Placental Abruption and Cardiovascular Event Risk (PACER): Design, data linkage, and preliminary findings.

BACKGROUND: Obstetrical complications impact the health of mothers and offspring along the life course, resulting in an increased burden of chronic diseases. One specific complication is abruption, a life-threatening condition with consequences for cardiovascular health that remains poorly studied. OBJECTIVES: To describe the design and data linkage algorithms for the Placental Abruption and Cardiovascular Event Risk (PACER) cohort. POPULATION: All subjects who delivered in New Jersey, USA, between 1993 and 2020. DESIGN: Retrospective, population-based, birth cohort study. METHODS: We linked the vital records data of foetal deaths and live births to delivery and all subsequent hospitalisations along the life course for birthing persons and newborns. The linkage was based on a probabilistic record-matching algorithm. PRELIMINARY RESULTS: Over the 28 years of follow-up, we identified 1,877,824 birthing persons with 3,093,241 deliveries (1.1%, n = 33,058 abruption prevalence). The linkage rates for live births-hospitalisations and foetal deaths-hospitalisations were 92.4% (n = 2,842,012) and 70.7% (n = 13,796), respectively, for the maternal cohort. The corresponding linkage rate for the live births-hospitalisations for the offspring cohort was 70.3% (n = 2,160,736). The median (interquartile range) follow-up for the maternal and offspring cohorts was 15.4 (8.1, 22.4) and 14.4 (7.4, 21.0) years, respectively. We will undertake multiple imputations for missing data and develop inverse probability weights to account for selection bias owing to unlinked records. CONCLUSIONS: Pregnancy offers a unique window to study chronic diseases along the life course and efforts to identify the aetiology of abruption may provide important insights into the causes of future CVD. This project presents an unprecedented opportunity to understand how abruption may predispose women and their offspring to develop CVD complications and chronic conditions later in life.

Chronic Hypertension and the Risk of Readmission for Postpartum Cardiovascular Complications.

OBJECTIVE: Preeclampsia is an important risk factor for cardiovascular disease (CVD, including heart disease and stroke) along the life course. However, whether exposure to chronic hypertension in pregnancy, in the absence of preeclampsia, is implicated in CVD risk during the immediate postpartum period remains poorly understood. Our objective was to estimate the risk of readmission for CVD complications within the calendar year after delivery for people with chronic hypertension. METHODS: The Healthcare Cost and Utilization Project's Nationwide Readmission Database (2010-2018) was used to conduct a retrospective cohort study of patients aged 15-54 years. International Classification of Diseases codes were used to identify patients with chronic hypertension and postpartum readmission for CVD complications within 1 year of delivery. People with CVD diagnosed during pregnancy or delivery admission, multiple births, or preeclampsia or eclampsia were excluded. Excess rates of CVD readmission among patients with and without chronic hypertension were estimated. Associations between chronic hypertension and CVD complications were determined from Cox proportional hazards regression models. RESULTS: Of 27,395,346 delivery hospitalizations that resulted in singleton births, 2.0% of individuals had chronic hypertension (n=544,639). The CVD hospitalization rate among patients with chronic hypertension and normotensive patients was 645 (n=3,791) per 100,000 delivery hospitalizations and 136 (n=37,664) per 100,000 delivery hospitalizations, respectively (rate difference 508, 95% CI 467-549; adjusted hazard ratio 4.11, 95% CI 3.64-4.66). The risk of CVD readmission, in relation to chronic hypertension, persisted for 1 year after delivery. CONCLUSION: The heightened CVD risk as early as 1 month postpartum in relation to chronic hypertension underscores the need for close monitoring and timely care after delivery to reduce blood pressure and related complications.

Landscape of baseline and acquired genomic alterations in circulating tumor DNA with abemaciclib alone or with endocrine therapy in advanced breast cancer.

PURPOSE: To identify potential predictors of response and resistance mechanisms in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with the CDK4/6 inhibitor abemaciclib +/- endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes. PATIENTS AND METHODS: MONARCH 3: postmenopausal women with HR+, HER2- ABC and no prior systemic therapy in the advanced setting were randomized to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2- metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomized to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed. RESULTS: Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib +/- NSAI included RB1 and MYC. CONCLUSIONS: In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis-generating, further exploration is warranted into mechanisms of resistance to abemaciclib and ET.

Risk of postpartum readmission for depression in relation to ischaemic placental disease: a population-based study.

