Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to the crinecerfont group and 34 to the placebo group; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (least-squares mean difference, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes.

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).

A pilot study of mealtime insulin administration and parental stress in youth with new-onset type 1 diabetes.

AIMS: To compare the stress level in parents of children with new-onset type 1 diabetes receiving a fixed insulin dose for a fixed range of carbohydrates (CHOs) to parents of children receiving a precise insulin dose for a precise number of CHOs using an insulin-to-carbohydrate ratio (ICR). METHODS: Twenty-four participants (8-14 years) were randomized to receive a fixed dose of insulin for a fixed range of CHOs (FD group) or a precise dose of insulin for a precise number of carbohydrates using an ICR (ICR group). The primary endpoint was parental stress measured with the parental stress survey (PSS) 1 to 4 months after diagnosis. Secondary endpoints included glycemic variability, glycated haemoglobin (HbA1C ) and safety. RESULTS: Compared to parents of children in the ICR group, those from the FD group reported less stress during the first 4 months after diagnosis (p = 0.022). Glycemic variability and HbA1C were similar in both groups. None of the patients from either group required an emergency department visit or hospitalization. CONCLUSIONS: In comparison to precise insulin dosing using an ICR, fixed insulin dosing for a fixed range of CHOs may be less stressful for parents to learn and employ when initially taught diabetes management skills for their child with new-onset type 1 diabetes.

Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial.

AIMS/HYPOTHESIS: Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses. RESULTS: Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections. CONCLUSIONS/INTERPRETATION: A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.org FUNDING: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN).

Transient central diabetes insipidus induced by ketamine infusion.

OBJECTIVE: Report a case of central diabetes insipidus (DI) associated with ketamine infusion. CASE SUMMARY: A 2-year-old girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and stable hypertrophic cardiomyopathy was admitted to the pediatric intensive care with pneumonia. She subsequently developed respiratory failure and required intubation. Continuous ketamine infusion was used for the sedation and facilitation of mechanical ventilation. Shortly after infusion of ketamine, the patient developed DI and responded appropriately to vasopressin. DISCUSSION: The Naranjo adverse drug reaction probability scale indicated a probable relationship between the development of central DI and ketamine. The most likely mechanism involves ketamine's antagonist action on N-methyl-d-aspartate receptors, resulting in inhibition of glutamate-stimulated arginine vasopressin release from the neurohypophysis. CONCLUSION: This is the second case report of ketamine-induced central DI and the only report in children. Clinicians who sedate children with continuous ketamine infusions should monitor patients for developing signs and symptoms of DI by measuring serum sodium and urine output prior to, during, and after ketamine infusion in order to make a timely diagnosis of this potentially serious complication.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Faster pharmacokinetics and increased patient acceptance of intradermal insulin delivery using a single hollow microneedle in children and adolescents with type 1 diabetes.

OBJECTIVE: In an effort to improve compliance with insulin therapy and to accelerate insulin pharmacokinetics, we tested the hypothesis that intradermal insulin delivery using a hollow microneedle causes less pain and leads to faster onset and offset of insulin pharmacokinetics in children and adolescents with type 1 diabetes (T1DM) compared with a subcutaneous, insulin pump catheter. RESEARCH DESIGN AND METHODS: In this repeated measures study, 16 children and adolescents with T1DM received Lispro insulin by microneedle and subcutaneous administration on separate days. Subjects rated the pain of insertion and infusion using a visual analog scale. Blood specimens were collected over 4 h to determine insulin and glucose concentrations. RESULTS: Microneedle insertion pain was significantly lower compared with insertion of the subcutaneous catheter (p = 0.005). Insulin onset time was 22 min faster (p = 0.0004) and offset time was 34 min faster (p = 0.017) after hollow microneedle delivery compared with subcutaneous delivery. CONCLUSIONS: In this study, intradermal insulin delivery using a single, hollow microneedle device resulted in less insertion pain and faster insulin onset and offset in children and adolescents with T1DM. A reduction in pain might improve compliance with insulin delivery. The faster onset and offset times of insulin action may enable closed-loop insulin therapy.

