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1.  Prognosis and Risk Factors for Deterioration in Patients Admitted to a Medical Emergency Department 
PLoS ONE  2014;9(4):e94649.
Patients that initially appear stable on arrival to the hospital often have less intensive monitoring of their vital signs, possibly leading to excess mortality. The aim was to describe risk factors for deterioration in vital signs and the related prognosis among patients with normal vital signs at arrival to a medical emergency department (MED).
Design and setting
Single-centre, retrospective cohort study of all patients admitted to the MED from September 2010-August 2011.
Patients were included when their vital signs (systolic blood pressure, pulse rate, respiratory rate, Glasgow Coma Scale, oxygen saturation and temperature) were within the normal range at arrival. Deterioration was defined as a deviation from the defined normal range 2–24 hours after arrival.
4292 of the 6257 (68.6%) admitted to the MED had a full set of vital signs at first presentation, 1440/4292 (33.6%) had all normal vital signs and were included in study, 44.0% were male, median age 64 years (5th/95th percentile: 21–90 years) and 446/1440 (31.0%) deteriorated within 24 hours. Independent risk factors for deterioration included age 65–84 years odds ratio (OR): 1.79 (95% confidence interval [CI]: 1.27–2.52), 85+ years OR 1.67 (95% CI: 1.10–2.55), Do-not-attempt-to-resuscitate order OR 3.76 (95% CI: 1.37–10.31) and admission from the open general ED OR 1.35 (95% CI: 1.07–1.71). Thirty-day mortality was 7.9% (95% CI: 5.5–10.7%) among deteriorating patients and 1.9% (95% CI: 1.2–3.0%) among the non-deteriorating, hazard ratio 4.11 (95% CI: 2.38–7.10).
Among acutely admitted medical patients who arrive with normal vital signs, 31.0% showed signs of deterioration within 24 hours. Risk factors included old age, Do-not-attempt-to-resuscitate order, admission from the open general ED. Thirty-day mortality among patients with deterioration was four times higher than among non-deteriorating patients. Further research is needed to determine whether intensified monitoring of vital signs can help to prevent deterioration or mortality among medical emergency patients.
PMCID: PMC3981818  PMID: 24718637
2.  Trail Making Test A Improves Performance Characteristics of the International HIV-Dementia Scale to Identify Symptomatic HAND 
Journal of neurovirology  2013;19(2):137-143.
Although HIV-Associated Dementia (HAD) occurs in less than 5% of individuals with access to combination antiretroviral therapy (cART), rates of milder forms of HIV-Associated Neurocognitive Disorder (HAND) are much higher. We sought to define an optimal cut-point for the International HIV-Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and Mild Neurocognitive Disorder (MND). We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study 75 seropositive adults in Bangkok, Thailand, subjects completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut-point was determined by Receiver Operating Characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut-point of ≤10 (sensitivity: 53.3%, specificity: 89.8%). The Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86% and specificity of 79%. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than two minutes to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings.
PMCID: PMC3644005  PMID: 23483520
HIV Dementia; Neuropsychology; Asia; Neuropsychological Tests; Trail Making Test
3.  Populations at Risk for Severe or Complicated Avian Influenza H5N1: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(3):e89697.
Little is known about risk factors for severe outcomes in patients infected with H5N1 and no systematic review has been conducted. Understanding risk factors is an important step for prioritizing prophylaxis or treatment in the event of a pandemic.
To systematically evaluate risk factors for severe outcomes in patients with avian influenza H5N1 infection.
Data sources
MEDLINE, EMBASE, CINAHL, GlobalHealth, and CENTRAL through March 2011
Eligibility criteria for selecting studies
Observational studies of any design published in English, French, Spanish, German or Korean that reported on risk factor-outcome combinations of interest in participants with confirmed H5N1 infections. Outcomes considered included death, ventilator support, hospital and ICU admission, pneumonia, and composite outcomes.
Study appraisal
Risk of bias was assessed using the Newcastle-Ottawa scale (NOS).
We identified 20 studies reporting on 999 patients infected with H5N1. The majority of studies (n = 14, 70%) were at intermediate risk of bias, i.e. 4–6 points on the NOS. Females were at increased risk of death (OR 1.75, 95% CI 1.27–2.44), while young age, in particular <5 years of age (OR 0.44, 95% CI 0.25–0.79 for death), was protective. Data on traditional risk factors was scarce and requires further studies. Another major limitation in the published literature was lack of adjustment for confounders.
