Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Growth Hormone Stimulation Testing Patterns Contribute to Sex Differences in Pediatric Growth Hormone Treatment.

INTRODUCTION: Males are twice as likely as females to receive pediatric growth hormone (GH) treatment in the USA, despite similar distributions of height z (HtZ)-scores in both sexes. Male predominance in evaluation and subspecialty referral for short stature contributes to this observation. This study investigates whether sex differences in GH stimulation testing and subsequent GH prescription further contribute to male predominance in GH treatment. METHODS: Retrospective chart review was conducted of all individuals, aged 2-16 years, evaluated for short stature or poor growth at a single large tertiary referral center between 2012 and 2019. Multiple logistic regression models were constructed to analyze sex differences. RESULTS: Of 10,125 children referred for evaluation, a smaller proportion were female (35%). More males (13.1%) than females (10.6%) underwent GH stimulation testing (p < 0.001) and did so at heights closer to average (median HtZ-score -2.2 [interquartile range, IQR -2.6, -1.8] vs. -2.5 [IQR -3.0, -2.0], respectively; p < 0.001). The proportion of GH prescriptions by sex was similar by stimulated peak GH level. Predictor variables in regression modeling differed by sex: commercial insurance predicted GH stimulation testing and GH prescription for males only, whereas lower HtZ-score predicted GH prescription for females only. CONCLUSIONS: Sex differences in rates of GH stimulation testing but not subsequent GH prescription based on response to GH stimulation testing seem to contribute to male predominance in pediatric GH treatment. That HtZ-score predicted GH prescription in females but not males raises questions about the extent to which sex bias - from children, parents, and/or physicians - as opposed to objective growth data, influence medical decision-making in the evaluation and treatment of short stature.

Infants Diagnosed with Athyreosis on Scintigraphy May Have a Gland Present on Ultrasound and Have Transient Congenital Hypothyroidism.

Scintigraphy using technetium-99m (99mTc) is the gold standard for imaging the thyroid gland in infants with congenital hypothyroidism (CHT) and is the most reliable method of diagnosing an ectopic thyroid gland. One of the limitations of scintigraphy is the possibility that no uptake is detected despite the presence of thyroid tissue, leading to the spurious diagnosis of athyreosis. Thyroid ultrasound is a useful adjunct to detect thyroid tissue in the absence of 99mTc uptake. AIMS: We aimed to describe the incidence of sonographically detectable in situ thyroid glands in infants scintigraphically diagnosed with athyreosis using 99mTc and to describe the clinical characteristics and natural history in these infants. METHODS: The newborn screening records of all infants diagnosed with CHT between 2007 and 2016 were reviewed. Those diagnosed with CHT and athyreosis confirmed on scintigraphy were invited to attend a thyroid ultrasound. RESULTS: Of the 488 infants diagnosed with CHT during the study period, 18/73 (24.6%) infants with absent uptake on scintigraphy had thyroid tissue visualised on ultrasound (3 hypoplastic thyroid glands and 15 eutopic glands). The median serum thyroid-stimulating hormone (TSH) concentration at diagnosis was significantly lower than that in infants with confirmed athyreosis (no gland on ultrasound and no uptake on scintigraphy) (74 vs. 270 mU/L), and median free T4 concentration at diagnosis was higher (11.9 vs. 3.9 pmol/L). Six of 10 (60%) infants with no uptake on scintigraphy but a eutopic gland on ultrasound had transient CHT. CONCLUSION: Absent uptake on scintigraphy in infants with CHT does not rule out a eutopic gland, especially in infants with less elevated TSH concentrations. Clinically, adding thyroid ultrasound to the diagnostic evaluation of infants who have athyreosis on scintigraphy may avoid committing some infants with presumed athyreosis to lifelong levothyroxine treatment.

Seagrass ecosystems of the Pacific Island Countries and Territories: A global bright spot.

