Medicine and Pharmacology

Abstract: Background/Objectives: Rotavirus vaccination reduces severe childhood gastroenteritis, but real-world effectiveness may vary across settings and calendar periods. We estimated the effectiveness of documented complete rotavirus vaccination against laboratory-confirmed rotavirus gastroenteritis and rotavirus-associated hospitalization among children younger than 5 years in Türkiye. Methods: This retrospective test-negative study included children aged 0–59 months who underwent stool rotavirus testing for clinically evaluated acute gastroenteritis at a tertiary hospital between January 2015 and June 2026. Tests occurring within 14 days in the same child were combined into one episode. Cases were rotavirus-positive episodes and controls were rotavirus-negative episodes. Complete vaccination was defined by an institutional record showing completion of the full schedule before the index test. Cluster-robust logistic regression adjusted for age group, sex, treatment setting, calendar year, and test month. Vaccine effectiveness (VE) was calculated as (1−adjusted odds ratio)×100%. Results: The analysis included 2,788 episodes among 2,242 children: 534 rotavirus-positive cases and 2,254 test-negative controls. Complete vaccination was documented in 81 cases (15.2%) and 539 controls (23.9%). Crude VE was 43.1% (95% confidence interval [CI], 26.2%–56.1%). Adjusted VE against laboratory-confirmed rotavirus gastroenteritis was 52.8% (95% CI, 37.6%–64.3%; P<0.001). Among hospitalized episodes, adjusted VE was 57.8% (95% CI, 33.5%–73.2%; P<0.001). Estimates were stable when vaccination completion was required at least 14 days before testing, when only the first episode per child was retained, and with 7- or 30-day episode definitions. Effectiveness varied markedly by calendar period: 15.3% (95% CI, −28.7% to 44.3%) in 2015–2019 and 77.7% (95% CI, 62.3%–86.8%) in 2022–2026. Conclusions: Documented complete rotavirus vaccination was associated with substantially lower odds of laboratory-confirmed rotavirus gastroenteritis and rotavirus-associated hospitalization. The marked period-specific variation indicates that the pooled estimate should be interpreted with attention to changes in epidemiology, testing, healthcare utilization, and residual confounding across the COVID-19 era.

Abstract: Catastrophic antiphospholipid syndrome (CAPS) is a severe form of the antiphospholipid syndrome, a rare autoimmune disease characterized by the presence of antiphospholipid antibodies (APAs) directed against endothelial and plasma proteins in association with recurrent venous and/or arterial thromboembolic events and/or foetal loss. CAPS is marked by small vessel thrombosis, multiorgan failure and a mortality rate of up to 50%. The currently preferred treatment regimen for CAPS includes: anticoagulants, glucocorticosteroids, plasmapheresis with or without intravenous immunoglobulins. Our case of a paediatric CAPS patient is unusual for two reasons: 1) the patient did not suffer from SLE or any other risk factor correlated with increased possibility of thrombosis or CAPS and 2) it is probably the first published case demonstrating successful a remission of CAPS with the immunosuppressant mycophenolate mofetil (MMF) and anti-coagulants. Thus, our case highlights the need for further clinical trials of the effectiveness of new immunosuppressants in the treatment of CAPS and APS.

Abstract: Background: Leigh syndrome is an uncommon mitochondrial neurodegenerative disease resulting from impaired cellular energy production, particularly abnormalities affecting oxidative phosphorylation. Among the nuclear genes implicated in the disorder, SURF1 is a recognized cause of childhood-onset disease and is frequently associated with lesions affecting the brainstem. Objective: This case report presents an unusual clinical phenotype of genetically confirmed SURF1 -related Leigh syndrome, with particular emphasis on ocular dyspraxia and clinically significant disturbances occurring during sleep. Materials and methods: Clinical records from a pediatric patient investigated for a suspected mitochondrial disease were retrospectively examined. The evaluation included neurological assessment, metabolic investigations, electrophysiological studies, serial brain magnetic resonance imaging, and molecular genetic testing. Whole-exome sequencing was performed to establish the underlying genetic diagnosis. Results: A 4-year-and-10-month-old boy was found to carry a homozygous pathogenic variant in SURF1. His clinical course was characterized by progressive motor deterioration, brainstem dysfunction, ocular dyspraxia, and recurrent nocturnal disturbances. Magnetic resonance imaging demonstrated symmetric bilateral abnormalities affecting the brainstem and pyramidal pathways, findings compatible with Leigh syndrome. Lactate levels remained persistently elevated, ranging from 2.7 to 8.6 mmol/L. The coexistence of ocular dyspraxia and prominent sleep-related symptoms represents an uncommon clinical pattern within the SURF1 -related Leigh syndrome spectrum. Conclusion: The present case contributes to the expanding clinical spectrum associated with SURF1 -related Leigh syndrome. It also emphasizes the value of careful assessment of ocular motor function and sleep behavior when evaluating children with suspected mitochondrial disease.

