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1.  Increased Frequency of α-Synuclein in the Substantia Nigra in HIV Infection 
Journal of neurovirology  2009;15(2):131-138.
The frequency of neurodegenerative markers among long surviving HIV infected individuals is unknown, therefore, the present study investigated the frequency of α-synuclein, β-amyloid and HIV-associated brain pathology in the brains of older HIV infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. The brain regions were examined for the presence of α-synuclein, β-amyloid and HIV-associated brain pathology. Neuritic α-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+ cases and none of the older control cases (0/18). β-amyloid deposits were prevalent and found in nearly all of the HIV+ cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+ adults HIV-associated brain pathology does not appear elevated; however, the frequency of both α-synuclein and β-amyloid is higher than that found in older healthy persons. The increased prevalence of α-synuclein and β-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease.
doi:10.1080/13550280802578075
PMCID: PMC3979854  PMID: 19115126
HIV; Brain Pathology; Aging; Substantia Nigra; Cognition
2.  Prospective Memory and Antiretroviral Medication Non-Adherence in HIV: An Analysis of Ongoing Task Delay Length Using the Memory for Intentions Screening Test 
Using McDaniel & Einstein’s (2000) multi-process framework, the current study examined whether the length of prospective memory (PM) delay intervals as measured by the 2- and 15- minute subscales of the Memory for Intentions Screening Test (MIST) have differential predictive value for antiretroviral (ARV) adherence. Participants included 74 HIV-infected individuals whose ARV adherence was tracked with an electronic monitoring system. Participants were classified as “adherent” (n = 49) or “non-adherent” (n = 25) based on recorded pill bottle openings of ≥90% of prescribed doses over 30 days. An adherence group by MIST delay interval interaction was observed, such that non-adherent participants had worse performance on the 15-min, but not 2-min delay PM MIST subscales. The observed MIST 15- min delay effects were significantly more pronounced on time- versus event-cued PM trials. Long-delay time-based PM was predictive of non-adherence independent of demographics, mood state, self-reported adherence, and general cognitive functioning. Findings from this clinical study indicate that ARV non-adherence may be particularly associated with deficits in strategic cue monitoring over longer PM delays, which may inform interventions to improve adherence among persons living with HIV infection.
doi:10.1017/S1355617712001051
PMCID: PMC3693472  PMID: 23095304
episodic memory; medication adherence; everyday functioning; neuropsychological assessment; executive functions; AIDS dementia complex
3.  Substance Use is a Risk Factor for Neurocognitive Deficits and Neuropsychiatric Distress in Acute and Early HIV Infection 
Journal of neurovirology  2012;19(1):65-74.
The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naïve adults with median duration of infection of 75 days, relative to sample a of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States (POMS), a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly five-fold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.
doi:10.1007/s13365-012-0141-y
PMCID: PMC3568179  PMID: 23250704
HIV; substance abuse; viral load; neuropsychiatry; AIDS dementia complex
4.  The Disruptive Effects of Pain on Complex Cognitive Performance and Executive Control 
PLoS ONE  2013;8(12):e83272.
Pain interferes and disrupts attention. What is less clear is how pain affects performance on complex tasks, and the strategies used to ensure optimal outcomes. The aim of the current study was to examine the effect of pain on higher-order executive control processes involved in managing complex tasks. Sixty-two adult volunteers (40 female) completed two computer-based tasks: a breakfast making task and a word generation puzzle. Both were complex, involving executive control functions, including goal-directed planning and switching. Half of those recruited performed the tasks under conditions of thermal heat pain, and half with no accompanying pain. Whilst pain did not affect central performance on either task, it did have indirect effects. For the breakfast task, pain resulted in a decreased ability to multitask, with performance decrements found on the secondary task. However, no effects of pain were found on the processes thought to underpin this task. For the word generation puzzle, pain did not affect task performance, but did alter subjective accounts of the processes used to complete the task; pain affected the perceived allocation of time to the task, as well as switching perceptions. Sex differences were also found. When studying higher-order cognitive processes, pain-related interference effects are varied, and may result in subtle or indirect changes in cognition.
doi:10.1371/journal.pone.0083272
PMCID: PMC3875458  PMID: 24386168
5.  Morphological Characterization of Mycobacterium tuberculosis in a MODS Culture for an Automatic Diagnostics through Pattern Recognition 
PLoS ONE  2013;8(12):e82809.
