Publications by authors named "Pim Brouwers"

43 Publications

Prescription Psychoactive Medication Use in Adolescent Survivors of Childhood Cancer and Association With Adult Functional Outcomes.

JNCI Cancer Spectr 2020 Oct 29;4(5):pkaa057. Epub 2020 Jun 29.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: This study estimates the prevalence and identifies predictors of psychoactive medication use in adolescent survivors of childhood cancer (aged 12-18 years) and its associations with functional outcomes at young adulthood (aged 18-28 years).

Methods: This retrospective cohort study includes 5665 adolescent survivors of childhood cancer at no less than 5 years postdiagnosis (53.8% male, median age = 15 years, interquartile range [IQR] = 13-16 years) and 921 adolescent sibling controls. Parent-reported psychoactive medication use during adolescence was collected at baseline. After a median of 8 years, functional outcomes and social attainment were self-reported during adulthood (n = 3114, median age = 22 years, IQR = 20-24 years). Multivariable log-binomial models evaluated associations among risk factors, medication use, and adult outcomes.

Results: Higher prevalence of psychoactive medication use was reported in survivors compared with siblings (18.3% vs 6.6%; 2-sided < .001), with trends for increasing antidepressant and stimulant use in recent treatment eras. After adjusting for cancer treatment and baseline cognitive problems, psychoactive medication use during adolescence was associated with impaired task efficiency (relative risk [RR] = 1.20, 95% confidence interval [CI] = 1.01 to 1.43) and memory (RR = 1.27, 95% CI = 1.05 to 1.52) during adulthood. Survivors who reported continued use of medications from adolescence to adulthood demonstrated poorer emotional regulation (RR = 1.68, 95% CI = 1.24 to 2.27) and organization (RR = 1.82, 95% CI = 1.28 to 2.59) compared with nonusers. Adolescent opioid use was associated with somatization symptoms (RR = 1.72, 95% CI = 1.09 to 2.73) during adulthood, after adjusting for cancer treatment and baseline behavioral problems. They were also more likely to not complete college (RR = 1.21, 95% CI = 1.04 to 1.41) or work full-time (RR = 1.60, 95% CI = 1.23 to 2.08) compared with nonusers.

Conclusion: Use of psychoactive medication is more prevalent among adolescent survivors compared with siblings and does not normalize adult outcomes, as evidenced by poorer functional outcomes during young adulthood.
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http://dx.doi.org/10.1093/jncics/pkaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583158PMC
October 2020

Sertraline Pharmacokinetics in HIV-Infected and Uninfected Children, Adolescents, and Young Adults.

Front Pediatr 2019 6;7:16. Epub 2019 Feb 6.

Department of Pediatrics-Rady Children's Hospital San Diego, University of California, San Diego, San Diego, CA, United States.

Due to potential disease and drug interactions, the appropriate sertraline starting dose and titration range may require adjustment in pediatric patients living with HIV. This is the first report of sertraline pharmacokinetics in HIV-infected youth. IMPAACT P1080 was a multicenter pilot study describing psychiatric medication pharmacokinetics in HIV-infected and uninfected youth. Participants were stable on sertraline, >6 to <25 years old, and (1) HIV-uninfected (HIV(-)), (2) HIV-infected taking efavirenz (EFV), or (3) HIV-infected taking boosting ritonavir/protease inhibitor (PI/r). Sampling occurred at pre-dose, 2, 4, 6, 12, and 24-h post-dose. Analyses were performed for sertraline and N-desmethylsertraline, and CYP2D6 phenotyping was completed with dextromethorphan. Thirty-one participants (16 HIV(-), 12 PI/r, and 3 EFV) had median (range) weight, age, and dose of 69.5 (31.5-118.2) kg, 21.8 (9.1-24.7) years, and 75.0 (12.5-150.0) mg once daily. Sertraline exposure was highest for HIV(-) and lowest for EFV cohorts; median dose-normalized was 1176 (HIV(-)), 791 (PI/r) and 473 (EFV) nghr/mL, and C was 32.7 (HIV(-)), 20.1 (PI/r), and 12.8 (EFV) ng/mL. The urinary dextromethorphan/dextrorphan (DXM/DXO) ratio was higher in HIV(-) vs. PI/r cohorts ( = 0.01). Four HIV(-) participants were CYP2D6 poor metabolizers (ln(DXM/DXO) of >-0.5). HIV(-) cohort had the highest sertraline exposure. Sertraline exposure was ~40% lower in the PI/r cohort than in HIV(-); the need to alter sertraline dose ranges for PI/r participants is not clear. The impact of efavirenz on sertraline needs further investigation due to limited numbers of EFV participants.
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http://dx.doi.org/10.3389/fped.2019.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372542PMC
February 2019

Propelling the Pediatric HIV Therapeutic Agenda With Science, Innovation, and Collaboration.

J Acquir Immune Defic Syndr 2018 08;78 Suppl 1:S32-S39

Division of AIDS Research, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

Background: A number of well-described obstacles to the pediatric therapeutic agenda have resulted in substantial delays in the introduction of new medications, formulations, strategies, and approaches to treat infants, children, and adolescents living with HIV.

Setting: Global landscape.

Methods: The authors will provide a summary of current and emerging initiatives to accelerate the pediatric therapeutic agenda including illustrative case studies of innovations and scientific discovery in diagnosis and treatment of very young children with HIV infection.

