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1.  Neurocognitive Change in the Era of HIV Combination Antiretroviral Therapy: The Longitudinal CHARTER Study 
CNS HIVAnti-Retroviral Therapy Effects Research examined incidence and predictors of neurocognitive (NC) change in 436 human immunodeficiency virus (HIV)-infected adults over 4–7 semiannual visits; 22.7% evidenced NC decline and 16.5% NC improvement. These changes were predicted by HIV disease and treatment factors, demographics, and comorbid conditions.
Background. Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery.
Methods. We investigated the incidence and predictors of NC change over 16–72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change.
Results. Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001).
Conclusions. NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.
doi:10.1093/cid/ciu862
PMCID: PMC4303775  PMID: 25362201
cognitive change; HIV; antiretroviral therapy; comorbidities
2.  Improved Method to Stratify Elderly Patients With Cancer at Risk for Competing Events 
Journal of Clinical Oncology  2016;34(11):1270-1277.
Purpose
To compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events.
Methods
We identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion.
Results
In each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8.
Conclusion
Compared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.
doi:10.1200/JCO.2015.65.0739
PMCID: PMC5070568  PMID: 26884579
3.  Cerebral white matter integrity during primary HIV infection 
AIDS (London, England)  2015;29(4):433-442.
Objective
Inflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown.
Design
We used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection.
Methods
Antiretroviral-naive PHI (defined as <1 year after infection, n = 62), chronic HIV infection (CHI, n = 16), and HIV-uninfected (n = 19) participants had DTI, laboratory, and neuropsychometric performance assessments. DTI metrics were examined using region of interest and whole brain voxelwise analyses. Linear mixed-effects models assessed correlations between DTI measures and laboratory and neuropsychometric performance values.
Results
PHI participants were assessed at a median 4.1 months after estimated infection, and had median CD4+ cell count of 573 cells/µl, and HIV-1 RNA viral load of 4.5 log10 copies/ml in plasma and 2.6 log10 copies/ml in cerebrospinal fluid (CSF). DTI metrics in PHI individuals were similar to HIV— participants and correlated with disruptions in the blood-brain barrier (indicated by CSF/plasma albumin ratio and CSF protein). CHI participants had significant loss of white matter integrity that correlated with biomarkers of infection and inflammation (blood viral load, CD4+ T-cell count, and neopterin, and CSF white blood cell). Within the PHI group, DTI metrics inversely correlated with increasing days since infection.
Conclusion
In individuals assessed during PHI, group DTI measures suggested relative preservation of white matter microstructural integrity, but were associated with disruption of the blood-brain barrier and estimated duration of infection.
doi:10.1097/QAD.0000000000000560
PMCID: PMC4916955  PMID: 25513818
corpus callosum; cerebrospinal fluid/plasma albumin ratio; diffusion tensor imaging; neopterin; neuropsychometric testing; primary HIV infection; white matter
5.  Predictors of New Onset Distal Neuropathic Pain in HIV-infected Individuals in the Era of Combination Antiretroviral Therapy 
Pain  2015;156(4):731-739.
Despite modern combination antiretroviral therapy (CART), distal neuropathic pain (DNP) continues to affect many individuals with HIV infection. We evaluated risk factors for new onset DNP in the CNS Antiretroviral Therapy Effects Research (CHARTER) study, an observational cohort. Standardized, semi-annual clinical evaluations were administered at six U.S. sites. DNP was defined by using a clinician-administered instrument standardized across sites. All participants analyzed were free of DNP at study entry. New onset DNP was recorded at the first follow-up visit at which it was reported. Mixed effects logistic regression was used to evaluate potential predictors including HIV disease and treatment factors, demographics, medical comorbidities and neuropsychiatric factors. Among 493 participants, 131 (27%) reported new DNP over 2,306 visits during a median follow-up of 24 months [interquartile range (IQR) 12-42]. In multivariable regression, after adjusting for other covariates, significant entry predictors of new DNP were older age, female sex, current and past antiretroviral treatment, lack of virologic suppression, and lifetime history of opioid use disorder. During follow-up, more severe depression symptoms conferred a significantly elevated risk. The associations with opioid use disorders and depression reinforce the view that the clinical expression of neuropathic pain with peripheral nerve disease is strongly influenced by neuropsychiatric factors. Delineating such risk factors might help target emerging preventive strategies, for example, to individuals with a prior history of opioid use disorder, or might lead to new treatment approaches such as the use of tools to ameliorate depressed mood.
