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Background: Incidence of hypertensive disorders of pregnancy is increasing in the United States. Early detection is important to prevent adverse maternal and offspring outcomes. This ecological study evaluated changes in rates of hypertensive disorders of pregnancy among states that expanded Medicaid compared with states that did not expand Medicaid. Methods: A quasi-experimental analysis using difference-in-differences models compared changes in rates of hypertensive disorders of pregnancy in Medicaid expansion states relative to non-Medicaid expansion states from 2012 to 2019. Maternal data from singleton first live births to individuals aged 20 to 39 years were obtained from the National Center for Health Statistics. Outcomes of interest included age-adjusted rates of de novo hypertension in pregnancy (gestational hypertension or preeclampsia) and prepregnancy hypertension. Results: Data from 7 764 965 individuals with a singleton first live birth were analyzed from 17 states and Washington, DC that expanded Medicaid and 15 states that did not. Rates of de novo hypertension in pregnancy increased over the study period in both expansion (54.34 [95% CI, 48.25–60.43] to 74.87 [95% CI, 71.20–78.55] per 1000 births) and nonexpansion states (68.32 [95% CI, 61.02–75.62] to 84.79 [95% CI, 80.67–88.91] per 1000 births). In adjusted difference-in-differences analyses, expansion status was associated with a greater increase in rates of de novo hypertension in pregnancy (difference-in-differences coefficient, +8.18 [95% CI, 4.00–12.36] per 1000 live births) but a decline in rates of de novo hypertension in pregnancy complicated by low birth weight (−7.20 [95% CI, −13.71 to −0.70] per 1000 births with hypertensive disorders of pregnancy). In adjusted difference-in-differences analyses, there were no significant changes in rates of prepregnancy hypertension in expansion relative to nonexpansion states (+1.13 [95% CI, −0.09 to +2.35] per 1000 live births). Conclusions: Between 2012 and 2019, states that expanded Medicaid had a significantly greater increase in rates of de novo hypertension, with some evidence of better outcomes among those with de novo hypertension diagnosed in pregnancy.

The power of CRISPRi to decrease targeted gene expression for clinical applications has been inhibited by delivery challenges. Existing constructs are too large to fit within the ∼4.7 kb packaging size limitation of adeno-associated virus (AAV), the only FDA approved viral vector for clinical use. Therefore, we optimized CRISPRi components to generate a single AAV vector that contains all functional elements and effectively knocks down expression of an endogenous gene in vivo. First, we increased nuclear targeting of Staphylococcus aureus deactivated Cas9 (SadCas9) 4-fold by using a helical linker and the c-Myc nuclear localization signal. Second, we identified an amino-terminal Krüppel associated box (KRAB) construct as the most effective in decreasing expression of target genes in vitro. Third, we optimized promoters for guide RNA and evaluated mini-promoters for expression of KRAB-SadCas9 in liver cells. Our final construct decreased protein convertase subtilisin/kexin type 9 (Pcsk9) mRNA and secreted protein 5-fold in vitro. The corresponding AAV2/8 vector was localized in nuclei of liver cells and decreased Pcsk9 mRNA and serum protein levels by 30% in vivo. This single AAV approach provides a potential clinically translatable method for decreasing targeted gene transcription by CRISPRi in vivo.

Introduction: In 2017, the ACC/AHA revised the blood pressure (BP) guideline to lower the BP threshold for diagnosing and treating hypertension in older adults. Pharmacologic treatment is recommended for systolic BP (SBP) ≥130 mmHg in all older adults aged ≥65 years. Data on BP changes before and after publication of the guideline are needed to inform quality of care initiatives. Methods: We included participants from the Atherosclerosis Risk in Communities Study who attended a pre-guideline (2016-2017) and post-guideline (2018-2019) visit with a pre-guideline SBP between 120-159 mm Hg. We categorized participants based on their pre-guideline SBP according to the 2017 guideline: not reclassified to treatment (SBP 120-129), reclassified to stage 1 hypertension (SBP 130-139), or reclassified to stage 2 hypertension (SBP 140-159). To estimate the association of the 2017 guideline with SBP change, we performed a quasi-experimental analysis using difference-in-differences (DiD) regression. We compared changes in SBP between participants affected (SBP 130-139, 140-159) and those not affected (SBP 120-129) by the new SBP target, adjusted for traditional risk factors. Results: Of 2195 participants aged 71-94 years, mean (SD) SBP was 137.2 (10.8) mm Hg, and 77% were on antihypertensive therapy at the pre-guideline visit. Among participants with SBP ≥130 pre-guideline, 31% were at goal SBP Table ). Results were similar when stratified by sex and race. Conclusions: In a sample of community-based older adults, the post-guideline period was associated with significantly lower SBP in those reclassified to Stage 1 or Stage 2 hypertension. However, significant gaps exist in BP control and only a minority met the updated treatment goal.

