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Objective To identify amygdalar volumetric differences associated with posttraumatic stress disorder (PTSD) in individuals with comorbid mild traumatic brain injury (mTBI) compared with those with mTBI-only and to examine the effects of intracranial volume (ICV) on amygdala volumetric measures. Setting Marine Corps Base and VA Healthcare System. Participants A cohort of veterans and active-duty military personnel with combat-related mTBI (N = 89). Design Twenty-nine participants were identified with comorbid PTSD and mTBI. The remaining 60 formed the mTBI-only control group. Structural images of brains were obtained with a 1.5-T MRI scanner using a T1-weighted 3D-IR-FSPGR pulse sequence. Automatic segmentation was performed in Freesurfer. Main measures Amygdala volumes with/without normalizations to ICV. Results The comorbid mTBI/PTSD group had significantly larger amygdala volumes, when normalized to ICV, compared with the mTBI-only group. The right and left amygdala volumes after normalization to ICV were 0.122% ± 0.012% and 0.118% ± 0.011%, respectively, in the comorbid group compared with 0.115% ± 0.012% and 0.112% ± 0.009%, respectively, in the mTBI-only group (corrected P Conclusions The ICV normalization analysis performed here may resolve previous literature discrepancies. This is an intriguing structural finding, given the role of the amygdala in the challenging neuroemotive symptoms witnessed in casualties of combat-related mTBI and PTSD.

Objectives To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. Study design The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5 years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. Results Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200 cells/μL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. Conclusions Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

Youth living with HIV (YLH) face significant problems with regularly attending their medical appointments. Poor attendance, consequently, predicts viral non-suppression and other negative HIV-related outcomes. To identity targets of intervention, this cross-sectional study examined correlates of past-year missed clinic visits among a diverse sample of YLH (ages 12 to 24; N = 2125) from HIV clinics in the United States and Puerto Rico. Our results revealed that 36% of YLH reported missing two or more visits in the past year. Several factors were associated with missed clinic visits in our multivariate logistic regression model based on adjusted odds ratios (AORs). Among sociodemographic characteristics and HIV disclosure status, females (AOR = 1.63, compared to males), Black YLH or YLH of mixed racial heritage (AORs = 1.76, 1.71, respectively, compared to White YLH), YLH with an unknown route of infection (AOR = 1.86, compared to YLH with perinatal infection), and YLH endorsing HIV disclosure (AOR = 1.37, compared to YLH not endorsing disclosure) were at greater risk for missed visits. In addition, number of times YLH moved residences was associated with missed visits (AOR = 1.07). Among behavioral health risks, YLH who endorsed marijuana use (AOR = 1.42), frequent other drug use (AOR = 1.60), or a history of incarceration (AOR = 1.27) had greater odds of missed visits than youth not endorsing these health risks. Finally, two social-cognitive factors emerged as protective against missed visits: adherence self-efficacy (AOR = .28) and adherence social support (AOR = .88). We conclude by discussing the ways in which providers and clinics working with YLH can improve this population’s retention outcomes by recognizing youth-specific individual, social, and structural barriers to treatment engagement.

Objective To define inflammatory pathways in youth living with HIV infection (YLWH), assessments of biomarkers associated with lymphocyte and macrophage activation, vascular injury, or bone metabolism were performed in YLWH in comparison with healthy controls (HC). Design Longitudinal multicenter study comparing biomarkers in YLWH suppressed on antiretroviral therapy (ART), those with ongoing viral replication, and HC were compared using single blood samples obtained at end of study. Methods Twenty-three plasma proteins were measured by ELISA or multiplex assays. Principal component analysis (PCA) was used to define contributions of individual biomarkers to define outcome groups. Results The study cohort included 129 predominantly African American, male participants, 21–25 years old at entry. Nine biomarkers of lymphocyte and macrophage activation and cardiovascular injury differed between HC and YLWH. Significant positive correlations were identified between lymphocyte and macrophage activation biomarkers among HC and YLWH. Correlations distinct to YLWH were predominantly between biomarkers of macrophage and vascular inflammation. PCA of outcome groups showed HC and suppressed YLWH clustering together for lymphocyte activation biomarkers, whereas macrophage activation markers showed all YLWH clustering distinct from HC. Cardiovascular biomarkers were indistinguishable across groups. Averaged variable importance projection to assess single biomarkers that maximally contribute to discriminate among outcome groups identified soluble CD27, CD14, and CD163 as the 3 most important with TNFα and LPS also highly relevant in providing separation. Conclusions Soluble inflammatory and lymphocyte biomarkers sufficiently distinguish YLWH from HC. Persistent macrophage activation biomarkers may provide a means to monitor consequences of HIV infection in fully suppressed YLWH.

