy [aOR 6.6 (2.46, 17.62)] and maternal obesity [aOR 1.5 (1.00, 2.30)]. SGA were associated with short stature [aOR 1.7 (1.22, 2.41)] and no antenatal bookings [aOR 4.0 (2.12, 7.57)]. INTERPRETATION: Several significant factors identified were malaria infection, obesity, betel nut and tobacco and no antenatal care, also validated by clinicians consulted. FUNDING: Australia National Health and Medical Research Council.

Maternal and neonatal outcomes of women with gestational diabetes and without specific medical conditions: an Australian population-based study comparing induction of labor with expectant management.

BACKGROUND/AIMS: To evaluate maternal birth and neonatal outcomes among women with gestational diabetes mellitus (GDM), but without specific medical conditions and eligible for vaginal birth who underwent induction of labour (IOL) at term compared with those who were expectantly managed. MATERIALS AND METHODS: Population-based cohort study of women with GDM, but without medical conditions, who had a singleton, cephalic birth at 38-41 completed weeks gestation, in New South Wales, Australia between January 2010 and December 2016. Women who underwent IOL at 38, 39, 40 weeks gestation (38-, 39-, 40-induction groups) were compared with those who were managed expectantly and gave birth at and/or beyond the respective gestational age group (38-, 39-, 40-expectant groups). Multivariable logistic regression analysis was used to assess the association between IOL and adverse maternal birth and neonatal outcomes taking into account potential confounding by maternal age, country of birth, smoking, residential location, residential area of socioeconomic disadvantage and birth year. RESULTS: Of 676 762 women who gave birth during the study period, 66 606 (10%) had GDM; of these, 34799 met the inclusion criteria. Compared with expectant management, those in 38- (adjusted odds ratio (aOR) 1.11; 95% CI, 1.04-1.18), 39- (aOR 1.21; 95% CI, 1.14-1.28) and 40- (aOR 1.50; 95% CI, 1.40-1.60) induction groups had increased risk of caesarean section. Women in the 38-induction group also had an increased risk of composite neonatal morbidity (aOR 1.10; 95% CI, 1.01-1.21), which was not observed at 39- and 40-induction groups. We found no difference between groups in perinatal death or neonatal intensive care unit admission for births at any gestational age. CONCLUSION: In women with GDM but without specific medical conditions and eligible for vaginal birth, IOL at 38, 39, 40 weeks gestation is associated with an increased risk of caesarean section.

Prenatal tobacco and alcohol exposures and the risk of anxiety symptoms in young adulthood: A population-based cohort study.

BACKGROUND: Epidemiological studies have linked prenatal tobacco and alcohol exposures to internalizing behaviours in children and adolescents with inconsistent findings. Dearth of epidemiological studies have investigated the associations with the risk of experiencing symptoms of anxiety in young adulthood. METHODS: Study participants (N = 1190) were from the Raine Study, a population-based prospective birth cohort based in Perth, Western Australia. Data on prenatal tobacco and alcohol exposures were available for the first and third trimesters of pregnancy. Experiencing symptoms of anxiety in young adulthood at age 20 years was measured by a short form of the Depression Anxiety Stress Scale (DASS 21). Relative risk (RR) of experiencing symptoms of anxiety in young adulthood for prenatal tobacco and alcohol exposures were estimated with log binomial regression. RESULTS: After adjusting for potential confounders, we observed increased risks of experiencing symptoms of anxiety in young adults exposed to prenatal tobacco in the first trimester [RR = 1.52, 95% CI: 1.12-2.06, p-value < 0.01] and third trimester [RR = 1.53, 95% CI: 1.10-2.13, p-value  = 0.02]. However, we found insufficient statistical evidence for an association between first trimester [RR = 1.01, 95% CI: 0.76-1.22, p-value = 0.90] and third trimester [RR = 1.03, 95% CI: 0.80-1.34, p-value = 0.91] prenatal exposure to alcohol and the risk of experiencing symptoms of anxiety in young adults. There was a dose response association between prenatal tobacco exposure and increasing anxiety symptoms in offspring. CONCLUSION: The findings of this study suggest that an association between prenatal tobacco exposure and risk of anxiety symptoms remains apparent into young adulthood.

Prenatal alcohol and tobacco exposures and the risk of cannabis use in offspring: Findings from a population-based cohort study.

BACKGROUND: There is a paucity of prospective longitudinal studies examining the associations between maternal use of alcohol and tobacco during pregnancy and the risk of cannabis use in offspring. The aim of this study was to examine the association between prenatal alcohol and tobacco exposures and offspring cannabis use. METHODS: Data were from the Raine Study, a longitudinal prospective birth cohort based in Western Australia. Cannabis use at 17 years of age was measured with a self-reported questionnaire developed to capture risky behaviors in adolescents. Associations between prenatal alcohol and tobacco exposures and the risk of cannabis use in offspring were examined using log-binomial regression models, computing relative risk (RR). We also computed the E-values (E) to estimate the extent of unmeasured confounding. RESULTS: After adjusting for potential confounders, we observed increased risks of cannabis use in offspring exposed to first trimester prenatal alcohol use (RR = 1.38, 95% CI: 1.09-1.75; E = 2.10, CI:1.40) and tobacco use (RR = 1.42, 95% CI: 1.08-1.86; E = 2.19, CI:1.37) as well as third trimester prenatal alcohol use (RR = 1.39, 95% CI: 1.09-1.79; E = 2.13, CI:1.40) and tobacco use (RR = 1.39, 95% CI: 1.09-1.79; E = 2.21, CI:1.34]. We also noted dose-response associations in which risk estimates in offspring increased with the level of exposures to prenatal alcohol and tobacco use. CONCLUSION: These findings provide epidemiological evidence for effects of prenatal alcohol and tobacco exposures on offspring cannabis use. Although these results should be confirmed by other studies, the present study adds to the mounting evidence suggesting that women should be encouraged to abstain from alcohol and tobacco during pregnancy.