Misregulation of cell adhesion molecules in the Ciona neural tube closure mutant bugeye.

Neural tube closure (NTC) is a complex multi-step morphogenetic process that transforms the flat neural plate found on the surface of the post-gastrulation embryo into the hollow and subsurface central nervous system (CNS). Errors in this process underlie some of the most prevalent human birth defects, and occur in about 1 out of every 1000 births. Previously, we discovered a mutant in the basal chordate Ciona savignyi (named bugeye) that revealed a novel role for a T-Type Calcium Channel (Cav3) in this process. Moreover, the requirement for CAV3s in Xenopus NTC suggests a conserved function among the chordates. Loss of CAV3 leads to defects restricted to anterior NTC, with the brain apparently fully developed, but protruding from the head. Here we report first on a new Cav3 mutant in the related species C. robusta. RNAseq analysis of both C. robusta and C. savignyi bugeye mutants reveals misregulation of a number of transcripts including ones that are involved in cell-cell recognition and adhesion. Two in particular, Selectin and Fibronectin leucine-rich repeat transmembrane, which are aberrantly upregulated in the mutant, are expressed in the closing neural tube, and when disrupted by CRISPR gene editing lead to the open brain phenotype displayed in bugeye mutants. We speculate that these molecules play a transient role in tissue separation and adhesion during NTC and failure to downregulate them leads to an open neural tube.

Lung transplantation after ex vivo lung perfusion versus static cold storage: An institutional cost analysis.

Ex vivo lung perfusion (EVLP) is a novel lung preservation strategy that facilitates the use of marginal allografts; however, it is more expensive than static cold storage (SCS). To understand how preservation method might affect postoperative costs, we compared outcomes and index hospitalization costs among matched EVLP and SCS preserved lung transplant (LTx) recipients at a single, high-volume institution. A total of 22 EVLP and 66 matched SCS LTx recipients were included; SCS grafts were further stratified as either standard-criteria (SCD) or extended-criteria donors (ECD). Median total preservation time was 857, 409, and 438 min for EVLP, SCD, and ECD lungs, respectively (p < .0001). EVLP patients had similar perioperative outcomes and posttransplant survival compared to SCS SCD and ECD recipients. Excluding device-specific costs, total direct variable costs were similar among EVLP, SCD, and ECD recipients (median $200,404, vs. $154,709 vs. $168,334, p =  .11). The median direct contribution margin was positive for EVLP recipients, and similar to that for SCD and ECD graft recipients (all p > .99). These findings demonstrate that the use of EVLP was profitable at an institutional level; however, further investigation is needed to better understand the financial implications of EVLP in facilitating donor pool expansion in an era of broader lung sharing.

Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin-Like Compounds.

Oxaliplatin, a platinum compound in broad clinical use, can induce cell death through a nucleolar stress pathway rather than the canonical DNA damage response studied for other Pt(II) compounds. Previous work has found that the oxaliplatin 1,2-diaminocyclohexane (DACH) ring but not the oxalate leaving group is important to the ability to induce nucleolar stress. Here we study the influence of DACH ring substituents at the 4-position on the ability of DACH-Pt(II) compounds to cause nucleolar stress. We determine that DACH-Pt(II) compounds with 4-position methyl, ethyl, or propyl substituents induce nucleolar stress, but DACH-Pt(II) compounds with 4-isopropyl substituents do not induce nucleolar stress. This effect is independent of whether the substituent is in the axial or equatorial position relative to the trans diamines of the ligand. These results suggest that spatially sensitive interactions could be involved in the ability of platinum compounds to cause nucleolar stress.

Thiol-Activated 1,2,4-Thiadiazolidin-3,5-diones Release Hydrogen Sulfide through a Carbonyl-Sulfide-Dependent Pathway.

Recent efforts have expanded the development of small molecule donors that release the important biological signaling molecule hydrogen sulfide (H2S). Previous work on 1,2,4-thiadiazolidin-3,5-diones (TDZNs) reported that these compounds release H2S directly, albeit inefficiently. However, TDZNs showed promising efficacy in H2S-mediated relaxation in ex vivo aortic ring relaxation models. Here, we show that TDZNs release carbonyl sulfide (COS) efficiently, which can be converted to H2S by the enzyme carbonic anhydrase (CA) rather than releasing H2S directly as previously reported.

N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release.

Hydrogen sulfide (H2S) is an important biomolecule, and self-immolative thiocarbamates have shown great promise as triggerable H2S donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient H2S donors. We report here the synthesis and study of a series of N-methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for H2S release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate N-methylation does block some side reactivity and increases the H2S release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-poor donors is likely due to other side reactions.

