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Infectious diseases are the leading cause of death in infants and children under 5 years of age. In utero exposure to viruses can lead to spontaneous abortion, preterm birth, congenital abnormalities or other developmental defects, often resulting in lifelong health sequalae. The underlying biological mechanisms are difficult to study in humans due to ethical concerns and limited sample access. Nonhuman primates (NHP) are closely related to humans, and pregnancy and immune ontogeny in infants are very similar to humans. Therefore, NHP are a highly relevant model for understanding fetal and postnatal virus-host interactions and to define immune mechanisms associated with increased morbidity and mortality in infants. We will discuss NHP models of viruses causing congenital infections, respiratory diseases in early life, and HIV. Cytomegalovirus (CMV) remains the most common cause of congenital defects worldwide. Measles is a vaccine-preventable disease, yet measles cases are resurging. Zika is an example of an emerging arbovirus with devastating consequences for the developing fetus and the surviving infant. Among the respiratory viruses, we will discuss influenza and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We will finish with HIV as an example of a lifelong infection without a cure or vaccine. The review will highlight (i) the impact of viral infections on fetal and infant immune development, (ii) how differences in infant and adult immune responses to infection alter disease outcome, and emphasize the invaluable contribution of pediatric NHP infection models to the design of effective treatment and prevention strategies, including vaccines, for human infants. [ABSTRACT FROM AUTHOR]

Background: Pediatric chronic kidney disease (CKD) requires reliable biomarkers for early detection and monitoring. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a potential marker due to its responsiveness to renal impairment and involvement in mineral metabolism. Objectives: To evaluate serum NGAL levels in pediatric CKD patients and explore correlations with estimated glomerular filtration rate (eGFR), ferritin, calcium-phosphorus (Ca*P) product, and total serum protein. Methods: A cross-sectional study included 54 pediatric CKD patients and 29 healthy controls. Laboratory assessments encompassed serum NGAL, creatinine, ferritin, calcium, phosphorus, and total serum protein. eGFR was calculated using the Schwartz formula. Pearson correlation and linear regression analyses determined associations between NGAL and other parameters. Results: NGAL levels were significantly higher in CKD patients compared to controls (median 453 ng/mL vs. 78 ng/mL, p < 0.001). A strong negative correlation existed between NGAL and eGFR (r = –0.81, p < 0.001). NGAL showed moderate positive correlations with ferritin (r = 0.56, p = 0.009) and CaP product (r = 0.57, p = 0.006) and a moderate negative correlation with total serum protein (r = –0.36, p = 0.225). Regression analysis confirmed NGAL as a significant predictor of eGFR, ferritin, and CaP product. Conclusions: Elevated serum NGAL levels are associated with decreased renal function and alterations in mineral metabolism in pediatric CKD patients. NGAL may serve as a valuable biomarker for assessing disease progression and guiding clinical management in this population. [ABSTRACT FROM AUTHOR]

Background: Pediatric chronic kidney disease (CKD) requires reliable biomarkers for early detection and monitoring. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a potential marker due to its responsiveness to renal impairment and involvement in mineral metabolism. Objectives: To evaluate serum NGAL levels in pediatric CKD patients and explore correlations with estimated glomerular filtration rate (eGFR), ferritin, calcium-phosphorus (Ca*P) product, and total serum protein. Methods: A cross-sectional study included 54 pediatric CKD patients and 29 healthy controls. Laboratory assessments encompassed serum NGAL, creatinine, ferritin, calcium, phosphorus, and total serum protein. eGFR was calculated using the Schwartz formula. Pearson correlation and linear regression analyses determined associations between NGAL and other parameters. Results: NGAL levels were significantly higher in CKD patients compared to controls (median 453 ng/mL vs. 78 ng/mL, p < 0.001). A strong negative correlation existed between NGAL and eGFR (r = –0.81, p < 0.001). NGAL showed moderate positive correlations with ferritin (r = 0.56, p = 0.009) and CaP product (r = 0.57, p = 0.006) and a moderate negative correlation with total serum protein (r = –0.36, p = 0.225). Regression analysis confirmed NGAL as a significant predictor of eGFR, ferritin, and CaP product. Conclusions: Elevated serum NGAL levels are associated with decreased renal function and alterations in mineral metabolism in pediatric CKD patients. NGAL may serve as a valuable biomarker for assessing disease progression and guiding clinical management in this population.

In 2020, the top 10 causes of death among children and adolescents between the ages of 1 and 19 years old included cancer, congenital anomalies, heart disease, and chronic respiratory disease; all these conditions are potentially treatable with medical intervention. However, children exhibit specific physiological and developmental characteristics that can significantly impact drug pharmacokinetics, pharmacodynamics, and safety profile. These factors illustrate the importance of a heightened focus on pediatric drug development. Traditional drugs lack proper circulation, permeability, targeting, accumulation, and release, and they often require dose adjustments or modifications, which can result in suboptimal therapeutic outcomes and increased risks of adverse effects in pediatric patients. Nanomedicines have emerged as efficient drug delivery systems because of their unique properties, which can improve the solubility and stability of drugs by encapsulating them in different forms of nanoparticles. This review discusses the challenges of pediatric therapy, and the current state of nanomedicines for pediatric diseases in terms of Food and Drug Administration‐approved nanomedicines, the types of diseases treated or diagnosed, and preclinical studies that have the potential to be translated to the clinic. In summary, nanomedicine holds significant potential for addressing the unique and pressing challenges associated with diagnosing and treating pediatric diseases. [ABSTRACT FROM AUTHOR]

