Medicine and Pharmacology

Abstract: Neonatal white matter injury (WMI) arises from the interaction of developmental vulnerability with hypoxic–ischaemic, inflammatory, oxidative, and metabolic perturbations. Although experimental models have substantially advanced the understanding of these mechanisms and supported the investigation of anti-inflammatory and neuroprotective strategies, their translation into neonatal clinical practice remains challenging. Neonates are neither small adults nor little children, and experimental animals are not scaled representations of human neonates. Similar molecular pathways, cellular targets, or anatomical features across species may therefore indicate concordance in individual characteristics without establishing biological or pharmacological equivalence. In this narrative review, we examine the translational gap between experimental models of neonatal WMI and human neonatal pharmacology, focusing on developmental differences in inflammatory pathways, white matter maturation, physiology, drug disposition, and target engagement. We discuss the apparent discordance between preclinical biological plausibility and clinical neuroprotection. Thereafter, we propose an intervention-specific framework (“The Reticulum Framework”) that organizes developmental concordance, evidence gaps and uncertainty across species; its predictive value requires empirical validation. The framework conceptualizes anatomy, physiology, biochemistry, and developmental pharmacology as interacting domains constrained by biophysical principles and introduces “comparative developmental physionemes” as biologically interpret descriptors whose concordance or discordance contributes to translational equivalence. In this sense, current validated biomarkers and surrogate measures could be used to analyse the interconnection between these domains across species, considering especially cellular and molecular dynamics through omics pipelines. The Reticulum Framework proposes that biological correspondence should be evaluated according to the functional meaning that a physioneme acquires within a specific developmental system rather than by isolated similarity. Translational relevance is therefore considered intervention-specific and is assessed across anatomical, physiological, biochemical, pharmacological, biophysical, temporal, and outcome concordance as a multidimensional profile. This framework may support model selection, interpretation of experimental anti-inflammatory efficacy, identification of translational mismatches, and prioritization of candidate neuroprotective interventions for neonatal trials.

Abstract: Background: A type 1 diabetes mellitus (T1DM) diagnosis is burdensome for pediatric patients and for healthcare systems globally. Glycemic control is pivotal in managing T1DM while the psychosocial aspects of the disease can be overlooked. Telemedicine provides a potential solution to enhance diabetes care and to reduce barriers faced by patients, particularly in remote areas. We aimed to explore the impact of monthly virtual clinics on glycemic control in pediatric patients and to assess psychosocial aspects of the disease by measuring parents’ satisfaction with these clinics. Methods: This single-center cohort study enrolled pediatric patients aged 14 years or younger with T1DM at the King Faisal Specialist Hospital and Research Center – Jeddah Branch. Data collection occurred over a six-month period with patients participating in monthly virtual consultations in addition to their regular in-person clinic visits. Parental satisfaction and compe-tence in diabetes management were assessed using a survey developed for study use. Clinical and demographic variables were compared before and after the intervention. Results: The study in-cluded 25 participants, with a median age of 11.0 years and 56.0% were male. Following the in-tervention, there was a significant improvement in HbA1c levels (pre-intervention: 9.3 ± 1.7, post-intervention: 8.8 ± 1.6, p-value = 0.0054) and a reduction in the number of hypoglycemia ep-isodes per week. Parental satisfaction and competence in managing T1DM remained consistent throughout the study. Conclusions: This study suggests that implementing monthly virtual clin-ics can positively impact glycemic control and reduce hypoglycemia episodes in pediatric T1DM patients in Saudi Arabia. Future research should explore the long-term benefits and scalability of telemedicine in managing chronic pediatric conditions and its acceptance by parents of Saudi children with T1DM.

