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Sensory signals are processed by the cerebellum to coordinate movements. Numerous cerebellar functions are thought to require the maintenance of a sensory representation that extends beyond the input signal. Granule cells receive sensory input, but they do not prolong the signal and are thus unlikely to maintain a sensory representation for much longer than the inputs themselves. Unipolar brush cells (UBCs) are excitatory interneurons that project to granule cells and transform sensory input into prolonged increases or decreases in firing, depending on their ON or OFF UBC subtype. Further extension and diversification of the input signal could be produced by UBCs that project to one another, but whether this circuitry exists is unclear. Here we test whether UBCs innervate one another and explore how these small networks of UBCs could transform spiking patterns. We characterized two transgenic mouse lines electrophysiologically and immunohistochemically to confirm that they label ON and OFF UBC subtypes and crossed them together, revealing that ON and OFF UBCs innervate one another. A Brainbow reporter was used to label UBCs of the same ON or OFF subtype with different fluorescent proteins, which showed that UBCs innervate their own subtypes as well. Computational models predict that these feed-forward networks of UBCs extend the length of bursts or pauses and introduce delays—transformations that may be necessary for cerebellar functions from modulation of eye movements to adaptive learning across time scales.

Monocular deprivation early in development causes amblyopia, a severe visual impairment. Prognosis is poor if therapy is initiated after an early critical period. However, clinical observations have shown that recovery from amblyopia can occur later in life when the non-deprived (fellow) eye is removed. The traditional interpretation of this finding is that vision is improved simply by the elimination of interocular suppression in primary visual cortex, revealing responses to previously subthreshold input. However, an alternative explanation is that silencing activity in the fellow eye establishes conditions in visual cortex that enable the weak connections from the amblyopic eye to gain strength, in which case the recovery would persist even if vision is restored in the fellow eye. Consistent with this idea, we show here in cats and mice that temporary inactivation of the fellow eye is sufficient to promote a full and enduring recovery from amblyopia at ages when conventional treatments fail. Thus, connections serving the amblyopic eye are capable of substantial plasticity beyond the critical period, and this potential is unleashed by reversibly silencing the fellow eye.

Background: Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia., Methods: In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity., Results: During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06)., Conclusions: The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.)., (Copyright © 2024 Massachusetts Medical Society.)

A 1-month-old male infant presented unwell with a fever and shock. Blood tests showed hypernatraemia, hyperchloraemia and raised urea and creatinine. Initially, he was treated for dehydration secondary to sepsis. However, high urine output combined with low urine osmolality and high plasma osmolality was suggestive of a disorder of arginine vasopressin (AVP), previously called diabetes insipidus (DI). On further endocrine testing, thyroxine (T4) level was low with an inappropriately normal thyroid-stimulating hormone level with no other anterior pituitary hormone abnormalities, a normal MRI head and ophthalmological assessment. Desmopressin, a synthetic form of AVP, was commenced, however, there was an inadequate response despite dose escalation, leading to a diagnosis of AVP resistance (previously nephrogenic DI) rather than AVP deficiency (previously cranial DI). Copeptin, an AVP precursor peptide and surrogate marker, was significantly elevated. A renal tubulopathy genetic screen demonstrated a likely pathogenic hemizygous variant in the AVP receptor 2 gene, which has previously been associated with X-linked vasopressin resistance. This case demonstrates the challenge of differentiating between AVP deficiency and resistance in infancy and the value of copeptin and genetic testing in confirming diagnosis. We outline an approach to fluid management in AVP disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: With one in five children in England living with obesity, we mapped the geographical distribution and format of child weight management services provided by acute National Health Service (NHS) trusts across England, to identify breadth of service provision., Design: A cross-sectional survey., Setting: The survey was sent to acute NHS trusts (n=148) in England in 2020, via a freedom of information request., Participants: Responses were received from 139 of 148 (94%) acute NHS trusts, between March 2020 to March 2021., Outcome Measures: The survey asked each acute NHS trust whether they provide a weight management service for children living with obesity. For those trusts providing a service, data were collected on eligibility criteria, funding source, personnel involved, number of new patients seen per year, intervention duration, follow-up length and outcome measures. Service characteristics were reported using descriptive statistics. Service provision was analysed in the context of ethnicity and Index of Multiple Deprivation score of the trust catchment area., Results: From the 139 survey respondents, 23% stated that they provided a weight management service for children living with obesity. There were inequalities in the proportion of acute NHS trusts providing a service across the different regions of England, ranging from 4% (Midlands) to 36% (London). For trusts providing a service, there was variability in the number of new cases seen per year, eligibility criteria, funding source, intervention format and outcome measures collected. A multidisciplinary approach was not routinely provided, with only 41% of services reporting ≥3 different staff disciplines., Conclusion: In 2020/2021, there were geographical inequalities in weight management service provision by acute NHS trusts for children living with obesity. Services provided lacked standardisation, did not routinely offer children multidisciplinary care and were insufficient in size to meet need., Competing Interests: Competing interests: JPHS is clinical lead for a tier 3 childhood obesity service in Bristol and will be a hub for the new 'Complications from Excess Weight' (CEW) clinics funded by NHS England., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: To establish short-term and medium-term complications 1-year postdiagnosis, of acute pancreatitis (AP) in children aged 0-14 years., Design: One-year follow-up of a prospective monthly surveillance of new cases of AP in children under 15 years through the British Paediatric Surveillance Unit (BPSU) from April 2013 to April 2014., Setting: A monthly surveillance of >3700 consultant paediatricians and paediatric surgeons in the UK and Ireland using the BPSU., Patients: Children aged 0-14 years with a new diagnosis of AP., Main Outcome Measures: The outcomes following AP, including the incidence of complications and comorbidity at diagnosis and at 1 year., Results: Of the 94 new confirmed cases of AP identified in the UK during the study period, 90 cases (96%) were included in the 1-year follow-up. 30 patients (32%) developed further episode(s) of AP. Over one-fifth of patients developed one or more major complication. At initial admission, the most common of these was pancreatic necrosis (n=8, 9%), followed by respiratory failure (n=7, 7%). Reported complications by 1 year were pseudocyst formation (n=9, 10%), diabetes requiring insulin therapy (n=4, 4%) and maldigestion (n=1, 1%). At 1-year postdiagnosis, only 59% of children made a full recovery with no acute or chronic complications or recurrent episodes of AP. Two patients died, indicating a case fatality of ~2.0%., Conclusions: AP in childhood is associated with significant short-term and medium-term complications and comorbidities including risk of recurrence in approximately a third of cases., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

PAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, and PAX8 gene methylation is reported to be sensitive to the periconceptional environment. Using a novel recall-by-epigenotype study in Gambian children, we found that PAX8 hypomethylation at age 2 years is associated with a 21% increase in thyroid volume and an increase in free thyroxine (T4) at 5 to 8 years, the latter equivalent to 8.4% of the normal range. Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density. Furthermore, offspring PAX8 methylation was associated with periconceptional maternal nutrition, and methylation variability was influenced by genotype, suggesting that sensitivity to environmental exposures may be under partial genetic control. Together, our results demonstrate a possible link between early environment, PAX8 gene methylation and thyroid gland development and function, with potential implications for early embryonic programming of thyroid-related health and disease.

Dysglycemia is a common complication of severe acute malnutrition (SAM) in children. Its prevalence and impact on short- and long-term outcomes are not well described. This systematic review was undertaken to review the available evidence on dysglycemia (either hypo- or hyperglycemia) in hospitalized children with SAM. The 2 primary objectives of this systematic review were to understand the prevalence of hypoglycemia and hyperglycemia in children with SAM. A secondary objective was to understand the relation between dysglycemia and clinical outcomes like mortality in children with SAM. MEDLINE was searched with terms related to children, SAM, and dysglycemia. A meta-analysis of proportions was completed to determine the hypoglycemia prevalence and a standard meta-analysis was done to determine the relation between hypoglycemia and mortality. The certainty of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 2148 articles were identified in the database search of which 16 met the inclusion criteria for the systematic review based on screening done by multiple reviewers. The overall prevalence of hypoglycemia in SAM across studies based on the meta-analysis of proportions was 9% (95% CI: 7%, 12%; I2 = 92%). Meta-analysis results showed that hypoglycemia was associated with a higher chance of mortality during hospitalization in children with SAM (OR: 4.29; 95% CI: 3.04, 6.05; I2 = 0%). According to the GRADE evaluation, the certainty of the evidence for the prevalence of hypoglycemia was low and for hyperglycemia was very low. For the relation between hypoglycemia and mortality, the certainty of the evidence was moderate. A meta-analysis was not carried out for the prevalence of hyperglycemia due to the wide range of definitions used for across studies, but the prevalence ranged from 2% to 38% in the literature. This systematic review highlights the need for further work in this area to include serial glucose measurements to understand the clinical importance of dysglycemia during hospitalization in children with SAM., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objectives Prader-Willi Syndrome (PWS) is characterised by hyperphagia often leading to obesity; a known risk factor for insulin resistance and type 2 (T2) diabetes. We present a prepubertal girl with PWS who developed diabetes. Case presentation Our case was diagnosed with PWS in infancy following investigation for profound central hypotonia and feeding difficulties. She commenced growth hormone (GH) aged 8 years for short stature and treatment improved linear growth. At age 12 years, she presented with polydipsia, polyuria and vulvovaginitis. She was overweight (BMI SDS +1.43). Diabetes was diagnosed (Blood glucose = 24.2 mmol/L, HbA1c = 121 mmol/mol or 13.2%). She was not acidotic and had negative blood ketones. Autoantibodies typical of type 1 diabetes were negative. She was initially treated with basal bolus insulin regime. GH was discontinued 3 months later due to concerns regarding GH-induced insulin resistance. Off GH, insulin requirements reduced to zero, allowing Metformin monotherapy. However off GH, she reported significant lethargy with static growth and increased weight. Combinations of Metformin with differing insulin regimes did not improve glucose levels. Liraglutide (GLP-1 agonist) and Metformin did not improve glucose levels nor her weight. Liraglutide and Empaglifozin (SGLT-2 inhibitor) therapy used in combination were well tolerated and demonstrated rapid normalisation of blood glucose and improvement in her HbA1c to within target (48 mmol/mol) which was sustained after 6 months of treatment. Conclusions Newer treatments for type 2 diabetes (e. g. GLP-1 agonists or SGLT-2 inhibitors) offer potential treatment options for those with diabetes and PWS when conventional treatments are ineffective.