Tuberculosis control efforts are hampered by a mismatch in diagnostic technology: modern optimal diagnostic tests are least available in poor areas where they are needed most. Lack of adequate early diagnostics and MDR detection is a critical problem in control efforts.
The Microscopic Observation Drug Susceptibility (MODS) assay uses visual recognition of cording patterns from Mycobacterium tuberculosis (MTB) to diagnose tuberculosis infection and drug susceptibility directly from a sputum sample in 7–10 days with a low cost.
An important limitation that laboratories in the developing world face in MODS implementation is the presence of permanent technical staff with expertise in reading MODS.
We developed a pattern recognition algorithm to automatically interpret MODS results from digital images. The algorithm using image processing, feature extraction and pattern recognition determined geometrical and illumination features used in an object-model and a photo-model to classify TB-positive images. 765 MODS digital photos were processed. The single-object model identified MTB (96.9% sensitivity and 96.3% specificity) and was able to discriminate non-tuberculous mycobacteria with a high specificity (97.1% M. avium, 99.1% M. chelonae, and 93.8% M. kansasii). The photo model identified TB-positive samples with 99.1% sensitivity and 99.7% specificity.
This algorithm is a valuable tool that will enable automatic remote diagnosis using Internet or cellphone telephony. The use of this algorithm and its further implementation in a telediagnostics platform will contribute to both faster TB detection and MDR TB determination leading to an earlier initiation of appropriate treatment.
doi:10.1371/journal.pone.0082809
PMCID: PMC3865090  PMID: 24358227
6.  Methamphetamine use and neuropsychiatric factors are associated with antiretroviral nonadherence 
AIDS care  2012;24(12):1504-1513.
The present study assesses the impact of methamphetamine (METH) on antiretroviral (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors (i.e., major depressive disorder (MDD), Antisocial Personality Disorder (ASPD), and Attention Deficit Disorder (ADHD)) for ART nonadherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+/METH+; n = 67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+/METH−; n = 50). Ancillary analyses compared these groups with a small group of HIV+/METH+ persons with current METH abuse/dependence (HIV+/CU METH+; n = 8). Nonadherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH− participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART nonadherence (p’s<0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART nonadherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of nonadherence) than lifetime METH+ users and HIV+/METH-participants, and that neurocognitive impairment was associated with nonadherence (p’s<0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication nonadherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking.
doi:10.1080/09540121.2012.672718
PMCID: PMC3466384  PMID: 22530794
HIV/AIDS; Cognition; Medication Adherence; Antiretroviral; Methamphetamine
7.  Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers 
AIDS (London, England)  2012;26(18):2327-2335.
Objective
The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer’s disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition.
Design
Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium.
Methods
We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥ 50 years], Aβ plaques, and their two-way interactions) and co-morbid factors.
Results
Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89–35.76 and 1.91–17.48], P=0.0003 and 0.0019, respectively, n=96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41–638.63], P=0.029, n=15), but not in non-ε4 carriers (n=57).
Conclusion
The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies.
doi:10.1097/QAD.0b013e32835a117c
PMCID: PMC3576852  PMID: 23018443
Apolipoprotein E; β-amyloid; HIV dementia; neurofibrillary pathology; phospho-Tau
8.  HIV-infected individuals with co-occurring bipolar disorder evidence poor antiretroviral and psychiatric medication adherence 
AIDS and behavior  2012;16(8):2257-2266.
