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The Journal of Investigative Dermatology Mar 2024The read-through therapy suppresses premature termination codons and induces read-through activity consequently restoring missing proteins. Aminoglycosides are widely...
The read-through therapy suppresses premature termination codons and induces read-through activity consequently restoring missing proteins. Aminoglycosides are widely studied as read-through drugs in different human genetic disorders including hereditary skin diseases. Our previous work revealed that aminoglycosides have effect on COL17A1 nonsense mutations and represent a therapeutic option to alleviate disease severity. However, the amount of restored type XVII collagen (C17) in C17 deficient junctional epidermolysis bullosa (JEB-C17) keratinocytes was less than 1% relative to normal keratinocytes and was achieved only after high dose gentamicin treatment, which induced deep transcriptional changes. Therefore, in this study, we designed a strategy for the read-through therapy to challenge with aminoglycosides limitation factors in clinical use and the chronic inflammation in JEB-C17 patients. We developed TRID-C5 containing low dosage of aminoglycosides, CC-90009, NMDI-14, melatonin and apocynin that was able to induce about 20% of missing C17 without cell toxicity and effect on in vitro wound closure. TRID-C5 significantly induced COL17A1 expression and reverted the proinflammatory phenotype of JEB-C17 keratinocytes. Evaluation of this drug cocktail regarding its stability, penetration and efficacy as a topical treatment remains to be determined. TRID-C5 might represent an improved therapeutic strategy for JEB and for other genetic skin disorders.
PubMed: 38522573
DOI: 10.1016/j.jid.2024.02.027 -
American Journal of Therapeutics
Topics: Humans; Hydroxychloroquine; Chloroquine; COVID-19; COVID-19 Drug Treatment; SARS-CoV-2; Antiviral Agents
PubMed: 38518275
DOI: 10.1097/MJT.0000000000001716 -
Frontiers in Pediatrics 2024Interventions using ultrasound-guided closed reduction and percutaneous pinning (UG-CRPP) of humeral lateral condylar fractures (HLCFs) have been increasingly applied;...
BACKGROUND
Interventions using ultrasound-guided closed reduction and percutaneous pinning (UG-CRPP) of humeral lateral condylar fractures (HLCFs) have been increasingly applied; however, their effectiveness for unstable HLCFs and the criteria for ultrasound outcomes remain unclear. This study assessed the outcomes of UG-CRPP for HLCFs and evaluated the success criteria in children.
METHODS
Data were retrospectively collected from 106 patients with unstable HLCFs admitted to three hospitals between January 2021 and August 2022. Fifty-five cases were left-sided and 51 cases were right-sided: 74 male patients and 32 female patients were included. Perioperative data, elbow function, complications, and criteria for UG-CRPP were analyzed.
RESULTS
The mean rate of UG-CRPP was 88%. The mean surgical time was 54.56 ± 21.07 min, and the mean fluoroscopy frequency was 9.25 ± 2.93 times. At the last follow-up, there were significant differences in elbow flexion between the affected side (135.82° ± 6.92°) and the unaffected side (140.58° ± 5.85°) ( = 0.01). The Mayo score of the affected side was 90.28° ± 4.97°, the Baumann angle was 71.4° ± 5.4°, condylar shaft angle was 39.9° ± 6.4°, and the carrying angle was 8.4° ± 3.6°. Seventy patients presented mild lateral spurs and 16 patients exhibited moderate spurs. Fourteen patients presented with pin infection, and one patient exhibited postoperative re-displacement. There was no premature physeal closure, varus, or valgus elbow deformity, delayed union, or non-union. Successful ultrasound-based outcome criteria for UG-CRPP were defined as follows: (i) absent or less than a cartilage thickness step on the cartilage hinge on coronal plane parallel articular surface scanning, (ii) no lateral displacement and intact distal end of the condylar and capitellum on coronal plane vertical articular surface scanning, (iii) no anteroposterior displacement and absent or less than a cartilage thickness step on sagittal plane vertical articular surface scanning, and (iv) intact posterior fracture line or less than a cortex step on posterolateral sagittal plane vertical articular surface scanning.
CONCLUSION
UG-CRPP is a procedure with minimal blood loss, less invasive, cosmetic, and no radiation exposure. It yielded good outcomes in unstable HLCFs. The successful criteria make it suitable for clinical application.
