Lower Insulin Sensitivity Through 36 Months of Life With in Utero HIV and Antiretroviral Exposure in Botswana: Results From the Tshilo Dikotla Study.

BACKGROUND: There are little data on changes in insulin sensitivity during the first few years of life following in utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure. METHODS: The Tshilo Dikotla study enrolled pregnant persons with HIV (PWH) (receiving tenofovir/emtricitabine or lamivudine plus dolutegravir or efavirenz) and pregnant individuals without HIV, as well as their liveborn children. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was assessed at birth and 1, 18, 24, and 36 months of life. We fit linear mixed-effects models to evaluate the association between in utero HIV/ARV exposure and average HOMA-IR from birth through 36 months of life, adjusting for confounders. RESULTS: A total of 419 children were included (287 with in utero HIV/ARV exposure and uninfected [CHEU] and 132 without in utero HIV/ARV exposure [CHUU]). CHEU were born to older women (29.6 vs 25.3 years of age) with higher gravidity (3 vs 1). HOMA-IR was persistently higher in CHEU versus CHUU in adjusted analyses (mean difference of 0.07 in log10 HOMA-IR, P  = .02) from birth through 36 months of life. Among CHEU, no differences in HOMA-IR were observed from birth through 36 months by in utero ARV exposure status or between AZT and NVP infant prophylaxis arms. CONCLUSIONS: In utero HIV/ARV exposure was associated with lower insulin sensitivity throughout the first 36 months of life, indicating persistent early life metabolic disturbances which may raise concern for poorer metabolic health later in life.

Longitudinal changes in body fat and metabolic complications in young people with perinatally acquired HIV.

BACKGROUND: The role of body fat on metabolic complications remains poorly understood in young people living with perinatally acquired HIV (YPHIV). OBJECTIVE: Our objective was to assess the association of changes in adiposity over 2 years with metabolic outcomes in YPHIV. METHODS: The PHACS Adolescent Master Protocol (AMP) study enrolled YPHIV from 2007 to 2009 across 15 US sites, including Puerto Rico. We included YPHIV aged 7-19 years with body composition data assessed by whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 2 years later. Metabolic outcomes included homeostatic model assessment of insulin resistance (HOMA-IR) and non-high-density lipoprotein cholesterol (non-HDL-C). We fitted linear regression models to assess the association of increase in body fat over 2 years with metabolic outcomes at years 2 and 3. RESULTS: In all, 232 participants had a second DXA and either HOMA-IR or non-HDL-C measured at year 2. Participant characteristics at the first DXA were: age 12 years (9-14) [median (Q1-Q3)], 69% Black, and median CD4 count 714 cells/µL; 70% with HIV RNA <400 copies/mL. In adjusted analyses for every 1% increase in body fat from baseline to year 2, HOMA-IR was higher by 1.03-fold at year 3 (95% CI: 1.00, 1.05). We observed that for every 1% increase in body fat from baseline to year 2, non-HDL-C was 0.72 mg/dL higher at year 2 (95% CI: -0.04-1.49) and 0.81 mg/dL higher at year 3 (95% CI: -0.05-1.66). CONCLUSIONS: Increases in adiposity over time may lead to downstream decreased insulin sensitivity and dyslipidaemia in YPHIV.

Electrolyte abnormalities and stress dosing predict illness-related hospitalizations among infants and toddlers with congenital adrenal hyperplasia.

OBJECTIVE: Infants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for morbidity/mortality arising from life-threatening adrenal crisis. Management of acute illnesses in CAH requires an understanding of factors leading to emergency department (ED) visits and hospitalizations in the first few years of life. We, therefore, examined adrenal crisis at prehospital and ED stages of illness in young children with CAH as they related to medical outcomes. PATIENTS AND DESIGN: Retrospective cohort study of 39 children with CAH due to 21-hydroxylase deficiency (0-4 years of age) and 27 age-matched controls. MEASUREMENTS: ED visit, acute illness symptoms (fever, vomiting, diarrhoea) and other characteristics (hospitalizations, administration of stress-dose hydrocortisone, electrolyte abnormalities). RESULTS: CAH infants and toddlers had significantly higher rates of ED visits (0.50 [0.25-0.88] per person-year) than controls (0 [0-0] per person-year; p < .001). Moreover, CAH children under 6 months old had significantly higher rates of ED visits compared with older ages. Only 50% (51/102) of illness-related ED visits in CAH children were preceded by the administration of either oral (46/51) or intramuscular (11/51) stress dosing by parents. A total of 10.8% of ED visits resulted in hospital admission. Controlling for age and 17-hydroxyprogesterone at diagnosis, electrolyte abnormalities and administration of parenteral hydrocortisone in the ED significantly predicted hospital admission. Receiving a hydrocortisone injection before the ED was a significant predictor of having electrolyte abnormalities. CONCLUSIONS: Infants and toddlers with classical CAH are at high risk for acute illness and hospitalizations and often do not receive adequate stress dosing before the ED.

