Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Shoulder dystocia in babies born to Aboriginal mothers with diabetes: a population-based cohort study, 1998-2015.

BACKGROUND: Australian Aboriginal and Torres Strait Islander women with diabetes in pregnancy (DIP) are more likely to have glycaemic levels above the target range, and their babies are thus at higher risk of excessive fetal growth. Shoulder dystocia, defined by failure of spontaneous birth of fetal shoulder after birth of the head requiring obstetric maneuvers, is an obstetric emergency that is strongly associated with DIP and fetal size. The aim of this study was to investigate the epidemiology of shoulder dystocia in Aboriginal babies born to mothers with DIP. METHODS: Stratifying by Aboriginal status, characteristics of births complicated by shoulder dystocia in women with and without DIP were compared and incidence and time-trends of shoulder dystocia were described. Compliance with guidelines aiming at preventing shoulder dystocia in women with DIP were compared. Post-logistic regression estimation was used to calculate the population attributable fractions (PAFs) for shoulder dystocia associated with DIP and to estimate probabilities of shoulder dystocia in babies born to mothers with DIP at birthweights > 3 kg. RESULTS: Rates of shoulder dystocia from vaginal births in Aboriginal babies born to mothers with DIP were double that of their non-Aboriginal counterparts (6.3% vs 3.2%, p < 0.001), with no improvement over time. Aboriginal mothers with diabetes whose pregnancies were complicated by shoulder dystocia were more likely to have a history of shoulder dystocia (13.1% vs 6.3%, p = 0.032). Rates of guideline-recommended elective caesarean section in pregnancies with diabetes and birthweight > 4.5 kg were lower in the Aboriginal women (28.6% vs 43.1%, p = 0.004). PAFs indicated that 13.4% (95% CI: 9.7%-16.9%) of shoulder dystocia cases in Aboriginal (2.7% (95% CI: 2.1%-3.4%) in non-Aboriginal) women were attributable to DIP. Probability of shoulder dystocia among babies born to Aboriginal mothers with DIP was higher at birthweights > 3 kg. CONCLUSIONS: Aboriginal mothers with DIP had a higher risk of shoulder dystocia and a stronger association between birthweight and shoulder dystocia. Many cases were recurrent. These factors should be considered in clinical practice and when counselling women.

Molecular Characterization of HER2-Low Invasive Breast Carcinoma by Quantitative RT-PCR Using Oncotype DX Assay.

BACKGROUND: HER2 immunohistochemistry (IHC) reproducibility is suboptimal for HER-low cases (IHC 1+ or 2+). METHODS: The Yale cohort included 214 stages I-II estrogen receptor positive breast cancers with IHC scores 0, 1+, and 2+ and routine Oncotype DX Recurrence Score (RS) results. The Exact Sciences (ES) cohort included 9 57 624 patients who had an Oncotype DX RS assay that assigns HER2-negative, equivocal, or positive status based on HER2 mRNA levels. RESULTS: HER2 mRNA levels varied across IHC categories but with increasing medians of 9.10 (n = 89), 9.20 (n = 71), and 9.45 (n = 54) in IHC 0, 1+, and 2+, respectively. 22.4% of HER2-low (1+/2+) cancer had RS > 25. Over 98% of HER-low cancers were HER2-negative by Oncotype DX assignment. CONCLUSIONS: Cancers with higher mRNA levels exist within IHC 0 and low categories, most of the HER2-low patients by IHC have low RS indicating no benefit from current adjuvant chemotherapies.

Early mortality among aboriginal and non-aboriginal women who had a preterm birth in Western Australia: A population-based cohort study.

