Glypican-3 deficiency in liver cancer upregulates MAPK/ERK pathway but decreases cell proliferation.

Glypican-3 (GPC3) is overexpressed in hepatocellular carcinomas and hepatoblastomas and represents an important therapeutic target but the biologic importance of GPC3 in liver cancer is unclear. To date, there are limited data characterizing the biological implications of GPC3 knockout (KO) in liver cancers that intrinsically express this target. Here, we report on the development and characterization of GPC3-KO liver cancer cell lines and compare to them to parental lines. GPC3-KO variants were established in HepG2 and Hep3B liver cancer cell lines using a lentivirus-mediated CRISPR/Cas9 system. We assessed the effects of GPC3 deficiency on oncogenic properties in vitro and in murine xenograft models. Downstream cellular signaling pathway changes induced by GPC3 deficiency were examined by RNAseq and western blot. To confirm the usefulness of the models for GPC3-targeted drug development, we evaluated the target engagement of a GPC3-selective antibody, GC33, conjugated to the positron-emitting zirconium-89 (89Zr) in subcutaneous murine xenografts of wild type (WT) and KO liver cancer cell lines. Deletion of GPC3 significantly reduced liver cancer cell proliferation, migration, and invasion compared to the parental cell lines. Additionally, the tumor growth of GPC3-KO liver cancer xenografts was significantly slower compared with control xenografts. RNA sequencing analysis also showed GPC3-KO resulted in a reduction in the expression of genes associated with cell cycle regulation, invasion, and migration. Specifically, we observed the downregulation of components in the AKT/NFκB/WNT signaling pathways and of molecules related to cell cycle regulation with GPC3-KO. In contrast, pMAPK/ERK1/2 was upregulated, suggesting an adaptive compensatory response. KO lines demonstrated increased sensitivity to ERK (GDC09994), while AKT (MK2206) inhibition was more effective in WT lines. Using antibody-based positron emission tomography (immunoPET) imaging, we confirmed that 89Zr-GC33 accumulated exclusively in GPC3-expression xenografts but not in GPC3-KO xenografts with high tumor uptake and tumor-to-liver signal ratio. We show that GPC3-KO liver cancer cell lines exhibit decreased tumorigenicity and altered signaling pathways, including upregulated pMAPK/ERK1/2, compared to parental lines. Furthermore, we successfully distinguished between GPC3+ and GPC3- tumors using the GPC3-targeted immunoPET imaging agent, demonstrating the potential utility of these cell lines in facilitating GPC3-selective drug development.

Infectious Keratitis in Patients Over 65: A Review on Treatment and Preserving Eyesight.

Infectious keratitis (IK) represents a significant global health concern, ranking as the fifth leading cause of blindness worldwide despite being largely preventable and treatable. Elderly populations are particularly susceptible due to age-related changes in immune response and corneal structure. However, research on IK in this demographic remains scarce. Age-related alterations such as increased permeability and reduced endothelial cell density further compound susceptibility to infection and hinder healing mechanisms. Additionally, inflammaging, characterized by chronic inflammation that develops with advanced age, disrupts the ocular immune balance, potentially exacerbating IK and other age-related eye diseases. Understanding these mechanisms is paramount for enhancing IK management, especially in elderly patients. This review comprehensively assesses risk factors, clinical characteristics, and management strategies for bacterial, viral, fungal, and acanthamoeba keratitis in the elderly population, offering crucial insights for effective intervention.

Informing knowledge translation for selective dorsal rhizotomy: A survey of Australian clinicians and people with lived experience of cerebral palsy.

