Search Results (30,014)

Background/Objectives: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the clonal proliferation of Langerhans-like dendritic cells and constitutive activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. Nearly 80% of ERK pathway activation can be attributed to B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E), and mitogen-activated protein kinase kinase 1 (MAP2K1) variants, with BRAF V600E specifically detected in approximately 50% of pediatric LCH cases and associated with a higher risk of severe disease and treatment failure. The use of the HistioTrak clinical assay to detect the presence of BRAF V600E mutations in peripheral blood mononuclear cells (PBMCs) has emerged as a useful diagnostic tool and biomarker. Methods: This study is a single-center retrospective study that explores the favorable outcomes of treatment with trametinib on a small number of patients with LCH. We retrospectively analyzed the records of 11 children with LCH treated with trametinib at diagnosis as front-line therapy (n = 6), due to progressive disease (n = 3) or intolerance (n = 1) to chemotherapy, or at relapse (n = 1). Results: HistioTrak identified the presence of BRAF V600E PBMCs in five patients. In this small single-center retrospective cohort, trametinib was associated with favorable short-term outcomes in all patients, and serial HistioTrak testing appeared feasible in selected patients. Conclusions: Prospective studies are needed before routine diagnostic or monitoring use can be recommended. Full article

Background and Objectives: The incidence of colorectal cancer (CRC) in developed Western countries is constantly growing. CRC represents the third most common cancer and the second leading cancer-related cause of death worldwide. Innate and adaptive immunity play a pivotal role in the tumor response, but many of these interactions are still not well understood. Granulysin (GNLY) is an effector, cytolytic molecule, present in human cytotoxic granules of different lymphocyte subpopulations, mainly in cytotoxic T cells and NK cells. Pore-forming proteins GNLY, perforin and granzymes play a key role in cell-mediated immune responses against tumors and infections. Materials and Methods: We aimed to analyze perforin and GNLY-mediated cytotoxicity in the peripheral blood of patients with CRC by flow cytometry. Simultaneously, the cells were labeled with monoclonal antibodies against perforin, GNLY and different surface antigens (CD3, CD4, CD8 and CD56). Phenotypes of lymphocyte subpopulation and expression of perforin and GNLY were analyzed using intracellular and surface immunofluorescence. Results: Total perforin and GNLY expressions in peripheral blood mononuclear cells (PBMC) were significantly lower than in the control group. Statistically significant differences were observed in the distribution of perforin and GNLY expression in different stages of tumors classified according to Dukes’, indicating that the percentage of total perforin and GNLY was significantly diminished in accordance with tumor progression. Perforin and GNLY expression were significantly reduced in NK and NKT cells, accompanied by reduced cytolytic potential in patients with CRC and a consequent reduction in their ability to eliminate tumors and infected cells. Conclusions: The determination of cytotoxic potential may provide a valuable assessment of a patient’s immune status and represent a novel therapeutic target. Patients with CRC exhibit markedly impaired perforin- and GNLY-mediated cytotoxicity that correlates with disease progression. Assessment and restoration of cytolytic potential may therefore serve as indicators of immune competence and promising therapeutic strategies to improve perioperative and oncologic outcomes. Full article

