PDf file - 74K

The mechanisms by which the APOE4 allele contributes to AD risk are unclear. Here, we tested the hypothesis that in cognitively normal adults, APOE4 allele is associated with a decrease in complement-related proteins and downregulation of complement-related pathways. Untargeted LC-MS/MS proteomics was conducted on CSF samples (n = 118) from APOE3/3, APOE3/4 and APOE4/4 individuals over age 60, with groups matched on age and sex. We developed a novel analytic approach (which we term “up/down analysis”) based on the directional consistency of the β-coefficients from a linear model for the intensities of peptides mapping to a given protein with respect to APOE4 carrier status ( APOE4 -/ APOE4 +). The analysis involves two steps: 1) The direction of the beta-coefficient (positive/up or negative/down) for the level of each peptide (the outcome variable) due to APOE4 carrier status was derived from linear regression models adjusting for age, sex, and study. 2) These β-coefficients were tallied for all peptides from a given protein (i.e. number of positive/up versus negative/down β-coefficients). We then tested the probability under a binomial distribution that the distribution of up versus down peptides from each protein would be as, or more extreme than what we found, with a = 0.05. Pathway enrichment analysis (using p-values from binomial tests) was conducted using GAGE and functional annotations based on KEGG. We used Benjamini-Hochberg for multiple comparison correction. We found 158 proteins for which the direction of peptide intensity was consistently up (+β-coefficient) or down (-β-coefficient) with respect to APOE4 status beyond what would be expected by chance. Of these 158 proteins, 37 were from the complement pathway. Pathway enrichment analysis further supports the role of the complement system; as the top differentially expressed pathway (FDR <0.05) was related to complement signaling. Our results suggest that APOE4 carriers have lower CSF levels of key complement cascade proteins, which has previously been viewed as an indicator of complement activation. These results may provide insights into the mechanisms by which APOE4 and associated complement-related proteins and signaling pathways ultimately contribute to increased AD risk.

Background Little is known about the prevalence and prognostic impact of preexisting frailty on acute care and in-hospital outcomes in older adults in the setting of acute myocardial infarction (AMI). Methods Preexisting frailty was assessed at baseline in consecutive AMI patients >= 65 years of age treated at 778 hospitals participating in the NCDR ACTION Registry between January 1, 2015 to December 31, 2016. Three domains of preexisting frailty (cognition, ambulation, and functional independence) were abstracted from chart review and summed in 2 ways: an ACTION Frailty Scale based on responses to 6 groups adapted from the Canadian Study of Health and Aging Clinical Frailty Scale and an ACTION Frailty Score derived by summing a rank score of 0-2 assigned for each grade (total ranged between 0 to 6). Multivariable logistic regression examined the association between assigned frailty by score or scale and in-hospital mortality. Results Among 143,722 older AMI patients, 108,059 (75.2%) were fit and/or well and 6,484 (4.5%) were vulnerable to frailty, while 7,527 (5.2%) had mild, 3,913 (2.7%) had moderate, 2,715 had (1.9%) severe, and 632 (0.4%) had very severe frailty according to the ACTION Frailty Scale, while 14,392 (10.0%) could not be categorized due to incomplete ascertainment. Frail patients were older, more frequently female, of non-white race and/or ethnicity, and less likely to be treated with guideline-recommended therapies. Increasing severity of frailty by this scale was associated with a step-wise higher risk for in-hospital mortality (P-trend < .001). Patient categories of the ACTION Frailty Score provided similar results. After adjustment, each 1-unit increase in Frailty Score was associated with a 12% higher mortality risk (OR 1.12, 95% CI 1.10-1.15). Conclusions Among older patients with acute myocardial infarction, frailty is common and independently associated with in-hospital mortality. These findings show the importance of pragmatic evaluation of frailty in hospital-level quality scores, guideline recommendations, and incorporation into other registry data collection efforts.

