Comparison of Clinical Decision Support Tools to Improve Pediatric Lipid Screening.

OBJECTIVE: To test whether different clinical decision support tools increase clinician orders and patient completions relative to standard practice and each other. STUDY DESIGN: A pragmatic, patient-randomized clinical trial in the electronic health record was conducted between October 2019 and April 2020 at Geisinger Health System in Pennsylvania, with 4 arms: care gap-a passive listing recommending screening; alert-a panel promoting and enabling lipid screen orders; both; and a standard practice-no guideline-based notification-control arm. Data were analyzed for 13 346 9- to 11-year-old patients seen within Geisinger primary care, cardiology, urgent care, or nutrition clinics, or who had an endocrinology visit. Principal outcomes were lipid screening orders by clinicians and completions by patients within 1 week of orders. RESULTS: Active (care gap and/or alert) vs control arm patients were significantly more likely (P < .05) to have lipid screening tests ordered and completed, with ORs ranging from 1.67 (95% CI 1.28-2.19) to 5.73 (95% CI 4.46-7.36) for orders and 1.54 (95% CI 1.04-2.27) to 2.90 (95% CI 2.02-4.15) for completions. Alerts, with or without care gaps listed, outperformed care gaps alone on orders, with odds ratios ranging from 2.92 (95% CI 2.32-3.66) to 3.43 (95% CI 2.73-4.29). CONCLUSIONS: Electronic alerts can increase lipid screening orders and completions, suggesting clinical decision support can improve guideline-concordant screening. The study also highlights electronic record-based patient randomization as a way to determine relative effectiveness of support tools. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04118348.

Characteristics and Outcomes of Patients With Pregnancy-Related End-Stage Kidney Disease.

Importance: The incidence of pregnancy-related acute kidney injury is increasing and is associated with significant maternal morbidity including progression to end-stage kidney disease (ESKD). Little is known about characteristics and long-term outcomes of patients who develop pregnancy-related ESKD. Objectives: To examine the characteristics and clinical outcomes of patients with pregnancy-related ESKD and to investigate associations between pre-ESKD nephrology care and outcomes. Design, Setting, and Participants: This was a cohort study of 183 640 reproductive-aged women with incident ESKD between January 1, 2000, and November 20, 2020, from the US Renal Data System and maternal data from births captured in the US Centers for Disease Control and Prevention publicly available natality data. Data were analyzed from December 2022 to June 2023. Exposure: Pregnancy-related primary cause of ESKD, per International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes reported at ESKD onset by the primary nephrologist on Centers for Medicare and Medicaid Services form 2728. Main Outcomes Measures: Multivariable Cox proportional hazards and competing risk models were constructed to examine time to (1) mortality, (2) access to kidney transplant (joining the waiting list or receiving a live donor transplant), and (3) receipt of transplant after joining the waitlist. Results: A total of 341 patients with a pregnancy-related primary cause of ESKD were identified (mean [SD] age 30.2 [7.3]). Compared with the general US birthing population, Black patients were overrepresented among those with pregnancy-related ESKD (109 patients [31.9%] vs 585 268 patients [16.2%]). In adjusted analyses, patients with pregnancy-related ESKD had similar or lower hazards of mortality compared with those with glomerulonephritis or cystic kidney disease (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.76-1.19), diabetes or hypertension (aHR, 0.49; 95% CI, 0.39-0.61), or other or unknown primary causes of ESKD (aHR, 0.60; 95% CI, 0.48-0.75). Despite this, patients with pregnancy-related ESKD had significantly lower access to kidney transplant compared with those with other causes of ESKD, including (1) glomerulonephritis or cystic kidney disease (adjusted subhazard ratio [aSHR], 0.51; 95% CI, 0.43-0.66), (2) diabetes or hypertension (aSHR, 0.81; 95% CI, 0.67-0.98), and (3) other or unkown cause (aSHR, 0.82; 95% CI, 0.67-0.99). Those with pregnancy-related ESKD were less likely to have nephrology care or have a graft or arteriovenous fistula placed before ESKD onset (nephrology care: adjusted relative risk [aRR], 0.47; 95% CI, 0.40-0.56; graft or arteriovenous fistula placed: aRR, 0.31; 95% CI, 0.17-0.57). Conclusion and Relevance: In this study, those with pregnancy-related ESKD had reduced access to transplant and nephrology care, which could exacerbate existing disparities in a disproportionately Black population. Increased access to care could improve quality of life and health outcomes among these young adults with high potential for long-term survival.