Results: The challenges posed by rapid physiologic and developmental changes that characterize the trajectory of childhood as well as the complex regulatory and fiscal milieu of HIV therapeutics have hampered pediatric HIV therapeutic research. Recent efforts to accelerate this agenda include prioritizing agents and formulations, defining dosing by weight bands, applying innovative study designs, synergizing work across research networks to achieve common goals, and the establishment of a global prioritized research agenda. A case study of initiatives to diagnose and effectively treat newborns and infants will illustrate the critical role of basic science research and novel approaches to study design and implementation that are informing global efforts to end AIDS.

Conclusions: A pediatric therapeutic agenda informed by basic science and achieved through innovation and global cooperation is essential to achieve an AIDS-free generation.
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http://dx.doi.org/10.1097/QAI.0000000000001747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044456PMC
August 2018

Long-term psychological and educational outcomes for survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

Cancer 2018 08 11;124(15):3220-3230. Epub 2018 Jun 11.

Yale University School of Medicine, New Haven, Connecticut.

Background: Neuroblastoma survivors may be at elevated risk for psychological impairments because of their young age at diagnosis and neurotoxic treatment, but this is not well described.

Methods: A total of 859 ≥5-year survivors of neuroblastoma younger than 18 years (diagnosed in 1970-1999), who had a median age at diagnosis of 0.8 years (range: 0.0-7.3 years) and a median follow-up of 13.3 years (range: 8.0-17.9 years), were compared with 872 siblings of childhood cancer survivors who were younger than 18 years with the parent-reported Behavior Problem Index (BPI) for psychological functioning. Age- and sex-adjusted multivariate log-binomial models were used to identify factors associated with impairment in BPI domains (scores worse than the sibling 10th percentile). The impact of psychological impairment on educational outcomes was examined among survivors.

Results: Compared with siblings, neuroblastoma survivors had an increased prevalence of impairment in the domains of anxiety/depression (19% vs 14%; P = .003), headstrong behavior (19% vs 13%; P < .001), attention deficits (21% vs 13%; P < .001), peer conflict/social withdrawal (26% vs 17%; P < .001), and antisocial behavior (16% vs 12%; P = .01). Common treatment exposures (vincristine, cisplatin, and retinoic acid) were not associated with impairment. Having 2 or more chronic health conditions predicted impairment in 4 domains (P < .001). Specifically, pulmonary disease predicted impairment in all 5 domains (P ≤ .004). Endocrine disease (P ≤ .004) and peripheral neuropathy (P ≤ .02) each predicted impairment in 3 domains. Psychological impairment was associated with special education service usage and educational attainment less than college.

Conclusions: Neuroblastoma survivors are at elevated risk for psychological impairment, which is associated with special education service usage and lower adult educational attainment. Those with chronic health conditions may represent a high-risk group for targeted screening and intervention. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168938PMC
August 2018

Long-term psychological and educational outcomes for survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

Cancer 2018 08 11;124(15):3220-3230. Epub 2018 Jun 11.

Yale University School of Medicine, New Haven, Connecticut.

Background: Neuroblastoma survivors may be at elevated risk for psychological impairments because of their young age at diagnosis and neurotoxic treatment, but this is not well described.

Methods: A total of 859 ≥5-year survivors of neuroblastoma younger than 18 years (diagnosed in 1970-1999), who had a median age at diagnosis of 0.8 years (range: 0.0-7.3 years) and a median follow-up of 13.3 years (range: 8.0-17.9 years), were compared with 872 siblings of childhood cancer survivors who were younger than 18 years with the parent-reported Behavior Problem Index (BPI) for psychological functioning. Age- and sex-adjusted multivariate log-binomial models were used to identify factors associated with impairment in BPI domains (scores worse than the sibling 10th percentile). The impact of psychological impairment on educational outcomes was examined among survivors.

Results: Compared with siblings, neuroblastoma survivors had an increased prevalence of impairment in the domains of anxiety/depression (19% vs 14%; P = .003), headstrong behavior (19% vs 13%; P < .001), attention deficits (21% vs 13%; P < .001), peer conflict/social withdrawal (26% vs 17%; P < .001), and antisocial behavior (16% vs 12%; P = .01). Common treatment exposures (vincristine, cisplatin, and retinoic acid) were not associated with impairment. Having 2 or more chronic health conditions predicted impairment in 4 domains (P < .001). Specifically, pulmonary disease predicted impairment in all 5 domains (P ≤ .004). Endocrine disease (P ≤ .004) and peripheral neuropathy (P ≤ .02) each predicted impairment in 3 domains. Psychological impairment was associated with special education service usage and educational attainment less than college.

Conclusions: Neuroblastoma survivors are at elevated risk for psychological impairment, which is associated with special education service usage and lower adult educational attainment. Those with chronic health conditions may represent a high-risk group for targeted screening and intervention. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168938PMC
August 2018

Assessing Psychiatric Symptoms in Youth Affected by HIV: Comparing a Brief Self-Administered Rating Scale with a Structured Diagnostic Interview.

J Clin Psychol Med Settings 2018 12;25(4):420-428

Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, NY, USA.