BACKGROUND:Advanced liver disease due to hepatitis C virus (HCV) is a leading cause of human immunodeficiency virus (HIV)-related morbidity and mortality. There remains a need to develop noninvasive predictors of clinical outcomes in persons with HIV/HCV coinfection.METHODS:We conducted a nested case-control study in 126 patients with HIV/HCV and utilized multiple quantitative metabolomic assays to identify a prognostic profile that predicts end-stage liver disease (ESLD) events including ascites, hepatic encephalopathy, hepatocellular carcinoma, esophageal variceal bleed, and spontaneous bacterial peritonitis. Each analyte class was included in predictive modeling, and area under the receiver operator characteristic curves (AUC) and accuracy were determined.RESULTS:The baseline model including demographic and clinical data had an AUC of 0.79. Three models (baseline plus amino acids, lipid metabolites, or all combined metabolites) had very good accuracy (AUC, 0.84-0.89) in differentiating patients at risk of developing an ESLD complication up to 2 years in advance. The all combined metabolites model had sensitivity 0.70, specificity 0.85, positive likelihood ratio 4.78, and negative likelihood ratio 0.35.CONCLUSIONS:We report that quantification of a novel set of metabolites may allow earlier identification of patients with HIV/HCV who have the greatest risk of developing ESLD clinical events.

OBJECTIVES: To assess the association of a clinical decision support (CDS) algorithm for hospital discharge disposition with spending, readmissions, and postdischarge emergency department (ED) use.STUDY DESIGN: A retrospective study in a cohort of fee-for-service Medicare patients 65 years or older linked to a database of patients receiving CDS.METHODS: We evaluated (1) patients whose discharge disposition was concordant with the CDS recommendation versus those whose disposition was not and (2) patients receiving CDS for discharge disposition versus those not receiving CDS, regardless of concordance. Outcomes w spending over a 90-day episode, 90-day readmissions, and postdischarge ED utilization not associated with a readmission.RESULTS: Analysis of concordant versus discordant cases showed decreased spending for concordant cases ($860 savings; 95% CI, $162-$1558; P = .016), a decrease in readmissions (adjusted odds ratio [OR], 0.920; 95% CI, 0.850-0.995; P = .038), and no change in rate of postdischarge ED use (adjusted OR, 0.990; 95% CI, 0.882-1.110; P= .858). Analysis of patients receiving CDS versus not receiving CDS showed no significant difference in spending ($221 savings; 95% CI, -$115 to $557; P = .198), ED use (adjusted OR, 0.959; 95% CI, 0.908-1.012; P = .128), or readmission rate (adjusted OR, 1.004; 95% CI, 0.966-1.043; P = .840).CONCLUSIONS: Following the recommendation of a CDS algorithm for hospital discharge disposition was associated with lower spending fewer readmissions, and no change in ED use over a 90-day episode of care.