The Potential Value of Performing Preoperative Urinalysis Prior to Total Knee Arthroplasty.

BACKGROUND: Although the practice of checking a urinalysis prior to elective total knee arthroplasty (TKA) is relatively common, very little has been reported on the association between a preoperative urinary tract infection (UTI) and adverse events in primary TKA. The goal of this study is to investigate the risk of postoperative complication following TKA as it relates to preoperative UTI. METHODS: Patients undergoing TKA were queried in the National Surgical Quality Improvement Program. Morbid events were classified as minor (transfusion, pneumonia, wound dehiscence, UTI, and renal insufficiency) and serious (wound infection, thromboembolic event, renal failure, myocardial infarction, prolonged ventilation, unplanned intubation, sepsis, and death). Risk factors for adverse events were analyzed in both univariate and multivariate fashion. RESULTS: A total of 203,851 patients undergoing TKA met inclusion criteria and 507 patients had a UTI present at time of surgery (UTI PATOS). A propensity matched analysis controlling for age, gender, body mass index, operative year, and American Society of Anesthesiologists score identified 507 patients without a UTI PATOS to serve as the control group. Following adjustment for baseline characteristics, operative year, and American Society of Anesthesiologists score, UTI PATOS was associated with increased risk for serious adverse events (odds ratio [OR] 2.746, 95% confidence interval [CI] 1.546-4.878, P = .0006), occurrence of any morbid event (OR 1.894, 95% CI 1.299-2.761, P = .0009), and reoperation (OR 4, 95% CI 2.592-6.169, P < .0001). CONCLUSION: This study suggests that a UTI present at time of TKA increases the risk of multiple postoperative complications and reoperation.

Changes in older adults' impairment, activity, participation and wellbeing as measured by the AusTOMs following participation in a Transition Care Program.

INTRODUCTION: Maintaining a continuum of care is vital to ensure adequate health among older adults, particularly during periods of care transitions, when they are vulnerable and at risk of poor health outcomes. The Transition Care Program in Australia is designed to support older adults following the conclusion of a hospital episode. Using the Australian Therapy Outcome Measures for Occupational Therapy (AusTOMs-OT), this study aimed to understand how the Transition Care Program impacts an older adult's occupational performance during care transitions. METHODS: Data were collected as a part of usual occupational therapy care from March 2016 to August 2017 from clients admitted to a Gold Coast Health Transition Care Program. Data from 110 clients were analysed on 5 AusTOMs-OT scales: functional walking and mobility, upper limb use, self care, domestic life-home, and community life/recreation/leisure/play. Change data from these scales were analysed using the Wilcoxon Signed Ranks Test. RESULTS: Clients in the Transition Care Program experienced statistically and clinically significant improvements in all AusTOMs-OT scales analysed as well as in each domain of impairment, activity limitation, participation restriction and distress/wellbeing. CONCLUSION: These results are meaningful for clients, occupational therapists and Australian Transition Care Programs. Clients demonstrated progress towards their goals, indicating maintenance or improvements in their occupational performance, confirming for occupational therapists that the provision of services is promoting goal achievement and leading to improved occupational performance. The study also highlighted the benefits for the use of outcome measures such as the AusTOMs-OT to quantify and validate client change.

8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells.

Ras converting enzyme 1 (Rce1) is an endoprotease that catalyzes processing of the C-terminus of Ras protein by removing -aaX from the CaaX motif. The activity of Rce1 is crucial for proper localization of Ras to the plasma membrane where it functions. Ras is responsible for transmitting signals related to cell proliferation, cell cycle progression, and apoptosis. The disregulation of these pathways due to constitutively active oncogenic Ras can ultimately lead to cancer. Ras, its effectors and regulators, and the enzymes that are involved in its maturation process are all targets for anti-cancer therapeutics. Key enzymes required for Ras maturation and localization are the farnesyltransferase (FTase), Rce1, and isoprenylcysteine carboxyl methyltransferase (ICMT). Among these proteins, the physiological role of Rce1 in regulating Ras and other CaaX proteins has not been fully explored. Small-molecule inhibitors of Rce1 could be useful as chemical biology tools to understand further the downstream impact of Rce1 on Ras function and serve as potential leads for cancer therapeutics. Structure-activity relationship (SAR) analysis of a previously reported Rce1 inhibitor, NSC1011, has been performed to generate a new library of Rce1 inhibitors. The new inhibitors caused a reduction in Rce1 in vitro activity, exhibited low cell toxicity, and induced mislocalization of EGFP-Ras from the plasma membrane in human colon carcinoma cells giving rise to a phenotype similar to that observed with siRNA knockdowns of Rce1 expression. Several of the new inhibitors were more effective at mislocalizing K-Ras compared to a potent farnesyltransferase inhibitor (FTI), which is significant because of the preponderance of K-Ras mutations in cancer.