BACKGROUND: Having a preterm (<37 weeks' gestation) birth may increase a woman's risk of early mortality. Aboriginal and Torres Strait Islander (hereafter Aboriginal) women have higher preterm birth and mortality rates compared with other Australian women. OBJECTIVES: We investigated whether a history of having a preterm birth was associated with early mortality in women and whether these associations differed by Aboriginal status. METHODS: This retrospective cohort study used population-based perinatal records of women who had a singleton birth between 1980 and 2015 in Western Australia linked to Death Registry data until June 2018. The primary and secondary outcomes were all-cause and cause-specific mortality respectively. After stratification by Aboriginal status, rate differences were calculated, and Cox proportional hazard regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and cause-specific mortality. RESULTS: There were 20,244 Aboriginal mothers (1349 deaths) and 457,357 non-Aboriginal mothers (7646 deaths) with 8.6 million person-years of follow-up. The all-cause mortality rates for Aboriginal mothers who had preterm births and term births were 529.5 and 344.0 (rate difference 185.5, 95% CI 135.5, 238.5) per 100,000 person-years respectively. Among non-Aboriginal mothers, the corresponding figures were 125.5 and 88.6 (rate difference 37.0, 95% CI 29.4, 44.9) per 100,000 person-years. The HR for all-cause mortality for Aboriginal and non-Aboriginal mothers associated with preterm birth were 1.48 (95% CI 1.32, 1.66) and 1.35 (95% CI 1.26, 1.44), respectively, compared with term birth. Compared with mothers who had term births, mothers of preterm births had higher relative risks of mortality from diabetes, cardiovascular, digestive and external causes. CONCLUSIONS: Both Aboriginal and non-Aboriginal women who had a preterm birth had a moderately increased risk of mortality up to 38 years after the birth, reinforcing the importance of primary prevention and ongoing screening.

Incorporating multidimensional behavior into a risk management tool for a critically endangered and migratory species.

Conservation of migratory species exhibiting wide-ranging and multidimensional behaviors is challenged by management efforts that only utilize horizontal movements or produce static spatial-temporal products. For the deep-diving, critically endangered eastern Pacific leatherback turtle, tools that predict where turtles have high risks of fisheries interactions are urgently needed to prevent further population decline. We incorporated horizontal-vertical movement model results with spatial-temporal kernel density estimates and threat data (gear-specific fishing) to develop monthly maps of spatial risk. Specifically, we applied multistate hidden Markov models to a biotelemetry data set (n = 28 leatherback tracks, 2004-2007). Tracks with dive information were used to characterize turtle behavior as belonging to 1 of 3 states (transiting, residential with mixed diving, and residential with deep diving). Recent fishing effort data from Global Fishing Watch were integrated with predicted behaviors and monthly space-use estimates to create maps of relative risk of turtle-fisheries interactions. Drifting (pelagic) longline fishing gear had the highest average monthly fishing effort in the study region, and risk indices showed this gear to also have the greatest potential for high-risk interactions with turtles in a residential, deep-diving behavioral state. Monthly relative risk surfaces for all gears and behaviors were added to South Pacific TurtleWatch (SPTW) (https://www.upwell.org/sptw), a dynamic management tool for this leatherback population. These modifications will refine SPTW's capability to provide important predictions of potential high-risk bycatch areas for turtles undertaking specific behaviors. Our results demonstrate how multidimensional movement data, spatial-temporal density estimates, and threat data can be used to create a unique conservation tool. These methods serve as a framework for incorporating behavior into similar tools for other aquatic, aerial, and terrestrial taxa with multidimensional movement behaviors.

Incorporación del comportamiento multidimensional a una herramienta de gestión de riesgos para una especie migratoria en peligro crítico Resumen La conservación de especies migratorias con comportamientos amplios y multidimensionales se enfrenta a los esfuerzos de gestión que sólo utilizan movimientos horizontales o que producen resultados espaciotemporales estáticos. La tortuga laúd, una especie de las profundidades en peligro crítico, necesita con urgencia herramientas que pronostiquen los lugares en donde las tortugas tienen mayor riesgo de interactuar con las pesquerías para prevenir una mayor declinación poblacional. Incorporamos los resultados de un modelo de movimiento horizontal-vertical a las estimaciones de la densidad del núcleo espaciotemporal y de los datos de amenaza (equipo de pesca específico) para desarrollar mapas mensuales del riesgo espacial. De manera más concreta, aplicamos modelos ocultos multiestado de Markov a un conjunto de datos de biotelemetría (n=28 rastros de tortugas laúd, 2004-2007). Usamos los rastros con información de inmersión para caracterizar el comportamiento de las tortugas como uno de tres estados: en tránsito, inmersión mixta o por residencia e inmersión profunda o por residencia. Integramos los datos recientes del esfuerzo de pesca tomados de Global Fishing Watch a los comportamientos pronosticados y las estimaciones del uso mensual del espacio para crear mapas del riesgo relativo de las interacciones tortuga-pesquería. La pesca con palangre de deriva (pelágica) tuvo el promedio mensual más alto de esfuerzo de pesca en la región de estudio. Los índices de riesgo indicaron que este equipo también tiene el potencial más elevado de interacciones de alto riesgo con las tortugas en estado residencial o de inmersión profunda. Añadimos los comportamientos y las superficies de riesgo relativo mensuales a South Pacific Turtle Watch (SPTW) (https://www.upwell.org/sptw), una herramienta dinámica para la gestión de esta población de laúdes. Estos cambios pulirán la capacidad de SPTW para proporcionar predicciones importantes de las áreas con potencial alto de riesgo de pesca accesoria para las tortugas con comportamientos específicos. Nuestros resultados demuestran cómo los datos de movimiento multidimensional, las estimaciones de densidad espaciotemporal y los datos de amenaza pueden ser usados para crear una herramienta única de conservación. Estos métodos sirven como marco para incorporar el comportamiento a herramientas similares para otros taxones acuáticos, aéreos y terrestres con comportamientos multidimensionales.