Introduction: Abnormal indices of cardiac structure and function likely cluster together. However, the clinical relevance of data-driven patterns of cardiac remodeling across a broad range of echocardiographic measures, particularly in mid-life, is not known. Hypothesis: Latent class analysis (LCA) will identify distinct clusters of cardiac structure and function based on echocardiographic indices in middle-aged adults that differ in risk of CVD. Methods: We included all CARDIA participants without CVD who underwent an echocardiogram. Continuous parameters were indexed to participant height (if appropriate), imputed with the SVDImpute algorithm (if missing), and filtered to remove pairwise correlations >0.6. We applied LCA using a total of 31 echocardiographic indices (standardized to mean 0 and standard deviation 1) to identify distinct groups based on model convergence, the Bayesian Information Criterion, and class membership >5%. We examined the association between groups and risk of premature CVD (coronary artery disease, stroke, or heart failure) with Cox regression adjusted for traditional risk factors. Results: Of 3,361 participants, mean (SD) age was 50.1 (3.6) years, 57% were female, and 46% were non-Hispanic Black. LCA identified 3 groups: (1) optimal cardiac mechanics; (2) impaired systolic function; and (3) impaired diastolic function ( FIGURE ). Over a median 8.9 years of follow-up, risk of CVD was higher in the impaired diastolic function group (unadjusted hazard ratio [HR] 4.08 [95% CI: 2.48, 6.71] and adjusted HR 1.95 [1.12, 3.40]) compared with the optimal group. The impaired systolic function group had a higher unadjusted risk of CVD (1.86 [1.10, 3.15], which attenuated after adjustment (1.36 [0.79, 2.36]). Conclusions: Unbiased, model-based clustering of cardiac structure and function in middle-aged adults identified distinct patterns of cardiac remodeling that were associated with risk of future CVD.

The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated that intensive blood pressure (BP) lowering (target

Background The prevalence of obesity in the population has increased in parallel with increasing rates of adverse pregnancy outcomes (APOs). Quantifying contemporary trends in prepregnancy obesity and associations with interrelated APOs (preterm birth, low birth weight, and pregnancy‐associated hypertension) together and individually can inform prevention strategies to optimize cardiometabolic health in women and offspring. Methods and Results We performed a serial, cross‐sectional study using National Center for Health Statistics birth certificate data including women aged 15 to 44 years with live singleton births between 2013 and 2018, stratified by race/ethnicity (non‐Hispanic White, non‐Hispanic Black, Hispanic, and non‐Hispanic Asian). We quantified the annual prevalence of prepregnancy obesity (body mass index ≥30.0 kg/m 2 ; body mass index ≥27.5 kg/m 2 if non‐Hispanic Asian). We then estimated adjusted associations using multivariable logistic regression (odds ratios and population attributable fractions) for obesity‐related APOs compared with normal body mass index (18.5–24.9 kg/m 2 ; 18.5–22.9 kg/m 2 if non‐Hispanic Asian). Among 20 139 891 women, the prevalence of prepregnancy obesity increased between 2013 and 2018: non‐Hispanic White (21.6%–24.8%), non‐Hispanic Black (32.5%–36.2%), Hispanic (26.0%–30.5%), and non‐Hispanic Asian (15.3%–18.6%) women ( P ‐trend P ‐trend Conclusions The prevalence of prepregnancy obesity and burden of obesity‐related APOs have increased, driven primarily by pregnancy‐associated hypertension, and vary across racial/ethnic subgroups.