Background: There are limited data on postpartum readmissions for depression in the United States (US). Specifically, the extent to which ischaemic placental disease (IPD) during pregnancy predisposes patients to develop postpartum depression remains poorly understood. We investigated whether IPD is associated with postpartum readmission for new-onset depression in the first year after delivery. Methods: In this population-based study, the 2010-2018 Nationwide Readmissions Database was utilised to evaluate rates of postpartum readmission for depression within the calendar year of delivery hospitalisation among patients with and without IPD. IPD was defined as preeclampsia, placental abruption, or small for gestational age (SGA) birth. We expressed associations between IPD and depression readmission based on a confounder-adjusted hazards ratio (HR) with a 95% confidence interval (CI). Findings: Of 33.3 million delivery hospitalisations, 3,027,084 (9.1%) had IPD. The total follow-up among those with and without IPD were 17,855,830 and 180,100,532 person-months, respectively, with a median follow-up of 5.8 months for both groups. Rates of depression readmission were 95.7 (n = 17,095) and 37.5 (n = 67,536) per 100,000 readmissions among patients with and without an IPD, respectively (HR, 2.39; 95% CI, 2.32-2.47); this risk was the highest for preeclampsia with severe features (HR, 3.14; 95% CI, 3.00-3.29). Patients had a greater risk of readmission if they had any two forms of IPD (HR, 3.02; 95% CI, 2.75-3.33), and those with a concurrent diagnosis of preeclampsia and abruption posed the highest risk (HR, 3.23; 95% CI, 2.71-3.86). Interpretation: These findings suggested that patients with IPD are at a substantially increased risk of readmission for depression within a year following delivery. This study underscores the need for increased surveillance, improved detection, and faster treatment of depression in this vulnerable population. Funding: This was an unfunded project.

Epidemiologic trends and risk factors associated with the decline in mortality from coronary heart disease in the United States, 1990-2019.

BACKGROUND: Despite the decline in the rate of coronary heart disease (CHD) mortality, it is unknown how the 3 strong and modifiable risk factors - alcohol, smoking, and obesity -have impacted these trends. We examine changes in CHD mortality rates in the United States and estimate the preventable fraction of CHD deaths by eliminating CHD risk factors. METHODS: We performed a sequential time-series analysis to examine mortality trends among females and males aged 25 to 84 years in the United States, 1990-2019, with CHD recorded as the underlying cause of death. We also examined mortality rates from chronic ischemic heart disease (IHD), acute myocardial infarction (AMI), and atherosclerotic heart disease (AHD). All underlying causes of CHD deaths were classified based on the International Classification of Disease 9th and 10th revisions. We estimated the preventable fraction of CHD deaths attributable to alcohol, smoking, and high body-mass index (BMI) through the Global Burden of Disease. RESULTS: Among females (3,452,043 CHD deaths; mean [standard deviation, SD] age 49.3 [15.7] years), the age-standardized CHD mortality rate declined from 210.5 in 1990 to 66.8 per 100,000 in 2019 (annual change -4.04%, 95% CI -4.05, -4.03; incidence rate ratio [IRR] 0.32, 95% CI, 0.41, 0.43). Among males (5,572,629 CHD deaths; mean [SD] age 47.9 [15.1] years), the age-standardized CHD mortality rate declined from 442.4 to 156.7 per 100,000 (annual change -3.74%, 95% CI, -3.75, -3.74; IRR 0.36, 95% CI, 0.35, 0.37). A slowing of the decline in CHD mortality rates among younger cohorts was evident. Correction for unmeasured confounders through a quantitative bias analysis slightly attenuated the decline. Half of all CHD deaths could have been prevented with the elimination of smoking, alcohol, and obesity, including 1,726,022 female and 2,897,767 male CHD deaths between 1990 and 2019. CONCLUSIONS: The decline in CHD mortality is slowing among younger cohorts. The complex dynamics of risk factors appear to shape mortality rates, underscoring the importance of targeted strategies to reduce modifiable risk factors that contribute to CHD mortality.

RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association Between TP53 Status and Clinical Outcome.

BACKGROUND: Ramucirumab plus erlotinib (RAM+ERL) demonstrated superior progression-free survival (PFS) in RELAY, a randomised Phase III trial in patients with untreated, metastatic, EGFR-mutated, non-small-cell lung cancer (EGFR+ NSCLC). Here, we present the relationship between TP53 status and outcomes in RELAY. MATERIALS AND METHODS: Patients received oral ERL plus intravenous RAM (10 mg/kg IV) or placebo (PBO+ERL) every 2 weeks. Plasma was assessed by Guardant 360 next-generation sequencing and patients with any gene alteration detected at baseline were included in this exploratory analysis. Endpoints included PFS, overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. The association between TP53 status and outcomes was evaluated. RESULTS: Mutated TP53 was detected in 165 (42.7%; 74 RAM+ERL, 91 PBO+ERL) patients, wild-type TP53 in 221 (57.3%; 118 RAM+ERL, 103 PBO+ERL) patients. Patient and disease characteristics and concurrent gene alterations were comparable between those with mutant and wildtype TP53. Independent of treatment, TP53 mutations, most notably on exon 8, were associated with worse clinical outcomes. In all patients, RAM+ERL improved PFS. While ORR and DCR were comparable across all patients, DoR was superior with RAM+ERL. There were no clinically meaningful differences in the safety profiles between those with baseline TP53 mutation and wild-type. CONCLUSION: This analysis indicates that while TP53 mutations are a negative prognostic marker in EGFR+ NSCLC, the addition of a VEGF inhibitor improves outcomes in those with mutant TP53. RAM+ERL is an efficacious first-line treatment option for patients with EGFR+ NSCLC, independent of TP53 status.