Seagrass ecosystems exist throughout Pacific Island Countries and Territories (PICTs). Despite this area covering nearly 8% of the global ocean, information on seagrass distribution, biogeography, and status remains largely absent from the scientific literature. We confirm 16 seagrass species occur across 17 of the 22 PICTs with the highest number in Melanesia, followed by Micronesia and Polynesia respectively. The greatest diversity of seagrass occurs in Papua New Guinea (13 species), and attenuates eastward across the Pacific to two species in French Polynesia. We conservatively estimate seagrass extent to be 1446.2 km2, with the greatest extent (84%) in Melanesia. We find seagrass condition in 65% of PICTs increasing or displaying no discernible trend since records began. Marine conservation across the region overwhelmingly focuses on coral reefs, with seagrass ecosystems marginalised in conservation legislation and policy. Traditional knowledge is playing a greater role in managing local seagrass resources and these approaches are having greater success than contemporary conservation approaches. In a world where the future of seagrass ecosystems is looking progressively dire, the Pacific Islands appears as a global bright spot, where pressures remain relatively low and seagrass more resilient.

Seagrass ecosystem contributions to people's quality of life in the Pacific Island Countries and Territories.

Seagrass ecosystems provide critical contributions (goods and perceived benefits or detriments) for the livelihoods and wellbeing of Pacific Islander peoples. Through in-depth examination of the contributions provided by seagrass ecosystems across the Pacific Island Countries and Territories (PICTs), we find a greater quantity in the Near Oceania (New Guinea, the Bismarck Archipelago and the Solomon Islands) and western Micronesian (Palau and Northern Marianas) regions; indicating a stronger coupling between human society and seagrass ecosystems. We also find many non-material contributions historically have been overlooked and under-appreciated by decision-makers. Closer cultural connections likely motivate guardianship of seagrass ecosystems by Pacific communities to mitigate local anthropogenic pressures. Regional comparisons also shed light on general and specific aspects of the importance of seagrass ecosystems to Pacific Islanders, which are critical for forming evidence-based policy and management to ensure the long-term resilience of seagrass ecosystems and the contributions they provide.

Provocative growth hormone testing in children: how did we get here and where do we go now?

OBJECTIVES: Provocative growth hormone (GH) tests are widely used for diagnosing pediatric GH deficiency (GHD). A thorough understanding of the evidence behind commonly used interpretations and the limitations of these tests is important for improving clinical practice. CONTENT: To place current practice into a historical context, the supporting evidence behind the use of provocative GH tests is presented. By reviewing GH measurement techniques and examining the early data supporting the most common tests and later studies that compared provocative agents to establish reference ranges, the low sensitivity and specificity of these tests become readily apparent. Studies that assess the effects of patient factors, such as obesity and sex steroids, on GH testing further bring the appropriateness of commonly used cutoffs for diagnosing GHD into question. SUMMARY AND OUTLOOK: Despite the widely recognized poor performance of provocative GH tests in distinguishing GH sufficiency from deficiency, limited progress has been made in improving them. New diagnostic modalities are needed, but until they become available, clinicians can improve the clinical application of provocative GH tests by taking into account the multiple factors that influence their results.

Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.

INTRODUCTION: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion. METHODS: In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels. RESULTS: We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy. CONCLUSIONS: We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.

Leg length and sitting height reference data and charts for children in the United States.

Population-specific reference data are required to interpret growth measurements in children. Sitting height and leg length (standing height minus sitting height) measurements are indicators of proportionality and can be used to evaluate children with disordered growth. NHANES III recorded sitting height and standing height measurements in a strategic random sample of the United States population from 1988 to 1994, and we have previously published reference charts for sitting height to standing height ratio in this population. In this study, we have developed separate sitting height and leg length reference charts for Non-Hispanic Black, Non-Hispanic White, and Mexican-American children in the United States. In addition, we provide mean (SD) and LMS data to support the use of these reference charts in clinical care.

