Investing in the future of young people.

Atrocious events seem to have multiplied in frequency recently. Sometimes it feels as if we have become almost inured to their obscenity. No sooner has the impact and aftermath of one event receded into the past than along comes another to test our reserves.

Antiretroviral treatment initiation does not differentially alter neurocognitive functioning over time in youth with behaviorally acquired HIV.

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18-24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n = 56); group 2 had CD4 >350 and were not initiating ART (n = 66); group 3 initiated ART with CD4 <350 (n = 59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification.

Three postpartum antiretroviral regimens to prevent intrapartum HIV infection.

BACKGROUND: The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants. METHODS: Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth. RESULTS: A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan-Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups). CONCLUSIONS: In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.).

Identification and treatment of scabies in infants.

Incidents of scabies are increasing nationally and globally, particularly among certain vulnerable groups. This article examines a rare and unusual case of scabies infestation in infancy and highlights the importance of recognising the differences in presentation of infestation in infants to enhance early diagnosis and treatment.

Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.).

Comprehension of a simplified assent form in a vaccine trial for adolescents.

INTRODUCTION: Future HIV vaccine efficacy trials with adolescents will need to ensure that participants comprehend study concepts in order to confer true informed assent. A Hepatitis B vaccine trial with adolescents offers valuable opportunity to test youth understanding of vaccine trial requirements in general. METHODS: Youth reviewed a simplified assent form with study investigators and then completed a comprehension questionnaire. Once enrolled, all youth were tested for HIV and confirmed to be HIV-negative. RESULTS: 123 youth completed the questionnaire (mean age=15 years; 63% male; 70% Hispanic). Overall, only 69 (56%) youth answered all six questions correctly. CONCLUSIONS: Youth enrolled in a Hepatitis B vaccine trial demonstrated variable comprehension of the study design and various methodological concepts, such as treatment group masking.

Assessment of suicidal intent in emergency care.

The assessment of suicidal intent in first-contact settings, including the emergency department, can be challenging. Inaccurate assessment can lead to increased incidence of self-harm and completion of suicide. This article focuses on factors that may affect review of this patient group, including healthcare professionals' personal and professional standards and values. Strategies to aid assessment of people presenting with suicidal ideation are discussed.

Anaphylaxis: diagnosis and treatment.

Anaphylaxis is a severe and potentially life-threatening condition that is becoming increasingly prevalent. Healthcare professionals working in a variety of settings need to know how to recognise this condition and the importance of treating it promptly. This article describes the pathophysiology, causes and treatment of anaphylaxis.

Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

BACKGROUND: The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). METHODS: This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. RESULTS: At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS: In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION: NCT00490412.

Acute pyelonephritis: risk factors, diagnosis and treatment.

Pyelonephritis is an acute urological condition that involves infection of one or both kidneys. The condition is not generally associated with high levels of mortality, but patients can become acutely ill and experience severe pain. Early recognition and treatment of pyelonephritis may limit morbidity. This article identifies patients at increased risk of pyelonephritis and discusses appropriate strategies to prevent serious complications.

Emergency care of children and adults with head injury.

Head injury is common and accounts for a significant proportion of patient attendances at emergency departments and minor injury units. While most injuries will not be serious in nature, some will be severe. Therefore assessment, investigation and early management of head injury are essential to reduce the potential risk of disability or even death. This article focuses on emergency care of children and adults with head injuries. Advice about the signs and symptoms of severe head injury, the importance of computed tomography and after care following head injury are outlined.

Pre-transplant lung function is predictive of survival following pediatric bone marrow transplantation.

BACKGROUND: Pulmonary toxicity is well described in recipients of bone marrow transplants (BMT), and accounts for a sizeable proportion of post-transplant mortality. The majority of the data on post-transplant pulmonary function is from adults, although several small pediatric case series have been described. In adults, pre-transplant lung function has been predictive of post-transplant respiratory failure and mortality. This use of pulmonary function testing, that is, for pre-transplant risk counseling, is novel but has never been applied to pediatric patients. We hypothesized that in children, as in adults, pre-transplant pulmonary function would also be predictive of outcome post-transplantation morbidity. PROCEDURE: Retrospective database analysis of pulmonary function tests of patients undergoing first myeloablative BMT at two large children's hospitals. RESULTS: Two hundred seventy-three subjects had at least one pre-transplant PFT, and 317 subjects had at least one post-transplant PFT available for analysis. While the majority of patients had normal or mildly reduced pre-transplant flows and lung volume, 25% had moderately or severely reduced diffusion. All lung function parameters decreased post-transplant with a slow improvement over ensuing years. The Lung Function Score, a combined measurement of FEV(1) and DLCO, was highly associated with post-transplant survival. Hazard ratios for mortality (compared to the best LFS) ranged from 1.654 to 2.454. CONCLUSIONS: Lung function prior to bone marrow transplant, especially diffusing capacity, is frequently abnormal. Lung function frequently decreases shortly post-transplant and tends to improve over time, but frequently remains abnormal even years after transplant. Post-transplant survival is related to pre-transplant lung function.

Distinguishing features of preseptal and orbital cellulitis.