AIM: Selective dorsal rhizotomy (SDR) is a neurosurgical intervention used to reduce spasticity in children with cerebral palsy (CP). There is minimal relevant, evidence-based information available for Australian families and clinicians. This study aims to investigate the knowledge of people with lived experience and clinicians regarding SDR, including how they currently access information and what information they seek. METHODS: Adults with CP, carers of children with CP and clinicians treating children with CP were invited to complete an online survey. Data regarding participant demographics, current knowledge and confidence in knowledge about CP and SDR, information source/s used and participants level of trust in these sources are presented as counts and percentages. Comparisons in knowledge between groups were analysed. RESULTS: A total of 114 surveys were completed: 63 clinicians, 48 carers, and 3 adults with CP. Eighty percent of clinicians were allied health professionals. People with lived experience were less confident in their knowledge about SDR compared to knowledge of CP (P < 0.001). Clinicians rated scientific research literature and the hospital team as the most useful and trustworthy information source. People with lived experience used a wider range of information sources including the internet, rating their community therapy team and other people with lived experience as the most useful. CONCLUSION: This study identified a lack of confidence in knowledge of SDR for people with lived experience, likely due to a gap in accessible and readable evidence-based information. While both groups differed in how they access information, there was agreement that greater information about SDR is needed.

Lower Extremity Trauma is Associated with an Increased Rate of New Mental Disorder Diagnosis and Suicide Attempt.

OBJECTIVES: To evaluate the risk of developing a new mental disorder diagnosis within two years of lower extremity fracture. METHODS: Design: Retrospective cohort study. SETTING: National insurance claims database. PATIENT SELECTION CRITERIA: Included were patients between the ages of 18 and 65 with lower extremity, pelvis and acetabular fractures without prior mental disorders as defined with ICD-9 and ICD-10 diagnosis codes. Mental disorders evaluated included alcohol use disorder, generalized anxiety disorder, bipolar disorder, major depressive disorder, drug use disorder, panic disorder, post-traumatic stress disorder, and suicide attempt.Outcome Measures and Comparisons: The individual lower extremity fracture cohorts were matched 1:4 with non-fracture controls. The specific groups of interest were pelvis fractures, acetabulum fractures, proximal femur fractures, femoral shaft fractures, distal femur fractures, patella fractures, tibia plateau fractures, tibia shaft fractures, ankle fractures, pilon fractures, calcaneus fractures, and Lisfranc fractures. Rates of mental disorders after primary lower extremity fractures within two years were compared using multivariable logistic regression. RESULTS: Overall, the 263,988 patient fracture group was 57.2% female with an average age of 46.6 years. Compared to controls with no fracture, patients who sustained pelvis, acetabulum, proximal femur, femoral shaft, distal femur, patella, tibia plateau, tibia shaft, pilon, calcaneus, or Lisfranc fracture had a statistically significant increased risk of being diagnosed with a queried mental disorder within two years of fracture. When comparing all fracture patients by location, those suffering from fractures proximal to the knee joint, including pelvis fractures (OR: 1.51, 95% CI: 1.39-1.64) and proximal femur fractures (OR: 1.36, 95% CI: 1.26-1.47), demonstrated greater risk of developing any of the queried mental disorders compared fractures distal to the knee, including ankle fractures (OR: 0.99, 95% CI: 0.95-1.03) and pilon fractures (OR: 1.05, 95% CI: 0.81-1.36). When comparing specific fracture patients to patients without fracture by mental disorder, patients demonstrated an increased risk of suicide attempt following fracture of the pelvis, acetabulum, femoral shaft, distal femur, and calcaneus, as well as patients suffering a Lisfranc fracture. CONCLUSIONS: There is an increased risk of being diagnosed with a new mental disorder following lower extremity trauma in patients without prior mental disorder diagnosis compared to matched individuals without a lower extremity fracture. Among the fractures studied, those that were more proximal, such as pelvis and proximal femur fractures, carried the greatest risk compared to more distal fracture sites, including ankle and pilon fractures. Patients who experienced certain lower extremity fractures had a significantly higher rate of suicide attempt compared to patients without fracture. Physicians should consider increased mental health screening and potential referral for mental health evaluation for patients following lower extremity trauma. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Smokeless Tobacco Use is Associated with Worse Outcomes Following Open Tibia Fracture.