Perinatal outcomes of Aboriginal women with mental health disorders.

OBJECTIVE: Maternal mental disorders have been associated with adverse perinatal outcomes such as low birthweight and preterm birth, although these links have been examined rarely among Australian Aboriginal populations. We aimed to evaluate the association between maternal mental disorders and adverse perinatal outcomes among Aboriginal births. METHODS: We used whole population-based linked data to conduct a retrospective cohort study (N = 38,592) using all Western Australia singleton Aboriginal births (1990-2015). Maternal mental disorders were identified based on the International Classification of Diseases diagnoses and grouped into six broad diagnostic categories. The perinatal outcomes evaluated were preterm birth, small for gestational age, perinatal death, major congenital anomalies, foetal distress, low birthweight and 5-minute Apgar score. We employed log-binomial/-Poisson models to calculate risk ratios and 95% confidence intervals. RESULTS: After adjustment for sociodemographic factors and pre-existing medical conditions, having a maternal mental disorder in the five years before the birth was associated with adverse perinatal outcomes, with risk ratios (95% confidence intervals) ranging from 1.26 [1.17, 1.36] for foetal distress to 2.00 [1.87, 2.15] for low birthweight. We found similar associations for each maternal mental illness category and neonatal outcomes, with slightly stronger associations when maternal mental illnesses were reported within 1 year rather than 5 years before birth and for substance use disorder. CONCLUSIONS: This large population-based study demonstrated an increased risk of several adverse birth outcomes among Aboriginal women with mental disorders. Holistic perinatal care, treatment and support for women with mental disorders may reduce the burden of adverse birth outcomes.

Severe maternal morbidity following stillbirth in Western Australia 2000-2015: a population-based study.

PURPOSE: There is scant literature about the management of stillbirth and the subsequent risk of severe maternal morbidity (SMM). We aimed to assess the risk of SMM associated with stillbirths compared with live births and whether this differed by the presence of maternal comorbidities. METHODS: In this retrospective cohort study, we used a population-based dataset of all stillbirths and live births ≥ 20 weeks' gestation in Western Australia between 2000 and 2015. SMM was identified using a published Australian composite for use with routinely collected hospital morbidity data. Maternal comorbidities were identified in the Hospital Morbidity Data Collection or the Midwives Notification System using a modified Australian chronic disease composite. Multivariable Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for factors associated with SMM in analyses stratified by the presence of maternal comorbidities. Singleton and multiple pregnancies were examined separately. RESULTS: This study included 458,639 singleton births (2319 stillbirths and 456,320 live births). The adjusted RRs for SMM among stillbirths were 2.30 (95% CI 1.77, 3.00) for those without comorbidities and 4.80 (95% CI 4.11, 5.59) (Interaction P value < 0.0001) for those with comorbidities compared to live births without and with comorbidities, respectively. CONCLUSION: In Western Australia between 2000 and 2015, mothers of stillbirths both with and without any maternal comorbidities had an increased risk of SMM compared with live births. Further investigation into why women who have had a stillbirth without any existing conditions or pregnancy complications develop SMM is warranted.