Abstract: Background/Objectives: Feeding difficulties are common during bronchiolitis hospital-ization and may lead to reduced caloric intake. Evidence evaluating the relationship between caloric adequacy and hospital length of stay (LOS) remains limited. We aimed to characterize daily caloric adequacy during bronchiolitis hospitalization and evaluate its relationship with LOS. Methods: An ambispective cohort study including children younger than 2 years hospitalized with non-severe bronchiolitis between 2013 and 2023 was conducted at a tertiary hospital. Daily caloric adequacy was defined as the percentage of caloric goals achieved according to WHO/FAO recommendations. Total caloric intake included formula feeding, breastfeeding, complementary feeding, and intravenous fluids. Breastfeeding intake was estimated using a published probabilistic model. As-sociations between caloric adequacy and LOS were evaluated using Spearman correlation analyses. Results: A total of 613 patients were included, with caloric intake data available for 607. Median LOS was 5 days (IQR 3–7). Lower caloric adequacy during the first days of hospitalization was associated with longer LOS. Hospitalization day 2 showed the strongest early association with LOS (ρ = −0.228; p < 0.001). Patients with LOS >6 days did not achieve ≥80% caloric adequacy until day 3, whereas those with LOS ≥9 days reached this threshold only by day 6. The association remained significant mainly in children younger than 12 months and in those with moderate acute malnutrition at admission. Conclusions: Early caloric adequacy was associated with LOS in children hospitalized with bronchiolitis. Achieving adequate caloric intake during the first 48 hours may represent an important early nutritional target.

Abstract: Newborn screening (NBS) is an essential public health intervention for early detection and secondary prevention of inherited disorders in asymptomatic infants at birth. Advances in this field and the accessibility of new screening methods and therapies in the last decade has surpassed insurmountably Malaysia's national NBS programme that has stagnated. Currently, our nationwide routine screening that is mandatory is limited to only two conditions: glucose-6-phosphate dehydrogenase deficiency and congenital hypothyroidism. While services such as universal newborn hearing and critical congenital heart disease screening are available in many settings, most treatable genetic and metabolic disorders remain unscreened. Consequently, preventable morbidity and mortality from inborn errors of immunity and metabolism, and genetic diseases persist. This position statement reviews the evidence for expanding the national NBS programme in Malaysia, arguing that a modernised, contemporary and pragmatic method is both clinically tenable and morally imperative. By embracing genomic-era advancements, Malaysia can safeguard children's right to an open future, fulfil intergenerational justice, and ensure no infant is left without the opportunity for life-saving care.

Abstract: Nutrition during early life is a critical determinant of long-term health. Preterm birth, affecting approximately 10% of deliveries worldwide, and intrauterine growth re-striction (IUGR) are major perinatal conditions associated with disrupted develop-mental programming. The Developmental Origins of Health and Disease (DOHaD) framework explains how early nutritional and environmental exposures permanently shape adult disease risk. This narrative review synthesizes epidemiological, cohort, animal, and interventional evidence on early nutrition and long-term outcomes in preterm and IUGR infants. Accelerated early growth, particularly after growth re-striction, increases the risk of metabolic syndrome components, including glucose in-tolerance, obesity, hypertension, and dyslipidemia. Preterm birth is independently as-sociated with a 53% higher risk of ischemic heart disease and with increased hyperten-sion, insulin resistance, and hyperlipidemia, whereas IUGR confers overlapping but distinct risks. Underlying mechanisms include epigenetic modification, structural or-gan deficits, hormonal reprogramming, gut-microbiome dysbiosis, and oxidative stress. Preterm infants pose a particular challenge, requiring nutrition that supports survival and neurodevelopment without amplifying later cardio-metabolic risk. The preconception and early postnatal periods, during which human milk, optimal pro-tein-energy balance, long-chain polyunsaturated fatty acids, and human-milk oligo-saccharides act, are pivotal. Individualized, evidence-based feeding strategies are needed to optimize immediate outcomes while limiting lifelong disease susceptibility.

