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Molecular Therapy. Nucleic Acids Sep 2024p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in...
p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in defective NADPH oxidase function in phagocytes. Due to its complex genomic context, the locus is not suited for safe gene editing with current genome editing technologies. Therefore, we developed a targeted coding sequence knock-in by CRISPR-Cas9 ribonucleoprotein and viral vector template delivery, to restore p47 expression under the control of the endogenous locus. encodes for p67 , an NADPH oxidase subunit that closely interacts with p47 and is predominantly expressed in myeloid cells. This approach restored p47 expression and NADPH oxidase function in p47-CGD patient hematopoietic stem and progenitor cells (HSPCs) and in p47 -deficient mouse HSPCs, with the transgene expression following a myeloid differentiation pattern. Adeno-associated viral vectors performed favorably over integration-deficient lentiviral vectors for template delivery, with fewer off-target integrations and higher correction efficacy in HSPCs. Such myeloid-directed gene editing is promising for clinical CGD gene therapy, as it leads to the co-expression of p47 and p67 , ensuring spatiotemporal and near-physiological transgene expression in myeloid cells.
PubMed: 38952440
DOI: 10.1016/j.omtn.2024.102229 -
Frontiers in Pediatrics 2024Preterm birth is a growing problem worldwide. Staying at a neonatal intensive care unit (NICU) after birth is critical for the survival of preterm infants whose feeding...
INTRODUCTION
Preterm birth is a growing problem worldwide. Staying at a neonatal intensive care unit (NICU) after birth is critical for the survival of preterm infants whose feeding often requires the use of nasogastric enteral feeding tubes (NEFT). These can be colonized by hospital-associated pathobionts that can access the gut of the preterm infants through this route. Since the gut microbiota is the most impactful factor on maturation of the immune system, any disturbance in this may condition their health. Therefore, the aim of this study is to assess the impact of NEFT-associated microbial communities on the establishment of the gut microbiota in preterm infants.
MATERIAL AND METHODS
A metataxonomic analysis of fecal and NEFT-related samples obtained during the first 2 weeks of life of preterm infants was performed. The potential sharing of strains isolated from the same set of samples of bacterial species involved in NICU's outbreaks, was assessed by Random Amplification of Polymorphic DNA (RAPD) genotyping.
RESULTS
In the samples taken 48 h after birth (NEFT-1 and Me/F1), spp. was the most abundant genera (62% and 14%, respectively) and it was latter displaced to 5.5% and 0.45%, respectively by . Significant differences in beta diversity were detected in NEFT and fecal samples taken at day 17 after birth (NEFT-3 and F3) ( = 0.003 and = 0.024, respectively). Significant positive correlations were found between the most relevant genera detected in NEFT-3 and F3. 28% of the patients shared at least one RAPD-PCR profile in fecal and NEFT samples and 11% of the total profiles were found at least once simultaneously in NEFT and fecal samples from the same patient.
CONCLUSION
The results indicate a parallel bacterial colonization of the gut of preterm neonates and the NEFTs used for feeding, potentially involving strain sharing between these niches. Moreover, the same bacterial RAPD profiles were found in neonates hospitalized in different boxes, suggesting a microbial transference within the NICU environment. This study may assist clinical staff in implementing best practices to mitigate the spread of pathogens that could threaten the health of preterm infants.
PubMed: 38952433
DOI: 10.3389/fped.2024.1397398 -
Frontiers in Artificial Intelligence 2024This study investigates key factors influencing dental caries risk in children aged 7 and under using machine learning techniques. By addressing dental caries'...
INTRODUCTION AND OBJECTIVES
This study investigates key factors influencing dental caries risk in children aged 7 and under using machine learning techniques. By addressing dental caries' prevalence, it aims to enhance early identification and preventative strategies for high-risk individuals.
METHODS
Data from clinical examinations of 356 children were analyzed using Logistic Regression, Decision Trees, and Random Forests models. These models assessed the influence of dietary habits, fluoride exposure, and socio-economic status on caries risk, emphasizing accuracy, precision, recall, F1 score, and AUC metrics.