Sex Hormones and Diabetes in 45- to 74-year-old Men and Postmenopausal Women: The Hispanic Community Health Study.

Previous studies demonstrated associations of endogenous sex hormones with diabetes. Less is known about their dynamic relationship with diabetes progression through different stages of the disease, independence of associations, and role of the hypothalamic-pituitary gonadal axis. The purpose of this analysis was to examine relationships of endogenous sex hormones with incident diabetes, prediabetes, and diabetes traits in 693 postmenopausal women and 1015 men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos and followed for 6 years. Baseline hormones included estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and, in men, testosterone and bioavailable testosterone. Associations were analyzed using multivariable Poisson and linear regressions. In men, testosterone was inversely associated with conversion from prediabetes to diabetes (incidence rate ratio [IRR] for 1 SD increase in testosterone: 0.821; 95% CI, 0.676, 0.997; P = 0.046), but not conversion from normoglycemia to prediabetes. Estradiol was positively associated with increase in fasting insulin and homeostatic model assessment of insulin resistance. In women, SHBG was inversely associated with change in glycosylated hemoglobin, postload glucose, and conversion from prediabetes to diabetes (IRR = 0.62; 95% CI, 0.44, 0.86, P = 0.005) but not from normoglycemia to prediabetes. Relationships with other hormones varied across glycemic measures. Stronger associations of testosterone and SHBG with transition from prediabetes to diabetes than from normoglycemic to prediabetes suggest they are operative at later stages of diabetes development. Biologic pathways by which sex hormones affect glucose homeostasis await future studies.

Exploring access to genomic risk information and the contours of the HIPAA public health exception.

Considerable resources have been invested in research to identify pathogenic and likely pathogenic variants that cause morbidity and mortality and also in returning these results to patients. The public health impact and cost-effectiveness of these efforts are maximized when probands' relatives are informed of their risk and offered testing. However, such 'Traceback' cascade testing programs face multiple obstacles, including perceived or actual legal and regulatory hurdles. Here, using genetic cancer syndromes as a test case, we explore the contours of the Public Health Exception to the HIPAA Privacy Rule to assess whether it is a viable pathway for implementing a Traceback program. After examining the Privacy Rule as well as state laws and regulations for reportable conditions and genetic privacy, we conclude that this is not currently a viable approach for Traceback programs. We conclude by reflecting on ethical considerations of leveraging HIPAA's public health exception to disclose PHI directly to at-risk relatives and offering insights for how legal hurdles to such a Traceback program could be overcome, if desired.

Arterial stiffness and contralateral differences in blood pressure: The Atherosclerosis Risk in Communities (ARIC) study.