Abstract: Background: Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by esophageal dysfunction and eosinophil-predominant inflammation. Its increasing recognition in children and risk of progressive remodeling demand effective, sustainable treatment. Methods: We conducted a narrative review of PubMed/MEDLINE, Embase, and Cochrane Library publications through 2026. Pediatric clinical studies, systematic reviews, meta-analyses, and international guidelines addressing dietary, pharmacological, and biologic therapies were qualitatively synthe-sized, with selected adult evidence included when pediatric data were unavailable. Results: Empiric elimination diets remain effective first-line options, with step-up strategies reducing unnecessary restriction and treatment burden. Elemental diets achieve histological remission in more than 90% of patients but are limited by palatability, cost, and adherence. Allergy test-directed diets have low predictive value and are not routinely recommended. Proton pump inhibitors and swallowed top-ical corticosteroids are established first-line therapies with favorable safety profiles. Real-world evidence suggests that treatment choice depends on age, phenotype, local practice, and family preference, whereas comparative effectiveness data remain limited. Dupilumab, the first biologic approved for EoE, produces substantial histological and endoscopic improvement across pediatric age groups and is particularly relevant for difficult-to-control disease or coexisting type 2 conditions. Other targeted agents reduce eosinophilia, but symptomatic benefit and pediatric evidence remain inconsistent. Conclusion: Pediatric EoE management should combine shared decision-making with objective histological monitoring and attention to growth, nutrition, adherence, and quality of life. Future research should define optimal treatment sequencing and maintenance, validate noninvasive biomarkers, and establish the long-term safety and effectiveness of emerging therapies in diverse pediatric populations and clinical settings.

Abstract: Norovirus infection has been increasingly recognized as a potential trigger of necrotizing enterocolitis (NEC) in preterm neonates. Although previous reports have described severe cases associated with intestinal pneumatosis, bowel ischemia, and the need for surgical intervention, the clinical spectrum of Norovirus-related intestinal disease remains poorly defined. We report the case of a 29-week gestational age preterm infant who developed abdominal distension on the 35th day of life. Stool reverse transcriptase polymerase chain reaction confirmed Norovirus infection. Abdominal radiographs showed progressive development of intestinal pneumatosis, leading to the confirmed diagnosis of a stage IIA NEC. Abdominal pneumatosis resolved completely within five days, without evidence of perforation or clinical deterioration. The infant received only supportive therapy and intravenous immunoglobulin (IVIG). This case highlighted the heterogeneous clinical spectrum of Norovirus-associated intestinal involvement in preterm infants and the possible protective and immunomodulatory role of the IVIG.

Abstract: Background: Pediatric pleural empyema remains a major complication of community-acquired pneumonia despite vaccination and advances in minimally invasive treatment. This narrative review summarizes current evidence on etiology, diagnosis, antimicrobial therapy, pleural drainage, fibrinolysis, and surgery. Methods: PubMed was searched from inception through July 2026 for English-language studies involving patients aged 0–18 years. Pediatric trials, observational studies, surveillance reports, guidelines, reviews, and relevant case series were considered. Of 42 publications assessed in full, 38 were included in the narrative synthesis. Results: Streptococcus pneumoniae, particularly serotype 3, Staphylococcus aureus, and Streptococcus pyogenes remain the principal pathogens. Chest ultrasound is preferred for characterizing pleural collections and guiding intervention, whereas computed tomography is reserved for atypical disease or suspected complications. Small, uncomplicated effusions may respond to antibiotics alone; large, purulent, or clinically significant collections generally require source control. Image-guided small-bore catheter drainage with protocol-based urokinase or tissue plasminogen activator is effective for many loculated effusions. Pediatric evidence does not support routine addition of DNase. Comparative trials show broadly similar clinical outcomes for fibrinolysis and video-assisted thoracoscopic surgery, although heterogeneous protocols and limited sample sizes preclude identification of a universally superior strategy. Thoracotomy is rarely required. Conclusions: Management should integrate respiratory and septic severity, pleural anatomy, microbiology, adequacy of drainage, clinical trajectory, and local expertise rather than rely on rigid staging. Long-term recovery is excellent in most previously healthy children receiving timely treatment. Standardized definitions, pediatric outcome sets, multicenter comparative trials, validated predictors of treatment failure, and studies of antimicrobial duration remain important research priorities.

