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Item Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline(American Academy of Neurology, 2017-11-21) Risacher, Shannon L.; Anderson, Wesley H.; Charil, Arnaud; Castelluccio, Peter F.; Shcherbinin, Sergey; Saykin, Andrew J.; Schwarz, Adam J.; Radiology and Imaging Sciences, School of MedicineOBJECTIVE: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. METHODS: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. RESULTS: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. CONCLUSIONS: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.Item Changes in insulin sensitivity over time and associated factors in HIV-infected adolescents(Lippincott, Williams & Wilkins, 2018-03-13) Geffner, Mitchell E.; Patel, Kunjal; Jacobson, Denise L.; Wu, Julia; Miller, Tracie L.; Hazra, Rohan; Gerschenson, Mariana; Sharma, Tanvi; Silio, Margarita; Jao, Jennifer; Takemoto, Jody K.; Van Dyke, Russell B.; Dimeglio, Linda A.; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of MedicineOBJECTIVE: To compare prevalence of insulin resistance between perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, but uninfected adolescents (PHEU), determine incidence of and contributory factors to new and resolved cases of insulin resistance in PHIV+, and evaluate glucose metabolism. DESIGN: Cross-sectional design for comparison of prevalence among PHIV+ and PHEU. Longitudinal design for incidence and resolution of insulin resistance among PHIV+ at risk for these outcomes. METHODS: The source population was adolescents from pediatric HIV clinics in the United States and Puerto Rico participating in the Pediatric HIV/AIDS Cohort Study, an ongoing prospective cohort study designed to evaluate impact of HIV infection and its treatment on multiple domains in preadolescents and adolescents. Insulin resistance was assessed by homeostatic model assessment of insulin resistance. Those with incident insulin resistance underwent 2-h oral glucose tolerance test and HbA1c. Baseline demographic, metabolic, and HIV-specific variables were evaluated for association with incident or resolved insulin resistance. RESULTS: Unadjusted prevalence of insulin resistance in PHIV+ was 27.3 versus 34.1% in PHEU. After adjustment for Tanner stage, age, sex, and race/ethnicity, there was no significant difference between groups. Factors positively associated with developing insulin resistance included female sex, higher BMI z score, and higher waist circumference; those associated with resolving insulin resistance included male sex and lower BMI z score. CONCLUSION: Prevalence of insulin resistance in PHIV+ and PHEU was substantially higher than that reported in HIV-uninfected nonoverweight youth, but similar to that in HIV-uninfected obese youth. Factors associated with incident or resolved insulin resistance among PHIV+ were similar to those reported in HIV-negative obese youth. However, a contributory role of HIV infection and/or its treatment to the incident risk of insulin resistance cannot be excluded.Item Is Low Health Literacy Associated with Increased Emergency Department Utilization and Recidivism?(Wiley Online Library, 2014-10) Griffey, Richard T.; Kennedy, Sarah K.; McGownan, Lucy; Kaphingst, Kimberly A.; Department of Emergency Medicine, IU School of MedicineOBJECTIVES: The objective was to determine whether patients with low health literacy have higher emergency department (ED) utilization and higher ED recidivism than patients with adequate health literacy. METHODS: The study was conducted at an urban academic ED with more than 95,000 annual visits that is part of a 13-hospital health system, using electronic records that are captured in a central data repository. As part of a larger, cross-sectional, convenience sample study, health literacy testing was performed using the short test of functional health literacy in adults (S-TOFHLA) and standard test thresholds identifying those with inadequate, marginal, and adequate health literacy. The authors collected patients' demographic and clinical data, including items known to affect recidivism. This was a structured electronic record review directed at determining 1) the median number of total ED visits in this health system within a 2-year period and 2) the proportion of patients with each level of health literacy who had return visits within 3, 7, and 14 days of index visits. Descriptive data for demographics and ED returns are reported, stratified by health literacy level. The Mantel-Haenszel chi-square was used to test whether there is an association between health literacy and ED recidivism. A negative binomial multivariable model was