Lower Insulin Sensitivity in Newborns With In Utero HIV and Antiretroviral Exposure Who Are Uninfected in Botswana.

BACKGROUND: Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU). METHODS: We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders. RESULTS: Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms. CONCLUSIONS: Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU. CLINICAL TRIALS REGISTRATION: NCT03088410.

Gut Dysfunction Markers Are Associated With Body Composition in Youth Living With Perinatally Acquired Human Immunodeficiency Virus.

BACKGROUND: The association between gut dysfunction and body fat composition in youth living with perinatal human immunodeficiency virus infection (YPHIV) has not been investigated. METHODS: We included YPHIV aged 7-19 years from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol with plasma available within 6 months of baseline whole-body dual energy x-ray absorptiometry (DXA) and HIV RNA ≤1000 copies/mL within 3 months of baseline DXA and a second DXA 2 years later. Plasma markers of bacterial translocation and gut barrier dysfunction (lipopolysaccharide binding protein [LBP], zonulin, and intestinal fatty acid binding protein [I-FABP]) were measured at baseline by enzyme-linked immunosorbent assay and log10 transformed. Adiposity outcomes included percentage total body, truncal, and extremity fat in kilograms from DXA. Linear regression models were fit using generalized estimating equations to assess associations of baseline gut markers (log10) on adiposity outcomes at baseline and 2 years, adjusted for demographic variables, current antiretroviral therapy exposure, and physical activity. RESULTS: Two hundred sixty-one youth were included; 128 had a second DXA. Median age at first DXA was 12 years (interquartile range, 10-14 years), 49% were female, and 69% were Black. After adjustment for potential confounders, log10 LBP was positively associated with percentage total body fat at baseline (ß = 4.08, P < .01) and zonulin with adiposity measures at both time points (ß = .94 to 6.50, P ≤ .01). I-FABP was inversely associated with percentage total body fat at baseline and year 2 (ß = -2.36 and -3.01, respectively, P ≤ .02). CONCLUSIONS: Despite viral suppression, gut damage and the resultant bacterial translocation are associated with body composition measures in YPHIV.

Distinct cord blood C-peptide, adipokine, and lipidomic signatures by in utero HIV exposure.

BACKGROUND: Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS: Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS: Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (ß = 0.295, p = 0.03) and C-peptide (ß = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization. CONCLUSION: Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure. IMPACT: There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.

A Rare Case of Diffuse-type Tenosynovial Giant Cell Tumor in a Teenager With Noonan Syndrome.

Noonan syndrome is a common autosomal dominant disorder associated with an increased risk of malignancy. We report a 16-year-old female with Noonan syndrome (KRAS gene variant, Q22R) and diffuse-type tenosynovial giant cell tumor, a proliferative disorder that has been rarely reported in this population. These tumors may represent a complication of the dysregulated RAS/MAPK signaling pathway that underlies Noonan syndrome. They lack typical clinical features, causing misdiagnosis and delays in management, which could lead to osseous invasion requiring more complicated surgical procedures. Increased awareness of this association will improve the clinical outcomes of patients with Noonan syndrome who develop diffuse-type tenosynovial giant cell tumors.

Components of metabolic syndrome associated with lower neurocognitive performance in youth with perinatally acquired HIV and youth who are HIV-exposed uninfected.

