Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors.

While vaccines and antivirals are now being deployed for the current SARS-CoV-2 pandemic, we require additional antiviral therapeutics to not only effectively combat SARS-CoV-2 and its variants, but also future coronaviruses. All coronaviruses have relatively similar genomes that provide a potential exploitable opening to develop antiviral therapies that will be effective against all coronaviruses. Among the various genes and proteins encoded by all coronaviruses, one particularly "druggable" or relatively easy-to-drug target is the coronavirus Main Protease (3CLpro or Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity-based protein profiling (ABPP)-based chemoproteomic approaches to discover and further optimize cysteine-reactive pyrazoline-based covalent inhibitors for the SARS-CoV-2 Mpro. Structure-guided medicinal chemistry and modular synthesis of di- and tri-substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine-reactive warheads enabled the expedient exploration of structure-activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS-CoV-2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan-coronavirus inhibitors.

Registered nurses' experience as disaster preparedness coordinators during a major incident: A qualitative study.

AIMS: To explore registered nurses' experiences as disaster preparedness coordinators of hospital incident command groups' during a major incident. DESIGN: A qualitative descriptive design using semi-structured interview. METHODS: This was a qualitative study based on one focus group discussion and six individual follow-up interviews. Participants were registered nurses in their capacity as disaster preparedness coordinators with experience from Major Incident simulations and a real-life Major Incident. The interviews were transcribed verbatim and analysed using content analysis. The COREQ checklist was used for reporting the findings. RESULTS: The analysis of data generated the main category: Expectations, previous experience and uncertainty affect hospital incident command group response during a Major Incident and three categories, (I) Gaining situational awareness (containing two subcategories), (II) Transitioning to management (containing three subcategories) and (III) Actions taken during uncertainty (containing two subcategories).

Emergency department registered nurses overestimate their disaster competency: A cross-sectional study.

BACKGROUND: Major incidents continue to pose a threat to health care systems by overwhelming them with a sudden surge of patients. A major factor impacting a hospital's surge capacity is the skills, abilities, and knowledge of emergency department (ED) registered nurses (RN). The level of disaster nursing competency they possess affects patient safety and outcome. ED RNs' ability to accurately assess their competency and knowledge is imperative for mitigating the effect of major incidents. ED RN's perception of overall disaster preparedness has not been thoroughly addressed. The aim of this study was to assess emergency department registered nurses' self-perceived disaster preparedness. METHOD: The study was a cross-sectional study per the STROBE checklist. A self-assessment questionnaire based on the results of a study identifying specific disaster nursing competencies for ED RNs was distributed to all ED RNs at six participating hospitals between January 10th to February 19th of 2019. A five-point Likert-type scale was used to assess competency. RESULTS: ED RNs' disaster preparedness according to the Total Disaster Competency mean was low. Furthermore, the results indicate that ED RNs' significantly overestimate their disaster nursing competency when compared to the Total Disaster Competency mean. Additionally, this study identified factors such as experience and education were positively associated with disaster preparedness and self-assessment ability. CONCLUSION: ED RNs' overestimate their disaster preparedness. However, ED RNs with experience and education may be better prepared. ED RNs with formal disaster education appeared to have better insight concerning their preparedness. Clinical experience, advanced levels of education, and training were positively associated with preparedness. Overestimating disaster competencies may negatively impact patient outcomes during a major incident.

Hospital incident command groups' performance during major incident simulations: a prospective observational study.

BACKGROUND: Hospital incident command groups' (HICG) performance may have a profound impact on hospital response to major incidents. Previous research has assessed hospital incident command group capacity as opposed to performance and factors associated to performance. The objective was to assess associations between decision-making and staff procedure skills of the hospital incident command group. METHODS: This was a prospective observational study using performance indicators to assess hospital incident command groups' decision-making and performance. A total of six hospitals in Stockholm, Sweden, with their respective HICGs participated. Associations between decision-making skills and staff procedure skills during major incident simulations were assessed using measurable performance indicators. RESULTS: Decision-making skills are correlated to staff procedure skills and overall HICG performance. Proactive decision-making skills had significantly lower means than reactive decision-making skills and are significantly correlated to staff procedure skills. CONCLUSION: There is a significant correlation between decision-making skills and staff procedural skills. Hospital incident command groups' proactive decision-making abilities tended to be less developed than reactive decision-making abilities. These proactive decision-making skills may be a predictive factor for overall hospital incident command group performance. A lack of proactive decision-making ability may hamper efforts to mitigate the effects of a major incident.

Hitting a Moving Target: Glioma Stem Cells Demand New Approaches in Glioblastoma Therapy.

BACKGROUND: Glioblastoma multiforme (GBM) continues to devastate patients and outfox investigators and clinicians despite the preponderance of research directed at its biology, pathogenesis and therapeutic advances. GBM routinely outlasts multidisciplinary treatment protocols, almost inevitably recurring in a yet more aggressive and resistant form with distinct genetic differences from the original tumor. Attempts to glean further insight into GBM point increasingly toward a subpopulation of cells with a stem-like phenotype. These cancer stem cells, similar to those now described in a variety of malignancies, are capable of tumorigenesis from a population of susceptible cells. CONCLUSIONS: Glioma stem cells have thus become a prevalent focus in GBM research for their presumed role in development, maintenance and recurrence of tumors. Glioma stem cells infiltrate the white matter surrounding tumors and often evade resection. They are uniquely suited both biochemically and environmentally to resist the best therapy currently available, intrinsically and efficiently resistant to standard chemo- and radiotherapy. These stem cells create an extremely heterogenous tumor that to date has had an answer for every therapeutic question, with continued dismal patient survival. Targeting this population of glioma stem cells may hold the long-awaited key to durable therapeutic efficacy in GBM.

Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy.

Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.

Natural products reveal cancer cell dependence on oxysterol-binding proteins.

Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.