Background and Objectives: Recognizing the crucial gaps in our understanding of pediatric pneumonia post-SARS-CoV-2 infection, this study aimed to assess the relationship between Pediatric Pneumonia Ultrasound Scores (PedPne) and inflammatory biomarkers. The primary objective of this study is to evaluate the predictive value of PedPne in comparison with inflammatory biomarkers (IL-6 and dNLR) for the development of pneumonia in pediatric patients following SARS-CoV-2 infection. Materials and Methods: This longitudinal observational study collected data from pediatric patients diagnosed with pneumonia after an acute SARS-CoV2 infection. The study focused on analyzing changes in PedPne scores and inflammatory markers such as IL-6 and dNLR from initial admission to follow-up at 7 days. Statistical analysis involved calculating the sensitivity, specificity, and Area Under the Curve (AUC) for each biomarker, alongside regression analysis to determine their hazard ratios for predicting pneumonia development. Results: The analysis identified significant cutoff values for dNLR at 1.88 (sensitivity 77.0%, specificity 85.7%, AUC 0.802, p < 0.001), IL-6 at 6.1 pg/mL (sensitivity 70.3%, specificity 92.9%, AUC 0.869, p < 0.001), and PedPne score at 3.3 (sensitivity 75.7%, specificity 78.6%, AUC 0.794, p < 0.001). Conversely, NLR showed lower diagnostic performance (AUC 0.485, p = 0.327). Regression analysis further highlighted the strong predictive power of these markers, with IL-6 showing a fourfold increase in pneumonia risk (HR = 4.25, CI: 2.07–9.53, p < 0.001), dNLR indicating more than a twofold increase (HR = 2.53, CI: 1.19–6.97, p = 0.006), and PedPne score associated with more than a doubling of the risk (HR = 2.60, CI: 1.33–5.18, p < 0.001). Conclusions: The study conclusively demonstrated that both PedPne ultrasound scores and specific inflammatory biomarkers such as dNLR and IL-6 are significant predictors of pneumonia development in pediatric patients post-COVID-19 infection. These findings advocate for the integration of these biomarkers in routine clinical assessments to enhance the diagnostic accuracy and management of pneumonia in children following SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Infectious diseases are the leading cause of death in infants and children under 5 years of age. In utero exposure to viruses can lead to spontaneous abortion, preterm birth, congenital abnormalities or other developmental defects, often resulting in lifelong health sequalae. The underlying biological mechanisms are difficult to study in humans due to ethical concerns and limited sample access. Nonhuman primates (NHP) are closely related to humans, and pregnancy and immune ontogeny in infants are very similar to humans. Therefore, NHP are a highly relevant model for understanding fetal and postnatal virus-host interactions and to define immune mechanisms associated with increased morbidity and mortality in infants. We will discuss NHP models of viruses causing congenital infections, respiratory diseases in early life, and HIV. Cytomegalovirus (CMV) remains the most common cause of congenital defects worldwide. Measles is a vaccine-preventable disease, yet measles cases are resurging. Zika is an example of an emerging arbovirus with devastating consequences for the developing fetus and the surviving infant. Among the respiratory viruses, we will discuss influenza and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We will finish with HIV as an example of a lifelong infection without a cure or vaccine. The review will highlight (i) the impact of viral infections on fetal and infant immune development, (ii) how differences in infant and adult immune responses to infection alter disease outcome, and emphasize the invaluable contribution of pediatric NHP infection models to the design of effective treatment and prevention strategies, including vaccines, for human infants.

Background Respiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection. Methods Tracheobronchial aspirates and blood samples were collected from control patients (n = 9) and those infected with RSV (n = 14) who were admitted to the pediatric intensive care unit. Monocytes (CD14+) were sorted and analyzed by RNA sequencing for transcriptomic profiling. Results Peripheral blood and airway monocytes of patients with RSV demonstrated increased expression of antiviral and interferon-responsive genes as compared with controls. Cytokine signaling showed a shared response between blood and airway monocytes while displaying responses that were more pronounced according to the tissue of origin. Airway monocytes upregulated additional genes related to migration and inflammation. Conclusions We found that the RSV-induced interferon response extends from the airways to the peripheral blood. Moreover, RSV induces a migration-promoting transcriptional program in monocytes. Unraveling the monocytic response and its role in the immune response to RSV infection could help the development of therapeutics to prevent severe disease. [ABSTRACT FROM AUTHOR]