Abstract: Human milk is increasingly recognized not only as a source of nutrition but also as a biological regulator of organ development in preterm infants. Beyond supporting growth, human milk contains a complex array of bioactive components that influence intestinal maturation, immune function, vascular development, and brain development during a critical period of extrauterine adaptation. This narrative review summarizes current evidence regarding the role of human milk in multi-organ development in preterm infants. We review clinical and mechanistic studies demonstrating associations between human milk exposure and reduced risks of necrotizing enterocolitis, late-onset sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity. Particular attention is given to the interconnected gut–immune–lung–retina–brain axis and the biological pathways through which human milk may influence developmental outcomes. We further discuss the importance of early enteral feeding, adequate protein delivery, and human milk–derived fortification in supporting growth quality, lean mass accretion, head growth, and structural brain development. Emerging evidence suggests that nutritional strategies promoting early and sustained human milk exposure may contribute not only to protection from major prematurity-related morbidities but also to improved neurodevelopmental trajectories. By integrating current biological and clinical evidence, this review highlights the role of human milk as a foundation for developmental nutrition in preterm infants and provides a practical perspective for optimizing nutritional care in the neonatal intensive care unit.

Abstract: A 4-year-old nonverbal boy with level 3 autism spectrum disorder and Duchenne muscular dystrophy (DMD) who was receiving chronic prednisone therapy presented to the emergency room with acute appendicitis. The diagnosis was significantly delayed due to atypical pain presentation, a potentially blunted inflammatory response from chronic steroid use, and the absence of classic abdominal examination findings due to DMD. The patient presented with five days of fever, poor oral intake, decreased stool output and behavioral changes. Initial physical examination and evaluation over two emergency department visits failed to establish the diagnosis. By the third visit, the patient exhibited abdominal distension, hypoactive bowel sounds, and bandemia. Computed tomography demonstrated perforated appendicitis with a walled-off abscess. Nonoperative management was unsuccessful, resulting in the development of multiple intra-abdominal abscesses that required percutaneous drainage. Following a 10-day hospitalization, the patient improved and was discharged. He subsequently underwent a scheduled laparoscopic appendectomy two months later, with pathology demonstrating persistent inflammation. This case raises awareness of the atypical presentation of pain in children with autism and the potential for DMD and chronic steroid therapy to mask expected examination findings. These factors should prompt clinicians to maintain a low threshold for advanced imaging when clinical concern is present. It also illustrates that non operative management of perforated appendicitis in immunosuppressed children may have an increased risk of failure.

Abstract: Seizures occur more frequently in the neonatal period than at any other time in life. Seizures and epileptic burden in the neonatal period- is correlated to neurodevelopmental outcomes and overall prognosis. Accurate diagnosis is essential for appropriate management; however, there are many diagnostic dilemmas. Seizures in the neonatal period are difficult to diagnose accurately. Many seizures are electrographic only with no clinical correlates, different kinds of paroxysmal events in neonates may mimic electroclinical seizures, and diagnosis based on clinical phenomena alone may result in inaccuracies . There is no universally accepted definition of a neonatal seizure or neonatal status epilepticus (Conventional EEG (CEEG) is the gold standard for diagnosis of a neonatal seizure. Continuous conventional video EEG monitoring (cVEEG) for 24 to 48 hours may be needed for detecting seizures in those at risk, to monitor therapy and to assess epileptic burden; it is not available for clinical care in most parts of the world . There are many therapeutic challenges in the treatment of seizures in the neonate. Most neonatal seizures are provoked or due to symptomatic aetiology. Genetic, metabolic and structural epilepsies are less frequent causes for neonatal seizures. The treatment paradigm is often similar initially, till a specific aetiology is suspected or identified. When to treat, what to treat with, how much to treat, and how long to treat are still being debated, with no uniform strategy. Early distinction between provoked seizures and neonatal onset epilepsy is important to guide therapy. The emergence of targeted therapies (some quite expensive), while exciting, has added to the therapeutic challenges and inequities associated with management of neonates with seizures. This review addresses many of the diagnostic dilemmas and therapeutic challenges encountered by a clinician in the management of neonates with seizures.