Background: Smoking is a known risk factor for complications after open tibia fractures, but it is unclear if smokeless tobacco confers a similar risk. Objective: The purpose of this study was to evaluate the rates of postoperative complications after surgical fixation of open tibia fractures in smokeless tobacco users as compared to matched tobacco naïve controls. Methods: A retrospective cohort study was conducted using the national PearlDiver database. For patients who had a unilateral open tibia fracture, smokeless tobacco users (n=121) and tobacco-naïve controls (n=242) were matched at a 1:2 ratio. Rates of bone complications within 1 year were compared using multivariable logistic regression. Results: Compared to controls, the smokeless tobacco user cohort demonstrated significantly higher rates of nonunion (OR: 3.42, 95% CI: 1.05 - 11.12), infection / inflammatory reaction of implant (OR: 12.45, 95% CI: 2.67 - 58.93), and osteomyelitis of the leg (OR: 6.15, 95% CI: 1.90 - 19.93) within 1 year of open tibia fracture. Compared to the most recent population figures, smokeless tobacco use was significantly under-reported in both males and females. Conclusions: Smokeless tobacco use confers an increased risk of fracture nonunion, infection or inflammatory response to implant, and osteomyelitis of the leg in patients with open tibia fractures. Surgeons should consider this risk when counseling patients and deciding on treatment plans for patients with tibia fractures.

A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium.

Purpose: To evaluate the safety and efficacy of CBT-001, a multitarget tyrosine kinase inhibitor eyedrop, for pterygia. Design: Phase II clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with primary or recurrent pterygia. Main Outcome Measures: The primary efficacy end point was lesion vascularity based on masked grading of photographs by an independent reading center. Other end points included dimensions of pterygia and safety. Methods: In stage 1, 24 eyes of 24 patients received 1 drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events (AEs) and blood drug levels. In stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed 3 times a day for 4 weeks with a 20-week follow-up. Results: In stage 1, the plasma maximum concentration values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/ml). The most commonly reported AEs were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, the mean change from baseline in pterygium vascularity scores was -0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle (P < 0.001; 95% confidence interval: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. The mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared with vehicle at weeks 2, 4, and 8 (P ≤ 0.014). The most commonly reported AEs were ocular, mild in severity, resolved after therapy, and did not result in discontinuation. Conclusions: CBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident.

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

The Jarring Reality: Adolescent and Pediatric Gunshot Trauma on the Rise in a Major Urban Institution.

INTRODUCTION: Firearms are the leading cause of death in the pediatric population, and the incidence of firearm injury is on the rise in the United States. The purpose of this study was to examine the incidence of pediatric gunshot wounds (GSWs) in New Orleans from 2012 to 2023 and evaluate factors that contribute to mortality. METHODS: A retrospective analysis of pediatric GSWs was conducted using the trauma database at a Level I trauma center in New Orleans, Louisiana. All patients aged 0 to 18 years with a GSW between January 1, 2012, and January 1, 2023, were evaluated. Demographic data, Injury Severity Score (ISS), hospital length of stay (LOS), discharge disposition, intent of injury, mortality, firearm type, orthopaedic injuries, and related surgical procedures were extracted from the database. Linear regression was used to assess the trend of GSWs over time, and logistic regression was used to identify variables that predicted mortality. Statistical significance was defined as α = 0.05. Geographic information system (GIS) mapping was conducted using the ZIP code location of injury to identify geographic areas with the greatest number of GSWs. RESULTS: A significant increasing trend was observed in the number of pediatric GSWs when adjusted for changes in population ( P = 0.014), and the number of GSWs increased 43.2% over the duration of the study. Higher ISS, shorter length of stay, and self-inflicted intent of injury were notable predictors of mortality. Three hundred fifty-four patients (31.4%) had at least one orthopaedic injury, and of the survivors, 365 patients (35.6%) required at least one surgical procedure in the operating room during their admission. DISCUSSION: The number of GSWs in the pediatric population in New Orleans presenting at a large level 1 trauma center demonstrated a statistically significant increasing trend over the past 11 years. ISS and self-inflicted intent were predictive of mortality within this pediatric patient population.

Current Evidence Regarding Shoulder Instability in the Paediatric and Adolescent Population.