Human interleukin‐5 (IL‐5) cytokine mediates the development of eosinophils and is involved in a variety of immune inflammatory responses that play a major role in the pathogenesis of childhood asthma, leukemia, and other pediatric allergic diseases. The immunomodulatory cytokine functions by binding to its cognate cell surface receptor IL‐5R in a sheet‐by‐sheet manner, which can be conformationally mimicked and competitively disrupted by a double‐stranded cyclic AF18748 peptide. In this study, we systematically examined the co‐crystallized complex structure of human IL‐5R with AF18748 peptide and rationally designed a halogen bond to glue at the protein–peptide complex interface by substituting the indole moiety of AF18748 Trp13 residue with a halogen atom (X = F, Cl, Br, or I). High‐level theoretical calculations imparted presence of the halogen bond between the oxygen atom (O) of IL‐5R Glu58 backbone and the halogen atom (X) of AF18748 Trp13 side chain. Experimental assays confirmed that the halogen bond can promote peptide binding moderately or considerably. More importantly, the halogen bond not only enhances peptide affinity to IL‐5R, but also improves peptide selectivity for its cognate IL‐5R over other noncognate IL‐R proteins. As might be expected, the affinity and selectivity conferred by halogen bond increase consistently in the order: H < F < Cl < Br < I. Structural modeling revealed that the halogen bond plus its vicinal π–cation–π stacking co‐define a ringed noncovalent system at the complex interface, which involves a synergistic effect to effectively improve the peptide binding potency and recognition specificity. [ABSTRACT FROM AUTHOR]

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions.

Background and Objectives: Recognizing the crucial gaps in our understanding of pediatric pneumonia post-SARS-CoV-2 infection, this study aimed to assess the relationship between Pediatric Pneumonia Ultrasound Scores (PedPne) and inflammatory biomarkers. The primary objective of this study is to evaluate the predictive value of PedPne in comparison with inflammatory biomarkers (IL-6 and dNLR) for the development of pneumonia in pediatric patients following SARS-CoV-2 infection. Materials and Methods: This longitudinal observational study collected data from pediatric patients diagnosed with pneumonia after an acute SARS-CoV2 infection. The study focused on analyzing changes in PedPne scores and inflammatory markers such as IL-6 and dNLR from initial admission to follow-up at 7 days. Statistical analysis involved calculating the sensitivity, specificity, and Area Under the Curve (AUC) for each biomarker, alongside regression analysis to determine their hazard ratios for predicting pneumonia development. Results: The analysis identified significant cutoff values for dNLR at 1.88 (sensitivity 77.0%, specificity 85.7%, AUC 0.802, p < 0.001), IL-6 at 6.1 pg/mL (sensitivity 70.3%, specificity 92.9%, AUC 0.869, p < 0.001), and PedPne score at 3.3 (sensitivity 75.7%, specificity 78.6%, AUC 0.794, p < 0.001). Conversely, NLR showed lower diagnostic performance (AUC 0.485, p = 0.327). Regression analysis further highlighted the strong predictive power of these markers, with IL-6 showing a fourfold increase in pneumonia risk (HR = 4.25, CI: 2.07–9.53, p < 0.001), dNLR indicating more than a twofold increase (HR = 2.53, CI: 1.19–6.97, p = 0.006), and PedPne score associated with more than a doubling of the risk (HR = 2.60, CI: 1.33–5.18, p < 0.001). Conclusions: The study conclusively demonstrated that both PedPne ultrasound scores and specific inflammatory biomarkers such as dNLR and IL-6 are significant predictors of pneumonia development in pediatric patients post-COVID-19 infection. These findings advocate for the integration of these biomarkers in routine clinical assessments to enhance the diagnostic accuracy and management of pneumonia in children following SARS-CoV-2 infection.

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high‐dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(−/−) mouse model of LS. While the dose–response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony‐stimulating Factor 1 receptor (CSF1R) macrophage super‐enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(−/−) animals, but onset of CNS lesions and sequalae in the Ndufs4(−/−), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(−/−) model. [ABSTRACT FROM AUTHOR]

Human orthopneumovirus (OPV) is a common respiratory virus that mostly causes respiratory illness in children. Development of therapeutic strategies to treat OPV infection has attracted considerable interest in the medicinal and biological communities. Over the past decades, significant effects have been addressed on disrupting membrane fusion events by targeting viral fusogenic glycoprotein (F-protein) with chemical small-molecule fusion inhibitors. Here, we focus on the rational design of biologic peptide inhibitors to disrupt the peptide-mediated interaction (PMI) between phosphoprotein (P-protein) and nucleoprotein (N-protein) involved in OPV genomic ribonucleoprotein complex. It is revealed that the core 9-mer peptide segment (C-peptide) derived from the C-terminal tail of P-protein is intrinsically disordered in an unbound state but would be structured into an ordered helical conformation when bound to N-protein, representing a biophysical process known as coupled folding-upon-binding. We demonstrated that the process is a compromise between the favorable enthalpy contribution and unfavorable entropy penalty, thus rendering the weak and transient nature of PMI, which could therefore be readily disrupted by competitive agents. Hydrocarbon stapling strategy was used to constrain the helical conformation of C-peptide in an unbound state by chemically introducing an all-hydrocarbon bridge spanning two [ i , i + 4 ] residues of C-peptide. The stapling is observed to considerably enhance the helical propensity of peptide in an unbound state and to effectively improve the binding affinity of peptide to N-protein. Structural modeling analysis suggests that the stapled counterparts can bind to the active site of N-protein in a similar mode with unstapled C-peptide, where the stapled peptide is folded into a helical-like conformation, its anchor residue Phe241 deeply roots in a small druggable pocket of the active site, and the all-hydrocarbon bridge, as designed, is out of N–C complex interface to avoid disrupting the complex interaction. The peptide-mediated interaction between OPV P-protein and N-protein is investigated systematically at structural, energetic and dynamic levels. A C-peptide is derived from the C-terminal tail of P-protein, which exhibits decreased disorder in free state and increased affinity to N-protein upon hydrocarbon stapling. [ABSTRACT FROM AUTHOR]

