Pediatric Research Research Articles

Molecular epidemiology and antimicrobial resistance in Clostridioides difficile strains isolated from children and adolescents in a tertiary referral pediatric hospital in Fortaleza, Brazil

BackgroundC. difficile has been increasingly reported as a cause of gastrointestinal disease in children, ranging from mild self-limiting diarrhea to severe conditions such as pseudomembranous colitis and toxic megacolon. Only two pediatric research groups reported the presence of C. difficile infection in Brazilian children, but no previous research has examined C. difficile infection among children in northeastern Brazil. This prospective cross-sectional study investigated the molecular epidemiology and antimicrobial resistance of C. difficile strains isolated from children and adolescents with diarrhea referred to a tertiary pediatric hospital in Brazil while exploring the associated risk factors. ResultsToxin positivity or C. difficile isolation was found in 30.4 % (17/56) samples. C. difficile was isolated from 35 % (6/17) samples. Four toxigenic strains were identified (tpi+, tcdA+, tcdB+, cdtB-, without tcdC deletions) belonging to PCR ribotypes and PFGE-pulsotypes: 046 (new pulsotype 1174), 106 (NAP11), 002 (new pulsotype 1274), 012 (new pulsotype NML-1235). Two of the six isolates belonging to ribotypes 143 and 133 were non-toxigenic. All toxigenic strains were sensitive to metronidazole and vancomycin. Regarding the clinical manifestation, diarrhea lasted an average of 11 days, ranging from 3 to 50 days and was often associated with mucus and/or blood. All six patients from whom the C. difficile was isolated had a chronic disease diagnosis, with these comorbidities as the main risk factors. ConclusionOur study enhances our understanding of the present epidemiological landscape of C. difficile-associated diarrhea (CDI) among children in northeastern Brazil, reveling a substantial CDI frequency of 30.4 %, with toxigenic strains detected in 76.4 % of cases, highlighting a higher prevalence compared to earlier Brazilian studies. In the globalized world, an understanding of disease-generating strains, the associated risk factors, clinical manifestation, and antimicrobial sensitivity has fundamental epidemiological importance and draws attention to preventive measures, allowing for more decisive action.

Pediatric Research Abstract.

Pediatric Research Abstract.

From Dose to Exposure: Shifting the Paradigm of Pediatric Clinical Pharmacology Research and Education.

From Dose to Exposure: Shifting the Paradigm of Pediatric Clinical Pharmacology Research and Education.

Survival outcomes in pediatric patients with metastatic Ewing sarcoma who achieve a rapid complete response of pulmonary metastases.

Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). This retrospective cohort study included children under 20years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p=.04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p=.14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p=.13), or WLI (38.8%) versus no WLI (46.0%, p=.32). Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Whole genome analysis reveals unique traits of SARS-CoV-2 in pediatric patients

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to challenge the global healthcare with emerging variants and higher infectivity as well as morbidities. This study investigated potential age-related variations through genomic characterization of the virus under common clinical settings. A cohort comprising 71 SARS-CoV-2 strains from both infected infants and accompanying adults, diagnosed via RT-PCR at a tertiary pediatric hospital and research center, underwent Illumina paired-end sequencing. The subsequent analysis involved standard genomic screening, phylogeny construction, and mutational analyses. The analyzed SARSCoV- 2 strains were compared with globally circulating variants. The overall distribution revealed 67.61 % Delta, 25.7 % Omicron, and 1 % either Kappa or Alpha variants. In 2021, Delta predominated at ∼ 94 %, with Alpha/Kappa accounting for around 5 %. However, in 2022, over 94 % of the samples were Omicron variants, signifying a substantial shift from Delta dominance. Delta variants constituted 69.5 % of infections in adults and 78.5 % in infants, while Omicron variants were responsible for 31 % of cases in infants and 18 % in adults. The Spike region harbored the majority of mutations, with T19R being the most prevalent mutation in the Delta lineage. Notably, the frequencies of this mutation varied between infants and adults. In Omicron samples, G142D emerged as the most prevalent mutation. Our dataset predominantly featured clade 21A and lineage B.1.617.2. This study underscores the differential clinical presentations and genomic characteristics of SARS-CoV-2 in pediatric patients and accompanying adults. Understanding the dynamic evolution of the SARS- CoV-2 in both pediatric and adults can help in strengthening prophylactic measures.