Context and Objectives: The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF)., Design & Participants: 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression., Results: Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers., Conclusions: Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Proopiomelanocortin (POMC) is a key mediator of satiety. Epigenetic marks such as DNA methylation may modulate POMC expression and provide a biological link between early life exposures and later phenotype. Animal studies suggest epigenetic marks at POMC are influenced by maternal energy excess and restriction, prenatal stress and Triclosan exposure. Postnatal factors including energy excess, folate, vitamin A, conjugated linoleic acid and leptin may also affect POMC methylation. Recent human studies suggest POMC DNA methylation is influenced by maternal nutrition in early pregnancy and associated with childhood and adult obesity. Studies in children propose a link between POMC DNA methylation and elevated lipids and insulin, independent of body habitus. This review brings together evidence from animal and human studies and suggests that POMC is sensitive to nutritional programming and is associated with a wide range of weight-related and metabolic outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

We undertook a feasibility study to reassess metabolic outcomes in young people with early onset obesity who attended a hospital-based lifestyle weight-loss intervention during adolescence. Comparisons of metabolic assessments, including body mass index standard deviation scores (BMI⁻SDSs), blood pressure (BP), oral glucose tolerance tests (OGTTs), lipid profile, and alanine transaminase (ALT), before and after treatment were made. Twenty-five subjects (10 males) with median ages (interquartile range, IQR) of 14.5 (12.6⁻15.4) years at the beginning of intervention and 18.2 (17.2⁻18.9) years at reassessment and who were 3.5 (2.4⁻6.5) years post-intervention were recruited. Twenty-eight percent had a ≥0.25 reduction in BMI⁻SDS from baseline (responders). Responders demonstrated significantly lower BMI⁻SDS, systolic BP, and glucose disposal at reassessment compared with baseline. They also showed significantly lower total fat percentage SDSs, trunk fat percentages, 120 min insulin, and ALT, as well as higher insulin sensitivity index (ISI comp ) than non-responders. Male gender and younger age at the initiation of intervention showed a non-significant trend towards greater success in weight loss. Long-term benefits were demonstrated in around one-quarter of obese adolescents after lifestyle modification treatment, with associated improvements in body composition and metabolic parameters.

Type 1 diabetes mellitus (T1DM) is a common chronic disease in children and young people. Living with diabetes can pose many challenges both medical and psychological. Disordered eating behaviours, intentional insulin omission and recognised eating disorders are common among young people with diabetes and are associated with increased risk of short-term and long-term complications and death. Recognition of these behaviours is important to ensure that relevant support is provided. Joint working between diabetes and mental health teams has challenges but is essential to ensure all needs are met during treatment and recovery., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Childhood leukaemia survivors treated with haematopoietic stem cell transplantation and total body irradiation (HSCT-TBI) have multiple risk factors for reduced bone mineral density (BMD) and growth failure; hence, BMD assessment must take body size into consideration. This study aimed to evaluate size-corrected BMD in leukaemia survivors treated with and without HSCT-TBI., Methods: Childhood leukaemia survivors treated with HSCT-TBI (n = 35), aged 17.3 (10.5-20.9) years, were compared with those treated with chemotherapy only, (n = 16) aged 18.5 (16.1-20.9) years, and population references. Outcome measures included anthropometric measurements and BMD by dual-energy X-ray absorptiometry. BMD was corrected for size as bone mineral apparent density (BMAD). Statistical analysis was performed by 1- and 2-sample t tests as well as regression analysis (5% significance)., Results: HSCT-TBI survivors were lighter and shorter with reduced spinal heights compared with chemotherapy-only subjects and population references. Compared with population references, HSCT-TBI survivors showed lower BMD standard deviation scores (SDS) (p = 0.008), but no difference in BMAD-SDS, and chemotherapy-only survivors showed no differences in neither BMD-SDS nor BMAD-SDS. All HSCT-TBI participants with BMD-SDS <-2 had BMAD-SDS >-2. BMAD-SDS was negatively associated with age (r = -0.38, p = 0.029) in HSCT-TBI survivors., Conclusions: Size-corrected BMD are normal in HSCT-TBI survivors in young adulthood, but may reduce overtime. BMD measurements should be corrected for size in these patients to be clinically meaningful., (© 2018 S. Karger AG, Basel.)