IMPORTANCE Lack of insurance is associated with worse care and outcomes among adults hospitalized for acute myocardial infarction (AMI). It is unclear whether states' decision to expand Medicaid eligibility under the Patient Protection and Affordable Care Act in 2014 were associated with improved quality of care and outcomes among low-income patients hospitalized with AMI. OBJECTIVE To investigate whether rates of uninsurance, quality of care, and outcomes changed among patients hospitalized for AMI 3 years after states elected to expand Medicaid compared with nonexpansion states. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study completed at hospitals participating in National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry. Participants were patients younger than 65 years hospitalized for AMI from January 1, 2012, to December 31, 2016. EXPOSURES State Medicaid expansion in 2014. MAIN OUTCOMES AND MEASURES Rates of uninsured and Medicaid-insured hospitalizations for AMI in states that expanded Medicaid vs those that did not. Comparison of in-hospital care quality, procedure use, and mortality between expansion and nonexpansion states for the years prior to and after Medicaid expansion. Hierarchical logistic regressions models were used to assess the association between Medicaid expansion and outcomes. RESULTS The initial cohort included 325 343 patients. Uninsured AMI hospitalizations declined in expansion states (18.0% [4395 of 24 358 hospitalizations] to 8.4% [2638 of 31382 hospitalizations]) and more modestly in nonexpansion states (25.6% [7963 of 31137 hospitalizations] to 21.1% [8668 of 41120 hospitalizations]) from 2012 to 2016 (P < .001 difference in trend expansion vs nonexpansion). Medicaid coverage increased from 7.5% (1818 of 24358 hospitalizations) to14.4% (4502 of 31382 hospitalizations) in expansion states and 6.2% (1924 of 31137 hospitalizations) to 6.6% (2717 of 41120 hospitalizations) in nonexpansion states (P < .001). The low-income cohort included 55 737 patients across 765 sites. In expansion states, low-income adults' odds of receipt of defect-free care increased (76.3% to 75.9%, adjusted odds ratio 1.11; 95% CI, 1.02-1.21) but to a lesser degree than in nonexpansion states (72.8% to 74.5%, adjusted odds ratio, 1.38; 95% CI, 1.30-1.47; P for interaction < .001). There was no change in use of most procedures (ie, percutaneous coronary intervention for non-ST-segment elevation myocardial infarction) in expansion compared with nonexpansion states. Improvement in in-hospital mortality was similar between expansion and nonexpansion states (3.2% to 2.8%, adjusted odds ratio, 0.93; 95% CI, 0.77-1.12 vs 3.3% to 3.0%, adjusted odds ratio, 0.85; 95% CI, 0.73-0.99: Pfor interaction = .48). CONCLUSIONS AND RELEVANCE Medicaid expansion was associated with a significant reduction in rates of uninsurance among patients hospitalized with AMI. Quality of care and outcomes did not improve among low-income adults in expansion compared with nonexpansion states. Hospital care for AMI may be less sensitive to insurance than has been recognized in the past.

Despite high rates of early readmission in patients with acute myocardial infarction (AMI) and heart failure (HF), little data exists regarding the impact of best practices on hospital-based transition-care measures. This project sought to evaluate early changes in AMI and HF program performance

Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.

Background We sought to determine temporal trends in use of evidence‐based therapies and clinical outcomes among myocardial infarction (MI) patients with chronic kidney disease (CKD). Methods and Results MI patients from the NCDR (National Cardiovascular Data Registry) Chest Pain–MI Registry between January 2007 and December 2015 were categorized into 3 groups by degree of CKD (end‐stage renal disease on dialysis, CKD [glomerular filtration rate <60 mL/min per 1.73 m2] not requiring dialysis, and no CKD [glomerular filtration rate ≥60 mL/min per 1.73 m2]). Logistic regression modeling was used to determine the association between calendar years (2014–2015 versus 2007–2008) and each outcome by degree of CKD. Among 325 396 patients with ST‐segment–elevation MI, 1.0% had end‐stage renal disease requiring dialysis, and 26.1% had CKD not requiring dialysis. Use of primary percutaneous coronary intervention increased over time regardless of the presence or degree of CKD (P=0.40 for interaction). In‐hospital mortality was temporally higher among patients with preserved renal function (odds ratio: 1.25; 95% confidence interval, 1.13–1.39; P<0.001) but not among patients with CKD (P=0.035 for interaction). Among 506 876 non–ST‐segment–elevation MI patients, 3.4% had end‐stage renal disease requiring dialysis, and 34.4% had CKD not requiring dialysis. P2Y12 inhibitor use within 24 hours increased over time only among dialysis patients (P for interaction <0.001). Use of coronary angiography and percutaneous coronary intervention also increased, with the greatest increase among dialysis patients (P for interaction <0.001 and <0.001, respectively). In‐hospital mortality was lower, regardless of the presence or degree of CKD (P=0.64 for interaction). Conclusions Uptake of evidence‐based medical and invasive therapies has increased over the past decade among MI patients with CKD, particularly dialysis patients, with improvement of in‐hospital mortality observed among patients with non–ST‐segment–elevation MI, but not ST‐segment–elevation MI, and CKD.