Females were at increased risk for complications following H5N1 infection while young age protected against severe outcomes. Research on traditional risk factors was limited and is required.
PMCID: PMC3948335  PMID: 24603885
4.  The Alzheimer Disease-8 and Montreal Cognitive Assessment as Screening Tools for Neurocognitive Impairment in HIV-Infected Persons 
Journal of neurovirology  2013;19(1):109-116.
The diagnosis of HIV-associated neurocognitive impairment is time-intensive and often omitted in busy outpatient settings. Brief screening tools are needed. The Montreal Cognitive Assessment (MoCA) and the Alzheimer’s disease (AD)-8 have been used in neurodegenerative disorders. We evaluated the sensitivity and specificity of these brief screening tools in HIV-infected persons. The AD-8, MoCA, and formal neuropsychological testing were administered to 200 HIV-infected patients followed at a single institution. Normalized scores on formal neuropsychological testing were used to define neurocognitive impairment. The sensitivity and specificity of the MoCA and AD-8 were assessed to diagnose impairment. Neurocognitive impairment was highly prevalent in this cohort: 127 persons (64%) were diagnosed with neurocognitive impairment based on formal testing. Using the AD-8 and MoCA, 113 (57%) and 101 (51%) persons were identified with neurocognitive impairment, respectively. The sensitivity and specificity of MoCA were 63% and 71%, respectively. The sensitivity and specificity of AD-8 were 61% and 51%, respectively. Our findings highlight that brief screening tools correlate with formal neuropsychological testing. However, the sensitivities of these screening tools are lower than desired. Nevertheless, given their ease in administration, these tools could assist as a first line for identifying individuals who may subsequently require formal neuropsychological testing.
PMCID: PMC3655767  PMID: 23345074
HIV; Neurocognitive Disorder; MoCA; AD-8; Neuropsychological Testing; Cognition
6.  Development of normative neuropsychological performance in Thailand for the assessment of HIV-associated neurocognitive disorders 
International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male=211, female=266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20–34; 35–49; 50–65) and four educational levels (no education or primary education, less than secondary certificate, high school/associates degree, Bachelor’s degree or greater). The Thai cohort was compared (using ANCOVA) on a number of measures to a seronegative US cohort (n=236; male=198 female=38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p<0.001) and memory (p<0.001), and measures of psychomotor speed (p<0.001). Education was a more powerful predictor of performance in the Thai cohort compared to the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups.
PMCID: PMC3682786  PMID: 23113809
7.  Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial 
The Lancet infectious diseases  2012;12(12):933-941.
The optimum time to start antiretroviral therapy for children diagnosed with HIV infection after 1 year of age is unknown. We assessed whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15% without affecting AIDS-free survival.
In our multicentre, randomised, open-label trial at nine research sites in Thailand and Cambodia, we enrolled children aged 1–12 years who were infected with HIV and had CD4 percentages of 15–24%. Participants were randomly assigned (1:1) by a minimisation scheme to start antiretroviral therapy at study entry (early treatment group) or antiretroviral therapy to start when CD4 percentages declined to less than 15% (deferred treatment group). The primary endpoint was AIDS-free survival (based on US Centers for Disease Control and Prevention category C events) at week 144, assessed with the Kaplan-Meier analysis and the log-rank approach. This study is registered with, number NCT00234091.
Between March 28, 2006, and Sept 10, 2008, we enrolled 300 Thai and Cambodian children infected with HIV, with a median age of 6·4 years (IQR 3·9–8·4). 150 children were randomly allocated early antiretroviral therapy (one participant was excluded from analyses after withdrawing before week 0) and 150 children were randomly allocated deferred antiretroviral therapy. Median baseline CD4 percentage was 19% (16–22%). 69 children (46%) in the deferred treatment group started antiretroviral therapy during the study. AIDS-free survival at week 144 in the deferred treatment group was 98·7% (95% CI 94·7–99·7; 148 of 150 patients) compared with 97·9% (93·7–99·3; 146 of 149 patients) in the early treatment group (p=0·6).