Paediatric and adolescent shoulder instability is caused by a unique combination of traumatic factors, ligamentous laxity, and pattern of muscle contractility. The multifactorial nature of its aetiology makes interpretation of the literature difficult as nomenclature is also highly variable. The purpose of this review is to summarize the existing literature and shed light on the nuances of paediatric and adolescent shoulder instability. The epidemiology, clinical features, imaging, and management of all forms of paediatric shoulder instability are presented. The main findings of this review are that structural abnormalities following a dislocation are uncommon in pre-pubertal paediatric patients. Young post-pubertal adolescents are at the highest risk of failure of non-operative management in the setting of traumatic instability with structural abnormality, and early stabilisation should be considered for these patients. Remplissage and the Latarjet procedure are safe treatment options for adolescents at high risk of recurrence, but the side-effect profile should be carefully considered. Patients who suffer from instability due to generalized ligamentous laxity benefit from a structured, long-term physiotherapy regimen, with surgery in the form of arthroscopic plication as a viable last resort. Those who suffer from a predominantly muscle patterning pathology do not benefit from surgery and require focus on regaining neuromuscular control.

Does Topical Vancomycin Powder Use in Fracture Surgery Change Bacteriology and Antibiotic Susceptibilities? An Analysis of the VANCO Trial.

OBJECTIVE: To determine whether intrawound vancomycin changes the bacteriology of surgical site infection pathogens and investigate the emergence of antibiotic-resistant pathogens. DESIGN: Secondary analysis of phase III, prospective, randomized clinical trial. SETTING: Thirty-six US trauma centers. PATIENT SELECTION CRITERIA: Patients who became infected after fixation of tibial plateau or pilon fracture. OUTCOME MEASURES AND COMPARISONS: Pathogen types and bacterial susceptibilities as determined from routine clinical culture in the operating room. RESULTS: Seventy-four patients were studied who were 67.5% male with a mean age of 48.6 years. A lower proportion of gram-positive cocci was observed in the vancomycin powder compared with the standard-of-care group (3.7% vs. 8.0%, P = 0.01). Methicillin-resistant Staphylococcus aureus infection incidence was comparable in both the vancomycin powder and the standard-of-care groups, but rates of methicillin-susceptible S. aureus infections were lower in the treatment group (1.4% vs. 4.8%, P = 0.01). The incidence of coagulase-negative Staphylococci and gram-negative rod infections were similar in both groups. There was no significant difference in susceptibilities between groups in rates of vancomycin-resistant enterococcus. CONCLUSIONS: Topical vancomycin powder decreases the likelihood of gram-positive infections consistent with the biologic activity of vancomycin. Fewer methicillin-susceptible S. aureus and coagulase-negative Staphylococci infections were observed in the group treated with vancomycin powder. An effect of vancomycin powder on methicillin-resistant S. aureus infection risk was not detected given the low incidence in both the intrawound vancomycin and the standard-of-care groups. There was no emergence of gram-negative rod infections or increased resistance patterns observed. Use of topical vancomycin powder does not seem to produce infections in these patients with greater antibiotic resistance than would have occurred without its use. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Three cases of recalcitrant Paecilomyces keratitis in Southern California within a short period.

BACKGROUND: The aim of this report is to describe the risk factors, clinical course, and characteristics of three cases of Paecilomyces keratitis presenting concurrently within three months in the same location. We used in vivo confocal microscopy and histopathology to corroborate our clinical findings. OBSERVATIONS: Three eyes of three elderly patients with culture-proven Paecilomyces keratitis were included in this series. These patients resided within a 15-mile radius and presented to a tertiary care eye institute in Southern California between February and April 2022. All three eyes experienced a prolonged, recalcitrant course with recurrence of keratitis in donor corneal tissue despite antifungal therapy and multiple therapeutic penetrating keratoplasties. In vivo confocal microscopy, histopathology, and microbiologic findings corroborated the diagnosis of fungal keratitis with Paecilomyces. With surgical intervention and extensive medical therapy, all three cases resolved after the addition of oral Posaconazole. CONCLUSIONS: Paecilomyces is a rare cause of infectious keratitis. Herein we report three similar cases in elderly patients. All had prolonged, recalcitrant infections that required multiple treatment modalities. Our cases, which were supported by in vivo confocal microscopy and histopathology, highlight the importance of timely and aggressive therapy to prevent recurrence.