AIM: To observe the surgical effects of slanted bilateral lateral recession (S-BLR) versus conventional bilateral lateral recession (C-BLR) in convergence insufficiency intermittent exotropia (CI-IXT). METHODS: Using a randomized, double-blind, prospective design, 22 patients with CI-IXT who were admitted to Renmin Hospital of Wuhan University from July 2019 to December 2020 were included. Patients were randomly divided into either S-BLR or C-BLR group for their subsequent strabismus surgery. All patients were followed up for 12mo. Near deviation, distant deviation, and near-distance difference (NDD) were measured in all patients. RESULTS: Twelve months after surgery, NDD improvement was 10 (8, 13) prismatic degrees (PD) in S-BLR group and 3 (1, 6) PD in C-BLR group (P=0.011). The near deviation of S-BLR group was 0 (-2, 2) PD, while that of C-BLR group was -4 (-6, -3) PD (P=0.005). Before and after surgery, the difference in the distant deviation between the two groups was not statistically significant. There was no statistically significant difference in near stereopsis between the two groups (P=0.380) at 12mo. The success rate at 12mo after operation was 90.91% and 72.73% in the two groups (P=0.280). CONCLUSION: CI-IXT patients treated with S-BLR have better surgical outcomes than those treated with C-BLR, which indicates S-BLR is a safe and effective operation pattern.

BackgroundBurkholderia cepacia (B. cepacia) is an emerging pathogen of nosocomial infection in pediatric patient carrying cystic fibrosis. The clinical diagnosis and treatment of B. cepacia infection remains poorly studied. This study outlined the risk factors, antimicrobial susceptibility, and clinical characteristics aiming to improve the treatment of B. cepacia infection.MethodsA retrospective study was conducted based on the 50 cases infection caused by B. cepacia in children without cystic fibrosis, which were diagnosed in the First Affiliated Hospital of Xiamen University, from January 1st, 2011 to December 31st, 2021.ResultsA total of 50 children were infected with B. cepacia, of whom 68% had an underlying health condition, such as cardiovascular disease (23.5%), respiratory disease (17.6%), nervous system disease (14.7%), and neoplastic disease (14.7%). At the onset of B. cepacia infection, 42 (84%) pediatric patients were in an intensive care unit (ICU), 33 (66%) underwent endotracheal intubation, and 32 (64%) had a central venous catheter (CVC). In addition, hospital-acquired cases were 46 (92%), and healthcare-acquired cases were 4 (12%). The most common infectious sites of B. cepacia were the respiratory tract (68%), followed by the blood (20%), and the urinary tract (12%). It indicated that B. cepacia was the most sensitive to ceftazidime (95.65%), followed by trimethoprim-sulfamethoxazole (88.68%), meropenem (82.98%), cefepime (77.78%), and levofloxacin (55.85%). The drug resistance rate of piperacillin-tazobactam, minocycline, aztreonam, cefoperazone-sulbactam and ceftriaxone was higher than 55%. 38 cases were cured or improved, eight had treatment terminated, and four died.ConclusionB. cepacia is an opportunistic pathogen normally found in immunocompromised pediatric patients and highly likely to lead to drug resistance. Nosocomial B. cepacia infections occurred mostly in patients in the ICU based on our observations. The surveillance of B. cepacia infections including changing epidemiology and increasing resistance of the microorganism is still very important. Treatment with effective antibiotics such as ceftazidime, meropenem, trimethoprim-sulfamethoxazole is associated with a favorable prognosis.

Gene therapy using adeno-associated virus (AAV) is a rapidly developing technology with widespread treatment potential. AAV2 vectors injected directly into the brain by stereotaxic brain surgery have shown good results in treating aromatic l- amino acid decarboxylase deficiency. Moreover, gene therapy using the AAV9 vector, which crosses the blood–brain barrier, has been performed in more than 2000 patients worldwide as a disease-modifying therapy for spinal muscular atrophy. AAV vectors have been applied to the development of gene therapies for various pediatric diseases. Gene therapy trials for hemophilia and ornithine transcarbamylase deficiency are underway. Clinical trials are planned for glucose transporter I deficiency, Niemann-Pick disease type C, and spinocerebellar ataxia type 1. The genome of AAV vectors is located in the episome and is rarely integrated into chromosomes, making the vectors safe. However, serious adverse events such as hepatic failure and thrombotic microangiopathy have been reported, and ongoing studies are focusing on developing more efficient vectors to reduce required dosages. [ABSTRACT FROM AUTHOR]

To determine molecular epidemiology and clinical features of enterovirus D68 (EV-D68) infections, we reviewed EV-D68–associated respiratory cases at a hospital in Barcelona, Spain, during 2014–2021. Respiratory samples were collected from hospitalized patients or outpatients with symptoms of acute respiratory tract infection or suggestive of enterovirus infection. Enterovirus detection was performed by real-time multiplex reverse transcription PCR and characterization by phylogenetic analysis of the partial viral protein 1 coding region sequences. From 184 patients with EV-D68 infection, circulating subclades were B3 (80%), D1 (17%), B2 (1%), and A (