doi:10.1097/01.j.pain.0000461252.75089.bf
PMCID: PMC4374054  PMID: 25659067
6.  Physical Activity Affects Brain Integrity in HIV + Individuals 
Prior research has suggested benefits of aerobic physical activity (PA) on cognition and brain volumes in HIV uninfected (HIV−) individuals, however, few studies have explored the relationships between PA and brain integrity (cognition and structural brain volumes) in HIV-infected (HIV +) individuals. Seventy HIV + individuals underwent neuropsychological testing, structural neuroimaging, laboratory tests, and completed a PA questionnaire, recalling participation in walking, running, and jogging activities over the last year. A PA engagement score of weekly metabolic equivalent (MET) hr of activity was calculated using a compendium of PAs. HIV + individuals were classified as physically active (any energy expended above resting expenditure, n = 22) or sedentary (n = 48). Comparisons of neuropsychological performance, grouped by executive and motor domains, and brain volumes were completed between groups. Physically active and sedentary HIV + individuals had similar demographic and laboratory values, but the active group had higher education (14.0 vs. 12.6 years, p = .034). Physically active HIV + individuals performed better on executive (p = .040, unadjusted; p = .043, adjusted) but not motor function (p = .17). In addition, among the physically active group the amount of physical activity (METs) positively correlated with executive (Pearson’s r = 0.45, p = 0.035) but not motor (r = 0.21; p = .35) performance. In adjusted analyses the physically active HIV + individuals had larger putamen volumes (p = .019). A positive relationship exists between PA and brain integrity in HIV + individuals. Results from the present study emphasize the importance to conduct longitudinal interventional investigation to determine if PA improves brain integrity in HIV + individuals.
doi:10.1017/S1355617715000879
PMCID: PMC4706152  PMID: 26581799
HIV; Exercise; Neuropsychology performance; Brain volume; Magnetic resonance imaging (MRI); Putamen
7.  Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people 
Neurology  2015;84(3):241-250.
Objective:
To investigate the effect of hepatitis C virus (HCV) on neurocognitive performance in chronically HIV-infected patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study.
Methods:
A total of 1,582 participants in CHARTER who were tested for HCV antibody underwent neurocognitive testing; serum HCV RNA was available for 346 seropositive patients. Neurocognitive performance was compared in 408 HCV-seropositive and 1,174 HCV-seronegative participants and in a subset of 160 seropositive and 707 seronegative participants without serious comorbid neurologic conditions that might impair neurocognitive performance, using linear regression and taking into account HIV-associated and demographic factors (including IV drug use) and liver function.
Results:
Neurocognitive performance characterized by global deficit scores and the proportion of individuals who were impaired were the same in the HCV-seropositive and HCV-seronegative groups. In univariable analyses in the entire sample, only verbal domain scores showed small statistically different superior performance in the HCV+ group that was not evident in multivariable analysis. In the subgroup without significant comorbidities, scores in all 7 domains of neurocognitive functioning did not differ by HCV serostatus. Among the HCV-seropositive participants, there was no association between neurocognitive performance and serum HCV RNA concentration.
