Inborn errors of metabolism (IEMs) are a group of genetic diseases that occur due to the either deficiency of an enzyme involved in a metabolic/biochemical pathway or other disturbances in the metabolic pathway including transport protein or activator protein deficiencies, cofactor deficiencies, organelle biogenesis, maturation or trafficking problems. These disorders are collectively significant due to their substantial impact on both the well-being and survival of affected individuals. In the quest for effective treatments, enzyme replacement therapy (ERT) has emerged as a viable strategy for patients with many of the lysosomal storage disorders (LSD) and enzyme substitution therapy in the rare form of the other inborn errors of metabolism including phenylketonuria and hypophosphatasia. However, a major challenge associated with enzyme infusion in patients with these disorders, mainly LSD, is the development of high antibody titres. Strategies focusing on immunomodulation have shown promise in inducing immune tolerance to ERT, leading to improved overall survival rates. The implementation of immunomodulation concurrent with ERT administration has also resulted in a decreased occurrence of IgG antibody development compared with cases treated solely with ERT. By incorporating the knowledge gained from current approaches and analysing the outcomes of immune tolerance induction (ITI) modalities from clinical and preclinical trials have demonstrated significant improvement in the efficacy of ERT. In this comprehensive review, the progress in ITI modalities is assessed, drawing insights from both clinical and preclinical trials. The focus is on evaluating the advancements in ITI within the context of IEM, specifically addressing LSDs managed through ERT.

Although appendicitis has been described for more than 300 years, its optimal management remains a topic of active investigation. Acute appendicitis is the most common cause of peritonitis in children, and rates of perforated appendicitis are much higher in children than in adults. Increased risk for perforated appendicitis in children is related to a delay in diagnosis due to age, size, access to care, and more. Surgical options include immediate appendectomy versus nonoperative management with intravenous antibiotics ± a drainage procedure, with a subsequent interval appendectomy. Microbiota of perforated appendicitis in children most often includes Escherichia coli, Bacteroides fragilis, Streptococcus, and more. Even though the most common organisms are known, there is a large variety of practice when it comes to postoperative antibiotic management in these patients. Studies discuss the benefits of mono- versus dual or triple therapy without a particular consensus regarding what to use. This is reflected across differing practices at various institutions. In this review, we aim to explore the implications of perforated appendicitis in pediatrics, common organisms seen, antibiotic regimen coverage, and the implications of variations of practice. Resistance to commonly used broad-spectrum antibiotics is evolving, therefore minimization of care variability is needed for improved patient outcomes and proper antibiotic stewardship.

In adults, sodium-glucose cotransporter type 2 inhibitors have revolutionised the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease. We aimed to review information on compassionate use, clinical pharmacology, efficacy, and safety of dapagliflozin and empagliflozin in children. We conducted a systematic review of published clinical trials, case reports, and observational studies in Medline, Excerpta Medica, and Web of Science databases from inception to September 2023. For the two randomised controlled trials on type 2 diabetes mellitus (T2DM), we implemented a meta-analysis on the primary outcome (mean difference in glycosylated haemoglobin [HbA1c] between intervention and placebo groups). Review Manager (RevMan), version 5.4.1, was used for this purpose. Thirty-five articles (nine case reports, ten case series, one prospective non-controlled trial, four controlled randomised trials, two surveys, six pharmacokinetic studies, and three pharmacovigilance studies) were selected, in which 415 children were exposed to either dapagliflozin or empagliflozin: 189 diabetic patients (mean age 14.7 ± 2.9 years), 32 children with glycogen storage disease type Ib (GSD Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, or severe congenital neutropenia type 4 (8.5 ± 5.1 years), 47 children with kidney disease or heart failure (11.2 ± 6.1 years), 84 patients in pharmacokinetic studies (15.1 ± 2.3 years), and 63 patients in toxicological series. The effect of dapagliflozin and empagliflozin in T2DM was demonstrated by HbA1c reduction in two randomised trials among a total of 177 adolescents, with a mean HbA1c difference of -0.82% (95% confidence interval -1.34 to -0.29) as compared to placebo (no heterogeneity, I2 = 0%). Dosage ranged between 5 and 20mg (mean 11.4 ± 3.7) once daily for dapagliflozin and between 5 and 25mg (mean 15.4 ± 7.4) once daily for empagliflozin. Among the paediatric cases of GSD Ib, empagliflozin 0.1-1.3mg/kg/day improved neutropenia, infections, and gastrointestinal health. Dapagliflozin (mean dosage 6.9 ± 5.2mg once daily) was well-tolerated in children with chronic kidney disease and heart failure. Side effects were generally mild, the most frequent being hypoglycaemia in children with GSD Ib (33% of patients) or T2DM (14% of patients) on concomitant hypoglycaemic drugs. Diabetic ketoacidosis is rare in children. Early evidence suggests that dapagliflozin and empagliflozin are well tolerated in children. A clinical pharmacology rationale currently exists only for adolescents with diabetes mellitus. CRD42023438162.

Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis of the small bowel and colon and potentially leading to sepsis, peritonitis, perforation, and death. Numerous research efforts have been made to better understand, treat, and prevent NEC. This review explores a variety of factors involved in the pathogenesis of NEC (prematurity, low birth weight, lack of human breast milk exposure, alterations to the microbiota, maternal and environmental factors, and intestinal ischemia) and reports treatment modalities surrounding NEC, including pain medications and common antibiotic combinations, the rationale for these combinations, and recent antibiotic stewardship approaches surrounding NEC treatment. This review also highlights the effect of early antibiotic exposure, infections, proton pump inhibitors (PPIs), and H2 receptor antagonists on the microbiota and how these risk factors can increase the chances of NEC. Finally, modern prevention strategies including the use of human breast milk and standardized feeding regimens are discussed, as well as promising new preventative and treatment options for NEC including probiotics and stem cell therapy.

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066L/h/46.4kg, 0.0055L/h/46.4kg, 0.0081L/h/46.4kg, 0.0029L/h/46.4kg, 0.6750L/46.4kg, and 1.19L/46.4kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

Alopecia areata (AA) lifetime incidence is around 2%, with many patients first experiencing symptoms during childhood. However, ritlecitinib is the only FDA-approved treatment for pediatric patients 12 years and older. This review outlines reported topical, injectable, and oral treatment options for pediatric patients with AA. Clinical studies were obtained via a PubMed search using the following search terms: alopecia areata, areata, universalis, or totalis and medication, therapy, treatment, drug, or management. Only studies with pediatric patients were included in this review. Commonly used therapies, including corticosteroids, methotrexate, and minoxidil, newer promising medications, such as Janus kinase inhibitors, and less frequently used topical and systemic treatments are included. A summary of the drug development pipeline and ongoing interventional clinical trials with pediatric patients is provided. Treatments demonstrate variable efficacy, and many patients require combination therapy for maximal response. More robust clinical data is needed for many of the medications reviewed in order to provide better care for these patients.

Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations.

Juvenile psoriatic arthritis (JPsA) is a heterogeneous type of non-systemic chronic inflammatory arthritis affecting children and young people. This review focuses on highlighting challenges in harmonising recommendations for the use of available therapies in JPsA, according to its distinct clinical phenotypes, and explores the similarities and differences between the disease classification and management across age. We further explore the emerging therapeutic landscape, summarising the recently completed clinical trials in JPsA, and ongoing studies in both JPsA and adults with psoriatic arthritis, highlighting unmet needs and barriers for translational research in JPsA. The novel therapeutic agents in clinical development in JPsA range from monoclonal antibodies targeting interleukin (IL)-17, IL-12/23 and IL-23 blockades to synthetic small molecules targeting Janus kinase and tyrosine kinase and phosphodiesterase-4 inhibition. In addition, there are head-to-head clinical trials comparing tumour necrosis factor-α blockade with both IL-17 and IL-23 inhibition. Most of these new therapies have been tested in adults with psoriatic arthritis and haveadvanced to the phase III stage of drug development or received license for use, suggesting promising signals for efficacy and potentially acceptable safety and tolerability for JPsA. Further translational research in JPsA is required to improve our understanding of the impact of age at onset on treatment efficacy, as well as to provide opportunities for better management of refractory disease and improved long-term outcomes in JPsA, for ultimate patient benefit.

