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BACKGROUND: Heart transplantation (HTx) after donation after circulatory death (DCD) is an expanding practice but is associated with increased warm ischemic time. The impact of DCD HTx on cardiac mechanics and myocardial fibrosis has not been reported. We aimed to compare cardiac mechanics and myocardial fibrosis using cardiovascular magnetic resonance (CMR) imaging in donation after brain death (DBD) and DCD HTx recipients and healthy controls. METHODS AND RESULTS: Consecutive HTx recipients between March 2015 and March 2021 who underwent routine surveillance CMR imaging were included. Cardiac mechanics were assessed using CMR feature tracking to compute global longitudinal strain, global circumferential strain, and right ventricular free-wall longitudinal myocardial strain. Fibrosis was assessed using late gadolinium enhancement imaging and estimation of extracellular volume. There were 82 (DBD n = 42, DCD n = 40) HTx recipients (aged 53 years, interquartile range 41-59 years, 24% female) who underwent CMR imaging at median of 9 months (interquartile range 6-14 months) after transplantation. HTx recipients had increased extracellular volume (29.7 ± 3.6%) compared with normal ranges (25.9%, interquartile range 25.4-26.5). Myocardial strain was impaired after transplantation compared with controls (global longitudinal strain -12.6 ± 3.1% vs -17.2 ± 1.8%, P < .0001; global circumferential strain -16.9 ± 3.1% vs -19.2 ± 2.0%, P = .002; right ventricular free-wall longitudinal strain -15.7 ± 4.5% vs -21.6 ± 4.7%, P < .0001). There were no differences in fibrosis burden (extracellular volume 30.6 ± 4.4% vs 29.2 ± 3.2%; P = .39) or cardiac mechanics (global longitudinal strain -13.1 ± 3.0% vs -12.1 ± 3.1%, P = .14; global circumferential strain -17.3 ± 2.9% vs -16.6 ± 3.1%, P = .27; right ventricular free-wall longitudinal strain -15.9 ± 4.9% vs -15.5 ± 4.1%, P = .71) between DCD and DBD HTx. CONCLUSIONS: HTx recipients have impaired cardiac mechanics compared with controls, with increased myocardial fibrosis. There were no differences in early CMR imaging characteristics between DBD and DCD heart transplants, providing further evidence that DCD and DBD HTx outcomes are comparable.

Background and Objectives:Exposure to socioeconomic disadvantage is associated with early-onset cognitive aging. Biological aging, the progressive loss of system integrity that occurs as we age is proposed as a modifiable process mediating this health inequality. We examined whether socioeconomic disparities in cognitive aging in mid-to late-life adults is explained by accelerated biological aging similarly across race, ethnicity and sex/gender.Methods:Data was from a prospective cohort study of the U.S. Health and Retirement Study DNA-methylation sub-study. Socioeconomic status (SES) was measured from years of education and household wealth at baseline. The extent and pace of biological aging were quantified using three DNA-methylation measures: PhenoAge, GrimAge, and DunedinPoAm. Cognitive aging was measured from repeated longitudinal assessments of immediate and delayed word recall. Latent growth curve modeling estimated participants’ level of memory performance and rate of decline over 2-11 follow-up assessments spanning 2-20 years. Multiple-group models were estimated to assess whether the relationship between SES and memory trajectories was mediated by biological aging across racial-ethnic by sex/gender subgroups.Results:Data from a total of 3,997 adults aged 50-100 were analyzed. Participants with lower SES had lower memory performance, faster decline and exhibited accelerated biological aging (SES effect size associations (β) ranged from .08 to .41). Accelerated biological aging was associated with decreased memory performance and faster memory decline (effect-size range .03 to .23). SES-biological aging associations were strongest for White men and women and weakest for Latinx women. The relationship between biological aging measures and memory was weaker for Black participants compared with White and Latinx people. In mediation analysis, biological aging accounted for 4-27% of the SES-memory gradient in White participants. There was little evidence of mediation in Black or Latinx participants.Discussion:Among a national sample of mid-to late-life adults, DNA-methylation measures of biological aging were variably associated with memory trajectories and SES across White, Black, and Latinx mid-to late-life adults. These results challenge the assumption that DNA-methylation biomarkers of aging that were developed in primarily White people can equivalently quantify aging processes affecting cognition in Black and Latinx mid-to late-life adults.

In cancer randomized controlled trials, surrogate endpoints are frequently time-to-event endpoints, subject to the competing risk from the time-to-event clinical outcome. In this context, we introduce a counterfactual-based mediation analysis for a causal assessment of surrogacy. We use a multistate model for risk prediction to account for both direct transitions towards the clinical outcome and indirect transitions through the surrogate outcome. Within the counterfactual framework, we define natural direct and indirect effects with a causal interpretation. Based on these measures, we define the proportion of the treatment effect on the clinical outcome mediated by the surrogate outcome. We estimate the proportion for both the cumulative risk and restricted mean time lost. We illustrate our approach by using 18-year follow-up data from the SPCG-4 randomized trial of radical prostatectomy for prostate cancer. We assess time to metastasis as a surrogate outcome for prostate cancer-specific mortality.

Background Patients receiving dialysis face a high risk of cardiovascular disease, arrhythmia and sudden cardiac death. Few patients, however, are aware of this risk. Implantable cardiac monitors are currently available for clinical use and can continuously monitor cardiac rhythms without the need for transvenous leads. Our goal was to gauge patients’ and family members’ perceptions of these risks and to identify their concerns about cardiac monitors. Methods Two 90-minute focus groups were conducted: one with patients receiving in-center hemodialysis and one with their family members. Trained moderators assessed: (1) knowledge of cardiovascular disease; (2) cardiovascular disease risk in dialysis; (3) risk of death due to cardiovascular disease; (4) best ways to convey this risk to patients/families; and (5) concerns about cardiac monitors. The sessions were audiotaped, transcribed, and independently analyzed by two reviewers to identify core themes. Emblematic quotations were chosen to illustrate the final themes. Results Nine adult patients and three family members participated. Patients felt education was inadequate and had little knowledge of arrhythmias. Patients’/families’ concerns regarding cardiac monitors were related to adverse effects, the notification process, and cosmetic effects. Patients/families felt that nephrologists, not dialysis staff, would be the best source for education. Conclusions The preliminary data from this small study population suggest that patients/families are not well aware of the high risk of arrhythmia and sudden cardiac death in dialysis. Further investigation is required to gauge this awareness among patients/families and to assess their impressions of implantable cardiac monitors for arrhythmia detection and management.