AIDS-free survival in both treatment groups was high. This low event rate meant that our study was underpowered to detect differences between treatment start times and thus additional follow-up of study participants or future studies are needed to answer this clinical question.
US National Institutes of Health, Division of AIDS; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; and National Institute of Mental Health.
PMCID: PMC3541427  PMID: 23059199
8.  Reducing shame in a game that predicts HIV risk reduction for young adult men who have sex with men: a randomized trial delivered nationally over the web 
Journal of the International AIDS Society  2013;16(3Suppl 2):18716.
Men who have sex with men (MSM) often face socially sanctioned disapproval of sexual deviance from the heterosexual “normal.” Such sexual stigma can be internalized producing a painful affective state (i.e., shame). Although shame (e.g., addiction) can predict risk-taking (e.g., alcohol abuse), sexual shame's link to sexual risk-taking is unclear. Socially Optimized Learning in Virtual Environments (SOLVE) was designed to reduce MSM's sexual shame, but whether it does so, and if that reduction predicts HIV risk reduction, is unclear. To test if at baseline, MSM's reported past unprotected anal intercourse (UAI) is related to shame; MSM's exposure to SOLVE compared to a wait-list control (WLC) condition reduces MSM's shame; and shame-reduction mediates the link between WLC condition and UAI risk reduction.
HIV-negative, self-identified African American, Latino or White MSM, aged 18–24 years, who had had UAI with a non-primary/casual partner in the past three months were recruited for a national online study. Eligible MSM were computer randomized to either WLC or a web-delivered SOLVE. Retained MSM completed baseline measures (e.g., UAI in the past three months; current level of shame) and, in the SOLVE group, viewed at least one level of the game. At the end of the first session, shame was measured again. MSM completed follow-up UAI measures three months later. All data from 921 retained MSM (WLC condition, 484; SOLVE condition, 437) were analyzed, with missing data multiply imputed.
At baseline, MSM reporting more risky sexual behaviour reported more shame (r s=0.21; p<0.001). MSM in the SOLVE intervention reported more shame reduction (M=−0.08) than MSM in the control condition (M=0.07; t(919)=4.24; p<0.001). As predicted, the indirect effect was significant (point estimate −0.10, 95% bias-corrected CI [−0.01 to −0.23] such that participants in the SOLVE treatment condition reported greater reductions in shame, which in turn predicted reductions in risky sexual behaviour at follow-up. The direct effect, however, was not significant.
SOLVE is the first intervention to: (1) significantly reduce shame for MSM; and (2) demonstrate that shame-reduction, due to an intervention, is predictive of risk (UAI) reduction over time.
PMCID: PMC3833191  PMID: 24242264
stigma; shame; intervention; serious games; SOLVE; HIV; AIDS; sexual risk-taking; men who have sex with men (MSM)
9.  A rare presentation of spinal epidural abscess 
BMJ Case Reports  2011;2011:bcr0820114647.
A 77-year-old retired engineer presented to accident and emergency with deteriorating shortness of breath that had been troubling him for several months. At that time, he was being investigated by a chest physician who had identified bilateral diaphragmatic paralysis on ultrasound and was awaiting further imaging. Clinical assessment and nerve conduction studies on this admission were compatible with a diagnosis of motor neuron disease but specialist neurology input recommended an MRI to rule out cord pathology. This proved problematic as the patient was non-invasive ventilation dependent and unable to lay supine as this further compromised his respiratory function. To ensure that a potentially reversible cause for his symptoms was identified, the patient was intubated for an MRI which subsequently demonstrated multi level spinal epidural empyema. The benefits of neurosurgical intervention were judged to be uncertain at best, and following discussion with the family, active care was withdrawn. The patient passed away shortly thereafter.
PMCID: PMC3207783  PMID: 22675058
10.  Reduced memory in fat mass and obesity-associated allele carriers among older adults with cardiovascular disease 
Much attention has been paid to the prevalence and predisposition of the fat mass and obesity-associated (FTO) gene to obesity, although only a few studies have characterized the extent to which this affects cognitive function. This study examined differences between risk allele carriers (i.e. FTO-AC/AA) and non-carriers (i.e. FTO-CC) on indices of attention/executive function/psychomotor speed, memory, language, and visual-spatial ability in a sample of older patients with cardiovascular disease.
