The impact of isolated obesity compared with obesity and other risk factors on risk of stillbirth: a retrospective cohort study.

BACKGROUND: Maternal obesity is associated with stillbirth, but uncertainty persists around the effects of higher obesity classes. We sought to compare the risk of stillbirth associated with maternal obesity alone versus maternal obesity and additional or undiagnosed factors contributing to high-risk pregnancy. METHODS: We conducted a retrospective cohort study using the Better Outcomes Registry and Network (BORN) for singleton hospital births in Ontario between 2012 and 2018. We used multivariable Cox proportional hazard regression and logistic regression to evaluate the relationship between prepregnancy maternal body mass index (BMI) class and stillbirth (reference was normal BMI). We treated maternal characteristics and obstetrical complications as independent covariates. We performed mediator analyses to measure the direct and indirect effects of BMI on stillbirth through major common-pathway complications. We used fully adjusted and partially adjusted models, representing the impact of maternal obesity alone and maternal obesity with other risk factors on stillbirth, respectively. RESULTS: We analyzed data on 681 178 births between 2012 and 2018, of which 1956 were stillbirths. Class I obesity was associated with an increased incidence of stillbirth (adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.35-1.78). This association was stronger for class III obesity (adjusted HR 1.80, 95% CI 1.44-2.24), and strongest for class II obesity (adjusted HR 2.17, 95% CI 1.83-2.57). Plotting point estimates for odds ratios, stratified by gestational age, showed a marked increase in the relative odds for stillbirth beyond 37 weeks' gestation for those with obesity with and without other risk factors, compared with those with normal BMI. The impact of potential mediators was minimal. INTERPRETATION: Maternal obesity alone and obesity with other risk factors are associated with an increased risk of stillbirth. This risk increases with gestational age, especially at term.

lncRNA SYTL5-OT4 promotes vessel co-option by inhibiting the autophagic degradation of ASCT2.

AIMS: Vessel co-option is responsible for tumor resistance to antiangiogenic therapies (AATs) in patients with colorectal cancer liver metastasis (CRCLM). However, the mechanisms underlying vessel co-option remain largely unknown. Herein, we investigated the roles of a novel lncRNA SYTL5-OT4 and Alanine-Serine-Cysteine Transporter 2 (ASCT2) in vessel co-option-mediated AAT resistance. METHODS: SYTL5-OT4 was identified by RNA-sequencing and verified by RT-qPCR and RNA fluorescence in situ hybridization assays. The effects of SYTL5-OT4 and ASCT2 on tumor cells were investigated by gain- and loss-of-function experiments, and those of SYTL5-OT4 on ASCT2 expression were analyzed by RNA immunoprecipitation and co-immunoprecipitation assays. The roles of SYTL5-OT4 and ASCT2 in vessel co-option were detected by histological, immunohistochemical, and immunofluorescence analyses. RESULTS: The expression of SYTL5-OT4 and ASCT2 was higher in patients with AAT-resistant CRCLM. SYTL5-OT4 enhanced the expression of ASCT2 by inhibiting its autophagic degradation. SYTL5-OT4 and ASCT2 promoted vessel co-option by increasing the proliferation and epithelial-mesenchymal transition of tumor cells. Combination therapy of ASCT2 inhibitor and antiangiogenic agents overcame vessel co-option-mediated AAT resistance in CRCLM. CONCLUSION: This study highlights the crucial roles of lncRNA and glutamine metabolism in vessel co-option and provides a potential therapeutic strategy for patients with AAT-resistant CRCLM.

Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix.

OBJECTIVE: Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis. DESIGN: TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on TCF21 DNA hypermethylation. Pericyte-conditional Tcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling. RESULTS: Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21high TPCs, termed 'matrix-pericytes', was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). Tcf21 depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21high TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair TCF21 DNA hypermethylation in TCF21high TPCs. CONCLUSION: This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.

Perinatal and pediatric outcomes associated with the use of fertility treatment: a population-based retrospective cohort study in Ontario, Canada.

