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There is limited information on the prevalence of SARS-CoV-2 infection in obstetric settings in Canada, beyond the first wave of the COVID-19 pandemic (February to June 2020). We sought to describe the prevalence of SARS-CoV-2 infection in pregnant people admitted to triage units at a tertiary care hospital in Ottawa, Canada.We conducted a descriptive study of pregnant people admitted to obstetric triage assessment units at The Ottawa Hospital between Oct. 19 and Nov. 27, 2020 (second local wave of the COVID-19 pandemic). Participants underwent SARS-CoV-2 polymerase chain reaction (PCR) (via naso- or oropharyngeal swabs) and serology testing upon admission. We excluded individuals younger than 18 years, those who did not speak English or French, those who enrolled in conflicting studies, those admitted for pregnancy termination and those triaged between 11:31 pm and 7:29 am. Swab and serology samples were analyzed using digital droplet PCR and enzyme-linked immunosorbent assays, respectively. We defined SARS-CoV-2 seropositivity as a positive result for immunoglobulin (Ig) G, either alone or in combination with IgM or IgA.Of the 632 eligible patients, 363 (57.4%) consented to participation and 362 collectively provided 284 swab and 352 blood samples eligible for analysis. Common reasons for declining participation included feeling overwhelmed or anxious, being worried about repercussions of testing, pain or discomfort with testing or disinterest in research. Participants were mostly multiparous (53.9%) and in their third trimester upon admission (88.4%). In all, 18 (4.9%) participants had evidence of SARS-CoV-2 exposure; 2 (0.7%) of 284 were positive for SARS-CoV-2 by PCR and 16 (4.5%) of 352 were positive for IgG antibodies to SARS-CoV-2.During the second local wave of the COVID-19 pandemic, the prevalence of active SARS-CoV-2 infection among obstetric patients in Ottawa was 0.7% and seroprevalence was 4.5%. Our low participation rate highlights the need for improvements in patient education and public health messaging on the benefits of SARS-CoV-2 testing programs.

Supplementary Figures, Legends and Methods

We used a prospective cohort of pregnant women at 12 to 20 weeks gestation between 2002 and 2008 in Ottawa and Kingston to evaluate the impact of early pregnancy folic acid supplementation on the risk of gestational diabetes mellitus. Among 7552 eligible women, 84 (1.11%) were diagnosed of gestational diabetes mellitus. Non-significant associations were observed between gestational diabetes mellitus and folate supplementation, homocysteine levels, and methylenetetrahydrofolate reductase 677 TT genotype. Although we found no significant associations between folic acid supplementation and the risk of gestational diabetes mellitus, genetic associations were not confounded by lifestyle or socioeconomic factors, which may have biased previous studies.

Background Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. Objectives This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. Methods For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. Results Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. Conclusions High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.

