TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry. MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load. ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups. ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

The effect of social contingencies on nursing students' reactions during a rural clinical placement.

Students' feedback of their practicum experiences are typically documented only in terms of established nursing competencies and learning objectives. How nursing students cope with social contingencies (e.g., personal health) while away on clinical placement is not commonly reported in the literature. A sample of Australian student nurses was surveyed as a way of contributing new knowledge about what and how social contingencies could impact on a practicum experience. An analysis of the survey data provided by 244 students revealed that of the 14 contingencies used, financial pressure, accommodation, and geographic location, were rated as having the most influence. All of these social contingencies were examined by a principal components analysis. Three factors were identified and interpreted as professional organization, home organization, and personal organization. Three subscales were then derived using these factors and other measures were also calculated. Bivariate and multivariate relationships were subsequently determined. One key finding was that the first year students, compared to their more senior counterparts, expressed less stress during their practicum. The first year students, as opposed to their more experienced peers, also attached less importance to the professional organizational contingencies. The implications of the study for university administrators, nursing education faculty, and managers of clinical facilities conclude the paper.

A comparison of preoperative airway assessment techniques: the modified Mallampati and the upper lip bite test.

The purpose of this study was to compare the preoperative anesthetic airway evaluation methods of the modified Mallamapti test (MMT) and upper lip bite test (ULBT) with the direct laryngoscopic views obtained during tracheal intubation. Positive relationships were predicted for the MMT and ULBT with direct laryngoscopic view and between the MMT and ULBT. We assessed 50 patients' airways preoperatively by MMT and ULBT. Intraoperatively, laryngoscopic views were graded on the Cormack and Lehane scale. Descriptive statistics and correlations were computed. There was no relationship between the MMT and the ULBT and the Cormack and Lehane scale. There was a significant relationship between the ULBT and the Cormack and Lehane scale (r = 0.512; P <.001 ). The ULBT was superior to the MMT in every measure in this study: sensitivity (55% vs 11%), specificity (97% vs 75%), positive predictive value (83% vs 9%), and accuracy (90% vs 64%). The findings of this study support those of a previous study of the ULBT. Because of the ease of the ULBT and the promising results of this small study, we recommend further research with a larger, more diverse sample.