Syngeneic mesenchymal stem cells loaded with telomerase-dependent oncolytic adenoviruses enhance anti-metastatic efficacy.

Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable.

Effects of vitamin D in pregnancy on maternal and offspring health-related outcomes: An umbrella review of systematic review and meta-analyses.

BACKGROUND: Vitamin D deficiency has been linked with several adverse maternal and fetal outcomes. OBJECTIVE: To summarize systematic reviews and meta-analyses evaluating the effects of vitamin D deficiency and of vitamin D supplementation in pregnancy on maternal and offspring health-related outcomes. METHODS: Prior to conducting this umbrella review, we registered the protocol in PROSPERO (CRD42022368003). We conducted searches in PubMed, Embase, and Cochrane Library for systematic reviews and meta-analyses on vitamin D in pregnancy, from database inception to October 2, 2023. All outcomes related to vitamin D in pregnancy obtained from the systematic reviews and meta-analyses were extracted. DATA EXTRACTION: Two reviewers independently chose studies and collected information on health outcomes. The quality of the included articles' methodology was assessed using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews-2). RESULTS: We identified 16 eligible systematic reviews and meta-analyses, which included 250,569 women. Our results demonstrated that vitamin D deficiency in pregnancy is associated with increased risk of preterm birth, small-for gestational age/low birth weight infants, recurrent miscarriage, bacterial vaginosis and gestational diabetes mellitus. Vitamin D supplementation in pregnancy increases birth weight, and reduces the risk of maternal pre-eclampsia, miscarriage, and vitamin D deficiency, fetal or neonatal mortality, as well as attention-deficit hyperactivity disorder, and autism spectrum disorder in childhood. In women with gestational diabetes mellitus, vitamin D supplementation in pregnancy can reduce the risk of maternal hyperbilirubinemia, polyhydramnios, macrosomia, fetal distress, and neonatal hospitalization. CONCLUSION: Due to the association with adverse maternal and offspring health outcomes, we recommend the vitamin D status in pregnancy should be monitored, particularly in women at high risk of vitamin D deficiency. It is suggested that pregnant women take a dose of >400 IU/day of vitamin D supplementation during pregnancy to prevent certain adverse outcomes.

Adverse pregnancy outcomes in pregnant women with chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of adverse pregnancy outcomes, but the risk at different stages of CKD (defined by estimated glomerular filtration rate, eGFR) compared with women without CKD has not been quantified in large cohorts. OBJECTIVES: To quantify the association between CKD and adverse pregnancy outcomes according to CKD definition, CKD stage and presence or absence of diabetes. SEARCH STRATEGY: A systematic search of EMBASE and MEDLINE from inception to 5 January 2023. SELECTION CRITERIA: English-language randomised controlled trials as well as cohort and case-control studies investigating adverse pregnancy outcomes in pregnant women with CKD. DATA COLLECTION AND ANALYSIS: Two reviewers conducted independent data extractions. A random-effects model was used to estimate risk. MAIN RESULTS: We included 19 studies with 3 251 902 women. Defining CKD using eGFR or serum creatinine produced results with greater effect size but wider confidence intervals. Compared with CKD stages 1-2, women with CKD stages 3-5 have a greater risk, but also greater imprecision in the risk estimate, of the following outcomes: pre-eclampsia (OR 55.18, 95% CI 2.63-1157.68, vs OR 24.74, 95% CI 1.75-348.70), preterm birth (OR 20.24, 95% CI 2.85-143.75, vs OR 8.18, 95% CI 1.54-43.46) and neonatal intensive care unit admission (OR 19.32, 95% CI 3.07-121.68, vs OR 9.77, 95% CI 2.49-38.39). Women with diabetic kidney disease, compared with women without diabetic kidney disease, have higher risks of maternal mortality, small-for-gestational-age neonates, pre-eclampsia and gestational hypertension. CONCLUSIONS: There is heterogeneity in the definition of CKD in pregnancy. Future studies should consider ways to standardise its definition and measurement in pregnancy.

Pregnancy-Associated Cancer: A Systematic Review and Meta-Analysis.