We investigated the association of metabolic syndrome (MetS) and its components [abdominal obesity, elevated triglycerides (TG), low HDL cholesterol, elevated blood pressure (BP), and impaired fasting glycemia (IFG)] with neurocognitive impairment in youth with perinatally acquired HIV (YPHIV) or who are perinatally HIV-exposed uninfected (YPHEU). This was an observational study with a comparison group of 350 YPHIV and 68 YPHEU ages 10-19 years. Youth with MetS components measured between 1 year before and 3 months after a baseline neurocognitive assessment (Wechsler Intelligence Scale) were selected from the Pediatric HIV/AIDS Cohort Study (PHACS). A sub-group completed another assessment 3 years later. We assessed the association of each baseline MetS component with five standardized neurocognitive indices at baseline and changes in indices over time. At baseline, 15% of YPHIV and 18% of YPHEU met criteria for ≥ 2 MetS components. Among YPHIV, there was no association between MetS components and neurocognitive indices at baseline; however, over time, elevated baseline BP was associated with a greater decrease in mean Perceptual Reasoning scores (-4.3;95%CI: -8.8,0.3) and ≥ 2 MetS components with a greater decrease in mean Processing Speed scores (-5.1;95%CI: -9.4, -0.8). Among YPHEU, elevated TG was associated with lower mean Verbal Comprehension, Perceptual Reasoning, and Full-scale IQ scores at baseline, and IFG with lower mean Verbal Comprehension scores. Components of MetS in YPHIV (elevated BP) and YPHEU (elevated TG and IFG) were associated with lower neurocognitive performance index scores. Studies to elucidate how modifying metabolic risk factors early in life may improve neurocognitive outcomes in this population are warranted.

No evidence for a difference in 2D:4D ratio between youth with elevated prenatal androgen exposure due to congenital adrenal hyperplasia and controls.

The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: ß = -0.001 (-0.008, 0.006); females: ß = -0.004 [-0.015, 0.007]; males: ß = 0.001, [-0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.

Glycemic control in youth-onset type 2 diabetes correlates with weight loss.

OBJECTIVE: To identify risk factors for glycemic failure in youth with type 2 diabetes (T2D). METHODS: A retrospective review of HbA1c, anthropomorphic measures, medication records, and laboratory studies was performed using registry data from a dedicated pediatric T2D clinic. Latent profile analysis (LPA) was performed to model longitudinal trajectory of HbA1c over 5 years. RESULTS: The registry includes 229 youth with T2D, of whom 80% self-identify as Latinx. The odds ratio (OR) for uncontrolled diabetes 5 years after diagnosis correlated with diagnostic HbA1c, with OR of 2.41 if HbA1c at diagnosis >8.5% (sensitivity 68%, specificity 54%, P = .015). LPA modeling identified three HbA1c profiles: (a) mean HbA1c <8% throughout the 5 years, (b) persistent elevation of mean HbA1c >9%, and (c) mean HbA1c of 12% at diagnosis, rapid decline to 6.4% by 4 to 6 months, and increase to 11% by 18 months. Our analysis of medication regimen showed that, amongst patients treated with metformin, the addition of multiple daily injections (MDI) did not improve HbA1c compared to those on basal insulin. Finally, weight loss over the 1 year after diagnosis correlated with improvement in HbA1c in both subjects prescribed metformin monotherapy, as well as insulin-containing regimen. CONCLUSION: Youth with T2D exhibit distinct HbA1c profiles. Patients with diagnostic HbA1c >8.5% are at high risk for glycemic failure, irrespective of short-term improvement in HbA1c. Weight management has the potential to improve short-term HbA1c outcome in youth with T2D. Additional studies are needed to determine the role of medication adherence on glycemic control.

Cardiometabolic health in Turner syndrome.

Individuals with Turner syndrome (TS) have a higher morbidity and mortality compared to the general population. Diabetes and cardiovascular disease are the major contributors to this burden. Precursors to diabetes and cardiovascular disease make up what is known as metabolic syndrome, including abdominal obesity, hypertension, dyslipidemia, and elevated fasting glucose. These features of poor cardiometabolic health are also prevalent among women with TS. Youth with TS also exhibit many of these features, indicating that the pathogenesis of these cardiometabolic conditions may begin early in life. The etiology of the increased risk of cardiometabolic conditions in TS is likely multifactorial, involving genetics, epigenetics, hypogonadism, medical comorbidities, medications, and lifestyle. Counseling for the increased risk of cardiometabolic diseases as well as efforts to prevent or lower this risk should be routinely provided in the care of all patients with TS. Clinical practice guidelines are now available to guide screening and treatment of cardiometabolic conditions in girls and women with TS.