Gene therapy using adeno-associated virus (AAV) is a rapidly developing technology with widespread treatment potential. AAV2 vectors injected directly into the brain by stereotaxic brain surgery have shown good results in treating aromatic l-amino acid decarboxylase deficiency. Moreover, gene therapy using the AAV9 vector, which crosses the blood–brain barrier, has been performed in more than 2000 patients worldwide as a disease-modifying therapy for spinal muscular atrophy. AAV vectors have been applied to the development of gene therapies for various pediatric diseases. Gene therapy trials for hemophilia and ornithine transcarbamylase deficiency are underway. Clinical trials are planned for glucose transporter I deficiency, Niemann-Pick disease type C, and spinocerebellar ataxia type 1. The genome of AAV vectors is located in the episome and is rarely integrated into chromosomes, making the vectors safe. However, serious adverse events such as hepatic failure and thrombotic microangiopathy have been reported, and ongoing studies are focusing on developing more efficient vectors to reduce required dosages.

Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene ( ACTA2 ) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutation ACTA2 R179H. In a first-in-kind approach, we performed mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the R179H sequence. To directly correct the R179H mutation, we screened dozens of configurations of base editors (comprised of Cas9 enzymes, deaminases, and gRNAs) to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We then created a murine model of MSMDS that exhibits phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this base editing strategy. Delivery of the customized base editor via an engineered SMC-tropic adeno-associated virus (AAV-PR) vector substantially prolonged survival and rescued systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta, and brain. Together, our optimization of a customized base editor highlights how bespoke CRISPR-Cas enzymes can enhance on-target correction while minimizing bystander edits, culminating in a precise editing approach that may enable a long-lasting treatment for patients with MSMDS., Competing Interests: Competing interests C.L.C., R.M., C.A.M., D.Y.C., B.P.K., M.E.L., and P.L.M. are inventors on a patent application filed by Mass General Brigham (MGB) that describes the development of genome editing technologies to treat MSMDS. C.R.R.A, R.A.S., J.F.dS., and B.P.K. are inventors on additional patents or patent applications filed by MGB that describe genome engineering technologies. S.Q.T. is an inventor on a patent covering CHANGE-seq. S.Q.T. is a member of the scientific advisory board of Prime Medicine and Ensoma. R.M., D.Y.C., C.A.M., B.P.K., M.E.L., and P.M.M received sponsored research support from Angea Biotherapeutics, a company developing gene therapies for vasculopathies. R.M. receives research funding from Amgen and serves as a consultant for Pharmacosmos, Myokardia/BMS, Renovacor, Epizon Pharma, and Third Pole and performs speaker bureaus through Vox Media, all of which are unrelated to the current work. C.A.M. has financial interests in Chameleon Biosciences, Skylark Bio, and Sphere Gene Therapeutics, companies developing Adeno Associated Virus (AAV) vector technologies for gene therapy applications. C.A.M. performs paid consulting work for all three companies. C.A.M.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. B.P.K. is a consultant for EcoR1 capital, Novartis Venture Fund, and Jumble Therapeutics, and is on the scientific advisory boards of Acrigen Biosciences, Life Edit Therapeutics, and Prime Medicine. B.P.K. has a financial interest in Prime Medicine, Inc., a company developing therapeutic CRISPR-Cas technologies for gene editing. B.P.K.’s interests were reviewed and are managed by MGH and MGB in accordance with their conflict-of-interest policies. The other authors declare no competing interests.

The incidence of Obstructive Sleep Apnea Syndrome (OSAS) in the pediatric population is about 2%. The diagnosis is based on the employment of questionnaires, and polysomnography (PSG) that is the gold standard also among children. The PSG allows to classify OSAS as mild in case of 1< Apnea Hypopnea Index (AHI) ≤5, moderate if 5< AHI ≤10 and severe OSAS when the AHI is >10. If polysomnography is not available, we need alternative diagnostic tests such as nocturnal oximetry studies and respiratory polygraphy. The risk factors identified are different from adults, first tonsillar hypertrophy wins over others. The symptoms and signs described are similar to adult population, but sleep enuresis, neurocognitive impairment and behavioral problems (attention-deficit/hyperactivity disorder, learning problems) are typical of pediatric OSAS.

To determine molecular epidemiology and clinical features of enterovirus D68 (EV-D68) infections, we reviewed EV-D68-associated respiratory cases at a hospital in Barcelona, Spain, during 2014-2021. Respiratory samples were collected from hospitalized patients or outpatients with symptoms of acute respiratory tract infection or suggestive of enterovirus infection. Enterovirus detection was performed by real-time multiplex reverse transcription PCR and characterization by phylogenetic analysis of the partial viral protein 1 coding region sequences. From 184 patients with EV-D68 infection, circulating subclades were B3 (80%), D1 (17%), B2 (1%), and A (<1%); clade proportions shifted over time. EV-D68 was detected mostly in children (86%) and biennially (2016, 2018, 2021). In patients <16 years of age, the most common sign/symptom was lower respiratory tract infection, for which 11.8% required pediatric intensive care unit admission and 2.3% required invasive mechanical ventilation; neurologic complications developed in 1. The potential neurotropism indicates that enterovirus surveillance should be mandatory. [ABSTRACT FROM AUTHOR]

Hereditary multiple exostosis (HME) is a rare skeletal genetic disorder with multiple and disseminated osteochondromas. Costal localization is found in 40% of cases. Surgery for asymptomatic lesions remains controversial, but some lesions can be life-threatening. We report the case of a 10-year-old girl with HME, who developed a sharp costal exostosis compressing the hepatic parenchyma, for which a prophylactic resection was decided. The complete excision of the lesion was performed through extraperitoneal approach under video-assisted laparoscopy control, without short- and mid-term complication. To our knowledge, our case is the first in the literature where exostosis threatens the hepatic parenchyma.

