Socioeconomic Disadvantage in Pregnancy and Postpartum Risk of Cardiovascular Disease.

BACKGROUND: Pregnancy is an educable and actionable life stage to address social determinants of health (SDOH) and lifelong cardiovascular disease (CVD) prevention. But the link between a risk score that combines multiple neighborhood-level social determinants in pregnancy and the risk of long-term CVD remains to be evaluated. OBJECTIVE: To examine whether neighborhood-level socioeconomic disadvantage measured by the Area Deprivation Index (ADI) in early pregnancy is associated with a higher 30-year predicted risk of CVD postpartum, as measured by the Framingham Risk Score. METHODS: An analysis of data from the prospective Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study longitudinal cohort. Participant home addresses during early pregnancy were geocoded at the Census-block level. The exposure was neighborhood-level socioeconomic disadvantage using the 2015 ADI by tertile (least deprived [T1], reference; most deprived [T3]) measured in the first trimester. Outcomes were the predicted 30-year risks of atherosclerotic CVD (ASCVD, composite of fatal and non-fatal coronary heart disease and stroke) and total CVD (composite of ASCVD plus coronary insufficiency, angina pectoris, transient ischemic attack, intermittent claudication, and heart failure) using the Framingham Risk Score measured 2-to-7 years after delivery. These outcomes were assessed as continuous measures of absolute estimated risk in increments of 1%, and, secondarily, as categorical measures with high-risk defined as an estimated probability of CVD >10%. Multivariable linear regression and modified Poisson regression models adjusted for baseline age and individual-level social determinants, including health insurance, educational attainment, and household poverty. RESULTS: Among 4,309 nulliparous individuals at baseline, the median age was 27 years (IQR: 23-31) and the median ADI was 43 (IQR: 22-74). At 2-to-7 years postpartum (median: 3.1 years, IQR: 2.5, 3.7), the median 30-year risk of ASCVD was 2.3% (IQR: 1.5, 3.5) and of total CVD was 5.5% (IQR: 3.7, 7.9); 2.2% and 14.3% of individuals had predicted 30-year risk >10%, respectively. Individuals living in the highest ADI tertile had a higher predicted risk of 30-year ASCVD % (adj. ß: 0.41; 95% CI: 0.19, 0.63) compared with those in the lowest tertile; and those living in the top two ADI tertiles had higher absolute risks of 30-year total CVD % (T2: adj. ß: 0.37; 95% CI: 0.03, 0.72; T3: adj. ß: 0.74; 95% CI: 0.36, 1.13). Similarly, individuals living in neighborhoods in the highest ADI tertile were more likely to have a high 30-year predicted risk of ASCVD (aRR: 2.21; 95% CI: 1.21, 4.02) and total CVD ≥10% (aRR: 1.35; 95% CI: 1.08, 1.69). CONCLUSIONS: Neighborhood-level socioeconomic disadvantage in early pregnancy was associated with a higher estimated long-term risk of CVD postpartum. Incorporating aggregated SDOH into existing clinical workflows and future research in pregnancy could reduce disparities in maternal cardiovascular health across the lifespan, and requires further study.

An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus.

The hippocampus contains many unique cell types, which serve the structure's specialized functions, including learning, memory and cognition. These cells have distinct spatial topography, morphology, physiology, and connectivity, highlighting the need for transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus across ten adult neurotypical donors. We defined molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization and transfer learning, we integrated these data to define gene expression patterns within the snRNA-seq data and infer the expression of these patterns in the SRT data. With this approach, we leveraged existing rodent datasets that feature information on circuit connectivity and neural activity induction to make predictions about axonal projection targets and likelihood of ensemble recruitment in spatially-defined cellular populations of the human hippocampus. Finally, we integrated genome-wide association studies with transcriptomic data to identify enrichment of genetic components for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders across cell types, spatial domains, and gene expression patterns of the human hippocampus. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.