Para-ovarian adrenal rest tumors: gynecologic manifestations of untreated congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is an inherited disorder of adrenal steroidogenesis often diagnosed in infancy. Gynecologists may encounter adult patients with CAH due to the clinical effects of increased androgens, e.g. hirsutism, clitoromegaly, oligomenorrhea, or, rarely, pelvic masses. This case report reviews the association of para-ovarian adrenal rest tumors with CAH, and the role of gynecologists in their evaluation and treatment. A 23-year-old woman with CAH (21-hydroxyase deficiency) untreated for the past 5 years presented with a pelvic mass and elevated serum testosterone (1433 ng/dL) and plasma ACTH (1117 pg/mL). Intraoperative findings revealed multiple retroperitoneal masses. Final pathology demonstrated adrenal rest tissue. Para-ovarian and ovarian adrenal rest tumors may present as a rare gynecologic manifestation in patients with untreated CAH.

For Debate: Combination Growth Hormone and Insulin-Like Growth Factor-I Therapy for Childhood Growth Disorders: Prime Time or Too Much Dime?

Although metabolic outcomes may be aided by dual therapy with GI and IGF-I, the one published study of the combination approach to treat children with non-GH-deficient short stature showed only a meager additional height response compared to that achieved with GH alone.

Birth Weight and Preterm Delivery Outcomes of Perinatally vs Nonperinatally Human Immunodeficiency Virus-Infected Pregnant Women in the United States: Results From the PHACS SMARTT Study and IMPAACT P1025 Protocol.

BACKGROUND: Pregnancy outcomes of perinatally human immunodeficiency virus-infected women (PHIV) are poorly defined. METHODS: We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. RESULTS: From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23-30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). CONCLUSION: The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. CLINICAL TRIALS REGISTRATION: PHACS SMARTT study, NCT01310023. CLINICAL TRIALS REGISTRATION: IMPAACT 1025, NCT00028145.

Testicular Adrenal Rest Tumors in Boys and Young Adults with Congenital Adrenal Hyperplasia.

PURPOSE: Testicular adrenal rest tumors are a well-known complication in males who have congenital adrenal hyperplasia with potential infertility in adulthood. We assessed the prevalence of testicular adrenal rest tumors in infants to young men presenting to a congenital adrenal hyperplasia Comprehensive Care Center. MATERIALS AND METHODS: A total of 35 males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency underwent scrotal ultrasonography, including 7 younger than 5 years, 9 who were 5 to 12 years old and 19 who were older than 12 years. Three and 35 patients had classic and nonclassic congenital adrenal hyperplasia, respectively. Bone age x-ray or advanced bone age x-ray history, glucocorticoid dose, fludrocortisone dose, and serum 17-hydroxyprogesterone, testosterone and androstenedione levels within 3 months of ultrasound were also recorded. RESULTS: Testicular adrenal rest tumors were detected in 5 of 35 patients (14%), including 1 of 9 (11%) who were 5 to 12 years old and 4 of 19 (21%) who were older than 12 years. The tumors were not detected in any patients younger than 5 years, including 1 infant with poor hormonal control. The youngest patient with positive findings was 6.6 years old. All patients with positive findings had bilateral disease and only 1 had suspicious physical findings. The glucocorticoid dose and 17-hydroxyprogesterone did not differ between patients with vs without a testicular adrenal rest tumor. Those with a tumor were more likely to have advanced bone age x-ray results (100% vs 42%, p = 0.04) and higher fludrocortisone dose (p <0.01). All males with nonclassic congenital adrenal hyperplasia had negative tumor findings. CONCLUSIONS: Testicular adrenal rest tumors were present in young males with classic congenital adrenal hyperplasia but not in infants or toddlers. These tumors were associated with higher fludrocortisone requirements and a history of advanced bone age x-ray results. However, the tumors did not develop in all poorly controlled males. Longitudinal studies are needed to understand the individual predisposition to testicular adrenal rest tumors and the age at which to begin screening patients with congenital adrenal hyperplasia.

Dynamic response of C-type natriuretic peptide and its aminoterminal propeptide (NTproCNP) to growth hormone treatment in children with short stature.