A large interarm difference in brachial systolic blood pressure (SBP) (≥10 or ≥15 mmHg) is strongly associated with elevated cardiovascular events and mortality. Evidence demonstrating whether such contralateral differences in SBP occur in ankle blood pressure and its association with arterial stiffness is scarce. The aims of this study were to characterize arm and ankle contralateral SBP differences in a sample of community-dwelling older adults (5077), and to determine whether this difference is associated with arterial stiffness assessed by pulse wave velocity (PWV) between the heart and ankle (haPWV), femoral artery and ankle (faPWV), and brachial artery and ankle (baPWV) in the right and left sides. Prevalence of interarm SBP differences ≥10 and ≥15 mmHg was 5.1% and .7%, respectively; the corresponding prevalence for interankle SBP was 24.9% and 12.0%. Higher BMI and lower ankle-brachial index (ABI) were significantly correlated with greater interarm SBP differences. Increased age, higher BMI, lower ABI, and greater contralateral differences in haPWV, faPWV, and baPWV were significantly correlated to greater interankle SBP differences. Interankle SBP difference ≥15 mmHg was significantly associated with contralateral differences of >80 cm/s in haPWV (OR = 1.94 [95% CI = 1.52-2.49]), >165 cm/s in faPWV (OR = 1.64 [95% CI = 1.27-2.12]), and >240 cm/s in baPWV (OR = 2.43 [95% CI = 1.94-3.05]). The associations remained significant after adjustment for age, sex, race, BMI, smoking status, and ABI. Compared with interarm differences, interankle differences in SBP are common in older adults. The magnitude of interankle, but not interarm, differences in SBP is associated with various measures of arterial stiffness.

Association Between Estimated Pulse Wave Velocity and Cognitive Performance in Older Black and White Adults in NHANES.

BACKGROUND: Aging-associated cognitive decline is greater in non-Hispanic Black (NHB) adults than non-Hispanic White (NHW) adults. An important risk factor for cognitive decline with aging is arterial stiffening, though the importance to racial variation remains poorly understood. OBJECTIVE: We examined the association of an estimate of arterial stiffness with cognitive function in a bi-racial sample of 60-85-year-old adults (N = 3,616, 26.5% NHB) enrolled in the National Health and Nutrition Examination Survey (NHANES) between 1999-2002 and 2011-2014. METHODS: As a measure of vascular aging, pulse wave velocity was estimated (ePWV) using an equation incorporating age and mean arterial pressure and expressed as m/s. Using the digit symbol substitution test (DSST), cognitive function was expressed as the number of correctly matched symbols (out of 133) within 120 s. Linear regression models examined associations between ePWV and DSST. RESULTS: In models that adjusted for sex, education, smoking, body mass index, history of cardiovascular disease, and hypertension, ePWV was inversely associated with DSST score in NHB adults (ß= -3.47, 95% CI = -3.9 to -3.0; p < 0.001) and NHW adults (ß= -3.51, 95% CI = -4.4 to -2.6; p < 0.001). CONCLUSION: ePWV is inversely associated with a measure of cognitive function in older Black and White adults. ePWV may be a useful measure of vascular aging that can offer insight into cognitive aging.

Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND & AIMS: Atherosclerosis and arteriosclerosis contribute to vascular aging and cardiovascular disease (CVD) risk. Both processes can be assessed simply in the lower-limbs and reflect systemic pathology. However, only atherosclerosis is routinely assessed, typically via ankle-brachial index (ABI). Arteriosclerosis can be assessed using femoral-ankle pulse wave velocity (faPWV), but no studies have identified whether ABI and faPWV similarly associate with overt CVD and risk factors, nor whether faPWV confers additional information. The aims of this study were to (i) compare associations of ABI and faPWV with traditional CVD risk factors, including age, sex, systolic blood pressure (SBP), high-density lipoprotein (HDL), total cholesterol (TC), smoking, and diabetes; and (ii) determine the independent and additive associations of ABI and faPWV with a composite measure of prevalent CVD. METHODS: We evaluated ABI and faPWV in 4330 older-aged (75.3 ± 5.0 years) adults using an oscillometric screening device. Associations between ABI and faPWV with CVD risk factors and CVD were determined using mixed-model linear- and logistic-regression. RESULTS: ABI and faPWV were associated with age, HDL, and smoking. ABI was associated with sex, TC, diabetes. faPWV was associated with SBP. Both ABI and faPWV were inversely associated with CVD. Low ABI (≤0.9 vs. >0.9) and low faPWV (≤9.94 vs. >9.94) increased the odds of CVD by 2.41-fold (95% CI:1.85,3.17) and 1.46-fold (95% CI:1.23,1.74), respectively. The inverse association between faPWV and CVD was independent of ABI and CVD risk factors. CONCLUSIONS: ABI and faPWV, measures of lower-limb atherosclerosis and arteriosclerosis, are independently associated with CVD risk factors and prevalent CVD. Assessment of faPWV may confer additional risk information beyond ABI.