Participation in children's hospitals: approaches to participatory formats for paediatric patients

Based on the UN Convention on the Rights of the Child, children and young people have the right to participate in all matters and decisions that affect them. This applies in particular when they are patients in a children's hospital. In the international context, established formats for the participation of young patients regarding health issues already exist, for example "Children's Councils" or "Young Person's Advisory Groups". In Germany, such approaches are still mostly lacking. It thus remains important to develop suitable formats that enable meaningful and effective participation of young patients in the health system. These formats must be chosen in such a way that they can realistically be implemented in clinical settings as well as in pediatric research, and that they can be sustained in the long term. In order to strengthen the consideration of children's rights in the health system, the advancement of such participatory formats as well as their sustainable implementation and evaluation are desirable.

Mapping of Data-Sharing Repositories for Paediatric Clinical Research—A Rapid Review

The reuse of paediatric individual patient data (IPD) from clinical trials (CTs) is essential to overcome specific ethical, regulatory, methodological, and economic issues that hinder the progress of paediatric research. Sharing data through repositories enables the aggregation and dissemination of clinical information, fosters collaboration between researchers, and promotes transparency. This work aims to identify and describe existing data-sharing repositories (DSRs) developed to store, share, and reuse paediatric IPD from CTs. A rapid review of platforms providing access to electronic DSRs was conducted. A two-stage process was used to characterize DSRs: a first step of identification, followed by a second step of analysis using a set of eight purpose-built indicators. From an initial set of forty-five publicly available DSRs, twenty-one DSRs were identified as meeting the eligibility criteria. Only two DSRs were found to be totally focused on the paediatric population. Despite an increased awareness of the importance of data sharing, the results of this study show that paediatrics remains an area in which targeted efforts are still needed. Promoting initiatives to raise awareness of these DSRs and creating ad hoc measures and common standards for the sharing of paediatric CT data could help to bridge this gap in paediatric research.

A Gentle Introduction to Latent Class Analysis for Researchers in Pediatrics

A Gentle Introduction to Latent Class Analysis for Researchers in Pediatrics

Should Children Be Included in Human Challenge Studies?

Human challenge studies, in which human research subjects are intentionally exposed to pathogens to contribute to scientific knowledge, raise many ethical complexities. One controversial question is whether it is ethically permissible to include children as participants. Commentary of the past decades endorses the exclusion of children, while new guidance suggests that pediatric human challenge studies can be ethically permissible. This paper argues that neither children's exclusion nor their inclusion are well justified. I examine and reject three arguments for exclusion, but suggest that these arguments establish pediatric human challenge studies as a complex ethical category of research that requires caution. I then argue for a strong presumption against children's inclusion, by drawing on an analogy to children's inclusion in phase I trials, emphasizing a requirement of necessity, and suggesting that accommodating children's vulnerability promotes an age de-escalation approach for pediatric human challenge studies research. In the final section, I suggest a procedure for ethics review.

Women's Representation as Principal Investigators Among Pediatric Orthopaedic Clinical Trials: An Analysis of ClinicalTrials.Gov.

Despite recent efforts to increase the participation of women in orthopaedic surgery, there remains a gender gap, particularly when compared with other medical specialties. Acting as a principal investigator (PI) in a clinical trial can give physicians notable exposure and national recognition, which can improve their chances of promotion and tenure. This study aims to assess the proportion of women serving as PIs in pediatric orthopaedic clinical trials, examine associated trial characteristics, and explore geographic distribution. A cross-sectional analysis of clinical trials was conducted using data from the ClinicalTrials.gov registry. Specific search terms were used to identify pediatric orthopaedic trials. Data on trial characteristics, including phase, status, funding source, and intervention type, were collected. PI sex was determined using Genderize.io, an application program interface that predicts the sex of individuals based on their name, and the geographic distribution of women PIs was examined. From 2007 to 2022, women PIs increased from zero to 26.86%. The United States saw no significant increase (β = 1.553; P = 0.125), but international trials did (β = 2.845; P = 0.008). Women PIs led more active/completed trials and trials with behavioral/other interventions. Geographic analysis showed higher representation in North America (38.47%), especially the Northeast (28.17%) and West (25.35%). The United States had 28.74% women PIs, with California (15.49%) leading. Progress toward gender parity in pediatric orthopaedic research is evident; however, disparities still exist. Efforts to provide additional research opportunities for women in orthopaedics may be crucial in attracting and retaining diverse talent in the field. Targeted initiatives may have potential in achieving equal representation in orthopaedics.

