The relationship between diabetes and depressive symptoms in men with or at risk of HIV infection.

OBJECTIVES: The aim of the study was to compare the prevalence of comorbid diabetes and depressive symptoms in men living with HIV (MLWH) with that in men without HIV infection and to determine associations between glycaemic control and depressive symptoms. METHODS: Participants included 920 MLWH and 840 men without HIV infection from the Multicenter AIDS Cohort Study (MACS) with available data regarding glycaemic status [categorized as normal for fasting blood glucose (FBG) < 100 mg/dL, prediabetes for FBG 100-125 mg/dL, and diabetes, defined by self-report, diabetes medication use or FBG ≥ 126 mg/dL on at least two consecutive visits, with diabetes classified as controlled if Hemoglobin A1c (HbA1C) < 7.5% and uncontrolled if HbA1C ≥ 7.5%]. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) score, with CES-D ≥ 16 scores classified as elevated depressive symptoms. A modified Poisson regression model with robust variance was used and adjusted for covariates including HIV serostatus. RESULTS: Compared to men without HIV infection, MLWH had a higher mean CES-D score, but a similar prevalence of diabetes (11.3% versus 12.8%, respectively; P = 0.33). The concomitant prevalence of diabetes and elevated depressive symptoms did not differ by HIV serostatus (P = 0.215). In an adjusted analysis, men with uncontrolled diabetes had a greater prevalence of depressive symptoms compared to men with normoglycaemia (prevalence ratio = 1.43; 95% confidence interval 1.11, 1.84). The association between glycaemic status and depressive symptoms did not differ by HIV serostatus (P = 0.22 for interaction). CONCLUSIONS: Both controlled and uncontrolled diabetes were independently associated with a greater prevalence of depressive symptoms, regardless of HIV serostatus. These results highlight the importance of identifying depression in people with diabetes.

Testosterone use and shorter electrocardiographic QT interval duration in men living with and without HIV.

OBJECTIVES: Testosterone usage (T-use) may alter risk factors for sudden cardiac death in men living with HIV (MLWH). Electrocardiographic QT interval prolongation, which could potentiate ventricular arrhythmias, has previously been associated with HIV infection and, separately, with low testosterone levels. We investigated whether T-use shortens the QT interval duration in MLWH and HIV-uninfected men. METHODS: We utilized data from the Multicenter AIDS Cohort Study, a prospective, longitudinal study of HIV infection among men who have sex with men. Multivariable linear regression analyses were used to evaluate associations between T-use and corrected QT interval (QTc) duration. RESULTS: Testosterone usage was more common in MLWH compared with HIV-uninfected men (19% vs. 9%). In a multivariable regression analysis, T-use was associated with a 5.7 ms shorter QT interval [95% confidence interval (CI): -9.5 to -1.9; P = 0.003). Furthermore, stronger associations were observed for prolonged duration of T-use and recent timing of T-use. CONCLUSIONS: This study is the first known analysis of T-use and QTc interval in MLWH. Overall, our data demonstrate that recent T-use is associated with a shorter QTc interval. Increased T-use duration above a threshold of ≥ 50% of visits in the preceding 5 years was associated with a shorter QTc interval while lesser T-use duration was not.

Subclinical cardiovascular disease in HIV controller and long-term nonprogressor populations.

OBJECTIVES: Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). METHODS: We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3 binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed. RESULTS: We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons. CONCLUSIONS: Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

To T or not to T: Differences in Testosterone Use and Discontinuation by HIV Serostatus among Men who Have Sex with Men.

