The Impact of Malnutrition on the Developing Lung and Long-Term Lung Health: A Narrative Review of Global Literature.

Worldwide, over 2 billion children under the age of 5 experience stunting, wasting, or are underweight. Malnutrition contributes to 45% of all deaths in this age group (approximately 3.1 million deaths) [1]. Poverty, food insecurity, suboptimal feeding practices, climate change, and conflict are all contributing factors. Malnutrition causes significant respiratory problems, including increased risk of respiratory infections, impaired lung function, and increased risk of subsequent adult respiratory disease, including asthma, COPD, and lung cancer. Childhood malnutrition not only has serious consequences for children's health but it also has numerous consequences on wellbeing and educational attainment. Childhood malnutrition is a complex and multifaceted problem. However, by understanding and addressing the underlying causes, and investing in prevention and treatment programs, it is possible to maximize children's health and wellbeing on a global scale. This narrative review will focus on the impact of childhood malnutrition on lung development, the consequent respiratory disease, and what actions can be taken to reduce the burden of malnutrition on lung health.

Impact of indoor environment on children's pulmonary health.

INTRODUCTION: A child's living environment has a significant impact on their respiratory health, with exposure to poor indoor air quality (IAQ) contributing to potentially lifelong respiratory morbidity. These effects occur throughout childhood, from the antenatal period through to adolescence. Children are particularly susceptible to the effects of environmental insults, and children living in socioeconomic deprivation globally are more likely to breathe air both indoors and outdoors, which poses an acute and long-term risk to their health. Adult respiratory health is, at least in part, determined by exposures and respiratory system development in childhood, starting in utero. AREAS COVERED: This narrative review will discuss, from a global perspective, what contributes to poor IAQ in the child's home and school environment and the impact that indoor air pollution exposure has on respiratory health throughout the different stages of childhood. EXPERT OPINION: All children have the right to a living and educational environment without the threat of pollution affecting their health. Action is needed at multiple levels to address this pressing issue to improve lifelong respiratory health. Such action should incorporate a child's rights-based approach, empowering children, and their families, to have access to clean air to breathe in their living environment.

Implementing a specialist paediatric clinical pharmacology service in a UK children's hospital.

AIMS: Royal College of Paediatrics and Child Health subspecialist training in Paediatric Clinical Pharmacology and Therapeutics has been delivered in the UK for 20 years, but no specialist clinical services have been set up previously. METHODS: Prospective audit and service evaluation of paediatric clinical pharmacology service pilot phase and dedicated service at a UK children's hospital. RESULTS: Pilot scheme (May-October 2019), then weekly service (established June 2020). Service covers the High Dependency Unit, and inpatients with polypharmacy. The pilot demonstrated high levels of acceptance, with 89% of suggested medication changes agreed by lead clinical team, and success, with 97.5% of suggested changes continued until discharge/pilot completion. Economic analysis estimated direct annualised cost savings on medications of up to £10 000. After 20 ward rounds of the established service, 270 potential medication changes were identified, 213 were carried out (78.9%). The most common were deprescribing (n = 143), prescribing (n = 47) and dose adjustment (n = 8). Seventy-five different medications were deprescribed, most commonly chloral hydrate (n = 12), Lactulose, ibuprofen, Bio-Kult and sodium alginate (all n = 4). The percentage of inpatients prescribed ≥10 medications decreased from 38.5 to 32.1%, while the subset prescribed ≥20 medications decreased from 11.0 to 5.67%. The mean number of medicines prescribed decreased from 9.0 to 8.0, while the median was unchanged at 7. Annual Yellow Card reports of suspected adverse drug reactions more than doubled (n = 66). CONCLUSION: A UK model for subspecialist paediatric clinical pharmacology service delivery has demonstrated a positive clinical impact and could be replicated at other UK secondary/tertiary children's hospitals.

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Pediatric asthma and COVID-19: The known, the unknown, and the controversial.

The novel coronavirus disease-2019 (COVID-19), caused by the pathogen severe acute respiratory syndrome-CoV-2, is causing a global pandemic, with over 26.9 million cases and 880,000 deaths as of September 6, 2020. While there has been speculation and observational research about the impact of COVID-19 on asthma, much remains unknown. The goal of this article is to provide a scoping review on pediatric asthma and COVID-19 and summarize what we do and do not know from the first wave of the pandemic.

Pharmacovigilance Reports Received from Children and Young People, and Development of Information to Aid Future Reporting from this Age Group.