Background: Despite considerable progress in the treatment of acute myocardial infarction (AMI), major disparities in care remain for the uninsured. Lack of insurance is associated with delays in seeking emergency care for AMI, and uninsured patients are less likely to receive guideline-directed medical therapy, invasive cardiac procedures, and have higher mortality rates than their insured counterparts. In 2014, Medicaid eligibility was expanded under the ACA, and millions of low-income adults gained insurance coverage in over 30 states. However, little is known about Medicaid expansions’ impact on the quality and outcomes of inpatient care for AMI. Methods: We studied 325,343 MI patients under 65 years of age treated at 860 hospitals in the ACTION-GWTG Registry between 2012 and 2016. Expansion states were those that implemented ACA Medicaid expansion during 2014. Our pre-expansion period included the two years prior to expansion (1/1/2012 to 12/31/2013) and our post-expansion period included the two years following expansion (1/1/2015 to 12/31/2016). We first characterized trends in AMI hospitalizations by insurance status during the study period in expansion and non-expansion states. We then identified a low-income cohort, defined as being covered by Medicaid or uninsured, and assessed the association between state expansion status and quality and outcome measures stratified by time periods using hierarchical logistic regression models. Results: In our overall cohort, from 2012 to 2016, the proportion of hospitalized AMI patients insured by Medicaid increased by 6.9% in expansion states (7.5% to 14.4%) and 0.4% in non-expansion states (6.2% to 6.6%). Uninsured hospitalizations also declined more in expansion states (18% to 8.4%) than in non-expansion states (25.6% to 21.1%). Our low-income cohort included 55,737 patients - 38,786 were uninsured and 16,951 were insured with Medicaid. Prior to expansion, states that eventually expanded Medicaid were more likely to provide defect free AMI care (all performance measures followed for eligible patients) compared with non-expansion states (aOR 1.26, 95% CI 1.10-1.45, p<0.001). In the post-expansion period, there was no significant difference in defect free AMI care (aOR 1.02, 95% CI 0.89-1.16, p=0.83, p for interaction<0.001). In addition, patients in expansion and non-expansion states had similar rates of in-hospital death both during the pre-expansion period (aOR 0.95, 95% CI 0.79-1.13, p=0.56) and the post-expansion period (aOR 1.03, 95% CI 0.87-1.24, p=0.71, p for interaction=0.48). Conclusions: States that elected to expand Medicaid did not experience significant improvements in AMI care quality or in-hospital mortality compared with non-expansion states.

Contemporary utilization patterns for targeted temperature management (TTM) among patients with acute myocardial infarction (MI) and out-of-hospital cardiac arrest (OHCA) have not been well characterized in the United States. In this nationwide evaluation of MI patients with OHCA (01/2015-03/2016; 691 hospitals), 34.1% (1792/5260) of OHCA patients received TTM. Patients who were treated with TTM had higher risk clinical features. A wide inter-hospital variation (ranging from 0% to 82%) in TTM use observed despite few differences in case mix.

PURPOSE:In the interferon era of hepatitis C virus (HCV) therapies, genotype/subtype, cirrhosis, prior treatment failure, sex, and race predicted relapse. Our objective is to validate a targeted proteomics platform of 17 peptides to predict sustained virologic response (SVR).EXPERIMENTAL DESIGN:Stored plasma from three, open-label, trials of HIV/HCV-coinfected subjects receiving interferon-containing regimens is identified. LC-MS/MS is used to quantitate the peptides directly from plasma, and IL28B genotyping is completed using stored peripheral blood mononuclear cells (PBMC). A logistic regression model is built to analyze the probability of SVR using responders and nonresponders to interferon-based regimens.RESULTS:The cohort (N = 35) is predominantly black (51.4%), male (86%), and with median age 48 years. Most patients achieve SVR (54%). Using multivariable models, it is verified that three human corticosteroid binding globulin (CBG) peptides are predictive of SVR in patients with the unfavorable IL28B genotypes (CT/TT). The model performs better than IL28B alone, with an area under the curve of 0.870.CONCLUSIONS AND CLINICAL RELEVANCE:In HIV/HCV-coinfected patients, three human CBG peptides that accurately predict treatment response with interferon-based therapy are identified. This study suggests that a stepwise approach combining a genetic predictor followed by targeted proteomics can improve the accuracy of clinical decision-making.