BACKGROUND:We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana.METHODS:HIV-infected and uninfected mothers enrolled in a prospective observational study (“Tshipidi”) in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics.RESULTS:We evaluated 670 children (313 HEU, 357 HUU) with ≥1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small.CONCLUSIONS:HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring.

Substance use is highly prevalent among youth living with HIV (YLWH) and negatively impacts HIV care. This study sought to determine whether the CRAFFT (Car, Relax, Alone, Forget, Friends, and Trouble), designed to screen for problematic substance use, is reliably associated with substance use behaviors among YLWH. A cross-sectional sample of 2216 youth (ages 12-26) were recruited through the adolescent medicine trials network for HIV/AIDS Interventions. Participants completed a self-administered survey. Over half screened positive on the CRAFFT (i.e., ≥2). Among frequent substance users, those older in age, behaviorally infected, with history of incarceration or unstably housed were more likely to screen positive on the CRAFFT. Study findings suggest that the CRAFFT reliably identifies youth who use substances. Thus, screening measures such as the CRAFFT should be utilized routinely in HIV clinical settings for youth.

Blast mild traumatic brain injury (mTBI) is a leading cause of sustained impairment in military service members and veterans. However, the mechanism of persistent disability is not fully understood. The present study investigated disturbances in brain functioning in mTBI participants using a source-imaging-based approach to analyze functional connectivity (FC) from resting-state magnetoencephalography (rs-MEG). Study participants included 26 active-duty service members or veterans who had blast mTBI with persistent post-concussive symptoms, and 22 healthy control active-duty service members or veterans. The source time courses from regions of interest (ROIs) were used to compute ROI to whole-brain (ROI-global) FC for different frequency bands using two different measures: 1) time-lagged cross-correlation and 2) phase-lock synchrony. Compared with the controls, blast mTBI participants showed increased ROI-global FC in beta, gamma, and low-frequency bands, but not in the alpha band. Sources of abnormally increased FC included the: 1) prefrontal cortex (right ventromedial prefrontal cortex [vmPFC], right rostral anterior cingulate cortex [rACC]), and left ventrolateral and dorsolateral prefrontal cortex; 2) medial temporal lobe (bilateral parahippocampus, hippocampus, and amygdala); and 3) right putamen and cerebellum. In contrast, the blast mTBI group also showed decreased FC of the right frontal pole. Group differences were highly consistent across the two different FC measures. FC of the left ventrolateral prefrontal cortex correlated with executive functioning and processing speed in mTBI participants. Altogether, our findings of increased and decreased regionalpatterns of FC suggest that disturbances in intrinsic brain connectivity may be the result of multiple mechanisms, and are associated with cognitive sequelae of the injury.

Individuals with HIV disease often evidence deficits in prospective memory (PM), which interfere with daily functioning and increase the risk of suboptimal health behaviours. This study examined the benefits of simple encoding and cueing supports on naturalistic time-based PM in 47 HIV-positive young adults. All participants completed a naturalistic time-based PM task in which they were instructed to text the examiner once per day for seven days at a specified time. Participants were randomised into (1) a Calendaring condition in which they created a calendar event in their mobile telephone for the specified texting time; (2) an Alarm condition in which they programmed an alarm into their mobile telephone for the specified texting time; (3) a Combined calendaring and alarm condition; and (4) a Control condition. Participants in the Combined condition demonstrated significantly better naturalistic PM performance than participants in the Control and Calendaring conditions. Findings indicate that HIV-positive young people may benefit from a combined calendaring and alarm supportive strategy for successful execution of future intentions in daily life.

In addition to individual characteristics, there may be a wide range of environmental or neighborhood stressors that contribute to elevated cannabis use in groups of youth living with HIV/AIDS (YLHIV); however, the effects of social disorganization on cannabis use in YLHIV to date have not been studied.We examined the effects of individual-level and neighborhood-level factors by developing hierarchical generalized linear models estimating odds of current cannabis use (any use during the past 3 months) and daily cannabis use among a sample of YLHIV (N = 1921) currently receiving medical care.The final model for daily cannabis use in the past 3 months included significant positive effects associated with hostility (O.R. = 1.08, 95% C.I.: 1.05, 1.11), being older (O.R. = 1.12, 95% C.I.: 1.05, 1.20), being a bisexual male (O.R. = 1.72, 95% C.I.: 1.10, 2.70), and residing in a community with a murder rate in the highest quartile (O.R. = 1.91, 95% C.I.: 1.27, 2.87), second highest quartile (O.R. = 1.62, 95% C.I.: 1.06, 2.46), or third highest quartile (O.R. = 1.52, 95% C.I.: 1.01, 2.30).This paper advances our knowledge of the multilevel factors associated with elevated cannabis use among groups of YLHIV and furthers our understanding of social and structural determinants of health in this population. Future research into cannabis use among YLHIV should consider, not only cannabis use within the context of the adjustment of living with HIV/AIDS, but also the stressors that characterize the environments in which groups of YLHIV live.

