Continuous Subcutaneous Recombinant Parathyroid Hormone (1-34) Infusion in the management of childhood Hypoparathyroidism associated with Malabsorption

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Hypoparathyroidism associated with malabsorption can be particularly challenging to manage due to limited and erratic intestinal absorption of calcium and vitamin D analogues, resulting in episodes of hypo- or hypercalcaemia. We evaluated the role of continuous subcutaneous recombinant parathyroid hormone (rhPTH 1–34) infusion (CSPI) in children with hypoparathyroidism associated with intestinal malabsorption resistant to conventional therapy. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; Four patients (8–13 years of age), with symptomatic hypocalcaemia resistant to conventional therapy, were started on CSPI (follow-up 3–8 years) in two paediatric endocrinology units in Europe. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Serum calcium normalized within 48 h of commencing treatment in all 4 patients. An average rhPTH 1–34 dose of 0.4 µg/kg/day resulted in a substantial reduction in symptomatic hypocalcaemia and hypo-/hypercalcaemia-related hospital admissions. An increased alkaline phosphatase activity was noted in the first 6 months on CSPI, indicating an increase in bone turnover. In 2 patients with elevated urinary calcium excretion before CSPI, this normalized in the first year on treatment. No significant side effects were noticed in the short or long term, with patient-reported preference of CSPI over conventional treatment. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; CSPI is a promising and effective treatment option for managing hypocalcaemia and hyperphosphataemia in children with hypoparathyroidism associated with intestinal malabsorption.</jats:p

A prospectus for bilingual early reading instruction

In this paper, we describe a framework for bilingual decoding instruction, with a call for collaborators. Decoding is the ability to apply knowledge of letter-sound correspondences to pronounce words. We adopt a standard phonological approach for early instruction that could be expanded to include practice with constructive morphemes, like prefixes and suffixes, and reading for meaning. Decades of research have shown that word decoding is a bottleneck in reading comprehension. Unless children develop sight-word reading capabilities, comprehension of texts is severely hampered. The present approach draws on children’s spoken vocabulary knowledge in their native language as a bridge to decoding in a second language. The goal is to develop a tutoring system that draws on current and forthcoming multimedia technologies, and to implement the system in multilingual countries, e.g.: USA, India, Ukraine and across national borders. As a starting point, the authors will use a web platform https://ethicalengineer.ttu.edu designed in 2017 by the USA, Indian, and Ukrainian collaborators, several of them being co-authors of this paper, as a model for the new website for reading instruction. The Ethical Engineer website demonstrates one mechanism through which instructors can reach out to establish connections within and outside their native country around topics and issues of common interest and support educator cooperation and research development. The new model hopes to achieve success comparable to that of the EthicalEngineer. Using computer-based instruction allows for empirical testing of teaching methods, thereby optimizing the educational process. It is important to take advantage of this to ensure the most effective methods are used in early reading instruction for children. Disclosure Statement No potential conflict of interest was reported by the authors. * Corresponding author: Roman Taraban,   0000-0002-1815-4687 [email protected]

Efficacy and treatment costs of Zoledronate versus Pamidronate in Paediatric Osteoporosis

Intravenous pamidronate has been used in the treatment of osteogenesis imperfecta (OI) in children for over 20 years. The more potent zoledronate is an attractive alternative as it is administered less frequently. This study compares the clinical efficacy of intravenous pamidronate (1.5 mg/kg/day over 2 days, every 3 months) versus zoledronate (0.05 mg/kg/dose every 6 months) in 40 children (20 per group) with mild to moderate OI and the treatment costs of the two drugs in a tertiary centre for children with osteoporosis. Lumbar spine bone mineral density and fracture rate did not differ between drug groups following 1 and 2 years of treatment, respectively. Total cost per treatment course per patient was £1157 for pamidronate and £498 for zoledronate. Therefore, zoledronate is a considerably cheaper alternative to pamidronate with comparable efficacy, resulting in substantial annual savings for healthcare providers and a more convenient option for patients due to fewer hospital visits.</jats:p

Phenotypic spectrum in osteogenesis imperfecta due to mutations in TMEM38B: unravelling a complex cellular defect.

