Showing papers by "Jeremy D. Walston published in 2016"

DNA methylation of cord blood cell types: Applications for mixed cell birth studies.

Abstract: Epigenome-wide association studies of disease widely use DNA methylation measured in blood as a surrogate tissue. Cell proportions can vary between people and confound associations of exposure or outcome. An adequate reference panel for estimating cell proportions from adult whole blood for DNA methylation studies is available, but an analogous cord blood cell reference panel is not yet available. Cord blood has unique cell types and the epigenetic signatures of standard cell types may not be consistent throughout the life course. Using magnetic bead sorting, we isolated cord blood cell types (nucleated red blood cells, granulocytes, monocytes, natural killer cells, B cells, CD4(+)T cells, and CD8(+)T cells) from 17 live births at Johns Hopkins Hospital. We confirmed enrichment of the cell types using fluorescence assisted cell sorting and ran DNA from the separated cell types on the Illumina Infinium HumanMethylation450 BeadChip array. After filtering, the final analysis was on 104 samples at 429,794 probes. We compared cell type specific signatures in cord to each other and methylation at 49.2% of CpG sites on the array differed by cell type (F-test P < 10(-8)). Differences between nucleated red blood cells and the remainder of the cell types were most pronounced (36.9% of CpG sites at P < 10(-8)) and 99.5% of these sites were hypomethylated relative to the other cell types. We also compared the mean-centered sorted cord profiles to the available adult reference panel and observed high correlation between the overlapping cell types for granulocytes and monocytes (both r=0.74), and poor correlation for CD8(+)T cells and NK cells (both r=0.08). We further provide an algorithm for estimating cell proportions in cord blood using the newly developed cord reference panel, which estimates biologically plausible cell proportions in whole cord blood samples.

Delirium After Spine Surgery in Older Adults: Incidence, Risk Factors, and Outcomes

Abstract: Objectives To characterize the incidence, risk factors, and consequences of delirium in older adults undergoing spine surgery. Design Prospective observational study. Setting Academic medical center. Participants Individuals aged 70 and older undergoing spine surgery (N = 89). Measurements Postoperative delirium and delirium severity were assessed using validated methods, including the Confusion Assessment Method (CAM), CAM for the Intensive Care Unit, Delirium Rating Scale-Revised-98, and chart review. Hospital-based outcomes were obtained from the medical record and hospital charges from data reported to the state. Results Thirty-six participants (40.5%) developed delirium after spine surgery, with 17 (47.2%) having purely hypoactive features. Independent predictors of delirium were lower baseline cognition, higher average baseline pain, more intravenous fluid administered, and baseline antidepressant medication. In adjusted models, the development of delirium was independently associated with higher quintile of length of stay (odds ratio (OR) = 3.66, 95% confidence interval (CI) = 1.48–9.04, P = .005), higher quintile of hospital charges (OR = 3.49, 95% CI = 1.35–9.00, P = .01), and lower odds of discharge to home (OR = 0.22, 95% CI = 0.07–0.69, P = .009). Severity of delirium was associated with higher quintile of hospital charges and lower odds of discharge to home. Conclusion Delirium is common after spine surgery in older adults, and baseline pain is an independent risk factor. Delirium is associated with longer stay, higher charges, and lower odds of discharge to home. Thus, prevention of delirium after spine surgery may be an important quality improvement goal.

The Association Between Preoperative Frailty and Postoperative Delirium After Cardiac Surgery.

Abstract: Delirium is common after cardiac surgery, and preoperative identification of high-risk patients could guide prevention strategies. We prospectively measured frailty in 55 patients before cardiac surgery and assessed postoperative delirium using a validated chart review. The prevalence of frailty was 30.9%. Frail patients had a higher incidence of delirium (47.1%) compared with nonfrail patients (2.6%; P < 0.001). In multivariable models, the relative risk of delirium was ≥2.1-fold greater in frail compared with nonfrail patients (relative risk, 18.3; 95% confidence interval, 2.1-161.8; P = 0.009). Frailty may identify patients who would benefit from delirium-prevention strategies because of increased baseline risk for delirium.