Diseases that affect the Central Nervous System (CNS) are one of the most exciting challenges of recent years, as they are ubiquitous and affect all ages. Although these disorders show different etiologies, all treatments share the same difficulty represented by the Blood-Brain Barrier (BBB). This barrier acts as a protective system of the delicate cerebral microenvironment, isolating it and making extremely arduous delivering drugs to the brain. To overtake the obstacles provided by the BBB it is essential to explore the changes that affect it, to understand how to exploit these findings in the study and design of innovative brain targeted formulations. Interestingly, the concept of age-related targeting could prove to be a winning choice, as it allows to consider the type of treatment according to the different needs and peculiarities depending on the disease and the age of onset. In this review was considered the prospective contribution of lipid-based formulations, namely Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), which have been highlighted as able to overcome some limitations of other innovative approaches, thus representing a promising strategy for the non-invasive specific treatment of CNS-related diseases. [ABSTRACT FROM AUTHOR]

In 2020, the top 10 causes of death among children and adolescents between the ages of 1 and 19 years old included cancer, congenital anomalies, heart disease, and chronic respiratory disease; all these conditions are potentially treatable with medical intervention. However, children exhibit specific physiological and developmental characteristics that can significantly impact drug pharmacokinetics, pharmacodynamics, and safety profile. These factors illustrate the importance of a heightened focus on pediatric drug development. Traditional drugs lack proper circulation, permeability, targeting, accumulation, and release, and they often require dose adjustments or modifications, which can result in suboptimal therapeutic outcomes and increased risks of adverse effects in pediatric patients. Nanomedicines have emerged as efficient drug delivery systems because of their unique properties, which can improve the solubility and stability of drugs by encapsulating them in different forms of nanoparticles. This review discusses the challenges of pediatric therapy, and the current state of nanomedicines for pediatric diseases in terms of Food and Drug Administration-approved nanomedicines, the types of diseases treated or diagnosed, and preclinical studies that have the potential to be translated to the clinic. In summary, nanomedicine holds significant potential for addressing the unique and pressing challenges associated with diagnosing and treating pediatric diseases., (© 2024 The Author(s). WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Carcinomas evade the host immune system by negatively modulating CD4+ and CD8+ T effector lymphocytes through forkhead box protein 3 (FOXP3) positive T regulatory cells' increased activity. Furthermore, interaction of the programmed cell death 1 (PD1) molecule and its ligand programmed cell death ligand 1 (PDL1) inhibits the antitumor activity of PD1+ T lymphocytes. Immunotherapy has become a powerful strategy for tailored cancer patients' treatment both in adult and pediatric patients aiming to generate potent antitumor responses. Nevertheless, immunotherapies can generate autoimmune responses. This study aimed to investigate the potential effect of the transformation-related protein 53 (p53) reactivation by a peptide-based inhibitor of the MDM2/MDM4 heterodimer (Pep3) on the immune response in a solid cancer, i.e. , thyroid carcinoma frequently presenting with thyroid autoimmunity. In peripheral blood mononuclear cell of thyroid cancer patients, Pep3 treatment alters percentages of CD8+ and CD4+ T regulatory and CD8+ and CD4+ T effector cells and favors an anticancer immune response. Of note that reduced frequencies of activated CD8+ and CD4+ T effector cells do not support autoimmunity progression. In evaluating PD1 expression under p53 activation, a significant decrease of activated CD4+PD1+ cells was detected in thyroid cancer patients, suggesting a defective regulation in the initial activation stage, therefore generating a protective condition toward autoimmune progression. [ABSTRACT FROM AUTHOR]

An uncommon congenital hamartomatous disorder called Proteus syndrome is characterized by multifocal tissue expansion originating from all three germinal layers. Diagnosis mainly relies on clinical and radiological criteria. Here, we present a case of a 13-year-old female child exhibiting bony, soft tissue, and vascular abnormalities, along with developmental delay. We conclude by highlighting the importance of imaging studies in conjunction with physical examination, which are characterized by general and specific criteria to diagnose this rare condition until a specific gene test becomes available., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Khaladkar et al.)