PubMed: 38510077
DOI: 10.3389/fped.2024.1373913 -
JAMA Network Open Mar 2024Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice.
IMPORTANCE
Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice.
OBJECTIVE
To determine the characteristics, progression, and output of randomized platform trials.
EVIDENCE REVIEW
In this systematic review of randomized platform trials, Medline, Embase, Scopus, trial registries, gray literature, and preprint servers were searched, and citation tracking was performed in July 2022. Investigators were contacted in February 2023 to confirm data accuracy and to provide updated information on the status of platform trial arms. Randomized platform trials were eligible if they explicitly planned to add or drop arms. Data were extracted in duplicate from protocols, publications, websites, and registry entries. For each platform trial, design features such as the use of a common control arm, use of nonconcurrent control data, statistical framework, adjustment for multiplicity, and use of additional adaptive design features were collected. Progression and output of each platform trial were determined by the recruitment status of individual arms, the number of arms added or dropped, and the availability of results for each intervention arm.
FINDINGS
The search identified 127 randomized platform trials with a total of 823 arms; most trials were conducted in the field of oncology (57 [44.9%]) and COVID-19 (45 [35.4%]). After a more than twofold increase in the initiation of new platform trials at the beginning of the COVID-19 pandemic, the number of platform trials has since declined. Platform trial features were often not reported (not reported: nonconcurrent control, 61 of 127 [48.0%]; multiplicity adjustment for arms, 98 of 127 [77.2%]; statistical framework, 37 of 127 [29.1%]). Adaptive design features were only used by half the studies (63 of 127 [49.6%]). Results were available for 65.2% of closed arms (230 of 353). Premature closure of platform trial arms due to recruitment problems was infrequent (5 of 353 [1.4%]).
CONCLUSIONS AND RELEVANCE
This systematic review found that platform trials were initiated most frequently during the COVID-19 pandemic and declined thereafter. The reporting of platform features and the availability of results were insufficient. Premature arm closure for poor recruitment was rare.
Topics: Humans; Pandemics; COVID-19; Cognition; Data Accuracy; Medical Oncology
PubMed: 38506807
DOI: 10.1001/jamanetworkopen.2024.3109 -
International Journal of Burns and... 2024The primary objective of this study was to juxtapose the union rate and incidence of complications in paediatric patients presenting early (≤ 7 days) following injury...
The primary objective of this study was to juxtapose the union rate and incidence of complications in paediatric patients presenting early (≤ 7 days) following injury with children presenting later (> 7 days) with femoral neck fractures. This critical appraisal evaluated 15 patients according to their timing of presentation and surgery from the initial day of injury (Group A: operated ≤ 7 days or Group B: > 7 days of injury). Patients with traumatic femoral neck fractures with Delbet 1 to 4 subtypes who were skeletally immature (age ≤ 16 years) were included in the study. Pathological fractures and post-infective fractures were not included. Each patient's secondary loss of reduction was calculated by measuring the Neck shaft angle (NSA) on the immediate post-operative radiograph and at the union. A change in NSA of ≥ 5 degrees was considered a significant loss of reduction. Ratliff's Criteria was used to analyze the final result, and a thorough record of complications was kept. There were no significant variations in the two groups' with respect to distributions of age, sex, injury mechanism, or fracture pattern. The most frequent injury culprit in both groups was falling from a height. Type II fracture pattern (54.54%) was more common in group A, while Type III and Type II fracture pattern was equally distributed in group B. In group A, the mean operation time was 55 ± 8.25 minutes, whereas in group B, it was 65 ± 15 minutes (-value > 0.05). In group A, 90.9% of patients underwent CCS fixation, and in group B, 75% underwent fixation by CCS. The quality of reduction in post-operative radiographs was anatomical in 10 (90.9%) patients and unacceptable in 1 (9.1%) patient. In group B, 2 (50%) patients had an anatomical reduction, while 2 (50%) patients had an unacceptable reduction. Timing of reduction and its association with complications showed that early stable reduction and fixation decrease the occurrence of complications in femoral neck fractures (-value = 0.033). Fracture union was seen in all our patients in both groups and none of our patients underwent non-union. The mean union time was 11.11 ± 7.06 weeks in group A and 16.5 ± 2.59 weeks in group B (-value = 0.0189). In group A, only 1 (9.1%) patient developed coxa vara. In group B, out of 4 patients, the femoral head of one patient underwent avascular necrosis, one patient exhibited coxa vara, and 1 patient developed premature physeal closure with limb length inequality. Management of femoral neck fractures in children is challenging because of the paediatric bone's peculiar anatomic and physiological considerations. In our study, patients operated within 7 days developed fewer complications as compared to patients who were operated after 7 days, which was statistically significant. Although AVN is a frequent adverse consequence of pediatric femoral neck fractures, early reduction and stable fixation lowers AVN rates, as observed in our study. Our short-term functional and radiological results using the Ratliff scoring system were comparable to previous studies owing to stable anatomic reduction. Based on our findings and the existing literature, we emphasize long-term follow-up and recommend an early stable anatomic reduction in the treatment of paediatric femoral neck fractures.
