The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease

TRPA1- FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p

YesRecent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD) where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline rich motif. Here, we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2 hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.Faculty of Biological Sciences at the University of Leeds, Wellcome Trust Seed Award, Royal Society Research Grant RG150100, MR/K021303/1, Swedish Research Council (2014-3801) and the Medical Faculty at Lund University

Musicisti e dolore cranio-facciale

LETTER TO EDITO

Pre-matriculation clinical experience positively correlates with Step 1 and Step 2 scores

Raj Shah,1 Cameron Johnstone,2 Douglas Rappaport,3 Leslie A Bilello,4 William Adamas-Rappaport5 1University of Arizona College of Medicine, Tucson, AZ, USA; 2University of Arizona College of Medicine, Tucson, AZ, USA; 3Department of Emergency Medicine, Mayo Clinic Hospital, Phoenix, AZ, USA; 4Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA; 5Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA Background: This study investigates whether students with pre-matriculation, formalized, clinical experience performed better in Step 1 and Step 2 of the United States Medical Licensing Exams (USMLE) compared to students without formal pre-matriculation clinical experience.Methods: This research investigation was a retrospective cohort study conducted at the University of Arizona College of Medicine in Tucson, Arizona, USA, and analyzed students in the Class of 2017 and Class of 2018. Formal clinical experience was defined as registered nurses, physician assistants, nurse practitioners, paramedics, emergency medical technicians, or licensed practical nurses for any amount of time prior to matriculation, as well as scribing for at least 6 months prior to matriculation. Students with any amount of shadowing experience were not considered to have clinical experience. The authors performed multiple regression analyses to investigate the effects of formal clinical experience on USMLE exam performance. Statistical significance was defined as P<0.05. All statistical analyses were performed using SAS 9.4.Results: Our study had a total of 227 students from the two classes, with 40 (17.6%) having formal pre-matriculation clinical experience, as already defined. Nine (3.96%) students were not assessed in USMLE Step 1 calculations, and 61 (26.9%) students were not assessed in USMLE Step 2 calculations due to an absence of recorded USMLE scores. Formal pre-matriculation clinical experience was a statistically significant positive predictor of USMLE Step 1 score (P=0.03) and USMLE Step 2 score (P<0.010).Conclusion: Formal pre-matriculation clinical experience, as defined previously, positively correlates with an increase in USMLE Step 1 and Step 2 scores. Keywords: medical education, medical school admissions, clinical experience, USMLE Step 1 and Step

Fourth-year medical students do not perform a focused physical examination during a case-based simulation scenario

Leslie A Bilello,1 Nicole M Dubosh,1 Jason J Lewis,1 Matthew M Hall,1 Jonathan Fisher,2 Edward A Ullman1 1Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Department of Emergency Medicine, Maricopa Medical Center, Phoenix, AZ, USA Background: The art of physical examination is one of the most valuable diagnostic tools bestowed upon new generations of medical students. Despite traditional educational techniques and significant attention on a national level, both trainees and educators have noticed a decrease in physical examination proficiency. Simulation has been identified as a potential way to improve physical examination techniques within undergraduate medical education. We sought to determine the utility of a cardiac case-based simulation scenario to assess physical examination performance of fourth-year medical students during an emergency medicine (EM) clerkship.Materials and methods: Fourth-year medical students enrolled in a 4-week EM clerkship were prospectively evaluated during a case-based scenario using a simulation mannequin (Laerdal SimMan®). The case involved a patient presenting with chest pain that evolved into cardiac arrest. All simulations were video recorded and two emergency physicians reviewed each video. The reviewers recorded whether or not each student completed the essential components of a focused physical examination.Results: Twenty-seven students participated in the simulation. The percentage of students completing each of the four components of the physical examination was as follows: cardiac auscultation 33.3% (95% CI 18.5–52.3), lung auscultation 29.6% (95% CI 15.7–48.7), pulse and extremity examination 55.6% (95% CI 37.3–72.4), and abdominal examination 3.70% (95% CI 0–19.8). None of the students completed all four of these components.Conclusion: Our study showed that fourth-year medical students did not uniformly perform components of a focused physical examination during a high-acuity chest pain simulation scenario. Although our study showed limited physical examination performance, simulation allows evaluators to observe and provide constructive feedback and may lead to an improvement in these skills. These findings call for improved technology to increase authenticity of simulators and continued faculty development for more creative, meaningful integration of physical examination skills into high-acuity simulation cases. Keywords: emergency medicine, medical student education, undergraduate medical education, physical examination skill