We recruited 120 older adults from an outpatient cardiology clinic who underwent blood draw and completed neuropsychological testing. Participants were classified into two groups: one for those who were homozygous for the non-risk-conferring allele (i.e. FTO-CC) (n = 49) and the other for those who had at least one copy of the obesity risk-conferring A allele (i.e. FTO-AC/AA) (n = 71).
Mancova analyses adjusting for age and years of education revealed the FTO-AC/AA group performed significantly worse on indices of memory (λ = 0.94, F(2, 115) = 3.58, P = 0.03, partial η2 = 0.06). Follow-up tests revealed a significant effect for the FTO-AC/AA group, relative to the non-carrier group, on encoding (i.e. California Verbal Learning Test Total Learning) and California Verbal Learning Test long-delay free recall (P < 0.05). No such differences between FTO carriers and non-carriers emerged on tests of attention/executive function/psychomotor speed, language, or visual-spatial ability (P > 0.05 for all).
These findings suggest that the FTO risk allele is associated with reduced memory performance, particularly on aspects of memory encoding and delayed recall. To elucidate underlying mechanisms, these findings will need to be replicated in larger samples that utilize neuroimaging.
PMCID: PMC3806216  PMID: 23551410
cardiovascular disease; cognitive function; FTO risk allele; memory; obesity
11.  Early Exposure to Traumatic Stressors Impairs Emotional Brain Circuitry 
PLoS ONE  2013;8(9):e75524.
Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder.
PMCID: PMC3779182  PMID: 24073270
12.  Cyclic Peptide Inhibitors of the β-Sliding Clamp in Staphylococcus aureus 
PLoS ONE  2013;8(9):e72273.
Interaction between pairs of Staphylococcus aureus replication proteins was detected in an Escherichia coli based two-hybrid analysis. A reverse two-hybrid system was constructed for selection of compounds that hindered interaction between interacting protein pairs. A number of cyclic peptides, from a library generated by the split intein-mediated circular ligation of peptides and proteins technology, were found to interfere with dimerization of the β-sliding clamp of the replisome. Two 8-mer peptides were analyzed in more detail. Both inhibited DNA replication, led to SOS induction, altered cell morphology and cell death. The peptides were active when added to bacterial cultures indicating that they could traverse the bacterial membrane to find their intracellular target. Peptide specificity was confirmed by overproduction of the putative target (DnaN) which resulted in resistance. The minimum inhibitory concentration was ∼50 μg/ml for S. aureus cells. These compounds may serve as lead candidates for future development into novel classes of antibiotics as well as provide information on the function of the S. aureus replication process.
PMCID: PMC3762901  PMID: 24023733
13.  Correlation between centromere protein-F autoantibodies and cancer analyzed by enzyme-linked immunosorbent assay 
Molecular Cancer  2013;12:95.
Centromere protein-F (CENP-F) is a large nuclear protein of 367 kDa, which is involved in multiple mitosis-related events such as proper assembly of the kinetochores, stabilization of heterochromatin, chromosome alignment and mitotic checkpoint signaling. Several studies have shown a correlation between CENP-F and cancer, e.g. the expression of CENP-F has been described to be upregulated in cancer cells. Furthermore, several studies have described a significant correlation between the expression of autoantibodies to CENP-F and cancer.
Autoantibodies to CENP-F were detected in a small number of samples during routine indirect immunofluorescence (IIF) analysis for anti-nuclear antibodies (ANA) using HEp-2 cells as substrate. Using overlapping synthetic peptides covering a predicted structural maintenance of chromosomes (SMC) domain, we developed an enzyme-linked immunosorbent assay (ELISA) for detection of CENP-F antibodies.
Analyzing the reactivity of the sera positive in IIF for CENP-F antibodies to overlapping CENP-F peptides, we showed that autoantibodies to several peptides correlate with the presence of antibodies to CENP-F and a diagnosis of cancer, as increased CENP-F antibody expression specific for malignant cancer patients to five peptides was found (A9, A12, A14, A16, A27). These antibodies to CENP-F in clinical samples submitted for ANA analysis were found to have a positive predictive value for cancer of 50%. Furthermore, the expression of cancer-correlated CENP-F antibodies seemed to increase as a function of time from diagnosis.