Abstract: Central nervous system (CNS) relapse remains a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Repeated isolated CNS relapse is particularly rare and associated with poor prognosis, while optimal therapeutic strategies remain insufficiently defined. Intensified CNS-directed therapy may improve disease control but is also associated with substantial long-term neurotoxicity and survivorship burden. We present the case of a boy with favourable-risk B-cell ALL who developed two isolated CNS relapses despite good initial response to frontline therapy and absence of classical CNS relapse risk factors. The second relapse was associated with extensive meningeal involvement and optic nerve infiltration. The patient underwent intensive multimodal CNS-directed therapy including repeated intrathecal chemotherapy, liposomal cytarabine administered according to the IntReALL 2010 protocol, cranial irradiation, and allogeneic hematopoietic stem cell transplantation (alloHSCT) from a matched sibling donor. Durable long-term remission was achieved despite the extremely unfavourable prognosis associated with second isolated CNS relapse. Fifteen-year follow-up extending into early adulthood revealed substantial late complications, including epilepsy, transient ischemic attack, optic nerve injury, endocrinopathies, obesity, secondary thyroid malignancy, neurocognitive difficulties, and depression requiring long-term psychiatric and psychological support. The present case illustrates the complex balance between effective CNS disease control and cumulative treatment-related neurotoxicity in paediatric ALL survivors. It also highlights the cumulative CNS injury and long-term survivorship burden associated with repeated CNS relapse and multimodal CNS-directed therapy.

Abstract: Background: Acute kidney injury (AKI) affects 12-40% of critically ill newborns which in-creases mortality risk significantly. Current diagnosis relies on serum creatinine, which rises only after substantial renal damage. Early biomarkers enabling timely intervention are urgently needed for this vulnerable population. Serum cystatin C (sCysC) is a candi-date since it is constantly produced by all nucleated cells. Aim: To investigate sCysC diag-nostic performance for early neonatal AKI detection. Methods: This systematic review fol-lowed PRISMA-DTA guidelines and is registered with PROSPERO (CRD420261302574). We searched four major databases for studies measuring sCysC in neonates (0-28 days) using validated assays, with creatinine-based AKI definitions as the reference standard. Studies were categorized by time-related design as either concurrent diagnostic or early predictive accuracy. The risk of bias was assessed using the QUADAS-2. Results: Fifteen studies involving 53,751 neonates were included. sCysC showed strong early predictive accuracy (AUC 0.670-1.000) and identified AKI 24 hours to 4 days earlier than serum cre-atinine. In the largest cohort (52,333 neonates), sCysC achieved 70% sensitivity and 65% specificity for early AKI detection. Other diagnostic studies reported 85-89% sensitivity and 62-75% specificity (AUC 0.844-0.849). Optimal sCysC cut-offs ranged from 1.25 to 2.87 mg/L. Fourteen studies (93%) had a high risk of bias in at least one domain. Conclusion: Serum cystatin C allows earlier detection of neonatal AKI, offering a 1-4-day advantage over current methods and supporting timely intervention. Implementing standardized as-says and population-specific thresholds is essential for clinical use. This time advantage marks a shift toward preventive neonatal nephrology.