Call rate of oyster toadfish (Opsanus tau) is affected by aggregate sound level but not by specific vessel passagesa).

Anthropogenic sound is a prevalent environmental stressor that can have significant impacts on aquatic species, including fishes. In this study, the effects of anthropogenic sound on the vocalization behavior of oyster toadfish (Opasnus tau) at multiple time scales was investigated using passive acoustic monitoring. The effects of specific vessel passages were investigated by comparing vocalization rates immediately after a vessel passage with that of control periods using a generalized linear model. The effects of increased ambient sound levels as a result of aggregate exposure within hourly periods over a month were also analyzed using generalized additive models. To place the response to vessel sounds within an ecologically appropriate context, the effect of environmental variables on call density was compared to that of increasing ambient sound levels. It was found that the immediate effect of vessel passage was not a significant predictor for toadfish vocalization rate. However, analyzed over a longer time period, increased vessel-generated sound lowered call rate and there was a greater effect size from vessel sound than any environmental variable. This demonstrates the importance of evaluating responses to anthropogenic sound, including chronic sounds, on multiple time scales when assessing potential impacts.

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Trends and burden of diabetes in pregnancy among Aboriginal and non-Aboriginal mothers in Western Australia, 1998-2015.

BACKGROUND: Diabetes in pregnancy (DIP), which includes pre-gestational and gestational diabetes, is more prevalent among Aboriginal women. DIP and its adverse neonatal outcomes are associated with diabetes and cardiovascular disease in the offspring. This study investigated the impact of DIP on trends of large for gestational age (LGA) in Aboriginal and non-Aboriginal populations, and added to the limited evidence on temporal trends of DIP burden in these populations. METHODS: We conducted a retrospective cohort study that included all births in Western Australia between 1998 and 2015 using linked population health datasets. Time trends of age-standardised and crude rates of pre-gestational and gestational diabetes were estimated in Aboriginal and non-Aboriginal mothers. Mixed-effects multivariable logistic regression was used to estimate the association between DIP and population LGA trends over time. RESULTS: Over the study period, there were 526,319 births in Western Australia, of which 6.4% were to Aboriginal mothers. The age-standardised annual rates of pre-gestational diabetes among Aboriginal mothers rose from 4.3% in 1998 to 5.4% in 2015 and remained below 1% in non-Aboriginal women. The comparable rates for gestational diabetes increased from 6.7 to 11.5% over the study period in Aboriginal women, and from 3.5 to 10.2% among non-Aboriginal mothers. LGA rates in Aboriginal babies remained high with inconsistent and no improvement in pregnancies complicated by gestational diabetes and pre-gestational diabetes, respectively. Regression analyses showed that DIP explained a large part of the increasing LGA rates over time in Aboriginal babies. CONCLUSIONS: There has been a substantial increase in the burden of pre-gestational diabetes (Aboriginal women) and gestational diabetes (Aboriginal and non-Aboriginal) in recent decades. DIP appears to substantially contribute to increasing trends in LGA among Aboriginal babies.

Patterns of recurrent preterm birth in Western Australia: A 36-year state-wide population-based study.

BACKGROUND: It is known that a previous preterm birth increases the risk of a subsequent preterm birth, but a limited number of studies have examined this beyond two consecutive pregnancies. AIMS: This study aimed to assess the risk and patterns of (recurrent) preterm birth up to the fourth pregnancy. MATERIALS AND METHODS: We used Western Australian routinely linked population health datasets to identify women who had two or more consecutive singleton births (≥20 weeks gestation) from 1980 to 2015. A log-binomial model was used to calculate risk ratios (RRs) and 95% confidence interval (CIs) for preterm birth risk in the third and fourth deliveries by the combined outcomes of previous pregnancies. RESULTS: We analysed 255 435 women with 651 726 births. About 7% of women had a preterm birth in the first delivery, and the rate of continuous preterm birth recurrence was 22.9% (second), 44.9% (third) and 58.5% (fourth) deliveries. The risk of preterm birth at the third delivery was highest for women with two prior indicated preterm births (RR 12.5, 95% CI: 11.3, 13.9) and for those whose first pregnancy was 32-36 weeks gestation, and second pregnancy was less than 32 weeks gestation (RR 11.8, 95% CI: 10.3, 13.5). There were similar findings for the second and fourth deliveries. CONCLUSIONS: Our findings demonstrate that women with any prior preterm birth were at greater risk of preterm birth in subsequent pregnancies compared with women with only term births, and the risk increased with shorter gestational length, and the number of previous preterm deliveries, especially sequential ones.