RATIONALE & OBJECTIVE: Current dietary guidelines recommend that chronic kidney disease (CKD) patients restrict individual nutrients, such as sodium, potassium, phosphorus and protein. This approach can be difficult for patients to implement and ignores important nutrient interactions. Dietary patterns are an alternative method to intervene on diet. Our objective was to define the associations of four healthy dietary patterns with risk of CKD progression and all-cause mortality among people with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,403 participants aged 21–74 years with an estimated glomerular filtration rate (eGFR) of 20–70 mL/min/1.73 m(2) and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires. OUTCOMES: 1) CKD progression defined as ≥50% eGFR decline, kidney transplantation, or dialysis and 2) all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: There were 855 cases of CKD progression and 773 deaths over a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of AHEI-2010, aMed, and DASH had lower adjusted risk of CKD progression with the strongest results for aMed (HR: 0.75, 95% CI: 0.62–0.90). Compared with participants with the lowest adherence, the highest adherence tertiles for all scores had lower adjusted risk of all-cause mortality for each index (24–31% lower risk). LIMITATIONS: Self-reported dietary intake. CONCLUSIONS: Greater adherence to several healthy dietary patterns is associated with a lower risk of CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns can be considered as a strategy for managing CKD. INDEX WORDS: dietary patterns, nutrition, kidney disease, renal, mortality

Supplemental Digital Content is available in the text., Background. Patients (20%–50%) undergoing renal transplantation experience acute kidney injury resulting in delayed graft function. ANG-3777 is an hepatocyte growth factor mimetic that binds to the c-MET receptor. In animal models, ANG-3777 decreases apoptosis, increases proliferation, and promotes organ repair and function. Methods. This was a randomized, double-blind, placebo-controlled, phase 2 trial of patients undergoing renal transplantation with

Background Many DNA methylation-based indicators have been developed as summary measures of epigenetic aging. We examine the associations between 13 epigenetic clocks, including 4 second generation clocks, as well as the links of the clocks to social, demographic, and behavioral factors known to be related to health outcomes: sex, race/ethnicity, socioeconomic status, obesity, and lifetime smoking pack-years. Methods The Health and Retirement Study is the data source which is a nationally representative sample of Americans over age 50. Assessment of DNA methylation was based on the EPIC chip and epigenetic clocks were developed based on existing literature. Results The clocks vary in the strength of their relationships with age, with each other and with independent variables. Second generation clocks trained on health-related characteristics tend to relate more strongly to the sociodemographic and health behaviors known to be associated with health outcomes in this age group. Conclusions Users of this publicly available data set should be aware that epigenetic clocks vary in their relationships to age and to variables known to be related to the process of health change with age.

Introduction Chronic kidney disease (CKD) may be associated with overt or subclinical hypothyroidism [SCH; defined as elevated serum thyroid-stimulating hormone (TSH) despite normal free thyroxine levels). Although some studies have demonstrated that thyroid replacement therapy may improve renal function in overt hypothyroidism, there is no consensus on its benefits in SCH. Clinical and limited economic outcomes were evaluated in levothyroxine-treated US veterans with CKD + SCH. Methods Veterans Health Administration claims data from April 2013 to March 2018 for levothyroxine-treated versus nontreated CKD + SCH patients were compared. Eligible patients with CKD + SCH (≥ 2 elevated TSH values recorded; ≥ 2 normal thyroxine values recorded) had ≥ 1 TSH values recorded during 24-month follow-up, and ≥ 1 estimated glomerular filtration rate (eGFR) measurement during baseline and follow-up. Continuous levothyroxine use (treatment cohort) was required during follow-up. The primary endpoint was eGFR at 6, 12, 18, and 24 months; secondary endpoints included eGFR change from baseline, CKD progression, and length of hospital stay (LOS). Propensity score matching (PSM) was performed. Results Of 453 eligible patients, 157 remained in each cohort after PSM. Most were male (96%) and white (88%); mean age was 75 years. No significant differences were observed between cohorts at any time point for eGFR, eGFR change from baseline, or CKD progression. Treated patients had numerically higher mean eGFR at 6 and 12 months, lower proportions of progression to higher CKD stages at 12, 18, and 24 months, and shorter mean all-cause LOS versus nontreated patients (1.92 vs. 3.30 days; P = 0.3483) within the 24-month follow-up period. A significantly shorter mean CKD-related LOS was observed versus nontreated patients (0.11 vs. 1.38 days; P

Background Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown. Methods In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician. Results There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg. Conclusions These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

Objective The study sought to evaluate a novel electronic health record (EHR) add-on application for chronic disease management that uses an integrated display to decrease user cognitive load, improve efficiency, and support clinical decision making. Materials and Methods We designed a chronic disease management application using the technology framework known as SMART on FHIR (Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources). We used mixed methods to obtain user feedback on a prototype to support ambulatory providers managing chronic obstructive pulmonary disease. Each participant managed 2 patient scenarios using the regular EHR with and without access to our prototype in block-randomized order. The primary outcome was the percentage of expert-recommended ideal care tasks completed. Timing, keyboard and mouse use, and participant surveys were also collected. User experiences were captured using a retrospective think-aloud interview analyzed by concept coding. Results With our prototype, the 13 participants completed more recommended care (81% vs 48%; P Discussion Participants completed more recommended care by taking more time when using our prototype. Interviews identified a tension between using the inefficient but familiar EHR vs learning to use our novel prototype. Concept coding of user feedback generated actionable insights. Conclusions Mixed methods can support the design and evaluation of SMART on FHIR EHR add-on applications by enhancing understanding of the user experience.

Supplemental Digital Content is available in the text., Background: The future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score, or coronary artery stenosis severity. We assessed whether noncalcified low-attenuation plaque burden on coronary CT angiography (CCTA) might be a better predictor of the future risk of myocardial infarction. Methods: In a post hoc analysis of a multicenter randomized controlled trial of CCTA in patients with stable chest pain, we investigated the association between the future risk of fatal or nonfatal myocardial infarction and low-attenuation plaque burden (% plaque to vessel volume), cardiovascular risk score, coronary artery calcium score or obstructive coronary artery stenoses. Results: In 1769 patients (56% male; 58±10 years) followed up for a median 4.7 (interquartile interval, 4.0–5.7) years, low-attenuation plaque burden correlated weakly with cardiovascular risk score (r=0.34; P

People with HIV (PWH) are at increased risk of cardiovasvular disease (CVD) and sudden cardiac death. Previous work has suggested an association between HIV infection and electrocardiographic (ECG) abnormalities. There are limited data on the burden of ECG abnormalities among PWH in a multiracial, multiethnic globally representative population.One hundred twenty sites in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).ECG findings were grouped into clinically relevant categories using sex-specific thresholds when indicated. We used the Fisher exact tests to assess associations of demographic characteristics and ECG abnormalities. We used logistic regression model to assess associations between demographic and HIV management measures, with adjustment.We analyzed data for 7720 PWH (99% of participants) (median age 50 years, 69% male participants). There were 3346 (43%) Black or African American, 2680 (35%) White, and 1139 (15%) Asian participants. Most of the participants (97%) had viral load that was400 copies/mL orlower limits of quantification. Nearly half of the participants had at least one ECG abnormality (44%). QTc prolongation was more common among male than female participants (9% vs. 6%, P = 0.001) and nearly twice as common among Asian participants (12%) when compared with other racial groups (7%) (P0.0001). Participants with viral load400 copies/mL had approximately twice the odds of prolonged QTc compared with those that were undetectable (adjusted OR: 2.05, 95% CI: 1.22 to 3.45).Prolonged QTc is common among male, Asian, and REPRIEVE participants with higher viral loads. These relationships warrant future investigation of linkages to ensuing CVD events among PWH.

