Insomnia as an Independent Predictor of Incident Cardiovascular Disease in HIV: Data from the Veterans Aging Cohort Study

Background: Insomnia is associated with increased cardiovascular disease (CVD) risk in the general population and is highly prevalent in people with HIV. The CVD risk conferred by insomnia in the HIV population is unknown. Methods: Using the Veterans Aging Cohort Study-Survey Cohort, insomnia symptoms were measured and dummy coded with the item, “Difficulty falling or staying asleep?” (5-point scale from no difficulty to bothers a lot). Incident CVD event ICD-9 codes (acute myocardial infarction, stroke, or coronary artery revascularization) were identified with VA and Medicare administrative data and VA fee-for-service data. Those with baseline CVD were excluded. Results: HIV-infected (N=3,108) veterans had a median follow-up time of 10.8 years, during which 267 CVD events occurred. Compared to HIV-infected veterans with no difficulty falling or staying asleep, HIV-infected veterans bothered a lot by insomnia symptoms had an increased risk of incident CVD after adjusting for demographics (HR=1.64, 95%CI=1.16-2.31, p=.005), CVD risk factors (HR=1.62, 95%CI=1.14-2.30, p=.007), additional potential confounders (hepatitis C infection, renal disease, anemia, alcohol use, cocaine use; HR=1.70, 95%CI=1.19-2.43, p=.003), and HIV-specific factors (HIV-1 RNA, CD4+ T-cell count, ART; HR=1.66, 95%CI=1.16-2.37, p=.005). Additional adjustment for non-benzodiazepine sleep medication (HR=1.62, 95%CI=1.13-2.32, p=.009) did not attenuate the association; however, it fell short of significance at p < .01 after adjustment for depressive symptoms (HR=1.51, 95%CI=0.98-2.32, p=.060) or antidepressant medication (HR=1.51, 95%CI=1.04-2.19, p=.031). Conclusion: Highly bothersome insomnia symptoms were significantly associated with incident CVD in HIV-infected veterans, suggesting that insomnia may be a novel, modifiable risk factor for CVD in HIV

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Inflammatory Biomarkers in Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), and HIV/HCV Coinfection.

Background:Inflammation in human immunodeficiency virus (HIV)-infected patients is associated with poorer health outcomes. Whether inflammation as measured by the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) adds information to existing prognostic indices is not known. Methods:We analyzed data from 2000 to 2012 in the Veterans Aging Cohort Study (VACS), overall and stratified by HIV/hepatitis C virus status (n = 89 786). We randomly selected a visit date at which all laboratory values of interest were available within 180 days; participants with HIV received at least 1 year of antiretroviral therapy. We followed patients for (1) mortality and (2) hepatic decompensation (HD) and analyzed associations using Cox regression, adjusted for a validated mortality risk index (VACS Index 2.0). In VACS Biomarker Cohort, we considered correlation with biomarkers of inflammation: interleukin-6, D-dimer, and soluble CD-14. Results:Neutrophil-to-lymphocyte ratio and PLR demonstrated strong unadjusted associations with mortality (P &lt; .0001) and HD (P &lt; .0001) and were weakly correlated with other inflammatory biomarkers. Although NLR remained statistically independent for mortality, as did PLR for HD, the addition of NLR and PLR to the VACS Index 2.0 did not result in significant improvement in discrimination compared with VACS Index 2.0 alone for mortality (C-statistic 0.767 vs 0.758) or for HD (C-statistic 0.805 vs 0.801). Conclusions:Neutrophil-to-lymphocyte ratio and PLR were strongly associated with mortality and HD and weakly correlated with inflammatory biomarkers. However, most of their association was explained by VACS Index 2.0. Addition of NLR and PLR to VACS 2.0 did not substantially improve discrimination for either outcome

Zinc deficiency and advanced liver fibrosis among HIV and hepatitis C co-infected anti-retroviral naïve persons with alcohol use in Russia

