CASE REPORT | doi:10.20944/preprints202103.0437.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Pediatrics; tuberculosis; miliary tuberculosis
Online: 17 March 2021 (11:31:46 CET)
Tuberculosis (TB) remains the leading cause of death from a single infectious agent. Among children, TB can have a wide range of non-specific clinical and radiological manifestations becoming a challenging diagnosis, particularly in areas with a low prevalence. We present the case of a 14 month-old female with a history of fever of unknown origin (FUO) and later diagnosed with miliary tuberculosis.
REVIEW | doi:10.20944/preprints202011.0224.v2
Subject: Medicine & Pharmacology, Pediatrics Keywords: acetaminophen; paracetamol; autism; pediatrics; safety
Online: 30 March 2022 (05:47:18 CEST)
A growing body of literature suggests a causative relationship between severe adverse neurological outcomes and early life exposure to paracetamol (acetaminophen) in the presence of oxidative stress. Review of the literature revealed that, although its use is not regularly monitored, paracetamol has achieved near universal acceptance, with exposure in some pediatric populations exceeding 90%. In addition, use of the drug as well as associated adverse outcomes may have risen as a result of pharmaceutical advertising rather than need, and inappropriate use of the drug, both in terms of dose and indication, is widespread. These findings indicate that many clinicians and patients do not, at the present time, evenly weigh the potential risks with the potential benefits of paracetamol exposure early in life. Although retrospective studies might be envisioned to further address the neurodevelopmental risks of paracetamol use during early development, in silico simulations demonstrated that such studies can be thwarted by very high rates of use of the drug combined with associations between paracetamol use and oxidative stressors that act as cofactors in the induction of neurodevelopmental injury. These findings suggest that, despite persistent uncertainty, clinicians and patients should be more aware of available information pointing toward the potential dangers for neurodevelopment of early life exposure to paracetamol. Most importantly, health care workers need to provide a more balanced view, weighing both risks and benefits, when providing advice for patients regarding paracetamol use during periods of brain development.
REVIEW | doi:10.20944/preprints202011.0173.v1
Subject: Medicine & Pharmacology, Allergology Keywords: acetaminophen; paracetamol; autism; pediatrics; safety
Online: 4 November 2020 (08:24:52 CET)
Although widely believed to be safe for use in infants and children when used as directed, increasing evidence indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental problems. Further, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was evaluated using a systematic literature search. Publications on PubMed between 1974 and 2017 that contained the keywords “infant” and either “paracetamol” or “acetaminophen” were considered. Of those initial 3096 papers, 218 were identified that made claims that paracetamol was safe for use with infants or children. Of these, a total of 103 papers were identified as sources of authority for the safety claim, and 36 of those contained actual experiments designed to test safety. The 36 experiments described had a median follow-up time of 24 hours, and none monitored neurodevelopment. Further, no trial considered total exposure to drug since birth, eliminating the possibility that the effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed.
REVIEW | doi:10.20944/preprints202112.0014.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: Pediatrics; Gait; Rehabilitation; Anti-gravity; Treadmill
Online: 1 December 2021 (12:57:48 CET)
The purpose of this scoping review was to examine the literature on the use of anti-gravity treadmill and its effects on lower limb motor functions in children and adolescents with locomotor impairments. Four databases (MEDLINE, CINAHL, Embase, Web of Science) were searched for articles from inception to August 2021. Inclusion criteria were: (1) experimental or quasi-experimental studies using the anti-gravity training as the primary intervention; (2) studies conducted in paediatricpediatric participants; (3) articles reporting outcomes related to the lower limb functions; and (4) studies published in French or English. Fifteen articles were included in the review. Studies included children and adolescents aged 4–18 years with locomotor impairments. The intervention duration was ranged from 2 and to 12 weeks, with 2-5 sessions per week. Included studies showed reported that anti-gravity training induces improvements in muscle strength, balance, spatiotemporal gait parameters, and walking endurance in children with locomotor impairments. This review provides relevant information about the modalities, outcomes and limits associated with the anti-gravity training protocol reported in the literature. Overall, the anti-gravity treadmill training could be viewed as a valuable training modality for children with cerebral palsy. However, more precise, and comprehensive description of anti-gravity rehabilitation protocols would be useful.