OBJECTIVES: This study aimed to determine the contribution of children and young people (CYP) to the Medicines and Healthcare Products Regulatory Agency (MHRA) Yellow Card Scheme (YCS), and to develop age appropriate information with CYP through focus groups to help aid future reporting by this cohort. METHODS: Reports for suspected adverse drug reactions (ADRs) in patients < 19 years of age received by the MHRA YCS from 1 January 2008 to 29 November 2018 were collated and analysed. Consultation activities with CYP from regional, national and international groups were undertaken from November 2017 to July 2018 to develop CYP-appropriate information from current available literature about reporting ADRs to the YCS. RESULTS: CYP contributed 2.3% of YCS reports for patients < 19 years (948 self-reports from a total of 41,630 YCS reports). Patients from 10 years of age contributed YCS reports, and the number of CYP reports represented in the total YCS reports rose by 3% in October 2018 compared with the previous year. Self-reported YCS from the CYP contain different suspected medications and reactions compared with YCS reported on behalf of patients aged < 19 years. The most reported medicines by self-reported YCS from CYP were adolescent vaccinations (such as the human papilloma virus [HPV] vaccine, n = 69), oral contraceptives, acne medication, anti-infectives, and antidepressants. The most commonly reported suspected ADRs submitted by CYP to the YCS were headache (n = 107), nausea and fatigue. CYP-generated reports included alternative suspected ADRs compared with adult reports about ADRs in CYP; these included depression, anxiety and suicidal ideation. The second part of the study used focus groups involving CYP from various backgrounds to develop two information leaflets regarding reporting suspected ADRs in the YCS; this was highlighted in phase I by CYP who identified divergent information needs dependent on age. Phase II-VI updated and improved the relevant information required for both age groups in a succinct and satisfactory manner. Overall, more than 300 CYP contributed to the development of the information. CONCLUSIONS: CYP's contribution to the YCS is limited, but increasing, and demonstrates distinct patterns of suspected medications and reactions. Age-appropriate information for CYP to aid reporting of suspected ADRs has been developed.

Identifying cisplatin-induced kidney damage in paediatric oncology patients.

Cisplatin is one chemotherapeutic agent used to treat childhood cancer in numerous treatment protocols, including as a single agent. It is likely to remain in clinical use over the long term. However, cisplatin-related toxicities, including neurotoxicity and nephrotoxicity, are common, affecting treatment, day-to-day life and survival of such children. With one in 700 young adults having survived childhood cancer, patients who have completed chemotherapy that includes cisplatin can experience long-term morbidity due to treatment-related adverse reactions. A better understanding of these toxicities is essential to facilitate prevention, surveillance and management. This review article discusses the effect of cisplatin-induced nephrotoxicity (Cis-N) in children and considers the underlying mechanisms. We focus on clinical features and identification of Cis-N (e.g. investigations and biomarkers) and the importance of magnesium homeostasis and supplementation.

TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity.

OBJECTIVES: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. METHODS: We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants. RESULTS: For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16). CONCLUSION: We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.

Properties of secondary and tertiary human enteric nervous system neurospheres.

UNLABELLED: Advances in enteric nervous system (ENS) stem cell biology have raised the possibility of treating Hirschsprung's disease with ENS stem/progenitor cell (ENSPC) transplantation. This study aimed to expand ENSPC numbers by the growth and redissociation of neurospheres and assess their differential potential. METHODS: Human ENS neurospheres were cultured as previously described and redissociated to generate secondary and tertiary neurospheres. Neurospheres were assessed for the presence of neuronal (PGP9.5), glial (S100), and stem cell (p75, nestin markers). The degree of immunofluorescence was quantified using the ImageJ program. Secondary/tertiary neurospheres were transplanted into mouse distal colon grown in tissue culture. RESULTS: Secondary/tertiary neurospheres could be generated with exponentially increasing numbers. Tertiary neurospheres showed a significant increase in the proportion of p75 staining but a significant decrease in the proportion of S100 staining. After transplantation, secondary/tertiary neurosphere-derived cells positive for PGP9.5 and S100 could be identified. CONCLUSIONS: It is possible to exponentially expand neurosphere and therefore ENSPC numbers by repeated dissociation and culture. There is a loss of S100-positive cells in secondary/tertiary neurospheres, but the ENSPCs remain capable of differentiating into neurons and glia when transplanted into an embryonic gut environment.

Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon.

BACKGROUND & AIMS: Recent advances have raised the possibility of treating enteric nervous system (ENS) disorders with transplanted progenitor cells (ENSPC). Although these cells have been shown to migrate and differentiate after transplantation, no functional effects have been demonstrated. We therefore aimed to investigate whether embryonic mouse and neonatal human ENSPC can regulate the contractility of aganglionic bowel. METHODS: Embryonic mouse and neonatal human ENSPC were grown as neurospheres before transplantation into aganglionic embryonic mouse hindgut explants and culture for 8-12 days. Engraftment and neural differentiation were confirmed using immunofluorescence and transmission electron microscopy. The contraction frequency of transplanted bowel was measured and compared with that of embryonic day 11.5 embryonic ganglionic and aganglionic bowel cultured for the same period. Calcium movement was measured at spatially defined points in bowel wall smooth muscle. Neural modulation of bowel contractility was assessed using tetrodotoxin. RESULTS: Both mouse and human ENSPC migrated and differentiated after neurosphere transplantation. Transmission electron microscopy demonstrated the existence of synapses. Transplantation restored the high contraction frequency of aganglionic bowel to the lower rate of ganglionic bowel. Calcium imaging demonstrated that neurosphere transplantation coordinates intracellular free calcium levels. Both these effects were reversed by the addition of tetrodotoxin, indicating the functional effect of neurosphere-derived neurons. CONCLUSIONS: Neonatal human gut is a source of ENSPC that can be transplanted to restore the contractile properties of aganglionic bowel by a neurally mediated mechanism. This may aid development of a stem cell-based treatment for Hirschsprung's disease.