Brief psychiatric assessment tools are needed for evaluating children affected by HIV for emotional and behavioral problems. We compared a self-administered symptom rating scale (CASI-4R) to a semi-structured diagnostic interview (DICA-P) in 136 U.S. children affected by HIV. Agreement and performance measures for the two instruments were computed for attention deficit hyperactivity disorder, depression, anxiety, and disruptive behavior. Correlations and regression analyses were conducted to compare the two instruments, and to evaluate their associations with social, academic, and global function. Higher CASI-4R symptom severity scores were associated with DICA diagnoses (p < 0.02 for all disorders). Agreement (κ) between DICA diagnoses and CASI-4R Clinical Cutoffs (which incorporated symptoms and impairment) was low to moderate (0.19-0.40 for all disorders). Thirty-two percent of cases with a DICA diagnosis were identified by the CASI-4R Clinical Cutoff (sensitivity), yet over 90% of DICA-negative cases were negative by the CASI-4R (specificity). Sensitivity was higher using CASI-4R Severity Score thresholds based on median scores compared to the DICA diagnoses. The presence and severity of psychiatric symptoms and impairment were associated with poorer academic, social, and global function. The CASI-4R symptom checklist can be used to inexpensively screen youth affected by HIV for emotional and behavioral problems, although it is important that there be appropriate mental health evaluation follow-up.
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http://dx.doi.org/10.1007/s10880-018-9550-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098977PMC
December 2018

The Behavior Rating Inventory of Executive Function (BRIEF) to Identify Pediatric Acute Lymphoblastic Leukemia (ALL) Survivors At Risk for Neurocognitive Impairment.

J Pediatr Hematol Oncol 2017 04;39(3):174-178

*Yale School of Public Health ‡Yale School of Medicine †Yale Cancer Center, New Haven, CT §University of Minnesota Medical School and University of Minnesota Amplatz Children's Hospital, Minneapolis, MN ∥National Institute of Mental Health, Bethesda, MD.

Neurocognitive problems, including executive dysfunction, are potential late effects of pediatric acute lymphoblastic leukemia treatment. Surveillance for neurocognitive impairment in a timely and efficient manner is imperative to ongoing clinical care. We sought to determine if the Behavior Rating Inventory of Executive Function (BRIEF) Parent Form identified leukemia survivors with cognitive impairment. In this 28-site cross-sectional study, parents of 256 children, a mean of 8.9±2.2 years after treatment for standard-risk precursor-B acute lymphoblastic leukemia and in first remission, completed the BRIEF. We used a multivariate logistic regression to calculate the association between elevated scores on 3 composite BRIEF indices (Behavioral Regulation Index, Metacognition Index, Global Executive Composite [GEC]) and special education and attention-deficit/hyperactivity disorder (ADHD) outcomes. All BRIEF index scores were significantly associated with receipt of special education services or ADHD. The BRI was most strongly associated with ADHD (odds ratios=4.33; 95% confidence interval, 1.72-10.9). The GEC was most strongly associated with ADHD (odds ratios=4.46; 95% confidence interval, 1.77-11.22). Elevated scores on the BRIEF GEC were associated with low sensitivity (24.1 to 39.1) for detecting the outcomes but better specificity (range, 87.7 to 89.3). These results suggest that the parent-completed BRIEF is associated with clinical outcomes but is not a sensitive tool to identify leukemia survivors that require a comprehensive neuropsychological assessment.
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http://dx.doi.org/10.1097/MPH.0000000000000761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364064PMC
April 2017

Creating Sustainable Collaborations for Implementation Science: The Case of the NIH-PEPFAR PMTCT Implementation Science Alliance.

J Acquir Immune Defic Syndr 2016 08;72 Suppl 2:S102-7

*Division of International Science, Policy, Planning and Evaluation and Center for Global Health Studies, Fogarty International Center, National Institutes of Health, Bethesda, MD; †Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; ‡Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC; §Office of the US Global AIDS Coordinator, US Department of State, Washington, DC; ‖Anova Health Institute, and School of Public Health & Family Medicine, University of Cape Town Johannesburg, South Africa; and ¶National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1097/QAI.0000000000001065DOI Listing
August 2016

The Association Between Motor Skills and Academic Achievement Among Pediatric Survivors of Acute Lymphoblastic Leukemia.

J Pediatr Psychol 2016 Apr 29;41(3):319-28. Epub 2015 Oct 29.

Section of Pediatric Hematology/Oncology, Yale University School of Medicine Yale Comprehensive Cancer Center, New Haven, CT, USA.

Objective: Assess the association between fine motor (FM) and visual-motor integration (VMI) skills and academic achievement in pediatric acute lymphoblastic leukemia (ALL) survivors.

Methods: In this 28-site cross-sectional study of 256 children in first remission, a mean of 8.9 ± 2.2 years after treatment for standard-risk precursor-B ALL, validated measures of FM, VMI, reading, math, and intelligence were administered at mean follow-up age of 12.8 ± 2.5 years. 

Results:  VMI was significantly associated with written math calculation ability (p < .0069) after adjusting for intelligence (p < .0001). VMI was more strongly associated with math in those with lower intelligence (p = .0141). Word decoding was also significantly associated with VMI but with no effect modification by intelligence. FM skills were not associated with either reading or math achievement.

Conclusion: These findings suggest that VMI is associated with aspects of math and reading achievement in leukemia survivors. These skills may be amenable to intervention.
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http://dx.doi.org/10.1093/jpepsy/jsv103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852216PMC
April 2016

A multi-disciplinary approach to implementation science: the NIH-PEPFAR PMTCT implementation science alliance.

J Acquir Immune Defic Syndr 2014 Nov;67 Suppl 2:S163-7

*Fogarty International Center, National Institutes of Health, Bethesda, MD; †Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC; ‡Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; §Office of the US Global AIDS Coordinator, US Department of State, Washington, DC; ‖Anova Health Institute, Johannesburg, South Africa; ¶National Institute of Mental Health, National Institutes of Health, Bethesda, MD; and #Office of Research on Women's Health, National Institutes of Health, Bethesda, MD.

