Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

Evaluating Injury Severity in Neonatal Encephalopathy Using Automated Quantitative Electroencephalography Analysis: A Pilot Study.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.

Design and Rationale of the Social Determinants of the Risk of Hypertension in Women of Reproductive Age (SAFE HEART) Study: An American Heart Association Research Goes Red Initiative.

BACKGROUND: Cardiovascular health literacy (CVHL) and social determinants of health (SDoH) play interconnected and critical roles in shaping cardiovascular health (CVH) outcomes. However, awareness of CVH risk has declined markedly, from 65% of women being aware that cardiovascular disease (CVD) is the leading cause of death for women in 2009 to just 44% being aware in 2019. The American Heart Association Research Goes Red (RGR) initiative seeks to develop an open-source, longitudinal, dynamic registry that will help women to be aware of and participate in research studies, and to learn about CVD prevention. We proposed to leverage this platform, particularly among Black and Hispanic women of reproductive age, to address CVHL gaps and advance health equity. METHODS: The primary objective of the study is to evaluate the cross-sectional association of cardiovascular health literacy (CVHL), SDoH using a polysocial score, and CVH in women of reproductive age at increased risk of developing hypertension (HTN). To achieve this we will use a cross-sectional study design, that engages women already enrolled in the RGR registry (registry-enrolled). To enhance the racial and ethnic/social economic diversity of the cohort, we will additionally enroll 300 women from the Baltimore and Washington D.C. community into the Social Determinants of the Risk of Hypertension in Women of Reproductive Age (SAFE HEART) Study. Community-enrolled and registry-enrolled women will undergo baseline social phenotyping including detailed SDoH questionnaire, CVH metrics assessment, and CVHL assessment. The secondary objective is to assess whether a 4-month active health education intervention will result in a change in CVHL in the 300 community-enrolled women. DISCUSSION: The SAFE HEART study examines the association between CVHL, SDoH, and CVH, with a focus on racial and ethnic minority groups and socioeconomically disadvantaged women of reproductive age, and the ability to improve these parameters by an educational intervention. These findings will inform the future development of community-engaged strategies that address CVHL and SDoH among women of reproductive age.

Association of diastolic blood pressure with coronary perfusion pressure during resuscitation in pediatric swine.

BACKGROUND: Diastolic blood pressure (DBP) is suggested as a surrogate for coronary perfusion pressure (CPP) during cardiopulmonary resuscitation. We examined the correlation between DBP and CPP and hypothesized that both would be associated with survival in a pediatric swine model of asphyxial cardiac arrest. METHODS: We performed a retrospective, secondary analysis of 102 pediatric swine resuscitations. DBP and CPP were recorded every 30 s during resuscitation. Values were compared between survivors and non-survivors. RESULTS: DBP mirrored CPP in survivors and non-survivors throughout resuscitation and both were associated with survival. Improvements in DBP and CPP after the first epinephrine administration were greater in survivors (DBP: 25.1 ± 3.0 vs. 5.4 ± 0.8 mmHg, p < 0.01; CPP: 24.9 ± 3.2 vs. 4.8 ± 0.9 mmHg, p < 0.01). DBP and CPP after epinephrine administration were highly predictive of survival, with an area under the curve of 0.95 (0.89-1.00) for DBP and 0.90 (0.81-0.99) for CPP. The optimal threshold for DBP was 22.5 mmHg, whereas that for CPP was 14.5 mmHg. CONCLUSIONS: DBP and CPP were associated with survival throughout resuscitation, and the response of both to the first epinephrine administration was highly predictive of survival in this model. Clinically, the availability of DBP makes it useful as a target for physiologic feedback during resuscitation. IMPACT: Diastolic blood pressure (DBP) mirrored coronary perfusion pressure (CPP) throughout prolonged resuscitation in a pediatric model of asphyxial cardiac arrest. Mean DBP and CPP were significantly greater in survivors than in non-survivors both before and after administration of epinephrine. The response of both DBP and CPP to the first dose of epinephrine was highly predictive of return of spontaneous circulation. Given the clinical availability of DBP, these findings support its use as a surrogate for CPP to guide high-quality cardiopulmonary resuscitation in this pediatric swine model.

Implantable Defibrillator System Shock Function, Mortality, and Cause of Death After Magnetic Resonance Imaging.