A Multi-Site Study to Develop and Validate First Trimester, Circulating Microparticle Biomarkers for Tiered Risk Stratification of Spontaneous Preterm Birth in Nulliparas.

BACKGROUND: Despite much research, advances in early prediction of spontaneous preterm birth (sPTB) has been slow. The evolving field of circulating microparticle (CMP) biology may identify novel blood-based, and clinically useful, biomarkers. OBJECTIVE: To test the ability of a previously identified, 7-marker set of CMP-derived proteins from the first trimester of pregnancy, in the form of an in vitro diagnostic multivariate index assay (IVDMIA), to stratify pregnant patients according to their risk for sPTB. STUDY DESIGN: We employed a previously validated set of CMP protein biomarkers, utilizing mass spectrometry assays and a nested case-control design in a subset of participants from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). We evaluated these biomarkers in the form of an IVDMIA to predict risk for sPTB at different gestational ages. Plasma samples collected at 9- to 13-weeks' gestation were analyzed. The IVDMIA assigned subjects to one of three sPTB risk categories: low risk (LR), moderate risk (MR), or high risk (HR). Independent validation on a set-aside set confirmed the IVDMIA's performance in risk stratification. RESULTS: Samples from 400 participants from the nuMoM2b cohort were used for the study; of these, 160 delivered <37 weeks and 240 delivered at term. Through Monte Carlo simulation in which the validation results were adjusted based on actual weekly sPTB incidence rates in the nuMoM2b cohort, the IVDMIA stratifications demonstrated statistically significant differences among the risk groups in time-to-event (birth) analysis (p < 0.0001). The incidence-rate adjusted cumulative risks of sPTB at ≤ 32 weeks' gestation were 0.4%, 1.6%, and 7.5%, respectively for the LR, MR, and HR groups, respectively. Compared to the LR group, the corresponding risk ratios (RR) of the IVDMIA assigned MR and HR group were 4.25 (95% CI 2.2 to 7.9) and 19.92 (95% CI 10.4 to 37.4), respectively. CONCLUSION: A first trimester CMP protein biomarker panel can be used to stratify risk for sPTB at different gestational ages. Such a multi-tiered stratification tool could be used to assess risk early in pregnancy to enable timely clinical management and interventions, and, ultimately, to enable the development of tailored care pathways for sPTB prevention.

Updates in Translational Science for Esophageal and Gastric Cancers.

In this article, the authors summarize the current state of translational science for esophageal and gastric cancers. The available targeted therapies, immunotherapies, and recently discovered molecular targets are reviewed. The authors introduce circulating tumor deoxyribonucleic acid and its promise as a biomarker to detect disease recurrence. The authors present patient-derived organoids as a new model for studying carcinogenesis and treatment responses. Finally, we discuss the implications of organoid models for precision oncology and describe exciting new work applying gene editing technology to organoids and studying tumor-microenvironment interactions using 3-dimensional co-culture systems.

Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.

Microscopic Small Airway Abnormalities Identified in Early Idiopathic Pulmonary Fibrosis In Vivo Using Endobronchial Optical Coherence Tomography.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) affects subpleural lung, but is considered to spare small airways. Micro-CT studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. We use EB-OCT to evaluate small airways in early IPF and control subjects in vivo. METHODS: EB-OCT was performed in 12 IPF and 5 control subjects (matched by age, sex, smoking-history, height, BMI). IPF subjects had early disease with mild restriction (FVC: 83.5% predicted), diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for UIP present) and less affected (some but not all criteria for UIP present) sites. Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. RESULTS: Compared to control subjects (mean: 11.2 bronchioles/cm3; SD: 6.2), there was significant bronchiole reduction in IPF subjects (42% loss; mean: 6.5/cm3; SD: 3.4; p=0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; p<0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; p=0.024) sites. Stereology metrics showed IPF affected small airways were significantly larger and more distorted/irregular than in IPF less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (p=0.36-1.0). CONCLUSION: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30 and 50%), even in areas minimally affected by disease, compared to matched controls. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

Genetic polymorphisms associated with adverse pregnancy outcomes in nulliparas.