PubMed: 38505344
DOI: 10.62347/ZQKE1542 -
Circulation. Cardiovascular... Mar 2024
Topics: Humans; Infant, Newborn; Ductus Arteriosus, Patent; Infant, Premature; Retrospective Studies; Septal Occluder Device; Treatment Outcome
PubMed: 38502722
DOI: 10.1161/CIRCINTERVENTIONS.123.013723 -
Journal of Molecular Medicine (Berlin,... May 2024Physical therapy is extensively employed in clinical settings. Nevertheless, the absence of suitable animal models has resulted in an incomplete understanding of the in...
Physical therapy is extensively employed in clinical settings. Nevertheless, the absence of suitable animal models has resulted in an incomplete understanding of the in vivo mechanisms and cellular distribution that respond to physical stimuli. The objective of this research was to create a mouse model capable of indicating the cells affected by physical stimuli. In this study, we successfully established a mouse line based on the heat shock protein 70 (Hsp70) promoter, wherein the expression of CreERT2 can be induced by physical stimuli. Following stimulation of the mouse tail, ear, or cultured calvarias with heat shock (generated by heating, ultrasound, or laser), a distinct Cre-mediated excision was observed in cells stimulated by these physical factors with minimal occurrence of leaky reporter expression. The application of heat shock to Hsp70-CreERT2; FGFR2-P253R double transgenic mice or Hsp70-CreERT2 mice infected with AAV-BMP4 at calvarias induced the activation of Cre-dependent mutant FGFR2-P253R or BMP4 respectively, thereby facilitating the premature closure of cranial sutures or the repair of calvarial defects. This novel mouse line holds significant potential for investigating the underlying mechanisms of physical therapy, tissue repair and regeneration, lineage tracing, and targeted modulation of gene expression of cells in local tissue stimulated by physical factor at the interested time points. KEY MESSAGES: In the study, an Hsp70-CreERT2 transgenic mouse was generated for heat shock-induced gene modulation. Heat shock, ultrasound, and laser stimulation effectively activated Cre expression in Hsp70-CreERT2; reporter mice, which leads to deletion of floxed DNA sequence in the tail, ear, and cultured calvaria tissues of mice. Local laser stimuli on cultured calvarias effectively induce Fgfr2-P253R expression in Hsp70-mTmG-Fgfr2-P253R mice and result in accelerated premature closure of cranial suture. Heat shock activated AAV9-FLEX-BMP4 expression and subsequently promoted the repair of calvarial defect of Hsp70-CreERT2; Rosa26-mTmG mice.
Topics: Animals; HSP70 Heat-Shock Proteins; Promoter Regions, Genetic; Mice, Transgenic; Mice; Bone Morphogenetic Protein 4; Heat-Shock Response; Skull; Gene Expression Regulation; Integrases
PubMed: 38492027
DOI: 10.1007/s00109-024-02433-9 -
The Cleft Palate-craniofacial Journal :... Mar 2024Craniosynostosis is a congenital condition characterized by the premature closure of one or more sutures in the skull after birth, often necessitating urgent surgical... (Review)
Review
Craniosynostosis is a congenital condition characterized by the premature closure of one or more sutures in the skull after birth, often necessitating urgent surgical intervention. Nevertheless, cranial vault reconstruction surgery can cause rapid and massive blood loss. This procedure requires a blood transfusion, which entails potential hazards. In addition, the hemostatic system in children differs significantly from that in adults, resulting in increased bleeding during surgical procedures. We conducted a comprehensive literature review in the PubMed, Scopus, and Web of Science databases, referring to their inception for studies on the use of tranexamic acid in pediatric craniosynostosis surgery. Selection criteria were based on the relevance of tranexamic acid, its clinical efficacy, and its safety profile in pediatric populations. Authoritative reviews were considered to ensure a comprehensive synthesis of current knowledge and practice trends in the field. We determined that a low loading dose of 10 mg/kg followed by a maintenance dose of 5 mg/kg/h is as effective as a high dose of 50 mg/kg followed by a maintenance dose of 10 mg/kg/h of tranexamic acid when administered after induction of anesthesia through skin closure and can reduce blood loss by up to 72% and total packed red blood cell transfusion by up to 85%. No difference in safety profile is observed. We concluded that a low dose of tranexamic acid, administered as a loading dose followed by a maintenance dose, is beneficial and safe for reducing blood loss and transfusion following craniosynostosis surgery.