In resource-limited countries, interventions to prevent mother-to-child HIV transmission (PMTCT) have not yet realized their full potential health impact, illustrating the common gap between the scientific proof of an intervention's efficacy and effectiveness and its successful implementation at scale into routine health services. For PMTCT, this gap results, in part, from inadequate adaptation of PMTCT interventions to the realities of the implementation environment, including client and health care worker behaviors and preferences, health care policies and systems, and infrastructure and resource constraints. Elimination of mother-to-child HIV transmission can only be achieved through understanding of key implementation barriers and successful adaptation of scientifically proven interventions to the local environment. Central to such efforts is implementation science (IS), which aims to investigate and address major bottlenecks that impede effective implementation and to test new approaches to identifying, understanding, and overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions. Advancing IS will require deliberate and strategic efforts to facilitate collaboration, communication, and relationship-building among researchers, implementers, and policy-makers. To speed the translation of effective PMTCT interventions into practice and advance IS more broadly, the US National Institutes of Health, in collaboration with the President's Emergency Plan for AIDS Relief launched the National Institutes of Health/President's Emergency Plan for AIDS Relief PMTCT IS Alliance, comprised of IS researchers, PMTCT program implementers, and policy-makers as an innovative platform for interaction and coordination.
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http://dx.doi.org/10.1097/QAI.0000000000000323DOI Listing
November 2014

Association between lymphocyte and monocyte subsets and cognition in children with HIV.

AIDS Res Ther 2014 Jan 22;11(1). Epub 2014 Jan 22.

HIV-NAT, The Thai Red Cross AIDS Research Centre, 104 Rajdumri Road, Pathumwan, Bangkok 10330, Thailand.

Background: This study assesses the relationships between lymphocyte and monocyte subsets and intelligence quotient (IQ) scores in antiretroviral therapy (ART)-naive, HIV-infected Thai children without advanced HIV disease.

Findings: Sixty-seven ART-naive Thai children with CD4 between 15-24% underwent cognitive testing by Weschler intelligence scale and had 13 cell subsets performed by flow cytometry including naive, memory and activated subsets of CD4+ and CD8+ T cells, activated and perivascular monocytes and B cells. Regression modelling with log10 cell count and cell percentage transformation was performed.Median age (IQR) was 9 (7-10) years, 33% were male, CDC stages N:A:B were 1:67:31%, median CD4% and count (IQR) were 21 (18-24)%, 597 (424-801) cells/mm3 and HIV RNA (IQR) was 4.6 (4.1-4.9) log10 copies/ml. Most (82%) lived at home, 45% had a biological parent as their primary caregiver, and 26 (49%) had low family income. The mean (SD) scores were 75 (13) for full scale IQ (FIQ), 73 (12) for verbal IQ (VIQ) and 80 (14) for performance IQ (PIQ). Adjusted multivariate regression analysis showed significant negative associations between B cell counts and FIQ, VIQ and PIQ (p < 0.01 for all); similar associations were found for B cell percentages (p < 0.05 for all).

Conclusions: High B cell counts and percentages were strongly associated with poorer FIQ, VIQ and PIQ scores. Prospective, long-term assessment of cell subsets and determination of relevant B cell subpopulations could help further elucidate associations between lymphocyte subsets and neurocognitive development.
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http://dx.doi.org/10.1186/1742-6405-11-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900937PMC
January 2014

Everyday executive function in standard-risk acute lymphoblastic leukemia survivors.

Child Neuropsychol 2015 16;21(1):78-89. Epub 2014 Jan 16.

a Children's National Medical Center & The George Washington University Medical Center , Washington , DC , USA.

We aimed to evaluate parent-rated executive function (EF) in pediatric standard risk acute lymphoblastic leukemia (SR-ALL) survivors compared to a healthy comparison (HC) group. We hypothesized that SR-ALL survivors would have greater reported executive dysfunction compared to HC, and that those younger at the time of treatment would demonstrate greater EF difficulties. A sample of 256 SR-ALL survivors evaluated an average nine years after treatment were compared to HC matched for gender, assessment age, and maternal education. Profile analysis was used to compare the groups across EF scales on the BRIEF. The prevalence of clinical elevations in the groups was compared via chi square, and odds ratios were calculated. Regression models were applied to examine the role of age at diagnosis and age at assessment in reported EF. Results indicated that SR-ALL survivors' mean scores of EF are similar to HC, except for flexibility and initiation. Survivors were rated as having clinical impairments with flexibility, initiation, working memory, and emotional control at rates two to three times that of HC. The risk of working memory and self-monitoring deficits was greater in survivors who were older when assessed. There was no relationship between age at diagnosis or treatment regimen on EF. These findings suggest sparing of extensive and severe EF deficits in SR-ALL survivors overall. However, a subset of survivors displays clinically significant executive dysfunction. There appears to be a heightened susceptibility to disrupted metacognitive functions as survivors age. This has implications for how we monitor neurocognitive development and functioning of SR-ALL survivors, and highlights opportunities for cognitive interventions.
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http://dx.doi.org/10.1080/09297049.2013.876491DOI Listing
January 2015

An analysis of select emerging executive skills in perinatally HIV-1-infected children.

Appl Neuropsychol Child 2014 13;3(1):10-25. Epub 2012 Sep 13.

a Department of Pediatrics , University of Maryland School of Medicine , Baltimore , Maryland.