Caesarean section following antepartum stillbirth in Western Australia 2010-2015: A population-based study.

BACKGROUND: There is scant literature about antepartum stillbirth management but guidelines usually recommend reserving caesarean sections for exceptional circumstances. However, little is known about caesarean section rates following antepartum stillbirth in Australia. AIMS: We aimed to describe the onset of labour, mode of birth, and use of analgesia and anaesthesia following antepartum stillbirth and to identify factors associated with caesarean section. MATERIAL AND METHODS: In this retrospective cohort study, we used a population-based dataset of all singleton antepartum stillbirths ≥20 weeks gestation in Western Australia between 2010-2015. The overall, primary and repeat caesarean section rates for antepartum stillbirths were calculated and multivariable Poisson regression analyses were performed to identify associated factors, and to calculate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: This study included 634 antepartum stillbirths. Labour was spontaneous for 134 (21.1%), induced for 457 (72.1%), and 43 (6.8%) had a prelabour caesarean section. The overall, primary and repeat caesarean section rates were 8.5%, 4.6% and 23.0% respectively and increased with gestation (P trends all <0.01). Other factors associated with an increased caesarean section risk included: any placenta praevia or placental abruption, birth at a metropolitan private hospital, large-for-gestational-age birthweight, and any maternal chronic condition. During labour, the most frequently used types of analgesia were systemic narcotics (46.0%) and regional blocks (34.7%) while among those who had a caesarean section, 40.7% had a general anaesthetic. CONCLUSIONS: In Western Australia between 2010-2015, the caesarean section rates among women with antepartum stillbirths were low, in line with current guidelines.

Comparison of stillbirth trends over two decades in Wales, United Kingdom and Western Australia: An international retrospective cohort study.

BACKGROUND: Stillbirth is a critical public health issue worldwide. While the rates in high-income countries are relatively low, there are persistent between-country disparities. OBJECTIVES: To compare stillbirth rates and trends in Wales and the State of Western Australia (WA), Australia, and provide insights into any differences. METHODS: In this international retrospective cohort study, we pooled population-based data collections of all births ≥24 weeks' gestation (excluding terminations for congenital anomalies) between 1993 and 2015, divided into six time periods. The stillbirth rate per 1000 births was estimated for each cohort in each time period. Multivariable Poisson regression analyses, adjusted for appropriateness of growth, socio-economic status, maternal age, and multiple birth, were performed to evaluate the interaction between cohort and time period. Relative risk (RR) and 95% confidence interval (CI) for each time period and cohort were calculated. RESULTS: There were 767 731 births (3725 stillbirths) in Wales and 648 373 (2431 stillbirths) in WA. The overall stillbirth rate declined by 15.9% over the study period in Wales (from 5.3 in 1993-96 to 4.5 per 1000 births in 2013-15; Ptrend  < .01) but by 40.4% in WA (from 4.9 to 2.9 per 1000 births in WA; Ptrend  < .01). Using 1993-96 in WA as the reference group, the adjusted RRs for stillbirths at 37-38 weeks' gestation in the most recent study period (2013-15) were 0.85 (95% CI 0.64, 1.13) in Wales and 0.51 (95% CI 0.36, 0.73) in WA. CONCLUSIONS: The stillbirth rates between Wales and WA have widened in the last two decades (especially among late-term births), although the absolute rates for both are distinctly higher than the best-performing nations. While the differences may be partly explained by timing of birth and maternal life style behaviours such as smoking, it is important to identify and ameliorate the associated risk factors to support a reduction in preventable stillbirths.

The impact of maternal prenatal mental health disorders on stillbirth and infant mortality: a systematic review and meta-analysis.