The differential diagnosis between orbital cellulitis and preseptal cellulitis is important as is the need to differentiate between an allergic response or infectious cellulitis of the eye. This article will examine the case of a 15-month-old boy who was brought to an emergency department with an oedematous right eye. The research about diagnosis and treatment will be evaluated and orbital cellulitis will be explored in more detail including the symptoms and complications.

The challenge of multisite epidemiologic studies in diverse populations: design and implementation of a 22-site study of tuberculosis in foreign-born people.

OBJECTIVES: We designed a population-based study of the epidemiology of tuberculosis among foreign-born people in the U.S. and Canada. Challenges included standardizing recruitment and data entry at 22 sites, enrolling individuals who did not speak English and may be undocumented, and obtaining clearance from 36 institutional review boards (IRBs). METHODS: We used stratified sampling to recruit patients through the Tuberculosis Epidemiologic Studies Consortium, a research consortium funded by the Centers for Disease Control and Prevention. Because recruitment sites were overseen by more than 30 local IRBs, we developed a simple process to designate a central IRB. We translated instruments into 10 main languages, arranged for fast translation of consent "short forms" into other languages, used one telephone interpretation service at all sites, and provided extensive interviewer training including mock interviews with simulated patients. RESULTS: We interviewed 1,696 participants in 19 states and provinces. Participants from 99 countries were interviewed in 40 languages. Twenty-three percent did not speak English at all; 64% needed an interpreter. More than 20% of participants reported they were undocumented. Participants' age, gender, and birthplaces were broadly similar to the target populations. One-third of local IRBs used the central IRB. CONCLUSIONS: Special confidentiality protections, substantial resources for translation and interpretation, and a centralized IRB made possible the recruitment of a representative sample of foreign-born people. The approaches may be applicable to studies of other diseases in multinational populations in the U.S. and Canada.

Sexually transmitted infections and immune activation among HIV-infected but virally suppressed youth on antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with chronic immune activation, and concurrent sexually transmitted infections (STIs) may increase immune activation. OBJECTIVES: Because HIV-infected youth are at high risk of STIs and little is known about the impact of STIs on immune activation in HIV-infected youth, we conducted an exploratory study examining the association between STIs and systemic inflammation and immune activation among HIV-infected adolescents. STUDY DESIGN: Forty-nine behaviorally infected U.S. youth ages 18-24 years with baseline CD4+ T-cells >350 who maintained viral suppression on therapy by week 48 were included. Evaluation for STIs (herpes simplex virus [HSV], Chlamydia trachomatis, syphilis, Neisseria gonorrhoeae) was conducted as standard of care and reported on case report forms. Measures of T-cell subsets, systemic immune activation, and soluble factors were examined at week 48 for differences between participants with an STI diagnosis during the 48 weeks compared to those without an STI. RESULTS: Forty-three participants (88%) were male; 57% had baseline CD4+ T-cell counts >500 cells/mm3. Eighteen youth were reported to have ≥1 STI. At week 48, participants with STIs demonstrated lower CD4+ T-cell counts (any STI vs. no STI, p = 0.024; HSV vs. no STI, p = 0.022) and evidence of increased systemic immune activation, including higher CD57 intensity, higher HLA-DR intensity, and lower CD28 percentage, when compared to those without STIs. There were no differences in soluble factors between STI groups. CONCLUSIONS: Results indicate novel activation of CD4+ T-cells among HIV-infected youth who have STIs other than HSV, which may contribute to disease progression.

Blood lead concentration and delayed puberty in girls.

BACKGROUND: Environmental lead exposure has been linked to alterations in growth and endocrine function. It is not known whether such exposure affects pubertal development. METHODS: We analyzed the relations between blood lead concentration and pubertal development among girls (defined as females 8 to 18 years of age) who were enrolled in a cross-sectional study (the third National Health and Nutrition Examination Survey) in which race was self-reported or proxy-reported: 600 were non-Hispanic white, 805 were non-Hispanic African-American, and 781 were Mexican-American girls. Puberty was measured on the basis of the age at menarche and Tanner stage for pubic-hair and breast development. RESULTS: Geometric mean lead concentrations were less than 3 microg per deciliter (0.144 micromol per liter) in all three groups. As compared with concentrations of 1 microg per deciliter (0.048 micromol per liter), lead concentrations of 3 microg per deciliter were associated with decreased height (P<0.001), after adjustment for age, race, and other factors, but not with body-mass index or weight. Blood lead concentrations of 3 microg per deciliter were associated with significant delays in breast and pubic-hair development in African-American and Mexican-American girls. The delays were most marked among African-American girls; in this group, the delays in reaching Tanner stages 2, 3, 4, and 5 associated with a lead concentration of 3 microg per deciliter as compared with 1 microg per deciliter were 3.8, 5.3, 5.8, and 2.1 months, respectively, for breast development and 4.0, 5.5, 6.0, and 2.2 months, respectively, for pubic-hair development; the associated delay in age at menarche was 3.6 months. In white girls, there were nonsignificant delays in all pubertal measures in association with a lead concentration of 3 microg per deciliter. CONCLUSIONS: These data suggest that environmental exposure to lead may delay growth and pubertal development in girls, although confirmation is warranted in prospective studies.