These results conform to previous findings that approximately 50% of those patients clinically tested for ANA analyses who express CENP-F antibodies are diagnosed with cancer, confirming that these antibodies may function as circulating tumor markers. Thus, a peptide-based CENP-F ELISA focused on the SMC domain may aid in identifying individuals with a potential cancer.
PMCID: PMC3844405  PMID: 23978088
Centromere protein-F; Autoantibodies; Immunofluorescence; ELISA; Cancer
14.  Cerebrovascular risk factors and brain microstructural abnormalities on diffusion tensor images in HIV-infected individuals 
Journal of neurovirology  2012;18(4):303-312.
HIV-associated neurocognitive disorder remains prevalent in HIV-infected individuals despite effective antiretroviral therapy. As these individuals age, comorbid cerebrovascular disease will likely impact cognitive function. Effective tools to study this impact are needed. This study used diffusion tensor imaging (DTI) to characterize brain microstructural changes in HIV-infected individuals with and without cerebrovascular risk factors. Diffusion-weighted MRIs were obtained in 22 HIV-infected subjects aged 50 years or older (mean age = 58 years, standard deviation = 6 years; 19 males, three females). Tensors were calculated to obtain fractional anisotropy (FA) and mean diffusivity (MD) maps. Statistical comparisons accounting for multiple comparisons were made between groups with and without cerebrovascular risk factors. Abnormal glucose metabolism (i.e., impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) was associated with significantly higher MD (false discovery rate (FDR) critical p value = 0.008) and lower FA FDR critical p value = 0.002) in the caudate and lower FA in the hippocampus (FDR critical p value = 0.004). Pearson correlations were performed between DTI measures in the caudate and hippocampus and age- and education-adjusted composite scores of global cognitive function, memory, and psychomotor speed. There were no detectable correlations between the neuroimaging measures and measures of cognition. In summary, we demonstrate that brain microstructural abnormalities are associated with abnormal glucose metabolism in the caudate and hippocampus of HIV-infected individuals. Deep gray matter structures and the hippocampus may be vulnerable in subjects with comorbid abnormal glucose metabolism, but our results should be confirmed in further studies.
PMCID: PMC3420956  PMID: 22585287
HIV; Cerebrovascular disease; Diffusion tensor imaging
15.  HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Naïve Patients 
PLoS ONE  2013;8(7):e70164.
Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury.
We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF).
The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions.
Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS.
PMCID: PMC3729685  PMID: 23936155
16.  Neuroimaging markers of Human Immunodeficiency Virus infection in South Africa 
Journal of neurovirology  2012;18(3):151-156.
Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV− controls from South Africa. Volumetric measures were obtained from six regions of interest--caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<.01), thalamus (p<.01) and total gray matter (inclusive of cortical and subcortical regions, p<.01). The current study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV Clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with ARVs are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.
PMCID: PMC3715135  PMID: 22528474
17.  Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV 
Antiviral therapy  2012;17(7):1233-1242.
Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir.
Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment.
Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r2=0.12), ME score (β=0.003, P=0.02), CD4+ T-cell nadir (β=0.001, P<0.01) and gender (β=−0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5–433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01).
ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.
PMCID: PMC3715550  PMID: 23018140
18.  Global NeuroAIDS Roundtable 
Journal of neurovirology  2013;19(1):1-9.
In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the “Global NeuroAIDS Roundtable” in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the “Global NeuroAIDS Roundtable”, presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.
PMCID: PMC3713197  PMID: 23354550
Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2); Acquired immunodeficiency syndrome (AIDS); HIV clade; NeuroAIDS; HIV-associated neurocognitive disorders (HAND); Neuropathogenesis
19.  Cognitive Function in Morbidly Obese Individuals With and Without Binge Eating Disorder 
Comprehensive Psychiatry  2011;53(5):490-495.
Obesity is associated with poorer cognitive function and impulsivity, which may contribute to binge eating disorder (BED). The objective of this study was to compare cognitive function in morbidly obese individuals with and without BED.
A total of 131 morbidly obese individuals (41 with past or present BED, 90 with no BED history) completed a computerized battery of cognitive tests including executive, memory, language, and attention.
Both groups of participants evidenced high rates of cognitive impairment, however, no significant differences emerged between persons with and without BED on cognitive testing. Comparison of persons without BED, current BED, and past BED also yielded no differences.