OBJECTIVES: The aim of the study was to characterize contemporary patterns and correlates of testosterone therapy (TTh) use and discontinuation by HIV serostatus among men in the Multicenter AIDS Cohort Study (MACS). METHODS: Self-reported testosterone use data were collected semiannually from 2400 (1286 HIV-infected and 1114 HIV-uninfected) men who have sex with men. Multivariable Poisson regression was used to estimate prevalence ratios for TTh use and predictors of TTh discontinuation (2012-2015). RESULTS: Use was higher among HIV-infected compared with HIV-uninfected men in all age strata, with an age-adjusted prevalence of 17% vs. 5%, respectively (adjusted prevalence ratio 3.7; P < 0.001). Correlates of use in the multivariable model were similar by HIV serostatus: white race, the Los Angeles (LA) site, more than one recent sexual partner, non-smoking status, and higher American Heart Association/American College of Cardiology (AHA/ACC) cardiovascular disease (CVD) risk score category (approximately 70% of testosterone users were in the high-risk category). Compared with HIV-uninfected men, HIV-infected men more frequently reported building muscle mass as a motivation for testosterone use. The TTh discontinuation rate was 20.9/100 person-years [95% confidence interval (CI) 17.3, 25.0/100 person-years]. Relative to HIV-uninfected men, HIV-infected men were half as likely to discontinue (adjusted incidence rate ratio 0.4; P < 0.001). Discontinuation was 40% higher in the period after the US Food and Drug Administration (FDA) safety communication for testosterone in 2014, independent of co-factors (P = 0.06). CONCLUSIONS: Given the high prevalence of both TTh use and CVD risk among HIV-infected men, the benefits and risks of TTh should be examined in future studies of aging HIV-infected men and monitored routinely in clinical practice.

The association between physical activity and cognition in men with and without HIV infection.

OBJECTIVES: HIV-associated neurocognitive disorders are highly prevalent, and physical activity (PA) is a modifiable behaviour that may affect neurocognitive function. Our objective was to determine the association between PA and neurocognitive function and the effect of HIV on this association. METHODS: PA was assessed in the Multicenter AIDS Cohort Study with the International Physical Activity Questionnaire. A neuropsychological test battery assessed global impairment and domain-specific impairment (executive function, speed of processing, working memory, learning, memory, and motor function) every 2 years. Semiannually, the Symbol Digit Modalities Test and Trail Making Test Parts A and B were performed. Adjusted logistic regression models were used to assess the PA-neurocognitive function association. Using longitudinal data, we also assessed the PA category-decline of neurocognitive function association with multivariate simple regression. RESULTS: Of 601 men, 44% were HIV-infected. Low, moderate, and high PA was reported in 27%, 25%, and 48% of the HIV-infected men vs. 19%, 32% and 49% of the HIV-uninfected men, respectively. High PA was associated with lower odds of impairment of learning, memory, and motor function [odds ratio (OR) ranging from 0.52 to 0.57; P < 0.05 for all]. The high PA-global impairment association OR was 0.63 [95% confidence interval (CI) 0.39, 1.02]. Among HIV-infected men only, across multiple domains, the high PA-impairment association was even more pronounced (OR from 0.27 to 0.49). Baseline high/moderate PA was not associated with decline of any domain score over time. HIV infection was marginally associated with a higher speed of decline in motor function. CONCLUSIONS: A protective effect of high PA on impairment in neurocognitive domains was observed cross-sectionally. Longitudinal PA measurements are needed to elucidate the PA-neurocognitive function relationship over time.

Vitamin D, osteoprotegerin/receptor activator of nuclear factor-kappaB ligand (OPG/RANKL) and inflammation with alendronate treatment in HIV-infected patients with reduced bone mineral density.

OBJECTIVES: The aim of the study was to determine the effect of alendronate (ALN) on inflammatory markers and osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL), and to explore the associations of baseline systemic inflammation and vitamin D status on the bone mineral density (BMD) response to ALN. METHODS: Eighty-two HIV-positive patients with lumbar spine T-score ≤ -1.5 were randomized to ALN 70 mg weekly or placebo for 48 weeks; all received calcium carbonate 500 mg/vitamin D3 200 IU twice daily. Serum C-telopeptide (CTx) and BMD were assessed at baseline and week 48. Stored plasma samples in 70 subjects were assayed for levels of 25-hydroxyvitamin D (25(OH)D), OPG, RANKL, interleukin (IL)-6 and soluble receptors for tumour necrosis factor (TNF)-α 1 and 2 (sTNFR 1 and 2). RESULTS: ALN increased BMD more than placebo at both the lumbar spine (difference ALN - placebo 2.64%; P = 0.011) and the total hip (difference 2.27%; P = 0.016). No within- or between-arm differences in OPG, RANKL or inflammatory markers were observed over 48 weeks. High baseline CTx and sTNFR2 were associated with a more robust BMD response to ALN over 48 weeks at the lumbar spine [difference 5.66%; 95% confidence interval (CI) 3.50, 7.82; P < 0.0001] and total hip (difference 4.99%; 95% CI 2.40, 7.57; P = 0.0002), respectively. Baseline 25(OH)D < 32 ng/mL was associated with larger increases in total hip BMD over 48 weeks, independent of ALN treatment (P = 0.014). CONCLUSIONS: Among HIV-positive patients, higher baseline bone resorption and TNF-α activity were associated with an increased BMD response to ALN. The greater BMD response in those with lower vitamin D reinforces the importance of vitamin D supplementation with bisphosphonate treatment.