Abstract: Ototoxicity associated with platinum compounds, especially cisplatin, remains one of the most important sequelae of paediatric cancer treatment because it is common, permanent, bilateral and disproportionately affects language, learning, neurodevelopment and quality of life. This review synthesises evidence on pharmacological prevention, early detection through audiological monitoring, biomarkers and genetic risk assessment in children treated for cancer, with particular attention to cisplatin. A structured rapid systematic review using the PRISMA 2020 framework was conducted, including studies, guidelines and regulatory documents relevant to pharmacological prevention, monitoring, biomarkers and pharmacogenomics. Current evidence shows that early detection still relies on serial audiological monitoring; extended high-frequency audiometry and distortion-product otoacoustic emissions may detect cochlear injury earlier than conventional audiometry. Sodium thiosulfate is the only otoprotective drug supported by high-level paediatric clinical evidence, whereas serum biomarkers remain experimental. Genetic susceptibility is biologically plausible and increasingly documented, but does not yet justify routine pharmacogenetic screening. Current risk stratification should therefore remain predominantly clinical, while integrated predictive models combining clinical, audiological, biomarker and genetic data are developed.

Abstract: The rise of multi-drug resistant (MDR) pathogens in the pediatric population represents a significant global health challenge, compounded by a historically stagnant antibiotic pipeline for children. While several novel antibiotics have been approved for adults in recent decades, pediatric labeling often lags due to the complexities of developmental pharmacology and to a certain precautionary prudence in introducing new drugs onto the market for this population. This review explores the landscape of "new" antibiotics, including advanced cephalosporins (ceftaroline, cefiderocol, ceftobiprole), novel beta-lactam/beta-lactamase inhibitor combinations (e.g., ceftazidime/avibactam, meropenem/vaborbactam), and long-acting glycopeptides. We analyze their approval trials, pediatric-specific PK/PD profiles, and the balance between on-label use and evidence-based off-label prescriptions. Furthermore, we emphasize the role of Antimicrobial Stewardship through the "3 Ds" rule and the evolution of Therapeutic Drug Monitoring (TDM) from reactive safety checks to proactive, Model-Informed Precision Dosing (MIPD). Finally, we advocate for a multidisciplinary synergy between pediatricians and pharmacologists as the cornerstone for optimizing outcomes and preserving the efficacy of the future antibiotic pipeline.

Abstract: Chromosome microarray analysis performed on 3,842 patients over 15 years (2009-2024), 92% with developmental disability/autism, yielded a total of 16,138 copy number variants (CNVs) averaging 4.2 per patient and qualified as benign (15,083 or 94%, most of size 11-99 kb), of uncertain significance (VUS, 216 or 1.3%, 0.5-0.75 Mb), or pathogenic (836 or 5.2%, 2-5 Mb). Despite considerable pathogenic-VUS size overlap in the 100kb-20Mb range, pathogenic variants provided diagnoses in 749 patients (20%). This increased to 21% among 2,470 patients (2015-2024) having karyotypes recorded, abnormal in 267 patients (11%) with microarray confirming/clarifying the abnormal karyotype in 187 (7.6%)/55 (2.2%). Diagnoses included 61 known chromosomal syndromes, 55 microdeletion/duplications occurring in 3 or more patients (61 in unique regions) with another 33 in 2 and 86 in 1. The 90 microdeletions averaged 6439 kb in length (chromosomes 6, 8, 17, 22 having most), the 90 microduplications 6895 kb (chromosomes 8, 14, 17, 22, X having most), conferring an average imbalance of 798,000 nucleotides per patient (0.75% of their genome). The demonstrated diagnostic efficacy of chromosome microarray analysis for neurodisabilities including autism, once improved by deep learning analyses of holistic variant-symptom databases, could eventually target predisposed newborns for presymptomatic therapies.

Abstract: Background: Autistic children may follow a qualitatively different trajectory of motor development, with differences in timing, speed and movement accuracy often leading to compensatory strategies later in childhood. Delays in identifying motor difficulties can affect intervention and long-term quality of life. Advances in sensor technology now offer opportunities for seamless collection of movement data during play. Method: “TangiBall”, developed iteratively with autistic children, families and patient groups, and engineered by a university medical device department, is an interactive toy designed to assess motor function. The device consists of a multi-coloured hub with sensor-equipped faceplates and animal-headed insertion jacks that light up and provide auditory rewards when correctly inserted. The system records movement accuracy and speed. This pilot study aimed to: (1) identify motor signatures in pre-school autistic children during play; (2) assess toy acceptability through parent and clinician interviews; and (3) obtain parent and clinician ratings. Results: Five autistic children (mean age 3 years 5 months) and five control children (mean age 4 years) participated. Mean age difference could explain some of the variance. More than 100,000 data points of real-time movement were collected across 5–10-minute sessions. Autistic children showed less controlled insertion and removal movements, greater variability in motor performance, and reduced engagement with the toy. Parents and clinicians rated TangiBall positively. Conclusion: Findings suggest differences in motor control between autistic and non-autistic children. This pilot study presents descriptive findings from a small sample (n = 5 per group). As such, results should be interpreted as exploratory and hypothesis-generating.