Conclusion:
In HIV-infected patients, HCV coinfection does not contribute to neurocognitive impairment, at least in the absence of substantial HCV-associated liver damage, which was not evident in our cohort.
doi:10.1212/WNL.0000000000001156
PMCID: PMC4335996  PMID: 25503616
8.  Self-Predictions of Prospective Memory in HIV-Associated Neurocognitive Disorders: Evidence of a Metamemory Deficit 
HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; “remembering to remember”), conferring risk of daily functioning declines. However, self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV−). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV− samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence).
doi:10.1093/arclin/acu061
PMCID: PMC4296161  PMID: 25404005
Executive functions; Metacognition; Everyday functioning
9.  Antigen-Presenting Phagocytic Cells Ingest Malaria Parasites and Increase HIV Replication in a Tumor Necrosis Factor α-Dependent Manner 
The Journal of Infectious Diseases  2014;210(10):1562-1572.
Background. Plasmodium falciparum infection induces human immunodeficiency virus (HIV) replication and accelerates a decline in CD4+ T-cell count. The mechanisms contributing to these interactions have not been fully elucidated.
Methods. We infected peripheral blood mononuclear cells (PBMCs) with HIV type 1 (HIV-1) and then cocultured them with P. falciparum–infected red blood cells (iRBCs) or uninfected RBCs (uRBCs). Levels of HIV-1 p24 antigen and activation-associated cytokines were measured in culture supernatants. T-cell surface activation was assessed by flow cytometry.
Results. It has been reported that iRBCs increase HIV replication, compared with uRBCs; that neutralizing tumor necrosis factor α (TNF-α) abrogates this increase; and that hemozoin enhances HIV production. In this study, we confirmed that TNF-α plays an important role in this interaction. We show that iRBCs increased CD4+ T-cell expression of HLA-DR+/CD38+ (P = .001), that monocyte/macrophage depletion reduced HIV production by 40%–50% (P < .001), and that hemozoin-laden monocytes/macrophages that were preincubated with iRBCs also stimulated HIV production.
Conclusions. iRBCs activate CD4+ T cells and stimulate HIV replication in a TNF-α–dependent manner following malarial antigen processing by monocytes/macrophages. These results suggest that the persistent elevation of HIV replication during and after acute bouts of P. falciparum malaria may be due, at least in part, to ongoing stimulation of CD4+ T cells by hemozoin-loaded antigen-presenting cells within lymphoid tissues.
doi:10.1093/infdis/jiu317
PMCID: PMC4215075  PMID: 24903666
HIV; P. falciparum; interaction; mechanism of increased viral load; malaria; co-infection
10.  FAT COMPOSITION CHANGES IN BONE MARROW DURING CHEMOTHERAPY AND RADIOTHERAPY 
Purpose/Objectives(s)
To quantify changes in bone marrow fat fraction and determine associations with peripheral blood cell counts.
Methods and Materials
In this prospective study, 19 patients received either highly myelotoxic (radiotherapy plus cisplatin, 5FU/MMC or cisplatin/5FU/cetuximab) or less myelotoxic treatment (capacitabine-radiotherapy or no concurrent chemotherapy). Patients underwent MR imaging and venipuncture at baseline, mid-treatment, and post-treatment visits. We performed mixed effects modeling of the mean proton density fat fraction (PDFF(%)) by linear-time, treatment, and vertebral column region (L4-S2 vs. T10-L3 vs. C3-T9), while controlling for cumulative mean dose and other confounders. Spearman rank correlations were performed by blood cell counts versus the difference in PDFF(%) pre- and post-treatment.
Results
Cumulative mean dose was associated with a 0.43% per Gy (p=.004) increase in PDFF(%). In the highly myelotoxic group, we observed significant changes in PDFF(%) per visit within L4-S2 (10.1%,p<.001) and within T10-L3 (3.93%,p=.01), relative to the reference C3-T9. In the less myelotoxic group, we did not observe significant changes in PDFF(%) per visit according to region. Within L4-S2, we observed a significant difference between treatment groups in the change in PDFF(%) per visit (5.36%,p=.04). Rank correlations of the inverse log difference in WBC versus the difference in PDFF(%) overall and within T10-S2 ranged from 0.69-0.78 (p<0.05). Rank correlations of the inverse log difference in ANC versus the difference in PDFF(%) overall and within L4-S2 ranged from 0.79-0.81 (p<0.05).