Importance Gestational diabetes is associated with adverse maternal and offspring outcomes. Objective To determine whether rates of gestational diabetes among individuals at first live birth changed from 2011 to 2019 and how these rates differ by race and ethnicity in the US. Design, Setting, and Participants Serial cross-sectional analysis using National Center for Health Statistics data for 12 610 235 individuals aged 15 to 44 years with singleton first live births from 2011 to 2019 in the US. Exposures Gestational diabetes data stratified by the following race and ethnicity groups: Hispanic/Latina (including Central and South American, Cuban, Mexican, and Puerto Rican); non-Hispanic Asian/Pacific Islander (including Asian Indian, Chinese, Filipina, Japanese, Korean, and Vietnamese); non-Hispanic Black; and non-Hispanic White. Main Outcomes and Measures The primary outcomes were age-standardized rates of gestational diabetes (per 1000 live births) and respective mean annual percent change and rate ratios (RRs) of gestational diabetes in non-Hispanic Asian/Pacific Islander (overall and in subgroups), non-Hispanic Black, and Hispanic/Latina (overall and in subgroups) individuals relative to non-Hispanic White individuals (referent group). Results Among the 12 610 235 included individuals (mean [SD] age, 26.3 [5.8] years), the overall age-standardized gestational diabetes rate significantly increased from 47.6 (95% CI, 47.1-48.0) to 63.5 (95% CI, 63.1-64.0) per 1000 live births from 2011 to 2019, a mean annual percent change of 3.7% (95% CI, 2.8%-4.6%) per year. Of the 12 610 235 participants, 21% were Hispanic/Latina (2019 gestational diabetes rate, 66.6 [95% CI, 65.6-67.7]; RR, 1.15 [95% CI, 1.13-1.18]), 8% were non-Hispanic Asian/Pacific Islander (2019 gestational diabetes rate, 102.7 [95% CI, 100.7-104.7]; RR, 1.78 [95% CI, 1.74-1.82]), 14% were non-Hispanic Black (2019 gestational diabetes rate, 55.7 [95% CI, 54.5-57.0]; RR, 0.97 [95% CI, 0.94-0.99]), and 56% were non-Hispanic White (2019 gestational diabetes rate, 57.7 [95% CI, 57.2-58.3]; referent group). Gestational diabetes rates were highest in Asian Indian participants (2019 gestational diabetes rate, 129.1 [95% CI, 100.7-104.7]; RR, 2.24 [95% CI, 2.15-2.33]). Among Hispanic/Latina participants, gestational diabetes rates were highest among Puerto Rican individuals (2019 gestational diabetes rate, 75.8 [95% CI, 71.8-79.9]; RR, 1.31 [95% CI, 1.24-1.39]). Gestational diabetes rates increased among all race and ethnicity subgroups and across all age groups. Conclusions and Relevance Among individuals with a singleton first live birth in the US from 2011 to 2019, rates of gestational diabetes increased across all racial and ethnic subgroups. Differences in absolute gestational diabetes rates were observed across race and ethnicity subgroups.