Associations between estimated and measured carotid-femoral pulse wave velocity in older Black and White adults: the atherosclerosis risk in communities (ARIC) study.

Introduction: Aortic stiffness offers important insight into vascular aging and cardiovascular disease (CVD) risk. The referent measure of aortic stiffness is carotid-femoral pulse wave velocity (cfPWV). cfPWV can be estimated (ePWV) from age and mean arterial pressure. Few studies have directly compared the association of ePWV to measured cfPWV, particularly in non-White adults. Moreover, whether ePWV and cfPWV correlate similarly with CVD risk remains unexplored. Aim: (1) To estimate the strength of the agreement between ePWV and cfPWV in both Black and White older adults; and (2) to compare the associations of ePWV and cfPWV with CVD risk factors and determine whether these associations were consistent across races. Methods and Results: We evaluated 4478 [75.2 (SD 5.0) years] Black and White older adults in the Atherosclerosis Risk in Communities (ARIC) Study. cfPWV was measured using an automated pulse waveform analyzer. ePWV was derived from an equation based on age and mean arterial pressure. Association and agreement between the two measurements were determined using Pearson's correlation coefficient (r), standard error of estimate (SEE), and Bland-Altman analysis. Associations between traditional risk factors with ePWV and cfPWV were evaluated using linear mixed regression models. We observed weak correlations between ePWV and cfPWV within White adults (r = 0.36) and Black adults (r = 0.31). The mean bias for Bland-Altman analysis was low at -0.17 m/s (95%CI: -0.25 to -0.09). However, the inspection of the Bland-Altman plots indicated systematic bias (P < 0.001), which was consistent across race strata. The SEE, or typical absolute error, was 2.8 m/s suggesting high variability across measures. In models adjusted for sex, prevalent diabetes, the number of prevalent cardiovascular diseases, and medication count, both cfPWV and ePWV were positively associated with heart rate, triglycerides, and fasting glucose, and negatively associated with body mass index (BMI) and smoking status in White adults (P < 0.05). cfPWV and ePWV were not associated with heart rate, triglycerides, and fasting glucose in Black adults, while both measures were negatively associated with BMI in Black adults. Conclusions: Findings suggest a weak association between ePWV and cfPWV in older White and Black adults from ARIC. There were similar weak associations between CVD risk factors with ePWV and cfPWV in White adults with subtle differences in associations in Black adults.

Sedentary Behavior Reduction: A Stepwise Approach to Increasing Physical Activity and Reducing Cardiovascular Disease Risk in Endometrial Cancer Survivors.

Endometrial cancer survivors experience high rates of cardiovascular disease (e.g., heart disease, obesity, diabetes). The heightened cardiovascular disease risk may be attributed to cancer treatment coupled with sub-optimal lifestyle behaviors following treatment, including high amounts of sedentary behavior (SB). Public health agencies have graded the association of evidence between SB and cardiovascular disease as strong. However, while clinicians may wish to prescribe SB substitution strategies to reduce SB, guidelines do not currently exist. An additional challenge to behavior change pertains to the unique barriers that endometrial cancer survivors face, including treatment-associated fatigue and limited self-efficacy. Engaging in healthy movement behaviors, including minimizing SB and achieving recommended amounts of physical activity, are critical for health and well-being as well as cardiometabolic disease prevention. The purpose of this perspective paper is to propose an informed approach to physical activity promotion aimed to initiate movement and promote long-term behavior change by starting with an emphasis on reducing SB in endometrial cancer survivors. First, we address why endometrial cancer survivors should be targeted with SB reduction. Then, we suggest a stepwise approach to increasing physical activity by starting with SB reduction, including consideration to behavioral theories. Finally, we provide suggestions for future directions.