Abstract: Background: Accurate field triage is a cornerstone of an inclusive trauma system, but paediatric undertriage remains poorly characterised outside North America. We aimed to estimate the rate of major trauma undertriage in a Spanish paediatric trauma centre, to identify patient factors associated with it, and to explore its relationship with early clinical outcomes. Methods: Retrospective cohort study (2016–2025) of children aged 0–14 years admitted to the paediatric intensive care unit (PICU) of the reference paediatric trauma centre for the province of Granada, Spain. Major trauma was defined using a composite of the Cribari Matrix (ISS > 15) and/or the Need for Trauma Intervention (NFTI) criteria. Undertriage was defined as delayed (> 2 hours) or non-direct transport to the trauma centre despite proximity (< 30 minutes). The primary outcomes were the undertriage rate and the patient factors associated with it, examined by bivariate analysis and by Firth-penalised logistic regression with intercept correction (FLIC). Clinical outcomes (Glasgow Outcome Scale, PICU and total hospital length of stay) were prespecified as exploratory and analysed with generalised linear models — binomial for binary outcomes and negative binomial for counts — and, as a sensitivity analysis, with targeted maximum likelihood estimation (TMLE). Results: Out of 1,716 PICU admissions during the study period, 131 (7.6%) were due to trauma and 93 children met major trauma criteria (median age 8.0 years; 73.1% male; 78.5% blunt trauma; median ISS 18.0). The undertriage rate was 23.7% (22/93; 95% CI 15.5–33.6). No patient characteristic differed significantly between undertriaged and correctly triaged children. Undertriaged children tended to be older (median 11.0 vs 7.0 years; p = 0.097) and heavier (36.5 vs 25.5 kg; p = 0.097), and the overall association between age category and undertriage did not reach significance in the FLIC model (p = 0.058). Two children (2.2%) died in PICU and 73 (78.5%) achieved a good functional recovery. Undertriage was not associated with functional outcome, PICU length of stay or total hospital length of stay in either unadjusted or adjusted analyses. Conclusions: Nearly one in four children with major trauma reaching this paediatric trauma centre had been undertriaged, a rate far above the 5% benchmark recommended by the American College of Surgeons. This rate is a lower bound, because children who died before transfer and those never transferred are structurally absent from the cohort. No patient characteristic identified undertriaged children, and no effect on early outcomes could be demonstrated in a cohort of this size. Multicentre studies are needed.

Abstract: Purpose: The usefulness of the Patient State Index (PSI), an electroencephalogram (EEG)-based tool recently introduced in pediatric critical care units (PICU) , and the clinical level of sedation has not been yet demonstrated in pediatric critical care patients. This study investigated the association between the Patient State Index (PSI) and the Richmond Agitation–Sedation Scale (RASS) in PICU patients to determine whether the PSI could serve as a reliable objective measure of sedation in critically ill children. Setting: a pediatric intensive care unit of a tertiary hospital. Methods: This prospective observational study continuously monitored PSI values using the SedLine® monitor (Masimo, Irvine, CA, USA). Monitoring began at the initiation of sedative therapy and continued for up to 2 hours after its discontinuation. PSI values were recorded immediately before each Richmond Agitation–Sedation Scale (RASS) assessment, which was performed by the attending physicians at the start of sedative therapy, at 6, 12, and 24 hours thereafter, and immediately before sedation withdrawal. Results: A total of 87 paired PSI and RASS measurements were obtained from 35 patients. The PSI showed a weak positive correlation with the RASS score (Spearman's rank correlation coefficient = 0.26; 95% confidence interval [CI], 0.049–0.467; p = 0.01). Agreement between the PSI and RASS was slight, with a Cohen's kappa coefficient of 0.14 (95% CI, 0.067–0.348; p = 0.09). PSI values did not differ significantly across RASS categories (Kruskal–Wallis test, p = 0.166). Receiver operating characteristic (ROC) curve analysis identified a PSI threshold of 39 for distinguishing light sedation (RASS ≥ −2) from deep sedation (RASS ≤ −3). The area under the ROC curve was 0.65 (95% CI, 0.534–0.766), with a sensitivity of 0.68 and a specificity of 2.38. Conclusions: The PSI showed only a weak correlation with the RASS in critically ill children. Therefore, it should be used cautiously as a standalone measure of sedation depth in the PICU. However, these findings do not negate its potential clinical value. Instead, the PSI should be interpreted as part of a multimodal neuromonitoring strategy, taking into account age-related EEG maturation, the clinical context, and the known limitations of EEG-derived indices in critically ill patients.