Sitting Height to Standing Height Ratio Reference Charts for Children in the United States.

OBJECTIVE: To create reference charts for sitting height to standing height ratio (SitHt/Ht) for children in the US, and to describe the trajectory of SitHt/Ht during puberty. STUDY DESIGN: This was a cross-sectional study using data from the 1988-1994 National Health and Nutrition Examination Survey III, a strategic random sample of the US population. Comparison between non-Hispanic White (NHW), non-Hispanic Black (NHB) and Mexican American groups was performed by ANOVA to determine if a single population reference chart could be used. ANOVA was used to compare SitHt/Ht in pre-, early, and late puberty. RESULTS: NHANES III recorded sitting height and standing height measurements in 9569 children aged 2-18 years of NHW (n = 2715), NHB (n = 3336), and Mexican American (n = 3518) ancestry. NHB children had lower SitHt/Ht than NHW and Mexican American children throughout childhood (P < .001). In both sexes, the SitHt/Ht decreased from prepuberty to early puberty and increased in late puberty. Sex-specific percentile charts of SitHt/Ht vs age were generated for NHB and for NHW and Mexican American youth combined. CONCLUSIONS: SitHt/Ht assessment can detect disproportionate short stature in children with skeletal dysplasia, but age-, sex-, and population-specific reference charts are required to interpret this measurement. NHB children in the US have significantly lower SitHt/Ht than other children, which adds complexity to interpretation. We recommend the use of standardized ancestry-specific reference charts in screening for skeletal dysplasias and have developed such charts in this study.

Optimal Timing of Repeat Newborn Screening for Congenital Hypothyroidism in Preterm Infants to Detect Delayed Thyroid-Stimulating Hormone Elevation.

OBJECTIVES: To evaluate the timing of a delayed rise in thyroid-stimulating hormone (TSH) levels in preterm infants with congenital hypothyroidism, and to determine whether cases of congenital hypothyroidism would be missed by using current consensus guidelines of repeat screening at approximately 2 weeks of age or 2 weeks after the first screening. STUDY DESIGN: The study was performed over a 13-year period (January 2004-December 2016). Whole-blood TSH samples were collected between 72 and 120 hours after birth. Repeat samples were collected weekly in preterm infants until the infant was term-corrected (37 weeks' gestation). Patients were followed up to determine whether congenital hypothyroidism was permanent or transient. RESULTS: Twenty-seven (50.9%) preterm infants born at <33 weeks of gestation who were diagnosed with congenital hypothyroidism had delayed TSH elevation and would not have been detected on first newborn screen. Twelve of these infants (40.7%) with delayed TSH elevation had decompensated hypothyroidism at diagnosis (free thyroxine [FT4] <10 pmol/L), and 4 had severe congenital hypothyroidism (FT4 <5.5 pmol/L) at diagnosis. If screening had been repeated only at 2 weeks of life, 13 infants (48%) with delayed TSH elevation would not have been identified. Of the 27 infants with delayed TSH elevation, 6 (22%) have permanent congenital hypothyroidism, and another 12 will be reevaluated at age 3 years. CONCLUSION: Repeat screening for congenital hypothyroidism in preterm infants is necessary to avoid missing cases of congenital hypothyroidism with delayed TSH elevation. Repeat screening once at 2 weeks of life will miss infants with delayed TSH elevation and decompensated permanent congenital hypothyroidism.

Performance testing protocol for closed-system transfer devices used during pharmacy compounding and administration of hazardous drugs.