Adaptive platform trials rather than randomised controlled trials for paediatric sepsis.

Adaptive platform trials (APTs) offer a promising alternative to traditional randomised controlled trials for evaluating treatments for paediatric sepsis. Randomised controlled trials, despite being the gold standard for establishing causality between interventions and outcomes, make many assumptions about disease prevalence, severity and intervention effects, which are often incorrect. As a result, the evidence for most treatments for paediatric sepsis are based on low-quality evidence. APTs use accrued data rather than assumptions to power trial adaptations. They can assess multiple treatments simultaneously with shared research infrastructure. As such, APTs offer a more efficient, flexible and more effective way to identify optimal treatments. The proposed Paediatric Adaptive Sepsis Platform Trial, leveraging the Paediatric Research in Emergency Departments International Collaborative network's infrastructure, will evaluate resuscitation fluids, vasoactive medications, corticosteroids and antimicrobials. This trial has the potential to substantially impact clinical practice and reduce global sepsis mortality in children.

Health Care for Youth With Neurodevelopmental Disabilities: A Consensus Statement.

Individuals with a neurodevelopmental disability (NDD) face significant health care barriers, disparities in health outcomes, and high rates of foregone and adverse health care experiences. The Supporting Access for Everyone (SAFE) Initiative was developed to establish principles of health care to improve equity for youth with NDDs through an evidence-informed and consensus-derived process. With the Developmental Behavioral Pediatric Research Network, the SAFE cochairs convened a consensus panel composed of diverse professionals, caregivers, and adults with NDDs who contributed their varied expertise related to SAFE care delivery. A 2-day public forum (attended by consensus panel members) was convened where professionals, community advocates, and adults with NDDs and/or caregivers of individuals with NDDs presented research, clinical strategies, and personal experiences. After this, a 2-day consensus conference was held. Using nominal group technique, the panel derived a consensus statement (CS) on SAFE care, an NDD Health Care Bill of Rights, and Transition Considerations. Ten CSs across 5 topical domains were established: (1) training, (2) communication, (3) access and planning, (4) diversity, equity, inclusion, belonging, and anti-ableism, and (5) policy and structural change. Relevant and representative citations were added when available to support the derived statements. The final CS was approved by all consensus panel members and the Developmental Behavioral Pediatric Research Network steering committee. At the heart of this CS is an affirmation that all people are entitled to health care that is accessible, humane, and effective.

Learning from conect4children: A Collaborative Approach towards Standardisation of Disease-Specific Paediatric Research Data

The conect4children (c4c) initiative was established to facilitate the development of new drugs and other therapies for paediatric patients. It is widely recognised that there are not enough medicines tested for all relevant ages of the paediatric population. To overcome this, it is imperative that clinical data from different sources are interoperable and can be pooled for larger post hoc studies. c4c has collaborated with the Clinical Data Interchange Standards Consortium (CDISC) to develop cross-cutting data resources that build on existing CDISC standards in an effort to standardise paediatric data. The natural next step was an extension to disease-specific data items. c4c brought together several existing initiatives and resources relevant to disease-specific data and analysed their use for standardising disease-specific data in clinical trials. Several case studies that combined disease-specific data from multiple trials have demonstrated the need for disease-specific data standardisation. We identified three relevant initiatives. These include European Reference Networks, European Joint Programme on Rare Diseases, and Pistoia Alliance. Other resources reviewed were National Cancer Institute Enterprise Vocabulary Services, CDISC standards, pharmaceutical company-specific data dictionaries, Human Phenotype Ontology, Phenopackets, Unified Registry for Inherited Metabolic Disorders, Orphacodes, Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP), and Observational Medical Outcomes Partnership. The collaborative partners associated with these resources were also reviewed briefly. A plan of action focussed on collaboration was generated for standardising disease-specific paediatric clinical trial data. A paediatric data standards multistakeholder and multi-project user group was established to guide the remaining actions—FAIRification of metadata, a Phenopackets pilot with RDCA-DAP, applying Orphacodes to case report forms of clinical trials, introducing CDISC standards into European Reference Networks, testing of the CDISC Pediatric User Guide using data from the mentioned resources and organisation of further workshops and educational materials.