Dermatologic care of patients with differences of sex development.

Background: Differences of sex development (DSD or disorders of sex development) are uncommon congenital conditions, characterized by atypical development of chromosomal, gonadal, or anatomic sex. Objective: Dermatologic care is an important component of the multidisciplinary care needed for individuals with DSD. This article discusses the most common primary dermatologic manifestations of DSD in addition to the cutaneous manifestations of hormonal and surgical therapies in individuals with DSD. Data sources: Published articles including case series and case reports on PubMed. Study selections: Selection was conducted by examining existing literature with a team of multidisciplinary specialists. Methods: Narrative review. Limitations: This article was not conducted as a systematic review. Results: In Klinefelter syndrome, refractory leg ulcers and incontinentia pigmenti have been described. Turner syndrome is associated with lymphatic malformations, halo nevi, dermatitis, and psoriasis. Virilization can be seen in some forms of congenital adrenal hyperplasia, where acne and hirsutism are common. Conclusion: Dermatologists should consider teratogenic risk for treatments of skin conditions in DSD depending on pregnancy potential. Testosterone replacement, commonly used for Klinefelter syndrome, androgen insensitivity syndrome, 5-alpha reductase deficiency, gonadal dysgenesis, or ovotesticular DSD, may cause acne.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Skin Vaccination with Ebola Virus Glycoprotein Using a Polyphosphazene-Based Microneedle Patch Protects Mice against Lethal Challenge.

Ebolavirus (EBOV) infection in humans is a severe and often fatal disease, which demands effective interventional strategies for its prevention and treatment. The available vaccines, which are authorized under exceptional circumstances, use viral vector platforms and have serious disadvantages, such as difficulties in adapting to new virus variants, reliance on cold chain supply networks, and administration by hypodermic injection. Microneedle (MN) patches, which are made of an array of micron-scale, solid needles that painlessly penetrate into the upper layers of the skin and dissolve to deliver vaccines intradermally, simplify vaccination and can thereby increase vaccine access, especially in resource-constrained or emergency settings. The present study describes a novel MN technology, which combines EBOV glycoprotein (GP) antigen with a polyphosphazene-based immunoadjuvant and vaccine delivery system (poly[di(carboxylatophenoxy)phosphazene], PCPP). The protein-stabilizing effect of PCPP in the microfabrication process enabled preparation of a dissolvable EBOV GP MN patch vaccine with superior antigenicity compared to a non-polyphosphazene polymer-based analog. Intradermal immunization of mice with polyphosphazene-based MN patches induced strong, long-lasting antibody responses against EBOV GP, which was comparable to intramuscular injection. Moreover, mice vaccinated with the MN patches were completely protected against a lethal challenge using mouse-adapted EBOV and had no histologic lesions associated with ebolavirus disease.

Dissolving microneedle patch for transdermal delivery of human growth hormone.

The clinical impact of biotechnology has been constrained by the limitations of traditional hypodermic injection of biopharmaceuticals. Microneedle patches have been proposed as a minimally invasive alternative. In this study, the translation of a dissolving microneedle patch designed for simple, painless self-administration of biopharmacetucials that generates no sharp biohazardous waste is assessed. To study the pharmacokinetics and safety of this approach, human growth hormone (hGH) was encapsulated in 600 µm-long dissolving microneedles composed of carboxymethylcellulose and trehalose using an aqueous, moderate-temperature process that maintained complete hGH activity after encapsulation and retained most activity after storage for up to 15 months at room temperature and humidity. After manual insertion into the skin of hairless rats, hGH pharmacokinetics were similar to conventional subcutaneous injection. After patch removal, the microneedles had almost completely dissolved, leaving behind only blunt stubs. The dissolving microneedle patch was well tolerated, causing only slight, transient erythema. This study suggests that a dissolving microneedle patch can deliver hGH and other biopharmaceuticals in a manner suitable for self-administration without sharp biohazardous waste.

Rhabdomyolysis due to rosuvastatin in a patient with ROHHAD syndrome.

We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects.

Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Type 1 diabetes results from autoimmune-mediated destruction of ß cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving ß-cell function in patients with recent-onset type 1 diabetes. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L-1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed). FINDINGS: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events. INTERPRETATION: A 26-week course of imatinib preserved ß-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required. FUNDING: Juvenile Research Diabetes Foundation.

Sampling interstitial fluid from human skin using a microneedle patch.

Tissue interstitial fluid (ISF) surrounds cells and is an underutilized source of biomarkers that complements conventional sources such as blood and urine. However, ISF has received limited attention due largely to lack of simple collection methods. Here, we developed a minimally invasive, microneedle-based method to sample ISF from human skin that was well tolerated by participants. Using a microneedle patch to create an array of micropores in skin coupled with mild suction, we sampled ISF from 21 human participants and identified clinically relevant and sometimes distinct biomarkers in ISF when compared to companion plasma samples based on mass spectrometry analysis. Many biomarkers used in research and current clinical practice were common to ISF and plasma. Because ISF does not clot, these biomarkers could be continuously monitored in ISF similar to current continuous glucose monitors but without requiring an indwelling subcutaneous sensor. Biomarkers distinct to ISF included molecules associated with systemic and dermatological physiology, as well as exogenous compounds from environmental exposures. We also determined that pharmacokinetics of caffeine in healthy adults and pharmacodynamics of glucose in children and young adults with diabetes were similar in ISF and plasma. Overall, these studies provide a minimally invasive method to sample dermal ISF using microneedles and demonstrate human ISF as a source of biomarkers that may enable research and translation for future clinical applications.

Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles.

BACKGROUND: Microneedles have previously been used to deliver insulin to animal models, but not in human subjects. This study tested the hypothesis that hollow microneedles can deliver insulin to modulate blood glucose levels in subjects with type 1 diabetes in a minimally invasive manner. METHODS: This study was carried out in two adults with type 1 diabetes and evaluated bolus delivery of lispro insulin using a hollow microneedle compared to a catheter infusion set (9 mm). The study first determined the minimum insulin delivery depth by administering insulin from microneedles inserted 1, 3.5, and 5 mm into the skin of fasting subjects and then assessed the efficacy of insulin delivery from microneedles inserted 1 mm into the skin to reduce postprandial glucose levels. Blood samples were periodically assayed for plasma free insulin and plasma glucose levels for up to 3.5 h. RESULTS: The first phase of the study indicated that microneedles inserted at the shallowest depth of 1 mm within the skin led to rapid insulin absorption and reduction in glucose levels. Bolus insulin delivery followed by consumption of a standardized meal in the second phase revealed that microneedles were effective in reducing postprandial glucose levels. Subjects reported no pain from microneedle treatments, and there were no adverse events. CONCLUSIONS: This study provides the first proof of concept that hollow microneedles can effectively deliver bolus insulin to type 1 diabetes subjects in a minimally invasive manner.

Neuroendocrine dysfunction in pediatric critical illness.

BACKGROUND: The extent of neuroendocrine dysfunction (NED) has not been well defined in critically ill children and likely varies significantly from that in adults. We sought to define the prevalence of neuroendocrine dysfunction in a group of children in a multidisciplinary pediatric intensive care unit and determine the relationship of neuroendocrine dysfunction with severity of illness and presence of sepsis. METHODS: Prospective observational study in a pediatric intensive care unit at a referral childrens hospital. Blood samples were evaluated within 12 hrs of admission for serum cortisol, thyroid stimulating hormone, total triiodothyronine (T3), reverse triiodothyroine (rT3), free thyroxine, and arginine vasopressin. Pediatric risk of mortality, pediatric logistic organ dysfunction scores, and length of stay were calculated. RESULTS: Seventy-three children were enrolled over a 13-month period. Median patient age was 72 months (range, 3-228 months). Overall prevalence of absolute adrenal insufficiency ranged from 7% to 58% based on cortisol cutoff chosen. Presence of absolute adrenal insufficiency, low T3 syndrome (LT3S), or vasopressin insufficiency did not differ between septic or nonseptic patients. NED did not correlate with pediatric logistic organ dysfunction, Pediatric Risk of Mortality Score III, length of stay, or mortality. Prevalence of multiple NED was 62% (28 of 45 children), where 62% had 2 neurohormonal deficiencies and 24% had 3 neurohormonal deficiencies. CONCLUSION: NED is common in both septic and nonseptic critically ill children in a single pediatric intensive care unit. Larger scale studies are necessary to determine whether presence of NED, or specific combinations of neurohormonal dysfunction, is important in predicting outcomes or benefit of early hormonal replacement therapies in critically ill children.