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Adverse Pregnancy Outcomes and Predicted 30-Year Risk of Maternal Cardiovascular Disease 2-7 Years After Delivery.

OBJECTIVE: To determine whether adverse pregnancy outcomes are associated with a higher predicted 30-year risk of atherosclerotic cardiovascular disease (CVD; ie, coronary artery disease or stroke). METHODS: This was a secondary analysis of the prospective Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be Heart Health Study longitudinal cohort. The exposures were adverse pregnancy outcomes during the first pregnancy (ie, gestational diabetes mellitus [GDM], hypertensive disorder of pregnancy, preterm birth, and small- and large-for-gestational-age [SGA, LGA] birth weight) modeled individually and secondarily as the cumulative number of adverse pregnancy outcomes (ie, none, one, two or more). The outcome was the 30-year risk of atherosclerotic CVD predicted with the Framingham Risk Score assessed at 2-7 years after delivery. Risk was measured both continuously in increments of 1% and categorically, with high predicted risk defined as a predicted risk of atherosclerotic CVD of 10% or more. Linear regression and modified Poisson models were adjusted for baseline covariates. RESULTS: Among 4,273 individuals who were assessed at a median of 3.1 years after delivery (interquartile range 2.5-3.7), the median predicted 30-year atherosclerotic CVD risk was 2.2% (interquartile range 1.4-3.4), and 1.8% had high predicted risk. Individuals with GDM (least mean square 5.93 vs 4.19, adjusted ß=1.45, 95% CI, 1.14-1.75), hypertensive disorder of pregnancy (4.95 vs 4.22, adjusted ß=0.49, 95% CI, 0.31-0.68), and preterm birth (4.81 vs 4.27, adjusted ß=0.47, 95% CI, 0.24-0.70) were more likely to have a higher absolute risk of atherosclerotic CVD. Similarly, individuals with GDM (8.7% vs 1.4%, adjusted risk ratio [RR] 2.02, 95% CI, 1.14-3.59), hypertensive disorder of pregnancy (4.4% vs 1.4%, adjusted RR 1.91, 95% CI, 1.17-3.13), and preterm birth (5.0% vs 1.5%, adjusted RR 2.26, 95% CI, 1.30-3.93) were more likely to have a high predicted risk of atherosclerotic CVD. A greater number of adverse pregnancy outcomes within the first birth was associated with progressively greater risks, including per 1% atherosclerotic CVD risk (one adverse pregnancy outcome: 4.86 vs 4.09, adjusted ß=0.59, 95% CI, 0.43-0.75; two or more adverse pregnancy outcomes: 5.51 vs 4.09, adjusted ß=1.16, 95% CI, 0.82-1.50), and a high predicted risk of atherosclerotic CVD (one adverse pregnancy outcome: 3.8% vs 1.0%, adjusted RR 2.33, 95% CI, 1.40-3.88; two or more adverse pregnancy outcomes: 8.7 vs 1.0%, RR 3.43, 95% CI, 1.74-6.74). Small and large for gestational age were not consistently associated with a higher atherosclerotic CVD risk. CONCLUSION: Individuals who experienced adverse pregnancy outcomes in their first birth were more likely to have a higher predicted 30-year risk of CVD measured at 2-7 years after delivery. The magnitude of risk was higher with a greater number of adverse pregnancy outcomes experienced.

Pregnancy Outcomes in Women Who Developed Elevated Blood Pressure and Stage I Hypertension after 20 Weeks Gestation.