Pediatric pain remains a highly prevalent and under-addressed health problem worldwide, largely due to educational gaps, limited humanization of care, and insufficient integration of digital and pedagogical innovations in higher education, and the purpose of this study is to describe and implement an international, higher education–driven model to improve training in humanized pediatric pain management. This multicenter mixed-methods study involves 15 universities from Europe, Africa, and Latin America and includes the development and cross-cultural validation of the HUPEDCARE-Q questionnaire to identify knowledge gaps, the design of an open-access, multilingual digital learning platform (PEDCARE) that integrates learning management and social networking functions, and the implementation of capacity-building workshops based on a training-the-trainers model for students, educators, health professionals, and families. The expected outcomes of the project include the establishment of a standardized instrument for assessing educational needs, the creation of a scalable digital educational environment, and the feasibility of international academic collaboration to strengthen competencies in pediatric pain care. The study suggests that higher education, combined with digital transformation and culturally sensitive approaches, may support the humanization of pediatric pain management and address educational and health inequities, although further research is needed to confirm these potential impacts. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disease influenced by several factors, including immune system imbalance, impairment of the epidermal barrier, and alterations in the composition of the gut and skin bacterial and fungal microbiota. This study combines metagenomic sequencing and culture-based methods to explore the impact of probiotic supplementation on the cutaneous microbiota and mycobiota of AD patients. Twenty-five adults diagnosed with AD were enrolled, and skin swabs were analyzed to characterize microbial diversity and load. Culturomic analyses identified 42 bacterial and 6 fungal species, confirming Staphylococcus aureus and Candida parapsilosis as predominant taxa. High-throughput sequencing revealed Staphylococcus spp. and Malassezia spp. as dominant genera, with notable interindividual variability. While probiotic use did not significantly influence bacterial diversity, it was associated with higher richness and evenness in fungal communities, as shown by alpha and beta diversity metrics. Malassezia restricta was more prevalent among probiotic users, whereas Candida parapsilosis and Rhodotorula mucilaginosa were enriched in non-users. These findings indicate an association between probiotic use and differences in the composition and diversity of the skin mycobiota compared with the bacterial microbiota, suggesting that fungal communities may be more responsive to probiotic-associated factors. Integrating metagenomic and culturomic approaches offers valuable insights into the complex interactions among host factors, microbial communities, and probiotic use in AD, paving the way for targeted microbiome-based therapeutic strategies. Full article

Background: Wolfram syndrome (WFS) is a rare neurodegenerative disease that is genetically determined and inherited in an autosomal recessive manner. Although the first clinical symptom appearing in early childhood is diabetes mellitus, subsequent symptoms are associated with optic nerve atrophy, followed by central nervous system atrophy. Methods: The aim of the study was to analyse magnetic resonance images (MRI) of the brain in combination with single-voxel magnetic resonance spectroscopy (MRS) and to assess the copy number of mitochondrial DNA (mtDNA-CN) in 10 patients with WFS compared with a control group of 17 healthy individuals. Results: A significant decrease in the amount of selected metabolites was observed in WFS patients compared to controls in all assessed brain regions (pons, cerebellum, white matter, thalamus, and hippocampus). For three metabolites, Glutamate (Glu), Glutamate + Glutamine (Glx) and total N-acetylaspartate (TNAA), significant differences in concentrations were found between the study groups in almost all matrices evaluating specific areas of the brain (p < 0.011), with the exception of a trend toward reduced TNAA in the hippocampus (p = 0.065). In addition, patients with WFS had a significant decrease in the mitochondrial-to-nuclear DNA ratio compared to controls (p < 0.0003). Some metabolites, such as N-acetylaspartate and total N-acetylaspartate, showed strong correlations with specific regions of the visual pathway on MRI scans in patients with WFS. Conclusions: Selected brain metabolites and mtDNA-CN may become potential markers of WFS, and the results of this study may be used to define indicators for future therapeutic strategies. Full article

Macrophage-mediated inflammation is a key driver of sepsis-induced acute lung injury (ALI). M1 macrophage polarization relies on metabolic reprogramming, yet the upstream regulatory factors remain unclear. Lysine acetyltransferase 6A (KAT6A), a MYST-family acetyltransferase, regulates transcriptional programs in immune cells, but its role in macrophage function and ALI progression remains unknown. Public single-cell and bulk transcriptomic datasets were used to assess KAT6A expression changes and its association with inflammatory and metabolic pathways in macrophages. KAT6A inhibition with WM1119 was used to evaluate effects on M1 polarization, cytokine production, metabolic reprogramming, and PI3K-AKT-mTOR signaling. The therapeutic potential of KAT6A inhibition was validated in a cecal ligation and puncture (CLP)-induced sepsis model by assessing lung injury, bacterial clearance, and survival. KAT6A expression was upregulated in sepsis and particularly enriched in M1 macrophages. Inhibition of KAT6A reduced inflammatory and glycolytic transcriptional programs, suppressed glycolysis and enhanced oxidative phosphorylation, leading to decreased cytokine production and limited M1 polarization accompanied by suppression of PI3K-AKT-mTOR pathway. In CLP-induced septic mice, treatment with the KAT6A inhibitor WM1119 alleviated lung injury, improved bacterial clearance, and prolonged survival. KAT6A expression is associated with macrophage glucose metabolism, pro-inflammatory responses, and M1 macrophage polarization in sepsis-induced acute lung injury. Pharmacologic inhibition of KAT6A may provide a promising therapeutic strategy for reducing macrophage-driven lung injury. Full article