Fall frequency and associated factors among men and women with or at risk for HIV infection.

OBJECTIVES: Falls and fall-related injuries are a major public health concern. HIV-infected adults have been shown to have a high incidence of falls. Identification of major risk factors for falls that are unique to HIV infection or similar to those in the general population will inform development of future interventions for fall prevention. METHODS: HIV-infected and uninfected men and women participating in the Hearing and Balance Substudy of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study were asked about balance symptoms and falls during the prior 12 months. Falls were categorized as 0, 1, or ≥ 2; proportional odds logistic regression models were used to investigate relationships between falls and demographic and clinical variables and multivariable models were created. RESULTS: Twenty-four per cent of 303 HIV-infected participants reported at least one fall compared with 18% of 233 HIV-uninfected participants (P = 0.27). HIV-infected participants were demographically different from HIV-uninfected participants, and were more likely to report clinical imbalance symptoms (P ≤ 0.035). In univariate analyses, more falls were associated with hepatitis C, female sex, obesity, smoking, and clinical imbalance symptoms, but not age, HIV serostatus or other comorbidities. In multivariable analyses, female sex and imbalance symptoms were independently associated with more falls. Among HIV-infected participants, smoking, a higher number of medications, and imbalance symptoms remained independent fall predictors, while current protease inhibitor use was protective. CONCLUSIONS: Similar rates of falls among HIV-infected and uninfected participants were largely explained by a high prevalence of imbalance symptoms. Routine assessment of falls and dizziness/imbalance symptoms should be considered, with interventions targeted at reducing symptomatology.

Body mass index and early CD4 T-cell recovery among adults initiating antiretroviral therapy in North America, 1998-2010.

OBJECTIVES: Adipose tissue affects several aspects of the cellular immune system, but prior epidemiological studies have differed on whether a higher body mass index (BMI) promotes CD4 T-cell recovery on antiretroviral therapy (ART). The objective of this analysis was to assess the relationship between BMI at ART initiation and early changes in CD4 T-cell count. METHODS: We used the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data set to analyse the relationship between pre-treatment BMI and 12-month CD4 T-cell recovery among adults who started ART between 1998 and 2010 and maintained HIV-1 RNA levels < 400 copies/mL for at least 6 months. Multivariable regression models were adjusted for age, race, sex, baseline CD4 count and HIV RNA level, year of ART initiation, ART regimen and clinical site. RESULTS: A total of 8381 participants from 13 cohorts contributed data; 85% were male, 52% were nonwhite, 32% were overweight (BMI 25-29.9 kg/m(2) ) and 15% were obese (BMI > 30 kg/m(2) ). Pretreatment BMI was associated with 12-month CD4 T-cell change (P < 0.001), but the relationship was nonlinear (P < 0.001). Compared with a reference of 22 kg/m(2) , a BMI of 30 kg/m(2) was associated with a 36 cells/µL [95% confidence interval (CI) 14, 59 cells/µL] greater CD4 T-cell count recovery among women and a 19 cells/µL (95% CI 9, 30 cells/µL) greater recovery among men at 12 months. At a BMI > 30 kg/m(2) , the observed benefit was attenuated among men to a greater degree than among women, although this difference was not statistically significant. CONCLUSIONS: A BMI of approximately 30 kg/m(2) at ART initiation was associated with greater CD4 T-cell recovery at 12 months compared with higher or lower BMI values, suggesting that body composition may affect peripheral CD4 T-cell recovery.

Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients.