Obstetrical patients are at risk of complications from COVID-19 and face increased stress due to the pandemic and changes in hospital birth setting. The objective was to describe the perinatal care experiences of obstetrical patients who gave birth during the early phases of the COVID-19 pandemic.A descriptive epidemiological survey was administered to consenting patients who gave birth at The Ottawa Hospital (TOH) between March 16th and June 16th, 2020. The participants reported on prenatal, in-hospital, and postpartum care experiences. COVID-19 pandemic related household stress factors were investigated. Frequencies and percentages are presented for categorical variables and median and interquartile range (IQR) for continuous variables.A total of 216 participants were included in the analyses. Median participants age was 33 years (IQR: 30-36). Collectively, 94 (43.5%) participants felt elevated stress for prenatal appointments and 105 (48.6%) for postpartum appointments because of COVID-19. There were 108 (50.0%) were scared to go to the hospital for delivery, 97 (44.9%) wore a mask during labour and 54 (25.0%) gave birth without a support person. During postpartum care, 125 (57.9%) had phone appointments (not offered prior to COVID-19), and 18 (8.3%) received no postpartum care at all.COVID-19 pandemic and public health protocols created a stressful healthcare environment for the obstetrical population where many were fearful of accessing services, experienced changes to standard care, or no care at all. As the pandemic continues, careful attention should be given to the perinatal population to reduce stress and improve continuity of care.RéSUMé: OBJECTIF: Les patients obstétriques sont à risque de complications de la COVID-19 et font face à un stress accru en raison de la pandémie et des changements dans le cadre de l’accouchement en milieu hospitalier. L’objectif était de décrire les expériences de soins périnataux des patients obstétriques qui ont accouché au cours des premières phases de la pandémie de COVID-19. MéTHODES: Un sondage épidémiologique descriptif a été menée auprès de patients qui ont accouché à L'Hôpital d'Ottawa (TOH) entre le 16 mars et le 16 juin 2020. Les participants ont fait un compte rendu de leurs expériences en matière de soins prénataux, hospitaliers et post-partum. Les facteurs de stress domestique liés à la COVID-19 ont été étudiés. Les fréquences et les pourcentages sont présentés pour les variables catégorielles et la médiane et l'écart interquartile (IQR) sont présentés pour les variables continues. RéSULTATS: Au total, 261 participants ont répondu au sondage. L'âge maternel médian était de 33 ans (IQR: 30–36). Collectivement, 94 participants (43,5%) ressentaient un stress élevé en lien avec les rendez-vous prénataux et 105 (48,6%) pour les rendez-vous post-partum en raison de la COVID-19. Il y avait 108 patients (50,0%) qui avaient peur d'aller à l'hôpital pour accoucher, 97 (44,9%) qui portaient un masque pendant leur travail et 54 (25,0%) qui ont accouché sans personne de soutien. En lien avec les soins post-partum, 125 (57,9%) ont eu des rendez-vous téléphoniques (non offerts avant la pandémie COVID-19) et 18 (8,3%) n'ont reçu aucun soin post-partum. CONCLUSION: La pandémie de COVID-19 et les politiques de santé publique ont créé un environnement de soins de santé stressant pour la population obstétrique où beaucoup avaient peur d'accéder aux services de soins, ont connu des changements dans les soins de base ou n’ont pas eu de soins du tout. Alors que la pandémie se poursuit, une attention particulière doit être accordée à la population périnatale afin de réduire le stress et améliorer la continuité des soins.

Background & Aims Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death–1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. Methods Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral–corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti–PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. Results When given to gastrin-deficient mice before tumors grew, anti–PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti–PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti–PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8+ T cells, and increased the response of tumors to anti–PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. Conclusions In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti–PD-1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.

Background & Aims Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed. Methods We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC–green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC–tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan–Meier survival analysis was performed to assess the effect on survival. Results In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis. Conclusions Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.

The bulk of the pancreas is primarily composed of long-lived acinar cells that are not considered a bona fide source for stem cells. However, certain acinar subpopulations possess a repopulating capacity during regeneration, raising the hypothesis as to the presence of regenerative progenitor-like populations in the adult pancreas. Here, we describe recent discoveries based on fate-mapping techniques that support the existence of progenitor-like acinar subpopulations, including active progenitor-like cells that maintain tissue homeostasis and facultative progenitor-like cells that drive tissue regeneration. A possible link between progenitor-like acinar cells and cancer initiators is proposed. Further analysis of these cellular components is needed, as it would help uncover possible cellular sources for regeneration and cancer, as well as potential targets for therapy.

Education is considered one of the most robust determinants of health. However, it is unclear whether maternal education and paternal education have differential impacts on perinatal health outcomes. We assess maternal and paternal education differences and their association with adverse birth outcomes in a large birth cohort from Ontario, Canada. The OaK Birth Cohort recruited patients from Ontario, Canada, between October 2002 and April 2009. We recruited mothers were recruited between 12 and 20 weeks’ gestation and collected both mother and infant data. The final sample size of the cohort was 8,085 participants. We use logistic regression to model the probability of preterm birth (less than 34 and 37 weeks’ gestation), small-for-gestational-age (SGA), or stillbirth as a function of maternal and paternal educational attainment. We adjust for household-level income, maternal and paternal race and ethnicity, and compare the strength of the association between maternal and paternal education on outcomes using Wald tests. 7,928 mother-father-offspring triads were available for the current analysis. 75% of mothers and fathers had college or university level education, and 8.7% of mothers experienced preterm delivery. Compared to mothers with college or university education, mothers with a high school education had an odds ratio of 1.37 (95% CI: 1.01–1.87) for SGA. Paternal education was not associated with infant outcomes. Comparing the odds ratios for maternal education and paternal education showed a stronger association than paternal education at the high school level for SGA birth (difference in odds ratio: 1.95, 95% CI: 1.13–3.36, p = .016) among women at least 25 years old. Maternal education was associated with SGA, and this effect was more robust than paternal education, but both associations were weaker than previously reported.