Limited data are available regarding asymptomatic COVID-19 among people with HIV (PWH). Data on a representative subset of PWH enrolled in Randomized Trial to Prevent Vascular Events in HIV, a global clinical trial, are presented here.Randomized Trial to Prevent Vascular Events in HIV is an atherosclerotic cardiovascular disease prevention trial among 7770 PWH on antiretroviral therapy. Beginning April 2020, targeted data on coronavirus disease 2019 (COVID-19) diagnosis and symptoms were collected during routine trial visits. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was defined as either COVID-19 clinical diagnosis or presence of SARS-CoV-2 Immunoglobulin G (IgG) or Immunoglobulin A (IgA) receptor binding domain protein (antispike) antibodies in the absence of prior COVID-19 vaccine.The group (N = 2464) had a median age 53 years, 35% female sex, 47% Black or African American race, median CD4 count 649 c/mm 3 , and 97% with HIV VL400 cp/m. SARS-CoV-2 infection occurred in 318 persons (13%): 58 with clinical diagnosis and 260 with detectable antibodies. Of these PWH, 304 completed symptom questionnaires: 121 (40%) reported symptoms, but 183 (60%) were asymptomatic. PWH with asymptomatic SARS-CoV-2 infection were more likely to be from low-income or middle-income regions, of Black or African American race, older in age, and with higher atherosclerotic cardiovascular disease risk score. Symptomatic COVID was more common with obesity, metabolic syndrome, and low HDL levels. CD4 counts and HIV viral suppression rates were similar among PWH with symptomatic vs. asymptomatic COVID.Asymptomatic SARS-CoV-2 infection is common among antiretroviral therapy-treated PWH globally. We determined that 60% of infections in PWH were asymptomatic. HIV clinicians must remain vigilant about COVID-19 testing among PWH to identify asymptomatic cases.

Background: People with type 2 diabetes mellitus (T2DM) have elevated cardiovascular (CV) risk, including for hospitalization for heart failure (HHF). Canagliflozin reduced CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS (CANagliflozin cardioVascular Assessment Study) Program and the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial.Objectives: The aim of this study was to assess the effects of canagliflozin on CV outcomes according to baseline estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) in pooled patient-level data from the CANVAS Program and CREDENCE trial.Methods: Canagliflozin effects on CV death or HHF were assessed by baseline eGFR (60 mL/min/1.73 m2) and UACR (300 mg/g). HRs and 95% CIs were estimated by using Cox regression models overall and according to subgroups.Results: A total of 14,543 participants from the CANVAS Program (N = 10,142) and the CREDENCE (N = 4,401) trial were included, with a mean age of 63 years, 35% female, 75% White, 13.2% with baseline eGFR 2, and 31.9% with UACR >300 mg/g. Rates of CV death or HHF increased as eGFR declined and/or UACR increased. Canagliflozin significantly reduced CV death or HHF compared with placebo (19.4 vs 28.0 events per 1,000 patient-years; HR: 0.70; 95% CI: 0.62-0.79), with consistent results across eGFR and UACR categories (all P interaction >0.40).Conclusions: Risk of CV death or HHF was higher in those with lower baseline eGFR and/or higher UACR. Canagliflozin consistently reduced CV death or HHF in participants with T2DM and high CV risk or nephropathy regardless of baseline renal function or level of albuminuria. (Canagliflozin Cardiovascular Assessment Study [CANVAS], NCT01032629; A Study of the Effects of Canagliflozin [JNJ-24831754] on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus [CANVAS-R], NCT01989754; and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy [CREDENCE], NCT02065791)

Objectives Coronavirus disease 2019 has been reported to be a prothrombotic condition; however, multicenter data comparing this with other viral pneumonias in those requiring extracorporeal membrane oxygenation are lacking. We conducted a multicenter study using whole-body CT to examine the prevalence, severity, and nature of vascular complications in coronavirus disease 2019 in comparison with patients with other viral pneumonias. Design We analyzed whole-body CT scans for the presence of vascular thrombosis (defined as pulmonary artery thrombus, venous thrombus, systemic arterial thrombus, or end-organ infarct). The severity, distribution, and morphology of pulmonary artery thrombus were characterized. Competing risk cumulative incidence analysis was used to compare survival with discharge. Setting Three centers of the English national extracorporeal membrane oxygenation service. Patients Consecutive patients admitted with either coronavirus disease 2019 or noncoronavirus disease 2019 viral pneumonia admitted from January 2019. Interventions None. Measurements and main results One-hundred thirty-six patients (45.2 ± 10.6 yr old, 39/146 [27%] female) requiring extracorporeal membrane oxygenation support underwent whole-body CT scans at admission. Of these, 86 had coronavirus disease 2019 pneumonia, and 50 had noncoronavirus disease 2019 viral pneumonia. Vascular thrombosis was seen more often in patients with coronavirus disease 2019 (odds ratio, 12.9 [95% CI 4.5-36.8]). In those with coronavirus disease 2019, 57 (73%) demonstrated pulmonary artery thrombus or pulmonary perfusion defects. Eighty-two percent of thrombus exhibited emboli-like morphology. The location of pulmonary artery thrombus and parenchymal perfusion defects was only concordant in 30% of cases. The risk of mortality was higher in those with coronavirus disease 2019 compared with noncoronavirus disease 2019 pneumonia (χ2 = 3.94; p = 0.047). Mortality was no different in coronavirus disease 2019 patients with or without vascular thrombosis (χ2 = 0.44; p = 0.51). Conclusions In patients who received extracorporeal membrane oxygenation, coronavirus disease 2019 is associated with a higher prevalence of vascular thrombosis compared with noncoronavirus disease viral pneumonias. The pattern of pulmonary vascular changes suggests concurrent embolic disease and small vessel disease. Despite this, vascular thrombosis was not linked to poorer short-term prognosis in those with coronavirus disease 2019.