Identifying expectant parents at risk for psychological distress in response to a confirmed fetal abnormality.

The aim of the study was to determine the incidence of psychological distress among expectant women carrying fetuses with prenatal diagnosed abnormalities and their partners. A 2-year retrospective medical chart review was completed of 1032 expectant mothers carrying fetuses with a confirmed anomaly, and 788 expectant fathers, who completed the CFDT Mental Health Screening Tool. Furthermore, 19.3 % of women and 13.1 % of men reported significant post-traumatic stress symptoms, and 14 % of men and 23 % of women scored positive for a major depressive disorder. Higher risk was noted among expectant parents of younger age and minority racial/ethnic status, and women with post-college level education and current or prior use of antidepressant medications. Heightened distress was noted within fetal diagnostic subgroups including neck masses, sacrococcygeal teratomas, neurological defects, and miscellaneous diagnoses. Incorporating screening tools into prenatal practice can help clinicians better identify the potential risk for psychological distress among expectant parents within high-risk fetal settings.

Social Media Use among Orthopedic Trauma Fellowship-trained Surgeons.

Objective: To quantify the use of social media platforms by orthopedic traumatologists with an emphasis on demographic, practice-based, and regional differences. Materials and Methods: Using the Orthopaedic Trauma Association (OTA) membership database, online searches were performed to identify professional profiles on numerous social media platforms. This presence was then quantified by a cumulative social media score which was correlated to the demographic information collected. Results: In total, 1,262 active fellowship-trained orthopedic traumatologists were identified. Surgeons practicing in an academic setting were found to be more likely to use numerous social media platforms and to present an overall greater social media score than those in private practices. No significant differences in use were found based on practice region. Conclusion: Social media platforms are currently underused by orthopedic traumatologists. Level of Evidence: IV.

Advances and Opportunities in H2S Measurement in Chemical Biology.

Hydrogen sulfide (H2S) is an important biological mediator across all kingdoms of life and plays intertwined roles in various disciplines, ranging from geochemical cycles to industrial processes. A common need across these broad disciplines is the ability to detect and measure H2S in complex sample environments. This Perspective focuses on key advances and opportunities for H2S detection and quantification that are relevant to chemical biology. Specifically, we focus on methods for H2S detection and quantification most commonly used in biological samples, including activity-based H2S probes, the methylene blue assay, the monobromobimane assay, and H2S-sensitive electrode measurements. Our goal is to help simplify what at first may seem to be an overwhelming array of detection and measurement choices, to articulate the strengths and limitations of individual techniques, and to highlight key unmet needs and opportunities in the field.

On the Rise: The Increasing Frequency of Pediatric Shoulder Stabilization Surgery in Children and Adolescents.

The management of shoulder instability in children and adolescents continues to evolve. The purpose of this study was to evaluate the epidemiology of shoulder stabilization procedures in a large, nationally representative pediatric population. The Pediatric Health Information System (PHIS) database was queried for patients 18 years and younger undergoing surgical shoulder stabilization between 2008 and 2017. Patients undergoing arthroscopic surgery were compared with patients undergoing complex (open or bony augment stabilization) procedures. Annual trends were calculated using linear regression. A total of 3925 procedures were performed, of which 92.9% were arthroscopic Bankart repairs. There was a significant increase in overall pediatric shoulder stabilizations and arthroscopic repairs between 2008 and 2017. Complex procedures were performed most often in the Northeast, but the annual frequency did not increase nationally. [Orthopedics. 2023;46(3):e167-e172.].

COVID as a catalyst: medical student perspectives on professional identity formation during the COVID-19 pandemic.

Background: As a result of the COVID-19 pandemic, a national decision was made to remove all medical students from clinical environments resulting in a major disruption to traditional medical education. Our study aimed to explore medical student perspectives of professional identity formation (PIF) during a nationally unique period in which there was no clinical training in medical undergraduate programs. Methods: We interviewed fifteen UBC medical students (years 1-4) regarding their perspectives on PIF and the student role in the setting of the COVID-19 pandemic. Data were analysed iteratively and continuously to create a codebook and identify themes of PIF based on interview transcripts. Results: We identified three key themes: (1) Medical students as learners vs contributing team members (2) Decreased competency as a threat to identity and (3) Doctors as heroes. Conclusions: The impact of disruptions due to COVID-19 catalyzed student reflections on their role within the healthcare system, as well as the role of self-sacrifice in physician identity. Simultaneously, students worried that disruptions to clinical training would prevent them from actualizing the identities they envisioned for themselves in the future. Ultimately, our study provides insight into student perspectives during a novel period in medical training, and highlights the unique ways in which PIF can occur in the absence of clinical exposure.