Comparison of Frailty Measures as Predictors of Outcomes After Orthopedic Surgery

Abstract: Objectives To apply the Frailty Phenotype (FP) and Frailty Index (FI) before major elective orthopedic surgery to categorize frailty status and assess associations with postoperative outcomes. Design Prospective cohort study. Setting Two tertiary hospitals in Boston, Massachusetts. Participants Individuals aged 70 and older undergoing scheduled orthopedic surgery enrolled in the Successful Aging after Elective Surgery (SAGES) Study (N = 415). Measurements Preoperative evaluation included assessment of frailty using the FP and FI. The weighted kappa statistic was used to determine concordance between the two frailty measures and multivariable modeling to determine associations between each measure and postoperative complications, postoperative length of stay (LOS) of longer than 5 days, discharge to postacute institutional care (PAC), and 300 day readmission. Results Frailty was highly prevalent (FP, 35%; FI, 41%). There was moderate concordance between the FP and FI (κ = 0.42, 95% confidence interval (CI) 0.36–0.49). When using the FP, being prefrail predicted greater risk of complications (relative risk (RR) = 1.6, 95% CI = 1.1–2.1) and discharge to PAC (RR = 1.8, 95% CI = 1.2–2.9) than being robust, and being frail predicted more complications (RR = 1.7, 95% CI = 1.1–2.1), LOS longer than 5 days (RR = 3.1, 95% CI = 1.1–8.8), and discharge to PAC (RR = 2.3 95% CI = 1.4–3.7). When using FI, being prefrail predicted LOS longer than 5 days (RR = 2.1, 95% CI = 1.0–4.8) and discharge to PAC (RR = 1.5, 95% CI = 1.4–2.1), as did being frail (RR = 1.9, 95% CI = 1.4–2.5; RR = 3.1, 95% CI = 1.4–6.8, respectively). The other outcomes were not significantly associated with frailty status. Conclusion FP and FI predict postoperative outcomes after major elective orthopedic surgery and should be considered for preoperative risk stratification.

Declines and Impairment in Executive Function Predict Onset of Physical Frailty

Abstract: Background Clinical cognitive impairment and physical frailty often co-occur. However, it is unclear whether preclinical impairment or decline in cognitive domains are associated with onset of physical frailty. We tested this hypothesis and further hypothesized that preclinical impairment and decline in executive functioning are more strongly associated with frailty onset than memory or general cognitive performance. Methods We used 9 years of data from the Women's Health and Aging Study II (six visits) that longitudinally measured psychomotor speed and executive functioning using the Trail Making Test, parts A and B, respectively, and immediate and delayed word-list recall from the Hopkins Verbal Learning Test. We used Cox proportional hazards models to regress time to frailty on indicators for impairment on these cognitive tests and on rates of change of the tests. Models adjusted for depressive symptoms, age, years of education, and race. Results Of the 331 women initially free of dementia and frailty, 44 (13%) developed frailty. A binary indicator of impaired executive functioning (Trail Making Test, part B [TMT-B]) was most strongly associated with hazard, or risk, of frailty onset (hazard ratio [HR] = 3.3, 95% confidence interval [CI] = 1.4, 7.6) after adjustment for covariates and other tests. Adjusting for baseline cognitive performance, faster deterioration on TMT-B (HR = 0.6, 95% CI = 0.4, 1.0) was additionally associated with hazard of frailty onset. Conclusions Findings inform the association of executive functioning with transitions to frailty, suggesting both impairments in and declines in executive functioning are associated with risk of frailty onset. It remains to be determined whether these associations are causal or whether shared aging related or other mechanisms are involved.

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Abstract: Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

Frailty and Health-Related Quality of Life in End Stage Renal Disease Patients of All Ages.

Abstract: BACKGROUND: Frailty is associated with worse health-related quality of life (HRQOL) in older adults and worse clinical outcomes in adults of all ages with end stage renal disease (ESRD). It is unclear whether frail adults of all ages with ESRD are more likely to experience worse HRQOL. OBJECTIVE: The goal of this study was to identify factors associated with worsening HRQOL in this population. DESIGN, SETTING AND MEASUREMENTS: We studied 233 adults of all ages with ESRD enrolled (11/2009-11/2013) in a longitudinal cohort study. Frailty status was measured at enrollment and HRQOL was reported (Excellent, Very Good, Good, Fair or Poor) at the initial assessment and follow-up (median follow-up 9.4 months). We studied factors associated with Fair/Poor HRQOL at follow-up using logistic regression and factors associated with HRQOL change using multinomial regression. All models were adjusted for age, sex, race, education, BMI, diabetes status, history of a previous transplant, type of dialysis and time between assessments. RESULTS: Fair/Poor HRQOL was reported by 28% at initial assessment and 33% at follow-up. 47.2% of participants had stable HRQOL, 22.8% better HRQOL, and 30.0% worse HRQOL at follow-up (P<0.001). In adjusted models, only frailty was associated with Fair/Poor HRQOL at follow-up (OR: 2.79, 95% CI: 1.32-5.90) and worsening HRQOL at follow-up (RR: 2.91, 95%CI: 1.08-7.80). CONCLUSIONS: Frail adults of all ages with ESRD are more likely to experience fair/poor HRQOL and worsening HRQOL over time. Frailty represents a state of decreased physiologic reserve that impacts not only clinical outcomes but also the patient-centered outcome of HRQOL.

Frailty and Cause-Specific Hospitalization Among Persons Aging With HIV Infection and Injection Drug Use.