OBJECTIVES: Cardiovascular disease and osteoporosis are common in HIV-infected patients and residual systemic inflammation is thought to contribute to both of these disorders. We performed a randomized placebo-controlled trial of omega-3-acid (O3A) ethyl esters in HIV-infected patients with hypertriglyceridaemia, hypothesizing that O3A would decrease serum levels of triglycerides, markers of systemic inflammation, and markers of bone turnover. METHODS: HIV-infected patients (n = 48 recruited at three sites) with CD4 count >200 cells/µL, suppressed viral load, and triglycerides >200 mg/dL were randomized to placebo or 3.6 g/d of O3A. Fasting lipid profiles and markers of inflammation and bone turnover were assessed at baseline and after 8 weeks of treatment. RESULTS: Baseline HIV status, lipid profile, bone metabolism and cardiovascular risk factors were similar between the groups. Inflammatory markers were similar between the treatment groups at baseline, except for interleukin (IL)-6 and tumour necrosis factor (TNF)-α, which were higher in the O3A group. The concentration of triglycerides in patients receiving O3A decreased by a median (interquartile range (IQR)) of -34 (-149, 9.5) mg/dL vs. a median increase of 46.5 (-51, 123) mg/dL in the placebo group (P = 0.01). The median percentage change in IL-6 was greater in the O3A group compared with the placebo group [-39% (-63, 12%) vs. 29% (10, 177%), respectively; P = 0.006]. Similar results were observed for TNF-α, but not other inflammatory or bone turnover markers. CONCLUSIONS: O3A ethyl esters decreased the concentrations of triglycerides, IL-6 and TNF-α in patients with well-controlled HIV infection and hypertriglyceridaemia. Larger studies are required to confirm these findings and investigate their clinical significance.

Ictal face perception disturbance, tattoos, and reclaiming the self.

We present a case of a young man with frightening ictal disturbance of face perception, or prosopometamorphopsia, arising from the left temporo-occipital region, leading to significant psychosocial impairment. A vivid forearm tattoo of the ictal experience conveyed its nature to the treating team and facilitated a psychotherapeutic process leading to significant psychosocial recovery. This case highlights the marked psychosocial and developmental impacts of epilepsy and the benefit of incorporating these into assessment and treatment.

Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia.

Glycogen storage disease type Ia (GSD-Ia) stems from glucose-6-phosphatase (G6Pase) deficiency and causes hypoglycemia, hepatomegaly, hypercholesterolemia and lactic acidemia. Three dogs with GSD-Ia were initially treated with a helper-dependent adenovirus encoding a human G6Pase transgene (HDAd-cG6Pase serotype 5) on postnatal day 3. Unlike untreated dogs with GSD-Ia, all three dogs initially maintained normal blood glucose levels. After 6-22 months, vector-treated dogs developed hypoglycemia, anorexia and lethargy, suggesting that the HDAd-cG6Pase serotype 5 vector had lost efficacy. Liver biopsies collected at this time revealed significantly elevated hepatic G6Pase activity and reduced glycogen content, when compared with affected dogs treated only by frequent feeding. Subsequently, the HDAd-cG6Pase serotype 2 vector was administered to two dogs, and hypoglycemia was reversed; however, renal dysfunction and recurrent hypoglycemia complicated their management. Administration of a serotype 2 HDAd vector prolonged survival in one GSD-Ia dog to 12 months of age and 36 months of age in the other, but the persistence of long-term complications limited HDAd vectors in the canine model for GSD-Ia.

Low free testosterone in HIV-infected men is not associated with subclinical cardiovascular disease.

OBJECTIVES: Low testosterone (T) is associated with cardiovascular disease (CVD) and increased mortality in the general population; however, the impact of T on subclinical CVD in HIV disease is unknown. This study examined the relationships among free testosterone (FT), subclinical CVD, and HIV disease. METHODS: This was a cross-sectional analysis in 322 HIV-uninfected and 534 HIV-infected men in the Multicenter AIDS Cohort Study. Main outcomes were coronary artery calcification presence, defined as a coronary artery calcium (CAC) score >10 (CAC score was the geometric mean of the Agatston scores of two computed tomography replicates), and far wall common carotid intima-media thickness (IMT)/carotid lesion presence by B-mode ultrasound. RESULTS: Compared with the HIV-uninfected men in our sample, HIV-infected men were younger, with lower body mass index (BMI) and more often Black. HIV-infected men had lower FT (age-adjusted FT 88.7 ng/dL vs. 101.7 ng/dL in HIV-uninfected men; P=0.0004); however, FT was not associated with CAC, log carotid IMT, or the presence of carotid lesions. HIV status was not associated with CAC presence or log carotid IMT, but was associated with carotid lesion presence (adjusted odds ratio 1.69; 95% confidence interval 1.06, 2.71) in HIV-infected men compared with HIV-uninfected men. CONCLUSIONS: Compared with HIV-uninfected men, HIV-infected men had lower FT, as well as more prevalent carotid lesions. In both groups, FT was not associated with CAC presence, log carotid IMT, or carotid lesion presence, suggesting that FT does not influence subclinical CVD in this population of men with and at risk for HIV infection.