Background The exchange of health information between primary care providers (PCPs) and surgeons is critical during transitions of care for older patients with multiple comorbidities; however, it is unknown to what extent this process occurs. This study was designed to characterize the extent to which factors associated with older patient's recovery, such as functional status, cognitive status, social status, and emotional factors, are shared among PCPs and surgical providers during care transitions. Materials and methods We prospectively identified 15 patients aged over 60 y with ≥3 comorbidities referred for general and vascular surgery procedures at a Veterans Administrative and academic medical center. Semistructured Critical Decision Method interviews were conducted with patients along with their surgical providers and referring PCPs. Thematic content analysis was performed independently by five reviewers on the cognitive processes associated with functional status, cognitive status, social status, and emotional factors. Interrater reliability between providers and patients was assessed using Cohen's kappa. Results Forty-seven Critical Decision Method interviews were conducted, which included 20 paired interviews between a PCP and a surgeon and 16 paired interviews that involved a patient and a provider. The majority of patients reported experiencing poor information exchange between their PCP and surgeon (58%) and feeling they were primarily responsible for communicating their own health information during care transitions (67%). In paired interviews between PCPs and surgeons, there was nearly perfect agreement for the shared knowledge of cognitive (kappa: 0.83) and emotional (kappa 1) factors. In contrast, there was only minimal agreement for shared knowledge of functional status (kappa 0.38) and social status (kappa: 0.34). Conclusions Information exchange between PCPs and surgical providers is often discordant during transitions of surgical care for medically complex older patients, particularly when it pertains to communicating their functional or social status.

OBJECTIVES: This study was designed to investigate whether coronary computed tomography angiography assessments of coronary plaque might explain differences in the prognosis of men and women presenting with chest pain. BACKGROUND: Important sex differences exist in coronary artery disease. Women presenting with chest pain have different risk factors, symptoms, prevalence of coronary artery disease and prognosis compared to men. METHODS: Within a multicenter randomized controlled trial, we explored sex differences in stenosis, adverse plaque characteristics (positive remodeling, low-attenuation plaque, spotty calcification, or napkin ring sign) and quantitative assessment of total, calcified, noncalcified and low-attenuation plaque burden. RESULTS: Of the 1,769 participants who underwent coronary computed tomography angiography, 772 (43%) were female. Women were more likely to have normal coronary arteries and less likely to have adverse plaque characteristics (p < 0.001 for all). They had lower total, calcified, noncalcified, and low-attenuation plaque burdens (p < 0.001 for all) and were less likely to have a low-attenuation plaque burden >4% (41% vs. 59%; p < 0.001). Over a median follow-up of 4.7 years, myocardial infarction (MI) occurred in 11 women (1.4%) and 30 men (3%). In those who had MI, women had similar total, noncalcified, and low-attenuation plaque burdens as men, but men had higher calcified plaque burden. Low-attenuation plaque burden predicted MI (hazard ratio: 1.60; 95% confidence interval: 1.10 to 2.34; p = 0.015), independent of calcium score, obstructive disease, cardiovascular risk score, and sex. CONCLUSIONS: Women presenting with stable chest pain have less atherosclerotic plaque of all subtypes compared to men and a lower risk of subsequent MI. However, quantitative low-attenuation plaque is as strong a predictor of subsequent MI in women as in men. (Scottish Computed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

Though T-cell immunosenescence is a major risk factor for age-related diseases, susceptibility to infections, and responses to vaccines, differences in T-cell subset counts and representation by age and sex have not been determined for a large sample representative of the national population of the United States. We evaluated the counts of T-cell subsets including total, CD4+, and CD8+ T cells and their naïve (Tn), effector memory (Tem), and effector subsets, in the context of age, sex, and exposure to cytomegalovirus (CMV) infection among 8 848 Health and Retirement Study participants, a nationally representative study of adults older than 55 years. Total T cells (CD3+) and CD4+ cells declined markedly with age; CD8+ T cells declined somewhat less. While CD4+ T cell declines with age occurred for both CMV-seropositive and CMV-seronegative groups, total T cells and CD8+ cells were both substantially higher among the CMV-seropositive group. Numbers of Tn CD4+ and CD8+ cells were strongly and inversely related to age, were better conserved among women, and were independent of CMV seropositivity. By contrast, accumulation of the CD8+ and CD4+ Tem and effector subsets was CMV-associated. This is the first study to provide counts of T-cell subsets by age and sex in a national sample of US adults older than the age of 55 years. Understanding T-cell changes with age and sex is an important first step in determining strategies to reduce its impact on age-related diseases and susceptibility to infection.

Radiomics, quantitative feature extraction from radiological images, can improve disease diagnosis and prognostication. However, radiomic features are susceptible to image acquisition and segmentation variability. Ideally, only features robust to these variations would be incorporated into predictive models, for good generalisability. We extracted 93 radiomic features from carotid artery computed tomography angiograms of 41 patients with cerebrovascular events. We tested feature robustness to region-of-interest perturbations, image pre-processing settings and quantisation methods using both single- and multi-slice approaches. We assessed the ability of the most robust features to identify culprit and non-culprit arteries using several machine learning algorithms and report the average area under the curve (AUC) from five-fold cross validation. Multi-slice features were superior to single for producing robust radiomic features (67 vs. 61). The optimal image quantisation method used bin widths of 25 or 30. Incorporating our top 10 non-redundant robust radiomics features into ElasticNet achieved an AUC of 0.73 and accuracy of 69% (compared to carotid calcification alone [AUC: 0.44, accuracy: 46%]). Our results provide key information for introducing carotid CT radiomics into clinical practice. If validated prospectively, our robust carotid radiomic set could improve stroke prediction and target therapies to those at highest risk.

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

BACKGROUND: Chronic kidney disease (CKD) progression can be a cause and potentially a consequence of anemia. Previous studies suggesting that anemia is associated with CKD progression have not utilized methodologic approaches to address time-dependent confounding. METHODS: We evaluated the association of anemia (defined using World Health Organization criteria of hemoglobin

Cows' milk is a relatively poor source of vitamin D but figures listed in UK food composition tables may be outdated. Samples of milk were collected for 1-year and vitamin D

OBJECTIVES To investigate how cardiometabolic-inflammatory risk factors are related to cognition among older adults in India and the United States. DESIGN The Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD) and the Harmonized Cognitive Assessment Protocol of the Health and Retirement Study (HRS-HCAP) in the United States conducted an in-depth assessment of cognition, using protocols designed for international comparison. SETTING Cognitive tests were conducted in hospital or household settings in India and in household settings in the United States. PARTICIPANTS Respondents aged 60 years and older from LASI-DAD (N = 1,865) and respondents aged 65 years and older from HRS-HCAP (N = 2,111) who provided venous blood specimen. MEASUREMENTS We used total composite scores from the common cognitive tests administered. Cardiovascular risk was indicated by systolic and diastolic blood pressure, pulse rate, pro-B-type natriuretic peptide (proBNP), and homocysteine. Metabolic risk was measured by body mass index, glycosylated hemoglobin (HbA1c), high-density lipoprotein cholesterol, and lipoprotein (a) (only in India). Inflammatory risk was indicted by white blood cell count, C-reactive protein, albumin, and uric acid (only in India). RESULTS The distribution of both total cognition scores and of cardiometabolic risk factors differed significantly between India and the United States. In both countries, lower cognition was associated with older age, lower education, elevated homocysteine, elevated proBNP, and lower albumin levels. The associations between HbA1c levels and cognitive measures were statistically significant in both countries, but in the opposite direction, with a coefficient of 1.5 (P