Risk Factors for Meibomian Gland Disease Assessed by Meibography.

Purpose: To elucidate risk factors for meibomian gland disease (MGD) and understand associated changes in meibography and in relation to ocular surface disease. Patients and Methods: As part of the standard workup for ocular surface disease at a tertiary academic center, 203 patients received an ocular history and lifestyle questionnaire. The questionnaire included detailed inquiries about ocular health and lifestyle, including makeup use, cosmetic eyelid procedures, screen time, and contact lens habits. Subjects also took the standardized patient evaluation of eye dryness (SPEED) II questionnaire. Meibomian gland (MG) dropout and structural changes were evaluated on meibography and scored by three independent graders using meiboscores. Statistical analysis was conducted to identify significant risk factors associated with MG loss. Results: This retrospective, cross-sectional study included 189 patients (378 eyes) with high-quality images for grading, and the average age was 67 years (77% female). Patients older than 45 years had significantly more dropout than younger patients (p < 0.01). Self-reported eye makeup use did not significantly impact MG loss. Patients with a history of blepharoplasty trended toward higher meiboscores, but the difference was not statistically significant. Self-reported screen time did not affect meiboscores. Contact lens use over 20 years was associated with significant MG loss (p < 0.05). SPEED II scores had no relationship to meiboscores (p = 0.75). Conclusion: Older age is a significant risk factor for MG loss. Any contact lens use over 20 years also impacted MG dropout. Highlighting the incongruence of symptoms to signs, SPEED II scores showed no relationship to the structural integrity of MGs.

Virtual Reality Planning in Reconstructive Surgery for Orbital Prosthetic Rehabilitation Using ImmersiveTouch Platform: Preliminary Report.

BACKGROUND/PURPOSE: Virtual reality (VR) is emerging as an effective and intuitive surgical planning and 3D visualization tool. Digital surgical planning is the gold standard for planning the placement of implants in maxillofacial prosthetics, but the field lacks a platform exclusively designed to perform the task. Virtual reality planning (VRP) specific for maxillofacial prosthetics offers the clinician improved control of the presurgical planning and the potential to limit the need to adapt other advanced segmentation software. Furthermore, the virtual plan can be directly translated to the patient through custom 3D printed (3DP) surgical guides and visual aids. To the best of our knowledge, this article outlines the development of the world's first virtual reality planning platform and workflow for pre-operatory planning within a VR environment for clinical use specific to facial prosthetics and anaplastology. METHOD: The workflow was applied to managing 2 patients presenting with unilateral total exenteration and severe contracture enucleation, respectively (n=2). A cone-beam CT was acquired for each patient, and their data set was directly imported into the ImmersiveView Surgical Plan VR environment (ImmersiveTouch Inc, Chicago, IL). The clinicians virtually selected appropriately sized craniofacial implants and placed the implants in the desired orientation. Various measurement tools are available to aid in clinical decision-making. The ideal location of craniofacial implants was set according to an orbital and auricular prosthetic reconstruction. The resultant VR plan was exported for 3DP. The patients were evaluated preoperatively and postoperatively using the proposed VRP treatment. The workflow's data accuracy was validated postoperatively by comparing posterative CT data and the proposed VRP. Analysis was performed using Mimics software (Materialise, Leuven, Belgium). RESULT: It takes, on average, 10 minutes to place 4 implants in the virtual reality space. The 3DP files resulting from VRP take ~2 hours to print and are constructed with a biocompatible resin appropriate for clinical use as surgical guides. Our user-friendly VRP workflow allows for an accurate simulation of surgical and nonsurgical procedures with an average displacement in XYZ of 0.6 mm and an SD of 0.3 mm. In addition, VRP is an excellent tool to simulate the craniofacial placement procedure and improves unsupervised self-learning teaching. CONCLUSION: VRP is an exciting tool for training clinicians and students in complex surgical procedures. This study shows the promising applicability and efficiency of VR in clinical planning and management of facial rehabilitation. Patients allowed to interact with VR have been engaged, which would aid their treatment acceptance and patient education. A valuable advantage of surgical simulation is the reduced costs associated with renting instruments, buying implant dummies, and surgical hardware. The authors will explore VR to plan and treat surgical and nonsurgical reconstructive procedures and improve soft tissue manipulation. This study outlines the development of an original platform and workflow for segmentation, preoperative planning, and digital design within a VR environment and the clinical use in reconstructive surgery and anaplastology.