This study aimed to systematically evaluate and quantify the risk of adverse maternal and neonatal outcomes in patients with pregnancy-associated cancer (PAC). This study was conducted from February 13, 2021, through July 24, 2023. A systematic search of MEDLINE, Embase, Web of Science Core Collection, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials was conducted to identify studies reporting outcomes for patients with PAC. The study was registered on PROSPERO. Two reviewers independently conducted screening, data extraction, and quality assessment. The associations were quantified using random-effects meta-analysis. The initial search produced 29,401 titles and abstracts, after which 147 unique full-text articles were screened, of which 22 articles with 59,190 pregnancies with PAC from 70,097,167 births were included in the meta-analysis. Women with PAC were at significantly increased risk of cesarean deliveries (risk ratio [RR], 1.58; 95% CI, 1.31-1.89), preterm birth (RR, 3.07; 95% CI, 2.37-3.98), venous thromboembolism (RR, 6.76; 95% CI, 5.08-8.99), and maternal death (RR, 41.58; 95% CI, 20.38-84.83). The only outcome with reduced risk was instrumental mode of delivery (RR, 0.67; 95% CI, 0.52-0.87). Pregnancy-associated cancer increases risk of adverse outcomes, including a 7-fold risk of venous thromboembolism and a 42-fold risk of maternal death. Further research is required to better understand the mechanisms leading to these adverse outcomes, especially for women who are not diagnosed until the postpartum period. Affected women should have counseling regarding their increased risk of adverse outcomes.

Is the Current Cut Point for Glycated Haemoglobin (HbA1c) Correct for Diagnosing Diabetes Mellitus in Premenopausal Women? Evidence to Inform Discussion.

INTRODUCTION: Women are on average diagnosed with diabetes mellitus at later age than men but have higher mortality. As the diagnosis of diabetes mellitus is primarily based on HbA1c, the use of a non-specific reference range and cut point for diabetes mellitus that does not account for gender differences in diabetes could potentially lead to underdiagnosis of diabetes mellitus in women and missed opportunities for intervention. We investigated whether a contributing factor to the later diagnosis in women may be a difference in distribution of HbA1c in premenopausal women versus men of the same age by comparing HbA1c values in men and women across multiple sites in the UK. METHODS: We analysed the HbA1c levels of 146,907 individuals who underwent single testing only and had HbA1c ≤ 50 mmol/mol between 2012 and 2019 in one laboratory (cohort 1). This was replicated in six laboratories with 938,678 individuals tested between 2019 and 2021 (cohort 2). RESULTS: In cohort 1, women < 50 years old had an HbA1c distribution markedly lower than that in men by a mean of 1.6 mmol/mol (p < 0.0001), while the difference in the distribution of HbA1c for individuals aged ≥ 50 years was less pronounced (mean difference 0.9 mmol/mol, p < 0.0001). For individuals under the age of 50, HbA1c in women lagged by up to 10 years compared to men. Similar findings were found in cohort 2. We estimated an additional 17% (n = 34,953) of undiagnosed women aged < 50 years in England and Wales could be reclassified to have diabetes mellitus, which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years. CONCLUSION: The HbA1c cut point for diagnosis of diabetes mellitus may need to be re-evaluated in women under the age of 50 years. Early identification of diabetes mellitus in women has the potential to improve women's health outcomes in the longer term.

Diabetes detection in women with gestational diabetes and polycystic ovarian syndrome.

Gestational diabetes mellitus (GDM) and polycystic ovarian syndrome (PCOS) represent two of the highest risk factors for development of type 2 diabetes mellitus in young women. As these increasingly common conditions generally affect younger women, early detection of dysglycemia is key if preventative measures are to be effective. While international guidance recommends screening for type 2 diabetes, current screening strategies suffer from significant challenges.First, guidance lacks consensus in defining which tests to use and frequency of monitoring, thereby sending mixed messages to healthcare professionals.Second, conformity to guidance is poor, with only a minority of women having tests at the recommended frequency (where specified). Approaches to improve conformity have focused on healthcare related factors (largely technology driven reminder systems), but patient factors such as convenience and clear messaging around risk have been neglected.Third, and most critically, current screening strategies are too generic and rely on tests that become abnormal far too late in the trajectory towards dysglycemia to offer opportunities for effective preventative measures. Risk factors show wide interindividual variation, and insulin sensitivity and ß cell function are often abnormal during pre-diabetes stage, well before frank diabetes.New, consistent, targeted screening strategies are required that incorporate early, prevention focused testing and personalised risk stratification.

Hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDP) are one of the most commonly occurring complications of pregnancy and include chronic hypertension, gestational hypertension, and pre-eclampsia. New developments in early pregnancy screening to identify women at high risk for pre-eclampsia combined with targeted aspirin prophylaxis could greatly reduce the number of affected pregnancies. Furthermore, recent advances in the diagnosis of pre-eclampsia, such as placental growth factor based testing, have been shown to improve the identification of those pregnancies at highest risk of severe complications. Evidence from trials has refined the target blood pressure and timing of delivery to manage chronic hypertension and pre-eclampsia with non-severe features, respectively. Importantly, a wealth of epidemiological data now links HDP to future cardiovascular disease and diabetes decades after an affected pregnancy. This review discusses the current guidelines and research data on the prevention, diagnosis, management, and postnatal follow-up of HDP. It also discusses the gap in knowledge regarding the long term risks for cardiovascular disease following HDP and illustrates the importance of improving adherence to postnatal guidelines to monitor hypertension and the need for more research focused on primary prevention of future cardiovascular disease in women identified as being at high risk because of HDP.

The Effect of the COVID-19 Pandemic on HbA1c Testing: Prioritization of High-Risk Cases and Impact of Social Deprivation.

INTRODUCTION: Studies show that the COVID-19 pandemic disproportionately affected people with diabetes and those from disadvantaged backgrounds. During the first 6 months of the UK lockdown, > 6.6 M glycated haemoglobin (HbA1c) tests were missed. We now report variability in the recovery of HbA1c testing, and its association with diabetes control and demographic characteristics. METHODS: In a service evaluation, we examined HbA1c testing across ten UK sites (representing 9.9% of England's population) from January 2019 to December 2021. We compared monthly requests from April 2020 to those in the equivalent 2019 months. We examined effects of (i) HbA1c level, (ii) between-practice variability, and (iii) practice demographics. RESULTS: In April 2020, monthly requests dropped to 7.9-18.1% of 2019 volumes. By July 2020, testing had recovered to 61.7-86.9% of 2019 levels. During April-June 2020, we observed a 5.1-fold variation in the reduction of HbA1c testing between general practices (12.4-63.8% of 2019 levels). There was evidence of limited prioritization of testing for patients with HbA1c > 86 mmol/mol during April-June 2020 (4.6% of total tests vs. 2.6% during 2019). Testing in areas with the highest social disadvantage was lower during the first lockdown (April-June 2020; trend test p < 0.001) and two subsequent periods (July-September and October-December 2020; both p < 0.001). By February 2021, testing in the highest deprivation group had a cumulative fall in testing of 34.9% of 2019 levels versus 24.6% in those in the lowest group. CONCLUSION: Our findings highlight that the pandemic response had a major impact on diabetes monitoring and screening. Despite limited test prioritization in the > 86 mmol/mol group, this failed to acknowledge that those in the 59-86 mmol/mol group require consistent monitoring to achieve the best outcomes. Our findings provide additional evidence that those from poorer backgrounds were disproportionately disadvantaged. Healthcare services should redress this health inequality.

Assessment of the effect of the COVID-19 pandemic on UK HbA1c testing: implications for diabetes management and diagnosis.