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. "Traceback" cascade testing -outreach to potential probands and relatives-is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program's feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program's feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.

Pediatric reporting of genomic results study (PROGRESS): a mixed-methods, longitudinal, observational cohort study protocol to explore disclosure of actionable adult- and pediatric-onset genomic variants to minors and their parents.

BACKGROUND: Exome and genome sequencing are routinely used in clinical care and research. These technologies allow for the detection of pathogenic/likely pathogenic variants in clinically actionable genes. However, fueled in part by a lack of empirical evidence, controversy surrounds the provision of genetic results for adult-onset conditions to minors and their parents. We have designed a mixed-methods, longitudinal cohort study to collect empirical evidence to advance this debate. METHODS: Pediatric participants in the Geisinger MyCode® Community Health Initiative with available exome sequence data will have their variant files assessed for pathogenic/likely pathogenic variants in 60 genes designated as actionable by MyCode. Eight of these genes are associated with adult-onset conditions (Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Lynch syndrome, MUTYH-associated polyposis, HFE-Associated Hereditary Hemochromatosis), while the remaining genes have pediatric onset. Prior to clinical confirmation of results, pediatric MyCode participants and their parents/legal guardians will be categorized into three study groups: 1) those with an apparent pathogenic/likely pathogenic variant in a gene associated with adult-onset disease, 2) those with an apparent pathogenic/likely pathogenic variant in a gene associated with pediatric-onset disease or with risk reduction interventions that begin in childhood, and 3) those with no apparent genomic result who are sex- and age-matched to Groups 1 and 2. Validated and published quantitative measures, semi-structured interviews, and a review of electronic health record data conducted over a 12-month period following disclosure of results will allow for comparison of psychosocial and behavioral outcomes among parents of minors (ages 0-17) and adolescents (ages 11-17) in each group. DISCUSSION: These data will provide guidance about the risks and benefits of informing minors and their family members about clinically actionable, adult-onset genetic conditions and, in turn, help to ensure these patients receive care that promotes physical and psychosocial health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03832985. Registered 6 February 2019.

Non-neutralizing Antibodies from a Marburg Infection Survivor Mediate Protection by Fc-Effector Functions and by Enhancing Efficacy of Other Antibodies.

Marburg virus (MARV) and Ebola virus (EBOV) belong to the family Filoviridae. MARV causes severe disease in humans with high fatality. We previously isolated a large panel of monoclonal antibodies (mAbs) from B cells of a human survivor with previous naturally acquired MARV infection. Here, we characterized functional properties of these mAbs and identified non-neutralizing mAbs targeting the glycoprotein (GP) 2 portion of the mucin-like domain (MLD) of MARV GP, termed the wing region. One mAb targeting the GP2 wing, MR228, showed therapeutic protection in mice and guinea pigs infected with MARV. The protection was mediated by the Fc fragment functions of MR228. Binding of another GP2 wing-specific non-neutralizing mAb, MR235, to MARV GP increased accessibility of epitopes in the receptor-binding site (RBS) for neutralizing mAbs, resulting in enhanced virus neutralization by these mAbs. These findings highlight an important role for non-neutralizing mAbs during natural human MARV infection.

Polycystic Ovary Syndrome Signs and Metabolic Syndrome in Premenopausal Hispanic/Latina Women: the HCHS/SOL Study.