RESULTS
Poor oral hygiene, high sugary diet, and low fluoride exposure were identified as significant caries risk factors. The Random Forest model demonstrated superior performance, illustrating the potential of machine learning in complex health data analysis. Our SHAP analysis identified poor oral hygiene, high sugary diet, and low fluoride exposure as significant caries risk factors.
CONCLUSION
Machine learning effectively identifies and quantifies dental caries risk factors in children. This approach supports targeted interventions and preventive measures, improving pediatric dental health outcomes.
CLINICAL SIGNIFICANCE
By leveraging machine learning to pinpoint crucial caries risk factors, this research lays the groundwork for data-driven preventive strategies, potentially reducing caries prevalence and promoting better dental health in children.
PubMed: 38952410
DOI: 10.3389/frai.2024.1392597 -
Bone Reports Jun 2024We report a case of a patient with a germline heterozygous truncating variant of gene (c.2172del, p.Tyr724Ter) causing neurodevelopmental disorder with spastic...
We report a case of a patient with a germline heterozygous truncating variant of gene (c.2172del, p.Tyr724Ter) causing neurodevelopmental disorder with spastic diplegia and visual defects syndrome (NEDSDV) associated with a new clinical feature - severe pediatric-onset osteoporosis and multiple fractures. A functional effect of the identified variant was demonstrated using adipose-tissue derived primary mesenchymal stem cells, where we detected the alteration of mRNA and β-catenin protein levels using real-time PCR and Western blot analysis.
PubMed: 38952406
DOI: 10.1016/j.bonr.2024.101777 -
Frontiers in Endocrinology 2024Lipodystrophy syndromes are rare diseases that can present with a broad range of symptoms. Delays in diagnosis are common, which in turn, may predispose to the... (Review)
Review
INTRODUCTION
Lipodystrophy syndromes are rare diseases that can present with a broad range of symptoms. Delays in diagnosis are common, which in turn, may predispose to the development of severe metabolic complications and end-organ damage. Many patients with lipodystrophy syndromes are only diagnosed after significant metabolic abnormalities arise. Prompt action by clinical teams may improve disease outcomes in lipodystrophy syndromes. The aim of the Rapid Action Plan is to serve as a set of recommendations from experts that can support clinicians with limited experience in lipodystrophy syndromes.
METHODS
The Rapid Action Plan was developed using insights gathered through a series of advisory meetings with clinical experts in lipodystrophy syndromes. A skeleton template was used to facilitate interviews. A consensus document was developed, reviewed, and approved by all experts.
RESULTS
Lipodystrophy is a clinical diagnosis. The Rapid Action Plan discusses tools that can help diagnose lipodystrophy syndromes. The roles of clinical and family history, physical exam, patient and family member photos, routine blood tests, leptin levels, skinfold measurements, imaging studies, and genetic testing are explored. Additional topics such as communicating the diagnosis to the patients/families and patient referrals are covered. A set of recommendations regarding screening and monitoring for metabolic diseases and end-organ abnormalities is presented. Finally, the treatment of lipodystrophy syndromes is reviewed.
DISCUSSION
The Rapid Action Plan may assist clinical teams with the prompt diagnosis and holistic work-up and management of patients with lipodystrophy syndromes, which may improve outcomes for patients with this rare disease.
Topics: Humans; Lipodystrophy; Disease Management; Syndrome
PubMed: 38952397
DOI: 10.3389/fendo.2024.1383318 -
Heliyon Jun 2024Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme -acetylgalactosamine-6-sulfate sulfatase...