OBJECTIVE: The American College of Obstetrics threshold for hypertension (≥140/90 mm Hg) differs from those of the American College of Cardiology (ACC) and the American Heart Association (AHA). It is unknown if ACC/AHA hypertension levels are associated with adverse pregnancy outcomes (APOs) after 20 weeks gestation. The purpose of this study is to analyze APOs in women with blood pressure (BP) in the elevated or stage 1 range after 20 weeks gestation. STUDY DESIGN: This was a secondary analysis of the nuMoM2b prospective cohort study of 10,038 nulliparous, singleton pregnancies between 2010 and 2014. BP was measured at three visits during the pregnancy using a standard protocol. Women without medical comorbidities, with normal BP by ACC/AHA guidelines (systolic BP [SBP] < 120 and diastolic BP [DBP] < 80 mm Hg) up to 22 weeks, were included. Exposure was BP between 22 and 29 weeks gestation: normal (SBP < 120 and DBP < 80 mm Hg), elevated (SBP: 120-129 and DBP < 80 mm Hg), and stage 1 (SBP: 130-139 or DBP: 80-89 mm Hg). The primary outcome was hypertensive disorder of pregnancy (HDP) at delivery. Secondary outcomes included fetal growth restriction (FGR), placental abruption, preterm delivery, and cesarean delivery. Multivariable-adjusted odds ratio (aORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. RESULTS: Of 4,460 patients that met inclusion criteria, 3,832 (85.9%) had BP in the normal range, 408 (9.1%) in elevated, and 220 (4.9%) in stage 1 range between 22 and 29 weeks. The likelihood of HDP was significantly higher in women with elevated BP (aOR 1.71, 95%CI: 1.18,2.48), and stage 1 BP (aOR: 2.79, 95%CI: 1.84,4.23) compared to normal BP (p < 0.001). Stage 1 BP had twice odds of FGR (aOR: 2.33, 95%CI: 1.22,4.47) and elevated BP had three times odds of placental abruption (aOR: 3.03; 95%CI: 1.24,7.39). CONCLUSION: Elevated or stage 1 BP >20 weeks of pregnancy are associated with HDP, FGR, and placental abruption. KEY POINTS: · Elevated and stage 1 BP increases risk for HDP.. · Elevated BP increases risk for placental abruption.. · Stage 1 BP increases risk for FGR..

Prediction of metabolic syndrome following a first pregnancy.

BACKGROUND: The prevalence of metabolic syndrome is rapidly increasing in the United States. We hypothesized that prediction models using data obtained during pregnancy can accurately predict the future development of metabolic syndrome. OBJECTIVE: This study aimed to develop machine learning models to predict the development of metabolic syndrome using factors ascertained in nulliparous pregnant individuals. STUDY DESIGN: This was a secondary analysis of a prospective cohort study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study [nuMoM2b-HHS]). Data were collected from October 2010 to October 2020, and analyzed from July 2023 to October 2023. Participants had in-person visits 2 to 7 years after their first delivery. The primary outcome was metabolic syndrome, defined by the National Cholesterol Education Program Adult Treatment Panel III criteria, which was measured within 2 to 7 years after delivery. A total of 127 variables that were obtained during pregnancy were evaluated. The data set was randomly split into a training set (70%) and a test set (30%). We developed a random forest model and a lasso regression model using variables obtained during pregnancy. We compared the area under the receiver operating characteristic curve for both models. Using the model with the better area under the receiver operating characteristic curve, we developed models that included fewer variables based on SHAP (SHapley Additive exPlanations) values and compared them with the original model. The final model chosen would have fewer variables and noninferior areas under the receiver operating characteristic curve. RESULTS: A total of 4225 individuals met the inclusion criteria; the mean (standard deviation) age was 27.0 (5.6) years. Of these, 754 (17.8%) developed metabolic syndrome. The area under the receiver operating characteristic curve of the random forest model was 0.878 (95% confidence interval, 0.846-0.909), which was higher than the 0.850 of the lasso model (95% confidence interval, 0.811-0.888; P<.001). Therefore, random forest models using fewer variables were developed. The random forest model with the top 3 variables (high-density lipoprotein, insulin, and high-sensitivity C-reactive protein) was chosen as the final model because it had the area under the receiver operating characteristic curve of 0.867 (95% confidence interval, 0.839-0.895), which was not inferior to the original model (P=.08). The area under the receiver operating characteristic curve of the final model in the test set was 0.847 (95% confidence interval, 0.821-0.873). An online application of the final model was developed (https://kawakita.shinyapps.io/metabolic/). CONCLUSION: We developed a model that can accurately predict the development of metabolic syndrome in 2 to 7 years after delivery.