Screening for Relative Energy Deficiency in Sport and Female Athlete Triad: A Survey of Pediatric Sports Medicine Professionals

BACKGROUND: Relative Energy Deficiency in Sport, or RED-S, is a multi-scale physiological response to a mismatch between energy intake and exercise energy expenditure that affects up to 50% of adolescent athletes. RED-S symptomology was first described as the Female Athlete Triad (the Triad) and includes specifically low energy availability with or without disordered eating, menstrual dysfunction, and low bone mineral density. Despite the wide impact of RED-S/the Triad, there is a lack of standardization of screening in adolescent athletes. Therefore, the purpose of this study was to assess if there are differences in practitioner demographics when screening for RED-S/the Triad in adolescent athletes. In addition, we sought to assess if providers’ screening habits differ based on specific patient characteristics. METHODS: We conducted a cross-sectional online questionnaire of members of the Pediatric Research in Sports Medicine (PRiSM) Society. PRiSM is an interdisciplinary group of professionals who are dedicated to advancing the research and medical care of young athletes. The questionnaire assessed screening tools that members used to assess for RED-S/the Triad, practices implemented when providers were concerned for RED-S/the Triad, demographic data, and type of training. RESULTS: Of 389 PRiSM members, 60 completed the survey and were included in subsequent analyses (15% response rate). Most participants were primary care sports medicine physicians (37%), orthopaedic surgeons (27%), or physical therapists (23%), and about half of respondents identified as a cis gender woman (55%). There was a trend toward more women screening for RED-S routinely than men (55% vs. 33%: p=0.10), and orthopaedic surgeons were less likely to screen than other specialties (25% vs. 52%, p = 0.06). Eating disorders (88%), menstrual dysfunction (76%), and bone stress injury (74%) were reported as specific red flags that make providers screen for RED-S/the Triad. Participants reported that lack of time (57%) and lack of resources (37%) were barriers to screen for RED-S/the Triad. The most commonly utilized tools to screen for RED-S/the Triad were the Female Athlete Screening Tool (FAST), Female Athlete Triad Risk Scale, Female Athlete Triad Consensus Panel Screening questions, and RED-S Specific Screening Tool (RST). CONCLUSION: Orthopaedic surgeons were less likely than other health care professionals to screen for RED-S/the Triad. Barriers that prevent healthcare providers from screening for RED-S/the Triad included limited time and resources. By describing current practices, we have identified gaps and areas of need to enhance screening for RED-S/the Triad across multiple sports medicine disciplines.

Current progress in international pediatric emergency medicine.

Over the past four decades, pediatric emergency Medicine (PEM) has witnessed significant global development, with a notable increase in training programs and official recognition by regulatory bodies. However, disparities persist in the recognition of PEM as an independent subspecialty, availability of training programs on a global scale, academic recognition, and the ability to provide high-quality care to children worldwide. There is paucity of published literature regarding development of PEM globally. This review explores the current trends and challenges in international pediatric emergency medicine. Current trends in international pediatric emergency medicine encompass the provision of training in pediatric-focused emergency and acute care, increased propagation of evidence-based guidelines specific to the care of children, the growth of collaborative research networks and interest groups within national and international societies. Simultaneously, the field continues to face challenges such as the lack of recognition, inequities in access, and a lack of dissemination of global PEM initiatives. While recent advancements have significantly enhanced the state of international pediatric emergency medicine, including pediatric specific research networks and training programs, barriers still hinder its overall quality. Many of these obstacles are not unique to pediatric emergency medicine but are directly affected by financial disparities and lack of governmental and public recognition of the essential role of pediatric emergency care.

Quality assessment of paediatric education and research in southwest China: A cross-sectional study.