BACKGROUND: Studies have shown that magnetic resonance imaging (MRI) does not have clinically important effects on the device parameters of non-MRI-conditional implantable cardioverter-defibrillators (ICDs). However, data on non-MRI-conditional ICD detection and treatment of arrhythmias after MRI are limited. OBJECTIVE: To examine if non-MRI-conditional ICDs have preserved shock function of arrhythmias after MRI. DESIGN: Prospective cohort study. (ClinicalTrials.gov: NCT01130896). SETTING: 1 center in the United States. PATIENTS: 629 patients with non-MRI-conditional ICDs enrolled consecutively between February 2003 and January 2015. INTERVENTIONS: 813 total MRI examinations at a magnetic field strength of 1.5 Tesla using a prespecified safety protocol. MEASUREMENTS: Implantable cardioverter-defibrillator interrogations were collected after MRI. Clinical outcomes included arrhythmia detection and treatment, generator or lead exchanges, adverse events, and death. RESULTS: During a median follow-up of 2.2 years from MRI to latest available ICD interrogation before generator or lead exchange in 536 patients, 4177 arrhythmia episodes were detected, and 97 patients received ICD shocks. Sixty-one patients (10% of total) had 130 spontaneous ventricular tachycardia or fibrillation events terminated by ICD shocks. A total of 210 patients (33% of total) are known to have died (median, 1.7 years from MRI to death); 3 had cardiac arrhythmia deaths where shocks were indicated without direct evidence of device dysfunction. LIMITATIONS: Data were acquired at a single center and may not be generalizable to other clinical settings and MRI facilities. Implantable cardioverter-defibrillator interrogations were not available for a subset of patients; adjudication of cause of death relied solely on death certificate data in a subset. CONCLUSION: Non-MRI-conditional ICDs appropriately treated detected tachyarrhythmias after MRI. No serious adverse effects on device function were reported after MRI. PRIMARY FUNDING SOURCE: Johns Hopkins University and National Institutes of Health.

Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.

Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1). For PD-L1 quantification, we first developed a small peptide-based fluorine-18-labeled PET imaging agent, [18F]DK222, which provided high-contrast images in preclinical models. We then quantified accessible PD-L1 levels in the tumor bed during treatment with anti-PD-1 and anti-PD-L1 mAbs. Applying mixed-effects models to these data, we found subtle differences in the pharmacodynamic effects of two anti-PD-1 mAbs (nivolumab and pembrolizumab). In contrast, we observed starkly divergent target engagement with anti-PD-L1 mAbs (atezolizumab, avelumab, and durvalumab) that were administered at equivalent doses, correlating with differential effects on tumor growth. Thus, we show that measuring PD-L1 pharmacodynamics informs mechanistic understanding of therapeutic mAbs targeting PD-L1 and PD-1. These findings demonstrate the value of quantifying target pharmacodynamics to elucidate the pharmacologic activity of mAbs, independent of mAb biophysical properties and inclusive of all physiological variables, which are highly heterogeneous within and across tumors and patients.

Surveillance and treatment of primary hepatocellular carcinoma (aka. STOP HCC): protocol for a prospective cohort study of high-risk patients for HCC using GALAD-score.

BACKGROUND: Vietnam and Saudi Arabia have high disease burden of primary hepatocellular carcinoma (HCC). Early detection in asymptomatic patients at risk for HCC is a strategy to improve survival outcomes in HCC management. GALAD score, a serum-based panel, has demonstrated promising clinical utility in HCC management. However, in order to ascertain its potential role in the surveillance of the early detection of HCC, GALAD needs to be validated prospectively for clinical surveillance of HCC (i.e., phase IV biomarker validation study). Thus, we propose to conduct a phase IV biomarker validation study to prospectively survey a cohort of patients with advanced fibrosis or compensated cirrhosis, irrespective of etiologies, using semi-annual abdominal ultrasound and GALAD score for five years. METHODS: We plan to recruit a cohort of 1,600 patients, male or female, with advanced fibrosis or cirrhosis (i.e., F3 or F4) and MELD ≤ 15, in Vietnam and Saudi Arabia (n = 800 each). Individuals with a liver mass ≥ 1 cm in diameter, elevated alpha-fetoprotein (AFP) (≥ 9 ng/mL), and/or elevated GALAD score (≥ -0.63) will be scanned with dynamic contrast-enhanced magnetic resonance imaging (MRI), and a diagnosis of HCC will be made by Liver Imaging Reporting and Data System (LiRADS) assessment (LiRADS-5). Additionally, those who do not exhibit abnormal imaging findings, elevated AFP titer, and/or elevated GALAD score will obtain a dynamic contrast-enhanced MRI annually for five years to assess for HCC. Only MRI nearest to the time of GALAD score measurement, ultrasound and/or AFP evaluation will be included in the diagnostic validation analysis. MRI will be replaced with an abdominal computed tomography scan when MRI results are poor due to patient conditions such as movement etc. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI will not be carried out in study sites in both countries. Bootstrap resampling technique will be used to account for repeated measures to estimate standard errors and confidence intervals. Additionally, we will use the Cox proportional hazards regression model with covariates tailored to the hypothesis under investigation for time-to-HCC data as predicted by time-varying biomarker data. DISCUSSION: The present work will evaluate the performance of GALAD score in early detection of liver cancer. Furthermore, by leveraging the prospective cohort, we will establish a biorepository of longitudinally collected biospecimens from patients with advanced fibrosis or cirrhosis to be used as a reference set for future research in early detection of HCC in the two countries. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov Registration date: 22 April 2022 Trial registration number: NCT05342350 URL of trial registry record.

Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates.

BACKGROUND: To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23 and 41 weeks' GA. METHODS: In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL. RESULTS: Overall, 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0-3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks' GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL. CONCLUSIONS: BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury. IMPACT: Normative data of six brain injury-related biomarkers is being proposed. When interpreting serum concentrations of brain injury biomarkers, it is key to adjust for gestational age at birth and day of life during the first week to correctly assess for clinical brain injury in neonates. Variation in levels of some biomarkers may be related to gestational and postnatal age and not necessarily pathology.

Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop.

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.

Adverse Pregnancy Outcomes and Cardiovascular Disease Risk: Unique Opportunities for Cardiovascular Disease Prevention in Women: A Scientific Statement From the American Heart Association.

This statement summarizes evidence that adverse pregnancy outcomes (APOs) such as hypertensive disorders of pregnancy, preterm delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss increase a woman's risk of developing cardiovascular disease (CVD) risk factors and of developing subsequent CVD (including fatal and nonfatal coronary heart disease, stroke, peripheral vascular disease, and heart failure). This statement highlights the importance of recognizing APOs when CVD risk is evaluated in women, although their value in reclassifying risk may not be established. A history of APOs is a prompt for more vigorous primordial prevention of CVD risk factors and primary prevention of CVD. Adopting a heart-healthy diet and increasing physical activity among women with APOs, starting in the postpartum setting and continuing across the life span, are important lifestyle interventions to decrease CVD risk. Lactation and breastfeeding may lower a woman's later cardiometabolic risk. Black and Asian women experience a higher proportion APOs, with more severe clinical presentation and worse outcomes, than White women. More studies on APOs and CVD in non-White women are needed to better understand and address these health disparities. Future studies of aspirin, statins, and metformin may better inform our recommendations for pharmacotherapy in primary CVD prevention among women who have had an APO. Several opportunities exist for health care systems to improve transitions of care for women with APOs and to implement strategies to reduce their long-term CVD risk. One proposed strategy includes incorporation of the concept of a fourth trimester into clinical recommendations and health care policy.

Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension.

OBJECTIVE: To evaluate the performance of pulmonary hypertension (PH) biomarkers in children with Down syndrome, an independent risk factor for PH, in whom biomarker performance may differ compared with other populations. STUDY DESIGN: Serum endostatin, interleukin (IL)-1 receptor 1 (ST2), galectin-3, N-terminal pro hormone B-natriuretic peptide (NT-proBNP), IL-6, and hepatoma-derived growth factor (HDGF) were measured in subjects with Down syndrome and PH (n = 29), subjects with Down syndrome and resolved PH (n = 13), subjects with Down syndrome without PH (n = 49), and subjects without Down syndrome with World Symposium on Pulmonary Hypertension group I pulmonary arterial hypertension (no Down syndrome PH group; n = 173). Each biomarker was assessed to discriminate PH in Down syndrome. A classification tree was created to distinguish PH from resolved PH and no PH in children with Down syndrome. RESULTS: Endostatin, galectin-3, HDGF, and ST2 were elevated in subjects with Down syndrome regardless of PH status. Not all markers differed between subjects with Down syndrome and PH and subjects with Down syndrome and resolved PH. NT-proBNP and IL-6 levels were similar in the Down syndrome with PH group and the no Down syndrome PH group. A classification tree identified NT-proBNP and galectin-3 as the best markers for sequentially distinguishing PH, resolved PH, and no PH in subjects with Down syndrome. CONCLUSIONS: Proteomic markers are used to improve the diagnosis and prognosis of PH but, as demonstrated here, can be altered in genetically unique populations such as individuals with Down syndrome. This further suggests that clinical biomarkers should be evaluated in unique groups with the development of population-specific nomograms.