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

BACKGROUND: Children with cancer have difficulty identifying and describing the multiple symptoms they experience during hospitalization and between clinical encounters. Mobile health resources, including apps, are potential solutions to support child-centric symptom reporting. This study evaluated the feasibility and acceptability of a newly developed game-based symptom reporting app for school-age children with cancer. PROCEDURE: Nineteen school-age children (6–12 years of age) receiving treatment for cancer at a COG institution in the Intermountain West of the United States used a game-based symptom reporting app between clinical visits. Feasibility was evaluated through a summary of actual days of app use and interaction with each of the app’s features. Children and their parents participated in interviews regarding the app’s acceptability. RESULTS: Children used the app a median of 4 days (range 1–12) and interacted most frequently with the symptom reporting and the drawing features. Children enjoyed aspects of the app that supported their creativity and provided choices. Parents endorsed the interactive nature of the app and the value of the child providing his/her own report. Both children and parents identified additional opportunities to enhance the child’s user experience. CONCLUSION: Study results support the preliminary feasibility and acceptability of the app. Children’s and parents’ responses supported the developmental relevance of the app and its role in enhancing the child’s autonomy and serving as an outlet for creativity. Future directions include optimizing the child user’s experience and investigating the app’s role as a resource to enhance shared decision making for symptom management.

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

RATIONALE & OBJECTIVE: Safe analgesic choices are limited in chronic kidney disease (CKD). We conducted a comparative analysis of harm from opioids versus nonsteroidal anti-inflammatory drugs in CKD. STUDY DESIGN: Prospective cohort study SETTING & PARTICIPANTS: 3939 patients with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: 30-day analgesic use reported at annual visits. OUTCOMES: a composite outcome of 50% glomerular filtration rate (GFR) reduction and kidney failure requiring kidney replacement therapy (KRT), as well as the outcomes of kidney failure requiring KRT, hospitalization, and pre-kidney failure death. ANALYTICAL APPROACH: Marginal structural models with time-updated exposures. RESULTS: Participants were followed for a median of 6.84 years with 391 (9.9%) and 612 (15.5%) reporting baseline opioid and NSAID (non-steroidal anti-inflammatory drug) use, respectively. Time-updated opioid use was associated with the kidney disease composite outcome, kidney failure with KRT, death (HRs of 1.4 [95% CI, 1.2-1.7], 1.4 [95% CI, 1.1-1.7], and 1.5 [95% CI, 1.2-2.0], respectively), and hospitalization (rate ratio (RR), 1.7; 95% CI, 1.6-1.9) versus opioid non-users. Similar results were found in an analysis restricted to a sub-cohort of participants reporting ever using other (non-opioid, non-NSAID) analgesics or tramadol. Time-updated non-steroidal anti-inflammatory drug use was associated with an increased risk for the kidney disease composite (HR, 1.2; 95% CI, 1.0-1.5) and hospitalization (RR, 1.1; 95% CI, 1.0-1.3); however, these associations were not significant in the sub-cohort. The association of non-steroid anti-inflammatory drug use with the kidney disease composite outcome varied by race, with a significant risk in blacks (HR, 1.3; 95% CI, 1.0-1.7). NSAID use was associated with a lower risk of kidney failure with KRT in women and individuals with GFR < 45 mL/min/1.73 m2 (HRs of 0.63 [95% CI, 0.45-0.88], 0.77 [95% CI, 0.59-0.99], respectively). LIMITATIONS: Limited periods of recall of analgesic use and potential confounding by indication CONCLUSION: Opioid use had a stronger association with adverse events than nonsteroidal anti-inflammatory drugs, with the latter’s association with kidney disease outcomes limited to specific sub-groups, notably those of black race.

Cardiovascular trials have traditionally been underpowered to assess advanced chronic kidney disease (CKD) outcomes, and when included as a secondary end point, trials have used progression of CKD as incidence of some variation of a composite of end-stage kidney disease (ESKD) outcomes. Such outcomes are infrequent or occur late in cardiovascular outcome trials, which highlights the need for alternate markers for assessing the impact of interventions on kidney function at an earlier stage of the disease and, from the prevention perspective, more relevant stage of the disease.Estimated glomerular filtration rate (eGFR) slope has demonstrated strong association with subsequent progression to ESKD. With adequate sample size, treatment effects in the range of 0.5 to 1.00 mL/min/1.73 m2/y had 96% probability of predicting CKD progression, defined as doubling of serum creatinine, eGFR less than 15 mL/min/1.73 m2, or ESKD. eGFR slope can be used in patients with higher baseline values and may provide CKD progression insights when few hard kidney events are observed, especially in trials with limited follow-up. However, among trials that have determined eGFR slope, significant variations exist regarding inclusion of baseline values, calculation of eGFR values, and the follow-up period, which make it difficult to compare and gauge the incremental benefit of the interventions. There are multiple challenges in computing eGFR slope in cardiovascular trials, such as accounting for initial eGFR dip, nonlinearity, and heteroscedasticity.eGFR slope may serve as a valuable marker to determine progression of CKD in cardiovascular trials. Further work is required to standardize data collection, follow-up duration, time points for kidney function assessment, and analytic methods to compute eGFR slope in cardiovascular trials.

Multiple clinical trials have demonstrated that renin-angiotensin system (RAS) blockade with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers effectively reduces chronic kidney disease (CKD) progression. However, most clinical trials excluded participants with advanced CKD (ie, estimated glomerular filtration rate [eGFR]30mL/min/1.73m

INTRODUCTION: Angina, myocardial ischemia, and coronary artery physiology in hypertrophic cardiomyopathy (HCM) are poorly understood. However, coronary computed tomography angiography (CCTA) with fractional flow reserve from CT (FFRCT) analysis offers a non-invasive method for evaluation of coronary artery volume to myocardial mass ratio (V/M) that may provide insight into such mechanisms. Thus, we sought to investigate changes in V/M in HCM. METHODS: A retrospective analysis was performed on 37 HCM patients and 37 controls matched for age, sex, and cardiovascular risk factors; CCTA-derived coronary artery lumen volume (V) and myocardial mass (M) were used to determine V/M. FFRCT values were calculated for the left anterior descending (LAD), left circumflex (LCx) and right coronary (RCA) arteries as well as the 3-vessel cumulative FFRCT values. RESULTS: HCM patients had significantly increased myocardial mass (176 ± 84 vs. 119 ± 27 g, p < 0.0001) and total coronary artery luminal volume (4112 ± 1139 vs. 3290 ± 924 mm3, p < 0.0001) that resulted from increases in segmented luminal volumes of both the left and right coronary artery systems. However, HCM patients had significantly decreased V/M (23.8 ± 5.9 vs. 26.5 ± 5.3 mm3/g; p = 0.026) which was further decreased when restricting V/M analysis to those HCM patients with septal hypertrophy (22.4 mm3/g, p = 0.01) that was mild-moderately predictive of HCM (AUC = 0.68). HCM patients also showed significantly lower nadir FFRCT values in the LCx (0.87 ± 0.06 vs. 0.91 ± 0.06, p = 0.02), and cumulative 3-vessel FFRCT values (2.58 ± 0.18 vs. 2.63 ± 0.14, p = 0.006). CONCLUSIONS: HCM patients demonstrate significantly greater coronary volume. Despite this, HCM patients suffer from decreased V/M. Further prospective studies evaluating the relationship between V/M, angina, and heart failure in HCM are needed.

Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid–femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause. The 2795 participants we enrolled had a mean age of 60 years, 56.4% were men, 47.3% had diabetes mellitus, and the average estimated glomerular filtration rate at entry was 44.4 mL/min per 1.73 m 2 . During follow-up, there were 504 ESRD events, 628 ESRD or halving of estimated glomerular filtration rate events, and 394 deaths. Patients with the highest tertile of PWV (>10.3 m/s) were at higher risk for ESRD (hazard ratio [95% confidence interval], 1.37 [1.05–1.80]), ESRD or 50% decline in estimated glomerular filtration rate (hazard ratio [95% confidence interval], 1.25 [0.98–1.58]), or death (hazard ratio [95% confidence interval], 1.72 [1.24–2.38]). PWV is a significant predictor of CKD progression and death in people with impaired kidney function. Incorporation of PWV measurements may help define better the risks for these important health outcomes in patients with CKDs. Interventions that reduce aortic stiffness deserve study in people with CKD.

Purpose To quantify the burden and distribution of asymptomatic atherosclerosis in a population with a low to intermediate risk of cardiovascular disease. Materials and Methods Between June 2008 and February 2013, 1528 participants with 10-year risk of cardiovascular disease less than 20% were prospectively enrolled. They underwent whole-body magnetic resonance (MR) angiography at 3.0 T by using a two-injection, four-station acquisition technique. Thirty-one arterial segments were scored according to maximum stenosis. Scores were summed and normalized for the number of assessable arterial segments to provide a standardized atheroma score (SAS). Multiple linear regression was performed to assess effects of risk factors on atheroma burden. Results A total of 1513 participants (577 [37.9%] men; median age, 53.5 years; range, 40-83 years) completed the study protocol. Among 46 903 potentially analyzable segments, 46 601 (99.4%) were interpretable. Among these, 2468 segments (5%) demonstrated stenoses, of which 1649 (3.5%) showed stenosis less than 50% and 484 (1.0%) showed stenosis greater than or equal to 50%. Vascular stenoses were distributed throughout the body with no localized distribution. Seven hundred forty-seven (49.4%) participants had at least one stenotic vessel, and 408 (27.0%) participants had multiple stenotic vessels. At multivariable linear regression, SAS correlated with age (B = 3.4; 95% confidence interval: 2.61, 4.20), heart rate (B = 1.23; 95% confidence interval: 0.51, 1.95), systolic blood pressure (B = 0.02; 95% confidence interval: 0.01, 0.03), smoking status (B = 0.79; 95% confidence interval: 0.44, 1.15), and socioeconomic status (B = -0.06; 95% confidence interval: -0.10, -0.02) (P < .01 for all). Conclusion Whole-body MR angiography identifies early vascular disease at a population level. Although disease prevalence is low on a per-vessel level, vascular disease is common on a per-participant level, even in this low- to intermediate-risk cohort. © RSNA, 2018 Online supplemental material is available for this article.

Background African Americans have persistently poor access to living donor kidney transplants (LDKT). We conducted a small randomized trial to provide preliminary evidence of the effect of informational decision support and donor financial assistance interventions on African American hemodialysis patients’ pursuit of LDKT. Methods Study participants were randomly assigned to receive (1) Usual Care; (2) the Providing Resources to Enhance African American Patients’ Readiness to Make Decisions about Kidney Disease (PREPARED); or (3) PREPARED plus a living kidney donor financial assistance program. Our primary outcome was patients’ actions to pursue LDKT (discussions with family, friends, or doctor; initiation or completion of the recipient LDKT medical evaluation; or identification of a donor). We also measured participants’ attitudes, concerns, and perceptions of interventions’ usefulness. Results Of 329 screened, 92 patients were eligible and randomized to Usual Care (n = 31), PREPARED (n = 30), or PREPARED plus financial assistance (n = 31). Most participants reported interventions helped their decision making about renal replacement treatments (62%). However there were no statistically significant improvements in LDKT actions among groups over 6 months. Further, no participants utilized the living donor financial assistance benefit. Conclusions Findings suggest these interventions may need to be paired with personal support or navigation services to overcome key communication, logistical, and financial barriers to LDKT. Trial registration ClinicalTrials.gov [NCT01439516] [August 31, 2011].

The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P 0.0001). Erythronate (R = 0.594, P 0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P 0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P 0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism.

BACKGROUND: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower Model for End-Stage Liver Disease-Sodium (MELD-Na) scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction. AIM: The aim of this study was to determine the gender differences in serum Cr, cystatin C and other endogenous GFR biomarkers, measured and estimated GFR, Cr clearance and Cr production rates. METHODS: We measured glomerular filtration rate (GFR) by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin and dimethylarginines. RESULTS: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs 0.82 mg/dL, P=0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P=0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-Cystatin C GFR Equation for Cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height and GFR, female gender remained associated with lower serum Cr levels (P=0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein and history of hypothyroidism. CONCLUSIONS: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-Cystatin C GFR Equation for Cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.

The present study was funded by the Souter Charitable Foundation and the Chest, Heart and Stroke Scotland Charity. The statistician was funded by TENOVUS, Tayside. JRWM is supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (Grant no. WT 085664) in the form of a Clinical Research Fellowship. Background: Arteriosclerosis (arterial stiffening) is associated with future cardiovascular events, with this effect postulated to be due to its effect on cardiac afterload, atherosclerosis (plaque formation) progression or both, but with limited evidence examining these early in disease formation. The aim of the current study is to examine the association between arteriosclerosis, atherosclerosis and ventricular remodelling in a population at low-intermediate cardiovascular risk. Methods: One thousand six hundred fifty-one subjects free of clinical cardiovascular disease and with a

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.

