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What does Infinity hold for the Marvel Universe? As the Infinity Stones come to Earth, so too comes the war for control over them. But none who wield the stones truly understand the power they contain...or comprehend what it would take to bring them to their end! The nature of the cosmos itself hangs in the balance as we learn the answer to the question on everyone's lips: Who is Requiem? The ramifications of this story will be felt throughout Infinity for years to come! As cosmic war begins to rage, Gerry Duggan and Mike Deodato Jr. gaze into the Infinite - and bring the truth to light!

It remains an enigma whether gestational hypertension (GH) and pre-eclampsia (PE) are distinct entities or different spectrum of the same disease. We aimed to compare the risk factors and outcomes between GH and PE. A total of 7,633 pregnant women recruited between 12 and 20 weeks of gestation in the Ottawa and Kingston Birth Cohort from 2002 to 2009 were included in the analysis. Cox proportional hazards model was used to identify and compare the risk factors for GH and PE by treating gestational age at delivery as the survival time. Logistic regression model was used to compare outcome. Subgroup analysis was performed for early- and late-onset PE. GH and PE shared most risk factors including overweight and obesity, nulliparity, PE history, type 1 and 2 diabetes, and twin birth. Effect size of PE history (RR = 14.1 for GH vs. RR = 6.4 for PE) and twin birth (RR = 4.8 for GH vs. RR = 10.3 for PE) showed substantial difference. Risk factors modified gestational age at delivery in patients with GH and PE in similar pattern. Subgroup analysis showed that early- and late-onset PE shared some risk factors with different effect sizes, whereas folic acid supplementation showed protective effect for early-onset PE only. PE was strongly associated with several adverse outcomes including cesarean section, placental abruption, small for gestational age, preterm birth, and 5 min Apgar score < 7, whereas GH was associated with increased risk of preterm birth only. GH and PE shared common risk factors. Differences in effect sizes of risk factors and outcomes indicate that the conditions may have different pathophysiology and mechanism.

To develop and internally validate a deep-learning algorithm from fetal ultrasound images for the diagnosis of cystic hygromas in the first trimester. 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. 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. 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.

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+/G12D pancreatic 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.

ABSTRACTBackgroundMaternal 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. MethodsWe 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. ResultsWe 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. InterpretationMaternal 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.

Current literature is unclear on the safety and optimal timing of delivery for pregnant individuals with gestational diabetes mellitus, which inspired our study team to conduct a web-based survey study exploring patient and provider opinions on delivery options. However, an incident of fraudulent activity with survey responses prompted a shift in the focus of the research project. Unfortunately, despite the significant rise of web-based surveys used in medical research, there remains very limited evidence on the implications of and optimal methods to handle fraudulent web-based survey responses. Therefore, the objective of this viewpoint paper was to highlight our approach to identifying fraudulent responses in a web-based survey study, in the context of clinical perinatal research exploring patient and provider opinions on delivery options for pregnancies with gestational diabetes mellitus. Initially, we conducted cross-sectional web-based surveys across Canada with pregnant patients and perinatal health care providers. Surveys were available through Research Electronic Data Capture, and recruitment took place between March and October 2023. A change to recruitment introduced a US $5 gift card incentive to increase survey engagement. In mid-October 2023, an incident of fraudulent activity was reported, after which the surveys were deactivated. Systematic guidelines were developed by the study team in consultation with information technology services and the research ethics board to filter fraudulent from true responses. Between October 14 and 16, 2023, an influx of almost 2500 responses (393 patients and 2047 providers) was recorded in our web-based survey. Systematic filtering flagged numerous fraudulent responses. We identified fraudulent responses based on criteria including, but not limited to, identical timestamps and responses, responses with slight variations in wording and similar timestamps, and fraudulent email addresses. Therefore, the incident described in this viewpoint paper highlights the importance of preserving research integrity by using methodologically sound practices to extract true data for research findings. These fraudulent events continue to threaten the credibility of research findings and future evidence-based practices.