726 Background: The development of new treatments in oncology is a long, costly, and, too often, unsuccessful process. Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials are needed. Methods: We used a mathematical model of tumor growth kinetics fit to serial radiographic tumor measurements or CA19-9 values to estimate rates of exponential tumor growth [g] and decay [d] during treatment for pancreatic ductal adenocarcinoma (PDAC). Results: We retrospectively collected and analyzed data from 2691 patients with stage III-IV PDAC who were enrolled in five clinical trials or were included in two large real-world data sets from Columbia University Irving Medical Center and Veterans Administration Medical Centers. Using log-rank comparison of Kaplan-Meier plots by quartile of g, we found that in patients with metastatic PDAC g correlates highly with overall (OS) and progression-free survival (PFS) (p

Objective To develop and internally validate a deep-learning algorithm from fetal ultrasound images for the diagnosis of cystic hygromas in the first trimester. Methods All first trimester ultrasound scans with a diagnosis of a cystic hygroma between 11 and 14 weeks gestation at our tertiary care centre in Ontario, Canada were studied. Ultrasound scans with normal nuchal translucency were used as controls. The dataset was partitioned with 75% of images used for model training and 25% used for model validation. Images were analyzed using a DenseNet model and the accuracy of the trained model to correctly identify cases of cystic hygroma was assessed by calculating sensitivity, specificity, and the area under the receiver-operating characteristic (ROC) curve. Gradient class activation heat maps (Grad-CAM) were generated to assess model interpretability. Results The dataset included 289 sagittal fetal ultrasound images;129 cystic hygroma cases and 160 normal NT controls. Overall model accuracy was 93% (95% CI: 88–98%), sensitivity 92% (95% CI: 79–100%), specificity 94% (95% CI: 91–96%), and the area under the ROC curve 0.94 (95% CI: 0.89–1.0). Grad-CAM heat maps demonstrated that the model predictions were driven primarily by the fetal posterior cervical area. Conclusions Our findings demonstrate that deep-learning algorithms can achieve high accuracy in diagnostic interpretation of cystic hygroma in the first trimester, validated against expert clinical assessment.

Objective:Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population.Design:Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration.Setting:Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009.Participants:Women were recruited when presenting for prenatal care in the early second trimester.Results:In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration.Conclusions:We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

To determine the efficacy of high-dose folic acid for the prevention of preeclampsia in twin pregnancies.Secondary analysis of a randomized controlled trial in 70 obstetrical sites in Argentina, Australia, Canada, Jamaica, and the UK between 2011 and 2015. Eligible women pregnant with twins who were aged 18 y or older and between 8 and 16 completed weeks' gestation were randomized between to receive daily high-dose folic acid (4.0-5.1 mg) or placebo. The primary outcome was preeclampsia, presenting as hypertension after 20 weeks' gestation with significant proteinuria. Secondary outcomes included severe preeclampsia, preterm birth, and adverse fetal and neonatal outcomes.Of 2464 participants randomized between 18 April 2011 and 14 December 2015, 462 (18.8%) had a confirmed twin pregnancy. Thirty-four of these participants withdrew consent or did not have primary outcome data available, and 428 women were analyzed. The rate of preeclampsia was significantly higher in the folic acid group compared to the placebo group in crude analyses (17.2 versus 9.9%; relative risk 1.75 [95% CI 1.06-2.88],High-dose folic acid supplementation was not significantly associated with preeclampsia in a subgroup of twin pregnancies. Although a suggested elevated risk cannot be confirmed, these results may help to gain novel insights in the etiology of preeclampsia, which continues to be poorly understood.ClinicalTrials.gov NCT01355159.