Currently, there is a limited analysis of medical education research both domestically and internationally. To enhance, improve the quality of medical education, this study conducted a quantitative analysis of teaching project data from an affiliated hospital during the period 2016-2022. The results indicated that a total of 133 teaching projects were initiated during this period, with an average age of project leaders being 42.73±6.45 years. Regarding professional ranks and titles, municipal-level project leaders had a high concentration of seniors (48.15%), while at the university-level, most project leaders held the title of deputy seniors (58.82%). At the university-level, project leaders were mainly distributed between deputy senior titles (37.08%) and intermediate titles (38.20%). In terms of research content, nearly half of the studies (46.62%) focused on teaching methods and models. Further regression analysis revealed that professional ranks and titles were an independent factor influencing the project level (P<0. 05). These findings suggest the need for improvement in medical education research, including addressing the uneven distribution of research topics, enhancing the research capacity of junior and mid-career medical education teachers, and improving the dissemination of research results.

Effect of pre-emptive rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients: A case series from the pediatric nephrology research consortium.

There are scant data on the effect of rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia. Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab. Twenty-six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1-10.3). EBV DNA load monitoring by qPCR was performed at 1-3 month intervals. EBV DNAemia onset occurred at a median of 73 days post-transplant (IQR 52-307), followed by DNAemia peak at a median of 268 days (IQR 112-536). Rituximab was administered at a median of 9 days post peak (IQR 0-118). Rituximab regimens varied; median dose 375 mg/m2 (IQR 375-439) weekly for 1-4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow-up (median 2094 days post-transplant [IQR 1538-3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons. In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short-term reduction in DNA load; however, recurrent DNAemia is common.

Performance of Febrile Infant Algorithms by Duration of Fever.

To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants ≤90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules.

The role of nutritional interventions in the prevention and treatment of chronic lung disease of prematurity.

Chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Nutrition may affect incidence and severity of BPD. In this context, the Section on Nutrition, Gastroenterology and Metabolism, the Pulmonary Section of the European Society for Paediatric Research (ESPR) and SPR have joined forces to review the current knowledge on nutritional issues related to BPD. The aim of this narrative review is to discuss the clinical implications for nutritional practice. Nutrient deficiencies may influence pathogenesis of BPD. Adequate nutrition and growth can play a crucial role in the prevention of and recovery from BPD. Optimal nutrition strategy is an important principle, especially in the early postnatal period. As optimal energy intake in infants at risk of BPD or with evolving BPD is not yet defined, further research with well-designed studies on nutritional strategies for preterm infants with BPD is urgently needed. IMPACT: Based on current evidence it seems reasonable to recommend that BPD diagnosed infants should receive an energy supply ranging from 120 to 150 Kcal/kg/d. Exclusive MOM feed with adequate fortification should be encouraged as this is associated with a significant reduction in the risk of BPD. Suboptimal nutritional delivery is often seen in preterm infants with BPD compared to controls.

Translating Value Across Telehealth Stakeholders: A Rapid Review of Telehealth Measurement Evidence and a New Policy Framework to Guide Telehealth Researchers.

Introduction: The surge in virtual care during the pandemic was accompanied by an increase in telehealth data of interest to policy stakeholders and other health care decision makers. However, these data often require substantial preprocessing and targeted analyses to be usable. By deliberately evaluating telehealth services with stakeholder perspectives in mind, telehealth researchers can more effectively inform clinical and policy decision making. Objective: To examine existing literature on telehealth measurement and evaluation and develop a new policy-oriented framework to guide telehealth researchers. Materials and Methods: A systematic rapid review of literature on telehealth measurement and evaluation was conducted by two independent reviewers in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The findings were analyzed and applied to the Supporting Pediatric Research on Outcomes and Utilization of Telehealth Evaluation and Measurement (STEM) Framework through the lens of key health care delivery decision makers to create a STEM Policy Framework Results: An initial search yielded 2,324 peer-reviewed articles and gray literatyre from 2012 to 2022, of which 56 met inclusion criteria. These measured and evaluated telehealth access (41.5%), quality (32.1%), cost (15.1%), experience (5.7%), and utilization (5.7%), consistent with the STEM Framework domains, but there was no universal approach. The STEM Policy Framework focuses this literature by describing data measures for each domain from the perspectives of five stakeholders. Conclusions: Literature describing measurement and evaluation approaches for telehealth is limited and not standardized, with few considering policy stakeholder perspectives. With this proposed STEM Policy Framework, we aim to improve this body of literature and support researchers seeking to inform telehealth policy through their work.