Evidence about the association between maternal mental health disorders and stillbirth and infant mortality is limited and conflicting. We aimed to examine whether maternal prenatal mental health disorders are associated with stillbirth and/or infant mortality. MEDLINE, Embase, PsycINFO, and Scopus were searched for studies examining the association of any maternal prenatal (occurring before or during pregnancy) mental health disorder(s) and stillbirth or infant mortality. A random-effects meta-analysis was used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). The between-study heterogeneity was quantified using the I2 statistic. Subgroup analyses were performed to identify the source of heterogeneity. Of 4487 records identified, 28 met our inclusion criteria with 27 contributing to the meta-analyses. Over 60% of studies examined stillbirth and 54% of them evaluated neonatal or infant mortality. Thirteen studies investigated the association between maternal depression and anxiety and stillbirth/infant mortality, pooled OR, 1.42 (95% CI, 1.16-1.73; I2, 76.7%). Another 13 studies evaluated the association between severe maternal mental illness and stillbirth/infant mortality, pooled OR, 1.47 (95% CI, 1.28-1.68; I2, 62.3%). We found similar results for the association of any maternal mental health disorders and stillbirth/infant mortality (OR, 1.59; 95% CI, 1.43-1.77) and in subgroup analyses according to types of fetal/infant mortality. We found no significant evidence of publication bias. Maternal prenatal mental health disorders appear to be associated with a moderate increase in the risk of stillbirth and infant mortality, although the mechanisms are unclear. Efforts to prevent and treat these disorders may reduce the scale of stillbirth/infant deaths.

Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17ß-Hydroxysteroid Dehydrogenase Type 3.

17ß-Hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17ß-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17ß-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17ß-HSD3 and as inhibitors of prostate cancer cell growth.

Parental occupational exposure to pesticides and risk of childhood cancer in Switzerland: a census-based cohort study.

BACKGROUND: Pesticide exposure is a suspected risk factor for childhood cancer. We investigated the risk of developing childhood cancer in relation to parental occupational exposure to pesticides in Switzerland for the period 1990-2015. METHODS: From a nationwide census-based cohort study in Switzerland, we included children aged < 16 years at national censuses of 1990 and 2000 and followed them until 2015. We extracted parental occupations reported at the census closest to the birth year of the child and estimated exposure to pesticides using a job exposure matrix. Cox proportional hazards models, adjusted for potential confounders, were fitted for the following outcomes: any cancer, leukaemia, central nervous system tumours (CNST), lymphoma, non-CNS solid tumours. RESULTS: Analyses of maternal (paternal) exposure were based on approximately 15.9 (15.1) million-person years at risk and included 1891 (1808) cases of cancer, of which 532 (503) were leukaemia, 348 (337) lymphomas, 423 (399) CNST, and 588 (569) non-CNS solid tumours. The prevalence of high likelihood of exposure was 2.9% for mothers and 6.7% for fathers. No evidence of an association was found with maternal or paternal exposure for any of the outcomes, except for "non-CNS solid tumours" (High versus None; Father: adjusted HR [95%CI] =1.84 [1.31-2.58]; Mother: 1.79 [1.13-2.84]). No evidence of an association was found for main subtypes of leukaemia and lymphoma. A post-hoc analysis on frequent subtypes of "non-CNS solid tumours" showed positive associations with wide CIs for some cancers. CONCLUSION: Our study suggests an increased risk for solid tumours other than in the CNS among children whose parents were occupationally exposed to pesticides; however, the small numbers of cases limited a closer investigation of cancer subtypes. Better exposure assessment and pooled studies are needed to further explore a possible link between specific childhood cancers types and parental occupational exposure to pesticides.

Molecular characterization of breast cancer needle core biopsy specimens by the 21-gene Breast Recurrence Score test.