Background/Objectives: Prior research suggests that it is possible to improve health outcomes in children with adverse childhood experiences (ACEs) through multi-component interventions that promote protective factors. We designed the Families Implementing Resilient Systems Together (FIRST) study to address the gaps in research on the potential effectiveness of screening for specific ACEs through pediatric practice. Methods: As part of our clinical quality improvement efforts to improve patient care for children impacted by ACEs, we trained a random sample of pediatricians on strategies to promote protective factors and encouraged them to make referrals to community health workers (CHWs) and parenting education resources. This manuscript describes our clinic data on practice changes associated with the FIRST physician training, and our data collection plan for our research study. Results: Physician training resulted in attitudinal shifts and measurable behavioral changes. Trained providers made referrals to CHWs for approximately 5–10% of well-child care visits. The majority (84%) of referrals were for multiple risk factors, most commonly ACEs and socioeconomic concerns. The most common ACEs were parental divorce/separation, parent–child verbal abuse, and caregiver mental health problems. Conclusions: FIRST training improves counseling, education and referrals for children exposed to ACEs. Our research study will evaluate the impact of the FIRST intervention and address important questions about associations between specific ACEs, protective factors, and biomarkers of toxic stress. Full article

Background: Rome IV criteria promote a symptom-based (“positive”) diagnosis of pediatric disorders of gut–brain interaction (DGBIs). In clinical practice, however, organic gastrointestinal diseases may mimic DGBIs and lead to diagnostic revision after further evaluation. We aimed to quantify the diagnostic stability of an initial Rome IV-oriented functional diagnosis in a tertiary pediatric outpatient setting and to identify symptom phenotypes associated with a higher likelihood of later organic reclassification. Methods: We performed a single-center retrospective cohort study (2014–14 May 2021) based on outpatient chart review. Eligible patients were children and adolescents aged 0–18 years with an initial Rome IV-oriented functional diagnosis. Diagnostic reassessment was based on follow-up data, available laboratory and instrumental investigations, and/or response to exclusion therapies. Final diagnoses after reassessment were categorized as functional only, organic, or mixed. Groups were compared using Pearson’s chi-square test. Results: The cohort included 220 males (50.0%) and 220 females (50.0%), with a mean age of 8.86 ± 4.65 years. After reassessment, 343/440 (77.95%) remained functional, 73/440 (16.59%) were reclassified as organic, and 24/440 (5.45%) were classified as mixed. Final diagnosis differed by GI tract involvement (p = 0.001) and by symptom cluster (p = 0.001). Upper GI/dyspepsia-spectrum presentations showed the highest organic yield (27.03%), followed by lower abdominal pain/IBS-spectrum presentations (19.61%). Diarrhea and vomiting/cyclic vomiting each showed 16.67% organic diagnoses (mixed: 10.0% and 7.14%, respectively), whereas constipation showed the greatest diagnostic stability (98.89% functional; 1.11% organic). Functional confirmation rates were similar before and during the pandemic (77.71% vs. 78.70%; p = 0.756). Monthly case volume was higher in 2020–2021 (6.29 vs. 4.61 cases/month). Conclusions: In this tertiary cohort, about one in six children initially diagnosed with a functional disorder were later found to have an organic disease, and an additional 5% had mixed organic–functional presentations. Diagnostic revision was associated with presenting phenotype, with the highest organic yield observed in dyspepsia/upper GI presentations and the lowest in constipation. These findings support symptom-stratified evaluation and follow-up alongside Rome IV criteria. Full article