The Effect of Mycophenolate Mofetil as First-Line Therapy on the Timing of Urine Protein-to-Creatinine Ratio Reduction in Immunosuppressant-Naive Patients With Lupus Nephritis at a Single Center.

BACKGROUND/OBJECTIVES: Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis (LN). The purpose of this study was to assess the effect of mycophenolate mofetil (MMF) on the timing of urine protein-to-creatinine ratio reaching 200 mg or less after starting MMF as initial therapy for class III, IV, or V in immunosuppressant-naive patients with LN. METHODS: Patients who had a diagnosis of biopsy-proven LN were included in this cohort study. The initial dose of MMF was 1000 mg twice daily. If no improvement, it was increased to 1500 mg twice daily after 1 month. For statistical analysis, exact binomial distribution 95% confidence intervals were calculated. RESULTS: Nine patients were identified. There were 3 patients with class III, 3 with class IV, 1 with class III to V, 1 with class II to V, and 1 with class V lupus nephritis. The majority were African Americans (70%). At baseline, proteinuria ranged between 0.41 and 4 g, and 88% had normal estimated glomerular filtration rate. Forty-four percent of patients reached 0.28 g of proteinuria within 8 weeks of starting MMF (95% confidence interval, 14%-79%), all of which maintained the same level of response and normal estimated glomerular filtration rate at 12 months. Thirty-three percent of patients achieved the American College of Rheumatology complete response at 8 weeks. CONCLUSIONS: This study demonstrates that only a minority of immunosuppressant-naive LN patients achieved the American College of Rheumatology complete response at 8 weeks after initiation of MMF. A rapid decline in the proteinuria to 0.28 g within the first 8 weeks of the treatment correlated strongly with achieving the same level of response at 12 months.

Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Association of Coronary Artery Atherosclerosis With Brain White Matter Hyperintensity.

Background and Purpose: We aim to determine, in healthy high-risk adults, the association between subclinical coronary artery disease and white matter hyperintensity (WMH) volume and location, independent of atherosclerotic risk factors. Methods: Seven hundred eighty-two asymptomatic first-degree relatives of index cases with early-onset coronary artery disease (<60 years old) from GeneSTAR (Genetic Study of Atherosclerosis Risk) with contemporaneous coronary computed tomography angiography and brain magnetic resonance imaging were analyzed. Multilevel mixed-effects linear regression models, accounting for family structure, evaluated the association of total WMH volume and 3 regions (deep WMH, periventricular WMH [PVWMH], or borderzone [cuff]) with markers of coronary artery disease. Separate models were created for total WMH, deep WMH, PVWMH, and cuff volumes, each, as dependent variables, across coronary computed tomography angiography variables, adjusted for covariates. Results: Mean age was 51 years ±10, with 58% women and 39% African American people. Participants with any coronary plaque had 52% larger WMH volumes than those without plaque (95% CI, 0.24­0.59). Per 1% greater coronary plaque volume, total WMH volumes were 0.07% larger (95% CI, 0.04­0.10). Every 1% higher total coronary plaque volume was associated with 5.03% larger deep WMH volume (95% CI, 4.67­5.38), 5.10% PVWMH larger volume (95% CI, 4.72­5.48), and 2.74% larger cuff volume (95% CI, 2.38­3.09) with differences in this association when comparing deep WMH to PVWMH (P interaction, 0.001) or cuff (P interaction, <0.001), respectively. Conclusions: In healthy, high-risk individuals, the presence and volume of coronary artery plaque are associated with larger WMH volumes, appearing the strongest for PVWMH. These findings in high-risk families suggest a disease relationship in 2 different vascular beds, beyond traditional risk factors, possibly due to genetic predisposition.

White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease.

INTRODUCTION: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. METHODS: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. RESULTS: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (ß = -0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: ß = -0.03, p = 0.003, C20: ß = -0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (ß = -0.0103, p = 0.027). CONCLUSIONS: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.

Cyclic guanosine monophosphate and 10-year change in left ventricular mass: the Multi-Ethnic Study of Atherosclerosis (MESA).