Event-based prospective memory (PM) tasks require individuals to remember to perform an action when they encounter a specific cue in the environment, and they have clear relevance for daily functioning for individuals with HIV. In many everyday tasks, not only must the individual maintain the intent to perform the PM task, but the PM task response also competes with the alternative and more habitual task response. The current study examined whether event-based PM can be improved by slowing down the pace of the task environment. Fifty-seven young adults living with HIV performed an ongoing lexical decision task while simultaneously performing a PM task of monitoring for a specific word (which was focal to the ongoing task of making lexical decisions) or syllable contained in a word (which was nonfocal). Participants were instructed to refrain from making task responses until after a tone was presented, which occurred at varying onsets (0-1600 ms) after each stimulus appeared. Improvements in focal and nonfocal PM accuracy were observed with response delays of 600 ms. Furthermore, the difference in PM accuracy between the low-demand focal PM task and the resource-demanding nonfocal PM task was reduced by half across increasingly longer delays, falling from 31% at 0-ms delay to only 14% at 1600-ms delay. The degree of ongoing task response slowing for the PM conditions, relative to a control condition that did not have a PM task and made lexical decisions only, also decreased with increased delay. Overall, the evidence indicates that delaying the task responses of younger HIV-infected adults increased the probability that the PM relevant features of task stimuli were adequately assessed prior to the ongoing task response, and by implication that younger HIV infected adults can more adequately achieve PM goals when the pace of the task environment is slowed down.

To examine the relationship between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected (PHIV+) and perinatally HIV-exposed but uninfected (PHEU) youth.Cross-sectional design within a prospective, 15-site US-based cohort study.Neurodevelopmental outcomes were evaluated in relation to nine selected vascular biomarkers in 342 youth (212 PHIV+, 130 PHEU). Serum levels were assessed for adiponectin, C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), monocyte chemoattractant protein (sMCP-1), intercellular adhesion molecule-1 (sICAM-1), and P-selectin (sP-selectin). The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was administered at entry, yielding a Full-Scale IQ score, and four index scores. Factor analysis was conducted to reduce the biomarkers to fewer factors with related biological roles. Structural equation models (SEMs) were used to measure associations between resulting factors and WISC-IV scores.Mean participant age was 11.4 years, 54% were female, 70% black. The nine biomarkers were clustered into three factor groups: F1 (fibrinogen, CRP, and IL-6); F2 (sICAM-1 and sVCAM-1); and F3 (MCP-1, sP-selectin, and sE-selectin). Adiponectin showed little correlation with any factor. SEMs revealed significant negative association of F1 with WISC-IV processing speed score in the total cohort. This effect remained significant after adjusting for HIV status and other potential confounders. A similar association was observed when restricted to PHIV+ participants in both unadjusted and adjusted SEMs.Aggregate measures of fibrinogen, CRP, and IL-6 may serve as a latent biomarker associated with relatively decreased processing speed in both PHIV+ and PHEU youth.

Medication adherence is critical to the success of antiretroviral therapies for children and youth with perinatally acquired HIV. Factors that influence successful transition of medication responsibility from caregivers to youth are poorly understood. The purpose of this study was to evaluate the relationship of medication adherence with demographic, cognitive, academic, and behavioral characteristics.Randomly selected youth, N = 151, aged 8 to 18 years, completed cognitive and academic measures, and they and their caregivers completed questionnaires assessing behavior and emotional well-being. An announced pill count and questionnaires completed by youth and their caregivers were used to evaluate adherence.Of 151 participants, 100 completed all adherence measures. Adherence rates varied by assessment method. Nonadherence (90%) by pill count was associated with older child age, greater youth responsibility for medications, and other demographic and medication regimen variables. Verbal impairment predicted better self-reported adherence and reading problems predicted better self- and caregiver-reported adherence. Youth-reported locus of control was associated with pill count nonadherence, and poor relationships with parents were associated with youth-reported nonadherence.Consideration of youth cognitive or academic status may be helpful in evaluating medication adherence in patients with perinatally acquired HIV infection, particularly when using self- or caregiver reports to assess adherence. Vigilance for adherence problems is indicated when youth are older, responsible for medications, report poor caregiver relationships, and/or sense a lack of control over their lives.