A Pilot Study Using Machine Learning Algorithms and Wearable Technology for the Early Detection of Postoperative Complications After Cardiothoracic Surgery.

OBJECTIVE: To evaluate whether a machine learning algorithm (i.e. the "NightSignal" algorithm) can be used for the detection of postoperative complications prior to symptom onset after cardiothoracic surgery. SUMMARY BACKGROUND DATA: Methods that enable the early detection of postoperative complications after cardiothoracic surgery are needed. METHODS: This was a prospective observational cohort study conducted from July 2021 to February 2023 at a single academic tertiary care hospital. Patients aged 18 years or older scheduled to undergo cardiothoracic surgery were recruited. Study participants wore a Fitbit watch continuously for at least 1 week preoperatively and up to 90-days postoperatively. The ability of the NightSignal algorithm-which was previously developed for the early detection of Covid-19-to detect postoperative complications was evaluated. The primary outcomes were algorithm sensitivity and specificity for postoperative event detection. RESULTS: A total of 56 patients undergoing cardiothoracic surgery met inclusion criteria, of which 24 (42.9%) underwent thoracic operations and 32 (57.1%) underwent cardiac operations. The median age was 62 (IQR: 51-68) years and 30 (53.6%) patients were female. The NightSignal algorithm detected 17 of the 21 postoperative events a median of 2 (IQR: 1-3) days prior to symptom onset, representing a sensitivity of 81%. The specificity, negative predictive value, and positive predictive value of the algorithm for the detection of postoperative events were 75%, 97%, and 28%, respectively. CONCLUSIONS: Machine learning analysis of biometric data collected from wearable devices has the potential to detect postoperative complications-prior to symptom onset-after cardiothoracic surgery.

Postpartum readmission risk: a comparison between stillbirths and live births.