CONTEXT: Polycystic ovary syndrome (PCOS), a condition of androgen excess in women, is associated with cardiometabolic risk factors; however, this association is not fully characterized in a population-based sample of premenopausal women and high-risk groups such as Hispanics/Latinas. OBJECTIVE: We examined the association of PCOS signs and metabolic syndrome (MetS) in premenopausal Hispanic/Latina women. METHODS: This cross-sectional analysis includes 1427 women age 24 to 44 years from the Hispanic Community Health Study/Study of Latinos. PCOS signs included menstrual cycle greater than 35 days or irregular, self-reported PCOS, and oral contraceptive use to regulate periods or acne, and a composite of 1 or more PCOS signs. We calculated odds ratios (OR) and 95% CI for MetS, accounting for sociodemographic factors and the complex survey design; an additional model included body mass index (BMI). RESULTS: The mean age was 34 years and 30% reported any PCOS sign. The odds of MetS were higher in women reporting cycles greater than 35 days or irregular (OR 1.63; CI: 1.07-2.49) vs cycles 24 to 35 days, self-reported PCOS (OR 2.49; CI: 1.38-4.50) vs no PCOS, and any PCOS sign (OR 1.58; CI: 1.10-2.26) vs none. We found no association between OC use to regulate periods or acne and MetS (OR 1.1; CI: 0.6-1.8). When adjusting for BMI, only the association of self-reported PCOS and MetS was attenuated (OR 1.78; CI: 0.92-3.44). CONCLUSIONS: In Hispanic/Latina women, irregular menstrual cycles, self-reported PCOS, and any PCOS sign were associated with MetS and could indicate women at metabolic disease risk.

Central arterial stiffness and retinal vessel calibers: the Atherosclerosis Risk in Communities Study-Neurocognitive Study.

BACKGROUND: The retinal microvasculature provides a window to the cerebral vasculature and enables examination of changes in retinal caliber that may mimic those occurring in cerebrovascular disease. The association of central arterial stiffness and retinal vessel caliber in a population sample is not fully understood. METHODS: In 1706 older adults (mean age 76.3, 58.1% women) from the population-based Atherosclerosis Risk in Communities Study, we examined the cross-sectional association of central arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)] with retinal vessel calibers [central retinal arteriolar equivalent (CRAE) and central retinal vein equivalent (CRVE)]. We estimated the association of cfPWV with CRAE narrowing (<25th percentile) and CRVE widening (>75th percentile) after adjustment for age, sex, race-field center, BMI, smoking, and type 2 diabetes. We tested for effect modification by sex, hypertension, and type 2 diabetes. RESULTS: Carotid-femoral PWV (m/s) was not associated with the odds of CRAE narrowing [odds ratio (OR): 0.99; 95% CI: 0.95-1.03]. The association of cfPWV with CRVE widening was stronger in those without hypertension (OR: 1.10; 95% CI: 1.01-1.20) versus those with hypertension (OR: 1.01 95% CI: 0.96-1.05) and slightly stronger in those with type 2 diabetes (OR: 1.07; 95% CI: 1.00-1.14) versus without type 2 diabetes (OR: 1.01; 95% CI: 0.96-1.06). CONCLUSIONS: In older adults, cfPWV was associated with wider retinal venular caliber, particularly in individuals without hypertension. Central arterial stiffening may be associated with cerebral microvascular changes, as exhibited in its retinal vasculature component.

The association of age at menopause and all-cause and cause-specific mortality by race, postmenopausal hormone use, and smoking status.

While a mean age at menopause of 51 years has been reported in the United States (U.S.), some U.S. women experience menopause before age 45, possibly increasing risk of cardiovascular mortality; however, the role in all-cause and cerebrovascular-related mortality is unclear. The purpose of this study was to investigate the association between age at menopause and all-cause and cause-specific mortality by race, hormone replacement therapy (HRT) use, and smoking status. REasons for Geographic and Racial Differences in Stroke (REGARDS) is a population-based study of 30,239 participants aged ≥45 years enrolled between 2003 and 2007 of whom 14,361 were postmenopausal women. Age at menopause was defined as <45 (early) or ≥45. All-cause and cause-specific mortality were ascertained through 2013. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between age at menopause and mortality, adjusting for baseline measures. Of 11,287 eligible women (6403 white; 4884 black), mean menopause age was 45.2 (SD 7.9) with 1524 deaths over 7.1 years. Significant interactions were detected between early age at menopause (39%) and HRT use in association with all-cause mortality (p < 0.01), mortality from coronary heart disease (p = 0.06), and mortality from all other causes (p = 0.04). An association between early age at menopause and all-cause mortality was observed among ever-HRT users (HR = 1.31, 95% CI: 1.10-1.56), but not never-HRT users (HR = 1.01, 95% CI: 0.85-1.20). There were no differences in associations examined by race or smoking status. Increased all-cause mortality risk was observed for ever-HRT users with menopause before age 45.