BACKGROUND AND OBJECTIVE: Recent COVID-19 pandemic guidelines recommend genomic assessment of core biopsies to help guide treatment decisions in estrogen receptor (ER)-positive early-stage breast cancer. Herein we characterize biopsy and excisional breast cancer specimens submitted for 21-gene testing. METHODS: US samples submitted to Genomic Health for 21-gene testing (01/2004-04/2020) were assessed by pathologists and analyzed by a standardized quantitative reverse transcription-polymerase chain reaction. Predefined cutoffs were: ESR1 (positive ≥6.5), PGR (positive ≥5.5), and ERBB2 (negative <10.7). ER status by immunohistochemistry (IHC) and lymph node status were determined locally. Median and interquartile range were reported for continuous variables, and total and percent for categorical variables. Distributions were assessed overall, by age, and by nodal involvement. RESULTS: Of 919 701 samples analyzed, 13% were biopsies and 87% were excisions. Initial assay success rates were 94.5% (biopsies) and 97.3% (excisions). ER IHC concordance with central ESR1 was 96.8% (biopsies) and 97.6% (excisions). Biopsy and excisional medians were: Recurrence Score results 16 (each); ESR1 10.2 (each); PGR 7.7 and 7.6; ERBB2 9.4 and 9.2, respectively. CONCLUSIONS: Biopsy submissions for 21-gene testing are common and consistently generate results that are very similar to the experience with excisions. The 21-gene test can be performed reliably on core biopsies.

Correction to: Profile of severely growth-restricted births undelivered at 40 weeks in Western Australia.

Unfortunately, after publication, we found errors in the extraction of data on gestational diabetes and threatened miscarriage.

Profile of severely growth-restricted births undelivered at 40 weeks in Western Australia.

PURPOSE: To investigate the proportion of severely growth-restricted singleton births < 3rd percentile (proxy for severe fetal growth restriction; FGR) undelivered at 40 weeks (FGR_40), and compare maternal characteristics and outcomes of FGR_40 births and FGR births at 37-39 weeks' (FGR_37-39) to those not born small-for-gestational-age at term (Not SGA_37+). METHODS: The annual rates of singleton FGR_40 births from 2006 to 2015 were calculated using data from linked Western Australian population health datasets. Using 2013-2015 data, maternal factors associated with FGR births were investigated using multinomial logistic regression to estimate odds ratios (OR) with 95% confidence intervals (CI) while relative risks (RR) of birth outcomes between each group were calculated using Poisson regression. Neonatal adverse outcomes were identified using a published composite indicator (diagnoses, procedures and other factors). RESULTS: The rate of singleton FGR_40 births decreased by 23.0% between 2006 and 2015. Factors strongly associated with FGR_40 and FGR_37-39 births compared to Not SGA_37+ births included the mother being primiparous (ORs 3.13: 95% CI 2.59-3.79; 1.69, 95% CI 1.47, 1.94, respectively) and ante-natal smoking (ORs 2.55, 95% CI 1.97, 3.32; 4.48, 95% CI 3.74, 5.36, respectively). FGR_40 and FGR_37-39 infants were more likely to have a neonatal adverse outcome (RRs 1.70, 95% CI 1.41, 2.06 and 2.46 95% CI 2.18, 2.46, respectively) compared to Not SGA 37+ infants. CONCLUSIONS: Higher levels of poor perinatal outcomes among FGR births highlight the importance of appropriate management including fetal growth monitoring. Regular population-level monitoring of FGR_40 rates may lead to reduced numbers of poor outcomes.

Parental smoking, maternal alcohol consumption during pregnancy and the risk of neuroblastoma in children. A pooled analysis of the ESCALE and ESTELLE French studies.

Neuroblastoma (NB) is the most common extra-cranial tumour in children. Little is known about the aetiology of NB. The early age at onset and the embryonic nature suggest a role for perinatal exposures. We conducted a pooled analysis of two French national population-based case-control studies to explore whether there was an association between parental smoking and alcohol consumption and the risk of NB. The mothers of 357 NB cases and 1,783 controls from general population, frequency matched by age and sex, were interviewed on demographic, socioeconomic and perinatal characteristics, maternal reproductive story, and life-style and childhood environment. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. A meta-analysis of our findings with those of previous studies was also conducted. Maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 [95% CI 0.9-1.7]; summary OR from meta-analysis 1.1 [95% CI 1.0-1.3]. Paternal smoking in the year before child's birth were not associated with NB as independent exposure (OR 1.1 [95% CI 0.9-1.4] but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 [95% CI 1.1-2.1]. No association was observed with maternal alcohol intake during pregnancy (OR 1.0 [95% CI 0.8-1.4], summary OR from meta-analysis 1.0 [95% CI 0.9-1.2]. Our findings provide some evidence of an association between maternal smoking during pregnancy and NB and add another reason to recommend that women refrain from smoking during pregnancy.