This study examined the effect of perinatal HIV-1 infection on emerging executive skills in children (n = 161) ages 8 to 12 years. HIV-positive (n = 76) and HIV-negative (n = 85) children were eligible to participate. The HIV-positive children included those who had experienced a CDC Class C event (greater severity, n = 22) and those who were HIV-positive but who had not experienced a CDC Class C event (less severity, n = 54). Measures of emerging executive functions completed by the children included subtests from the Developmental Neuropsychological Assessment (NEPSY), the Trail-Making Test-Part B, and a subtest from the Woodcock-Johnson Battery-Revised. Ratings of executive functions were obtained from caretakers using the Behavior Rating Inventory of Executive Functions. Generalized estimating equations methods, discriminate analyses, and global deficit score analyses were performed to determine whether differences emerged between the three clinical groups while using strict controls. The present results revealed significant group differences in unadjusted mean scores measuring executive functioning. However, such differences did not remain statistically significant when moderating variables were taken into consideration in the models. The apparent deficit in executive functioning for the HIV-positive children was found to be largely due to differential psychosocial and environmental factors rather than HIV disease and its severity, and in this cohort, the effects of HIV-1 infection on emerging executive functions appeared to be negligible when controlling for treatment and moderating psychosocial variables.
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http://dx.doi.org/10.1080/21622965.2012.686853DOI Listing
July 2014

Assessing psychological well-being: self-report instruments for the NIH Toolbox.

Qual Life Res 2014 Feb 16;23(1):205-15. Epub 2013 Jun 16.

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, 625 North Michigan Ave., Suite 2700, Chicago, IL, 60611, USA,

Objective: Psychological well-being (PWB) has a significant relationship with physical and mental health. As a part of the NIH Toolbox for the Assessment of Neurological and Behavioral Function, we developed self-report item banks and short forms to assess PWB.

Study Design And Setting: Expert feedback and literature review informed the selection of PWB concepts and the development of item pools for positive affect, life satisfaction, and meaning and purpose. Items were tested with a community-dwelling US Internet panel sample of adults aged 18 and above (N = 552). Classical and item response theory (IRT) approaches were used to evaluate unidimensionality, fit of items to the overall measure, and calibrations of those items, including differential item function (DIF).

Results: IRT-calibrated item banks were produced for positive affect (34 items), life satisfaction (16 items), and meaning and purpose (18 items). Their psychometric properties were supported based on the results of factor analysis, fit statistics, and DIF evaluation. All banks measured the concepts precisely (reliability ≥0.90) for more than 98% of participants.

Conclusion: These adult scales and item banks for PWB provide the flexibility, efficiency, and precision necessary to promote future epidemiological, observational, and intervention research on the relationship of PWB with physical and mental health.
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http://dx.doi.org/10.1007/s11136-013-0452-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883907PMC
February 2014

Participation and retention of youth with perinatal HIV infection in mental health research studies: the IMPAACT P1055 psychiatric comorbidity study.

J Acquir Immune Defic Syndr 2013 Jul;63(3):401-9

Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA 02115, USA.

Background: Obtaining accurate estimates of mental health problems among youth perinatally infected with HIV (PHIV) helps clinicians develop targeted interventions but requires enrollment and retention of representative youth into research studies.

Methods: The study design for IMPAACT P1055, a US-based, multisite prospective study of psychiatric symptoms among PHIV youth and uninfected controls aged 6 to 17 years old, is described. Participants were compared with nonparticipants by demographic characteristics and reasons were summarized for study refusal. Adjusted logistic regression models were used to evaluate the association of psychiatric symptoms and other factors with loss to follow-up (LTFU).

Results: Among 2281 youth screened between 2005 and 2006 at 29 IMPAACT research sites, 580 (25%) refused to participate, primarily because of time constraints. Among 1162 eligible youth approached, 582 (50%) enrolled (323 PHIV and 259 Control), with higher participation rates for Hispanic youth. Retention at 2 years was significantly higher for PHIV than Controls (84% vs 77%, P = 0.03). In logistic regression models adjusting for sociodemographic characteristics and HIV status, youth with any self-assessed psychiatric condition had higher odds of LTFU compared with those with no disorder (adjusted odds ratio = 1.56, 95% confidence interval: 1.00 to 2.43). Among PHIV youth, those with any psychiatric condition had 3-fold higher odds of LTFU (adjusted odds ratio = 3.11, 95% confidence interval: 1.61 to 6.01).

Conclusions: Enrollment and retention of PHIV youth into mental health research studies is challenging for those with psychiatric conditions and may lead to underestimated risks for mental health problems. Creative approaches for engaging HIV-infected youth and their families are required for ensuring representative study populations.
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http://dx.doi.org/10.1097/QAI.0b013e318293ad53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683105PMC
July 2013

Emotion assessment using the NIH Toolbox.

Neurology 2013 Mar;80(11 Suppl 3):S76-86

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, USA.

One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to identify or develop brief measures of emotion for use in prospective epidemiologic and clinical research. Emotional health has significant links to physical health and exerts a powerful effect on perceptions of life quality. Based on an extensive literature review and expert input, the Emotion team identified 4 central subdomains: Negative Affect, Psychological Well-Being, Stress and Self-Efficacy, and Social Relationships. A subsequent psychometric review identified several existing self-report and proxy measures of these subdomains with measurement characteristics that met the NIH Toolbox criteria. In cases where adequate measures did not exist, robust item banks were developed to assess concepts of interest. A population-weighted sample was recruited by an online survey panel to provide initial item calibration and measure validation data. Participants aged 8 to 85 years completed self-report measures whereas parents/guardians responded for children aged 3 to 12 years. Data were analyzed using a combination of classic test theory and item response theory methods, yielding efficient measures of emotional health concepts. An overview of the development of the NIH Toolbox Emotion battery is presented along with preliminary results. Norming activities led to further refinement of the battery, thus enhancing the robustness of emotional health measurement for researchers using the NIH Toolbox.
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http://dx.doi.org/10.1212/WNL.0b013e3182872e11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662334PMC
March 2013

Norming plans for the NIH Toolbox.