OBJECTIVES: The United States National Institute for Occupational Safety and Health (NIOSH) is developing a protocol to assess the containment performance of closed system transfer devices (CSTDs) when used for drug preparation (task 1) and administration (task 2) and published a draft protocol in September 2016. Nine possible surrogates were proposed by NIOSH for use in the testing. The objectives of this study were to: (A) select the most appropriate surrogate; (B) validate the NIOSH protocol using this surrogate; and (C) determine the containment performance of four commercial CSTDs as compared with an open system of needle and syringe using the validated NIOSH protocol. METHODS: 2-Phenoxyethanol (2-POE) was selected as a surrogate based on its water solubility, Henry's volatility constant, detectability by mass spectrometry, and non-toxicity. Standard analytical validation methods including system suitability, limit of detection (LOD), and limit of quantitation (LOQ) as well as system cleaning validation were performed. The amount of 2-POE released when the CSTDs were manipulated according to two tasks defined by NIOSH was determined using mass spectrometry coupled to thermal desorption and gas chromatography. This approach allows sensitivity of detection below 1 part per billion (ppb). Equashield, Tevadaptor (OnGuard), PhaSeal, and ChemoClave were assessed according to manufacturers' instructions for use. RESULTS: 2-POE was tested and validated for suitability of use within the NIOSH protocol. A simple and efficient cleaning protocol achieved consistently low background values, with an average value, based on 85 measurements, of 0.12 ppb with a 95% confidence interval (CI) of ±0.16 ppb. This gives an LOD for the tests of 0.35 ppb and an LOQ of 0.88 ppb. The Equashield, Tevadaptor (OnGuard), and PhaSeal devices all showed average releases, based on 10 measurements from five tests, that were less than the LOQ (i.e. < 0.88 ppb), while the ChemoClave Vial Shield with Spinning Spiros showed average releases of 2.9±2.3 ppb and 7.5±17.9 ppb for NIOSH tasks 1 and 2 respectively at the 95% confidence level. The open system of needle and syringe showed releases, based on two measurements from a single test, of 4.2±2.2 ppb and 5.1±1.7 ppb for NIOSH tasks 1 and 2 respectively at the 95% confidence level. CONCLUSIONS: 2-POE proved to be an ideal surrogate for testing of CSTDs using the NIOSH protocol. We propose that a CSTD can be qualified using the NIOSH testing approach if the experimental LOQ is less than 1 ppb and the release values are below the LOQ. Equashield, Tevadaptor (OnGuard), and PhaSeal meet these acceptance criteria and can therefore all be qualified as CSTDs, but the ChemoClave system does not and so would not qualify as a CSTD.

Tulongicin, an Antibacterial Tri-Indole Alkaloid from a Deep-Water Topsentia sp. Sponge.

Antibacterial-guided fractionation of an extract of a deep-water Topsentia sp. marine sponge led to the isolation of two new indole alkaloids, tulongicin A (1) and dihydrospongotine C (2), along with two known analogues, spongotine C (3) and dibromodeoxytopsentin (4). Their planar structures were determined by NMR spectroscopy. Their absolute configurations were determined through a combination of experimental and computational analyses. Tulongicin (1) is the first natural product to contain a di(6-Br-1H-indol-3-yl)methyl group linked to an imidazole core. The coexistence of tri-indole 1 and bis-indole alcohol 2 suggests a possible route to 1. All of the compounds showed strong antimicrobial activity against Staphylococcus aureus.

CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations.

Context: The P450 enzyme CYP24A1 is the principal inactivator of vitamin D metabolites. Biallelic loss-of-function mutations in CYP24A1 are associated with elevated serum levels of 1,25-dihydroxyvitamin D3 with consequent hypercalcemia and hypercalciuria and represent the most common form of idiopathic infantile hypercalcemia (IIH). Current management strategies for this condition include a low-calcium diet, reduced dietary vitamin D intake, and limited sunlight exposure. CYP3A4 is a P450 enzyme that inactivates many drugs and xenobiotics and may represent an alternative pathway for inactivation of vitamin D metabolites. Objective: Our goal was to determine if rifampin, a potent inducer of CYP3A4, can normalize mineral metabolism in patients with IIH due to mutations in CYP24A1. Methods: We treated two patients with IIH with daily rifampin (10 mg/kg/d, up to a maximum of 600 mg). Serum calcium, phosphorus, parathyroid hormone (PTH), liver, and adrenal function and vitamin D metabolites, as well as urinary calcium excretion, were monitored during treatment of up to 13 months. Results: Prior to treatment, both patients had hypercalcemia, hypercalciuria, and nephrocalcinosis with elevated serum 1,25-dihydroxyvitamin D3 and suppressed serum PTH. Daily treatment with rifampin was well tolerated and led to normalization or improvement in all clinical and biochemical parameters. Conclusion: These observations suggest that rifampin-induced overexpression of CYP3A4 provides an alternative pathway for inactivation of vitamin D metabolites in patients who lack CYP24A1 function.