REVIEW | doi:10.20944/preprints201810.0328.v1
Subject: Life Sciences, Microbiology Keywords: Bifidobacterium breve; probiotics; pediatrics; therapeutic microbiology
Online: 15 October 2018 (17:03:26 CEST)
The human intestinal microbiota, establishing a symbiotic relationship with the host, plays a significant role for the human health. It is also well known that a disease status is frequently characterized by a dysbiotic condition of the gut. A probiotic treatment can represent an alternative therapy for enteric disorders and human pathologies not apparently linked to the gut environment. Among bifidobacteria, strains of the species Bifidobacterium breve are widely used in pediatrics. B. breve is the dominant species in the gut of breast-fed infants and it has also been isolated from human milk. It has antimicrobial activity against human pathogens, it does not possess transmissible antibiotic resistance traits, it is not cytotoxic and it has immuno-stimulating abilities. This review describes the applications of B. breve strains mainly for the prevention/treatment of pediatric pathologies. The target pathologies range from widespread gut diseases, including diarrhea and infant colics, to celiac disease, obesity, allergic and neurological disorders. Moreover, B. breve strains are used for the prevention of side infections in pre-term newborns and during antibiotic treatments or chemotherapy. With this documentation, we hope to increase knowledge on this species to boost the interest in the emerging discipline known as “therapeutic microbiology”.
ARTICLE | doi:10.20944/preprints202012.0437.v1
Subject: Medicine & Pharmacology, Allergology Keywords: malnutrition; translation; physiologically based pharmacokinetics; PBPK; pediatrics
Online: 17 December 2020 (16:03:40 CET)
Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on a) the differences in body composition between healthy and malnourished adults and b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.
REVIEW | doi:10.20944/preprints202009.0073.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: genomics; pediatrics; lung disease; pulmonary arterial hypertension
Online: 3 September 2020 (15:29:36 CEST)
Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.
ARTICLE | doi:10.20944/preprints202209.0002.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: COVID-19; vaccine hesitancy; children; pediatrics; public health
Online: 1 September 2022 (02:25:22 CEST)
Background: This study describes the attitudes and practices of Brazilian adults regarding the mandatory vaccination for COVID-19 and the hesitancy to children´s vaccination. Methods: The participants answered an online questionnaire disseminated on social networks. An adaptation of the SAGE-WG questionnaire was used to measure the children's vaccination hesitancy. Results: Among 1,007 participants, 677 (67.4%) believed that vaccination for COVID-19 among adults should be mandatory. Just over half of the participants (51.5%) believe that parents and guardians should be free to decide whether their children should be vaccinated against COVID-19, and 9.1% were unsure about this. Younger, non-religious people who have higher self-perceptions of risk for COVID-19, and who evaluate the federal government's performance in combating the disease as bad or very bad, have a higher agreement with mandatory vaccination, a lower agreement that parents and guardians should be free to vaccinate their children, and lower child vaccination hesitancy scores. Conclusion: In Brazil, mandatory COVID-19 vaccination for adults is far from a consensus, and an expressive part of the population believes that parents and guardians should be free to choose whether or not to vaccinate their children. These perceptions and vaccine hesitancy for children are associated with religious and political inclinations.
REVIEW | doi:10.20944/preprints202204.0174.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: cerebral palsy; locomotion; robotic rehabilitation; Lokomat; physiotherapy; pediatrics
Online: 19 April 2022 (04:07:24 CEST)
About 70% of children and adolescents with cerebral palsy experience gait impairments which affect their autonomy and well-being. Robotic-assisted gait training using the Lokomat is particu-larly promising for rehabilitation as it provides a standardized environment favoring the massive repetition of the movement, in which physical demands are low on the therapist and high training loads can be achieved. As no guidelines exist regarding training protocols and Lokomat settings, the goal of this study was to review the literature on Lokomat-assisted gait therapy and possibly make training recommendations. The twelve studies reviewed reported both positive and null effects of Lokomat training on gait. Half of the studies combined Lokomat with other types of training and only five used a control intervention to assess its benefit. Overall, training was administered 1-5 times per week for 20-60 minutes, over 1-12 weeks. Although Lokomat settings were not always described, progressively decreasing body-weight support and guidance, while increasing treadmill speed appear to be prioritized. The variety of training protocols and settings used did not allow pooling of the studies to assess effects of interventions on gait parameters in children and adoles-cents with cerebral palsy. This review highlights the need for homogenization of interventions so that clear guidelines can emerge and be applied in rehabilitation centers.