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme -acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Previously, it was reported the production of an active human recombinant GALNS (rGALNS) in BL21(DE3). However, this recombinant enzyme was not taken up by HEK293 cells or MPS IVA skin fibroblasts. Here, we leveraged a glyco-engineered strain to produce a recombinant human GALNS bearing the eukaryotic trimannosyl core glycan, ManGlcNAc (rGALNSGly). The glycosylated GALNS was produced at 100 mL and 1.65 L scales, purified and characterized with respect to pH stability, enzyme kinetic parameters, cell uptake, and KS clearance. The results showed that the addition of trimannosyl core glycans enhanced both protein stability and substrate affinity. rGALNSGly was capture through a mannose receptor-mediated process. This enzyme was delivered to the lysosome, where it reduced KS storage in human MPS IVA fibroblasts. This study demonstrates the potential of a glyco-engineered for producing a fully functional GALNS enzyme. It may offer an economic approach for the biosynthesis of a therapeutic glycoprotein that could prove useful for MPS IVA treatment. This strategy could be extended to other lysosomal enzymes that rely on the presence of mannose N-glycans for cell uptake.
PubMed: 38952373
DOI: 10.1016/j.heliyon.2024.e32555 -
Journal of Korean Medical Science Jul 2024Despite medical advancements in neonatal survival rates, many children have poor neurological outcomes. Because the law in Korea restricts the withdrawal of...
BACKGROUND
Despite medical advancements in neonatal survival rates, many children have poor neurological outcomes. Because the law in Korea restricts the withdrawal of life-sustaining treatment to only cases of imminent death, treatment discontinuation may not be an option, even in patients with poor neurological prognosis. This study investigated the opinions of the general population and clinicians regarding life-sustaining treatment withdrawal in such cases using hypothetical scenarios.
METHODS
We conducted a cross-sectional study on the general population and clinicians using a web-based questionnaire. The sample of the general population from an online panel comprised 500 individuals aged 20-69 years selected by quota sampling. The clinician sample comprised 200 clinicians from a tertiary university hospital. We created hypothetical vignettes and questionnaire items to assess attitudes regarding mechanical ventilation withdrawal for an infant at risk of poor neurological prognosis due to birth asphyxia at 2 months and 3 years after the incidence.
RESULTS
Overall, 73% of the general population and 74% of clinicians had positive attitudes toward mechanical ventilator withdrawal at 2 months after birth asphyxia. The proportion of positive attitudes toward mechanical ventilator withdrawal was increased in the general population (84%, < 0.001) and clinicians (80.5%, = 0.02) at 3 years after birth asphyxia. Religion, spirituality, the presence of a person with a disability in the household, and household income were associated with the attitudes of the general population. In the multivariable logistic regression analysis of the general population, respondents living with a person with a disability or having a disability were more likely to find the withdrawal of the ventilator at 2 months and 3 years after birth asphyxia not permissible. Regarding religion, respondents who identified as Christians were more likely to find the ventilator withdrawal at 2 months after birth asphyxia unacceptable.
CONCLUSION
The general population and clinicians shared the perspective that the decision to withdraw life-sustaining treatment in infants with a poor neurological prognosis should be considered before the end of life. A societal discussion about making decisions centered around the best interest of pediatric patients is warranted.
Topics: Humans; Male; Female; Adult; Prognosis; Surveys and Questionnaires; Withholding Treatment; Middle Aged; Cross-Sectional Studies; Respiration, Artificial; Infant; Aged; Young Adult; Infant, Newborn; Asphyxia Neonatorum; Republic of Korea; Attitude of Health Personnel
PubMed: 38952347
DOI: 10.3346/jkms.2024.39.e196 -
Journal of Korean Medical Science Jul 2024The increasing number of vaccines and the complexity of immunization programs, along with continuous changes in the epidemiology of infectious diseases, necessitate a...
BACKGROUND
The increasing number of vaccines and the complexity of immunization programs, along with continuous changes in the epidemiology of infectious diseases, necessitate a systematic approach to vaccine effectiveness (VE) evaluation. This study presents a preliminary survey to establish a VE evaluation framework in Korea, focusing on the National Immunization Program.
METHODS
Experts' opinions were collected through a two-round online survey targeting key stakeholders. The first round consisted of two multiple-choice questions and two open-ended questions. The second round was a quantitative survey with 17 questionnaires based on five domains derived by analyzing the results of the first-round survey.