Glargine co-administration with intravenous insulin in pediatric diabetic ketoacidosis is safe and facilitates transition to a subcutaneous regimen.

BACKGROUND: Diabetes ketoacidosis (DKA) is a common presentation and complication of type 1 diabetes (T1D). While intravenous insulin is typically used to treat acute metabolic abnormalities, the transition from intravenous to subcutaneous treatment can present a challenge. We hypothesize that co-administration of glargine, a subcutaneous long-acting insulin analog, during insulin infusion may facilitate a flexible and safe transition from intravenous to subcutaneous therapy. OBJECTIVE: To determine if the practice of administering subcutaneous glargine during intravenous insulin is associated with an increased risk of hypoglycemia, hypokalemia, or other complications in children with DKA. METHODS: Retrospective chart review of patients aged 2 to 21 years, presenting to our center with DKA between April 2012 and June 2014. Patients were divided into two groups: those co-administered subcutaneous glargine with intravenous insulin for over 4 hours (G+); and patients with less than 2 hours of overlap (G-). RESULTS: We reviewed 149 DKA admissions (55 G+, 94 G-) from 129 unique patients. There was a similar incidence of hypoglycemia between groups (25% G+ vs 20% G-, P = 0.46). Hypokalemia (<3.5 mmol/L) occurred more frequently in the G+ group (OR = 3.4, 95% CI 1.7-7.0, P = 0.001). Cerebral edema occurred in 2/55 (3.6%) of the G- group and none of the G+ subjects. CONCLUSION: Co-administration of glargine early in the course of DKA treatment is well tolerated and convenient for discharge planning; however, this approach is associated with an increased risk of hypokalemia.

Late Presentation of Fulminant Necrotizing Enterocolitis in a Child with Hyperinsulinism on Octreotide Therapy.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In cases of diazoxide-unresponsive HI, alternative medical and surgical approaches may be required to reduce the risk of hypoglycemia. Octreotide, a somatostatin analog, often has a role in the management of these children, but a dose-dependent reduction in splanchnic blood flow is a recognized complication. Necrotizing enterocolitis (NEC) has been reported within the first few weeks of initiating predominantly high doses of octreotide. We describe the case of an infant with Beckwith-Wiedemann syndrome and diazoxide-unresponsive HI, who had persistent hypoglycemia after two pancreatectomy surgeries. She developed NEC 2 months after beginning octreotide therapy at a relatively low dose of 8 µg/kg/day. This complication has occurred later, and at a lower dose, than has previously been described. We review the case and identify the known and suspected multifactorial risk factors for NEC that may contribute to the development of this complication in patients with HI.

Discovery of a novel trimebutine metabolite and its impact on N-desmethyltrimebutine quantification by LC-MS/MS.

BACKGROUND: A failure in incurred sample reanalysis (ISR) for N-desmethyltrimebutine (NDMT), during the analysis of a trimebutine-containing drug GIC-1001 Phase I study, led to the discovery of a never-before reported metabolite of trimebutine. RESULTS: A positive bias for NDMT during the ISR and post-reconstitution stability evaluations indicated the presence of an unstable metabolite of NDMT. Precursor ion scans performed on freshly extracted samples enabled the identification of this metabolite to be the NDMT glucuronide conjugate and its fragmentation pattern suggested that the glucuronide moiety was attached at the N-terminal of NDMT. CONCLUSIONS: An acidification step was introduced in the extraction procedure to completely hydrolyze the glucuronide and measure the total NDMT in plasma, rendering this method a successful fit-for-purpose assay.