Purpose: Cyclic guanosine monophosphate (cGMP) is a second messenger for natriuretic peptide (NP) and nitric oxide pathways; its enhancement a target for heart failure and cardiovascular disease (CVD). We evaluated whether plasma cGMP was associated with change in left ventricular mass (LVM) among individuals free of CVD and if this differed by sex.Methods and Results: In 611 men and 612 women aged 45-84 years with plasma cGMP measured at baseline and cardiac MRI performed at baseline and 10 years later, we tested associations of cGMP [log-transformed, per 1 SD increment] with LVM, adjusting for CVD risk factors and N-terminal pro-B-type-NP (NT-proBNP). Participants had mean (SD) age of 63.1(8.5) years and cGMP 4.8(2.6) pmol/mL. Cross-sectionally, higher cGMP was associated with lesser LVM, non-lin- early. In contrast, longitudinally, higher cGMP was associated with increase in LVM [1.70g (0.61, 2.78)] over 10 years. Higher cGMP was associated with greater LVM change in men [2.68g (1.57, 3.79)] but not women [0.24g ((-0.92, 1.39); p-interaction < 0.001].Conclusion: In conclusion, in a community-based cohort, higher cGMP levels were associated with increase in LVM over 10 years independent of CVD risk factors and NT-proBNP in men, perhaps reflecting compensatory changes. Further studies are needed to understand mechanistic roles of cGMP in LV remodelling and associated sex differences.

Effects of clinical depression on left ventricular dysfunction in patients with acute coronary syndrome.

Depression is associated with heart failure independent of traditional cardiovascular disease risk factors. Enhanced platelet activation has been suggested as a potential mechanism and has been associated with negative inotropic effects that can affect left ventricular ejection fraction (LVEF). We examined 131 consecutive acute coronary syndrome (ACS) patients to assess whether depression increased the risk for developing LV dysfunction, and to determine the effects of platelet serotonin signaling in this relationship. Major depression was assessed using the Structured Clinical Interview and depressive symptoms were measured using the Beck Depression Inventory (BDI), with BDI ≥ 10 defined as abnormal. LV dysfunction was defined as LVEF ≤ 45%. Platelet serotonin response was measured by serotonin augmented platelet aggregation and platelet serotonin receptor density. Mean age of ACS participants was 59 years, 78.6% male and 74.0% Caucasian. 34.4% of patients had a reduced LVEF ≤ 45% on presentation. Almost half (47.0%) of patients had BDI ≥ 10 and 18.0% had major depressive disorder. Platelet serotonin response was found to be augmented in depressed patients with low LVEF compared to depressed patients with normal LVEF (p < 0.020). However, the presence of LV dysfunction was found to be similar in both depressed (32.3%) and non-depressed (36.2%) patients (p = 0.714). This suggests alternative factors contribute to poor cardiovascular outcomes in depressed patients that are independent of LV function in post ACS patients.

Predictive factors for fertility preservation in pediatric and adolescent girls with planned gonadotoxic treatment.

PURPOSE: To characterize female pediatric and adolescent patients seen for fertility preservation consultation at an academic medical center and to describe the association between demographic or clinical factors and the use of fertility preservation treatment (FPT). METHODS: This is a retrospective chart analysis of female pediatric and adolescent patients seen for fertility preservation consultation at an academic fertility center over a 14-year period from 2005 to 2019. RESULTS: One hundred six females aged 3-21 years were seen for fertility preservation consultation with a mean age of 16.6 years. Diagnoses included hematologic malignancies (41.5%), gynecologic malignancies (9.4%), other malignancies (31.1%), non-malignant hematologic disease (14.2%), and non-malignant conditions (3.8%). Overall, 64.2% of subjects pursued fertility preservation, including oocyte cryopreservation (35.8%) and ovarian tissue cryopreservation (23.6%). Overall, age, minority race, diagnosis, time since diagnosis, and median household income were not significantly associated with odds of completing an FPT procedure. Among all patients, those who underwent gonadotoxic therapy prior to consultation had a lower odds of receiving FPT (OR= 0.24, 95% CI 0.10-0.55). Among patients without chemotherapy exposure, no factors were associated with FPT. CONCLUSIONS: Among pediatric and adolescent patients at an academic center undergoing a fertility preservation consultation, there were no socioeconomic or clinical barriers to FPT use in those who had not yet undergone gonadotoxic therapy. The only factor that was negatively associated with odds of pursuing FPT was prior chemotherapy exposure.

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. METHODS: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. RESULTS: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient - 50.235 and - 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC. CONCLUSIONS: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.