AIMS: The COVID-19 pandemic, and the focus on mitigating its effects, has disrupted diabetes healthcare services worldwide. We aimed to quantify the effect of the pandemic on diabetes diagnosis/management, using glycated haemoglobin (HbA1c) as surrogate, across six UK centres. METHODS: Using routinely collected laboratory data, we estimated the number of missed HbA1c tests for 'diagnostic'/'screening'/'management' purposes during the COVID-19 impact period (CIP; 23 March 2020 to 30 September 2020). We examined potential impact in terms of: (1) diabetes control in people with diabetes and (2) detection of new diabetes and prediabetes cases. RESULTS: In April 2020, HbA1c test numbers fell by ~80%. Overall, across six centres, 369 871 tests were missed during the 6.28 months of the CIP, equivalent to >6.6 million tests nationwide. We identified 79 131 missed 'monitoring' tests in people with diabetes. In those 28 564 people with suboptimal control, this delayed monitoring was associated with a 2-3 mmol/mol HbA1c increase. Overall, 149 455 'screening' and 141 285 'diagnostic' tests were also missed. Across the UK, our findings equate to 1.41 million missed/delayed diabetes monitoring tests (including 0.51 million in people with suboptimal control), 2.67 million screening tests in high-risk groups (0.48 million within the prediabetes range) and 2.52 million tests for diagnosis (0.21 million in the pre-diabetes range; ~70 000 in the diabetes range). CONCLUSIONS: Our findings illustrate the widespread collateral impact of implementing measures to mitigate the impact of COVID-19 in people with, or being investigated for, diabetes. For people with diabetes, missed tests will result in further deterioration in diabetes control, especially in those whose HbA1c levels are already high.

Home blood pressure monitoring detects unrevealed hypertension in women with a history of preeclampsia: Results of the BP-PRESELF study.

Objectives: The risk of cardiovascular disease more than doubles after hypertensive disorders of pregnancy. As early onset chronic hypertension contributes to cardiovascular risk, implementation of screening strategies, using home blood pressure monitoring (HBPM), may help to improve long-term cardiovascular health.We evaluated whether HBPM among women with a history of preeclampsia/HELLP syndrome is feasible for early detection and management of hypertension. Methods: The BP-PRESELF study is a multicenter randomized controlled trial. Participants were randomized to intervention group with HBPM for the duration of 1 year or the control group with 'usual care'. The primary outcome was feasibility of HBPM during 1 year of follow-up, defined as protocol adherence, protocol persistence and patient acceptance. Secondary outcomes were blood pressure levels and prevalence of hypertension. Results: We recruited 198 women with a mean age of 45 years. Protocol adherence decreased during the first 6 months, after which it stabilized. Protocol persistence remained high throughout follow-up. During the study period, 33 women (34%) in the intervention group were diagnosed with hypertension versus only 10 women (11%) in the control group, P<0.001. At 1-year follow-up, mean systolic blood pressure (SD) was 120.4 (11.6) mmHg in the intervention group versus 126.1 (14.3) mmHg in the control group, P=0.003. Mean diastolic blood pressure (SD) values were 77.1 (8.0) mmHg versus 81.7 (9.4) mmHg, P<0.001, respectively. Adjusted systolic and diastolic differences (95% confidence interval) were -6.81 (-10.17, -3.45) and -4.93 (-7.26, -2.61) mm Hg, with 80% less hypertension at 1-year follow-up in the intervention group. Conclusions: HBPM appears to be feasible for follow-up of blood pressure in women after preeclampsia/HELLP syndrome, while it detected hypertension and blood pressure levels reduced in one-third of women in this group.

Maternal Glycemic Spectrum and Adverse Pregnancy and Perinatal Outcomes in a Multiracial US Cohort.

Diabetes mellitus (pregestational (PDM) and gestational (GDM)) is associated with adverse pregnancy outcomes (APOs). However, studies exploring the association of APOs with maternal glycemia among women without PDM/GDM are limited. We utilized data from 4119 women (307-PDM; 582-GDM; 3230-non-PDM/GDM) in the Boston Birth Cohort (1998-2016). Women in the non-PDM/GDM group were subdivided by tertiles of 1 h, 50 g oral glucose load test at 24-32 weeks: T1: 50-95 mg/dL (n = 1166), T2: 96-116 mg/dL (n = 1151), T3: 117-201 mg/dL (n = 913). Using multivariable logistic regression, we examined the association of maternal glycemia with APOs-preterm birth (PTB) and hypertensive disorders of pregnancy (HDP)-and adverse perinatal outcomes-high birth weight (HBW), cesarean section (CS), and sub-analyses by race-ethnicity. Compared to women in T1, women in T2 and T3 had a higher prevalence of pre-existing hypertension (T1: 2.8% vs. T2: 5.2% vs. T3: 6.3%) and obesity (T1: 13.3% vs. T2: 18.1% vs. T3: 22.9%). Women in T2 and T3 had higher odds of HBW (adjusted odds ratio aOR T2: 1.47 [1.01-2.19] T3: 1.68 [1.13-2.50]) compared to women in T1. Additionally, women in T2, compared to T1, had higher odds of HDP (aOR 1.44 [1.10-1.88]). Among non-Hispanic Black (NHB) women, those in T2 and T3 had higher odds of HDP compared to T1 (aOR T2 1.67 [1.13-2.51]; T3: 1.68 [1.07-2.62]). GDM and PDM were associated with higher odds of HBW, CS, PTB, and HDP, compared to women in T1. In this predominantly NHB and Hispanic cohort, moderate maternal glycemia without PDM/GDM was associated with higher odds of HBW and HDP, even more strongly among NHB women. If confirmed, a review of current guidelines of glucose screening and risk stratification in pregnancy may be warranted.