PubMed: 38483820
DOI: 10.1177/10556656241239527 -
Early Human Development Apr 2024Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited...
Active versus restrictive ligation strategy for patent ductus arteriosus - A retrospective two-center study of extremely preterm infants born between 22 + 0 and 25 + 6 weeks of gestational age.
BACKGROUND
Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited in the most extremely premature infants <26 weeks of gestational age (GA), where clinical problems are most significant and patients are most vulnerable.
AIMS
To investigate whether different approaches to surgical closure of PDA in two large Swedish centers has an impact on clinical outcomes including mortality in extremely preterm infants born <26 weeks GA.
STUDY DESIGN
Retrospective, two-center, cohort study.
SUBJECTS
Infants born at 22-25 weeks GA between 2010 and 2016 at Uppsala University Children's Hospital (UUCH; n = 228) and Queen Silvia Children's Hospital Gothenburg (QSCHG; n = 220).
MAIN OUTCOME MEASURES
Survival, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP).
RESULTS
Surgical closure of PDA was more common and performed earlier at QSCHG (50 % vs 16 %; median age 11 vs 44 days; p < 0.01). Survival was similar in both centres. There was a higher incidence of severe BPD and longer duration of mechanical ventilation at UUCH (p < 0.01). There was a higher incidence of ROP, IVH and sepsis at QSCH (p < 0.05, p < 0.01 and p < 0.01). A sub-group analysis matching all surgically treated infants at QSCHG with infants at UUCH with the same GA showed similar results as the total cohort.
CONCLUSION
Earlier and higher rate of surgical PDA closure in this cohort of extremely preterms born <26 weeks GA did not impact mortality but was associated with lower rates of severe BPD and higher rates of severe ROP.
Topics: Infant; Female; Child; Infant, Newborn; Humans; Infant, Extremely Premature; Ductus Arteriosus, Patent; Gestational Age; Retrospective Studies; Cohort Studies; Bronchopulmonary Dysplasia; Retinopathy of Prematurity
PubMed: 38452632
DOI: 10.1016/j.earlhumdev.2024.105976 -
Journal of Neurosurgery. Case Lessons Mar 2024Myelomeningocele (MMC) is the most serious form of spina bifida, a congenital defect in neural tube development. Defect closure in a patient with an extremely low birth...
BACKGROUND
Myelomeningocele (MMC) is the most serious form of spina bifida, a congenital defect in neural tube development. Defect closure in a patient with an extremely low birth weight presents unique challenges and risks; lower birth weight is associated with multiple organ system concerns, homeostasis is difficult, and local tissue is underdeveloped. To the authors' knowledge, the present case is the lowest reported weight (490 g) for a neonate with postnatal MMC repair.
OBSERVATIONS
A preterm male with a prenatally diagnosed lumbosacral MMC and associated Chiari malformation type II was born at 23 weeks 1 day to a 29-year-old mother, gravidity 6 parity 4. The patient was medically stabilized and underwent MMC closure on day of life 5. His weight was 490 g at the time of this repair, and he did not have any surgical complications. At age 16 months, he underwent endoscopic third ventriculostomy with choroid plexus cauterization; he has not required any further hydrocephalus treatments since the last follow-up at 30 months of age.
LESSONS
To the authors' knowledge, this case is the lowest birth weight ex utero MMC closure reported in the literature. Challenges of prematurity and size required appropriate preoperative stabilization, careful hemostasis and temperature regulation, and meticulous surgical technique.
PubMed: 38437685
DOI: 10.3171/CASE23556