The creation of the Global Scales for Early Development (GSED) for children aged 0-3 years: combining subject matter expert judgements with big data.

INTRODUCTION: With the ratification of the Sustainable Development Goals, there is an increased emphasis on early childhood development (ECD) and well-being. The WHO led Global Scales for Early Development (GSED) project aims to provide population and programmatic level measures of ECD for 0-3 years that are valid, reliable and have psychometrically stable performance across geographical, cultural and language contexts. This paper reports on the creation of two measures: (1) the GSED Short Form (GSED-SF)-a caregiver reported measure for population-evaluation-self-administered with no training required and (2) the GSED Long Form (GSED-LF)-a directly administered/observed measure for programmatic evaluation-administered by a trained professional. METHODS: We selected 807 psychometrically best-performing items using a Rasch measurement model from an ECD measurement databank which comprised 66 075 children assessed on 2211 items from 18 ECD measures in 32 countries. From 766 of these items, in-depth subject matter expert judgements were gathered to inform final item selection. Specifically collected were data on (1) conceptual matches between pairs of items originating from different measures, (2) developmental domain(s) measured by each item and (3) perceptions of feasibility of administration of each item in diverse contexts. Prototypes were finalised through a combination of psychometric performance evaluation and expert consensus to optimally identify items. RESULTS: We created the GSED-SF (139 items) and GSED-LF (157 items) for tablet-based and paper-based assessments, with an optimal set of items that fit the Rasch model, met subject matter expert criteria, avoided conceptual overlap, covered multiple domains of child development and were feasible to implement across diverse settings. CONCLUSIONS: State-of-the-art quantitative and qualitative procedures were used to select of theoretically relevant and globally feasible items representing child development for children aged 0-3 years. GSED-SF and GSED-LF will be piloted and validated in children across diverse cultural, demographic, social and language contexts for global use

Protocol for validation of the Global Scales for Early Development (GSED) for children under 3 years of age in seven countries

IntroductionChildren’s early development is affected by caregiving experiences, with lifelong health and well-being implications. Governments and civil societies need population-based measures to monitor children’s early development and ensure that children receive the care needed to thrive. To this end, the WHO developed the Global Scales for Early Development (GSED) to measure children’s early development up to 3 years of age. The GSED includes three measures for population and programmatic level measurement: (1) short form (SF) (caregiver report), (2) long form (LF) (direct administration) and (3) psychosocial form (PF) (caregiver report). The primary aim of this protocol is to validate the GSED SF and LF. Secondary aims are to create preliminary reference scores for the GSED SF and LF, validate an adaptive testing algorithm and assess the feasibility and preliminary validity of the GSED PF.Methods and analysisWe will conduct the validation in seven countries (Bangladesh, Brazil, Côte d’Ivoire, Pakistan, The Netherlands, People's Republic of China, United Republic of Tanzania), varying in geography, language, culture and income through a 1-year prospective design, combining cross-sectional and longitudinal methods with 1248 children per site, stratified by age and sex. The GSED generates an innovative common metric (Developmental Score: D-score) using the Rasch model and a Development for Age Z-score (DAZ). We will evaluate six psychometric properties of the GSED SF and LF: concurrent validity, predictive validity at 6 months, convergent and discriminant validity, and test–retest and inter-rater reliability. We will evaluate measurement invariance by comparing differential item functioning and differential test functioning across sites.Ethics and disseminationThis study has received ethical approval from the WHO (protocol GSED validation 004583 20.04.2020) and approval in each site. Study results will be disseminated through webinars and publications from WHO, international organisations, academic journals and conference proceedings.Registration detailsOpen Science Frameworkhttps://osf.io/on 19 November 2021 (DOI 10.17605/OSF.IO/KX5T7; identifier: osf-registrations-kx5t7-v1).</jats:sec

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. Methods We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. Findings Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. Interpretation As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. Funding Bill & Melinda Gates Foundation

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Contrasting effect of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide

Objective: Among the many actions of nitric oxide (NO) are those on endocrine and feeding behaviour. Based on NO involvement in the GH-releasing effect of the CH-releasing peptides (GHRPs) and the reported orexigenic activity of these compounds, we sought to evaluate the effect of the combined administration of a long-acting NO donor, molsidomine, and the newly synthesized GHRP EP92632 on food intake and GH secretion in rats. Moreover, to verify the specificity of a potential NO involvement, we evaluated whether or not the effects of GHRPs were abolished by a pre-treatment with an inhibitor of NO synthase, N-nitro-arginine-methyl-ester (NAME). Methods: In the food intake experiments, adult Sprague-Dawley male rats underwent acute administration of: (1) EP92632 (160 mug/kg. s.c.): (2) molsidomine (100 mg/kg, i.p.); (3) EP92632+molsidomine: (4) L-NAME (40 and 60 mg/kg, i.p,): (5) EP92632+L-NAME (60 mg/kg, i.p.): (6) EP92632+molsidomine+L-NAME (60 mg/kg, i.p.): and (7) 0.9%, saline (0.1 ml/kg, i.p.). After treatments, the cumulative food intake in the 6 post-treatment hours was carefully evaluated. In the neuroendocrine experiments, rats were given the same compounds according to the above reported schedule, except for the use of one dose of NAME (60 mg/kg, i.p.) and a lower EP92632 dose (80 mug/kg. s.c.), and were sampled via atrial cannula. Results: EP92632 significantly stimulated food intake, an effect which was further enhanced by molsidomine, though the latter did not elicit per se any orexigenic effect. L-NAME given alone significantly decreased food intake and abolished the orexigenic effect of the GHRP and the enhancing effect of molsidomine. Plasma GH levels increased significantly following administration of EP92632 but, in contrast to the food intake experiments, molsidomine significantly inhibited both basal and EP92632-stimulated GH secretion: moreover, NAME had a biphasic effect on the EP92632-stimulated GH release: initially inhibitory and then, from 45 min on, stimulatory. NAME did not affect basal GH levels but, surprisingly, combined administration of molsidomine and NAME induced a striking inhibition of both basal and the peptide-stimulated GH release. Conclusions: In summary. these data indicate that NO in the rat is physiologically involved in a stimulatory way in the GHRP-mediated effect on food intake, but exerts a dual action, probably stimulatory at hypothalamic and inhibitory at pituitary levels, on basal and GHRP-stimulated CH secretion

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide

Objective: Evidence has been presented that in both animals and humans the rebound secretion of growth hormone (GH) following withdrawal of an infusion of somatostatin (SS) is due to the functional activation of the hypothalamic GH-releasing hormone (GH-RH) neurons of the recipient organism. Based on this premise, this study has sought to assess the existence of functional interactions between endogenous GHRH released by a SS infusion withdrawal (SSIW) and growth hormone-releasing peptides (GHRPs), a class of compounds allegedly acting via GHRH. Methods: Five young dogs (3 to 4 years old, 2 male and 3 female) were administered, on different occasions, three consecutive intravenous boli of physiological saline (0.1 ml/kg), or GHRH (2 mug/kg), or EP92632 (125 mug/kg), a GHRP compound, or GHRH plus EP92632 at the end of three cycles of 1-h SS infusions (8 mug/(kgxh)) or during a 6-h infusion of saline. Results: Under saline infusion (SALI), plasma GH levels were unaltered, whereas each SSIW cycle was followed by similar GH secretory episodes. Administration of the first GHRH bolus under SALI induced a rise in plasma GH concentrations slightly higher than that induced by the first cycle of SSIW, but the GH response to the second and third GHRH boli was similar to that after SSIW. Following SSIW, the response to the first bolus of GHRH was higher than that during SALI, but the second and third cycles of SSIW induced GH responses similar to those evoked by the GHRH bolus. During SALI administration of the first bolus of EP92632 induced a rise in plasma GH which was higher than that induced by the first GHRH bolus, the second bolus elicited a GH peak of lesser amplitude and there was a partial restoration of the GH response to the third peptide bolus. SSIW strikingly enhanced the GH release to the first EP92632 bolus, a pattern also present, although to a lesser extent, with the second and third cycles of SSIW. Under SALI combined administration of GHR-H and EP92632 had a synergistic effect on GH release, but a progressive reduction was present in the GH response to the second and third GHRH plus EP92632 boli. SSIW increased only weakly the GH response to the first co-administration of the peptides over that present after administration of EP92632 alone, and did not induce a GH response higher than that present during SALI when the second bolus of the peptides was administered; after the third SSIW a GH rise higher than that present during SALI was elicited by the combined administration of the peptides. Conclusions: (i) the uniformity of the GH rebound responses to multiple cycles of SSIW may indicate that the latter activate a physiological mechanism which mimics that normally controlling GH pulse generation; (ii) EP92632 elicits, under our experimental conditions, a plasma GH rise higher than that induced by GHRH; (iii) SSIW enhances the GH response to EP92639 alone, to an extent reminiscent of that following combined administration of GHRH and EP92632. This pattern reinforces the view that SSIW elicits release of endogenous GHRH, and infers that the GHRP challenge after SSIW may be exploited in humans to distinguish between healthy and GH-deficient adults