Background and aims Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia. Methods This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naïve HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc \u3c0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders. Results The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62–2.61, p = 0.51) nor in exploratory analyses. Conclusions In this cohort of Russians with HIV/HCV co-infection, who are anti-retroviral treatment naïve and have heavy alcohol use, we did not detect an association between zinc deficiency or zinc levels and advanced liver fibrosis

Liver fibrosis and accelerated immune dysfunction (immunosenescence) among HIV-infected Russians with heavy alcohol consumption - an observational cross-sectional study

The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing CD28-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets

Duration of Lactation and Risk Factors for Maternal Cardiovascular Disease

To examine dose-response relationships between the cumulative number of months women lactated and postmenopausal risk factors for cardiovascular disease

Cystatin C based estimation of glomerular filtration rate and association with atherosclerosis imaging markers in people living with HIV

Introduction: Reduced estimated glomerular filtration rate (eGFR) is associated with increased risk of cardiovascular disease among people living with HIV (PLWH). It is unclear whether eGFR equations incorporating Cystatin C (CysC) measurements are more predictive of preclinical CVD than those using only creatinine (Cr). Objectives: The study aimed to determine which of the three Chronic Kidney Disease Epidemiology (CKD-EPI) eGFR equations is most associated with carotid intima media thickness (CIMT) and coronary artery calcium (CAC) score. Methods: This cross-sectional analysis of pooled data from three large cohorts compared the associations between the three CKD-EPI eGFR equations (Cr, CysC, and Cr-CysC) with CIMT and CAC score using multivariable regression analysis. eGFR and CIMT were analyzed as continuous variables. CAC scores were analyzed as a binary variable (detectable calcification versus nondetectable) and as a log10 Agatston score in those with detectable CAC. Results: 1487 participants were included, and of these 910 (562 HIV+, 348 HIV-) had CIMT measurements and 366 (296 HIV+, 70 HIV-) had CAC measurements available. In HIV- participants, GFR estimated by any CKD-EPI equation did not significantly correlate with CIMT or CAC scores. When PLWH were analyzed separately including HIV-specific factors, only GFR estimated using Cr-Cys C correlated with CIMT [β= -0.90, 95% CI (-1.67,-0.13) μm; p=0.023]. Similarly, eGFR correlated with Agatston scores only when using cystatin C-based eGFR [β= -8.63, 95% CI (-16.49,-0.77) HU; p=0.034]. Associations between other eGFR formulas and CAC did not reach statistical significance. Conclusion: In PLWH, preclinical atherosclerosis may be more closely correlated with eGFR using formulae that incorporate CysC measurements than Cr alone

Depression and All-Cause Mortality Risk in HIV-infected and HIV-uninfected U.S. Veterans: A cohort study

Objectives: The contribution of depression to mortality in adults with and without HIV infection is unclear. We hypothesized that depression increases mortality risk and that this association is stronger among those with HIV infection. Methods: Veterans Aging Cohort Study (VACS) data were analysed from the first clinic visit on or after 1 April 2003 (baseline) to 30 September 2015. Depression definitions were: (1) major depressive disorder defined using International Classification of Diseases, Ninth Revision (ICD-9) codes; (2) depressive symptoms defined as Patient Health Questionnaire (PHQ)-9 scores ≥ 10. The outcome was all-cause mortality. Covariates were demographics, comorbid conditions and health behaviours. Results: Among 129 140 eligible participants, 30% had HIV infection, 16% had a major depressive disorder diagnosis, and 24% died over a median follow-up time of 11 years. The death rate was 25.3 [95% confidence interval (CI) 25.0-25.6] deaths per 1000 person-years. Major depressive disorder was associated with mortality [hazard ratio (HR) 1.04; 95% CI 1.01, 1.07]. This association was modified by HIV status (interaction P-value = 0.02). In HIV-stratified analyses, depression was significantly associated with mortality among HIV-uninfected veterans but not among those with HIV infection. Among those with PHQ-9 data (n = 7372), 50% had HIV infection, 22% had PHQ-9 scores ≥ 10, and 28% died over a median follow-up time of 12 years. The death rate was 27.3 (95% CI 26.1-28.5) per 1000 person-years. Depressive symptoms were associated with mortality (HR 1.16; 95% CI 1.04, 1.28). This association was modified by HIV status (interaction P-value = 0.05). In HIV-stratified analyses, depressive symptoms were significantly associated with mortality among veterans with HIV infection but not among those without HIV infection. Conclusions: Depression was associated with all-cause mortality. This association was modified by HIV status and method of depression ascertainment