Immunotherapy, which can produce durable responses in some cancers, has generally proven ineffective in PDAC, partially due to an immunosuppressive tumor immune microenvironment (TIME). Adjunctive therapies to sensitize PDAC to immunotherapy have the potential to greatly improve survival for patients with PDAC. We have shown that parasympathetic signaling via the vagus nerve inhibits PDAC by suppressing cancer stem cells. Cholinergic signaling through the Muscarinic Acetylcholine Receptor 1 (Chrm1) mediates this phenomenon. The effect of cholinergic signaling on the tumor immune microenvironment is unknown. Our objective is to investigate if loss of Chrm1 or cholinergic signaling impairs anti-tumor immune responses. We used two models of PDAC a) the KRasLSL G12D/+;Trp53R172H/+;Pdx1-Cre (KPC) autochthonous mouse model of PDAC crossed with Chrm1 knockout mice (KPCM) and b) orthotopic PDAC transplantation models. The composition of the TIME and tumor kinetics of these models were assessed, and the effect of genetic loss or pharmacological inhibition of CHRM1 on T lymphocytes function was examined. Inflammatory markers were analyzed in plasma samples from PDAC patients enrolled in a Phase 0/window of opportunity study of the cholinergic agonist, bethanechol, prior to surgery. Results show that loss of Chrm1 is associated with decreased T cell infiltration in the TIME of PDAC and increased tumor growth. CD8+ T cells deficient in Chrm1 demonstrate impaired proliferation, activation and suppression of TCF1, a transcription factor with well described roles in T cell development and maintenance of effector T cell function. Analysis of paired plasma samples obtained from patients treated with the cholinergic agonist, bethanechol show increased expression of CCL5, a chemokine with known roles in T cell migration in the TIME as well as suppression of a number of other inflammatory cytokines including TNF-alpha. These data suggest that cholinergic signaling via CHRM1 on T lymphocytes promotes CD8+ T cell infiltration into the TIME and maintenance of anti-tumor immune responses. Citation Format: Ruth A. White, Quin T. Waterbury, Yosuke Ochiai, Leah B. Zamechek, Susan E. Bates, Timothy C. Wang. Cholinergic modulation of T lymphocytes in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR020.

BACKGROUND: Data on the effect of cesarean delivery on maternal request (CDMR) on maternal and neonatal outcomes are inconsistent and often limited by inadequate case definitions and other methodological issues. Our objective was to evaluate the trends, determinants and outcomes of CDMR using an intent-to-treat approach. METHODS: We designed a population-based retrospective cohort study using data on low-risk pregnancies in Ontario, Canada (April 2012–March 2018). We assessed temporal trends and determinants of CDMR. We estimated the relative risks for component and composite outcomes used in the Adverse Outcome Index (AOI) related to planned CDMR compared with planned vaginal delivery using generalized estimating equation models. We compared the Weighted Adverse Outcome Score (WAOS) and the Severity Index (SI) across planned modes of delivery using analysis of variance. RESULTS: Of 422 210 women, 0.4% (n = 1827) had a planned CDMR and 99.6% (n = 420 383) had a planned vaginal delivery. The prevalence of CDMR remained stable over time at 3.9% of all cesarean deliveries. Factors associated with CDMR included late maternal age, higher education, conception via in vitro fertilization, anxiety, nulliparity, being White, delivery at a hospital providing higher levels of maternal care and obstetrician-based antenatal care. Women who planned CDMR had a lower risk of adverse outcomes than women who planned vaginal delivery (adjusted relative risk 0.42, 95% confidence interval [CI] 0.33 to 0.53). The WAOS was lower for planned CDMR than planned vaginal delivery (mean difference −1.28, 95% CI −2.02 to −0.55). The SI was not statistically different between groups (mean difference 3.6, 95% CI −7.4 to 14.5). Interpretation: Rates of CDMR have not increased in Ontario. Planned CDMR is associated with a decreased risk of short-term adverse outcomes compared with planned vaginal delivery. Investigation into the long-term implications of CDMR is warranted.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.

BACKGROUND: Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects; however, the extent to which recommendations are met through dietary sources and supplements is not clear. OBJECTIVES: Our objective was to evaluate the dietary and supplemental intakes of FA in a Canadian pregnancy cohort and to determine the proportions of pregnant women exceeding the Estimated Average Requirement (EAR) and Tolerable Upper Intake Level (UL). METHODS: FACT (the Folic Acid Clinical Trial) was an international multicenter, randomized, double-blinded, placebo-controlled, phase III trial investigating FA for the prevention of pre-eclampsia in high-risk pregnancies. Participants were enrolled from Canadian sites at 8–16 weeks of gestation. Dietary and supplemental FA intake data were collected through participant interviews and FFQs at the time of FACT enrollment. Categorical data were summarized as n (%) and continuous data as median (IQR). RESULTS: This study included 1198 participants. Participants consumed 485 μg dietary folate equivalents (DFE)/d (IQR: 370–630 μg DFE/d) from dietary sources of folate and FA. Through diet alone, 43.4% of participants consumed ≥520 μg DFE/d, the EAR for pregnant individuals. Of the 91.9% of participants who consumed daily FA supplements, 0.4% consumed

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.