Abstract Background CLN6-Batten disease is a rare neurodevelopmental disorder characterized pathologically by the accumulation of lysosomal storage material, glial activation and neurodegeneration, and phenotypically by loss of vision, motor coordination, and cognitive ability, with premature death occurring in the second decade of life. In this study, we investigate whether sex differences in a mouse model of CLN6-Batten disease impact disease onset and progression. Results A number of noteworthy differences were observed including elevated accumulation of mitochondrial ATP synthase subunit C in the thalamus and cortex of female Cln6 mutant mice at 2 months of age. Moreover, female mutant mice showed more severe behavioral deficits. Beginning at 9 months of age, female mice demonstrated learning and memory deficits and suffered a more severe decline in motor coordination. Further, compared to their male counterparts, female animals succumbed to the disease at a slightly younger age, indicating an accelerated disease progression. Conversely, males showed a marked increase in microglial activation at 6 months of age in the cortex relative to females. Conclusions Thus, as female Cln6 mutant mice exhibit cellular and behavioral deficits that precede similar pathologies in male mutant mice, our findings suggest the need for consideration of sex-based differences in CLN6 disease progression during development of preclinical and clinical studies.

Aim: Hydatid cyst is a zoonotic infestation caused by helminthes of the Echinococcus genus and humans are intermediate hosts infected with the contaminated fresh food or water. The cases in Turkey are confined to Eastern Anatolia region. Evaluating the prevalence, symptoms and signs of hydatid cysts along with the treatment procedures and response in pediatric cases are vital for better diagnostic and treatment approaches in children. Material and Methods: The study was conducted retrospectively with a total of 27 children diagnosed with hydatid cyst admitted to Research and Education Hospital of Kafkas University Medical School, Turkey in 2016 and 2019. Results: The mean age of 27 cases reported here was 11.59±4.95. Liver involvement was observed in all of patients reported here and all patients were seropositive. Ten patients underwent Puncture Aspiration Injection Re-aspiration procedure and 17 patients did not undergo. After the Puncture Aspiration Injection Re-aspiration treatment, there was an improvement in all patients for the marker levels. Conclusion: We think that Puncture Aspiration Injection Re-aspiration is superior to non-surgical medical treatment in pediatric patients. [ABSTRACT FROM AUTHOR]

Background: A number of serious human adenovirus (HAdV) outbreaks have been recently reported: HAdV-B7 (Israel, Singapore, and USA), HAdV-B7d (USA and China), HAdV-D8, -D54, and -C2 (Japan), HAdV-B14p1 (USA, Europe, and China), and HAdV-B55 (China, Singapore, and France).Methods: To understand the epidemiology of HAdV infections in Singapore, we studied 533 HAdV-positive clinical samples collected from 396 pediatric and 137 adult patients in Singapore from 2012 to 2018. Genome sequencing and phylogenetic analyses were performed to identify HAdV genotypes, clonal clusters, and recombinant or novel HAdVs.Results: The most prevalent genotypes identified were HAdV-B3 (35.6%), HAdV-B7 (15.4%), and HAdV-E4 (15.2%). We detected 4 new HAdV-C strains and detected incursions with HAdV-B7 (odds ratio [OR], 14.6; 95% confidence interval [CI], 4.1-52.0) and HAdV-E4 (OR, 13.6; 95% CI, 3.9-46.7) among pediatric patients over time. In addition, immunocompromised patients (adjusted OR [aOR], 11.4; 95% CI, 3.8-34.8) and patients infected with HAdV-C2 (aOR, 8.5; 95% CI, 1.5-48.0), HAdV-B7 (aOR, 3.7; 95% CI, 1.2-10.9), or HAdV-E4 (aOR, 3.2; 95% CI, 1.1-8.9) were at increased risk for severe disease.Conclusions: Singapore would benefit from more frequent studies of clinical HAdV genotypes to identify patients at risk for severe disease and help guide the use of new antiviral therapies, such as brincidofovir, and potential administration of HAdV 4 and 7 vaccine. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to investigate the utility of serum resistin levels as a prognostic indicator for mortality in neonates diagnosed with sepsis. Methodology This one-year prospective study at Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, India, included 151 neonates categorized into two groups based on blood culture results: group 1 (n=86) included those with culture-negative, probable sepsis and group 2 (n=65) included those with culture-positive, proven sepsis. Blood samples obtained pre-treatment underwent comprehensive analysis, including complete blood count, C-reactive protein assessment, micro-erythrocyte sedimentation rate, and resistin level measurement via enzyme-linked immunosorbent assay. The comparison between groups was conducted using either the Student t-test or the Mann-Whitney U test, while correlations were assessed using the Spearman correlation. These analyses were employed to identify the optimal resistin cut-off for distinguishing patients with sepsis. A p-value of <0.05 was considered statistically significant. Results This study with 151 neonates diagnosed with sepsis found a significant association (p < 0.05) between elevated serum resistin levels and increased mortality risk. Multivariate analysis confirmed an independent predictive role of resistin. Elevated resistin levels correlate with higher chances of requiring mechanical ventilation and prolonged hospital stays. These findings highlight serum resistin's potential as a prognostic tool for the early identification of high-risk neonatal sepsis patients. Conclusion This study highlights the link between elevated serum resistin levels and increased mortality risk in neonatal sepsis, supported by strong multivariate analysis, indicating an independent predictive role. Additionally, resistin correlates with higher chances of mechanical ventilation and prolonged hospitalization, suggesting its potential as a prognostic marker for early identification of high-risk neonatal sepsis cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Jain et al.)