The contribution of bipolar disorder (BD), a prevalent serious mental illness characterized by impulsivity and mood instability, to antiretroviral (ART) and psychiatric medication adherence among HIV-infected (HIV+) individuals is unknown. We examined medication adherence among 44 HIV+/BD+ persons as compared to 33 demographically- and medically-comparable HIV+/BD− persons. Classification of adherent (≥90%) or non-adherent (<90%) based on proportion of correctly taken doses over 30 days was determined using electronic medication monitoring devices. HIV+/BD+ persons were significantly less likely to be ART adherent (47.7%) as compared to HIV+/BD− (90.9%) persons. Within the HIV+/BD+ group, mean psychiatric medication adherence was significantly worse than ART medication adherence, although there was a significant correlation between ART and psychiatric adherence levels. Importantly, 30-day ART adherence was associated with plasma virologic response among HIV+/BD+ individuals. Given the high overlap of HIV and BD, and the observed medication adherence difficulties for these persons, specialized adherence improvement interventions are needed.
doi:10.1007/s10461-011-0072-2
PMCID: PMC3351543  PMID: 22041931
Medication Adherence; HIV/AIDS; Bipolar Disorder
9.  Correction: Genetic Diversity and Transmission Characteristics of Beijing Family Strains of Mycobacterium tuberculosis in Peru 
PLoS ONE  2013;8(9):10.1371/annotation/a38090da-2437-4af0-b84a-0bb5de59805f.
doi:10.1371/annotation/a38090da-2437-4af0-b84a-0bb5de59805f
PMCID: PMC3763987  PMID: 24039672
10.  Preliminary Evidence for Feasibility, Use, and Acceptability of Individualized Texting for Adherence Building for Antiretroviral Adherence and Substance Use Assessment among HIV-Infected Methamphetamine Users 
AIDS Research and Treatment  2013;2013:585143.
The feasibility, use, and acceptability of text messages to track methamphetamine use and promote antiretroviral treatment (ART) adherence among HIV-infected methamphetamine users was examined. From an ongoing randomized controlled trial, 30-day text response rates of participants assigned to the intervention (individualized texting for adherence building (iTAB), n = 20) were compared to those in the active comparison condition (n = 9). Both groups received daily texts assessing methamphetamine use, and the iTAB group additionally received personalized daily ART adherence reminder texts. Response rate for methamphetamine use texts was 72.9% with methamphetamine use endorsed 14.7% of the time. Text-derived methamphetamine use data was correlated with data from a structured substance use interview covering the same time period (P < 0.05). The iTAB group responded to 69.0% of adherence reminder texts; among those responses, 81.8% endorsed taking ART medication. Standardized feedback questionnaire responses indicated little difficulty with the texts, satisfaction with the study, and beliefs that future text-based interventions would be helpful. Moreover, most participants believed the intervention reduced methamphetamine use and improved adherence. Qualitative feedback regarding the intervention was positive. Future studies will refine and improve iTAB for optimal acceptability and efficacy. This trial is registered with ClinicalTrials.gov NCT01317277.
doi:10.1155/2013/585143
PMCID: PMC3776360  PMID: 24078868
11.  Antioxidant Sestrin-2 Redistribution to Neuronal Soma in Human Immunodeficiency Virus-Associated Neurocognitive Disorders 
Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1-infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer's disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronalsoma predominance (S; P < 0.0001, Chi-square test for linear trend). Among HIV cases showing the NS or S pattern, HAND cases were preferentially associated with the S pattern (n = 10 of 20) compared to cognitively intact cases (n = 1 of 11; P = 0.047, Fisher's exact test). In AD brains, sestrin-2 immunoreactivity was mostly intense in the neuropil and co-localized with phospho-Tau immunoreactivity in a subset of neurofibrillary lesions. Phospho-Tau-immunoreactive neurofibrillary lesions were rare in HIV cases and their occurrence was not associated with HAND. Levels of isocortical 8-hydroxy-deoxyguanosine (marker of nucleic acid oxidation) immunoreactivity were not significantly altered in HAND cases compared to cognitively intact HIV cases. In conclusion, the sestrin-2 immunoreactivity redistribution to neuronal soma in HAND suggests unique involvement of sestrin-2 in the pathophysiology of HAND, which is different from the role of sestrin-2 in AD pathogenesis. Alternatively, the difference in sestrin-2 immunoreactivity distribution between HAND and AD may be related to different degrees of severity or stages of oxidative stress.