Abstract: Anaemia is almost universal during the neonatal course of extremely preterm infants and red blood cell transfusion (BT) remains one of the most frequently used treatments in neonatal intensive care. The fall in haemoglobin after preterm birth reflects developmental physiology compounded by shortened RBC survival, impaired erythropoietin response, rapid somatic growth, iron availability and iatrogenic blood loss. Although haemoglobin (Hb) concentration remains the principal laboratory measure used to guide transfusion, it provides an incomplete assessment of oxygen delivery and erythropoietic reserve. Recent evidence has therefore renewed interest in complementary measures including fetal haemoglobin (HbF), absolute reticulocyte count and reticulocyte haemoglobin content. High risk infants such as those with fetal growth restriction (FGR) may represent a distinct haematological phenotype because chronic placental insufficiency alters fetal erythropoiesis and iron utilisation before birth. Large randomised trials and a subsequent international guideline now support restrictive haemoglobin-based transfusion thresholds in very preterm infants, but substantial variation in practice persists. Furthermore, transfusion with adult donor RBCs changes more than haemoglobin concentration: it replaces HbF-rich neonatal cells with HbA-rich adult cells, altering oxygen affinity and endogenous erythropoiesis. This narrative review examines the developmental physiology and contemporary management of neonatal anaemia, with particular focus on HbF, reticulocyte parameters, FGR, transfusion thresholds and emerging approaches to individualised transfusion. Future strategies should move beyond haemoglobin concentration alone towards integration of haematological and physiological markers of oxygen delivery.

Abstract: Diagnostic invalidation—the dismissal, minimization, or delegitimization of a patient’s reported symptoms or illness experience—may be an underrecognized source of pediatric medical trauma. Existing pediatric medical traumatic stress frameworks emphasize acute illness, invasive procedures, intensive care, and other visibly threatening events. This narrative review integrates literature on pediatric medical traumatic stress, symptom invalidation, diagnostic overshadowing, epistemic injustice, functional and chronic symptoms, patient–clinician trust, and trauma-informed care. It proposes that repeated invalidation may contribute to traumatic stress through prolonged suffering, loss of bodily and epistemic agency, relational betrayal, stigmatization, unpredictability, and dependence on healthcare systems perceived as unsafe. Downstream effects may include altered symptom disclosure, delayed or avoidant care-seeking, hypervigilance, distrust, fragmented care, and reluctance to engage in appropriate psychological treatment. The review distinguishes validation from premature diagnostic agreement and presents a six-part clinical framework—Hear, Acknowledge, Explain, Respond, Reassess, and Partner—for maintaining diagnostic rigor while preserving relational safety. A conceptual model describes a recursive pathway through which invalidation-related stress responses may contribute to increasingly difficult clinical encounters and further skepticism. Because direct longitudinal pediatric evidence remains limited, the model is hypothesis-generating. Recognizing diagnostic invalidation as a relational and patient-safety concern may broaden trauma-informed pediatric practice beyond procedural distress.

Abstract: Limosilactobacillus reuteri DSM 17938 feeding to healthy newborn mice modulates gut microbiota and boosts beneficial metabolites. We assessed whether DSM 17938 supplementation in pregnant dams alters breast milk (BM) metabolites and shapes the infant gut metabolomic profile, aimed to improve offspring immunity and overall health. To do this, we evaluated metabolite changes in BM from lactating dams carrying Thy1.2 congenic marker, and in stool from their cross-fostered Thy1.1 pups. Stool samples showed a significantly higher number of altered metabolites (of which 272 were up- and 199 were down-regulated) compared to BM-fed (9 up- and 82 down-regulated). Compared to water-treated controls, BM from DSM 17938-treated dams showed significant upregulation of several anti-inflammatory metabolites, including phosphonolpyruvate (PEP), tryptophan-derived indoles, and the stable adenosine metabolite inosine. Additionally, leucine and glycine were upregulated, reflecting their roles in metabolic regulation. In the stools of cross-fostered pups raised by DSM 17938-treated dams, upregulated fecal metabolites included dipeptides, vitamins, inosine, and the polyamines spermine and spermidine, which actively protect the intestinal epithelium against mucosal injury. Maternal DSM 17938 supplementation altered BM composition by enhancing pathways in immune regulation, neurodevelopment, and metabolic function. Crucially, these metabolic shifts were reflected downstream in the stools of cross-fostered pups, underscoring their potential role in supporting infant gut health.