performed to examine whether health literacy affects ED use, including variables significant at the 0.1 alpha level on bivariate analysis and retaining those significant at an alpha of 0.05 in the final model. RESULTS: Among 431 patients evaluated, 13.2% had inadequate, 10% had marginal, and 76.3% had adequate health literacy as identified by S-TOFHLA. Patients with inadequate health literacy had higher ED utilization compared to those with adequate health literacy (p = 0.03). Variables retained in the final model included S-TOFHLA score, number of medications, having a personal doctor, being a property owner, race, insurance, age, and simple comorbidity score. During the study period, 118 unique patients each made at least one return ED visit within a 14-day period. The proportion of patients with inadequate health literacy making at least one return visit was higher than that of patients with adequate health literacy at 14 days, but was not significantly higher within 3 or 7 days. CONCLUSIONS: In this single-center study, higher utilization of the ED by patients with inadequate health literacy when compared to those with adequate health literacy was observed. Patients with inadequate health literacy made a higher number of return visits at 14 days but not at 3 or 7 days.Item Microbial translocation and metabolic and body composition measures in treated and untreated HIV infection(Mary Ann Liebert, Inc., 2014-03) Timmons, Tamara; Shen, Changyu; Aldrovandi, Grace; Rollie, Adrienne; Gupta, Samir K.; Stein, James H.; Dube´, Michael P.; Biostatistics, School of MedicineCirculating levels of microbial products such as lipopolysaccharide (LPS) are increased in HIV infection. Microbial translocation promotes obesity, insulin resistance, and dyslipidemia in other settings. We examined data from 178 subjects: an Indiana University (IU) cross-sectional study [N=49 on antiretroviral therapy (ART), N=47 not on ART], and a 24 week prospective study of ART initiation ACTG 5152s (N=82). Pearson correlations were used to describe relationships of plasma LPS levels and soluble CD14 (sCD14), a marker of monocyte activation, with metabolic and body composition measures. HOMA-IR (a measure of insulin resistance) and LPS were correlated for the combined cohorts (r=0.19, p=0.02), particularly in the 5152s ART-naive cohort (r=0.41, p<0.01). Triglycerides were correlated with LPS in the combined cohort (r=0.32, p<0.01), and all subsets excluding the IU on ART subset. There were negative correlations between sCD14 and high-density lipoprotein (HDL) cholesterol in all subjects (r=-0.21, p<0.01), as well as the IU subset not on ART (r=-0.32, p=0.04). Large particle HDL as measured by NMR spectroscopy, but not HDL cholesterol, was negatively correlated with LPS (r=-0.18, p=0.02), particularly among the IU subset receiving ART (r=-0.33, p=0.03). In the combined cohorts, sCD14 was negatively correlated with lean mass as well as trunk and limb fat. There is a relationship between microbial translocation markers and metabolic effects, particularly lipoproteins. During prolonged ART, microbial translocation was associated with an adverse effect on large HDL and thus may contribute to the increased cardiovascular disease risk observed during chronic treatment of HIV.Item Pharmacogenomics of Hypertension in CKD: The CKD-PGX Study.(American Society of Nephrology, 2022-02) Eadon, Michael T.; Maddatu, Judith; Moe, Sharon M.; Sinha, Arjun D.; Ferreira, Ricardo Melo; Miller, Brent W.; Sher, S. Jawad; Su, Jing; Pratt, Victoria M.; Chapman, Arlene B.; Skaar, Todd C.; Moorthi, Ranjani N.BACKGROUND: Patients with CKD often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may affect the metabolism or efficacy of antihypertensive agents. We report changes in hypertension control after providing a panel of 11 pharmacogenomic predictors of antihypertensive response. METHODS: A prospective cohort with CKD and hypertension was followed to assess feasibility of pharmacogenomic testing implementation, self-reported provider utilization, and BP control. The analysis population included 382 subjects with hypertension who were genotyped for cross-sectional assessment of DGIs, and 335 subjects followed for 1 year to assess systolic BP (SBP) and diastolic BP (DBP). RESULTS: Most participants (58%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.85-fold (95% CI, 1.2- to 2.8-fold) higher odds of uncontrolled hypertension, as compared with those without a DGI, adjusted for race, health system (safety-net hospital versus other locations), and advanced CKD (eGFR <30 ml/min). CYP2C9-reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (odds ratio [OR], 5.2; 