doi:10.1007/s11481-012-9357-0
PMCID: PMC3573843  PMID: 22450766
Alzheimer's disease; HIV dementia; Neurofibrillary pathology; Oxidative stress; SESN2
12.  The Functional Impact of HIV-Associated Neuropsychological Impairment in Spanish-Speaking Adults: A Pilot Study 
Among English-speaking adults, HIV-associated neuropsychological (NP) impairments have been associated with problems in everyday functioning, including ability to function at work and drive an automobile. Latinos account for a disproportionate number of HIV/AIDS cases nationwide, and a significant segment of this population is primarily Spanish speaking. We have previously developed an assessment that evaluates English-speakers on a variety of instrumental activities of daily living. In this pilot study, we used Spanish-language translations of our functional battery to investigate the cultural relevance of such measures, and to explore relationships between NP status and ability to perform important everyday tasks in HIV-infected Spanish-speakers. Sixteen HIV-infected monolingual Spanish-speaking adults received comprehensive, Spanish language NP testing and functional assessments included the following domains: Medication Management, Cooking, Finances, Shopping, and Restaurant Scenario. Results revealed that most of the functional tasks appeared culturally relevant and appropriate with minor modifications. NP-impaired participants were significantly more functionally impaired compared to NP-normals (88% vs. 13%, p<.01). Performances on the functional assessment and the NP battery were also related to indicators of real world functioning, including employment status and quality of life. These results, though preliminary, suggest that Spanish language functional assessments are potentially valid tools for detecting everyday functioning deficits associated with NP impairments in HIV-infected Spanish-speakers.
doi:10.1076/jcen.25.1.122.13634
PMCID: PMC3737066  PMID: 12607177
13.  Neurocognitive deficits are associated with unemployment in chronic methamphetamine users 
Drug and alcohol dependence  2012;125(0):146-153.
Background
Unemployment rates are high among chronic methamphetamine (MA) users and carry a significant economic burden, yet little is known about the neurocognitive and psychiatric predictors of employment in this vulnerable population.
Methods
The present study examined this issue in 63 participants with recent MA dependence and 47 comparison subjects without histories of MA use disorders. All participants completed a comprehensive neurocognitive, psychiatric and neuromedical evaluation. Individuals with HIV infection, severe neuropsychological or psychiatric conditions that might affect cognition (e.g., seizure disorder, schizophrenia), or a positive Breathalyzer or urine toxicology screen on the day of testing were excluded.
Results
Consistent with previous research, a logistic regression revealed MA dependence as a significant, independent predictor of full-time unemployment status. Within the MA-dependent sample, greater impairment in global neurocognitive functioning and history of injection drug use emerged as significant independent predictors of unemployment status. The association between worse global cognitive functioning and unemployment was primarily driven by deficits in executive functions, learning, verbal fluency, and working memory.
Conclusion
These findings indicate that neurocognitive deficits play a significant role in the higher unemployment rates of MA-dependent individuals, and highlight the need for vocational rehabilitation and supported employment programs that assess and bolster cognitive skills in this population.
doi:10.1016/j.drugalcdep.2012.04.002
PMCID: PMC3735422  PMID: 22560676
Functional status; Substance abuse; Cognitive impairment; Neuropsychological assessment; Employment
14.  Increased cortical expression of FK506 binding protein-51 in HIV-associated neurocognitive disorders 
Journal of Neurovirology  2012;18(4):313-322.
FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p<0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p=0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p=0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.
doi:10.1007/s13365-011-0076-8
PMCID: PMC3374917  PMID: 22234543
FKBP4; FKBP5; HIV dementia; Immunophilin; NR3C1
15.  HIV-infected persons with bipolar disorder are less aware of memory deficits as compared to HIV-infected persons without bipolar disorder 
Episodic memory deficits are common in HIV infection and bipolar disorder, but patient insight into such deficits remains unclear. Thirty-four HIV-infected individuals without bipolar disorder l(HIV+/BD−) and 47 HIV+ individuals with comorbid bipolar disorder (HIV+/BD+) were administered the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised to examine objective learning/memory functioning. Subjective memory complaints were assessed via the memory subscale of the Patient’s Assessment of Own Functioning Inventory. HIV+/BD+ individuals performed poorer on tests of visual learning and visual/verbal recall compared to HIV+/BD− participants (ps<0.05). Memory complaints only predicted verbal learning (at a trend level, p=0.10) and recall (p=0.03) among the HIV+/BD− individuals. Memory complaints were not associated with memory performance within the HIV+/BD+ group (ps>0.10). Memory complaints were associated with affective symptoms in both groups. These complaints were also predictive of immunosuppression, higher unemployment, and greater dependence on Activities of Daily Living among the HIV+/BD+ individuals (ps<0.05). Awareness of memory abilities was particularly poor among HIV+/BD+ individuals (i.e., objective learning/memory did not correspond to reported complaints), which has important implications for the capacity of these individuals to engage in error-monitoring and compensatory strategies in daily life. Memory complaints are associated with depressed mood regardless of group membership. Among HIV+/BD+ individuals, these complaints may also signify worse HIV disease status and problems with everyday functioning. Clinicians and researchers should be cognizant of what these complaints indicate in order to lead treatment most effectively; use of objective neurocognitive assessments may still be warranted when working with these populations.
doi:10.1080/13803395.2012.682974
PMCID: PMC3718038  PMID: 22571839
Self report; Infectious Diseases; Affective Disorders; Episodic Memory; Cognition
16.  Alternative Methods of Diagnosing Drug Resistance—What Can They Do for Me? 
The Journal of Infectious Diseases  2011;204(Suppl 4):S1110-S1119.
During the last decade considerable attention has been focussed upon the development of new technologies and methodologies for detection of drug resistance in Mycobacterium tuberculosis. There is a growing acknowledgement that the redundancy in testing a full panel of first-line drugs is an unaffordable indulgence; since only resistance at baseline to either (or both) of the two most potent agents, isoniazid (H) and rifampicin (R), would usually prompt therapeutic modification there is a shift towards initial RH (or R alone for selected genotypic technologies) drug susceptibility testing (DST) followed, if necessary by further extended first and second line agent (currently phenotypic) DST. Most of the new drug susceptibility tests endorsed by the World Health Organization since 2007 deliver rapid RH (or R alone for selected genotypic technologies) DST. Targeting of patient groups with risk factors for drug resistance increases the proportion of tests that identify drug resistance, but in many settings at least as many patients with drug resistant disease will have no identifiable risk factors—equity of care demands that universal RH DST at baseline should be the goal. We review the bewildering array of choices facing TB program directors and attempt to provide objective information to help in deciding what tools may be best suited to different environments.
doi:10.1093/infdis/jir448
PMCID: PMC3192546  PMID: 21996693
17.  Prevalence and Factors Associated With Sleep Disturbances Among Early-Treated HIV-Infected Persons 
Persons infected with human immunodeficiency virus (HIV) have a high prevalence of insomnia (46%) and daytime drowsiness (30%). Factors associated with insomnia among patients with HIV infection include depression and increased waist size. Screening for sleep disturbances should be considered among HIV-infected persons.
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
doi:10.1093/cid/cis192
PMCID: PMC3334363  PMID: 22431801
18.  Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons 
Neurology  2013;80(4):371-379.
Objective:
To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls.
Methods:
We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV−) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm3) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests.
Results:
HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm3, and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm3). NCI was diagnosed among 38 (19%, 95% confidence interval 14%–25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV− patients.