Conclusion
MRI fat quantification is sensitive to marrow composition changes that result from (chemo)radiotherapy. These changes are associated with peripheral blood cell counts. This study supports a rationale for bone marrow sparing treatment planning to reduce the risk of hematologic toxicity.
doi:10.1016/j.ijrobp.2014.05.041
PMCID: PMC4159416  PMID: 25015207
11.  Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline 
Neurology  2014;82(23):2055-2062.
Objective:
While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline).
Methods:
A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7–63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood.
Results:
The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1–3.6; p = 0.02) for SR, 5.8 (CI 3.2–10.7; p < 0.0001) for PB, and 3.2 (CI 2.0–5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not.
Conclusions:
This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.
doi:10.1212/WNL.0000000000000492
PMCID: PMC4118496  PMID: 24814848
12.  HIV-Associated Distal Neuropathic Pain is Associated with Smaller Total Cerebral Cortical Gray Matter 
Journal of neurovirology  2014;20(3):209-218.
Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.
doi:10.1007/s13365-014-0236-8
PMCID: PMC4040150  PMID: 24549970
HIV Distal Neuropathic Pain; Structural MRI; Cortical Volume
13.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
doi:10.1093/arclin/acu009
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
14.  Randomized Trial of Central Nervous System–Targeted Antiretrovirals for HIV-Associated Neurocognitive Disorder 
Antiretroviral therapy (ART) targeted to the central nervous system did not benefit neurocognitive function more than untargeted ART. A planned secondary analysis demonstrating a subgroup benefit in patients with undetectable viral loads before entry should be verified in future studies.
Background. Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection.
Methods. This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non–CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16.
Results. The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent-to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4+ T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], −31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, −.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T.
Conclusions. This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded.
Clinical Trials Registration NCT00624195.
doi:10.1093/cid/cit921
PMCID: PMC3952601  PMID: 24352352
HIV; AIDS; cognitive disorders/dementia; antiretroviral therapy
15.  Fast Implementation for Normal Mixed Effects Models With Censored Response 
We propose an EM algorithm for computing the maximum likelihood and restricted maximum likelihood for linear and nonlinear mixed effects models with censored response. In contrast with previous developments, this algorithm uses closed-form expressions at the E-step, as opposed to Monte Carlo simulation. These expressions rely on formulas for the mean and variance of a truncated multinormal distribution, and can be computed using available software. This leads to an improvement in the speed of computation of up to an order of magnitude. A wide class of mixed effects models is considered, including the Laird–Ware model, and extensions to different structures for the variance components, heteroscedastic and autocorrelated errors, and multilevel models. We apply the methodology to two case studies from our own biostatistical practice, involving the analysis of longitudinal HIV viral load in two recent AIDS studies.
The proposed algorithm is implemented in the R package lmec. An appendix which includes further mathematical details, the R code, and datasets for examples and simulations are available as the online supplements.
doi:10.1198/jcgs.2009.07130
PMCID: PMC4377318  PMID: 25829836
Detection limit; EM algorithm; HIV viral load; Maximum likelihood; Truncated multinormal distribution
16.  Levels of Protein C and Soluble Thrombomodulin in Critically Ill Patients with Acute Kidney Injury: A Multicenter Prospective Observational Study 
PLoS ONE  2015;10(3):e0120770.