Diffuse midline gliomas (DMGs) are rare but highly aggressive central nervous system (CNS) tumors that can present in both pediatric and adult populations. These tumors were redefined in the 2016 WHO classification of CNS tumors based on integrated histopathological and molecular features, and were initially designated as “DMG, H3 K27M-mutant”. In the 2021 WHO update, DMGs were incorporated into the newly defined category of primarily pediatric-type diffuse high-grade gliomas, and nomenclature was changed to “DMG, H3 K27-altered” to encompass additional molecular drivers beyond the canonical H3 K27M mutation. Clinically, DMGs arise as expansile, infiltrating tumors within midline structures and may present as non-enhancing or enhancing lesions on imaging. Diagnosis is based on neuroimaging and molecular confirmation by immunohistochemistry or sequencing when tissue is available. DMGs are categorized as WHO grade 4 malignant tumors due to their aggressive biology leading to rapid and infiltrative growth. Owing to their deep and midline location, surgical resection is typically not feasible. Radiation therapy is the backbone of treatment, but there is no standard regimen of chemotherapy that has demonstrated durable efficacy. Recent progress in therapeutic approaches has led to a major breakthrough on 6 August 2025 when the U.S. Food and Drug Administration granted the accelerated approval of dordaviprone (ONC201), marking it as the first systemic therapy for progressive DMG harboring H3 K27M mutation. Other novel approaches, including chimeric antigen receptor (CAR) T-cell directed therapies and convection-enhanced delivery, are actively under investigation. We aim to comprehensively review DMGs, including the recent insights into their biology, the evolving therapeutic landscape, and the opportunities to fuel this new momentum against one of the most formidable gliomas. Full article

Background/Objectives: Surfactant has been delivered via less-invasive surfactant administration (LISA) in our neonatal intensive care unit (NICU) since 2020. Data have been monitored and the literature regularly reviewed to improve our LISA practice. The purpose of this project is to share the clinical practice changes made to help other NICU providers fine-tune their LISA practice. Methods: The original LISA criteria included babies with GA 27–36 6/7 w, on > 21% O₂, on continuous positive airway pressure (CPAP), pCO₂ < 70 if a blood gas was obtained, and radiographic and/or clinical evidence of respiratory distress syndrome (RDS). Current criteria include GA 25–35 6/7 w and minimum CPAP + 6. This manuscript highlights the changes made since 2023. To monitor these changes, targeted data from the entire cohort were examined before and after each change. Results: LISA was attempted on 399 babies (average (SD) GA 31.7 (2.7), birth weight 1752 (590), with a procedural success rate of 97%. Overall, 18% required intubation within 7 days after LISA. The median (IQR) for FiO₂ was 32 (28, 40) prior to LISA and 23 (21, 30) post-LISA and the hour of age of LISA was 4 (2.5, 9.9). LISA procedure success rate was increased by the use of video laryngoscopy as well as reinforcement of the use of sucrose sedation and swaddling; our first attempt success increased overall from 39% to 52%. After the introduction of a clinical RDS score (Downes), there was an expected and logical increase in the number of infants requiring intubation within 7 days of LISA indicating likely over-treatment prior to this change. After implementation of a clearly described plan for babies <28 w gestation there was a decrease in the hour of age of LISA from 3 (2.5, 4.5) to 2 (0.8, 3) h. Conclusions: It is critical to continually evaluate a new practice and identify strategic changes. We offer our changes to assist others starting or using LISA. Full article