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Background: The maternal microbiome represents the first microbial environment for the developing infant, with emerging evidence linking maternal dysbiosis to adverse pregnancy outcomes and lifelong offspring health. Aims: This review synthesizes evidence on the maternal-infant microbial continuum, examining microbial dynamics during pregnancy, vertical transmission pathways, infant microbiome trajectories, and intervention strategies. Key Findings: Dynamic changes in maternal gut, vaginal, and oral microbiomes during pregnancy influence fetal development through mechanisms including hormonal modulation (e.g., Clostridium innocuum-mediated 17β-estradiol degradation), immune programming via short-chain fatty acids, and barrier integrity maintenance. Delivery mode exerts persistent effects, with Cesarean-section associated with higher allergy risk (OR=1.5-2.2), while probiotic supplementation may mitigate this risk (RR=0.6-0.8). Conclusion: The maternal-infant microbiome continuum represents a critical therapeutic target. Standardized longitudinal research and personalized intervention strategies are urgently needed to translate mechanistic insights into clinical practice.

Abstract: Background/Objectives: Juvenile-onset systemic lupus erythematosus (jSLE) is a multisystem disease requiring disease control, glucocorticoid minimization, and treat-to-target assessment. We characterized phenotype, treatment exposure, childhood lupus low disease activity state (cLLDAS), and outcomes. Methods: This retrospective cohort included 54 patients followed during 2020–2025. One patient who died 10 days after diagnosis contributed to baseline and cumulative analyses but not longitudinal or last-visit analyses (n=53); all survivors had ≥6 months of follow-up. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and Paediatric Rheumatology European Society (PReS)-endorsed cLLDAS were assessed; paired changes were analyzed with the Wilcoxon signed-rank test. Results: Forty-three patients (79.6%) were female; median age at diagnosis was 15.0 years and median follow-up among survivors was 34.6 months. Cumulative hematologic and mucocutaneous involvement occurred in 64.8% and 61.1%, respectively. Biopsy-proven lupus nephritis occurred in 29.6%, with class IV in 13/16 cases (81.3%). Hydroxychloroquine was used in 53/54 (98.1%), and oral prednisolone in 46/54 (85.2%) for a median 17.5 months. Median SLEDAI-2K decreased from 8.0 to 4.0 (p< 0.001); anti-double-stranded DNA antibody (anti-dsDNA), complement C3, and spot urine protein-to-creatinine ratio improved significantly. At last follow-up, 29/53 (54.7%) fulfilled cLLDAS. Flare, infection-related hospitalization, intensive care unit (ICU) admission, and mortality occurred in 22.2%, 20.4%, 5.6%, and 1.9%, respectively. Conclusions: Disease activity and serological and renal markers improved, and just over half achieved cLLDAS, although residual disease activity and infection-related morbidity remained relevant.