Conclusions:
HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.
doi:10.1212/WNL.0b013e31827f0776
PMCID: PMC3589242  PMID: 23303852
19.  Sustained Attention Deficits Among HIV-Positive Individuals With Comorbid Bipolar Disorder 
Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD−), using the Conners’ Continuous Performance Test–II (CPT–II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT–II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD− participants. When examining CPT–II performance over the six study blocks, both HIV+/BD+ and HIV+/BD− participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT–II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD− participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT–II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes.
doi:10.1176/appi.neuropsych.11010028
PMCID: PMC3575087  PMID: 22450615
20.  Exercise-induced vasodilation is associated with menopause stage in healthy middle-aged women 
Leg exercise hemodynamics during single-leg knee extensions were compared among healthy groups of early perimenopausal (n = 15), late perimenopausal (n = 12), and early postmenopausal (n = 11) women. Femoral blood flow (FBF) and vascular conductance (FVC) at rest and during very light work rates (0 and 5 W) were similar among all three menopause stage groups. Vascular responses at 10 W (FBF) and 20 W (FBF and FVC) were significantly higher (P < 0.05) in early perimenopausal compared with late perimenopausal women. At 15 and 25 W, FBF and FVC were similar between late perimenopausal and early postmenopausal groups but higher (P < 0.05) in early perimenopausal women as compared with the other two menopausal groups. In the combined sample of all three menopause stage groups, follicle-stimulating hormone was significantly correlated with vascular conductance during submaximal (15 W) exercise (R = −0.56, P < 0.001), even after adjustment for age, fitness, LDL cholesterol, and abdominal fat (R = −0.46, P = 0.005). Collectively, these findings suggest that in middle-aged women, there is an association between menopause stage and leg vascular responsiveness during exercise.
doi:10.1139/h2012-015
PMCID: PMC3570043  PMID: 22486379
exercise hyperemia; menopause transition; reproductive hormones
21.  Lifetime Suicidal Ideation and Attempt is Common Among HIV+ Individuals 
Journal of Affective Disorders  2011;136(3):993-999.
Background
Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART).
Method
Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204).
Results
Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters.
Limitations
Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt.
Conclusions
High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggests that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.
doi:10.1016/j.jad.2011.06.044
PMCID: PMC3222733  PMID: 21784531
HIV; depression; suicide
22.  Identification of an Abbreviated Test Battery for Detection of HIV-Associated Neurocognitive Impairment in an Early-Managed HIV-Infected Cohort 
PLoS ONE  2012;7(11):e47310.
Background
HIV-associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral treatment (ART), and it is essential to have a sensitive and specific HAND screening tool.
Methods
Participants were 200 HIV-infected US military beneficiaries, managed early in the course of HIV infection, had few comorbidities, and had open access to ART. Participants completed a comprehensive, seven-domain (16-test), neuropsychological battery (∼120 min); neurocognitive impairment (NCI) was determined using a standardized score derived from demographically adjusted T-scores (global deficit score ≥0.5). Restricting the estimated administration time of the screening battery to < = 20 minutes, we examined the sensitivity and specificity of detecting NCI for all possible combinations of 2-, 3-, and 4- tests from the comprehensive battery.
Results
Participants were relatively healthy (median CD4 count: 546 cells/mm3) with 64% receiving ART. Prevalence of NCI was low (19%). The best 2-test screener included the Stroop Color Test and the Hopkins Verbal Learning Test-Revised (11 min; sensitivity = 73%; specificity = 83%); the best 3-test screener included the above measures plus the Paced Auditory Serial Addition Test (PASAT; 16 min; sensitivity = 86%; specificity = 75%). The addition of Action Fluency to the above three tests improved specificity (18 min; sensitivity = 86%; specificity = 87%).