ARTICLE | doi:10.20944/preprints202102.0465.v1
Subject: Medicine & Pharmacology, Allergology Keywords: food allergy; oral immunotherapy; IgE, reaction; anaphylaxis; pediatrics
Online: 22 February 2021 (12:20:56 CET)
The prevalence of food allergy has increased in recent years, especially in children. Food allergen avoidance and symptomatic drugs in case of an allergic reaction remain the standard of care in food allergy. Nevertheless, increasing attention has been given to the possibility to treat food allergy, through immunotherapy, particularly oral immunotherapy (OIT). Several OIT protocols and clinical trials have been published. Most of them focus on children allergic to milk, egg, or peanuts, although recent studies developed protocols for other foods, such as wheat and different nuts. OIT efficacy in randomized controlled trials is usually evaluated as the possibility for patients to achieve desensitization, while the issue of a possible long-term sustained unresponsiveness has not been completely addressed. Here, we evaluated current OIT knowledge, focusing on the results of clinical trials and current guidelines. Specifically, we wanted to highlight what is known in terms of OIT efficacy and effectiveness, safety, and impact on quality of life. For each aspect, we reported the pros and the cons, inferable from published literature. In conclusion, even though many protocols, reviews and meta-analysis have been published on this topic, OIT remains a controversial therapy and no definitive generalized conclusion may be drawn so far. It should be an option provided by specialized teams, when both patients and their families are prone to adhere to the proposed protocol. Efficacy, long-term effectiveness, possible role of adjuvant therapies, risk of severe reactions including anaphylaxis or eosinophilic esophagitis, and impact on the quality of life of both children and caregivers are all aspects that should be discussed before starting OIT. Future studies are needed to provide firm clinical and scientific evidence, which should also consider patient reported outcomes.
ARTICLE | doi:10.20944/preprints202110.0094.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: nutrition; pediatrics; geographic information systems; acute respiratory infections; diarrhea; growth
Online: 6 October 2021 (09:00:12 CEST)
Infectious disease is the leading cause of mortality in children under five. This study has investigated environmental factors related to the morbidity of acute respiratory infections (ARIs), diarrhea, and growth using geographical information systems (GIS) technology. Anthropometric, address and disease prevalence data were collected through the SEEM study in Matiari, Pakistan. Publicly available map data was used to compile coordinates of healthcare facilities. A Pearson correlation coefficient (r) was used to calculate the correlation between distance from healthcare facilities and participant growth and morbidity. Other continuous variables influencing these outcomes were analyzed using a random forest regression model. In this study of 416 children, we found participants living closer to secondary hospitals had lower prevalence of ARI (r=0.154, p<0.010) and diarrhea (r=0.228, p<0.001) as well as participants living closer to Maternal Health Centers (MHCs): ARI (r=0.185, p<0.002) and diarrhea (r=0.223, p<0.001) compared to those living near primary facilities. Our random forest model showed distance to have high variable importance in the context of disease prevalence. Our results indicated that participants closer to more basic healthcare facilities reported a higher prevalence of both diarrhea and ARI than those near more urban facilities, highlighting potential public policy gaps in ameliorating rural health.
ARTICLE | doi:10.20944/preprints201801.0073.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: breastfeeding; feeding practices; infant feeding; nutrition; malnutrition; pediatrics; primary health care
Online: 9 January 2018 (05:23:01 CET)
Infant malnutrition remains as an important cause of death and disability, Haiti has the highest prevalence in America, so preventive strategies are needed. Our objective was to assess infant and young children malnutrition in Haiti and to study an association to World Health Organization (WHO) recommended feeding practices adherence. Cross-sectional study of children younger than 2 years old, recruited at Saint Espri Health Center, Port Au Prince (August to September 2014). We registered feeding practices, social and demographic data, and performed anthropometry (WHO-2006 standard). We evaluated 278 infants and young children, 8.08 ± 6.5 months old, 53.2% female. 18.35% had underweight; 13.31% were stunted and 13.67% had moderate or severe wasting. Malnutrition was associated to male gender, older age, lower education of mothers and higher number of siblings. The adherence to WHO recommended practices for breastfeeding was from 11.8 to 97.9% and was related to a lower prevalence of malnutrition. For complementary food, adherence was 9.7 to 90.3%, also associated to lower malnutrition. Conclusion: Prevalence of infant and young children malnutrition in this Haitian Health Center population was high, related to some risk factors. The adherence to WHO recommended feeding practices was associated to a better nutritional status.