Gestational diabetes mellitus and hypertensive disorders of pregnancy increase the risk for future adverse health outcomes in the pregnant woman and baby, and disparities exist in the rates of gestational diabetes mellitus and hypertensive disorders of pregnancy by race/ethnicity. The objective of this study is to identify the differences in gestational diabetes mellitus and hypertensive disorders of pregnancy rates by maternal place of birth within race/ethnicity groups.In women aged 15-44 years at first live singleton birth in U.S. surveillance data between 2014 and 2019, age-standardized rates of gestational diabetes mellitus and hypertensive disorders of pregnancy and the rate ratios of gestational diabetes mellitus and hypertensive disorders of pregnancy in women born outside versus those born in the U.S. were evaluated, stratified by race/ethnicity. Analyses were conducted in 2021.Of 8,574,264 included women, 6,827,198 were born in the U.S. (mean age=26.2 [SD 5.7] years), and 1,747,066 were born outside the U.S. (mean age=28.2 [SD=5.8] years). Overall, the gestational diabetes mellitus rate was higher in women born outside than in those born in the U.S. (70.3, 95% CI=69.9, 70.7 vs 53.2, 95% CI=53.0, 53.4 per 1,000 live births; rate ratio=1.32, 95% CI=1.31, 1.33), a pattern observed in most race/ethnic groups. By contrast, the overall hypertensive disorders of pregnancy rate was lower in those born outside than in those born in the U.S. (52.5, 95% CI=52.2, 52.9 vs 90.1, 95% CI=89.9, 90.3 per 1,000 live births; rate ratio=0.58, 95% CI=0.58, 0.59), a pattern observed in most race/ethnic groups.In the U.S., gestational diabetes mellitus rates were higher and hypertensive disorders of pregnancy rates were lower in women born outside the U.S. than in those born in the U.S. in most race/ethnicity groups.

Introduction: Poor cardiometabolic health is a major contributor to growing rates of maternal morbidity and mortality. Given known state-level variation in maternal outcomes, we sought to describe the geographic distribution of pre-pregnancy cardiometabolic health as it could inform policy changes to optimize maternal and offspring outcomes. Hypothesis: We hypothesized that pre-pregnancy cardiometabolic health has declined over time and varies by state. Methods: We conducted a nationwide, serial cross-sectional analysis using maternal birth record data from the CDC Natality Files 2016-2018, which include all live births in the US. We included all live births to women aged 20-44 years (N= 10,693,708). Pre-pregnancy cardiometabolic health was quantified by number of pre-pregnancy risk factors: overweight or obesity (body mass index > 25 kg/m 2 ), diabetes, and/or hypertension. We calculated annual age-standardized prevalence of favorable (no risk factors), suboptimal (any single risk factor), or poor ( > 2 risk factors) pre-pregnancy cardiometabolic health and quantified percentage change between 2016-2018 by state. Results: From 2016-2018, the percentage of live births to women with favorable cardiometabolic health decreased from 43.5% (43.4, 43.6) to 41.3% (41.2, 41.3), suboptimal health increased from 51.1% (51.1, 51.2) to 53.3% (53.3, 53.4), and poor health increased from 2.1% (2.1, 2.1) to 2.4% (2.4, 2.4). All states experienced declines in favorable cardiometabolic health. There was significant geographic variation with prevalence of favorable pre-pregnancy cardiometabolic health ranging from 32.7% (32.2, 33.3) in Mississippi to 48.2% (47.7, 48.6) in Utah in 2018 (FIGURE) ; poor health ranged from 1.3% (1.3, 1.4) in California to 4.6% (4.4, 4.8) in Louisiana in 2018. Conclusions: Less than half of women had favorable pre-pregnancy cardiometabolic health between 2016-2018, with significant geographic heterogeneity. Public health efforts to improve pre-conception cardiometabolic health are needed.

Introduction: Individual pre-pregnancy risk factors such as obesity, hypertension, and diabetes disproportionately affect minority women and are associated with adverse maternal and offspring outcomes. However, quantification of pre-pregnancy cardiovascular health (CVH) and association with pregnancy outcomes is lacking and can help identify at-risk women and children. Hypothesis: Suboptimal pre-pregnancy CVH is associated with higher risk of adverse maternal and fetal outcomes. Methods: We conducted a cross-sectional study using the CDC Natality files, which include all pregnancies in the US that resulted in live birth or fetal death after 20 weeks. Our study sample consisted of data from singleton live births or fetal deaths to women aged 15-44 years in 2018. Four maternal metrics (body mass index, smoking, diabetes, and hypertension) were assigned 1 point each for pre-pregnancy BMI < 25.0 kg/m 2 , non-smoking, and absence of hypertension or diabetes to construct a pre-pregnancy clinical CVH score ranging from 0-4. We examined the distribution of CVH by race/ethnicity. We then quantified associations of CVH with maternal ICU admission, preterm birth (PTB), low birthweight (LBW), and fetal death using logistic regression (CVH = 4 as the referent) adjusted for maternal age, race/ethnicity, education, prenatal care, and parity. Results: Of 3,582,832 pregnancies in 2018, more than half of women had a suboptimal CVH score (CVH = 3: 51.8%; CVH = 2: 6.7%; CVH = 0/1: 0.4%). Suboptimal CVH score (Figure) . There were consistent and inverse graded associations between CVH score of 3, 2, and 0/1 (compared with 4 as the referent) and maternal ICU admission, PTB, LBW, and fetal death (p Conclusions: Pre-pregnancy clinical CVH score has strong, graded associations with adverse maternal and fetal outcomes, with disproportionate impact of suboptimal CVH in non-Hispanic Black and Hispanic women.