Patient Navigation for Colonoscopy Completion: Results of an RCT.

INTRODUCTION: Colorectal cancer is a leading cause of cancer-related death in the U.S. Although screening reduces colorectal cancer incidence and mortality, screening rates among U.S. adults remain less than optimal, especially among disadvantaged populations. This study examined the efficacy of patient navigation to increase colonoscopy screening. STUDY DESIGN: RCT. SETTING/PARTICIPANTS: A total of 843 low-income adults, primarily Hispanic and non-Hispanic blacks, aged 50-75 years referred for colonoscopy at Boston Medical Center were randomized into the intervention (n=429) or control (n=427) groups. Participants were enrolled between September 2012 and December 2014, with analysis following through 2015. INTERVENTION: Two bilingual lay navigators provided individualized education and support to reduce patient barriers and facilitate colonoscopy completion. The intervention was delivered largely by telephone. MAIN OUTCOME MEASURE: Colonoscopy completion within 6 months of study enrollment. RESULTS: Colonoscopy completion was significantly higher for navigated patients (61.1%) than control group patients receiving usual care (53.2%, p=0.021). Based on regression analysis, the odds of completing a colonoscopy for navigated patients was one and a half times greater than for controls (95% CI=1.12, 2.03, p=0.007). There were no differences between navigated and control groups in regard to adequacy of bowel preparation (95.3% vs 97.3%, respectively). CONCLUSIONS: Navigation significantly improved colonoscopy screening completion among a racially diverse, low-income population. Results contribute to mounting evidence demonstrating the efficacy of patient navigation in increasing colorectal cancer screening. Screening can be further enhanced when navigation is combined with other evidence-based practices implemented in healthcare systems and the community.

Effect of Fontan geometry on exercise haemodynamics and its potential implications.

OBJECTIVE: Exercise intolerance afflicts Fontan patients with total cavopulmonary connections (TCPCs) causing a reduction in quality of life. Optimising TCPC design is hypothesised to have a beneficial effect on exercise capacity. This study investigates relationships between TCPC geometries and exercise haemodynamics and performance. METHODS: This study included 47 patients who completed metabolic exercise stress test with cardiac magnetic resonance (CMR). Phase-contrast CMR images were acquired immediately following supine lower limb exercise. Both anatomies and exercise vessel flow rates at ventilatory anaerobic threshold (VAT) were extracted. The vascular modelling toolkits were used to analyse TCPC geometries. Computational simulations were performed to quantify TCPC indexed power loss (iPL) at VAT. RESULTS: A highly significant inverse correlation was found between the TCPC diameter index, which factors in the narrowing of TCPC vessels, with iPL at VAT (r=-0.723, p<0.001) but positive correlations with exercise performance variables, including minute oxygen consumption (VO2) at VAT (r=0.373, p=0.01), VO2 at peak exercise (r=0.485, p=0.001) and work at VAT/weight (r=0.368, p=0.01). iPL at VAT was negatively correlated with VO2 at VAT (r=-0.337, p=0.02), VO2 at peak exercise (r=-0.394, p=0.007) and work at VAT/weight (r=-0.208, p=0.17). CONCLUSIONS: Eliminating vessel narrowing in TCPCs and reducing elevated iPL at VAT could enhance exercise tolerance for patients with TCPCs. These findings could help plan surgical or catheter-based strategies to improve patients' exercise capacity.

Effective Treatment of Depressive Disorders in Medical Clinics for Adolescents and Young Adults Living With HIV: A Controlled Trial.

OBJECTIVE: Preliminary test of a manualized, measurement-guided treatment for depression for adolescents and young adults in care at 4 sites of the Adolescent Trials Network for HIV/AIDS Interventions. DESIGN: The US sites were randomly assigned to either a 24-week, combination cognitive behavioral therapy and medication management algorithm (COMB) tailored for youth living with HIV (YLWH) or to treatment as usual (TAU). METHODS: Youth at TAU sites had access to therapists and medication management as needed. COMB-site clinicians were trained in the manualized intervention and participated in supervision calls to monitor intervention fidelity. RESULTS: Over the course of the study with 44 participants, those in COMB, compared with those in TAU, reported fewer depressive symptoms, P < 0.01 (as measured by the Quick Inventory for Depression symptoms) and were more likely to be in remission, P < 0.001 (65% vs. 10% at week 24, end of treatment, and 71% vs. 7% at week 48, final follow-up). A greater proportion of COMB participants received psychotherapy (95% vs. 45%, P < 0.001) and attended more sessions (12.6 vs. 5, P < 0.001) than those in TAU. Viral load decreased in both groups and was associated (P < 0.05) with reduction in depressive symptoms. CONCLUSIONS: A 24-week manualized, measurement-guided psychotherapy and medication management algorithm tailored for YLWH was more effective in achieving and sustaining remission from depression than TAU at HIV care clinic sites. Given observed treatment efficacy, this structured combination treatment could be disseminated to medical clinics to successfully treat YLWH, who are at particular risk for depression.