Abstract: Background Hospitalization events exact a substantial toll across the age spectrum. Frailty is associated with all-cause hospitalization among HIV-uninfected adults aged 65 years and older. Limited data exist on the frailty relationship to hospitalization among HIV-infected persons or those aged less than 65 years. Comparative investigation of the frailty relationship to specific classes of hospitalizations has rarely been reported among adults of any age. This study sought to determine the frailty relationship to three distinct classes of hospitalization events among HIV-infected persons and their uninfected counterparts. Methods Frailty was ascertained semiannually among persons with prior injection drug use using the five Fried phenotypic domains. Hospitalization events were categorized using Agency for Healthcare Research and Quality clinical classification software into chronic, infectious, and nonchronic, noninfectious conditions. Cox proportional hazards models were used to examine the frailty relationship to time to first hospitalization event. Results Among 1,303 subjects, mean age was 48 years; 32% were HIV-infected. Adjusting for sociodemographics, comorbidity, substance use, and HIV disease stage, time-updated frailty status was associated with risk for all hospitalization classes. Baseline frailty was significantly associated with all-cause (hazards ratio [HR] 1.41; 95% confidence interval [CI], 1.06, 1.87), chronic (HR 2.13; 95% CI, 1.46, 3.11), and infectious disease hospitalization (HR 2.51; 95% CI, 1.60, 3.91) but not with nonchronic, noninfectious hospitalization risk (HR 1.09; 95% CI, 0.74, 1.61). Conclusion The frailty phenotype predicts vulnerability to chronic and infectious disease-related hospitalization. Frailty-targeted interventions may mitigate the substantial burden of infectious and chronic disease-related morbidity and health care utilization in HIV-infected and uninfected populations.

Angiotensin-Converting Enzyme Inhibitors and Parameters of Sarcopenia: Relation to Muscle Mass, Strength and Function: Data from the Berlin Aging Study-II (BASE-II).

Abstract: Pharmacological options for the treatment of sarcopenia currently do not exist However, off-label treatment options of some established drugs have been suggested The aim of this study was to assess differences in various muscle and physical performance parameters in relation to the intake of angiotensin-converting enzyme (ACE) inhibitors in a cohort of community-dwelling older people Eight hundred and thirty-eight participants from the Berlin Aging Study-II (BASE-II) were included Appendicular lean mass was assessed with dual-energy X-ray absorptiometry and related to height and body mass index Muscle strength was measured by grip strength and related to muscle mass (arm muscle quality) and functional status was assessed via the timed “Up and Go” test Users of ACE inhibitors had higher lean mass related to height but significantly lower lean mass related to body mass index (p = 0001 for women and p < 00001 for men) Moreover, they exhibited lower arm muscle quality (p = 0032 for women and p = 0031 for men) and reported difficulties in climbing stairs more often than non-users (p = 0014 for women and p = 0004 for men) After adjustment for confounders, there were no significant differences regarding lean mass, arm muscle quality and the timed “Up and Go” test according to the use of ACE inhibitors In BASE-II, no positive relationship was found between the intake of ACE inhibitors and lean mass, strength, muscle quality or function Moreover, remarkable differences between parameters of absolute and relative lean mass in relation to the use of ACE inhibitors became evident Fat mass proved to be an important confounder and therefore muscle mass cannot be viewed irrespectively of whole body composition

Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats.

Abstract: Rapamycin is known to extend lifespan We conducted a randomized placebo-controlled study of enteric rapamycin-treatment to evaluate its effect on physical function in old low capacity runner (LCR) rats, a rat model selected from diverse genetic background for low intrinsic aerobic exercise capacity without genomic manipulation and characterized by increased complex disease risks and aging phenotypes The study was performed in 12 male and 16 female LCR rats aged 16-22 months at baseline The treatment group was fed with rapamycin-containing diet pellets at approximately 224mg/kg body weight per day and the placebo group with the same diet without rapamycin for six months Observation was extended for additional 2 months Physical function measurements include grip strength measured as maximum tensile force using a rat grip strength meter and maximum running distance (MRD) using rat physical treadmill test The results showed that rapamycin improved grip strength by 13% (p=036) and 60% (p=001) from its baseline in female and male rats, respectively Rapamycin attenuated MRD decline by 66% (p=001) and 46% (p=319) in females and males, respectively These findings provide initial evidence for beneficial effect of rapamycin on physical functioning in an aging rat model of high disease risks with significant implication in humans

Physical Frailty Assessment in Older Women: Can Simplification Be Achieved Without Loss of Syndrome Measurement Validity?