BACKGROUND: Around 2% of births in Ontario, Canada involve the use of assisted reproductive technology (ART), and it is rising due to the implementation of a publicly funded ART program in 2016. To better understand the impact of fertility treatments, we assessed perinatal and pediatric health outcomes associated with ART, hormonal treatments, and artificial insemination compared with spontaneously conceived births. METHODS: This population-based retrospective cohort study was conducted using provincial birth registry data linked with fertility registry and health administrative databases in Ontario, Canada. Live births and stillbirths from January 2013 to July 2016 were included and followed to age one. The risks of adverse pregnancy, birth and infant health outcomes were assessed by conception method (spontaneous conception, ART - in vitro fertilization and non-ART - ovulation induction, intra-uterine or vaginal insemination) using risk ratios and incidence rate ratios with 95% confidence intervals (CI). Propensity score weighting using a generalized boosted model was applied to adjust for confounding. RESULT(S): Of 177,901 births with a median gestation age of 39 weeks (IQR 38.0-40.0), 3,457 (1.9%) were conceived via ART, and 3,511 (2.0%) via non-ART treatments. There were increased risks (adjusted risk ratio [95% CI]) of cesarean delivery (ART: 1.44 [1.42-1.47]; non-ART: 1.09 [1.07-1.11]), preterm birth (ART: 2.06 [1.98-2.14]; non-ART: 1.85 [1.79-1.91]), very preterm birth (ART: 2.99 [2.75-3.25]; non-ART: 1.89 [1.67-2.13]), 5-min Apgar < 7 (ART: 1.28 [1.16-1.42]; non-ART: 1.62 [1.45-1.81]), and composite neonatal adverse outcome indicator (ART: 1.61 [1.55-1.68]; non-ART: 1.29 [1.25-1.34]). Infants born after fertility treatments had increased risk of admission to neonatal intensive care unit (ART: 1.98 [1.84-2.13]; non-ART: 1.59 [1.51-1.67]) and prolonged birth admission (≥ 3 days) (ART: 1.60 [1.54-1.65]; non-ART: 1.42 [1.39-1.45]). The rate of emergency and in-hospital health services use within the first year was significantly increased for both exposure groups and remained elevated when limiting analyses to term singletons. CONCLUSION(S): Fertility treatments were associated with increased risks of adverse outcomes; however, the overall magnitude of risks was lower for infants conceived via non-ART treatments.

Association between maternal marginalization and infants born with congenital heart disease in Ontario Canada.

BACKGROUND: This study aims to evaluate the impact of socioeconomic status (SES) on the risk of congenital heart disease (CHD) since previous studies have yielded inconsistent results. METHODS: We conducted a population-based retrospective cohort study, including all singleton live and still births in Ontario hospitals from April 1, 2012, to March 31, 2018. We used linked records from the Better Outcomes Registry & Network Information System, the Canadian Institute for Health Information databases, and the Ontario Marginalization Index (ON_Marg). ON_Marg was estimated at a dissemination area level using Canadian Census 2016 data and categorized into quintiles. Multivariable logistic regression models were performed to examine the relationships between four ON_Marg indices (material deprivation, dependency, ethnic concentration, residential instability), as proxies for maternal SES and the risk of infant CHD. We adjusted for maternal age at birth, assisted reproductive technology, obesity, pre-existing health conditions, substance use during pregnancy, mental health conditions before and during pregnancy, rural residence, and infant's sex in the analysis. RESULTS: Among the cohort of 776,799 singletons, 9,359 infants had a diagnosis of CHD. Of those, 3,069 were severe CHD and 493 cases were single ventricle CHD. The prevalence of all infant CHD types was higher for males relative to females. Compared to mothers living in neighbourhoods with the lowest material deprivation, mothers with highest material deprivation had a 27% (adjusted OR = 1.27; 95% CI: 1.18-1.37) higher odds of having an infant diagnosed with CHD. Mothers living in neighbourhoods with the highest minority ethnic and immigrant concentration tend to have infants with 11% lower odds of CHD (adjusted OR = 0.89; 95% CI: 0.82-0.97) as compared to those living in the least ethnically diverse communities. Maternal dependency and residential stability quintiles were not significantly associated with the risk of CHD. CONCLUSION: Higher maternal material deprivation was associated with increasing odds of infant CHD, whereas neighbourhood minority ethnic concentration was inversely associated with the odds of infant CHD. Our study further confirms that poverty is associated with CHD development. Future investigations might focus on the causal pathways between social deprivation, immigrant status, ethnicity, and the risk of infant CHD.

Associations of congenital heart disease with deprivation index by rural-urban maternal residence: a population-based retrospective cohort study in Ontario, Canada.