Essentials Low-molecular-weight heparin (LMWH) is used to prevent venous thromboembolism (VTE) in pregnancy. We evaluated the association between LMWH and large for gestational age (LGA) infants. We found no significant associations between LMWH use and LGA. LMWH does not appear to increase the risk for the delivery of an LGA infant. SUMMARY: Background Low-molecular-weight heparin (LMWH), an anticoagulant, is the recommended drug for thromboprophylaxis and treatment of venous thromboembolism (VTE) in pregnancy. During pregnancy, LMWH is routinely prescribed to mothers with an increased risk of VTE or with a history of thrombosis. Although clinical reports of larger offspring born to women administered LMWH have been noted, no studies to date have evaluated or associated the use of LMWH and large for gestational age (LGA) infants. Objectives To determine whether there is an association between LMWH usage in mothers and the prevalence of LGA. Patients/Methods We performed an analysis of the Ottawa and Kingston (OaK) Birth Cohort and report characteristics of LMWH and association LGA (> 10%ile). We used coarsened exact matching (CEM) methods to account for bias and confounding. Results A total of 7519 women from the OaK Birth Cohort were included; 59 were administered LMWH during pregnancy (0.78%). Mothers prescribed LMWH had significantly greater BMI (P = 0.0001), age (P = 0.0001) and parity (P = 0.02). Gestational length was shorter among women administered LMWH compared to those without treatment (37.7 ± 2.0 vs. 39.2 ± 2.0, P

4158 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Novel strategies for advanced PDAC are a critical need. A DNA hypomethylating agent (HMA) increased tumor-infiltrating effector T cells and significantly prolonged survival in combination with immune checkpoint blockade (ICB) in a PDAC mouse model (Gonda et al 2020). We hypothesized that combining HMA with ICB will lead to therapeutic benefit in pts with advanced PDAC. Methods: This is an open-label, single-arm, single-center, Phase 2 trial of AZA plus pembro in pts with unresectable or metastatic PDAC. Pts were treated with AZA 50 mg/m2 subcutaneous daily for 5 days Q4W beginning week 1 day 1 followed by pembro 200 mg IV Q3W starting week 3 day 1. Key eligibility criteria included documented progression on or following first-line systemic treatment, ECOG PS 0-1, and adequate organ function. The primary objective was progression-free survival (PFS). Thirty-one evaluable pts were required to detect an improvement in PFS from 2 mo to 4 mo with a one-sided p-value of 0.05 and 80% power. Secondary endpoints included safety and tolerability, overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Data cutoff was February 10, 2022. Results: Between Oct 2017 and Sept 2021, 36 pts were enrolled (median age 62.5, 75% white, 72% male). At data cutoff, 34 and 31 pts received at least 1 dose of AZA and pembro, respectively. Median PFS for ≥1 dose of AZA was 1.48 mo (95% CI: 1.35, 1.74) and for ≥1 dose of pembro was 1.51 mo (95% CI, 1.38, 3.42). The median OS was 4.67 months. Among the 34 pts, 3 (8.8%) experienced a partial response (PR) by RECIST with a DCR of 32.4%. Of the 3 pts with PR, 2 received 35 doses of pembro and continued beyond 2 years with an ongoing PR. One pt remains on pembro 20 months after study completion. None of the pts with a PR were microsatellite instability-high or tumor mutation burden high, and next-generation sequencing of the 3 cancers identified a BRCA1 variant and POLE variant. Treatment-related AEs (TRAEs) occurred in 20/34 pts (59%), the most common of which were diarrhea and fatigue. Grade ≥3 occurred in 7/34 (21%) including 1 immune-related grade 5 event (encephalitis). Conclusions: AZA plus pembro demonstrated a tolerable safety profile but no PFS benefit compared to historical controls. Our data suggests combined epigenetic therapy and ICB may expand therapeutic options in a subset of pts with PDAC. Further investigation is needed to identify biomarkers to predict response and elucidate effective timing, sequencing, and combination of epigenetic agents. Follow-up for OS is ongoing. Correlative analysis of epigenetic effects and characterization of the tumor immune microenvironment will be reported. Clinical trial information: NCT03264404.