Intensification of Solvent Extraction in an Additively Manufactured Microfluidic Separator

Solvent extraction is an integral chemical and biochemical separation process that is drastically intensified in microfluidic systems. A novel high-throughput micro-separator was additively manufactured for the intensification of liquid–liquid separation. The micro-posts array within the flow plate generated a capillary pressure gradient on the non-wetting organic phase, enabling continuous, membrane-free, and density-independent phase separation. The device was integrated with an upstream micromixer for aqueous isobutanol extraction, allowing equilibrium extraction levels within 0.25 s. By capitalizing on the high depth-to-width aspect ratio of binder jetting, hydraulic pressure drops were substantially reduced, avoiding a detrimental effect on separation observed in current micro-separators. This novel architecture also enabled the rare ability to separate both “slug flow” and the highly effective but challenging “dispersed droplet flow”. Near-complete separation of the aqueous and organic phases was attained at flow rates up to 15 ml/min, under interfacial tensions of 48.9 and 10.9 mN/m, and aqueous:organic inlet flow ratios of 1:1 and 2:1. Separation performance deteriorated at 20 ml/min due to an increase of velocity gradients near the outlets, leading the wetting aqueous phase to exit from the organic outlet. Owing to its simplicity, manufacturing merits, and robust separation performance, this device addresses key requirements for achieving industrial-level throughputs using a “scale-up via number-up” approach

Effects of Internet Cognitive-Behavioral Therapy on Depressive Symptoms and Surrogates of Cardiovascular Risk in Human Immunodeficiency Virus: A Pilot, Randomized, Controlled Trial

Background Depression is associated with an increased risk of cardiovascular disease in human immunodeficiency virus (HIV). We hypothesized that reducing depressive symptoms would improve HIV-related cardiovascular risk. Methods We conducted a single-center, randomized (1:1), controlled, parallel-group, assessor-blinded, pilot trial comparing Beating the Blues US (BtB)—an evidence-based, 8-session, internet cognitive-behavioral therapy for depression—with usual care (UC) in HIV-positive participants receiving virologically suppressive antiretroviral therapy and with Patient Health Questionnaire (PHQ)-9 scores ≥10. The primary endpoint was change in brachial artery flow-mediated dilation (FMD) at 12 weeks. Secondary endpoints were FMD change at 24 weeks and inflammation, coagulation, and metabolic biomarker changes at 12 and 24 weeks. Results Fifty-four participants were randomized (27 in each arm). Mean reductions in PHQ-9 scores were significantly greater with BtB versus UC at 12 weeks (−5.60 vs −1.52; P = .007) and 24 weeks (−6.00 vs −1.38; P = .008); reductions in the Hopkins Symptom Checklist Depression Scale-20 scores were also significantly greater with BtB versus UC at 24 weeks (−0.72 vs −0.35; P = .029). Changes in FMD between arms were not significantly different at 12 or 24 weeks. Significantly larger reductions in soluble (s)CD14 and sCD163 with BtB versus UC were found at 12 and 24 weeks, respectively. Conclusions Compared with UC, internet cognitive-behavioral therapy using BtB resulted in greater improvements in depressive symptoms and monocyte activation markers but did not improve FMD in this pilot trial. These data support performing larger studies to determine the potential salutatory effects of behavioral therapies for depression on HIV-related inflammation