BACKGROUND: The risk of congenital heart disease (CHD) has been found to vary by maternal socioeconomic status (SES) and rural-urban residence. In this study, we examined associations of CHD with two maternal SES indicators and stratified the analysis by maternal rural-urban residence. METHODS: This was a population-based retrospective cohort study. We included all singleton stillbirths and live hospital births from April 1, 2012 to March 31, 2018 in Ontario, Canada. We linked the BORN Information System and Canadian Institute for Health Information databases. Multivariable logistic regression models were used to examine associations of CHD with material deprivation index (MDI), social deprivation index (SDI), and maternal residence while adjusting for maternal age at birth, assisted reproductive technology, obesity, pre-pregnancy maternal health conditions, mental health illness before and during pregnancy, substance use during pregnancy, and infant's sex. MDI and SDI were estimated at a dissemination area level in Ontario and were categorized into quintiles (Q1-Q5). RESULTS: This cohort study included 798,173 singletons. In maternal urban residence, the p trend (Cochran-Armitage test) was less than 0.0001 for both MDI and SDI; while for rural residence, it was 0.002 and 0.98, respectively. Infants living in the most materially deprived neighbourhoods (MDI Q5) had higher odds of CHD (aOR: 1.21, 95% CI: 1.12-1.29) compared to Q1. Similarly, infants living in the most socially deprived neighbourhoods (SDI Q5) had an 18% increase in the odds of CHD (aOR: 1.18, 95% CI: 1.1-1.26) compared to Q1. Rural infants had a 13% increase in the odds of CHD compared to their urban counterparts. After stratifying by maternal rural-urban residence, we still detected higher odds of CHD with two indices in urban residence but only MDI in rural residence. CONCLUSION: Higher material and social deprivation and rural residence were associated with higher odds of CHD. Health interventions and policies should reinforce the need for optimal care for all families, particularly underprivileged families in both rural and urban regions. Future studies should further investigate the effect of social deprivation on the risk of CHD development.

Neighbourhood maternal socioeconomic status indicators and risk of congenital heart disease.

BACKGROUND: This study aimed to examine the relationships between various maternal socioeconomic status (SES) indicators and the risk of congenital heart disease (CHD). METHODS: This was a population-based retrospective cohort study, including all singleton stillbirths and live births in Ontario hospitals from April 1, 2012 to March 31, 2018. Multivariable logistic regression models were performed to examine the relationships between maternal neighbourhood household income, poverty, education level, employment and unemployment status, immigration and minority status, and population density and the risk of CHD. All SES variables were estimated at a dissemination area level and categorized into quintiles. Adjustments were made for maternal age at birth, assisted reproductive technology, obesity, pre-existing maternal health conditions, substance use during pregnancy, rural or urban residence, and infant's sex. RESULTS: Of 804,292 singletons, 9731 (1.21%) infants with CHD were identified. Compared to infants whose mothers lived in the highest income neighbourhoods, infants whose mothers lived in the lowest income neighbourhoods had higher likelihood of developing CHD (adjusted OR: 1.29, 95% CI: 1.20-1.38). Compared to infants whose mothers lived in the neighbourhoods with the highest percentage of people with a university or higher degree, infants whose mothers lived in the neighbourhoods with the lowest percentage of people with university or higher degree had higher chance of CHD (adjusted OR: 1.34, 95% CI: 1.24-1.44). Compared to infants whose mothers lived in the neighbourhoods with the highest employment rate, the odds of infants whose mothers resided in areas with the lowest employment having CHD was 18% higher (adjusted OR: 1.18, 95% CI: 1.10-1.26). Compared to infants whose mothers lived in the neighbourhoods with the lowest proportion of immigrants or minorities, infants whose mothers resided in areas with the highest proportions of immigrants or minorities had 18% lower odds (adjusted OR: 0.82, 95% CI: 0.77-0.88) and 16% lower odds (adjusted OR: 0.84, 95% CI: 0.78-0.91) of CHD, respectively. CONCLUSION: Lower maternal neighbourhood household income, poverty, lower educational level and unemployment status had positive associations with CHD, highlighting a significant social inequity in Ontario. The findings of lower CHD risk in immigrant and minority neighbourhoods require further investigation.

Racial differences in contribution of prepregnancy obesity and excessive gestational weight gain to large-for-gestational-age neonates.