Objective To summarize information on the maternal and perinatal outcomes among pregnant women with a maternal age greater or equal to 45 years old compared with women with a maternal age of less than 45. Methods A comprehensive systematic search of online databases from January 1946 through June 2015 was completed. The maternal outcomes were: fetal loss, preterm birth, full-term birth, complications of pregnancy, the type of delivery, and periconception hemorrhage. The fetal outcomes were: intrauterine growth restriction/LGA, fetal anomalies, APGAR score, and neonatal death. Results Twenty articles were included in the systematic review and 15 included in the meta-analysis. There was a 2.60 greater likelihood of fetal loss ( I 2 = 99%). Newborns of women of a very advanced maternal age were 2.49 more likely to have a concerning 5-minute APGAR score. Very advanced maternal age women had a 3.32 greater likelihood of pregnancy complications ( I 2 = 91%). There was a 1.96 greater likelihood of preterm birth at very advanced maternal age ( I 2 = 91%) and a 4 times greater likelihood of having to deliver through Caesarean section ( I 2 = 97%). Conclusion This systematic review showed an increased risk of adverse maternal and perinatal outcomes. The large amount of heterogeneity among most outcomes that were investigated suggest results must be interpreted with caution.

Objectives It is well established that delivery by caesarean section is associated with lower rates of breastfeeding initiation; however, little is known about breastfeeding among women who plan to have a cesarean delivery on maternal request (CDMR). Our objective is to compare the rate of exclusive breastfeeding at discharge between a planned CDMR group and a planned vaginal birth (VD) group using an “intent-to-treat” approach. Methods This was a population-based retrospective cohort study of singleton pregnancies using data from the BORN Ontario registry (Apr ‘12-Mar ’17). Generalized estimating equation models with log link function were used to estimate the adjusted risk ratio (aRR) of exclusive breastfeeding at discharge between planned CDMR and planned VD. A sensitivity analysis comparing planned cesarean section for medical indication with planned VD was conducted. Results Out of 668,468 pregnancies in our study, 0.72% (4,821) had planned CDMR and 85.2% (569,212) had planned VD. The exclusive breastfeeding rate was 42.3% for planned CDMR and 55.4% for planned VD. Women who planned CDMR were less likely to exclusively breastfeed at discharge than those in the planned VD group (aRR: 0.72; 95% CI 0.70-0.75). Women with planned cesarean section with medical indication were also less likely to exclusively breastfeed at discharge than those in the planned VD group (aRR: 0.75; 95% CI 0.75-0.76). Conclusions Planned CDMR is associated with a decreased rate of exclusive breastfeeding compared to planned VD. Additional work to determine the factors influencing breastfeeding is needed to inform on improvements to breastfeeding supports for this population.

Background: The prevalence of cannabis use among pregnant individuals in Canada is increasing. In the design of new cohort studies to evaluate the patterns and outcomes of cannabis use in pregnancy, consideration must be given to the factors influencing participation, data sharing, and contribution of biological samples. Our objective was to assess the willingness of pregnant individuals to participate in prospective research during pregnancy. Methods: We surveyed pregnant individuals receiving obstetrical care through The Ottawa Hospital in Ottawa, Canada. The survey consisted of 23 dichotomous (yes/no), multiple-choice, Likert scale, and open-ended questions. Individuals were provided with a hypothetical research scenario and asked to report on the likelihood of their participation, use and storage of personal health information and contribution of maternal and newborn samples. Individuals provided motivating and deterring factors related to research participation. Descriptive statistics included frequencies (n) and percentages (%) for categorical variables. Continuous variables were described using means and standard deviations. Results: A total of 84 survey responses were collected. The mean age of respondents was 32.6(±5.3) years. Respondents were predominantly Caucasian (79%), college/university educated (85%) with a household income of ≥$100,000 (64%). There was a high degree of willingness to participate in prospective research by sharing data and biological samples. The most commonly cited motivating and deterring factors for participating in future research were a desire to contribute to science and health information (79%) and fear of privacy invasion (17%), respectively. Conclusions: Pregnant individuals receiving care at The Ottawa Hospital are willing to participate in prospective research studies, including those related to cannabis use. Survey respondents were predominantly of higher socioeconomic status, and few individuals reported cannabis use during pregnancy. Future studies should accommodate multiple recruitment strategies and flexible study designs to encourage enrollment from and retention across diverse sociodemographic communities.