INTRODUCTION: Rates of gestational diabetes mellitus (GDM) are increasing in parallel with rates of overweight and obesity. This analysis examines nationwide trends in the population-attributable fraction for GDM associated with prepregnancy overweight and obesity. METHODS: A serial, cross-sectional study was performed using U.S. population-based Birth Data Files maintained by the National Center for Health Statistics between 2011 and 2019. Live singleton births to nulliparous women aged 15–44 years were included, and all analyses were stratified by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, non-Hispanic Asian). Prevalences of prepregnancy overweight (25.0–29.9 kg/m(2), 23.0–27.4 kg/m(2)) and obesity (≥30.0 kg/m(2), ≥27.5 kg/m(2)) based on standard and Asian-specific BMI categories, respectively, were quantified. Logistic regression estimated adjusted associations between prepregnancy overweight and obesity and GDM with normal weight (18.0–24.9 kg/m(2), 18.0–22.9 kg/m(2)) as the ref. Annual population-attributable fractions for GDM associated with prepregnancy overweight and obesity were calculated, which account for both prevalence of the risk factor and the associated risk of GDM. RESULTS: Among 11,950,881 included women, mean maternal age was 26.3 years. Population-attributable fractions for GDM associated with overweight were stable (Hispanic: 12.0% to 11.3%, non-Hispanic Asian: 12.1% to 11.6%, p≥0.20) or decreased (non-Hispanic White: 10.8% to 9.4%, non-Hispanic Black: 12.3% to 9.2%, p

Hypertension is a highly prevalent and causal risk factor for cardiovascular disease (CVD). Quantitative cardiovascular (CV) risk assessment is a new paradigm for stratifying hypertensive patients into actionable groups for clinical management and prevention of CVD. The large heterogeneity in hypertensive patients makes this evaluation complex, but recent advances have made CV risk assessment more feasible. In this review, we first describe the prognostic significance of various levels and temporal patterns of blood pressure (BP). We then discuss CV risk prediction equations and the rationale of taking global risk into account in hypertensive patients. Finally, we review several adjunctive biomarkers that may refine risk assessment in certain patients. We observe that, beyond individual cross-sectional measurements, both short-term and long-term BP patterns are associated with incident CVD; that current CV risk prediction performs well, and its incorporation into hypertension management is associated with potential population benefit; and that adjunctive biomarkers of target organ damage show the most promise in sequential screening strategies that target biomarker measurement to patients in whom the results are most likely to change clinical management. Implementation of quantitative risk assessment for CVD has been facilitated by tools and direct electronic health record integrations that make risk estimates accessible for counseling and shared decision making for CVD prevention. However, it should be noted that treatment does not return an individual to the risk of someone who never develops hypertension, underscoring the need for primordial prevention in addition to continued innovation in risk assessment.