In the present sample, morbidly obese individuals with and without BED were clinically indistinguishable on tests of cognitive function. Our findings suggest that obesity, rather than binge eating, may be more directly related to cognition. Future studies should further examine this relationship, as it might provide greater insight into the neural mechanisms for this BED.
PMCID: PMC3321396  PMID: 22036317
20.  Drug Abuse and Hepatitis C Infection as Comorbid Features of HIV Associated Neurocognitive Disorder: Neurocognitive and Neuroimaging Features 
Neuropsychology review  2009;19(2):215-231.
Substance abuse and co-infection with hepatitis C (HCV) are two highly relevant determinants of neurocognitive and neuroimaging abnormalities associated with HIV. Substance abuse and HCV are common in the HIV population and there is increasing evidence that the CNS is directly compromised by these comorbid conditions via additive or synergistic processes. In this article we review the current literature regarding mechanisms of neuronal injury as well as the neuropsychological and neuroimaging signatures associated with substance abuse and HCV status among HIV patients. We discuss specific methodological challenges and threats to validity associated with studies of HIV and comorbid substance use disorders or HCV and review potential strategies for minimizing their confounding effects. Efforts to understand the interactions between HIV, substance abuse and HCV co-infection will lead to more complete models of neuropathogenesis of HIV and a greater understanding of the variability in neuropsychological expression of HIV Associated Neurocognitive Disorder.
PMCID: PMC3635478  PMID: 19468837
HIV; Drug abuse; Hepatitis C; Addiction; Neurocognition; Neuroimaging; Dementia
21.  Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures 
Neurocognitive impairment remains prevalent in HIV infected (HIV+) individuals despite highly active anti-retroviral therapy (HAART). We assessed the impact of HIV, HAART, and aging using structural neuroimaging.
Seventy-eight participants (HIV− (n=26), HIV+ on stable HAART (HIV+/HAART+; n=26), HIV+ naive to HAART (HIV+/HAART−; n=26)) completed neuroimaging and neuropsychological testing. A subset of HIV+ subjects (n = 12) performed longitudinal assessments before and after initiating HAART. Neuropsychological tests evaluated memory, psychomotor speed, and executive function and a composite neuropsychological score was calculated based on normalized performances (NPZ-4). Volumetrics were evaluated for the amygdala, caudate, thalamus, hippocampus, putamen, corpus callosum, cerebral grey and white matter. A three-group one way analysis of variance assessed differences in neuroimaging and neuropsychological indices. Correlations were examined between NPZ-4 and volumetrics. Exploratory testing using a broken stick regression model evaluated self-reported duration of HIV infection on brain structure.
HIV+ individuals had significant reductions in brain volumetrics within select subcortical regions (amygdala, caudate, and corpus callosum) compared to HIV− participants. However, HAART did not affect brain structure as regional volumes were similar for HIV+/HAART− and HIV+/HAART+. No association existed between NPZ-4 and volumetrics. HIV and aging were independently associated with volumetric reductions. Exploratory analyses suggest caudate atrophy due to HIV slowly occurs after self-reported seroconversion.
HIV associated volumetric reductions within the amygdala, caudate, and corpus callosum occurs despite HAART. A gradual decline in caudate volume occurs after self-reported seroconversion. HIV and aging independently increase brain vulnerability. Additional longitudinal structural MRI studies, especially within older HIV+ participants, are required.
PMCID: PMC3302928  PMID: 22269799
HIV; HAART; aging; brain volume
22.  NeuroAIDS in Africa 
Journal of neurovirology  2010;16(3):189-202.
In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting “NeuroAIDS in Africa.” This meeting was held in Cape Town, South Africa, and was affiliated with the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Presentations began with an overview of the epidemiology of HIV in sub-Saharan Africa, the molecular epidemiology of HIV, HIV-associated neurocognitive disorders (HANDs), and HAND treatment. These introductory talks were followed by presentations on HAND research and clinical care in Botswana, Cameroon, Ethiopia, The Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, and Zambia. Topics discussed included best practices for assessing neurocognitive disorders, patterns of central nervous system (CNS) involvement in the region, subtype-associated risk for HAND, pediatric HIV assessments and neurodevelopment, HIV-associated CNS opportunistic infections and immune reconstitution syndrome, the evolving changes in treatment implementation, and various opportunities and strategies for NeuroAIDS research and capacity building in the region.