ObjectiveThe objectives of this study were to: (1) document violent and controlling behaviours within intimate partnerships during the perinatal period; and (2) determine individual, interpersonal and household-level factors influencing the risk of perinatal intimate partner violence (IPV).DesignCross-sectional survey.SettingThe Ottawa Hospital, Department of Obstetrics and Gynecology, Ottawa, Ontario, Canada.ParticipantsPatients who gave birth at The Ottawa Hospital and were >20 days post partum between 17 March and 16 June 2020.Main outcomes and measuresPerinatal IPV was defined as regular controlling behaviours or act-based forms of emotional/physical/sexual abuse in the 12 months before pregnancy, during pregnancy and/or post partum. Log-binomial multivariable regression models were used to compute adjusted risk ratios (aRRs) and 95% CIs to identify potential risk factors for IPV: maternal age, postpartum depression, parity, increase in partner substance use and household income.ResultsAmong 216 participants, the median maternal age was 33 years (IQR: 30–36). In total, 52 (24.07%) reported some form of perinatal IPV, 37 (17.13%) reported regular controlling behaviour and 9 (4.17%) reported both. Household income below the municipal median was the strongest risk factor for perinatal IPV (aRR: 3.24, 95% CI: 1.87 to 5.59). There was no apparent association between maternal age (aRR: 0.99, 95% CI: 0.94 to 1.04), postpartum depression (aRR: 1.03, 95% CI: 1.00 to 1.07), nulliparity (aRR: 1.18, 95% CI: 0.71 to 1.97) or increases in partner substance use (aRR: 0.73, 95% CI: 0.42 to 1.25) with IPV.ConclusionOne in four individuals in this study experienced perinatal IPV. Household income was the strongest risk factor, and surprisingly, many hypothesised risk factors (eg, mental health, partner substance use, etc) were not significantly associated with perinatal IPV in this sample. This highlights the challenges in both measuring IPV and identifying individuals exposed to perinatal IPV during the high stress of the COVID-19 pandemic.

ObjectiveTo examine the association between BMI and folate concentrations in serum and red blood cells (RBC) in pregnant women.DesignA cross-sectional comparison of folate concentrations in serum and RBC sampled simultaneously from the same individual.SettingThe Ottawa Hospital and Kingston General Hospital, Ontario, Canada.SubjectsPregnant women recruited between 12 and 20 weeks of gestation.ResultsA total of 869 pregnant women recruited from April 2008 to April 2009 were included in the final analysis. Serum folate was inversely associated and RBC folate positively associated with BMI, after adjusting for folic acid supplementation, age, gestational age at blood sample collection, race, maternal education, annual income, smoking and MTHFR 677C→T genotype. In stratified analyses, this differential association was significant in women with the MTHFR CC variant. In women with the CT and TT variants, the differential associations were in the same direction but not significant. Folic acid supplementation during pregnancy did not alter the differential association of BMI with serum and RBC folate concentration. This indicates that the current RBC folate cut-off approach for assessing risk of neural tube defects in obese women may be limited.ConclusionsBMI is inversely associated with serum folate and positively associated with RBC folate in pregnant women, especially for those with the MTHFR CC variant.

ObjectiveLong-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression.DesignWe crossed LSL-Kras+/G12D;Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples.ResultsKC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras+/G12Dpancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8+T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1+B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival.ConclusionWe show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.

Objectives To evaluate the trends, determinants and outcomes of CDMR in Ontario. Methods This was a population-based retrospective cohort study of singleton pregnancies in Ontario from 2012 to 2017. Multivariate logistic regression models were used to examine the association of sociodemographic, obstetric and neonatal factors with CDMR. Outcomes were assessed via an ‘intent-to-treat’ approach. Generalized estimating equation models with log-link function were used to estimate the adjusted risk ratio of the Adverse Outcome Index (AOI) between planned CDMR and vaginal births. Differences of Weighted Adverse Outcome Score (WAOS) and Severity Index (SI) between planned mode of delivery were compared. Results Of 668,468 women, 0.7% (4,821) planned CDMR and 85.6% (569,212) planned vaginal deliveries. The prevalence of CDMR was stable at 3.0% of all cesarean deliveries. Older age, higher education, IVF, anxiety, nulliparity, Caucasian race and maternal level IIc hospital deliveries were associated with CDMR. The AOI rate was 5.6% for planned CDMR and 10.3% for planned vaginal birth. Women who planned CDMR had fewer adverse outcomes than women who planned vaginal deliveries (aRR:0.59 [95% CI 0.52–0.67]). The WAOS was lower for planned CDMR than planned vaginal delivery (2.6 v 3.6). The SI was higher with planned CDMR (47.5 v 34.5), in part due to points accumulated from “unanticipated operative procedures.” Conclusions CDMR rates have not increased in Ontario over the last 5 years. Planned CDMR is associated with decreased risk of short-term adverse outcomes, compared to planned vaginal delivery. Analysis of longer-term breastfeeding, infant and pediatric outcomes following CDMR is warranted.