Voriconazole pharmacokinetics are highly variable in pediatricpatients, and the optimal dosage has yet to be determined. The purpose of this study was to describe voriconazole pharmacokinetic and pharmacodynamic targets achieved and evaluate the efficacy and safety of voriconazole for critically ill pediatrics. This is a single-center retrospective study conducted at a pediatric intensive care unit at a tertiary/quaternary hospital. Pediatrics admitted to the pediatric intensive care unit and who received voriconazole for a proven or suspected fungal infection with at least one measured trough concentration were included. The primary outcomes included the percentage of pediatric patients who achieved the pharmacokinetic and pharmacodynamic targets. Secondary outcomes included assessing the correlation between voriconazole trough concentrations and clinical/microbiological outcomes. All statistical analyses were performed using the R statistical software and Microsoft Excel. Multiple logistic regression was used to assess the predictors of both clinical and microbiologic cures. Multiple linear regression was used to determine significant factors associated with trough concentrations. A total of 129 voriconazole trough concentrations were measured from 71 participants at steady state after at least three doses of voriconazole. The mean (± standard deviation) of the first and second trough concentrations were 2.9 (4.2) and 2.3 (3.3) mg/L, respectively. Among the first trough concentrations, only 33.8% were within the therapeutic range (1-5 mg/L), 46.5% were below the therapeutic range, and 19.7% were above the therapeutic range. A clinical cure occurred in 78% of patients, while a microbiologic cure occurred in 80% of patients. Voriconazole trough concentrations vary widely in critically ill pediatric patients and only a third of the patients achieved therapeutic concentrations with initial doses.

Anti-disialoganglioside (anti-GD2) monoclonal antibodies are effective immunotherapeutic drugs for treating neuroblastoma, yet their toxicity spectrum is unclear. This study aimed to assess the toxicity profiles of three anti-GD2 monoclonal antibodies (dinutuximab, dinutuximab β, and naxitamab) in clinical applications by mining and evaluating the adverse drug reaction (ADR) signals from the US Food and Drug Administration Adverse Event Reporting System. Data in the US Food and Drug Administration Adverse Event Reporting System from the time anti-GD2 monoclonal antibodies became available in the market to the first quarter of 2023 were searched. The signals of anti-GD2 monoclonal antibody-associated ADRs were quantified using four types of algorithms, including the reporting odds ratio, the proportional reporting ratio, the combination of the proportional reporting ratio and χ2 statistic method used by the UK Medicines and Healthcare Products Regulatory Agency, and the Bayesian confidence propagation neural network. The ADRs were categorized by System Organ Class based on the Medical Dictionary for Regulatory Activities, and were sorted according to the frequency and signal strength of ADRs. A total of 370 adverse drug event reports with anti-GD2 monoclonal antibodies listed as the 'primary suspected drugs' were identified, with 116 ADR signals detected, of which 22 were not in the drug labels. Among the adverse drug event reports, 276 reports concerned dinutuximab/dinutuximab β as primary suspected drugs with 90 ADR signals, involving 19 System Organ Classes, of which 21 signals were not in the label; 94 adverse drug event reports concerned naxitamab as the primary suspected drug with 26 ADR signals, involving 11 System Organ Classes, of which one was not in the label. For dinutuximab/dinutuximab β-related ADRs, the top five most frequent were "fever", "abdominal pain", "elevated aspartate aminotransferase (AST)", "elevated alanine aminotransferase (ALT)" and "hypotension"; the top five most intensive signals were "hypoalbuminemia", "elevated AST", "capillary leakage syndrome", "hypoxia" and "elevated ALT". For naxitamab-related ADRs, the top five most frequent were "hypotension", "pain", "urticarial", "hypertension" and "rash"; the top five most intensive signals were "hypotension", "urticaria", "hypoxemia", "bronchospasm" and "hypertension". Involved System Organ Classes included "investigations" and "respiratory, thoracic and mediastinal disorders" containing the most types of ADR signals in dinutuximab/dintuximab β-related ADRs and naxitamab-related ADRs, respectively. Our study comprehensively analyzed the toxicity profiles of anti-GD2 monoclonal antibodies and provides an important reference for clinical monitoring and ADR identification of these drugs.