Endothelial dysfunction contributes to the development of acute kidney injury (AKI) in animal models of ischemia reperfusion injury and sepsis. There are limited data on markers of endothelial dysfunction in human AKI. We hypothesized that Protein C (PC) and soluble thrombomodulin (sTM) levels could predict AKI. We conducted a multicenter prospective study in 80 patients to assess the relationship of PC and sTM levels to AKI, defined by the AKIN creatinine (AKI Scr) and urine output criteria (AKI UO). We measured marker levels for up to 10 days from intensive care unit admission. We used area under the curve (AUC) and time-dependent multivariable Cox proportional hazard model to predict AKI and logistic regression to predict mortality/non-renal recovery. Protein C and sTM were not different in patients with AKI UO only versus no AKI. On intensive care unit admission, as PC levels are usually lower with AKI Scr, the AUC to predict the absence of AKI was 0.63 (95%CI 0.44-0.78). The AUC using log10 sTM levels to predict AKI was 0.77 (95%CI 0.62-0.89), which predicted AKI Scr better than serum and urine neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, urine kidney injury molecule-1 and liver-fatty acid-binding protein. In multivariable models, PC and urine NGAL levels independently predicted AKI (p=0.04 and 0.02) and PC levels independently predicted mortality/non-renal recovery (p=0.04). In our study, PC and sTM levels can predict AKI Scr but are not modified during AKI UO alone. PC levels could independently predict mortality/non-renal recovery. Additional larger studies are needed to define the relationship between markers of endothelial dysfunction and AKI.
doi:10.1371/journal.pone.0120770
PMCID: PMC4366245  PMID: 25790110
17.  Comparisons of Reported Sexual Behaviors from a Retrospective Survey Versus a Prospective Diary in the Botswana Defence Force 
This study compares self-reported sexual behaviors from a retrospective survey and a prospective diary among Botswana Defence Force (BDF) personnel. One hundred sixty-one male participants, aged 18–30, completed two weekly prospective diaries and a retrospective survey querying them about behaviors reported during the same time frame as the diaries. Most reported behaviors were similar between the two data collection methods. However, there was low agreement for reporting sex with a spouse and exchanging material goods for sex with a casual partner; frequency of sex and condom use rates (CURs) among married participants also differed. When comparing survey condom use frequencies to diary CURs, the level of agreement diminished from the always to occasionally condom use categories. Inconsistencies in reporting may be due to the frequency of the sexual behavior, question sensitivity, the data collection setting, and the interpretation of response categories. Further research is needed to improve accurate reporting of sexual behaviors.
doi:10.1521/aeap.2013.25.6.495
PMCID: PMC4309744  PMID: 24245596
18.  The effect of cell subset isolation method on gene expression in leukocytes 
Multiple scientific disciplines require the isolation of specific subsets of blood cells from patient samples for gene expression analysis by microarray or RNA-sequencing, preserving disease- or treatment-related signatures. However, little is known with respect to the impact of different cell isolation methods on gene expression and the effects of positive selection, negative selection and fluorescence activated cell sorting (FACS) have not previously been assessed in parallel. To address this knowledge gap, CD4+ T cells, CD8+ T cells, B cells and monocytes were isolated from blood samples from 5 independent donors using positive immunomagnetic selection, negative immunomagnetic selection and FACS. We hypothesized that positive selection and FACS would yield higher purity but may have an impact on gene expression since both methods utilize antibodies that bind surface receptors of the cell type of interest. Moreover, FACS might upregulate stress response genes due to passage of the cells through the sorter. Microarray gene expression data was generated and subjected to unsupervised clustering and differential gene expression analysis. Surprisingly, these analyses revealed that gene expression signatures were more similar between cells isolated by negative selection and FACS compared to cells isolated by positive selection. Moreover, genes that are involved in the response to stress generally had the highest expression in cells isolated by negative or positive selection and not FACS. Thus, FACS is the recommended method for isolation of leukocyte subsets for gene expression studies since this method results in the purest subset populations and does not appear to induce a stress response.
doi:10.1002/cyto.a.22352
PMCID: PMC3975050  PMID: 24115734
negative immunomagnetic selection; positive immunomagnetic selection; fluorescent activated cell sorting; CD4+ T cell; CD8+ T cell; B cell; monocyte; gene expression; microarray
19.  Interval Estimation of Random Effects in Proportional Hazards Models with Frailties 
Statistical methods in medical research  2013;10.1177/0962280212474059.