Objectives The impact of gestational weight loss (GWL) on fetal growth in women with obesity remains controversial. Our study aims to examine the respective associations of GWL (net weight loss from pre-pregnancy to delivery) with small for gestational age (SGA 90th percentile) neonates among women with obesity. Methods We conducted a population-based retrospective cohort study of women with obesity (pre-pregnancy body mass index ≥30 kg/m2) who had a singleton birth between 2012 and 2017 in Ontario. Adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for the association between GWL and fetal growth were estimated by using multivariate regression models. Interaction effects were examined to determine whether the impact of GWL on fetal growth varied by obesity classes (I: 30–34.9 kg/m2, II: 35–39.9 kg/m2 and III: 40 kg/m2 or higher). Results Among 89,835 eligible women, 5,276 (5.9%) women with obesity experienced GWL during pregnancy. Overall, GWL in women with obesity had an increased risk of SGA (aRR: 1.43, 95% CI 1.24–1.64) and a decreased risk of LGA (aRR: 0.84, 95% CI 0.74–0.94), compared to the recommended gestational weight gain group. There were significant interaction effects between GWL and obesity classes on SGA (Wald p Conclusions Our study demonstrated GWL in women with obesity was significantly associated with increased risk of SGA neonates. GWL should not be recommended in this population.

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras+/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458–73. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333

Background Homocysteine is an intermediate metabolite implicated in the risk of placenta-mediated complications, including preeclampsia, placental abruption, fetal growth restriction, and pregnancy loss. Large cohort and case-control studies have reported inconsistent associations between homocysteine and these complications. The purpose of this study was to investigate whether elevated maternal plasma homocysteine concentration in the early to mid-second trimester is associated with an increased risk of placenta-mediated complications. We examined the following potential moderating factors that may explain discrepancies among previous studies: high-risk pregnancy and the MTHFR 677C>T polymorphism. Methods We analyzed data from participants recruited to the Ottawa and Kingston (OaK) Birth Cohort from 2002 to 2009 in Ottawa and Kingston, Canada. The primary outcome was a composite of any placenta-mediated complication, defined as a composite of small for gestational age (SGA) infant, preeclampsia, placental abruption, and pregnancy loss. Secondary outcomes were, individually: SGA infant, preeclampsia, placental abruption, and pregnancy loss. We conducted multivariable logistic regression analyses with homocysteine as the primary continuous exposure, adjusting for gestational age at the time of bloodwork and explanatory maternal characteristics. The functional form, i.e., the shape of the homocysteine association with the outcome was examined using restricted cubic splines and information criteria (Akaike’s/Bayesian Information Criterion statistics). Missing data were handled with multiple imputation. Results 7587 cohort participants were included in the study. Maternal plasma homocysteine concentration was significantly associated (linearly) with an increased risk of both the composite outcome of any placenta-mediated complication (p = 0.0007), SGA (p = 0.0010), severe SGA, and marginally with severe preeclampsia, but not preeclampsia, placental abruption and pregnancy loss. An increase in homocysteine concentration significantly increased the odds of any placenta-mediated complication (odds ratio (OR) for a 5 μmol/L increase: 1.63, 95% Confidence Interval (CI) 1.23–2.16) and SGA (OR 1.76, 95% CI 1.25–2.46). Subgroup analyses indicated some potential for modifying effects of the MTHFR 677C>T genotype and high-risk pregnancy, although the interaction was not statistically significant (high-risk subgroup OR 2.37, 95% CI 1.24–4.53, p-value for interaction =0.14). Conclusions Our results suggest an independent effect of early to mid-pregnancy elevated maternal homocysteine on placenta-mediated pregnancy complications. Electronic supplementary material The online version of this article (10.1186/s12884-019-2219-5) contains supplementary material, which is available to authorized users.