Antibody-Mediated Protective Mechanisms Induced by a Trivalent Parainfluenza Virus-Vectored Ebolavirus Vaccine.

Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to sera from guinea pigs receiving the monovalent vaccines, sera from guinea pigs receiving the trivalent vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus infection survivors demonstrated that the immune sera block the binding of antibodies specific for the GP glycan cap, the GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.IMPORTANCE The symptoms of the disease caused by the ebolaviruses Ebola, Bundibugyo, and Sudan are similar, and their areas of endemicity overlap. However, because of the limited antigenic relatedness of the ebolavirus glycoprotein (GP) used in all candidate vaccines against these viruses, they protect only against homologous and not against heterologous ebolaviruses. Therefore, a broadly specific pan-ebolavirus vaccine is required, and this might be achieved by administration of a cocktail of vaccines. The effects of cocktail administration of ebolavirus vaccines on the antibody repertoire remain unknown. Here, an in-depth analysis of the antibody responses to administration of a cocktail of human parainfluenza virus type 3-vectored vaccines against individual ebolaviruses was performed, which included analysis of binding to GP, neutralization of individual ebolaviruses, epitope specificity, Fc-mediated functions, and protection against the three ebolaviruses. The results demonstrated potent and balanced responses against individual ebolaviruses and no significant reduction of the responses compared to that induced by individual vaccines.

Antibody Repertoires to the Same Ebola Vaccine Antigen Are Differentially Affected by Vaccine Vectors.

Comparative immune response profiling is important for selecting next-generation vaccines. We comprehensively evaluated the antibody responses from a panel of nine respiratory vaccines against Ebola virus (EBOV) derived from human and avian paramyxoviruses expressing EBOV glycoprotein (GP). Most vaccines were protective in guinea pigs but yielded antibody repertoires that differed in proportion targeting key antigenic regions, avidity, neutralizing antibody specificities, and linear epitope preferences. Competition studies with monoclonal antibodies from human survivors revealed that some epitopes in GP targeted for neutralization were vector dependent, while EBOV-neutralizing titers correlated with the response magnitude toward the receptor-binding domain and GP1/GP2 interface epitopes. While an immunogen determines the breadth of antibody response, distinct vaccine vectors can induce qualitatively different responses, affecting protective efficacy. These data suggest that immune correlates of vaccine protection cannot be generalized for all vaccines against the same pathogen, even if they use the exact same immunogen.

Transient Antenatal Bartter's Syndrome: A Case Report.

Antenatal Bartter's syndrome is a rare inherited disorder characterized by fetal polyhydramnios and polyuria that is usually detected between 24 and 30 weeks of gestation. However, a rare, severe, but transient form of antenatal Bartter's syndrome due to an x-linked melanoma-associated antigen D2 (MAGED2) mutation has recently been described. This transient type results in the earlier onset of severe polyhydramnios and preterm birth, but spontaneously resolves postnatally. Here, we present a case of a 29-week gestation male born to a mother with severe polyhydramnios, who was subsequently found to have a novel mutation for MAGED2 not previously reported. This is the first and only case not to be treated with indomethacin, yet still resulted in spontaneous resolution of symptoms. Our case suggests the need for awareness of and testing for this new mutation in cases of severe antenatal polyhydramnios and discusses the perinatal treatment of this condition.

Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants.

PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient-participants and their clinicians. We queried patient-participants' electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient-participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient-participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer-including a stage 1C fallopian tube cancer-via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.