Semi-parametric frailty models are widely used to analyze clustered survival data. In this paper, we propose the use of the hierarchical likelihood interval for individual frailties of the clusters, not the parameters of the frailty distribution. We study the relationship between hierarchical likelihood, empirical Bayesian, and fully Bayesian intervals for frailties. We show that our proposed interval can be interpreted as a frequentist confidence interval and Bayesian credible interval under a uniform prior. We also propose an adjustment of the proposed interval to avoid null intervals. Simulation studies show that the proposed interval preserves the nominal confidence level. The procedure is illustrated using data from a multicenter lung cancer clinical trial.
doi:10.1177/0962280212474059
PMCID: PMC4270953  PMID: 23361438
Empirical Bayes; Hierarchical likelihood; Interval estimator; Random effects; Survival analysis
20.  Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency 
Background
Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.
Methods
Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.
Results
Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.
Conclusion
Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.
PMCID: PMC4191860  PMID: 25309945
Vancomycin; Children; Pediatrics; Renal disease; Renal insufficiency; Antibiotic; Methicillin-resistant Staphylococcus aureus (MRSA); Staphylococcus aureus; Antibiotic resistance; Pharmacokinetic-pharmacodynamic; Population-based pharmacokinetic modeling; Monte Carlo simulation; Area-under-the curve
21.  HIV Clades B and C are Associated With Reduced Brain Volumetrics 
Journal of neurovirology  2013;19(5):10.1007/s13365-013-0202-x.
Objective
HIV has multiple genetic clades with varying prevalence throughout the world. Both HIV-clade C (HIV-C) and HIV-clade B (HIV-B) can cause cognitive impairment but it is unclear if these clades are characterized by similar patterns of brain dysfunction. We examined brain volumetrics and neuropsychological performance among highly active anti-retroviral therapy (HAART) naïve HIV-B and HIV-C participants.
Design
Thirty-four HAART-naïve HIV-infected (HIV+) participants [(17 HIV-B (United States); 17 HIV-C (South Africa)] and 34 age and education-matched HIV-uninfected (HIV−) participants were evaluated.
Methods
All participants underwent similar laboratory, neuropsychological, and neuroimaging studies. Brain volume measures were assessed within the caudate, putamen, amygdala, thalamus, hippocampus, corpus callosum and cortical (grey and white matter) structures. A linear model that included HIV status, region, and their interaction assessed the effects of the virus on brain volumetrics.
Results
HIV− and HIV+ individuals were similar in age. On laboratory examination, HIV-C participants had lower CD4 cell counts and higher plasma HIV viral loads than HIV-B individuals. In general, HIV+ participants performed significantly worse on neuropsychological measures of processing speed and memory and had significantly smaller relative volumetrics within the thalamus, hippocampus, and corpus callosum and cortical grey and white matter compared to respective HIV− controls. Both HIV-clades B and C are associated with similar volumetric declines when compared to matched HIV− controls.
Conclusions
HIV-B and C were associated with significant reductions in brain volumetrics and poorer neuropsychological performance; however, no specific effect of HIV clade subtype was evident. These findings suggest that HIV-B and HIV-C both detrimentally affect brain integrity.
doi:10.1007/s13365-013-0202-x
PMCID: PMC3845807  PMID: 24078556
HIV clade; brain volumetrics; magnetic resonance imaging; neuropsychological performance
22.  An Intervention Study Examining the Effects of Condom Wrapper Graphics and Scent on Condom Use in the Botswana Defence Force 
AIDS care  2013;26(7):890-898.
Free condoms provided by the government are often not used by Botswana Defence Force (BDF) personnel due to a perceived unpleasant scent and unattractive wrapper. Formative work with the BDF found that scented condoms and military inspired (camouflage) wrapper graphics were appealing to personnel. A non-randomized intervention study was implemented to determine if condom wrapper graphics and scent improved condom use in the BDF. Four military sites were selected for participation. Two sites in the south received the intervention condom wrapped in a generic wrapper and two sites in the north received the intervention condom wrapped in a military inspired wrapper; intervention condoms were either scented or unscented. 211 male soldiers who ever had sex, aged 18–30 years, and stationed at one of the selected sites consented to participate. Sexual activity and condom use were measured pre- and post-intervention using sexual behavior diaries. A condom use rate (CUR; frequency of protected sex divided by total frequency of sex) was computed for each participant. Mean CURs significantly increased over time (85.7% baseline vs. 94.5% post-intervention). Adjusted odds of condom use over time were higher among participants who received the intervention condom packaged in the military wrapper compared with the generic wrapper. Adjusted odds of condom use were also higher for participants who reported using scented versus unscented condoms. Providing scented condoms and condoms packaged in a miltiary inspired wrapper may help increase condom use and reduce HIV infection among military personnel.