Resveratrol (RSV), a bioactive polyphenol, has emerged as a pleiotropic modulator within the integrated pathophysiology of cardiovascular disease (CVD) across the life course. Effective CVD management requires a transition from organ-centric frameworks to systems-level models that acknowledge dynamic crosstalk among metabolic, renal, and cardiovascular networks. Oxidative stress constitutes a central unifying axis in this interconnected biology, propagating cross-organ injury from early developmental stages onward. Mechanistically, RSV acts as a redox-responsive gene regulator by activating the Nrf2–ARE pathway, restoring nitric oxide bioavailability, and orchestrating SIRT1, AMPK, and NF-κB signaling to recalibrate mitochondrial function, inflammatory tone, and endothelial integrity. Within the Developmental Origins of Health and Disease (DOHaD) paradigm, RSV exhibits reprogramming potential that attenuates the intergenerational transmission of hypertension, kidney disease, and metabolic dysfunction. Although clinical translation is constrained by limited bioavailability and rapid metabolism, advanced delivery systems and artificial intelligence-enabled optimization strategies provide promising avenues to enhance therapeutic precision and scalability. This narrative review integrates mechanistic and translational insights to position RSV as a systems-oriented life-course intervention with sustained and intergenerational relevance in CVD. Full article

Background/Objectives: Survival after pediatric intensive care unit (PICU) admission has improved, yet many children experience post-intensive care syndrome in pediatrics (PICS-p), including persistent feeding difficulties that impair growth and quality of life. An intensive feeding program (IFP), also known as intensive interdisciplinary behavioral treatment (IIBT), reduces tube dependence and improves oral intake; however, outcomes in PICU survivors remain understudied. This study aimed to evaluate feeding outcomes in children with prior PICU admission who completed IIBT. Methods: This study was a retrospective case series of children (0–18 years) admitted to the HDVCH, Corewell Health, Grand Rapids, Michigan, who subsequently completed IIBT (from 2007 to 2024). Variables included demographics, PICU course (admission indication, complications, length of stay, ventilation, and nutrition status) and IIBT outcomes (feeding modality, oral skills, and malnutrition status). Feeding outcomes were compared pre- and post-IIBT. Results: Sixteen patients were included (62.5% female; mean age 1.44 ± 1.21 years). Primary PICU admission causes were post-operative recovery (68.8%) and acute respiratory failure (25%). PICU complications included acute respiratory failure (43.8%) and the need for respiratory support beyond baseline (62.5%). At PICU discharge, 75% remained tube-fed and 18.8% were malnourished. The mean time from PICU discharge to IIBT initiation was 641 ± 385 days. At IIBT baseline, 75% were tube-fed and all were non-self-feeders. Following IIBT completion (mean length of stay 4.8 ± 0.9 weeks), 58% of tube-fed patients achieved tube removal eligibility; 44% transitioned to partial or full self-feeding; problematic mealtime behaviors decreased (45.7% → 9.9%); oral acceptance improved (62% → 95%); and mouth clearance improved (59% → 96%). Malnutrition prevalence decreased (20% → 12%). Conclusions: Children with prior PICU admission demonstrated substantial feeding and behavioral improvement during IIBT participation, with over half achieving tube-weaning eligibility. The time from referral to program start reflects barriers that delay intervention. Full article

Background: Exclusive enteral nutrition (EEN) is the recommended first-line therapy for induction of remission in pediatric mild-to-moderate Crohn’s disease (CD), but its restrictive nature often limits adherence and long-term sustainability. A modified version of the Crohn’s Disease Exclusion Diet (CDED), integrating Mediterranean dietary principles, was developed to offer a more acceptable alternative while preserving therapeutic efficacy. Methods: We conducted a retrospective, single-center study comparing short- and long-term outcomes of a Mediterranean-adapted CDED (M-CDED) with partial enteral nutrition (PEN) versus standard EEN in children with mild-to-moderate CD. Clinical remission was assessed after 8 and 16 weeks, while long-term outcomes were assessed after 1 and 2 years. Results: Data collected from thirty-two patients were analyzed (EEN, 14; M-CDED, 18). Clinical remission rates were comparable after 8 weeks (92.8% EEN vs. 94.4% M-CDED) and 16 weeks (100% in both groups). However, at 12 and 24 months, M-CDED was associated with significantly higher rates of clinical and biochemical remission and a markedly lower need for biologic drugs (12-month biologic initiation: 50% EEN vs. 11.1% M-CDED; p = 0.01). Adherence to M-CDED was excellent throughout follow-up. Conclusions: M-CDED with PEN appears to be as effective as EEN for remission induction, with improved long-term disease control and reduced therapeutic escalation. These findings support the feasibility of M-CDED as a sustainable option for long-term management of pediatric CD. Prospective studies are needed to confirm these results. Full article