Abstract: Background/Objectives: Late-onset hyponatremia (LOH), often develops after the second week of life in preterm infants and has been associated with poor growth and adverse neurodevelopmental outcomes. Human milk, including pasteurized donor breast milk (DBM), has less sodium content than preterm infants require. There is paucity of studies examining the association between DBM and LOH. We evaluated the association between feeding type and LOH beyond the second week of life. Methods: This was a single-center retrospective cohort study that included preterm neonates born at gestational age < 32 weeks or birth weight < 1500 grams, between January 2017 and October 2022. Eligible infants had serum sodium levels measured after 14 days of life and after achieving full enteral feeds. Hyponatremia was defined as serum sodium < 135 mEq/L. Results: Of 373 infants, 43% (n=159) developed LOH. Using multivariable regression analysis, increased DBM intake, lower gestational age, use of chlorothiazide, and mild-moderate bronchopulmonary dysplasia were independently associated with higher odds of developing LOH. The use of furosemide, formula, and patent ductus arteriosus were not associated with LOH. Conclusion: A higher proportion of DBM intake, lower gestational age, chlorothiazide use, and mild-to-moderate BPD were independently associated with LOH. Preterm infants receiving DBM and long-acting diuretics like chlorothiazide are at increased risk for LOH and should be monitored closely.

Abstract: Myelination in the developing brain emerges from a dynamic interplay among oligodendrocytes, astrocytes, neurons, vascular components, and immune cells. Although astrocyte–oligodendrocyte interactions are increasingly recognized as critical for myelin formation, maintenance, and metabolic homeostasis, their developmental organization remains incompletely understood, particularly in extremely preterm infants, in whom mature astrocytic functions are not yet fully established. This narrative review examines how oligodendrocyte maturation and white-matter metabolism may be supported across development and how perinatal insults can perturb this evolving cellular cooperation. Evidence from experimental, neuropathological, metabolic, and neuroimaging studies indicates that oligodendrocytes are not passive recipients of astrocytic support but active metabolic, signaling, and immunological partners whose functions evolve alongside astroglial maturation. In the immature white matter, this relationship is further shaped by neuronal activity, vascular substrate delivery, inflammatory signaling, and the intrinsic vulnerability of pre-oligodendrocytes. Hypoxia–ischemia, oxidative stress, iron dyshomeostasis, ferroptosis, and glycemic instability may therefore interfere with multiple components of this developing network. Human and experimental evidence from perinatal white-matter injury is particularly informative, showing the coexistence of reactive astrogliosis, pre-oligodendrocyte injury and maturation arrest, and subsequent impairment of myelination. Quantitative neuroimaging, radiomics, proteomics, and lipidomics provide complementary observational scales through which these processes may be investigated, although imaging markers of myelin remain biologically non-specific. Taken together, the available evidence does not support a single cellular substitute for mature astrocytic function. Rather, oligodendrocyte maturation appears to depend on a developmentally changing division of metabolic, homeostatic, and signaling labour across multiple cellular compartments. We propose that glial coupling itself should therefore be considered a developmentally constructed process whose disruption may contribute to white-matter vulnerability in the preterm brain.

Abstract: Childhood overweight and obesity are escalating global health challenges with conse-quences that extend across the life course. This narrative review examines the epide-miology, clinical complications, socioeconomic burden, and management of excess weight in children and adolescents across diverse socioeconomic settings. Evidence was identified through searches of MEDLINE (via PubMed), Scopus, Web of Science, Embase, and the Cochrane Library, supplemented by manual screening of reference lists. The literature indicates that excess adiposity, particularly visceral fat, promotes insulin resistance, hypertension, dyslipidemia, hepatic steatosis, and other early mani-festations of cardiometabolic disease, while also contributing to respiratory, orthope-dic, and psychosocial complications. These risks frequently persist into adulthood, in-creasing premature morbidity, mortality, healthcare utilization, and direct and indi-rect societal costs. The burden is unevenly distributed: poverty, stigma, discrimination, food and built environments, and limited access to preventive and clinical services shape both obesity risk and outcomes, with particularly severe consequences in re-source-constrained settings. Early identification of excess weight and associated risk factors, systematic screening for comorbidities, and timely, family-centered multidis-ciplinary care are therefore essential. Effective prevention and treatment must also address the broader social and commercial determinants of health through coordinat-ed action across healthcare, education, food systems, and public policy.