Aim: To assess cholesterol screening of children with Type 1 diabetes by diabetes professionals using a survey of current practice, given that National Institute of Health and Care Excellence guidelines on childhood Type 1 diabetes do not recommend cholesterol screening, yet the National Paediatric Diabetes Audit has an annual cholesterol measure (> 12 years) as a key outcome indicator., Methods: An online survey was sent to 280 members of the Association of Children's Diabetes Clinicians to assess cholesterol screening practice in children., Results: A total of 87 diabetes professionals (31%) responded. The results showed that 94% of respondents measured cholesterol, 33% did this annually on all children, and 7% measured fasting cholesterol. A total of 63% used no guidelines to decide treatment or further investigation. The definition of 'high' cholesterol varied from > 4.5 to > 8 mmol/l, with 40% giving no response or specific level. Only 14% of clinicians had started statin therapy in their diabetes clinic in the previous 5 years., Conclusion: Whilst the majority of diabetes professionals measured cholesterol in children with Type 1 diabetes, there was marked variability in sampling, in children screened and in action taken if levels were considered abnormal. It is debatable whether cholesterol measures should be undertaken, certainly more than once, and whether cholesterol level should feature as a key outcome in the national audit in future., (© 2017 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Purpose: Adequate nutrition during adolescence is important for optimal physical and cognitive development and for pregnancy either during adolescence or later life. Thinness among adolescent girls in low- and middle-income countries has been little studied., Methods: We used body mass index data from 40 countries from the Global School Health Survey to estimate the prevalence of moderate and severe thinness in 12- to 18-year-olds using the World Health Organization 2007 growth reference. Self-report data on going to bed hungry were used as a proxy for household food insecurity. We used multilevel models to assess whether national wealth (gross domestic product), income inequality (Gini index), national gender inequality (Gender Inequality Index), and food security (Global Food Security Index) were associated with undernutrition., Results: Prevalence rates of moderate and severe thinness across 61,603 girls from 40 countries were 6.30% (95% confidence interval [CI]: 5.71-6.95) and 1.34% (1.12-1.59), respectively, with higher rates in Asia. Combined moderate/severe thinness was more common among early (12-14 years) than later adolescents (15-18 years). Going to bed hungry sometimes was associated with increased risk of moderate/severe thinness (odds ratio [OR]: 1.102; 95% CI: 1.007-1.206). A significant inverse relationship was found between thinness and gross domestic product (OR: .94; 95% CI: .88-.99) and Global Food Security Index (OR: .96; 95% CI: .93-.99) but not Gini or Gender Inequality Index., Conclusion: Thinness remains prevalent in adolescent schoolgirls in low- and middle-income countries and poses a significant threat to their health and that of the next generation. Further research is needed to assess potential interventions for this group., (Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Sensitivity regulation enables the visual system to function effectively from the absorption of a few photons at the lowest visual threshold to the absorption of enough photons to bleach nearly all the light-sensitive photopigment in the eye. Here, we investigate sensitivity regulation in the rod (or scotopic) range from -3.8 to -0.8 log(10) scotopic trolands. Over most of this range, the rate of photon absorption per rod is too low for sensitivity regulation to be practicable within the rod photoreceptor itself, so that regulation must occur postreceptorally. We measured adaptation-dependent changes in visual sensitivity and visual delay, which together provide a much more complete characterization of the effects of light adaptation than the usual method of measuring sensitivity changes alone. Our results demonstrate clearly that changes in scotopic sensitivity with increasing light levels are achieved in large part by a speeding up of the scotopic response and a decrease in the temporal integration time. Thus, the scotopic and the photopic systems both regulate their steady-state sensitivity using the same strategy, even though the scotopic system does it largely postreceptorally and the photopic system largely receptorally.