Inaccurate hemoglobin A(1C) levels in patients with type 1 diabetes and hereditary persistence of hemoglobin F.

We report 2 African-American boys with type 1 diabetes and hereditary persistence of hemoglobin F. The diagnosis came to light after both patients exhibited inconsistent hemoglobin A(1C) (HbA(1C)) levels with respect to serum glucose measurements. This demonstrates the importance of frequent glucose monitoring and interpreting the HbA(1C) level in light of serum glucose measurements.

Compression force sensing regulates integrin αIIbß3 adhesive function on diabetic platelets.

Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin αIIbß3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to αIIbß3 adhesive function that leads to a distinct prothrombotic phenotype in diabetes.

Environmental health disparities: environmental and social impact of industrial pollution in a community - the model of Anniston, AL.

The health and well-being of children are critically dependent on the environment in which they live. This article explores the complex relationship between the environment in which a child lives and the environmental factors that can adversely affect health and development. It also examines how awareness of these adverse factors can be helpful in promoting optimal health for children through the societal infrastructures that deal with health, the environment, and social justice.

Impact of Dietary Intake on Bone Turnover in Patients with Phenylalanine Hydroxylase Deficiency.

Phenylalanine hydroxylase (PAH) deficiency is a genetic disorder characterized by deficiency of the PAH enzyme. Patients follow a phenylalanine-restricted diet low in intact protein, and must consume synthetic medical food (MF) to supply phenylalanine-free protein. We assessed relationships between dietary intake and nutrient source (food or MF) on bone mineral density (BMD) and bone turnover markers (BTM) in PAH deficiency. Blood from 44 fasted females 11-52 years of age was analyzed for plasma phenylalanine, serum BTM [CTx (resorption), P1NP (formation)], vitamin D, and parathyroid hormone (PTH). BTM ratios were calculated to assess resorption relative to formation (CTx/P1NP). Dual energy X-ray absorptiometry measured total BMD and age-matched Z-scores. Three-day food records were analyzed for total nutrient intake, nutrients by source (food, MF), and compliance with MF prescription. Spearman's partial coefficients (adjusted for age, BMI, energy intake, blood phenylalanine) assessed correlations. All had normal BMD for age (Z-score >-2). Sixty-four percent had high resorption and normal formation indicating uncoupled bone turnover. CTx/P1NP was positively associated with food phenylalanine (r 2 = 0.39; p-value = 0.017), energy (r 2 = 0.41; p-value = 0.011) and zinc (r 2 = 0.41; p-value = 0.014). CTx/P1NP was negatively associated with MF fat (r 2 = -0.44; p-value = 0.008), MF compliance (r 2 = -0.34; p-value = 0.056), and positively with food sodium (r 2 = 0.43; p-value = 0.014). CTx/P1NP decreased significantly with age (p-value = 0.002) and higher PTH (p-value = 0.0002). Phenylalanine was not correlated with any bone indicator. Females with PAH deficiency had normal BMD but elevated BTM, particularly resorption. More favorable ratios were associated with nutrients from MF and compliance. Younger females had less favorable BTM ratios. Promoting micronutrient intake through compliance with MF may impact bone metabolism in patients with PAH deficiency. SYNOPSIS: Bone mineral density was normal in 44 females with PAH deficiency; however, bone turnover markers suggested uncoupling of bone resorption and formation, particularly in younger patients. Adequate nutrient intake from medical food and overall medical food compliance may positively impact bone turnover.