BACKGROUND: Stillbirth occurs more commonly among pregnant people with comorbid conditions and obstetrical complications. Stillbirth also independently increases maternal morbidity and imparts a psychosocial hazard when compared with live birth. These distinct needs and burden may increase the risk for postpartum readmission after stillbirth. OBJECTIVE: This study aimed to examine the risk for maternal postpartum readmission after stillbirth in comparison with live birth and to identify indications for readmission and the associated risk factors. STUDY DESIGN: This was a retrospective cohort of patients with singleton stillbirths or live births, delivered at ≥20 weeks' gestation, who were identified from the 2019 Nationwide Readmissions Database. The primary outcome was all-cause readmission within 6 weeks of discharge from the childbirth hospitalization. The association between stillbirth (vs live birth) and risk for readmission was assessed using multivariable regression models with adjustment for maternal age, sociodemographic characteristics, maternal and obstetrical conditions, and delivery characteristics. Within the stillbirth group, risk factors for readmission were further examined using multivariable regression. The secondary outcomes included principal indication for readmission (categorized based on principal diagnosis code of the readmission hospitalization) and timing of readmission (number of weeks after childbirth hospitalization). Differences in these secondary outcomes were compared between the stillbirth and live birth groups using chi-square tests. All analyses accounted for the complex sample design to generate nationally representative estimates. RESULTS: Postpartum readmission occurred in 2.7% of 16,636 patients with stillbirths, whereas it occurred in 1.6% of 2,870,677 patients with live births (unadjusted risk ratio, 1.65; 95% confidence interval, 1.47-1.86). The higher risk for readmission after stillbirth (vs live birth) persisted after adjusting for maternal, obstetrical, and delivery characteristics (adjusted risk ratio, 1.27; 95% confidence interval, 1.11-1.46). The distribution of principal indication for readmission differed after stillbirth and after live birth and included hypertension (30.2% vs 39.5%; unadjusted risk ratio, 0.76; 95% confidence interval, 0.63-0.93), mental health or substance use disorders (6.8% vs 3.6%; unadjusted risk ratio, 1.90; 95% confidence interval, 1.15-3.16), and venous thromboembolism (5.8% vs 2.0%; unadjusted risk ratio, 2.87; 95% confidence interval, 1.60-5.17). Among patients with stillbirths, 56.0% of readmissions occurred within 1 week, 71.8% within 2 weeks, and 88.1% within 4 weeks; the timing of readmission did not differ significantly between the stillbirth and live birth cohorts. Pregestational diabetes (adjusted risk ratio, 1.87; 95% confidence interval, 1.20-2.93), gestational diabetes (adjusted risk ratio, 1.67; 95% confidence interval, 1.03-2.71), hypertensive disorders of pregnancy (adjusted risk ratio, 1.80; 95% confidence interval, 1.31-2.47), obesity (adjusted risk ratio, 1.46; 95% confidence interval, 1.01-2.12), and primary cesarean delivery (adjusted risk ratio, 1.74; 95% confidence interval, 1.17-2.58) were associated with a higher risk for readmission after stillbirth, whereas higher household income was associated with a lower risk for readmission (eg, adjusted risk ratio for income ≥$82,000 vs $1-$47,999, 0.48; 95% confidence interval, 0.30-0.77). CONCLUSION: When compared with live births, the risk for postpartum readmission was higher after stillbirths, even after adjustment for differences in the patient demographic and clinical characteristics. Readmission for mental health or substance use disorders and venous thromboembolism is more common after stillbirths than after live births.

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

Infection and Sepsis Trends during United States' Delivery Hospitalizations from 2000 to 2020.

OBJECTIVE: This study aimed to evaluate trends, risk factors, and outcomes associated with infections and sepsis during delivery hospitalizations in the United States. STUDY DESIGN: The 2000-2020 National Inpatient Sample was used for this repeated cross-sectional analysis. Delivery hospitalizations of patients aged 15 to 54 with and without infection and sepsis were identified. Common infection diagnoses during delivery hospitalizations analyzed included (i) pyelonephritis, (ii) pneumonia/influenza, (iii) endometritis, (iv) cholecystitis, (v) chorioamnionitis, and (vi) wound infection. Temporal trends in sepsis and infection during delivery hospitalizations were analyzed. The associations between sepsis and infection and common chronic health conditions including asthma, chronic hypertension, pregestational diabetes, and obesity were analyzed. The associations between clinical, demographic, and hospital characteristics, and infection and sepsis were determined with unadjusted and adjusted logistic regression models with unadjusted odds ratio (OR) and adjusted odds ratios with 95% confidence intervals as measures of association. RESULTS: An estimated 80,158,622 delivery hospitalizations were identified and included in the analysis, of which 2,766,947 (3.5%) had an infection diagnosis and 32,614 had a sepsis diagnosis (4.1 per 10,000). The most common infection diagnosis was chorioamnionitis (2.7% of deliveries) followed by endometritis (0.4%), and wound infections (0.3%). Infection and sepsis were more common in the setting of chronic health conditions. Evaluating trends in individual infection diagnoses, endometritis and wound infection decreased over the study period both for patients with and without chronic conditions, while risk for pyelonephritis and pneumonia/influenza increased. Sepsis increased over the study period for deliveries with and without chronic condition diagnoses. Risks for adverse outcomes including mortality, severe maternal morbidity, the critical care composite, and acute renal failure were all significantly increased in the presence of sepsis and infection. CONCLUSION: Endometritis and wound infections decreased over the study period while risk for sepsis increased. Infection and sepsis were associated with chronic health conditions and accounted for a significant proportion of adverse obstetric outcomes including severe maternal morbidity. KEY POINTS: · Sepsis increased over the study period for deliveries with and without chronic condition diagnoses.. · Endometritis and wound infection decreased over the study period.. · Infection and sepsis accounted for a significant proportion of adverse obstetric outcomes..