Deep learning algorithms have demonstrated remarkable potential in clinical diagnostics, particularly in the field of medical imaging. In this study, we investigated the application of deep learning models in early detection of fetal kidney anomalies. To provide an enhanced interpretation of those models’ predictions, we proposed an adapted two-class representation and developed a multi-class model interpretation approach for problems with more than two labels and variable hierarchical grouping of labels. Additionally, we employed the explainable AI (XAI) visualization tools Grad-CAM and HiResCAM, to gain insights into model predictions and identify reasons for misclassifications. The study dataset consisted of 969 ultrasound images from unique patients; 646 control images and 323 cases of kidney anomalies, including 259 cases of unilateral urinary tract dilation and 64 cases of unilateral multicystic dysplastic kidney. The best performing model achieved a cross-validated area under the ROC curve of 91.28% ± 0.52%, with an overall accuracy of 84.03% ± 0.76%, sensitivity of 77.39% ± 1.99%, and specificity of 87.35% ± 1.28%. Our findings emphasize the potential of deep learning models in predicting kidney anomalies from limited prenatal ultrasound imagery. The proposed adaptations in model representation and interpretation represent a novel solution to multi-class prediction problems.

To evaluate the efficacy, safety, and maternal satisfaction of a newly established integrative postpartum community-based clinic providing comprehensive support for mothers during the first month after discharge from the hospital. Our primary interests were breastfeeding rates, readmission and patient satisfaction. A randomized controlled trial was conducted in Ottawa, Canada, where 472 mothers were randomized via a 1:2 ratio to either receive standard of care (n = 157) or to attend the postpartum breastfeeding clinic (n = 315). Outcome data were captured through questionnaires completed by the participants at 2, 4, 12 and 24 weeks postpartum. Unadjusted and adjusted logistic regression models were conducted to determine the effect of the intervention on exclusive breastfeeding at 12 weeks (primary outcome). Secondary outcomes included breastfeeding rate at 2, 4 and 24 weeks, breastfeeding self-efficacy scale, readmission rate, and satisfaction score. More mothers in the intervention group (n = 195, 66.1%) were exclusively breastfeeding at 12 weeks compared to mothers in the control group (n = 81, 60.5%), however no statistically significant difference was observed (OR = 1.28; 95% CI:0.84-1.95)). The rate of emergency room visits at 2 weeks for the intervention group was 11.4% compared to the standard of care group (15.2%) (OR = 0.69; 95% CI: 0.39-1.23). The intervention group was significantly more satisfied with the overall care they received for breastfeeding compared to the control group (OR = 1.96; 95% CI: 3.50-6.88)). This new model of care did not significantly increase exclusive breastfeeding at 12 weeks. However, there were clinically meaningful improvements in the rate of postnatal problems and satisfaction that support this new service delivery model for postpartum care. A community-based multidisciplinary postpartum clinic is feasible to implement and can provide appropriate and highly satisfactory care to mother-baby dyads. This model of care may be more beneficial in a population that is not already predisposed to breastfeed. ClinicalTrials.gov NCT02043119.

This prospective cohort study designed to assess the effect of folic acid supplementation in pregnancy on the risk of preeclampsia (PE) took place in Ottawa, ON and Kingston, ON, Canada, from September 1, 2002 to August 31, 2008. Pregnant women, less than 20 weeks gestational age were recruited and delivered in the Ottawa region and the Kingston General Hospital. Demographic characteristics of the study participants and the patterns of supplementation of folic acid were described and occurrence of PE between women with folic acid supplementation during pregnancy and women without were compared. Multiple logistic regression was used in the estimation of the independent effect of supplementation of folic acid. Additional analyses assessing the effect of low RBC and serum folate and dose-response relationship were performed. Analyses were performed in all study participants, and then in high risk and low risk sub-groups, respectively. A total of 7,669 participants were included in the final analysis. Ninety five percent of the study participants were taking folic acid supplementation in early second trimester. The rate of PE was lower in the supplementation group than in the no supplementation group, and the difference was statistically significant in high risk women. Similar patterns of associations were observed in analysis by RBC and serum folate levels and in dose-response analysis. Folic acid supplementation in pregnancy may reduce PE risk in pregnant women, especially in those women with increased risk of developing PE.