Variability in Test Interval Is Linked to Glycated Haemoglobin (HbA1c) Trajectory over Time.

Aims: We previously showed that the glycated haemoglobin (HbA1c) testing frequency links to diabetes control. Here, we examine the effect of variability in test interval, adjusted for the frequency, on change in HbA1c (ΔHbA1c). Materials & Methods. HbA1c results were collected on 83,872 people with HbA1c results at baseline and 5 years (±3 months) later and ≥6 tests during this period. We calculated the standard deviation (SD) of test interval for each individual and examined the link between deciles of SD of the test interval and ΔHbA1c level, stratified by baseline HbA1c. Results: In general, less variability in testing frequency (more consistent monitoring) was associated with better diabetes control. This was most evident with moderately raised baseline HbA1c levels (7.0-9.0% (54-75 mmol/mol)). For example, in those with a starting HbA1c of 7.0-7.5% (54-58 mmol/mol), the lowest SD decile was associated with little change in HbA1c over 5 years, while for those with the highest decile, HbA1c rose by 0.4-0.6% (4-6 mmol/mol; p < 0.0001). Multivariate analysis showed that the association was independent of the age/sex/hospital site. Subanalysis suggested that the effect was most pronounced in those aged <65 years with baseline HbA1c of 7.0-7.5% (54-58 mmol/mol). We observed a 6.7-fold variation in the proportion of people in the top-three SD deciles across general practices. Conclusions: These findings indicate that the consistency of testing interval, not the just number of tests/year, is important in maintaining diabetes control, especially in those with moderately raised HbA1c levels. Systems to improve regularity of HbA1c testing are therefore needed, especially given the impact of COVID-19 on diabetes monitoring.

New approaches suggest term and preterm human fetal membranes may have distinct biomechanical properties.

Preterm prelabour rupture of membranes is the leading cause of preterm birth and its associated infant mortality and morbidity. However, its underlying mechanism remains unknown. We utilized two novel biomechanical assessment techniques, ball indentation and Optical Coherence Elastography (OCE), to compare the mechanical properties and behaviours of term (≥ 37 weeks) and preterm (33-36 weeks) human fetal membranes from ruptured and non-ruptured regions. We defined the expression levels of collagen, sulfated glycosaminoglycans (sGAG), matrix metalloproteinase (MMP-9, MMP-13), fibronectin, and interleukin-1ß (IL-1ß) within membranes by biochemical analysis, immunohistochemical staining and Western blotting, both with and without simulated fetal movement forces on membrane rupture with a new loading system. Preterm membranes showed greater heterogeneity in mechanical properties/behaviours between ruptured and non-ruptured regions compared with their term counterparts (displacement rate: 36% vs. 15%; modulus: 125% vs. 34%; thickness: 93% vs. 30%; collagen content: 98% vs. 29%; sGAG: 85% vs 25%). Furthermore, simulated fetal movement forces triggered higher MMP-9, MMP-13 and IL-1ß expression in preterm than term membranes, while nifedipine attenuated the observed increases in expression. In conclusion, the distinct biomechanical profiles of term and preterm membranes and the abnormal biochemical expression and activation by external forces in preterm membranes may provide insights into mechanisms of preterm rupture of membranes.

In-Hospital Complications in Pregnancies Conceived by Assisted Reproductive Technology.

