Helicobacter pylori (Hp) vacuolating cytotoxin (VacA) is a bacterial exotoxin that enters host cells and induces mitochondrial dysfunction. However, the extent to which VacA-dependent mitochondrial perturbations affect overall cellular metabolism is poorly understood. We report that VacA perturbations in mitochondria are linked to alterations in cellular amino acid homeostasis, which results in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and subsequent autophagy. mTORC1, which regulates cellular metabolism during nutrient stress, is inhibited during Hp infection by a VacA-dependent mechanism. This VacA-dependent inhibition of mTORC1 signaling is linked to the dissociation of mTORC1 from the lysosomal surface and results in activation of cellular autophagy through the Unc 51-like kinase 1 (Ulk1) complex. VacA intoxication results in reduced cellular amino acids, and bolstering amino acid pools prevents VacA-mediated mTORC1 inhibition. Overall, these studies support a model that Hp modulate host cell metabolism through the action of VacA at mitochondria.

Category: Trauma; Ankle Introduction/Purpose: Ankle fractures are one of the most common conditions treated by orthopaedic surgeons. Many of these injuries are unstable and require surgical open reduction and internal fixation (ORIF) for optimal treatment. While much has been published regarding surgical management and post-operative outcomes of unstable ankle fractures, there are scant epidemiological studies regarding this subject. The purpose of this study is to evaluate the epidemiology of unstable ankle fractures and post-surgical outcomes at an academic hospital and tertiary care center in an urban setting with particular attention paid to gender and ethnicity in this patient population. Methods: Patients that incurred unstable ankle fractures and received surgical ORIF as treatment between January 2011 and August 2020 were reviewed retrospectively and included in this study. Patients' gender, ethnicity, age, body mass index (BMI), medical co-morbidities, smoking status, surgical diagnoses, and procedures were recorded. Exclusion criteria included ankle fractures that were (1) open, (2) treated nonsurgically, (3) seen initially at or after 4 weeks from the time of injury, and (4) in skeletally immature patients. Post-surgical complications and the need for further surgical treatment was documented. Data analysis was performed using the Statistical Package for the Social Sciences (IBM SPSS, Version 24.0. Armonk, NY: IBM Corp). Chi- square analysis was used to identify factors associated with varying incident fracture types and postoperative complications. Logistic regression, reported as an odds ratio, was used to confirm and characterize associations of significance. A p-value less than 0.05 was considered statistically significant. Results: 304 eligible patients had ankle fractures that received ORIF. 65% and 35% of patients were female and male respectively. 50.0%, 24.0%, 17.8%, and 3.3% of patients were Black, Latino, White, and Asian respectively. 46.4%, 28.3%, and 25.3% of patients had a unimalleolar, bimalleolar, and trimalleolar fracture respectively. Men had 42.4% and 47.3% decreased odds of medial and posterior malleolar fracture respectively with 96% increased odds of syndesmotic injury compared to women. Black patients had 150% increased odds of syndesmotic injury compared to other ethnicities. Rate of post-operative complications was 11.5%, where painful implants to necessitate surgical removal as treatment was the most common post-surgical adverse event. Black and Latino patients had a 75.6% and 69.7% decreased odds of having complications respectively compared to White patients. Conclusion: This study provides valuable information upon unstable ankle fractures and post-surgical outcomes with regard to differences in gender and ethnicity. Women were at higher odds for having a medial and posterior malleolar fracture and lower odds for having syndesmotic injury than men. White/Caucasian patients were at higher odds for post-surgical complications than those from other ethnicities. Further study in larger populations may be needed to confirm these findings.

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