PMCID: PMC3549534  PMID: 20500018
HIV; neurodevelopment; neurology; neuropsychology; subtypes
23.  Recent Clinical History and Cognitive Dysfunction for Attention and Executive Function among Human Immunodeficiency Virus-Infected Patients 
This study examined the association between recent trends in CD4 and viral loads and cognitive test performance with the expectation that recent history could predict cognitive performance. Eighty-three human immunodeficiency virus (HIV)-infected patients with a mean CD4 count of 428 copies/ml were examined in this study (62% with undetectable plasma viral load [PVL]). We investigated the relationships between nadir CD4 cell count, 1-year trends in immunologic function/PVLs, and cognitive performance across several domains using linear regression models. Nadir CD4 cell count was predictive of current executive function (p = .004). One year clinical history for CD4 cell counts and/or PVLs were predictive of executive function, attention/working memory, and learning/memory measures (p < .05). Models that combined recent clinical history trends and nadir CD4 cell counts suggested that recent clinical trends were more important in predicting current cognitive performance for all domains except executive function. This research suggests that recent CD4 and viral load history is an important predictor of current cognitive function across several cognitive domains. If validated, clinical variables and cognitive dysfunction models may improve our understanding of the dynamic relationships between disease evolution and progression and CNS involvement.
PMCID: PMC3243921  PMID: 21873325
HIV; Cognition; Neuropsychology; Executive function; Recent clinical history
24.  Screening for Cognitive Impairment in Human Immunodeficiency Virus 
Clinicians are struggling with screening issues related to cognitive impairment given new information noting impairment in about 1/2 of community dwelling human immunodeficiency virus-positive patients. This impairment may impact daily functioning and medication adherence. Unfortunately, major limitations exist in current screening tools.
Recent publications estimate the prevalence of human immunodeficiency virus (HIV)–associated neurocognitive disorders (HAND) exceeds 50%, and this rate is likely higher among older patients. Cognitive impairment may impact medication adherence, and symptomatic impairment has been linked to all-cause mortality providing some impetus for early detection. There are currently insufficient data to inform solid recommendations on screening methods. Most HIV-specific tools have poor performance characteristics for all but the most severe form of impairment, which accounts for <5% of cases. Reliance on symptoms is likely to miss a substantial proportion of individuals with HAND due to poor insight, confounding mood disturbances, and lack of well-informed proxies. In the aging HIV-positive population, broader screening tools may be required to allow sensitivity for both HIV and neurodegenerative disorders. We describe the clinical presentation of HAND, review existing data related to screening tools, and provide preliminary and practical recommendations in the absence of more definitive studies.
PMCID: PMC3174098  PMID: 21921226
25.  Neuroimaging Signatures and Cognitive Correlates of the Montreal Cognitive Assessment Screen in a Nonclinical Elderly Sample 
The Montreal Cognitive Assessment (MoCA) screen was developed as a brief instrument to identify mild cognitive impairment and dementia among older individuals. To date, limited information is available regarding the neuroimaging signatures associated with performance on the scale, or the relationship between the MoCA and more comprehensive cognitive screening measures. The present study examined performances on the MoCA among 111 non-clinical older adults (ages 51–85) enrolled in a prospective study of cognitive aging. Participants were administered the MoCA, Mini-Mental State Exam (MMSE), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A subset of participants (N = 69) underwent structural 3 T magnetic resonance imaging (MRI) to define the volumes of total frontal gray matter, total hippocampus, T2-weighted subcortical hyperintensities (SH), and total brain volume. The results revealed significant correlations between the total score on the MoCA and total score on the RBANS and MMSE, though the strength of the correlations was more robust between the MoCA and the RBANS. Modest correlations between individual subscales of the MoCA and neuroimaging variables were evident, but no patterns of shared variance emerged between the MoCA total score and neuroimaging indices. In contrast, total brain volume correlated significantly with total score on the RBANS. These results suggest that additional studies are needed to define the significance of MoCA scores relative to brain integrity among an older population.
PMCID: PMC3142949  PMID: 21642663
Mild cognitive impairment; Neuroimaging (structural)

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