ARTICLE | doi:10.20944/preprints202108.0309.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: sex differences; fundamental motor skill; motor skills; physical activity; exercise effects; pediatrics
Online: 14 August 2021 (14:45:07 CEST)
The aim of this study was to determine gender differences in the level of motor skills and effects of a multi-year exercise program on the level of motor skills in 161 preschool children (5-6 yo). Patricipants were deployed into one control and three experimental groups. Motor skills were assessed with the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2). To determine difference in scores for each BOT-2 tests between control and experimental groups, one-way ANOVA was used for girls and boys separately while two-way ANOVA was employed to determine difference between the gender in the overall BOT-2 score. The results indicates that one-year multilateral exercise program has a positive effect on the level of motor skills in preschool children. Interestingly, additional years of participation in exercise program yielded in maintenance of acquired motor skills level. Also, exercise program affected more girls than preschool boys considering both individual and composite BOT-2 scores. According to the findings of this study, presented exercise program could have potential benefits on multilateral development of the motor skills in preschool children which could facilitate balance of locomotor and manipulative skills. Therefore, integration of multilateral program intended for preschool children could be considered for implementation within the kindergarten curriculum.
BRIEF REPORT | doi:10.20944/preprints201806.0014.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: development; milestones; screening; poverty; stunting; lead exposure; developmental risk; child health; global health; pediatrics
Online: 1 June 2018 (11:11:19 CEST)
There is a need for developmental screening that is easily administered in resource-poor settings. 1) We hypothesized that known risk factors would predict failed developmental screening on an adapted screening tool in East African children living in poverty. 2) The sample included 100 healthy Ugandan children aged 6-59 months. We adapted a parent-reported developmental screener based on the Child Development Review chart. The primary outcome was failure to meet age-appropriate milestones for any developmental domain. Venous blood was analyzed for lead, and caregivers completed a demographics questionnaire. We used multivariate logistic regression models to determine if elevated blood lead and stunting predicted failure on the screener, controlling for maternal education level, age in months past the lower bound of the child’s developmental age group, and absence of home electricity. 3) In the sample, 14% (n=14) of children failed one or more milestones on the screener. Lead levels or stunting did not predict failing the screener after controlling for covariates. 4) Though this tool was feasibly administered, it did not demonstrate preliminary construct validity and is not yet recommended for screening in high-risk populations. Future research should include a larger sample size and cognitive interviews to ensure it is contextually relevant.
ARTICLE | doi:10.20944/preprints202208.0135.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: physiologically based pharmacokinetic modelling; propofol; low cardiac output; pharmacokinetics; neonate; developmental pharmacology; asphyxia; hypothermia; pediatrics; pharmacokinetics
Online: 8 August 2022 (06:12:36 CEST)
Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.
Subject: Medicine & Pharmacology, Gastroenterology Keywords: ulcerative colitis; inflammatory bowel disease; pediatrics; FMT; probiotics; synbiotics; antibiotics; prebiotics; fecal microbiota transplant; colitis-associated cancer; colorectal cancer; CAC; CRC; dysbiosis
Online: 20 September 2021 (14:20:39 CEST)
Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn’s disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we will discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.
REVIEW | doi:10.20944/preprints202102.0462.v1
Subject: Medicine & Pharmacology, Allergology Keywords: paediatrics; pediatrics; delivery of care; health technology; digital poverty; confidentiality; usage guidelines; continuity of care; technology to supplement; personalised approach and user design.
Online: 22 February 2021 (11:52:50 CET)
Background: The use of technology in paediatrics is increasing, and new health technology will change the way in which paediatric care is delivered in the future. This review is part of the Royal College of Paediatrics and Child Health Paediatrics 2040 project, which is developing a credible vision for the future of paediatrics in the UK. Aims: To summarise the impact of health technology on the delivery of paediatric care over the last ten years. To learn from existing technology use and make recommendations for future implementation. Methods: A search strategy was developed and two databases (Cochrane Library and PubMed) were systematically searched in August 2019 for relevant publications in English. Searches were limited to papers published between January 2009 and August 2019 (with further rapid review of papers published between September 2019 and November 2020). We included papers that studied young people up to the age of 24 or on those providing care for this population. A thematic synthesis of the data from the included studies was undertaken using seven domains of paediatric care. Results: 128 studies were included, grouped by domain of care. Most included studies were defined as digital (n=55) or communication (n=37). Studies looked at the different types of health technology used within different domains of care, including secondary and tertiary care (n=39), public health and prevention (n=29), and community (n=20). Studies were assessed on delivery of care outcomes using positive, negative, mixed and no effect. The most common outcomes reported were adherence and satisfaction. Discussion: This review highlights the growing importance of technology in delivering paediatric care. Six themes emerged: the importance of clear guidelines, continuity of care, confidentiality and privacy, digital poverty, using a personalised approach, and using technology to supplement rather than replace. In future, technology development should involve the end user throughout the design process.