Neurology 2013 Mar;80(11 Suppl 3):S87-92

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Objective: The NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox) is a comprehensive battery of brief assessment tools. The purpose of this article is to describe plans to establish normative reference values for the NIH Toolbox measures.

Methods: A large sample will be obtained from the US population for the purpose of calculating normative values. The sample will be stratified by age (ages 3-85 years), sex, and language preference (English or Spanish) and have a total sample size of at least 4,205. The sample will include a minimum of 25-100 individuals in each targeted demographic and language subgroup.

Results: Norming methods will include poststratification adjustment calculated using iterative proportional fitting, also known as raking, so that the weighted sample will have the same distribution on key demographic variables as the US population described in the 2010 Census.

Conclusions: As with any set of norms, users should be mindful of the reference population and make conclusions consistent with the limitations of normative sampling, since it is not a probability-based sample. However, the NIH Toolbox norming study has been designed to minimize bias and maximize representativeness and precision of estimates. The availability of a "toolbox" of normed measures will be an important foundation for addressing critical research questions in neurologic and behavioral health.
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http://dx.doi.org/10.1212/WNL.0b013e3182872e70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662345PMC
March 2013

Cognitive function and neurodevelopmental outcomes in HIV-infected Children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study.

Pediatr Infect Dis J 2013 May;32(5):501-8

HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Background: We previously reported similar AIDS-free survival at 3 years in children who were >1 year old initiating antiretroviral therapy (ART) and randomized to early versus deferred ART in the Pediatric Randomized to Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) study. We now report neurodevelopmental outcomes.

Methods: Two hundred eighty-four HIV-infected Thai and Cambodian children aged 1-12 years with CD4 counts between 15% and 24% and no AIDS-defining illness were randomized to initiate ART at enrollment ("early," n = 139) or when CD4 count became <15% or a Centers for Disease Control (CDC) category C event developed ("deferred," n = 145). All underwent age-appropriate neurodevelopment testing including Beery Visual Motor Integration, Purdue Pegboard, Color Trails and Child Behavioral Checklist. Thai children (n = 170) also completed Wechsler Intelligence Scale (intelligence quotient) and Stanford Binet Memory test. We compared week 144 measures by randomized group and to HIV-uninfected children (n = 319).

Results: At week 144, the median age was 9 years and 69 (48%) of the deferred arm children had initiated ART. The early arm had a higher CD4 (33% versus 24%, P < 0.001) and a greater percentage of children with viral suppression (91% versus 40%, P < 0.001). Neurodevelopmental scores did not differ by arm, and there were no differences in changes between arms across repeated assessments in time-varying multivariate models. HIV-infected children performed worse than uninfected children on intelligence quotient, Beery Visual Motor Integration, Binet memory and Child Behavioral Checklist.

Conclusions: In HIV-infected children surviving beyond 1 year of age without ART, neurodevelopmental outcomes were similar with ART initiation at CD4 15%-24% versus <15%, but both groups performed worse than HIV-uninfected children. The window of opportunity for a positive effect of ART initiation on neurodevelopment may remain in infancy.
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http://dx.doi.org/10.1097/INF.0b013e31827fb19dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664246PMC
May 2013

Prevalence and predictors of prescription psychoactive medication use in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

J Cancer Surviv 2013 Mar 8;7(1):104-14. Epub 2012 Dec 8.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Purpose: Childhood cancer survivors are at risk for late effects which may be managed pharmacologically. The purposes of this study were to estimate and compare the prevalence of psychoactive medication use of adult survivors of childhood cancer and sibling controls, identify predictors of medication use in survivors, and investigate associations between psychoactive medications and health-related quality of life (HRQOL).

Methods: Psychoactive medication use from 1994 to 2010 was evaluated in 10,378 adult survivors from the Childhood Cancer Survivor Study. A randomly selected subset of 3,206 siblings served as a comparison group. Multivariable logistic regression models were used to calculate odds ratios (OR) for baseline and new onset of self-reported psychoactive medication use and HRQOL.

Results: Survivors were significantly more likely to report baseline (22 vs. 15 %, p < 0.001) and new onset (31 vs. 25 %, p < 0.001) psychoactive medication use compared to siblings, as well as use of multiple medications (p < 0.001). In multivariable models, controlling for pain and psychological distress, female survivors were significantly more likely to report baseline and new onset use of antidepressants (OR = 2.66, 95 % CI = 2.01-3.52; OR = 2.02, 95 % CI = 1.72-2.38, respectively) and multiple medications (OR = 1.80, 95 % CI = 1.48-2.19; OR = 1.77, 95 % CI = 1.48-2.13, respectively). Non-cranial radiation and amputation predicted incident use of analgesics >15 years following diagnosis. Antidepressants were associated with impairment across all domains of HRQOL, with the exception of physical function.

Conclusions: Prevalence of psychoactive medication use was higher among survivors for most medication classes, as was the use of multiple medications. Clinicians should be aware of the possible contribution of psychoactive medications to HRQOL.

Implications For Cancer Survivors: Survivors of childhood cancer are more likely to be prescribed psychoactive medication than their sibling counterparts, though use of such medication does not appear to normalize quality of life. Survivors are encouraged to consider additional interventions, including psychosocial support and physical exercise.
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http://dx.doi.org/10.1007/s11764-012-0250-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568188PMC
March 2013

Psychoactive medication use and neurocognitive function in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor study.

Pediatr Blood Cancer 2013 Mar 27;60(3):486-93. Epub 2012 Jul 27.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer.

Procedure: Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study (CCSS) using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors' report of prescription medication use.