Can a 5-to-90-day Mortality Predictor Perform Consistently Across Time and Equitably Across Populations?

Advance care planning (ACP) facilitates end-of-life care, yet many die without it. Timely and accurate mortality prediction may encourage ACP. However, performance of predictors typically differs among sub-populations (e.g., rural vs. urban) and worsens over time ("concept drift"). Therefore, we assessed performance equity and consistency for a novel 5-to-90-day mortality predictor across various demographies, geographies, and timeframes (n = 76,812 total encounters). Predictions were made for the first day of included adult inpatient admissions on a retrospective dataset. AUC-PR remained at 29% both pre-COVID (throughout 2018) and during COVID (8 months in 2021). Pre-COVID-19 recall and precision were 58% and 25% respectively at the 12.5% certainty cutoff, and 12% and 44% at the 37.5% cutoff. During COVID-19, recall and precision were 59% and 26% at the 12.5% cutoff, and 11% and 43% at the 37.5% cutoff. Pre-COVID, compared to the overall population, recall was lower at the 12.5% cutoff in the White, non-Hispanic subgroup and at both cutoffs in the rural subgroup. During COVID-19, precision at the 12.5% cutoff was lower than that of the overall population for the non-White and non-White female subgroups. No other significant differences were seen between subgroups and the corresponding overall population. Overall performance during COVID was unchanged from pre-pandemic performance. Although some comparisons (especially precision at the 37.5% cutoff) were underpowered, precision at the 12.5% cutoff was equitable across most demographies, regardless of the pandemic. Mortality prediction to prioritize ACP conversations can be provided consistently and equitably across many studied timeframes and sub-populations.

The Snuffbox: The Effect of Smokeless Tobacco Use on Scaphoid Fracture Healing.

BACKGROUND: Smoking has been demonstrated to be a risk factor for nonunion of scaphoid fractures, but it is unclear if chewing tobacco confers similar risk. The purpose of this study was to evaluate rates of bone-related complications after nonsurgical management of scaphoid fractures in smokeless tobacco users compared with matched control subjects and compared with smokers. METHODS: A retrospective cohort study was conducted using the PearlDiver database. For patients who underwent nonsurgical management of scaphoid fractures, 212 smokeless tobacco users and 6,048 smokers were matched 1:4 with control subjects (n = 848 and 24,192, respectively) and 212 smokeless tobacco users were matched 1:4 with 848 smokers. Rates of bone-related complications within 2 years of initial injury were compared using multivariable logistic regression. RESULTS: From weeks 12 through 104 after initial injury, compared with control subjects who do not use tobacco, the smokeless tobacco cohort demonstrated markedly higher rates of nonunion (5.7% vs 2.7%, OR: 2.07). Compared with control subjects who do not use tobacco, the smoking cohort demonstrated markedly higher rates of nonunion (4.3% vs 2.6%, OR: 1.91), repair of nonunion (1.5% vs 0.9%, OR: 1.87), and four corner fusion and proximal row carpectomy (0.3% vs 0.1%, OR: 3.17). Smokeless tobacco use was markedly underdiagnosed in the adult male cohort of unilateral scaphoid fractures with 2 years of follow-up found in the database (372 of 25,704, 1.45%) relative to Centers for Disease Control estimates for adult male smokeless tobacco use (4.5%) ( P < 0.001). CONCLUSION: Given the higher rates of nonunion diagnoses after nonsurgical management in this cohort, surgeons should consider asking all patients with scaphoid fractures if they use smokeless tobacco or smoke and consider adding this to the patient's intake history to further identify patients at risk for nonunions. Tobacco cessation counseling is indicated for all tobacco users, including smokeless with scaphoid fractures.