Hip bone geometry in HIV/HCV-co-infected men and healthy controls.

UNLABELLED: People with both HIV and hepatitis C are more likely than those with HIV alone to have wrist, hip, and spine fractures. We compared hip strength between HIV/HCV-co-infected men and healthy men and found that HIV/HCV-co-infected men had decreased hip strength due to lower lean body mass. INTRODUCTION: Hepatitis C co-infection is a risk factor for fragility fracture among HIV-infected populations. Whether bone strength is compromised in HIV/HCV-co-infected patients is unknown. METHODS: We compared dual-energy x-ray absorptiometry (DXA)-derived hip geometry, a measure of bone strength, in 88 HIV/HCV-co-infected men from the Johns Hopkins HIV Clinic to 289 men of similar age and race and without HIV or HCV from the Boston Area Community Health Survey/Bone Survey. Hip geometry was assessed at the narrow neck, intertrochanter, and shaft using hip structural analysis. Lean body mass (LBM), total fat mass (FM), and fat mass ratio (FMR) were measured by whole-body DXA. Linear regression was used to identify body composition parameters that accounted for differences in bone strength between cohorts. RESULTS: HIV/HCV-co-infected men had lower BMI, LBM, and FM and higher FMR compared to controls (all p < 0.05). At the narrow neck, significant differences were observed between HIV/HCV-co-infected men and controls in bone mineral density, cross-sectional area, section modulus, buckling ratio, and centroid position. After adjustment for race, age, smoking status, height, and weight, only buckling ratio and centroid position remained significantly different between cohorts (all p < 0.05). Substituting LBM, FM, and FMR for weight in the multivariate model revealed that differences in LBM, but not FM or FMR, accounted for differences in all narrow neck parameters between cohorts, except buckling ratio and centroid position. CONCLUSION: HIV/HCV-co-infected men have compromised hip strength at the narrow neck compared to uninfected controls, which is attributable in large part to lower lean body mass.

Differences in Muscle Quantity and Quality by HIV Serostatus and Sex.

OBJECTIVE: People with HIV (PWH) experience greater declines in both muscle function and muscle mass with aging. Whether changes in muscle quality and quantity with aging differ between men and women with HIV and the implications on muscle function are not established. DESIGN: In coordinated substudies of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study, participants completed physical function and falls assessments; total trunk/thigh density, inversely related to fatty infiltration, and area were quantified from computed tomography (CT) scans. METHODS: Generalized linear models were used to explore variables affecting density/area, and associations between area/density and physical function and falls. RESULTS: CT scans were available on 387 men (198 PWH) and 184 women (118 PWH). HIV serostatus was associated with greater lateralis, paraspinal, and hamstring area, but lower psoas area and density. Older age and female sex were associated with smaller trunk muscle area and lower density. Both lower muscle area and muscle density were associated with several measures of impaired physical function. The odds of falling were lower with greater hamstring density, but not associated with other measurers of muscle area or density. CONCLUSIONS: In summary, older adults with HIV appear to have smaller and less dense (fattier) psoas, a key component in truncal stability and hip flexion that could have implications on physical function. The longitudinal associations of muscle area and density with physical function require careful investigation, with a particular focus on characteristics and interventions that can preserve muscle area, density, and function over time.

Associations between subcutaneous fat density and systemic inflammation differ by HIV serostatus and are independent of fat quantity.