Background/Objectives: Sleep disturbances have an impact on children’s physical and psychological development, yet little is known about the changes and factors influencing sleep after PICU discharge. To explore the trajectory of changes in sleep quality of critically ill children and to identify factors affecting sleep quality three months after Pediatric Intensive Care Unit (PICU) discharge. Methods: A longitudinal observation study was conducted between November 2022 and November 2023 at a tertiary children’s hospital. The Children’s Sleep Habits Questionnaire (CSHQ) was used at six time points: PICU-admission (T0), 1 week (T1), 2 weeks (T2), 1 month (T3), 2 months (T4), and 3 months (T5) after PICU discharge. The CSHQ is a 33-item parent-report outcome measure evaluating sleep problems. Total scores range between 33 and 99 points. A score of ≤41 indicates normal sleep; a score of >41 indicates sleep disturbance. Data were analyzed using the latent category growth model, univariate analysis, and multifactorial logistic regression. Results: Parents of 237 children completed all follow-up surveys. Prevalence of sleep disorders at T0-T5 of children with a score >41 were 46.5%, 83.5%, 69.7%, 54.3%, 50.2%, and 51.7%, respectively. General linear modeling revealed significant changes in CSHQ scores over time (F = 63.77, p < 0.05). The trajectories of identifying sleep changes were divided into three latent categories: High Sleep Disorder Group (n = 15, 6.33%), Moderate Sleep Disorder Group (n = 110, 45.2%), and No Sleep Disorder Group (n = 115, 48.52%). The trajectories were significantly different among preschool age, baseline sleep habit scores, surgery, and length-of-stay in pediatric wards (p < 0.05). The child’s age and surgical history were independent factors of sleep disturbance. Conclusions: The observed peak in sleep disturbances at 1-month post-PICU suggests that this period may be a critical window to develop and implement targeted interventions to improve sleep. The persistent sleep disorders highlight the need for long-term monitoring. Full article

Background/Objectives: Pediatric intussusception, a condition where part of the intestine telescopes into an adjacent segment, predominantly affects children aged 6–18 months. Prompt diagnosis and management are crucial to prevent serious complications such as ischemia or necrosis. This systematic review aims to comprehensively evaluate and synthesize existing research on predictive and prognostic biomarkers associated with pediatric intussusception that can aid in early diagnosis, severity assessment, outcome prediction, and treatment. Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science using specific MeSH and free-text terms related to intussusception, biomarkers, and the pediatric population. The review followed PRISMA guidelines, with independent screening, data extraction, and quality assessment using the Joanna Briggs Institute critical appraisal tools. A total of 47 studies, mostly retrospective cohorts from diverse countries, with over 20,000 patients, were included. Results: The studies identified numerous biomarkers associated with disease severity, including hematological markers and indices (e.g., WBC counts and neutrophil-to-lymphocyte ratio), inflammatory markers (CRP and cytokines), biochemical markers (serum lactate, D-dimer, and electrolytes), and novel molecular markers (I-FABP, MCP-1, and transfer RNA fragments). Elevated inflammatory markers and derived ratios consistently predicted bowel necrosis, ischemia, and need for surgery. Biochemical markers like serum lactate and D-dimer correlated with ischemic severity. Emerging molecular biomarkers show promise for early, non-invasive risk stratification. However, heterogeneity in study designs, assay methods, and cutoff values currently limits immediate clinical application. Conclusions: Biomarker research offers valuable tools for improving pediatric intussusception management, with the potential to enhance early diagnosis and outcome prediction. While traditional markers are useful, novel molecular and protein biomarkers hold promise for more specific and rapid assessment. Validation through multicenter, prospective studies and standardized protocols is essential before routine implementation. Integrating biomarkers with clinical and imaging data could refine decision-making, ultimately reducing morbidity and improving prognosis in affected children. Full article