Epidemiology and trends in stroke mortality in the USA, 1975-2019.

BACKGROUND: Whether changes in stroke mortality are affected by age distribution and birth cohorts, and if the decline in stroke mortality exhibits heterogeneity by stroke type, remains uncertain. METHODS: We undertook a sequential time series analysis to examine stroke mortality trends in the USA among people aged 18-84 years between 1975 and 2019 (n = 4 332 220). Trends were examined for overall stroke and by ischaemic and haemorrhagic subtypes. Mortality data were extracted from the US death files, and age-sex population data were extracted from US census. Age-standardized stroke mortality rates and incidence rate ratio (IRR) with 95% confidence interval [CI] were derived from Poisson regression models. RESULTS: Age-standardized stroke mortality declined for females from 87.5 in 1975 to 30.9 per 100 000 in 2019 (IRR 0.27, 95% CI 0.26, 0.27; average annual decline -2.78%, 95% CI -2.79, -2.78). Among males, age-standardized mortality rate declined from 112.1 in 1975 to 38.7 per 100 000 in 2019 (RR 0.26, 95% CI 0.26, 0.27; average annual decline -2.80%, 95% CI -2.81, -2.79). Stroke mortality increased sharply with advancing age. Decline in stroke mortality was steeper for ischaemic than haemorrhagic strokes. CONCLUSIONS: Stroke mortality rates have substantially declined, more so for ischaemic than haemorrhagic strokes.

Evolving stillbirth rates among Black and White women in the United States, 1980-2020: A population-based study.

Background: Given slowing secular declines and persistent racial disparities, stillbirth remains a major health burden in the US. We investigate changes in stillbirth rates overall and for Black and White women, and determine how maternal age, delivery year (period), and birth year (cohort) have shaped trends. Methods: We designed a sequential time-series analysis utilising the 1980 to 2020 US vital records data of live births and stillbirths at ≥24 weeks gestation. Stillbirth rates overall and among Black and White women were examined. We undertook an age-period-cohort analysis to evaluate temporal changes in stillbirth trends. Findings: Of 157,192,032 live births and 710,832 stillbirths between 1980 and 2020, stillbirth rates per 1000 births declined from 10.6 (95% confidence interval [CI] 10.5, 10.7) in 1980 to 5.8 (95% CI 5.7, 5.8) in 2020. Stillbirth rates declined from 9.2 to 5.0 per 1000 births among White women (rate ratio [RR] 0.54, 95% CI 0.53, 0.55), and from 17.4 to 10.1 per 1000 births among Black women (RR 0.57, 95% CI 0.55, 0.59). Black women experienced persistent two-fold higher rates compared to White women (2.01, 95% CI 1.97, 2.05 in 2020). Stillbirth rates declined until 2005, increased from 2005 to the mid-2010s and plateaued thereafter. Strong cohort effects contributed to declining rates in earlier cohorts (1930-1955) and increasing rates among women born after 1980. Interpretation: Age, period, and birth cohorts greatly influenced US stillbirth rates over the last forty years. The decline in stillbirth rate was evident between 1980 and 2005, however subsequent declines have been minimal, reflecting no further gains for cohorts of women born in 1955-1980 and stagnation of period effects starting in 2005. A significant racial disparity persisted with a two-fold excess in stillbirth rates for Black compared to White women, underscoring the need for targeted health and social policies to address disparities. Funding: None.

Historical and Recent Changes in Maternal Mortality Due to Hypertensive Disorders in the United States, 1979 to 2018.

[Figure: see text].

The Period protein homolog LIN-42 regulates germline development in C. elegans.

Germline stem cells are maintained in the distal region of the C. elegans gonad. These cells undergo mitotic divisions, and GLP-1/Notch signaling dictates whether they remain in this state. The somatic distal tip cell (DTC) caps the end of the distal gonad and is essential for maintenance of the germline mitotic zone. As germ cells move away from the DTC they exit mitosis and enter early meiotic prophase. Here we identify the Period protein homolog LIN-42 as a new regulator of germline development in C. elegans. LIN-42 is expressed in almost all somatic cells including the DTC, and LIN-42 functions as a transcription factor in the heterochronic pathway and to regulate molting. We found that the mitotic proliferative zone size in the distal gonad was significantly reduced by ~25% in lin-42 mutants compared to WT N2 worms. A lin-42 mutation also reduced the mitotic proliferative zone size caused by glp-1 partial loss-of-function and gain-of-function alleles. LIN-42 mediates this effect, at least in part, by regulating expression of the GLP-1/Notch ligand LAG-2. We further show that lin-42 expression itself is regulated by ATX-2, which promotes germline proliferation and is the homolog of the RNA binding protein ataxin-2 that is implicated in human neurodegenerative diseases. Altogether our results establish a new role for the conserved, important Period protein homolog LIN-42 in regulating early germline development. These results also suggest that in addition to regulating behavioral rhythms, the circadian clock plays an important role in communicating environmental signals to essential reproductive pathways.

Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response.

Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 × 10-7 to p = 1.76 × 10-5, by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available.