Results: Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR = 1.80, 95% CI = 1.47-2.21), organization (OR = 1.83, 95% CI = 1.48-2.25), memory (OR = 1.53, 95% CI = 1.27-1.84), and emotional regulation (OR = 2.06, 95% CI = 1.70-2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR = 2.46, 95% CI = 1.29-4.69; OR = 2.82, 95% CI = 1.61-4.93, respectively) and memory (OR = 2.08, 95% CI = 1.13-3.82; OR = 2.69, 95% CI = 1.59-4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory, and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS).

Conclusions: These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained.
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http://dx.doi.org/10.1002/pbc.24255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494805PMC
March 2013

Associations of cytokines, sleep patterns, and neurocognitive function in youth with HIV infection.

Clin Immunol 2012 Jul 2;144(1):13-23. Epub 2012 May 2.

Baylor College of Medicine, Department of Pediatrics and Texas Children's Hospital, Houston, TX 77030, USA.

Youth infected with HIV at birth often have sleep disturbances, neurocognitive deficits, and abnormal psychosocial function which are associated with and possibly resulted from elevated blood cytokine levels that may lead to a decreased quality of life. To identify molecular pathways that might be associated with these disorders, we evaluated 38 HIV-infected and 35 uninfected subjects over 18-months for intracellular cytokine levels, sleep patterns and duration of sleep, and neurodevelopmental abilities. HIV infection was significantly associated with alterations of intracellular pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12), sleep factors (total time asleep and daytime sleep patterns), and neurocognitive factors (parent and patient reported problems with socio-emotional, behavioral, and executive functions; working memory-mental fatigue; verbal memory; and sustained concentration and vigilance. By better defining the relationships between HIV infection, sleep disturbances, and poor psychosocial behavior and neurocognition, it may be possible to provide targeted pharmacologic and procedural interventions to improve these debilitating conditions.
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http://dx.doi.org/10.1016/j.clim.2012.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377781PMC
July 2012

A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings.

J Neurovirol 2011 Oct 23;17(5):438-47. Epub 2011 Jul 23.

University of North Carolina, Chapel Hill, NC 27599-7025, USA.

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.
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http://dx.doi.org/10.1007/s13365-011-0044-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362044PMC
October 2011

Folate pathway polymorphisms predict deficits in attention and processing speed after childhood leukemia therapy.

Pediatr Blood Cancer 2011 Sep 25;57(3):454-60. Epub 2011 May 25.

Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX, USA.

Background: Neurocognitive impairment occurs in 20-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.

Procedure: Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), serine hydroxymethyltransferase (SHMT 1420C>T), methionine synthase (MS 2756 A>G), methionine synthase reductase (MTRR 66A>G), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype.

Results: General impairment on the neurocognitive battery was related to MTHFR 1298A>C (P = 0.03) and MS 2756A>G (P = 0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (P = 0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (P = 0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (P = 0.03). Survivors with ≥6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (P = 0.06) and 14.5 point lower TMTB score (P = 0.002) than survivors with <6 risk alleles.

Conclusions: Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy.
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http://dx.doi.org/10.1002/pbc.23162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134130PMC
September 2011

Co-occuring psychiatric symptoms in children perinatally infected with HIV and peer comparison sample.

J Dev Behav Pediatr 2010 Feb-Mar;31(2):116-28

Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY 11794-8790, USA.

Objective: To compare the rates of psychopathology in youths perinatally infected with HIV (N = 319) with a comparison sample of peers (N = 256) either HIV-exposed or living in households with HIV-infected family members.

Method: Participants were randomly recruited from 29 sites in the United States and Puerto Rico and completed an extensive battery of measures including standardized DSM-IV-referenced ratings scales.

Results: The HIV+ group was relatively healthy (73% with CD4% >25%), and 92% were actively receiving antiretroviral therapy. Youths with HIV (17%) met symptom and impairment criteria for the following disorders: attention-deficit/hyperactivity disorder (12%), oppositional defiant disorder (5%), conduct disorder (1%), generalized anxiety disorder (2%), separation anxiety disorder (1%), depressive disorder (2%), or manic episode (1%). Many youths with HIV (27%) and peers (26%) were rated (either self- or caregiver report) as having psychiatric problems that interfered with academic or social functioning. With the exception of somatization disorder, the HIV+ group did not evidence higher rates or severity of psychopathology than peers, although rates for both groups were higher than the general population. Nevertheless, self-awareness of HIV infection in younger children was associated with more severe symptomatology, and youths with HIV had higher lifetime rates of special education (44 vs 32%), psychopharmacological (23 vs 12%), or behavioral (27 vs 17%) interventions. Youth-caregiver agreement was modest, and youths reported more impairment.

Conclusion: HIV infection was not associated with differentially greater levels of current psychopathology; nevertheless, investigation of relations with developmental changes and specific illness parameters and treatments are ongoing.
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http://dx.doi.org/10.1097/DBP.0b013e3181cdaa20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868331PMC
May 2010

Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia.

J Clin Oncol 2009 Dec 2;27(35):5986-92. Epub 2009 Nov 2.

Section of Pediatric Hematology-Oncology, Yale University School of Medicine, New Haven, CT, USA.

Purpose: For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared.

Patients And Methods: In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment.

Results: Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications.

Conclusion: This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group.
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http://dx.doi.org/10.1200/JCO.2009.23.5408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793042PMC
December 2009

Mental health treatment patterns in perinatally HIV-infected youth and controls.

Pediatrics 2009 Aug 13;124(2):627-36. Epub 2009 Jul 13.

Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Background: Youths perinatally infected with HIV often receive psychotropic medication and behavioral treatment for emotional and behavioral symptoms. We describe patterns of intervention for HIV-positive youth and youth in a control group in the United States.