Abstract: Background: Acute bronchiolitis is among the most common causes of lower respiratory tract infection in infancy and remains a clinically heterogeneous syndrome. Current international guidelines recommend supportive management and generally discourage routine bronchodilator administration; however, physiological responsiveness may exist in a subset of patients. Tidal breathing analysis (TBA) provides a non-invasive, bedside method for objectively assessing respiratory mechanics and may objectively quantify physiological changes following bronchodilator administration. Case Presentation: We report a 23-month-old boy presenting with severe RSV bronchiolitis-like wheezing illness complicated by acute respiratory failure. Bronchodilator responsiveness was evaluated using predefined TBA parameters before and after inhaled bronchodilator administration. Following treatment, time to peak tidal expiratory flow (tPTEF) increased from 0.17 to 0.33 s (+94%), while the tPTEF/TE ratio increased from 0.12 to 0.27 (+125%). Expiratory time (TE) and total respiratory cycle duration (Ttot) decreased by 12.6% and 5.1%, respectively, whereas tidal volume (VT) and minute ventilation (MV) increased by 12.1% and 18.3%. Peak expiratory flow remained unchanged (0.14 L/s before and after bronchodilator administration). Discussion: To our knowledge, this is among the first reports using bedside TBA to characterize acute bronchodilator responsiveness in severe bronchiolitis-like illness. The improvement in expiratory timing indices, accompanied by shorter expiratory time without changes in peak expiratory flow, is consistent with improved expiratory flow dynamics following bronchodilator administration. These findings support the hypothesis that a bronchodilator-responsive physiological phenotype may exist. Previous studies have demonstrated an association between severe bronchiolitis during infancy and subsequent recurrent wheezing or asthma; however, whether acute bronchodilator responsiveness, measured objectively by TBA, represents a testable hypothesis for future longitudinal studies. Conclusions: This case illustrates the feasibility of bedside TBA for identifying physiological bronchodilator responsiveness in severe bronchiolitis-like illness. Prospective longitudinal studies are warranted to determine whether TBA-defined responsiveness represents an early physiological marker requiring prospective validation and whether such physiological stratification may support individualized follow-up strategies.

Abstract: Congenital colonic stenosis (CCS) is an exceptionally rare gastrointestinal anomaly. It presents with nonspecific clinical symptoms and can mimic other pediatric bowel disorders. We report a 1-year-old girl with a history of prematurity who presented to the emergency department with progressive abdominal distension and vomiting. She had maintained steady growth and age-appropriate weight gain during early infancy because a liquid-based milk diet allowed soft stool to pass through a pinhole-sized narrowing. The transition to solid foods at a corrected age of 9 months produced formed stools, precipitating an acute mechanical large bowel obstruction and precipitous weight loss. A repeat fluoroscopic contrast enema successfully identified a classic, concentric "ring sign" characteristic of structural stenosis, correcting an earlier misinterpreted study. A short-segment resection and primary anastomosis were curative.