Background Assisted reproductive technology (ART) has emerged as a common treatment option for infertility, a problem that affects an estimated 48 million couples worldwide. Advancing maternal age with increasing prepregnancy cardiovascular risk factors, such as chronic hypertension, obesity, and diabetes, has raised concerns about pregnancy complications associated with ART. However, in-hospital complications following pregnancies conceived by ART are poorly described. Methods and Results To assess the patient characteristics, obstetric outcomes, vascular complications and temporal trends of pregnancies conceived by ART, we analyzed hospital deliveries conceived with or without ART between January 1, 2008, and December 31, 2016, from the United States National Inpatient Sample database. We included 106 248 deliveries conceived with ART and 34 167 246 deliveries conceived without ART. Women who conceived with ART were older (35 versus 28 years; P<0.0001) and had more comorbidities. ART-conceived pregnancies were independently associated with vascular complications (acute kidney injury: adjusted odds ratio [aOR], 2.52; 95% CI 1.99-3.19; and arrhythmia: aOR, 1.65; 95% CI, 1.46-1.86), and adverse obstetric outcomes (placental abruption: aOR, 1.57; 95% CI, 1.41-1.74; cesarean delivery: aOR, 1.38; 95% CI, 1.33-1.43; and preterm birth: aOR, 1.26; 95% CI, 1.20-1.32), including in subgroups without cardiovascular disease risk factors or without multifetal pregnancies. Higher hospital charges ($18 705 versus $11 983; P<0.0001) were incurred compared with women who conceived without ART. Conclusions Pregnancies conceived by ART have higher risks of adverse obstetric outcomes and vascular complications compared with spontaneous conception. Clinicians should have detailed discussions on the associated complications of ART in women during prepregnancy counseling.

Health Care Professional's Knowledge of Pregnancy Complications and Women's Cardiovascular Health: An International Study Utilizing Social Media.

Background: Despite guidelines recommending the evaluation of adverse pregnancy outcomes (APOs) as a part of the atherosclerotic cardiovascular disease (ASCVD) risk assessment in women, there is limited awareness of this issue in health care professionals. We sought to evaluate the extent of this gap in knowledge. Methods: An online study using a standardized questionnaire was advertised through newsletters and websites of professional organizations. After a low response rate, the link to the survey was announced on Twitter and via personal email invitations. Differences between groups of respondents were evaluated with z-tests of proportion. Results: Out of 446 complete responses, there were 315 cardiologists and 112 obstetricians and gynecologists (OBGyns). There was an >90% awareness of association of adverse maternal outcomes with gestational hypertension and gestational diabetes with ASCVD, but only <60% awareness of association of adverse maternal outcomes with preterm birth. There were significant differences in ASCVD risk assessment and awareness of the association of APOs with adverse outcomes between cardiologists and OBGyns, and between female and male cardiologists. A greater proportion of female cardiologists thought that the guidelines recommended annual follow-up for high-risk women. Conversely, a greater proportion of male cardiologists were unsure of the frequency of follow-up of such women in the relevant guidelines. A higher proportion of U.K. respondents thought that women with high-risk pregnancies should never be screened for cardiovascular disease postpartum compared with U.S. respondents. Conclusions: In a self-selected group of health care professionals interested in women's cardiovascular health, there remains a large gap in knowledge and awareness of the association of APOs with ASCVD risk, in particular, a lack of awareness of the association of ASCVD risk with preterm delivery. Specific target groups for improving knowledge regarding these sex-specific risk enhancers include male cardiologists and health care professionals practicing in the United Kingdom.

The Impact of Charlson Comorbidity Index on De Novo Cardiac Implantable Electronic Device Procedural Outcomes in the United States.