Contexte: En réponse à la pandémie de la COVID-19, la décision a été prise de retirer les étudiants en médecine des milieux cliniques à l'échelle nationale, ce qui a entraîné une perturbation majeure de l'enseignement médical traditionnel. Notre étude visait à explorer les opinions des étudiants en médecine sur la formation de l'identité professionnelle (FIP) au cours de cette période unique marquée par l'absence de formation clinique dans les programmes d'études médicales pré-doctorales. Méthodes: Nous avons sondé quinze étudiants en médecine de l'Université de Colombie-Britannique (1re à 4e année) pour recueillir leur point de vue sur la FIP et sur le rôle des étudiants dans le contexte de la pandémie. Les données ont été analysées de manière itérative et continue afin de créer une liste de codes et de dégager les thèmes en rapport avec la FIP à partir des transcriptions de ces entretiens. Résultats: Nous avons identifié trois thèmes clés : (1) les étudiants en médecine, en tant qu'apprenants versus en tant que membres actifs d'une équipe (2), la diminution des compétences comme menace pour l'identité et (3) les médecins comme héros. Conclusions: L'impact des perturbations dues à la COVID-19 a suscité chez les étudiants une réflexion sur leur rôle au sein du système de santé, ainsi que sur le rôle de l'abnégation dans l'identité du médecin. Parallèlement, les étudiants craignaient que les bouleversements de la formation clinique les empêchent de concrétiser leur identité professionnelle telle qu'ils l'envisageaient. En somme, notre étude donne un aperçu des réflexions des étudiants au cours d'une période inédite de la formation médicale et met en évidence les façons uniques dont l'identité professionnelle peut se construire en l'absence d'exposition clinique.

CFTR modulators increase risk of acute pancreatitis in pancreatic insufficient patients with cystic fibrosis.

Patients with pancreatic insufficient cystic fibrosis rarely develop acute pancreatitis due to insufficient acinar reserve. We describe a series of five patients under the age of 18 (range 8-16 years) with pancreatic insufficient cystic fibrosis who developed a phenotype in keeping with acute pancreatitis following initiation of CFTR modulator therapy. This occurred at a median of 30 months following CFTR modulator initiation. 3/5 of these patients also developed pancreatic sufficiency or at least an intermediary pancreas status, indicated by fecal elastases above 100 µg/g. This series highlights a mostly unrecognized potential side effect of this therapy as well as the potential of CFTR modulator therapies to improve exocrine pancreatic function, even in adolescent patients.

Orthopaedic Surgery Residency Program Websites: A Five-Year Update and the Rise of Social Media.

Objective  The importance of online information in the form of residency program websites has been well documented. With the rise of popularity of social media, another potential vital source of online information distribution exists. We aimed to examine the changes in orthopaedic surgery residency program websites and determine the use of social media by these programs. Methods A list of orthopaedic residency programs was obtained. Websites were then assessed for presence of numerous criteria. The presence of a social media account on Instagram, Twitter, and Facebook platforms was then determined. Results One hundred ninety-five websites out of 197 programs were identified. The most commonly present criterion was resident rotation schedule with 187 (96%) listings. Meanwhile, information on virtual sessions for prospective applicants was the least present at 26 (13%). Out of the 33 criteria assessed, websites contained an average of 20.4 criteria. Approximately half of the programs were noted to have a social media presence. Conclusion Website utilization and accessibility have improved over time as the importance of online information has continued to grow in the orthopaedic surgery residency application process. In order to increase their online presence, numerous programs have recently created or enhanced the profiles on social media platforms which may reach more users than websites alone.

What Are the Causes and Consequences of Delayed Surgery for Pediatric Tibial Spine Fractures? A Multicenter Study.