Abstract: Numerous lines of evidence have previously allowed us to conclude that exposure of susceptible individuals to acetaminophen triggers many if not most cases of autism spectrum disorders (ASD), which have steadily increased in the US since 1980. Reasons for increasing acetaminophen exposure early in life include the switch from aspirin to acetaminophen in the early 1980s, dramatically increased marketing of acetaminophen in the 1990s, the development of acetaminophen use for opioid sparing protocols in response to the opioid crisis of the 2010s, and continued use of acetaminophen for vaccination as the vaccine schedule increased between 1980 and the present time. More recently, two sets of data from the US, one from the California Public School system and another from the NIH-sponsored ECHO study, indicate that the prevalence of autism spectrum disorders (ASD) is increasing dramatically in a manner dependent on low socioeconomic status. Some evidence suggests that a potential adverse drug-drug interaction between acetaminophen and cannabis use disorder may underlie this trend, with an increase in cannabis use disorder resulting from the legalization of recreational cannabis use. Although increasing use of acetaminophen and potentially changing environmental factors that enhance acetaminophen toxicity can explain the sustained rise in ASD, data consistent with the acetaminophen/autism model continue to be misinterpreted by those considered experts in the field, hampering progress. Most errors involve over-correction for mediating factors in large sibling-controlled studies, although more recent data involving socioeconomic-dependent disparities in ASD prevalence have also been misinterpreted.

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Background/Objectives: Pediatric extracorporeal membrane oxygenation (ECMO) exposes blood to surfaces, mechanical forces, and inflammatory perturbations that disrupt hemostatic homeostasis. These effects are superimposed on developmental differences in coagulation, platelet, endothelial, anticoagulant, and fibrinolytic systems. This review proposes the Integrated Hemostatic Network (IHN) as a conceptual framework for understanding ECMO-associated dyshemostasis and precision hemostatic management. Methods: Evidence addressing developmental hemostasis and determinants of ECMO-associated dyshemostasis was synthesized within a framework of blood–circuit interactions, platelet and von Willebrand factor biology, coagulation, anticoagulant pathways, fibrinolysis, endothelial dysfunction, complement, innate immunity, inflammation, hemolysis, and extracellular vesicles. Implications were examined through multimodal monitoring, phenotypic assessment, anticoagulant management, targeted therapy, transfusion stewardship, and circuit optimization. Results: The evidence supports a model in which interconnected mechanisms reshape the hemostatic phenotype during pediatric ECMO. Prothrombotic stimuli may coexist with platelet dysfunction, acquired von Willebrand abnormalities, fibrinogen depletion, altered fibrinolysis, endothelial injury, and anticoagulant effects. Three phenotypes—bleeding-predominant, thrombosis-predominant, and mixed bleeding–thrombotic—provide a framework for assessment and therapeutic reasoning. Multimodal interpretation of anticoagulation assays, viscoelastic testing, platelet and fibrinogen status, biological markers, and patient/circuit findings is preferable to reliance on laboratory targets. Conclusions: Pediatric ECMO-associated dyshemostasis reflects dynamic perturbation of an interconnected IHN, in which mechanical, developmental, cellular, coagulation, endothelial, inflammatory, fibrinolytic, and circuit-related processes interact to shape an evolving hemostatic phenotype. Precision hemostatic management should therefore be phenotype-oriented, mechanism-directed, and dynamically reassessed. The IHN framework provides a conceptual and testable platform for phenotype-adaptive management; prospective multicenter studies are needed to determine whether this approach improves patient-centered outcomes.

Abstract: Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disorder that results from a deficiency of the arylsulfatase A (ARSA) enzyme and leads to progressive neurodegeneration and demyelination. Due to its narrow pre-symptomatic window of opportunity for disease-modifying therapies, the implementation of newborn screening (NBS) for MLD seems crucial and the incorporation of MLD screening into existing NBS programs is required. In many NBS programs, DNA-based assays have already been established, for instance to screen for severe combined immunodeficiency, sickle cell disease, or spinal muscular atrophy. Utilizing these DNA eluates, we established high-multiplex mutation testing (HMMT), a novel DNA-based method, as a genetic first-tier to screen for MLD. By multiplex allele-specific amplification, the assay detects thirteen frequent ARSA variants within the European population identifying newborns with MLD with a modelled, gnomAD-based sensitivity of approximately 92%. Anonymized DNA eluates from 3,078 newborns were tested retrospectively. Variants were identified in nine samples (0.3%) confirmed by an allele-specific differentiation assay and next-generation sequencing. HMMT proved capable to identify frequent ARSA variants as a genetic first-tier test, while panel composition and achievable sensitivity remain to be tested and optimised in a real-world cohort. When biochemical testing cannot be implemented as first tier screening, our approach might be useful to set up as simple screening algorithm for MLD.