The Role of the Mind-Body Connection in Children with Food Reactions and Identified Adversity: Implications for Integrating Stress Management and Resilience Strategies in Clinical Practice.

Child adversity is often associated with poor quality of life in pediatric gastrointestinal disorders, including non-allergic food reactions (food intolerances), which may be improved using mind-body interventions. We conducted an observational study to (1) describe child adversity (stressors) and resilience factors in children with food intolerances, and (2) explore the association between stressors and self-reported use of integrative modalities. A retrospective chart review of children ≥4-years-old presenting to a pediatric food intolerances clinic from 2017 to 2020 was performed (n = 130). Use of integrative medicine at intake, demographic, illness, and social history data were collected. Qualitative analysis identified exposure to stressors and resilience strategies. Correlation was assessed using a chi-square test. Management of the medical condition was the most common stressor, indicating impact on quality of life. Resilience strategies included themes of self-coping and social support. Individuals with one or more stressors were more likely to be using an integrative modality (most commonly, mind-body interventions) prior to their visit (X2 = 8.1, p = 0.004). Our hypothesis-generating study suggests that screening for child adversity and integrative medicine use may be used to better address quality of life and personalized approaches to treat pediatric food intolerances.

Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

Trends in the Treatment of Adolescent Clavicle Fractures: Are We Listening to the Evidence?

BACKGROUND: From 1999 to 2011, studies demonstrated an increasing trend toward surgical management of adolescent clavicle fractures. The purpose of this study was to examine more recent trends of surgical management of closed clavicle fractures in adolescent patients over the past decade. METHODS: A retrospective cohort study was conducted using the PearlDiver database. Patients with clavicle fractures from 2011 to 2021 were identified and stratified by age, sex, and year of their fracture. Categorical variables were compared with a chi square test, and continuous variables were compared with the Welch t test or Mann-Whitney U test. RESULTS: Overall, there was a significant increase in the percentage of patients surgically treated by open reduction and internal fixation from 2016 to 2021 compared with 2011 to 2015 (8.58% vs. 7.34%, P < 0.001). When stratified by age, both the 10 to 14-year group (3.80% vs. 3.10%, P < 0.001) and the 15 to 18-year group (15.41% vs. 12.84%, P < 0.001) demonstrated significant increases in the percentage of patients surgically treated. CONCLUSION: Despite increasing literature demonstrating high revision surgery rates for surgical treatment of adolescent clavicle fractures with no difference in functional outcomes, this study demonstrated a notable increase in the rate of surgical treatment of adolescent clavicle fractures from 2011 to 2021 in the United States.

Goal setting, goal attainment and quality of life of children following selective dorsal rhizotomy.

AIM: The aim of this study is to describe the individualized occupational performance issues identified by parents/carers and children prior to selective dorsal rhizotomy (SDR) surgery and analyse change up to 2 years post surgery in goal attainment and quality of life (QoL). METHOD: The Australian SDR Research Registry (trial registration: ACTRN12618000985280) was used to extract data for individualized goals, goal attainment and QoL based on the Canadian Occupational Performance Measure (COPM) and the Cerebral Palsy Quality of Life Questionnaire for Children (CP QOL-Child parent-proxy) at baseline and 1 and 2 years following SDR. Change in mean scores was analysed using linear mixed models. RESULTS: Fifty-two children had COPM scores at baseline and 1 and/or 2 years post, of which 28 had two QoL scores. COPM problem areas included leisure (n = 39), productivity (n = 37) and self-care (n = 173). The most common goals were walking (26.1%), participation in physical activities (17.7%) and transitions (14.1%). Mean COPM scores improved significantly between baseline to 1 year and baseline to 2 years (P < 0.001). Mean QoL scores improved between baseline to 1 year for functional QoL domains: participation and physical health (P = 0.003) and pain and impact of disability (P = 0.011). CONCLUSIONS: Collaborative goal setting is an integral part of family-centred rehabilitation practice. The COPM was an appropriate individualized outcome measure in identifying meaningful goals for our SDR cohort. Results demonstrate improved scores in goal attainment and improvement in functional QoL domains. This paper highlights the need to include outcomes that measure daily life experiences.