OBJECTIVE: To investigate the utility of Charlson comorbidity index (CCI) as a measure of comorbidity burden to predict procedural outcomes after de novo cardiac implantable electronic device (CIED) implantation. METHODS: All de novo CIED implantations in the United States National Inpatient Sample between 2015 and 2018 were retrospectively analyzed, stratified by CCI score (0=no comorbidity burden, 1=mild, 2=moderate, ≥3=severe). Multivariable logistic regression models were performed to examine the association between unit CCI score (scale) and in-hospital outcomes (major adverse cerebrovascular and cardiovascular events [MACCE]: composite of all-cause mortality, acute ischemic stroke, thoracic and cardiac complications, and device-related complications; and MACCE individual components). RESULTS: Of 474,475 CIED procedures, the distribution of CCI score was as follows: CCI=0 (17.7%), CCI=1 (21.8%), CCI=2 (18.7%), and CCI=3+ (41.8%). Charlson comorbidity index score was associated with increased odds ratios of MACCE (1.10; 95% CI, 1.09 to 1.11), all-cause mortality (1.23; 95% CI, 1.21 to 1.25), and acute stroke (1.45; 95% CI, 1.44 to 1.46). This finding was consistent across all CIED groups except the cardiac resynchronization therapy groups in which CCI was not associated with increased risk of mortality. A higher CCI score was not associated with increased odds of procedural (thoracic and cardiac) and device-related complications. CONCLUSION: In a nationwide cohort of CIED procedures, higher comorbidity burden as measured by CCI score was associated with an increased risk of in-hospital mortality and acute ischemic stroke, but not procedure-related (thoracic and cardiac) or device-related complications. Objective assessment of comorbidity burden is important to risk-stratify patients undergoing CIED implantation for better prognostication of their in-hospital survival.

The Pro-Survival Oct4/Stat1/Mcl-1 Axis Is Associated with Poor Prognosis in Lung Adenocarcinoma Patients.

The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma.

The Fourth Trimester: Pregnancy as a Predictor of Cardiovascular Disease.

Pregnancy identifies women who may be at a greater risk of cardiovascular disease (CVD), based on the development of adverse pregnancy outcomes (APOs), and may identify women who may benefit from atherosclerotic CVD (ASCVD) risk reduction efforts. APOs are common and although they are separate diagnoses, all these disorders seem to share an underlying pathogenesis. What is not clear is whether the APO itself initiates a pathway that results in CVD or whether the APO uncovers a woman's predisposition to CVD. Regardless, APOs have immediate risks to maternal and foetal health, in addition to longer-term CVD consequences. CVD risk assessment and stratification in women remains complex and, historically, has underestimated risk, especially in young women. Further research is needed into the role of ASCVD risk assessment and the effect of aggressive ASCVD risk modification on CVD outcomes in women with a history of APOs.

In-Hospital Complications in Pregnant Women With Current or Historical Cancer Diagnoses.

OBJECTIVE: To assess the temporal trends, characteristics and comorbidities, and in-hospital cardiovascular and obstetric complications and outcomes of pregnant women with current or historical cancer diagnosis at the time of admission for delivery. METHODS: We analyzed delivery hospitalizations with or without current or historical cancer between January 1, 2004, and December 31, 2014, from the US National Inpatient Sample database. RESULTS: We included 43,132,097 delivery hospitalizations with no cancer, 39,118 with current cancer, and 67,336 with historical diagnosis of cancer. The 5 most common types of current cancer were hematologic, thyroid, cervical, skin, and breast cancer. Women with current and historical cancer were older (29 years and 32 years vs 27 years) and incurred higher hospital costs ($4131 and $4078 vs $3521) compared with women without cancer. Most of the cancer types were associated with preterm birth (hematologic: adjusted odds ratio [aOR], 1.48 [95% CI, 1.35 to 1.62]; cervical: aOR, 1.47 [95% CI, 1.32 to 1.63]; breast: aOR, 1.93 [95% CI, 1.72 to 2.16]). Current hematologic cancer was associated with the highest risk of peripartum cardiomyopathy (aOR, 12.19 [95% CI, 7.75 to 19.19]), all-cause mortality (aOR, 6.50 [95% CI, 2.22 to 19.07]), arrhythmia (aOR, 3.82 [95% CI, 2.04 to 7.15]), and postpartum hemorrhage (aOR, 1.31 [95% CI, 1.11 to 1.54]). Having a current or historical cancer diagnosis did not confer additional risk for stillbirth; however, metastases increased the risk of maternal mortality and preterm birth. CONCLUSION: Women with a current or historical diagnosis of cancer at delivery have more comorbidities compared with women without cancer. Clinicians should communicate the risks of multisystem complications to these complex patients.