OBJECTIVES: Adipose tissue (AT) density measurement may provide information about AT quality among people living with HIV. We assessed AT density and evaluated relationships between AT density and immunometabolic biomarker concentrations in men with HIV. DESIGN: Cross-sectional analysis of men enrolled in the Multicenter AIDS Cohort Study. METHODS: Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density (Hounsfield units, HU; less negative = more dense) were quantified from computed tomography (CT) scans. Multivariate linear regression models described relationships between abdominal AT density and circulating biomarker concentrations. RESULTS: HIV+ men had denser SAT (-95 vs -98 HU HIV-, P < 0.001), whereas VAT density was equivalent by HIV serostatus men (382 HIV-, 462 HIV+). Historical thymidine analog nucleoside reverse transcriptase inhibitor (tNRTI) use was associated with denser SAT but not VAT. In adjusted models, a 1 s.d. greater SAT or VAT density was associated with higher levels of adiponectin, leptin, HOMA-IR and triglyceride:HDL cholesterol ratio and lower hs-CRP concentrations in HIV- men. Conversely, in HIV+ men, each s.d. greater SAT density was not associated with metabolic parameter improvements and was significantly (P < 0.05) associated with higher systemic inflammation. Trends toward higher inflammatory biomarker concentrations per 1 s.d. greater VAT density were also observed among HIV+ men. CONCLUSIONS: Among men living with HIV, greater SAT density was associated with greater systemic inflammation independent of SAT area. AT density measurement provides additional insight into AT density beyond measurement of AT quantity alone, and may have implications for metabolic disease risk.

Polygenic risk for psychiatric disorders correlates with executive function in typical development.

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome-wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.

The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV.

BACKGROUND: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown. OBJECTIVES: The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area). DESIGN: Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials. SETTING: U.S. and Canadian sites. PARTICIPANTS: People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease ≥8%). INTERVENTION: Tesamorelin or placebo. MEASUREMENTS: Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm. RESULTS: Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p<0.005), and the lean anterolateral/abdominal and rectus muscles (1.39 and 1.78 Hounsfield units; both p<0.005) compared to placebo. Significant increases were also seen in total area of the rectus and psoas muscles (0.44 and 0.46 centimeters2; p<0.005), and in the lean muscle area of all four truncal muscle groups (0.64-1.08 centimeters2; p<0.005). CONCLUSIONS: Among those with clinically significant decrease in visceral adipose tissue on treatment, tesamorelin was effective in increasing skeletal muscle area and density. Long term effectiveness of tesamorelin among people with and without HIV, and the impact of these changes in daily life should be further studied.

Brief report: Circulating markers of fibrosis are associated with immune reconstitution status in HIV-infected men.

INTRODUCTION: Lymphoid tissue fibrosis may contribute to incomplete immune reconstitution on antiretroviral therapy (ART) via local CD4+ T lymphocyte (CD4) depletion. Hyaluronic acid (HA) increases with fibrotic burden. CXCL4 concentrations increase in response to pro-fibrotic stimuli, but lower CXCL4 concentrations in HIV-infected individuals may reflect successful immune evasion by HIV. We investigated relationships between circulating HA and CXCL4 concentrations and immune reconstitution on ART in HIV-infected Multicenter AIDS Cohort Study participants. METHODS: HIV-infected men on ART for >1 year with cryopreserved plasma samples and suppressed post-ART HIV-1 RNA were included. Men with post-ART CD4 <200 cells/mm3 were defined as immunologic non-responders (n = 25). Age-/race-matched men with post-ART CD4 >500 cells/mm3 served as controls (n = 49). HA and CXCL4 concentrations were measured via ELISA. RESULTS: Median pre-ART CD4 was 297 cells/mm3 for non-responders vs 386 cells/mm3 for controls. Median post-ART CD4 was 141 cells/mm3 for non-responders and 815 cells/mm3 for controls. HIV infection duration was 23 years, with median time on ART 13 years for non-responders vs 11 years for controls. Pre-ART HA and CXCL4 concentrations did not vary by eventual immune reconstitution status. Post-ART HA concentrations tended to be higher (85 vs 36 ng/mL, p = 0.07) and CXCL4 concentrations were lower (563 vs 1459 ng/mL, p = 0.01) among non-responders. Among men with paired pre-/post-ART samples, non-responders had greater HA increases and CXCL4 decreases than controls (HA: 50 vs 12 ng/mL, p = 0.04; CXCL4: -1258 vs -405 ng/mL, p = 0.01). CONCLUSIONS: Higher circulating concentrations of HA and lower concentrations of CXCL4 are associated with failure of immune reconstitution on ART.

Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.