Strategies to combine 3D vasculature and brain CTA with deep neural networks: Application to LVO.

Automated tools to detect large vessel occlusion (LVO) in acute ischemic stroke patients using brain computed tomography angiography (CTA) have been shown to reduce the time for treatment, leading to better clinical outcomes. There is a lot of information in a single CTA and deep learning models do not have an obvious way of being conditioned on areas most relevant for LVO detection, i.e., the vasculature structure. In this work, we compare and contrast strategies to make convolutional neural networks focus on the vasculature without discarding context information of the brain parenchyma and propose an attention-inspired strategy to encourage this. We use brain CTAs from which we obtain 3D vasculature images. Then, we compare ways of combining the vasculature and the CTA images using a general-purpose network trained to detect LVO. The results show that the proposed strategies allow to improve LVO detection and could potentially help to learn other cerebrovascular-related tasks.

Association of Mild Iodine Insufficiency during Pregnancy with Child Neurodevelopment in Patients with Subclinical Hypothyroidism or Hypothyroxinemia.

OBJECTIVE: Our objective was to evaluate whether iodine status in pregnant patients with either subclinical hypothyroidism or hypothyroxinemia in the first half of pregnancy is associated with measures of behavior and neurodevelopment in children through the age of 5 years. STUDY DESIGN: This is a secondary analysis of a multicenter study consisting of two randomized, double-masked, placebo-controlled treatment trials conducted in parallel. Patients with a singleton gestation before 20 weeks' gestation underwent thyroid screening using serum thyrotropin and free thyroxine. Participants with subclinical hypothyroidism or hypothyroxinemia were randomized to levothyroxine replacement or an identical placebo. At randomization, maternal urine was collected and stored for subsequent urinary iodine excretion analysis. Urinary iodine concentrations greater than 150 µg/L were considered iodine sufficient, and concentrations of 150 µg/L or less were considered iodine insufficient. The primary outcome was a full-scale intelligence quotient (IQ) score at the age of 5 years, the general conceptual ability score from the Differential Ability Scales-II at the age of 3 if IQ was not available, or death before 3 years. RESULTS: A total of 677 pregnant participants with subclinical hypothyroidism and 526 with hypothyroxinemia were randomized. The primary outcome was available in 1,133 (94%) of children. Overall, 684 (60%) of mothers were found to have urinary iodine concentrations >150 µg/L. Children of iodine-sufficient participants with subclinical hypothyroidism had similar primary outcome scores when compared to children of iodine-insufficient participants (95 [84-105] vs. 96 [87-109], P adj = 0.73). After adjustment, there was also no difference in IQ scores among children of participants with hypothyroxinemia at 5 to 7 years of age (94 [85 - 102] and 91 [81 - 100], Padj 1/4 0.11). Treatment with levothyroxine was not associated with neurodevelopmental or behavioral outcomes regardless of maternal iodine status (p > 0.05). CONCLUSION: Maternal urinary iodine concentrations ≤150 µg/L were not associated with abnormal cognitive or behavioral outcomes in offspring of participants with either subclinical hypothyroidism or hypothyroxinemia. KEY POINTS: · Most pregnant patients with subclinical thyroid disease are iodine sufficient.. · Mild maternal iodine insufficiency is not associated with lower offspring IQ at 5 years.. · Iodine supplementation in subclinical thyroid disease is unlikely to improve IQ..