Abstract: There remains a clear gap between product development and real-world drug administration, particularly for medicines intended for delivery via enteral feeding tubes (EFTs). While drug formulation and manufacturing quality is often systematically addressed via the Quality by Design (QbD) framework, where the Quality Target Product Profile (QTPP) proactively defines the quality characteristics needed to achieve intended clinical performance at the development stage, considerations related to drug administration quality are generally handled in a reactive manner. Assessment of suitability for administration often occurs only after formulations have been optimised for their primary route, creating a mismatch between product characteristics and administration requirements. In the EFT administration context, this often involves off-label manipulation which leads to risks including drug loss, tube occlusion, as well as patient and caregiver burden. In response to the need for a comprehensive framework for translating administration needs into measurable quality attributes, risk assessments, and control strategies, this paper introduces QTAP using enteral feeding tube medications as an exemplar of complex administration requiring rigorous quality design. QTAP is positioned not as a replacement for QTPP but as a lens focusing on the administration element. The QTAP framework is described as a three-step process that begins with characterisation of the administration context and ends with identification of the Critical Administration Attributes (CAAs) that require control. It is then applied to representative EFT administration scenarios to demonstrate how administration quality varies across dosage forms. Integration of QTAP into pharmaceutical development would enable administration quality to be proactively designed, measured, and controlled within existing QbD workflows.

Abstract: Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of neonatal mortality and long-term neurodevelopmental disability despite therapeutic hypothermia, which provides only partial neuroprotection. Among adjunctive therapies, magnesium sulphate (MgSO4) has emerged as one of the most biologically plausible neuroprotective agents because of its ability to modulate glutamate-mediated excitotox-icity, intracellular calcium influx, oxidative stress, neuroinflammation and apoptotic pathways. Nevertheless, encouraging molecular and preclinical findings have not translated into consistent clinical benefit. This narrative review critically examines the translational gap between the molecular mechanisms of magnesium sulphate and its clinical performance in neonatal HIE. Evi-dence from experimental models, clinical studies and recent meta-analyses was integrated to identify the biological and methodological factors potentially responsible for this dis-crepancy. We discuss the evolving pathophysiology of HIE across the primary, latent, secondary and tertiary phases of brain injury and analyse how the timing of intervention, lesion heterogeneity and inadequate biological stratification may influence therapeutic responsiveness. Current clinical research has largely evaluated broad neurological outcomes, particularly cerebral palsy, despite the heterogeneous neuropathological substrates underlying ne-onatal brain injury. We argue that this strategy may dilute genuine treatment effects by grouping together distinct lesion phenotypes with different biological mechanisms. Accordingly, we propose the **Neuroprotection per Effective Therapy (NET)** framework, a conceptual translational model integrating molecular targets, experimental evidence, MRI-defined lesion phenotypes, methodological quality and advanced statistical ap-proaches to improve patient stratification and outcome selection. Rather than questioning the biological efficacy of magnesium sulphate itself, this review suggests that future progress will depend on aligning molecular mechanisms with clinically meaningful phenotypes. Precision-based translational strategies may ultimately allow magnesium sulphate and other neuroprotective therapies to demonstrate their true therapeutic potential in neonatal HIE.

Abstract: Background Cow's milk-derived fortifiers (CMDFs) are widely used to improve the nutritional adequacy of human milk for very preterm infants. Although generally well tolerated, some infants develop feeding intolerance. Identifying these infants may facilitate more individualized nutritional strategies. Objective To identify clinical characteristics associated with adverse feeding events following CMDF use in infants receiving donor human milk (DHM) and to identify infants who may derive greater benefit from an exclusive human milk diet (EHMD). Methods This retrospective nationwide cohort study used the Japanese Human Milk Bank Database. Infants receiving DHM followed by CMDF were included. Clinical characteristics were compared between infants with and without adverse feeding events. Multivariable logistic regression analysis identified independent risk factors. Results Among 2,587 infants receiving DHM followed by CMDF, 2,476 had complete data. Adverse feeding events occurred in 315 infants (12.7%), most commonly abdominal distension, increased gastric residuals, vomiting, and suspected cow's milk protein allergy. Infants with adverse feeding events had lower gestational age and birth weight and required longer to reach an enteral feeding volume of 100 mL/kg/day. After adjustment, only delayed achievement of 100 mL/kg/day remained independently associated with adverse feeding events. Routine clinical variables showed limited predictive ability (AUC 0.611). Conclusions Most preterm infants tolerate CMDF well. However, infants with delayed progression to enteral feeding may derive additional benefit from EHMD. These findings support preferential use of EHMD in selected high-risk infants while complementing its established benefits in reducing major neonatal morbidities.