This article focuses on the use of Bayesian concepts and methods in the trans-study projection of genomic biomarkers for the analysis of oncogene deregulation in breast cancer. The objective of the study is to determine the extent to which patterns of gene expression associated with experimentally induced oncogene pathway deregulation can be used to investigate oncogene pathway activity in real human cancers. This is often referred to as the in vitro to in vivo translation problem, which is addressed using Bayesian sparse factor regression analysis for model-based translation and refinement of in vitro generated signatures of oncogene pathway activity into the domain of human breast tumour tissue samples. The article first provides an overview of the role of oncogene pathway deregulation in human cancers before discussing the details of modelling and data analysis. It then considers the findings based on biological evaluation and Bayesian pathway annotation analysis.

Background Electronic medical record (EMR) computed algorithms allow investigators to screen thousands of patient records to identify specific disease cases. No computed algorithms have been developed to detect all cases of human immunodeficiency virus (HIV) infection using administrative, laboratory, and clinical documentation data outside of the Veterans Health Administration. We developed novel EMR-based algorithms for HIV detection and validated them in a cohort of subjects in the Duke University Health System (DUHS). Methods We created 2 novel algorithms to identify HIV-infected subjects. Algorithm 1 used laboratory studies and medications to identify HIV-infected subjects, whereas Algorithm 2 used International Classification of Diseases, Ninth Revision (ICD-9) codes, medications, and laboratory testing. We applied the algorithms to a well-characterized cohort of patients and validated both against the gold standard of physician chart review. We determined sensitivity, specificity, and prevalence of HIV between 2007 and 2011 in patients seen at DUHS. Results A total of 172 271 patients were detected with complete data; 1063 patients met algorithm criteria for HIV infection. In all, 970 individuals were identified by both algorithms, 78 by Algorithm 1 alone, and 15 by Algorithm 2 alone. The sensitivity and specificity of each algorithm were 78% and 99%, respectively, for Algorithm 1 and 77% and 100% for Algorithm 2. The estimated prevalence of HIV infection at DUHS between 2007 and 2011 was 0.6%. Conclusions EMR-based phenotypes of HIV infection are capable of detecting cases of HIV-infected adults with good sensitivity and specificity. These algorithms have the potential to be adapted to other EMR systems, allowing for the creation of cohorts of patients across EMR systems.

Sex differences in Alzheimer’s disease (AD) biology and progression are not yet fully characterized. The goal of this study is to examine the effect of sex on cognitive progression in subjects with high likelihood of mild cognitive impairment (MCI) due to Alzheimer’s and followed up to 10 years in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cerebrospinal fluid total-tau and amyloid-beta (Aβ42) ratio values were used to sub-classify 559 MCI subjects (216 females, 343 males) as having “high” or “low” likelihood for MCI due to Alzheimer’s. Data were analyzed using mixed-effects models incorporating all follow-ups. The worsening from baseline in Alzheimer’s Disease Assessment Scale-Cognitive score (mean, SD) (9 ± 12) in subjects with high likelihood of MCI due to Alzheimer’s was markedly greater than that in subjects with low likelihood (1 ± 6, p < 0.0001). Among MCI due to AD subjects, the mean worsening in cognitive score was significantly greater in females (11.58 ± 14) than in males (6.87 ± 11, p = 0.006). Our findings highlight the need to further investigate these findings in other populations and develop sex specific timelines for Alzheimer’s disease progression.