Context: Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux. Objectives: Clinical and bone material phenotype description and osteoblast differentiation studies. Design and Setting: Natural history study in paediatric research centres. Patients: Eight patients with type XIV OI. Main Outcome Measures: Clinical examinations included: bone mineral density, radiographs, echocardiography and muscle biopsy. Bone biopsy samples (n=3) were analysed using histomorphometry, quantitative backscattered electron microscopy and Raman microspectroscopy. Cellular differentiation studies were performed on proband and control osteoblasts and normal murine osteoclasts. Results: The clinical phenotype of type XIV OI ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband L1-L4 bone density Z-score was reduced (median -3.3 [range -4.77 to +0.1; n=7]), and increased by +1.7 (1.17 to 3.0; n=3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone matrix mineralization is normal and nanoporosity low. We demonstrate a complex osteoblast differentiation defect with decreased expression of early markers and increased late and mineralization-related markers. Predominance of TRIC-B over TRIC-A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover. Conclusions: OI type XIV has a bone histology, matrix mineralization and osteoblast differentiation pattern that is distinct from OI with collagen defects. Probands are responsive to bisphosphonates and some show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities

Spontaneous fractures during 13-cis retinoic acid therapy for neuroblastoma.

peer reviewe

Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (&gt;20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.</p

Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− mice

AngII (angiotensin II) induces atherosclerosis and AAAs (abdominal aortic aneurysms) through multiple proposed mechanisms, including chemotaxis. Therefore, we determined the effects of whole-body deficiency of the chemokine receptor CCR2 (CC chemokine receptor 2) on these diseases. To meet this objective, apoE (apolipoprotein E)−/− mice that were either CCR2+/+ or CCR2−/−, were infused with either saline or AngII (1000 ng·kg−1 of body weight·min−1) for 28 days via mini-osmotic pumps. Deficiency of CCR2 markedly attenuated both atherosclerosis and AAAs, unrelated to systolic blood pressure or plasma cholesterol concentrations. During the course of the present study, we also observed that AngII infusion led to large dilatations that were restricted to the ascending aortic region of apoE−/− mice. The aortic media in most of the dilated area was thickened. In regions of medial thickening, distinct elastin layers were discernable. There was an expansion of the distance between elastin layers in a gradient from the intimal to the adventitial aspect of the media. This pathology differed in a circumscribed area of the anterior region of ascending aortas in which elastin breaks were focal and almost transmural. All regions of the ascending aorta of AngII-infused mice had diffuse medial macrophage accumulation. Deficiency of CCR2 greatly attenuated the AngII-induced lumen dilatation in the ascending aorta. This new model of ascending aortic aneurysms has pathology that differs markedly from AngII-induced atherosclerosis or AAAs, but all vascular pathologies were attenuated by CCR2 deficiency

Infigratinib in children with achondroplasia:the PROPEL and PROPEL 2 studies

BACKGROUND: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. OBJECTIVES: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. DESIGN: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. METHODS AND ANALYSIS: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. ETHICS: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. DISCUSSION: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. REGISTRATION: ClinicalTrials.gov: NCT04035811; NCT04265651

A meta-analysis of the prevalence of Different functions of non-suicidal self-injury.

Background A broad variety of different functions can underlie acts of Non-suicidal self-injury (NSSI). Whilst research so far has identified many of the commonly reported functions, no reliable estimates of prevalence currently exist for these different NSSI functions. Understanding the prevalence of NSSI functions represents a key to better understanding the phenomenology of NSSI and addressing the differing needs of the NSSI population. We conducted a systematic review and meta-analysis of the prevalence of NSSI functions in community and clinical samples. Method A literature search of electronic databases PsycINFO, Medline, and Web of Science from date of inception to March 2017 was undertaken. A pre-specified framework for categorising different functions of NSSI was used to collate data from across studies. A random-effects meta-analysis of prevalence was then undertaken on these data. Results Intrapersonal functions (66–81%), and especially those concerning emotion regulation were most commonly reported by individuals who engage in NSSI (63–78%). Interpersonal functions (e.g., expressing distress) were less common (33–56%). Limitations The review was limited to English-language articles. Reviewed articles were inconsistent in their measurement of NSSI. Inconsistency within pooled prevalence estimates was high when moderators were not accounted for. Conclusions Findings indicate that intrapersonal functions of NSSI are most common and are present for the majority of participants. This finding supports dominant emotion-regulation models of NSSI, and the use of interventions that work to improve emotion-regulation ability. However, interpersonal functions remain endorsed by a substantial portion of participants