Methods: Three hundred nineteen HIV-positive youth and 256 controls, aged 6 to 17 years, enrolled in the International Maternal Adolescent AIDS Clinical Trials 1055, a prospective, 2-year observational study of psychiatric symptoms. One hundred seventy-four youth in the control group were perinatally exposed to HIV, and 82 youth were uninfected children living in households with HIV-positive members. Youth and their primary caregivers completed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-referenced symptom-rating scales. Children's medication and behavioral psychiatric intervention histories were collected at entry. We evaluated the association of past or current psychiatric treatment with HIV status, baseline symptoms, and impairment by using multiple logistic regression, controlling for potential confounders.

Results: HIV-positive youth and youth in the control group had a similar prevalence of psychiatric symptoms (61%) and impairment (14% to 15%). One hundred four (18%) participants received psychotropic medications (stimulants [14%], antidepressants [6%], and neuroleptic agents [4%]), and 127 (22%) received behavioral treatment. More HIV-positive youth than youth in the control group received psychotropic medication (23% vs 12%) and behavioral treatment (27% vs 17%). After adjusting for symptom class and confounders, HIV-positive children had twice the odds of children in the control group of having received stimulants and >4 times the odds of having received antidepressants. Caregiver-reported symptoms or impairment were associated with higher odds of intervention than reports by children alone.

Conclusions: HIV-positive children are more likely to receive mental health interventions than control-group children. Pediatricians and caregivers should consider available mental health treatment options for all children living in families affected by HIV.
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http://dx.doi.org/10.1542/peds.2008-2441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764487PMC
August 2009

A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia.

Blood 2009 Aug 22;114(9):1746-52. Epub 2009 Jun 22.

Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.

In previous clinical trials of childhood acute lymphoblastic leukemia (ALL), dexamethasone resulted in higher event-free survival rates than prednisone, presumably due to greater central nervous system penetration. Dexamethasone's association with long-term neurocognitive toxicity is unknown. In this multisite study, we measured neurocognitive functioning in 92 children with standard-risk ALL, 1 to 9.99 years at diagnosis, at a mean of 9.8 years after randomization to prednisone (n = 41) or dexamethasone (n = 51) on Children's Cancer Group (CCG) 1922. No significant overall differences in mean neurocognitive and academic performance scores were found between the prednisone and dexamethasone groups after adjusting for age, sex, and time since diagnosis. The exception was that patients receiving dexamethasone scored one-third of a standard deviation worse on word reading (98.8 +/- 1.7 vs 104.9 +/- 1.8; P = .02). There were no group differences in the distribution of test scores or the parents' report of neurologic complications, psychotropic drug use, and special education. Further analyses suggested for the dexamethasone group, older age of diagnosis was associated with worse neurocognitive functioning; for the prednisone group, younger age at diagnosis was associated with worse functioning. In conclusion, our study did not demonstrate any meaningful differences in long-term cognitive functioning of childhood ALL patients based on corticosteroid randomization. This study is registered with http://www.clinicaltrials.gov under NCT00085176.
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http://dx.doi.org/10.1182/blood-2008-12-186502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738566PMC
August 2009

Sex-specific attention problems in long-term survivors of pediatric acute lymphoblastic leukemia.

Cancer 2009 Sep;115(18):4238-45

Department of Psychology, University of Houston, and Child Psychology, Texas Children's Hospital, Houston, Texas, USA.

Background: Neurocognitive problems are a frequent outcome of chemotherapy for pediatric leukemia, although individual differences exist in patient outcome. Sex of the patient and age at diagnosis are 2 characteristics that have been associated with differential outcomes. The relation between these patient characteristics and specific attention deficits (ie, initiating, inhibiting, shifting, focusing, sustaining attention, and working memory) has not been well researched. The purpose of this study was to evaluate the pattern of attention problems in male and female long-term survivors of pediatric acute lymphoblastic leukemia (ALL).

Methods: One hundred three long-term survivors (ie, >or=5 years from diagnosis; 51% boys, mean age at diagnosis of 3.9 years, and mean time since diagnosis 7.5 years) completed standardized measures of basic and complex attention skills related to anterior (ie, inhibition, shifting attention, working memory), posterior (ie, focusing), and subcortical brain systems (ie, sustaining).

Results: Treatment intensity was related to sustained attention, with those patients treated on high-risk protocols displaying significantly lower performance. Girls performed worse than boys on measures related to the anterior attention system (ie, shifting attention, P<.042) and the subcortical attention system (ie, sustained attention, P<.001), whereas boys performed worse than girls on different measures of anterior control (ie, inhibition, P<.039; working memory, P<.003).

Conclusions: The results of this study suggest that children diagnosed with and treated for pediatric ALL perform poorly on select measures of attention and executive control, and that this performance is influenced by sex and treatment intensity.
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http://dx.doi.org/10.1002/cncr.24464DOI Listing
September 2009

Early immunological predictors of neurodevelopmental outcomes in HIV-infected children.

Clin Infect Dis 2009 Feb;48(3):338-46

Division of Infectious Diseases, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

Background: A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8(+) T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis.

Methods: Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (5% CD8(+)HLA-DR(+) cells or >25% CD8(+)CD38(+) cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models.

Results: Absence of immune activation, measured as
Conclusions: In this prospective cohort study of HIV-infected children, there was a significant favorable association of low immune activation in peripheral T cells at age 1 or 2 months, measured by a low percentage of CD8(+)HLA-DR(+) cells, with subsequent psychomotor and mental development. This association was independent of other indices of severity and progression of HIV infection.
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http://dx.doi.org/10.1086/595885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671733PMC
February 2009