This review aims to provide the state of the art on polymeric and lipid nanoparticles, used or suggested to approach pediatric diseases’ problems and needs, and to inspire new researches in this field. Several drugs are currently not available in formulations suitable for pediatric patients. The United States Pediatric Formulation Initiative suggested applying new technologies to pediatric drug formulations, for instance, nanotechnology. The literature analysis showed that polymeric and lipid nanoparticles have been widely studied to treat pediatric diseases, and albumin nanoparticles and liposomes are already used in clinical practice. Nevertheless, these studies are focused almost exclusively on pediatric cancer treatment. Although nanomedicine may solve many needs of pediatric diseases and medicines, the unavailability of data on pharmacokinetics, safety and efficacy of both drugs and nanoparticles in pediatric patients limits the development of new pediatric medicines based on nanoparticles. Therefore, nanomedicine applied in pediatrics remains a significant challenge in the near future.

Support for research involving children has a complicated history. Pediatricians and families have a unique opportunity to share perspectives about the relevance of pediatric clinical research. A national broadcast film on pediatric clinical research was developed to improve knowledge about and willingness to consider a clinical study. The film was delivered to a public audience employing a pre-post design comparing knowledge about clinical research before and after watching If Not for Me: Children and Clinical Studies. Change was measured by the difference in number of questions answered correctly prior to and after viewing the film. Engagement was measured by survey and a live feedback qualitative component. Adults viewing the program demonstrated a significant (P < .0001) difference in knowledge about pediatric clinical research across all domains. This format appears to be a viable approach for improving public education and as a support tool for pediatricians and pediatric researchers about this topic. [ABSTRACT FROM AUTHOR]

Congenital heart diseases are an important cause of mortality and morbidity in pedatric patients. Fallot Type Double outlet right ventricle is a rare heterogenous congenital heart disease characterized by a complex group of lesions similar with Tetralogy of Fallot. Surgical approach depends on the anatomy of associated lesions, therefore in order to perform a successful correction, a careful review of the anatomy and a detailed diagnostic is needed due to complexity of intracardiac anomalies. The main diagnostic tool used nowadays for the diagnosis of double outlet right ventricle is echocardiography exam, a non-invasive examination that can provide information about anatomical features, but it will not allow the full description of the coronary anatomy. Therefore, preoperative assessment should include, extensive imaging assessment (echocardiography exam, angio-CT exam) for a correct management of surgical strategy prior to surgical correction. [ABSTRACT FROM AUTHOR]

Background: Cystic Fibrosis (CF) is the most important cause of chronic pulmonary disease in children and the main cause of exocrine pancreas failure in early life. The aim of this study was to determine the relationship between Forced Expiratory Volume in One Second (FEV1) and quality of life in patients with CF. Methods: This cross-sectional study was conducted on 76 children with CF aged 7-14 years referred to the CF clinic of Tehran Medical Center in 2015. For data collection, quality of life, CF conditions and demographic information of children were recorded. Collected data were analyzed in SPSS V. 18 software using descriptive and inferential statistics (t-test, ANOVA and Chi-square test). Results: Of 76 children, 59 were males and 41 female; 30-47% of them were newly diagnosed patients, 44% were relatives, and 55.3% had pulmonary symptoms at first diagnosis. There was no significant association between body mass index and FEV1. The quality of life of children was evaluated in terms of physical, emotional, social and educational performance. The Mean±SD FEV1 was 75.9±21.72, and there was a significant association between FEV1 and educational performance. Moreover, there was a significant correlation between reduction of oxygen saturation (SpO2) after performing 6-Min Walk Test (6MWT) and FEV1 reduction and also between the traveled distance, FEV1 and SpO2 before the 6MWT and mileage test. Conclusions: Quality of life and 6MWT can be used as an auxiliary measure along with FEV1 and other criteria for assessing the cardiovascular function in CF patients. The amount of traveled distance and SpO2 before 6MWT were noticeable considering that the quality of life of CF patients in Iran is lower than in other countries. Health and treatment decisions at micro/macro levels is recommended to improve the quality of life of CF patients.

Objective: To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome.Study Design: This retrospective analysis reviewed commercially insured and Medicaid-insured claims from October 1, 2015 to December 31, 2019 to assess HRU in patients with Alagille syndrome. As there is no specific International Classification ofDiseases-10 code for Alagille syndrome, patients were identified using the following algorithm: ≥1 claim with diagnosis code Q44.7 (other congenital malformations of the liver); <18 years of age, with no history of biliary atresia (International Classification ofDiseases-10 code: Q44.2); and ≥6 months of insurance eligibility prior to diagnosis. HRU was summarized per patient per year over all available claims postdiagnosis.Results: A total of 171 commercially insured and 215 Medicaid-insured patients with Alagille syndrome were available for analysis. Annually, commercially insured and Medicaid-insured patients averaged 31 medical visits (range, 1.5-237) and 48 medical visits (range, 0.7-690), respectively. The most common visits were outpatient with the majority encompassing lab/imaging and primary care visits (commercially insured: 21 [range, 0.0-183]; Medicaid-insured: 26 [range, 0.0-609]). Inpatient visits were the highest driver of costs in both the commercial and Medicaid populations.Conclusions: Patients with Alagille syndrome have a substantial HRU burden driven largely by numerous outpatient visits and costly inpatient stays. Given the complexity and variability of Alagille syndrome presentation, patients may benefit from multidisciplinary and subspecialized care. [ABSTRACT FROM AUTHOR]