RESULTS
The results emphasize the necessity and urgency of a government-led VE evaluation system and the establishment of a multidisciplinary evaluation organization. Key considerations include personnel, budget, data integration, legal standards, and surveillance system enhancements.
CONCLUSION
These findings provide valuable insights for policymakers, emphasizing the need for collaboration, financial support, and robust data management in developing evidence-based vaccination policies.
Topics: Humans; Immunization Programs; Republic of Korea; Surveys and Questionnaires; Vaccines; Vaccination; Health Policy
PubMed: 38952346
DOI: 10.3346/jkms.2024.39.e193 -
Turkish Journal of Orthodontics Jun 2024The aim of this study was to examine the quality of life and behavioral disorders in children with obstructive sleep apnea (OSA) or primary snoring, as well as how these...
OBJECTIVE
The aim of this study was to examine the quality of life and behavioral disorders in children with obstructive sleep apnea (OSA) or primary snoring, as well as how these problems changed after monobloc treatment.
METHODS
Fourteen children with primary snoring and 16 children with OSA who had skeletal class II malocclusion due to mandibular retrognathia were treated with monobloc appliances. To investigate the relationship between behavioral disorders and quality of life, parents were asked to complete four questionnaires: attention deficit and hyperactivity disorder (ADHD) scale, strength and difficulties questionnaire (SDQ), pediatric sleep questionnaire (PSQ), and Pittsburgh sleep quality scale (PSQS). Mann-Whitney U and Wilcoxon signed-rank tests were used to evaluate the data.
RESULTS
According to the results of the PSQ and PSQS, an increase in sleep quality was observed after monobloc treatment. The decrease in the total ADHD score at the end of the treatment was found to be statistically significant in both the OSA (p<0.01) and snoring (p<0.01) groups. According to the SDQ scores, the increase in the social behavior score and the decrease in the peer bullying score in the snoring group were statistically significant (p<0.05).
CONCLUSION
The use of a monobloc appliance in pediatric patients exhibiting primary snoring and OSA resulted in a notable reduction in sleep-breathing disorder symptoms and a notable enhancement in their overall quality of life. Based on the analyses of the questionnaires, it was concluded that the increase in sleep quality improved the pediatric patients' quality of life after orthodontic treatment with orthodontic monobloc appliances.
PubMed: 38952285
DOI: 10.4274/TurkJOrthod.2023.2023.78 -
Turkish Journal of Orthodontics Jun 2024To compare the reliability of two scoring systems for detecting white spot lesions (WSLs) from clinical photographs captured during debonding of fixed orthodontic...
OBJECTIVE
To compare the reliability of two scoring systems for detecting white spot lesions (WSLs) from clinical photographs captured during debonding of fixed orthodontic appliances.
METHODS
Digital images of 58 healthy adolescents (34 females and 24 males) were examined, depicting 384 buccal surfaces of maxillary incisors, canines, and first premolars. Three trained examiners (E1, E2 and E3) independently evaluated the fully anonymized photos in a randomized order using the Gorelick index (GI) and the modified International Caries Detection and Assessment System (ICDAS II). A 1-2-week interval separated the scorings. Spearman's rank correlation coefficient, Fisher's z-test, and the interclass correlation coefficient (ICC) were applied to compare the scoring methods and express examiner agreement.
RESULTS
The two scoring systems showed a moderate to strong positive relationship, but inter-examiner variations were significant (p<0.05). We found moderate to good reliability (ICC 0.60 to 0.84) with the ICDAS II system and good to excellent values with the GI (ICC 0.72 to 0.94), depending on the examiner. The agreement concerning the sound surfaces and the most severe WSLs was perfect, whereas the scoring of the milder lesion stages appeared more uncertain.
CONCLUSION
A moderate to strong positive relationship was demonstrated between the two methods when scoring the presence and severity of WSLs from digital images. Significant inter-examiner variations affected reliability.
PubMed: 38952228
DOI: 10.4274/TurkJOrthod.2023.2022.58