Investigation of small molecule inhibitors of the SARS-CoV-2 papain-like protease by all-atom microsecond modelling, PELE Monte Carlo simulations, and in vitro activity inhibition.

The SARS-CoV-2 papain-like (PLpro) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PLpro inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PLpro. Although not potent as GRL-0617 (45.8 vs 1.6 µM for protease activity, respectively), in vitro fluorogenic enzymatic assays with hypericin show concentration-dependent inhibition of both PLpro protease and deubiquitinating activities. Given its use in supplementations and the FDA conditional approval of a synthetic version, further evaluation of hypericin as a potential SARS-CoV-2 antiviral is warranted.

Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication. Therefore, the need for the development of potent antivirals is still of importance. In this context, the SARS-CoV-2 main protease (Mpro) is a critical target and numerous clinical trials, predominantly in the private domain, are currently in progress. Here, our aim was to extend our previous studies, with hypericin and cyanidin-3-O-glucoside, as potential inhibitors of the SARS-CoV-2 Mpro. Firstly, we performed all-atom microsecond molecular dynamics simulations, which highlight the stability of the ligands in the Mpro active site over the duration of the trajectories. We also invoked PELE Monte Carlo simulations which indicate that both hypericin and cyanidin-3-O-glucoside preferentially interact with the Mpro active site and known allosteric sites. For further validation, we performed an in vitro enzymatic activity assay that demonstrated that hypericin and cyanidin-3-O-glucoside inhibit Mpro activity in a dose-dependent manner at biologically relevant (µM) concentrations. However, both ligands are much less potent than the well-known covalent antiviral GC376, which was used as a positive control in our experiments. Nevertheless, the biologically relevant activity of hypericin and cyanidin-3-O-glucoside is encouraging. In particular, a synthetic version of hypericin has FDA orphan drug designation, which could simplify potential clinical evaluation in the context of COVID-19.

Exploring Variation in Transformation of Primary Care Practices to Patient-Centered Medical Homes: A Mixed Methods Approach.

The objective was to quantify the activities required for patient-centered medical home (PCMH) transformation in a sample of small to medium-sized National Committee for Quality Assurance (NCQA) recognized practices, and explore barriers and facilitators to transformation. Eleven small to medium-sized PCMH practices in Southeastern Pennsylvania completed a survey, which was adapted from the 2011 NCQA standards. Semistructured follow-up interviews were conducted, descriptive statistics were computed for the quantitative analysis, and a process of thematic coding was deployed for the qualitative analysis. Practices had considerable quantitative variation in their workforce composition and the PCMH-related activities they implemented. Most practices improved access and continuity through staff training and team-based care as well as expanded data collection for population management. The barriers to PCMH recognition were least burdensome for the largest practices. The heterogeneity of the small PCMH practices within the study sample underscore the need to understand the key transformation issues as efforts to disseminate the PCMH model continue.

Incidence and prevalence of basal cell carcinoma (BCC) and locally advanced BCC (LABCC) in a large commercially insured population in the United States: A retrospective cohort study.

BACKGROUND: Accurate evaluation of basal cell carcinoma (BCC) in the United States was not possible before the 2011 release of BCC-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes. OBJECTIVE: We sought to describe BCC (including locally advanced BCC [LABCC]) incidence/prevalence and the characteristics of patients in a commercially insured US population. METHODS: This retrospective cohort study used Truven Health MarketScan database insurance claims. Patients, aged 18 years or older with 2 or more BCC claims at least 30 days apart from October 1, 2011, to September 30, 2012, were continuously enrolled in medical and pharmacy benefits for 12 months before and after the index claim. A specific algorithm was used to classify patients with LABCC. RESULTS: A total of 56,987 patients with BCC were identified (39,035 incident cases; 17,952 prevalent cases). Age-adjusted BCC incidence and prevalence were 226.09 and 342.64 per 100,000 persons, respectively. These values project to 542,782 patients (incidence) and 822,593 patients (prevalence) in the 2012 US population. LABCC was uncommon (471 cases identified; projected US incidence and prevalence: 4399 and 7940 patients, respectively). LIMITATIONS: Use of medical claims data and retrospective analysis are limitations. CONCLUSION: In a study designed to distinguish patients with LABCC from the general BCC population based on BCC-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes, 0.8% were found to have LABCC, the majority having pre-existing disease.