Background: The uncommon nature of tibial spine fractures (TSFs) may result in delayed diagnosis and treatment. The outcomes of delayed surgery are unknown. Purpose: To evaluate risk factors for, and outcomes of, delayed surgical treatment of pediatric TSFs. Study Design: Cohort study; Level of evidence, 3. Methods: The authors performed a retrospective cohort study of TSFs treated surgically at 10 institutions between 2000 and 2019. Patient characteristics and preoperative data were collected, as were intraoperative information and postoperative complications. Surgery ≥21 days after injury was considered delayed based on visualized trends in the data. Univariate analysis was followed by purposeful entry multivariate regression to adjust for confounders. Results: A total of 368 patients (mean age, 11.7 ± 2.9 years) were included, 21.2% of whom underwent surgery ≥21 days after injury. Patients who experienced delayed surgery had 3.8 times higher odds of being diagnosed with a TSF at ≥1 weeks after injury (95% CI, 1.1-14.3; P = .04), 2.1 times higher odds of having seen multiple clinicians before the treating surgeon (95% CI, 1.1-4.1; P = .03), 5.8 times higher odds of having magnetic resonance imaging (MRI) ≥1 weeks after injury (95% CI, 1.6-20.8; P < .007), and were 2.2 times more likely to have public insurance (95% CI, 1.3-3.9; P = .005). Meniscal injuries were encountered intraoperatively in 42.3% of patients with delayed surgery versus 21.0% of patients treated without delay (P < .001), resulting in 2.8 times higher odds in multivariate analysis (95% CI, 1.6-5.0; P < .001). Delayed surgery was also a risk factor for procedure duration >2.5 hours (odds ratio, 3.3; 95% CI, 1.4-7.9; P = .006). Patients who experienced delayed surgery and also had an operation >2.5 hours had 3.7 times higher odds of developing arthrofibrosis (95% CI, 1.1-12.5; P = .03). Conclusion: Patients who underwent delayed surgery for TSFs were found to have a higher rate of concomitant meniscal injury, longer procedure duration, and more postoperative arthrofibrosis when the surgery length was >2.5 hours. Those who experienced delays in diagnosis or MRI, saw multiple clinicians, and had public insurance were more likely to have a delay to surgery.

Epidemiology of Meniscal Allograft Transplantation at Children's Hospitals in the United States.

BACKGROUND: Meniscal allograft transplantation (MAT) was developed with the goal of delaying the progression of degenerative disease in the setting of substantial meniscal deficiency. This may be especially important in children and adolescents; however, there is a paucity of literature on MAT in this population. PURPOSE: To evaluate the epidemiology of MAT at pediatric hospitals in the United States, with specific attention to regional and characteristic trends. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The Pediatric Health Information System, a national database consisting of 49 children's hospitals, was queried for all patients younger than 25 years who underwent MAT between 2011 and 2018. Characteristic information and surgical history were collected for each patient. The database was also queried for all patients who underwent other meniscal surgeries (including debridement, meniscectomy, and meniscal repair) during the same period (controls). Characteristic and geographic data from the control group were compared with those of the patients who underwent MAT. Univariate analysis was followed by purposeful entry multivariate regression to adjust for confounding factors. RESULTS: A total of 27,168 meniscal surgeries were performed in 47 hospitals, with MAT performed 67 times in 17 hospitals. Twelve (18%) patients underwent a subsequent procedure after transplantation. In multivariate analysis, each year of increasing age resulted in 1.1 times higher odds of having undergone MAT (95% CI, 1.03-1.1; P = .002) compared with repair or meniscectomy. Patients who underwent MAT also had 2.0 times higher odds of being women (95% CI, 1.2-3.3; P = .01) and 2.0 times higher odds of being privately insured (95% CI, 1.1-3.6; P = .02). MAT was performed most frequently in the Northeast (4.9/1000 meniscal surgeries) and least often in the South (1.1/1000 meniscal surgeries) (P < .001). CONCLUSION: In the United States, pediatric and adolescent patients who underwent MAT were older and more likely to be female and have private insurance than those undergoing meniscal repair or meniscectomy. MAT was only performed in 17 of 47 children's hospitals that perform meniscal surgery. These trends highlight the need for further research, especially regarding differences along the lines of sex and insurance status.

Pregnancy-Associated Perivascular Epithelioid Cell Tumor of the Tarsal Navicular: A Case Report.

CASE: A 30-year-old pregnant woman with perivascular epithelioid cell tumor (PEComa) of the tarsal navicular underwent intralesional curettage with allograft at 30 weeks' gestation. She had an uncomplicated delivery at term and is ambulating without tumor recurrence at 1-year follow-up. CONCLUSION: PEComas are rare tumors most commonly found in soft tissues but have been reported in bone and are occasionally associated with pregnancy. To the best of our knowledge, this is the first reported case of pregnancy-associated PEComa of bone.