doi:10.1080/09540121.2013.860420
PMCID: PMC3991928  PMID: 24266459
HIV; sexual behaviors; condom use; military; HIV prevention intervention
23.  Predictors of virologic response in persons who start antiretroviral therapy during recent HIV infection 
AIDS (London, England)  2014;28(6):841-849.
Objective
Despite evidence supporting antiretroviral therapy (ART) in recent HIV infection, little is known about factors that are associated with successful ART. We assessed demographic, virologic, and immunologic parameters to identify predictors of virologic response.
Design
A 24-week observational study of ART on persons enrolled within 6 months of their estimated date of infection (EDI) evaluated baseline demographics and the collection of blood and gut specimens.
Methods
Flow cytometry analyses of blood and gut lymphocytes allowed characterization of CD4+ and CD8+ T cells at study entry and end. Additional assessments included soluble CD14 (sCD14), lipopolysaccharide, CD4+ T-cell counts, and HIV RNA levels.
Results
Twenty nine participants initiated ART, and 17 achieved undetectable HIV RNA by study end. A longer time from EDI to ART, older age, higher sCD14, lower proportions of central memory CD4+ T cells, and higher proportions of activated CD8+ T cells were associated with detectable viremia. Multivariable logistic regression found only older age and elevated sCD14 were independently associated with persistent viremia. Additionally, we observed that ART in recent infection did not result in discernible recovery of CD4+ T cells in the gut.
Conclusion
In persons who started ART within 3–33 weeks from EDI, age and microbial translocation were associated with detectable HIV RNA. As observed in other cohorts, ART in recent infection did not improve proportions of total CD4+ T cells in gut-associated lymphoid tissue (GALT). This lends support to further evaluate the use of more potent ART or regimens that protect the GALT in recent HIV infection.
doi:10.1097/QAD.0000000000000149
PMCID: PMC4049563  PMID: 24401640
antiretroviral therapy; gut-associated lymphoid tissue; microbial translocation; recent HIV; virologic response
24.  Etravirine in CSF is highly protein bound 
Objectives
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Methods
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Results
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Conclusions
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
doi:10.1093/jac/dks517
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
25.  Condom Use Behaviors and Correlates of Use in the Botswana Defence Force 
International journal of STD & AIDS  2013;24(11):883-892.
Preventing HIV infection is a priority for militaries. HIV prevention research is needed to monitor existing programs, identify areas for modification, and develop new interventions. Correct and consistent condom use is highly effective against HIV. However, use among soldiers is lower than ideal. This study describes condom use behaviors and examines correlates of use in the Botswana Defence Force (BDF). Analyses were based on 211 male personnel, aged 18–30, who completed a cross-sectional survey that collected baseline data for an intervention study. Results showed that 51% of participants reported always using condoms, 35% used condoms most times, and 14% used condoms occasionally/never. Condom use varied by partner type and was typically higher with casual partners in comparison to regular partners. After adjustment for age and marital status, factors associated with lower condom use included excessive alcohol use, perception that using condoms reduce sexual pleasure, and having a trusted partner. However, higher levels of HIV knowledge and reports of being circumcised were protective against lower condom use. HIV interventions aimed at increasing condom use in the BDF should address condom perceptions, alcohol abuse, and issues of trust. Innovative ways to increase condom use in this population should also be explored.
doi:10.1177/0956462413486889
PMCID: PMC3989099  PMID: 23970609
HIV/AIDS; military populations; sexual behaviors; condom use

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