Abstract: Background: Pediatric bacterial meningitis remains an important cause of death and long-term neurological disability despite advances in vaccination, antimicrobial therapy, and supportive care. Because host inflammation contributes substantially to secondary neuronal injury, adjunctive cor-ticosteroids have been investigated as a strategy to reduce inflammation-mediated complications. This narrative review aims to critically evaluate the current evidence on corticosteroid therapy in pediatric meningitis, with particular emphasis on acute bacterial meningitis, major clinical and neurological outcomes, treatment timing, pathogen-specific effects, and the impact of changing post-vaccination epidemiology. Methods: A structured search of PubMed/MEDLINE, Scopus, and Web of Science was conducted for relevant publications available up to June 2026. Randomized controlled trials, observational studies, systematic reviews, meta-analyses, and international guide-lines involving patients aged 0–18 years were considered. Evidence was synthesized narratively, focusing on mortality, hearing loss, neurological sequelae, long-term outcomes, safety, causative pathogen, and timing of corticosteroid administration. Results: Adjunctive dexamethasone does not consistently reduce mortality, hospital stay, intensive care utilization, or healthcare costs. Its most reproducible benefit is a reduction in sensorineural hearing loss, particularly in Haemophilus influenzae type b meningitis. Benefits in pneumococcal meningitis are less consistent, while evidence supporting routine use in meningococcal disease remains limited. Efficacy is greatest when dexa-methasone is administered before or with the first antibiotic dose and appears less pronounced in the post-vaccination era. In tuberculous meningitis, corticosteroids improve survival, whereas rou-tine use is not supported in viral or fungal meningitis. Conclusion: Current evidence supports a se-lective, pathogen- and context-specific approach to corticosteroid therapy in pediatric meningitis. Dexamethasone is best regarded as a neuroprotective adjunct, with hearing preservation repre-senting its most consistent clinical benefit.

Abstract: Background: Extraspinal sacrococcygeal ependymoma is a rare pediatric neoplasm that frequently presents as a superficial sacrococcygeal mass, closely resembling benign conditions such as pilonidal disease or cysts. As a result, preoperative diagnosis is often uncorrect, leading to incomplete surgical excision and delayed clinical management. We conducted a comprehensive descriptive review of the pediatric literature to examine its epidemiology, clinical presentation, diagnostic challenges, pathological characteristics, treatment strategies and outcomes. Materials and Methods: A systematic search of PubMed, Scopus, and Web of Science from database inception to June 2026 was conducted. Only English studies reporting histologically confirmed extraspinal sacrococcygeal ependymoma in patients younger than 18 years were included. Discussion: Histologically, the vast majority of extraspinal sacrococcygeal ependymomas are of the myxopapillary subtype. Historically classified as grade 1 tumors by World Health Organization (WHO), they were reclassified as WHO grade 2 in the 2021 WHO Classification of Tumors of the Central Nervous System. This change reflects the rising recognition of the clinically relevant risk of local recurrence and metastatic dissemination of these tumors, despite a relatively indolent growth pattern. Because extraspinal sacrococcygeal ependymomas may recur many years after initial treatment and occasionally metastasize to lymph nodes, lungs, liver, bone, or other distant sites, they should not be considered as entirely benign lesions. Then, their management requires an oncological approach despite their often innocuous clinical appearance. Conclusions: Given the risk of delayed recurrence and distant metastasis, long-term follow-up is mandatory. Increased awareness of this singular entity, appropriate preoperative imaging of atypical sacrococcygeal lesions, and multidisciplinary management are essential to optimize outcomes. Future multicenter collaborative studies are needed to establish evidence-based recommendations for diagnosis, treatment, and surveillance.