The power of CRISPRi to decrease targeted gene expression for clinical applications has been inhibited by delivery challenges. Existing constructs are too large to fit within the ∼4.7 kb packaging size limitation of adeno-associated virus (AAV), the only FDA approved viral vector for clinical use. Therefore, we optimized CRISPRi components to generate a single AAV vector that contains all functional elements and effectively knocks down expression of an endogenous gene in vivo. First, we increased nuclear targeting of Staphylococcus aureus deactivated Cas9 (SadCas9) 4-fold by using a helical linker and the c-Myc nuclear localization signal. Second, we identified an amino-terminal Krüppel associated box (KRAB) construct as the most effective in decreasing expression of target genes in vitro. Third, we optimized promoters for guide RNA and evaluated mini-promoters for expression of KRAB-SadCas9 in liver cells. Our final construct decreased protein convertase subtilisin/kexin type 9 (Pcsk9) mRNA and secreted protein 5-fold in vitro. The corresponding AAV2/8 vector was localized in nuclei of liver cells and decreased Pcsk9 mRNA and serum protein levels by 30% in vivo. This single AAV approach provides a potential clinically translatable method for decreasing targeted gene transcription by CRISPRi in vivo., Graphical Abstract, Proper cellular localization and maximal function of components that modify gene transcription are central to clinically relevant therapeutic interventions. The authors optimized nuclear targeting and transcriptional repression using deactivated Cas9 as a model system. Subsequent in vivo studies with a single adeno-associated virus revealed decreased genomic expression of a target gene.

Introduction: Clinicians widely use cardiac troponins I and T, sensitive and specific biomarkers of myocardial damage, as diagnostic criteria for myocardial infarction (MI). A common approach, dichotomizing based on whether troponin levels meet thresholds for MI, may miss meaningful heterogeneity in degree and pattern of troponin elevation, with wider clinical implications. Hypothesis: Using latent class trajectory modeling (LCTM) with patients’ patterns of troponin elevations will yield trajectories that represent clinically and prognostically distinct groups of patients. Methods: We used Northwestern Medicine’s Enterprise Data Warehouse to identify patients with at least 3 troponin measurements of which at least one was elevated during their inpatient stay. We built a LCTM to capture troponin trajectories from 13,432 patients with 65,162 measurements since 2000, using Bayesian Information Criterion to select the final model (# of classes varied from 3-7). We then described the clinical and prognostic factors associated with trajectory class membership. Results: LCTM identified 3 troponin trajectories: stable low (77.3%), moderate rise (9.5%), and severe rise-fall (13.2%). The average posterior probability of assignment was >0.95 for all classes. The low group had the most comorbidities vs moderate/severe groups, including cancer (21.9% vs 13.9%/11.3%), heart failure (12.6% vs 8.9%/7.5%), and COPD (15.0% vs 11.8%/10.1%). The moderate/severe rising trajectories had a greater rate of clinically-diagnosed MI than the stable group (34.5%/44.1% vs 5.6%), with relatively more ST-elevation MI in the severe group (19.8% vs 5.3%) and Non-ST-elevation MI in the moderate group (29.3% vs 24.3%). One-year mortality was greatest in the low group vs moderate/severe groups (25.5% vs 21.4%/18.8%). Conclusions: In a cohort of hospitalized patients with elevated troponins, LCTM identified 3 distinct, clinically interpretable troponin trajectories which were associated with differing clinical phenotypes.

This cross-sectional study uses data from the National Health and Nutrition Examination Survey to assess age at diagnosis of diabetes by race/ethnicity in the US from 2011 to 2018.

Static Random Access Memory (SRAM) is an important memory device for storing data on‐chip. Advantages of SRAM include its fast read/write speed and meta‐stability. However, the continuing technology scaling requires future generations of SRAM to be small and power efficient—both qualities are difficult to achieve by simply scaling the size of transistors in the nanometer regime. In this chapter, we study several SRAM array architectures that utilize dual word line 6‐transistor SRAM and novel operation schemes. Simulation results show that these novel approaches have numerous advantages over the conventional SRAM array implementation.

FinFET, which is a double‐gate field effect transistor (DGFET), is more versatile than traditional single‐gate field effect transistors because it has two gates that can be controlled independently. Usually, the second gate of FinFETs is used to dynamically control the threshold voltage of the first gate in order to improve circuit performance and reduce leakage power. However, we can also utilize the second gate to implement circuits with fewer transistors. This is important since area efficiency is one of the main concerns in modern circuit design. This chapter presents an overview of independent‐gate FinFET logic synthesis methodology and provides examples of circuits synthesized using this methodology.