OBJECTIVES: To examine the racial differences in the population attributable fraction (PAF) of prepregnancy obesity and excessive gestational weight gain to large-for-gestational-age (LGA) neonates. METHODS: We conducted a population-based retrospective cohort study among all women who had prenatal screening and had a singleton live birth in a hospital (1 April 2016-31 March 2017) using data from Ontario birth registry in Canada. We used multivariable log-binomial regression models to estimate the PAF and 95% confidence interval (CI) of LGA neonates due to prepregnancy obesity and excessive gestational weight gain. All models were stratified by race (White, Asian, and Black). RESULTS: Of the 74,402 eligible women, the prevalence of prepregnancy obesity, excessive gestational weight gain, and LGA neonate was 21.1%, 60.0%, and 11.3%, respectively, for Whites; 9.3%, 45.9%, and 5.4%, respectively, for Asians; and 28.6%, 52.4%, and 7.9%, respectively, for Blacks. The association of prepregnancy obesity was greater than that of excessive gestational weight gain on LGA for all racial groups. Excessive gestational weight gain contributed more than prepregnancy obesity in Whites (PAF 32.9%, 95% CI [30.3-35.5%] and 16.6%, 95% CI [15.3-17.9%], respectively, for excessive gestational weight gain and prepregnancy obesity) and in Asians (PAF 32.1%, 95% CI [27.2-36.7%] and 11.8%, 95% CI [9.5-14.1%], respectively, for excessive gestational weight gain and prepregnancy obesity). Prepregnancy obesity (PAF 22.8%, 95% CI [17.1-28.1%]) and excessive gestational weight gain (PAF 20.1%, 95% CI [4.7-33.0%]) contributed to LGA neonates almost the same in Blacks. CONCLUSIONS: Excessive gestational weight gain contributed more to LGA neonates than prepregnancy obesity in Whites and Asians, while there was no difference between excessive gestational weight gain and prepregnancy obesity in their contributions to the LGA neonates in Blacks. The differences are mostly driven by the differential prevalence of the two risk factors across racial groups.

Agreement assessment of key maternal and newborn data elements between birth registry and Clinical Administrative Hospital Databases in Ontario, Canada.

PURPOSE: Since 2012, BORN Ontario, a maternal-newborn registry, has collected data on every birth in Ontario. To ensure data quality, we assessed the reliability of key elements collected in BORN by comparing these with like data elements in the Canadian Institute for Health Information-Discharge Abstract Database (CIHI-DAD). METHODS: We used provincial health card numbers to deterministically link live or stillbirth records and their corresponding mothers' records in the BORN database to the CIHI-DAD in the fiscal years 2012-2013 to 2014-2015. Percentage agreement and Cohen Kappa statistics were used to assess agreement on main elements in both databases. RESULTS: The percentage agreement and Kappa coefficients were 99.98% and 0.740 (95% CI: 0.677-0.803) on live/stillbirth, respectively. The Kappa coefficients for infant sex, gestational age at birth, induction of labour, and caesarean birth were 0.989 (95% CI: 0.988-0.989), 0.920 (95% CI: 0.919-0.920), 0.782 (95% CI: 0.780-0.785), and 0.995 (95% CI: 0.995-0.996), respectively. Kappa agreement for the number of fetuses in a pregnancy was 0.979 (95% CI: 0.977-0.981). Percentage agreement was very high for infants' birthdates (99.9%), infant postal codes (91.8%), infants' birth weight in grams (95.5%), and mothers' dates of birth (99.1%). CONCLUSIONS: Overall, the BORN and CIHI-DAD databases had concordance on key birth and maternal data elements; however, additional work is needed to understand discrepancies identified.

Association Between a Dietary Inflammatory Index and Prostate Cancer Risk in Ontario, Canada.

BACKGROUND: Evidence exists showing that various aspects of diet are implicated in the etiology of prostate cancer, although results across studies remain inconsistent. METHODS: We examined the ability of the dietary inflammatory index (DII) to predict prostate cancer in a case-control study conducted in Kingston, Ontario, Canada, between 1997 and 1999. The study included 72 cases of incident primary prostate cancer patients and 302 controls of urology clinic patients who had prostate conditions other than prostate cancer. The DII was computed based on intake of 18 nutrients assessed using a 67-item food frequency questionnaire. Univariate and multivariate logistic regression models were used to estimate odds ratios (ORs). RESULTS: Men with higher DII scores were at increased risk of prostate cancer using DII score fit both as a continuous [OR = 1.58, 95% confidence interval (CI) 1.05-2.38] and categorical variable [compared to men in the lowest DII quartile, men in the highest quartile were at elevated risk (OR = 3.50, 95% CI 1.25-9.80; ptrend = 0.02)]. There was no significant heterogeneity by weight status, but stronger association was observed in men with body mass index >25 kg/m2 versus <25 kg/m2. CONCLUSION: These findings suggest that a proinflammatory diet, as indicated by increasing DII score, is a risk factor for prostate cancer.