HIV infection has been reclassified as a chronic medical condition, leading to increased study of the long-term mental health care needs of people with HIV. Children and adolescents with HIV experience significant, multiple risks to mental health and quality of life, including viral infection of the central nervous system, viral and drug exposure in utero, developmental delays, poverty, inadequate support networks, unstable housing, and parental mental illness.1 These factors place children and adolescents with HIV at risk for adverse behavioral outcomes, including symptoms of attention-deficit hyperactivity disorder (ADHD).1 With an estimated prevalence of 5 to 7% among school-aged children, ADHD is one of the most common pediatric neurobehavioral disorders.2 The prevalence is higher in children who have comorbid developmental conditions such as intellectual disability and autism spectrum disorders.3,4 Clinical concerns specific to the presence of comorbid HIV and untreated ADHD are that inattentiveness might impair a child’s or adolescent’s ability to adhere to antiretroviral treatment, whereas impulsivity might impair an adolescent’s ability to practice health-promoting behaviors (e.g., safe sex). Psychopharmacologic treatments for ADHD include stimulants and nonstimulants, both commonly prescribed for children with HIV and ADHD. Stimulant efficacy in children and adolescents is well established.2,5,6 For a variety of reasons, including stimulant failure or intolerance, stigma, and potential for abuse, clinicians often prescribe nonstimulants to treat ADHD. One of the most disputed adverse side effects of stimulant medication is growth attenuation in children.2 Although some evidence suggests that age-related increases in height and weight may be diminished in children treated with stimulants,7,8 the clinical relevance of the growth delay remains controversial.9,10 Clinical trials have not demonstrated significant growth attenuation in children treated with nonstimulants.11,12 Children and adolescents with HIV are at risk for growth failure as a complication of their disease.13,14 For children with comorbid HIV and ADHD, the use of stimulants to treat ADHD may exacerbate the risk of growth failure related to HIV. There has been little empirical investigation into growth rates in children with HIV taking stimulants or nonstimulants for ADHD. The primary objective of this study was to examine the relationship between physical growth, as measured by height and weight, in children and adolescents with HIV and the use of commonly prescribed medications for treatment of ADHD. We hypothesized that children with prescriptions for stimulants would be smaller for age and would gain height and weight more slowly than their peers with HIV who were not prescribed stimulant medications.

Advances in medical treatment, through combination antiretroviral therapy (ART) and highly active ART (HAART) with protease inhibitors (PIs), have resulted in improved health outcomes among children with human immunodeficiency virus (HIV) infection (DeMartino et al., 2000; Gortmaker et al., 2001). Adherence to HAART regimens is difficult, however, due to the demanding nature of antiretroviral treatment and other unique challenges faced by children and adolescents with HIV and their caregivers. Antiretroviral medications, particularly regimens containing PIs, share characteristics that amplify the inherent difficulties of medication adherence in children and adolescents: poor palatability, heavy pill burden, dietary restrictions, acute and long-term side effects, and restrictions on daily schedules (Reddington et al., 2000; Van Dyke et al., 2002). Children and adolescents with HIV often face other life stressors that affect their ability to achieve adherence, including parental HIV disease, poverty, and limited or inconsistent social support (Steele, Nelson, & Cole, 2007). Adherence failure is dangerous in HIV disease as it may result in diminished treatment efficacy, development of genotypically resistant mutations, viral rebound, and subsequent reduction in HIV treatment options. Despite the importance of adherence in HIV disease, our understanding of factors predictive of adherence in children and adolescents remains incomplete. Prior studies of adherence in children with HIV infection, while often atheoretical, have identified multiple contextual factors associated with adherence, including disease characteristics, features of the medication regimen, and characteristics of the caregiver and family, such as caregiver education and problem-solving skills, caregiver relationship to the child, and child and caregiver stress (Hammani et al., 2004; Martin et al., 2007; Mellins, Brackis-Cott, Dolezal, & Abrams, 2004; Naar-King et al., 2006; Pontali, 2005). Child and adolescent developmental issues, including older age, knowledge of HIV diagnosis, and adjustment to chronic illness have also been implicated, although findings remain inconsistent (Simoni et al., 2007; Williams et al., 2006). Neurocognitive impairment, due to the neuropathological effects of HIV infection, is a significant complication of perinatally acquired HIV infection (Van Rie, Harrington, Dow, & Robertson, 2007). It has been associated with nonadherence in adults with HIV (Hinkin et al., 2004) and may provoke similar risk in children and adolescents. Global or mild cognitive deficits, if present, may impede or delay development of those functional skills essential for adherence, such as understanding and following parental and provider directions, remembering schedules and dosage, and communicating needs effectively. The purpose of this study was to examine cognitive functioning in children and adolescents with HIV, and to evaluate its relationship with medication adherence. We hypothesized that adherence to ART and HAART with PIs will be compromised in the presence of neurocognitive deficits in children and adolescents with HIV infection. We also evaluated potential confounding factors, including demographic characteristics, biological markers of health, medication and adherence factors, and child and family psychosocial characteristics that have been associated with medication adherence in previous investigations.