Conclusions
Combinations of widely accepted neuropsychological tests with brief implementation time demonstrated good sensitivity and specificity compared to a time intensive neuropsychological test battery. Tests of verbal learning, attention/working memory, and processing speed are particularly useful in detecting NCI. Utilizing validated, easy to administer, traditional neuropsychological tests with established normative data may represent an excellent approach to screening for NCI in HIV.
doi:10.1371/journal.pone.0047310
PMCID: PMC3493574  PMID: 23144815
23.  Pharmacokinetics of Rifampin in Peruvian Tuberculosis Patients with and without Comorbid Diabetes or HIV 
For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (Cmax) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin Cmax was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P < 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different Cmax results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P < 0.001) and the time to maximum concentration of drug in serum (Tmax) at 2 h (P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.
doi:10.1128/AAC.06059-11
PMCID: PMC3346648  PMID: 22330931
24.  Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection 
Objective
Mild forms of HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of combination antiretroviral therapy (cART). Although elevated LPS and immune activation are implicated in HAND pathogenesis, relationships of LPS and inflammatory markers to mild forms of HAND or impairment in specific cognitive domains are unknown. To examine these relationships, we compared plasma soluble CD14 (sCD14), CCL2, and LPS levels to neurocognitive test scores in a cART era cohort.
Methods
We analyzed plasma from HIV+ subjects (n=97) with nadir CD4 counts <300 and high frequency of HCV co-infection and illicit drug use for relationships between sCD14, CCL2, and LPS levels and neurocognitive test scores.
Results
Plasma sCD14 levels were higher in subjects with test scores indicating global impairment (p=0.007), particularly in attention and learning domains (p=0.015 and p=0.03, respectively), regardless of HAND diagnosis. Plasma sCD14 levels correlated inversely with global, attention, and learning T scores (p=0.036, 0.047, and 0.007, respectively), and yielded higher AUROC values for predicting impaired scores than single-marker models based on plasma or CSF viral load or CD4 count (AUROC 0.71, 0.81, and 0.71, respectively), and in four-marker models based on plasma sCD14 and three conventional markers compared to the three-marker models.
Conclusions
Plasma sCD14 is a biomarker associated with impaired neurocognitive testing in attention and learning domains in HIV-infected individuals with advanced disease, suggesting involvement of cortical and limbic pathways by inflammatory processes in the cART era. Plasma sCD14 is a potential biomarker to monitor HAND progression and therapeutic responses.
doi:10.1097/QAI.0b013e3182237e54
PMCID: PMC3159710  PMID: 21646912
HIV; AIDS; HIV-associated neurocognitive disorders; HCV; biomarkers; drug abuse
25.  Demographically Corrected Norms for African Americans and Caucasians on the Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Stroop Color and Word Test, and Wisconsin Card Sorting Test 64-Card Version 
Memory and executive functioning are two important components of clinical neuropsychological (NP) practice and research. Multiple demographic factors are known to affect performance differentially on most NP tests, but adequate normative corrections, inclusive of race/ethnicity, are not available for many widely used instruments. This study compared demographic contributions for widely used tests of verbal and visual learning and memory (Brief Visual Memory Test-Revised, Hopkins Verbal Memory Test-Revised), and executive functioning (Stroop Color and Word Test, Wisconsin Card Sorting Test-64) in groups of healthy Caucasians (n = 143) and African-Americans (n = 103). Demographic factors of age, education, gender, and race/ethnicity were found to be significant factors on some indices of all four tests. The magnitude of demographic contributions (especially age) was greater for African-Americans than Caucasians on most measures. New, demographically corrected T-score formulas were calculated for each race/ethnicity. The rates of NP impairment using previously published normative standards significantly overestimated NP impairment in African-Americans. Utilizing the new demographic corrections developed and presented herein, NP impairment rates were comparable between the two race/ethnicities and unrelated to the other demographic characteristics (age, education, gender) in either race/ethnicity group. Findings support the need to consider extended demographic contributions to neuropsychological test performance in clinical and research settings.
doi:10.1080/13803395.2011.559157
PMCID: PMC3154384  PMID: 21547817

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