Evidence suggests that sleep disorders are common in individuals with CKD, but the influence of sleep duration and quality on CKD progression is unknown. We examined the association of habitual sleep duration and quality with CKD progression in 431 Chronic Renal Insufficiency Cohort (CRIC) Study participants, of whom 48% were women and 50% had diabetes (mean age of 60 years old, mean eGFR =38 ml/min per 1.73 m2, and median urine protein-to-creatinine ratio [UPCR] =0.20 g/g). We assessed sleep duration and quality by 5–7 days of wrist actigraphy and self-report. Primary outcomes were incident ESRD, eGFR slope, log-transformed UPCR slope, and all-cause death. Participants slept an average of 6.5 hours per night; mean sleep fragmentation was 21%. Over a median follow-up of 5 years, we observed 70 ESRD events and 48 deaths. In adjusted analyses, greater sleep fragmentation associated with increased ESRD risk (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07 per 1% increase in fragmentation). In adjusted mixed effects regression models, shorter sleep duration (per hour less) and greater sleep fragmentation (per 1% more) each associated with greater eGFR decline (−1.12 and −0.18 ml/min per 1.73 m2 per year, respectively; P=0.02 and P

Background People with advanced chronic kidney disease are at risk for the development of end-stage renal disease (ESRD), but also many other adverse outcomes, including cardiovascular disease (CVD) events and death. Determination of risk factors that explain the variability in prognosis and timing of these adverse outcomes can aid patient counseling and medical decision making. Study Design Prospective research cohort. Setting & Participants 1,798 participants with estimated glomerular filtration rates (eGFRs) 2 in the CRIC Study were followed up for a median of 5.5 years. Predictors Age, race, sex, eGFR, proteinuria, diabetes mellitus, body mass index, ejection fraction, systolic blood pressure, history of CVD, and smoking history. Outcomes ESRD, CVD (congestive heart failure, stroke, myocardial infarction, and peripheral artery disease), and death. Results Baseline age of the cohort was 60 years, 46% were women, and 46% were African American. Although 52.3% of participants progressed to ESRD during follow-up, the path by which this occurred was variable. For example, predicted 1-year probabilities for a hypothetical 60-year-old white woman with eGFR of 30mL/min/1.73m 2 , urine protein excretion of 1.8g/d, and no diabetes or CVD (risk characteristics similar to the average participant) were 3.3%, 4.1%, and 0.3%, for first developing CVD, ESRD, and death, respectively. For a 40-year-old African American man with similar characteristics but higher systolic blood pressure, the corresponding 1-year probabilities were 2.4%, 13.2%, and 0.1%. For all participants, the development of ESRD or CVD increased the risk for subsequent mortality, with no differences by patient race or body mass index. Limitations The CRIC population was specifically recruited for kidney disease, and the vast majority had seen a nephrologist. Conclusions The prognosis and timing of adverse outcomes in chronic kidney disease vary by patient characteristics. These results may help guide the development of personalized approaches for managing patients with advanced CKD.

The learning health care system promotes development and application of evidence generated within the health care system to enhance the quality of patient care. The purpose of this study was to understand resident attitudes about quality improvement (QI) in Accreditation Council for Graduate Medical Education–approved programs. Four focus groups were conducted with 45 residents at the University of Utah School of Medicine during September and October 2014. Residents discussed the perceived value of QI and their experiences with QI. Qualitative analysis was conducted iteratively, resulting in a set of constructs that were then consolidated into overarching themes. Five themes emerged from the qualitative analysis. Four of these represented QI participation barriers: challenges with understanding the vision of QI, confusion about basic aspects of QI, a sense that resident contributions to QI are not valued/valuable to the QI process, and challenges with prioritizing responsibilities relating to QI compared with other responsibilities. One theme represented a facilitator of successful QI: factors that make QI work successfully (e.g., clear goals and a sense of being on the “same page”). If resident attitudes about QI do not improve, the culture of the learning health care system is threatened. An important step in enhancing the perceived value of QI is resolving the perceived tension between providing excellent patient care and satisfying other goals. Involving residents more effectively in QI may result in improved attitudes and promote development of a better-functioning learning health care system.

Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher‐risk patients who otherwise may not be candidates for such a therapeutic approach. In this double‐blind, randomized, placebo‐controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4‐week period). The co‐primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24‐hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA‐IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event‐based trials.

Objective: Recurrent hyperkalemia frequently limits use of renin–angiotensin–aldosterone system inhibitors (RAASi) in chronic kidney disease (CKD) patients with hypertension, diabetes, and/or heart failure. Patiromer is a sodium-free, nonabsorbed potassium (K+)-binding polymer approved by the US Food and Drug Administration for the treatment of hyperkalemia. This post-hoc analysis of OPAL-HK examined the effectiveness and safety of patiromer in reducing serum K+ in hyperkalemic CKD patients on RAASi, with hypertension, receiving diuretic therapy versus those not on diuretics. Methods: Depending on the degree of hyperkalemia at baseline, CKD patients with serum K+ from 5.1 to less than 6.5 mmol/l on RAASi (n = 243) were assigned to a patiromer of total dose 8.4 or 16.8 g, divided twice daily. Changes in serum K+, and tolerability and safety were assessed over 4 weeks in patients on and not on diuretics. Results: At baseline, 132 patients used diuretics and 111 were not on diuretics, mean age was 64.3 and 64.0 years, respectively, and 63 and 51% were men. Similar reductions in serum K+ were seen over 4 weeks in both subgroups. At week 4, serum K+ fell by −0.95 ± 0.04 mmol/l with any diuretic and −1.04 ± 0.05 mmol/l with no diuretic. Patiromer was well tolerated, with mild-to-moderate constipation reported as the most common adverse event (7.6 and 14.4% of patients on any diuretic or no diuretic, respectively). Hypokalemia (s-K+

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P 1% indicate a probability of active rejection.

PURPOSE The ubiquitous adoption of electronic health records (EHRs) with family health history (FHH) data provides opportunities for tailoring cancer screening strategies to individuals. We aimed to enable a standards-based clinical decision support (CDS) platform for identifying and managing patients who meet guidelines for genetic evaluation of hereditary cancer. METHODS The CDS platform ( www.opencds.org ) was used to implement algorithms based on the 2018 National Comprehensive Cancer Network guidelines for genetic evaluation of hereditary breast/ovarian and colorectal cancer. The platform was designed to be interfaced with different EHR systems via the Health Level Seven International Fast Healthcare Interoperability Resources standard. The platform was integrated with the Epic EHR and evaluated in a pilot study at an academic health care system. RESULTS The CDS platform was executed against a target population of 143,012 patients; 5,245 (3.7%) met criteria for genetic evaluation based on the FHH recorded in the EHR. In a clinical pilot study, genetic counselors attempted to reach out to 71 of the patients. Of those patients, 25 (35%) scheduled an appointment, 10 (14%) declined, 2 (3%) did not need genetic counseling, 7 (10%) said they would consider it in the future, and 27 (38%) were unreachable. To date, 13 (52%) of the scheduled patients completed visits, and 2 (15%) of those were found to have pathogenic variants in cancer predisposition genes. CONCLUSION A standards-based CDS platform integrated with EHR systems is a promising population-based approach to identify patients who are appropriate candidates for genetic evaluation of hereditary cancers.

There has been a tremendous growth quantity of high-quality imaging evidence in the area of acute and stable ischemic heart disease (SIHD). A number of recent comparative effectiveness trials have spurned significant controversies in the field of cardiovascular imaging. The result of this evidence is that many health care policies and national guidelines have undergone significant revisions. With all of this evidence, many challenges remain and the optimal evaluation strategy for evaluation of patients presenting with chest pain remains ill-defined. This paper enlisted the guidance of numerous experts in the field of cardiovascular imaging to garner their perspective on available imaging research in chest pain syndromes. Each of these vignettes represent editorial perspectives and diverse opinions as to which, if any, should be the primary test in the evaluation of stable chest pain. These perspectives are not meant to be all inclusive but to highlight many of the commonly discussed controversies in the evaluation of chest pain symptoms. These perspectives are presented as a pre-amble to an upcoming American College of Cardiology/American Heart Association clinical practice guideline that is undergoing revision from the previous report published in 2012. The evidence has changed considerably since the 2012 SIHD guideline, and the current perspectives represent the diversity of available evidence as to the optimal imaging strategy for evaluation of the symptomatic patient.