Safety, tolerability and pharmacokinetics of trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) in a randomized phase I integrated design study: single and multiple ascending doses and effect of food in healthy volunteers.

PURPOSE: Trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers. METHODS: GIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m(2). The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated. FINDINGS: The most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, Tmax of trimebutine ranged from 1.0 to 1.5 hours. Cmax and AUCT were linear (nonlinearity P ≥ 0.05) and proportional (P < 0.05) over the studied dose range. Food increased the Cmax and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84-234) and 174% (138-221), respectively. In the MAD study portion, the Tmax of trimebutine ranged from 0.5 to 2 hours and AUCτ increased from 38 to 170 ng · h/mL. AUCτ and Cmax were linear and proportional over the studied dose range. IMPLICATIONS: GIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.).

Fear of hypoglycemia in parents of children with type 1 diabetes.

AIM: The aim of this study is to determine if parental hypoglycaemia fear is associated with worse glycaemic control and increased resource utilisation and to identify risk factors for increased hypoglycaemia fear. METHODS: Parents of children with diabetes completed a modified Hypoglycaemia Fear Survey. Demographic data, phone contacts and mean glycosylated haemoglobin A1c (HbA1c) were also recorded over a 1 year study period. RESULTS: A total of 106 parents participated. Mean patient age was 11.1 years, and duration of diabetes was 4.8 years. Fifty-two per cent were male, and 48% were on insulin pump therapy. Fear of hypoglycaemia was highest among parents of 6- to 11-year-olds. Parents of children with HbA1c less than 7.5% had less hypoglycaemia fear. Previous seizures and increased frequency of phone calls to the diabetes team were not associated with increased fear. CONCLUSION: Fear of hypoglycaemia is associated with worse glycaemic control. It is highest among parents of 6- to 11-year-olds but is not affected by previous severe hypoglycaemia or associated with increased contact with the diabetes team.

Ketotic hypercalcemia: a case series and description of a novel entity.

CONTEXT: The ketogenic diet is increasingly used in refractory epilepsy and is associated with clinically significant effects on bone and mineral metabolism. Although hypercalciuria and loss of bone mineral density are common in patients on the ketogenic diet, hypercalcemia has not previously been described. OBJECTIVE: The aim of the study was to describe three children who developed hypercalcemia while on the ketogenic diet. DESIGN: A retrospective chart review of three children on the ketogenic with severe hypercalcemia was conducted. RESULTS: We describe three children on the ketogenic diet for refractory seizures who presented with hypercalcemia. Case 1 was a 5.5-year-old male with an undiagnosed, rapidly progressive seizure disorder associated with developmental regression. Case 2 was a 2.5-year-old male with a chromosomal deletion of 2q24.3, and case 3 was a 4.6-year-old male with cerebral cortex dysplasia. Patients had been on a ketogenic diet for 6 to 12 months before presentation. Daily intake of calcium and vitamin D was not excessive, and all three patients were not acidotic because they were taking supplemental bicarbonate. Each child had elevated serum levels of calcium and normal serum phosphate levels, moderately elevated urinary calcium excretion, and low levels of serum alkaline phosphatase, PTH, and 1,25-dihydroxyvitamin D. All patients responded to calcitonin. CONCLUSIONS: Hypercalcemia is an uncommon complication of the ketogenic diet, and these children may represent the severe end of a clinical spectrum of disordered mineral metabolism. The mechanism for hypercalcemia is unknown but is consistent with excess bone resorption and impaired calcium excretion.