OBJECTIVE: C-type natriuretic peptide (CNP) and its aminoterminal propeptide (NTproCNP) are potential biomarkers of recombinant human growth hormone (rhGH) efficacy. The objective of this study was to describe the pharmacodynamics of plasma CNP and NTproCNP levels in response to rhGH treatment and to identify the optimal time of sampling after starting rhGH. DESIGN: This was a prospective, observational study. Subjects were treated with rhGH for 1 year, with blood sampled at regular intervals. PATIENTS: Eighteen prepubertal children, eight with low levels of GH on biochemical testing and ten with idiopathic short stature, completed the study. MEASUREMENTS: Blood levels of CNP, NTproCNP, GH, insulin-like growth factor-I, leptin and bone-specific alkaline phosphatase were measured. Anthropometrics were obtained. RESULTS: Plasma levels of both CNP and NTproCNP reached peak levels 7-28 days after starting rhGH treatment and then declined to intermediate levels through the first year. Plasma NTproCNP levels after 14 days trended towards a correlation with height velocity after 6 and 12 months of treatment. Unexpectedly, serum GH levels measured 2 and 28 days after starting rhGH correlated strongly with height velocity after 6 and 12 months of treatment. CONCLUSIONS: This study identified 14 days after starting rhGH treatment as the optimal time for assessing CNP and NTproCNP levels as biomarkers of rhGH efficacy. Additionally, we identified GH levels as a potential biomarker. Larger, prospective studies are now needed to test the clinical utility of these biomarkers.

Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study.

OBJECTIVE: The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. RESEARCH DESIGN AND METHODS: Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. MAIN OUTCOME MEASURES: Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. RESULTS: Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. CONCLUSIONS: Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.

Benefits and barriers to participating in longitudinal research of youth-onset type 2 diabetes: Results from the TODAY retention survey.

BACKGROUND/AIMS: Conducting longitudinal research related to chronic illness in adolescents is inherently challenging due to developmental changes and psychosocial stressors. Participants in the Treatment Options for type 2 Diabetes in Adolescents and Youth clinical trial were socioeconomically disadvantaged as well. This study assessed attitudes and beliefs about retention in Treatment Options for type 2 Diabetes in Adolescents and Youth to shed light on the factors that potentially promote and detract from the likelihood of sustained participation. METHODS: After an average 7.3 years of follow-up (range 4.9-9.5), Treatment Options for type 2 Diabetes in Adolescents and Youth participants completed a survey examining their perceptions of the benefits and barriers to sustained involvement in the protocol. RESULTS: The most common reasons for staying in Treatment Options for type 2 Diabetes in Adolescents and Youth included having a strong relationship with the medical team, getting study-provided diabetes care, access to free diabetes medicine and supplies, and being part of a large study to learn more about how to care for youth-onset type 2 diabetes. The most commonly endorsed challenges included scheduling conflicts, possibly disappointing others, difficulties getting to study visits, and the occurrence of other medical issues. CONCLUSIONS: Similar to other published reports, a supportive relationship with study staff was commonly endorsed as a benefit of engagement in the longitudinal study, suggesting that rapport, staff consistency, and relationship quality are important components of optimal retention. Moreover, our findings suggest the value of trying to remove logistical barriers, such as transportation and scheduling challenges, in order to promote long-term participation in research. Further research is recommended to evaluate factors that contribute to attrition versus retention in an a priori manner within longitudinal studies, especially protocols involving cohorts that are more vulnerable to attrition due to developmental transitions and/or socioeconomic challenges. Additional efforts to optimize quantitative and qualitative measurement of barriers would also help to expand our understanding of how to optimally retain participants in longitudinal protocols.

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing.

Advances in chelation therapy and noninvasive monitoring of iron overload have resulted in substantial improvements in the survival of transfusion-dependent patients with thalassemia major. Myocardial decompensation and sepsis remain the major causes of death. Although endocrine abnormalities are a well-recognized problem in these iron-overloaded patients, adrenal insufficiency and its consequences are underappreciated by the hematology community. The aims of this study were to determine the prevalence of adrenal insufficiency in thalassemia major subjects, to identify risk factors for adrenal insufficiency, and to localize the origin of the adrenal insufficiency within the hypothalamic-pituitary-adrenal axis. Eighteen subjects with thalassemia major (18.9±9.3 y old, 7 female) were tested for adrenal insufficiency using a glucagon stimulation test. Those found to have adrenal insufficiency (stimulated cortisol <18 µg/dL) subsequently underwent an ovine corticotropin-releasing hormone (oCRH) stimulation test to define the physiological basis for the adrenal insufficiency. The prevalence of adrenal insufficiency was 61%, with an increased prevalence in males over females (92% vs. 29%, P=0.049). Ten of 11 subjects who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol responses to oCRH, indicating a possible hypothalamic origin to their adrenal insufficiency.