Background Coronary artery calcification is a significant contributor to reduced accuracy of coronary computed tomographic angiography (CTA) in the assessment of coronary artery disease severity. The aim of the current study is to assess the impact of a prototype calcium deblooming algorithm on the diagnostic accuracy of CTA. Methods 40 patients referred for invasive catheter angiography underwent CTA and invasive catheter angiography. The CTA were reconstructed using a standard soft tissue kernel (CTASTAND) and a deblooming algorithm (CTADEBLOOM). CTA studies were read with and without the deblooming algorithm blinded to the invasive coronary angiogram findings. Sensitivity, specificity, accuracy, positive predictive value and negative predictive value for the detection of stenosis ≥50% or ≥70% were evaluated using quantitative coronary angiography as the reference standard. Image quality was assessed using a 5-point scale, and the presence of image artifact recorded. Results All studies were diagnostic with 548 segments available for evaluation. Image score was 3.64 ± 0.72 with CTADEBLOOM, versus 3.56 ± 0.72 with CTASTAND (p = 0.38). CTADEBLOOM had significantly less calcium blooming artifact than CTASTAND (12.5% vs. 47.5%, p = 0.001). Based on a 50% stenosis threshold for defining significant disease, the Sensitivity/Specificity/PPV/NPV/Accuracy were 65.9/84.9/27.6/96.6/83.4 for CTADEBLOOM and 75.0/81.9/26.6/97.4/81.4 for CTASTAND using a ≥50% threshold. CTADEBLOOM specificity was significantly higher than CTASTAND (84.9% vs. 81.5%, p = 0.03), with no difference between the algorithms in sensitivity (p = 0.22), or accuracy (p = 0.15). These results remained unchanged when a stenosis threshold of ≥70% was used. Interobserver agreement was fair with both techniques (CTADEBLOOM k = 0.38, CTASTAND k = 0.37). Conclusion In this proof of concept study, coronary calcification deblooming using a prototype post-processing algorithm is feasible and reduces calcium blooming with an improvement of the specificity of the CTA exam.

Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on serum electrolytes were evaluated using pooled data from studies of patients with type 2 diabetes mellitus (T2DM). Analyses were performed using two datasets, each including four placebo-controlled studies: Population 1 (N = 2215), patients with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (mean = 89.6 mL/min/1.73 m2) and Population 2 (N = 721), patients with baseline eGFR ≥45 and 2 (mean = 53.3 mL/min/1.73 m2). ClinicalTrials.gov identifier: NCT01081834. ClinicalTrials.gov identifier: NCT01106625. ClinicalTrials.gov identifier: NCT01106677. ClinicalTrials.gov identifier: NCT01106690. ClinicalTrials.gov identifier: NCT01032629. ClinicalTrials.gov identifier: NCT01064414. ClinicalTrials.gov identifier: NCT01106651. Mean percent changes from baseline in serum electrolytes (potassium, sodium, magnesium, bicarbonate, phosphate, calcium) and outlier analyses were assessed in patients receiving canagliflozin 100 and 300 mg or placebo. Potassium changes were further evaluated based on baseline therapy with anti-hypertensive agents that interfere with potassium excretion (renin-angiotensin aldosterone system-acting agents and/or potassium-sparing diuretics). Mean percent changes from baseline in potassium with canagliflozin 100 and 300 mg and placebo were 0.6%, 1.0%, and 0.5%, respectively (Week 26; Population 1); and 1.7%, 2.8%, and 0.7%, respectively (Week 18/26; Population 2). The proportion of patients who had potassium elevations meeting pre-defined outlier criteria (>5.4 mmol/L [5.4 mEq/L] and >15% increase from baseline) with canagliflozin 100 and 300 mg and placebo was 4.5%, 6.8%, and 4.7% (Population 1); and 5.2%, 9.1%, and 5.5% (Population 2). In both populations, potassium elevations were usually

Key Points Question Is an electronic health record add-on app for neonatal bilirubin management associated with time savings for clinicians and improved quality of care? Findings In this quality improvement study, an electronic health record add-on app for neonatal bilirubin management saved clinicians a mean of 66 seconds for bilirubin management tasks compared with a commonly used tool. In a retrospective pre-post analysis, the odds of clinically appropriate phototherapy orders during hospitalization increased significantly by 84%. Meaning These findings suggest that well-designed electronic health record add-on apps may be associated with time savings for physicians and improvements in patient care., Importance The usefulness of electronic health record (EHR) systems could be significantly enhanced by innovative, third-party EHR add-on apps. Objective To evaluate whether an EHR add-on app for neonatal bilirubin management can save clinicians time and improve patient care. Design, Setting, and Participants This quality improvement study was conducted at the University of Utah Health Well Baby nursery and outpatient clinics and consisted of 4 substudies: (1) time savings were estimated in an experimental task-timing study comparing the time required for physicians to manage newborns’ bilirubin levels with and without the add-on app, (2) app use was estimated from app logs, (3) health care use measures and guideline compliance were compared retrospectively before and after the intervention, and (4) clinician-perceived usability was measured through System Usability Scale surveys. The study took place between April 1, 2016, and September 3, 2019. Data analyses were conducted from October 30, 2018, to September 23, 2019. Interventions At baseline, clinicians used a manual approach to ensure compliance with an evidence-based clinical guideline for neonatal bilirubin management. To facilitate guideline compliance, an EHR add-on app that automatically retrieves, organizes, and visualizes relevant patient data was developed. The app provides patient-specific assessments and recommendations, including the risk of rebound hyperbilirubinemia following phototherapy based on a predictive model. The add-on app was integrated with the University of Utah Health EHR on April 12, 2017. Main Outcomes and Measures Clinician time savings, app use, health care use measures, guideline-compliant phototherapy ordering, and perceived usability as measured by the System Usability Scale survey. The survey is composed of 10 statements with responses ranging from 1 (strongly disagree) to 5 (strongly agree). The survey results in a single score ranging from 0 to 100, with ratings described as worst imaginable (mean System Usability Scale score, 12.5), awful (20.3), poor (35.7), okay (50.9), good (71.4), excellent (85.5), and best imaginable (90.9). Results In 2018, the application was used 20 516 times by clinicians for 91.84% of eligible newborns. Use of the app saved 66 seconds for bilirubin management tasks compared with a commonly used tool (95% CI, 53-79 seconds; P, This quality improvement study evaluates whether an electronic health record add-on app for neonatal bilirubin management is associated with clinician time savings and improvements in patient care.