95% CI, 1.9 to 14.7). CYP2D6-intermediate or -poor metabolizers had less frequent uncontrolled hypertension compared with normal metabolizers taking metoprolol or carvedilol (OR, 0.55; 95% CI, 0.3 to 0.95). In 335 subjects completing 1-year follow-up, SBP (-4.0 mm Hg; 95% CI, 1.6 to 6.5 mm Hg) and DBP (-3.3 mm Hg; 95% CI, 2.0 to 4.6 mm Hg) were improved. No significant difference in SBP or DBP change were found between individuals with and without a DGI. CONCLUSIONS: There is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.Item The Resilience in Illness Model Part 2: Confirmatory Evaluation in Adolescents and Young Adults With Cancer(Wolters Kluwer, 2017-11) Haase, Joan E.; Kintner, Eileen K.; Robb, Sheri L.; Stump, Timothy E.; Monahan, Patrick O.; Phillips, Celeste; Stegenga, Kristin A.; Burns, Debra S.; School of NursingBACKGROUND: Empirically derived and tested models are necessary to develop effective, holistic interventions to improve positive health outcomes in adolescents and young adults (AYA) with cancer, yet few exist. This article is the second of 2 articles reporting on evaluation of the Resilience in Illness Model (RIM) as a predictive model to guide positive health research and practice. OBJECTIVE: The aim of this study was to report the confirmatory model evaluation of the RIM. METHODS: A confirmatory evaluation of RIM was done using baseline data from a sample of 113 AYA aged 11 to 24 years who were undergoing hematopoietic stem cell transplant and enrolled in a randomized controlled trial of a behavioral intervention to enhance resilience. Data were analyzed using latent variable structural equation modeling. RESULTS: Goodness-of-fit indices supported RIM as a confirmed model that accounted for large amounts of variance in the outcomes of self-transcendence (62%) and resilience (72%), and in 3 of 5 mediators, specifically social integration (74%), courageous coping (80%), and hope-derived meaning (87%), as well as small to moderate amounts of variance in the remaining mediators of defensive coping (1%) and family environment (35%). CONCLUSIONS: Findings establish the RIM as a plausible predictive framework for explaining ways AYA with cancer transcend their illness and achieve resilience resolution and for guiding intervention studies in this population. Additional research is needed to explore RIM's transferability based on stage of illness, other chronic diseases, and cultural diversity. IMPLICATIONS FOR PRACTICE: Results support the RIM as an appropriate guide for developing and evaluating interventions to foster positive adjustment in AYA with cancer.Item Serum high mobility group box 1 protein levels are not associated with either histological severity or treatment response in children and adults with nonalcoholic fatty liver disease(PLOS, 2017-11-02) Yates, Katherine P.; Deppe, Ross; Comerford, Megan; Masuoka, Howard; Cummings, Oscar W.; Tonascia, James; Chalasani, Naga; Vuppalanchi, Raj; Medicine, School of MedicineAim Serum high mobility group box 1 protein (HMGB1) is a proinflammatory molecule that could potentially serve as a biomarker for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to its correlation with degree of liver fibrosis. The aim of the current study was to examine the cross-sectional and longitudinal relationships between serum HMGB1 levels and liver histology in adults and children with NAFLD participating in two large randomized controlled trials. Methods Serum HMGB1 levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively. PIVENS trial compared vitamin E or pioglitazone to placebo in adults whereas TONIC trial compared vitamin E or metformin to placebo in children. Participants had liver biopsies at baseline and the end of treatment (96 weeks), and liver histology was reviewed by a central committee of study pathologists. Results In the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children. Serum HMGB1 levels did not change significantly during treatment either with placebo, vitamin E therapy (P = 0.81) or pioglitazone (P = 0.09) in the PIVENS trial. Similarly, serum HMGB1 levels did not change significantly during treatment either with placebo, metformin (P = 0.15) or vitamin E (P = 0.23) in the TONIC trial. In the longitudinal analyses (n = 105 for PIVENS and 109 for TONIC), changes in serum HMGB1 levels did not correlate with histologic improvement or resolution of NASH in either adults or children. There was no relationship between serum HMGB1 and ALT levels in either adults or children with NAFLD. Conclusion Serum HMGB1 levels were not associated with histological severity or treatment response in either children or adults with NAFLD.