Abstract: Different phenotypes have increasingly been used as tools for clinical characterization of frailty among older adults. Although there have been studies about the comparability and effectiveness of various simplifications and approximations of existing frailty phenotypes for risk prediction, there have been no studies in which investigators evaluated the stability of the clinical characterization achieved. In the present study, we used baseline (1992-1996) data from 786 community-dwelling women who were 70-79 years of age in the Women's Health and Aging Study I and II to compare physical frailty phenotypes (PFPs). Using the 5 criteria set forth by Fried, we created 15 PFPs that were positive for various combinations of 3 or 4 of those criteria and compared them with the PFP that included all 5 criteria in order to assess construct validity with regard to frailty syndrome characterization and predictive validity for adverse outcomes of aging. All PFPs exhibited high specificity and negative predictive values for identifying frailty syndrome. Three-item PFPs were insensitive but were the best performers for positive predictive value, with the highest positive predictive value of 0.86 seen in the PFP characterized by the combination of weakness, exhaustion, and weight loss. In comparison, the 5-criterion PFP achieved a sensitivity of 0.82 but a positive predictive value of only 0.53. With regard to predictive validity, it was not merely the number of criteria used to characterize the PFPs but rather the specific criteria combinations that predicted the risk of adverse outcomes. Our findings show that there clinically important contexts in which simplified PFPs cannot be used interchangeably.

Herpesvirus Infections and Risk of Frailty and Mortality in Older Women: Women's Health and Aging Studies.

Abstract: Objectives To examine the relationship between herpesvirus infections and mortality and incident frailty risks in community-dwelling older women. Design Nested prospective cohort study. Setting Women's Health and Aging Studies I and II. Participants Community-dwelling older women aged 70 to 79 (n = 633). Measurements Baseline serum antibody (immunoglobulin G) levels against four herpesviruses (herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), 7 Epstein-Barr virus (EBV)), 3-year incident frailty rates, and 5-year mortality. Results Women seropositive for HSV-1 and HSV-2, but not VZV and EBV, had higher risk of 3-year incident frailty (HSV-1: hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 0.96–3.74; HSV-2: HR = 2.10, 95% CI = 1.05–4.37) and 5-year mortality (HR = 1.73, 95% CI = 0.93–3.20; HR = 1.80, 95% CI = 0.94–3.44, respectively) than seronegative women. Incremental increases in serum HSV-1 and HSV-2 antibody levels were associated with incrementally higher risks of incident frailty and mortality. After adjustment for potential confounders, only higher serum HSV-2 antibody level was independently predictive of higher risk of mortality in older women (for each unit increase in antibody index, HR = 1.47, 95% CI = 1.05–2.07). Conclusion HSV-1 and HSV-2 antibody levels are not independently associated with risk of incident frailty in older women. Only HSV-2 antibody level is independently predictive of 5-year mortality risk, with each incremental increase in the antibody level adding further risk.

Association Between Mortality and Heritability of the Scale of Aging Vigor in Epidemiology

Abstract: Objectives To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology (SAVE), to determine its value for genetic analyses. Design Longitudinal, community-based cohort study. Setting The Long Life Family Study (LLFS) in the United States and Denmark. Participants Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551). Measurements The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component–based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models. Results Heritability of the SAVE was 0.23 (P < .001) overall (n = 3,599), 0.31 (P < .001) in probands (n = 1,479), and 0.26 (P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5–6: hazard ratio (HR) = 2.83, 95% confidence interval (CI) = 1.46–5.51; score 7–10: HR = 3.40, 95% CI = 1.72–6.71) than lower scores (0–2). Conclusion The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses.

Renal Toxicity Associated with Salsalate in Elderly Adults with Anemia.

Abstract: Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Shoji, Tighe, Imel: analysis and interpretation of data, drafting manuscript, revising manuscript, final approval of version to be published. Dautovich, McCrae: concept and design, acquisition of data, revising manuscript, final approval of version to be published. Sponsor’s Role: None.

Supramolecular hydrogels containing angiotensin receptor blockers for targeted treatment of diabetic wounds

Abstract: The invention described herein provides novel ampiphilic compounds that self-assemble into a hydrogel composition useful for treating wounds, including chronic wounds and diabetic wounds. The compounds of the invention have structural characteristics, such as hydrophilic and hydrophobic moieties, that enable self-assembly into discrete nanostructures, which then entangle to form the hydrogel. Also provided are methods for treating wounds.

Angiotensin receptor autoantibodies as biomarker for effective usage of angiotensin receptor blockers

Abstract: The invention described herein provides methods for treating a disease or disorder associated with angiotensin receptor signaling in a patient exhibiting elevated levels of ATIR autoantibodies. The invention also provides methods of identifying a patient suffering from a disease or disorder associated with angiotensin receptor signaling that may benefit from treatment with an angiotensin receptor blocker. Patients with elevated levels of ATIR autoantibodies are identified as candidates that particularly benefit from treatment with an angiotensin receptor blocker.