Large-Scale Virtual Screening for the Discovery of SARS-CoV-2 Papain-like Protease (PLpro) Non-covalent Inhibitors.

The rapid global spread of the SARS-CoV-2 virus facilitated the development of novel direct-acting antiviral agents (DAAs). The papain-like protease (PLpro) has been proposed as one of the major SARS-CoV-2 targets for DAAs due to its dual role in processing viral proteins and facilitating the host's immune suppression. This dual role makes identifying small molecules that can effectively neutralize SARS-CoV-2 PLpro activity a high-priority task. However, PLpro drug discovery faces a significant challenge due to the high mobility and induced-fit effects in the protease's active site. Herein, we virtually screened the ZINC20 database with Deep Docking (DD) to identify prospective noncovalent PLpro binders and combined ultra-large consensus docking with two pharmacophore (ph4)-filtering strategies. The analysis of active compounds revealed their somewhat-limited diversity, likely attributed to the induced-fit nature of PLpro's active site in the crystal structures, and therefore, the use of rigid docking protocols poses inherited limitations. The top hits were assessed against recombinant viral proteins and live viruses, demonstrating desirable inhibitory activities. The best compound VPC-300195 (IC50: 15 µM) ranks among the top noncovalent PLpro inhibitors discovered through in silico methodologies. In the search for novel SARS-CoV-2 PLpro-specific chemotypes, the identified inhibitors could serve as diverse templates for the development of effective noncovalent PLpro inhibitors.

The Anti-Obesity Compound Asperuloside Reduces Inflammation in the Liver and Hypothalamus of High-Fat-Fed Mice

Obesity produces a systemic low-grade inflammation associated with many adverse health conditions and, as we recently learned, with complications of COVID-19. Functional studies in animal models have demonstrated that asperuloside, an iridoid glycoside found in many medicinal plants, has produced promising anti-obesity results. However, the safety profile and the anti-inflammatory properties of asperuloside remain unknown. Here, we confirmed the previously reported anti-obesity properties of asperuloside, and, importantly, we performed toxicity studies assessing cell viability providing a dose reference for future animal experiments. Asperuloside significantly reduced blood levels of leptin and the mRNA levels of orexigenic peptides, such as NPY and AgRP in mice consuming HFD, with no effect on mice eating a standard chow diet. In addition, our results indicate that ASP reduced both hypothalamic and hepatic mRNA levels of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-αas well as the blood levels of plasminogen activator inhibitor-1 (PAI-1), which are known to play a major role in the development of insulin resistance and cardiovascular complications. Collectively, our findings suggest that asperuloside is a safe compound for long-term use in animal models and that it reduces the elevated levels of pro-inflammatory cytokines occurring in obesity.

SNAPTIMED study: does the Scottish and Newcastle Antiemetic Protocol achieve timely intervention and management from the emergency department to discharge for paracetamol poisoning?

BACKGROUND: This study aimed to establish whether the modified 12-hour Scottish and Newcastle Antiemetic Protocol (SNAP) for paracetamol poisoning is associated with improvement in hospital length of stay (LoS), as well as to validate the performance of the protocol for the prevention of anaphylactoid reactions and total infusion duration. METHODS: Retrospective chart review from 25 March 2019 to 25 September 2020. Patients aged 16 or older with a diagnosis of suspected or confirmed paracetamol overdose were included in the analysis if they received treatment for paracetamol poisoning, and the protocol used could be identified. Data were collected for LoS, number of extended treatment infusions used and evidence of anaphylactoid reaction. RESULTS: 1167 records were assessed for eligibility, and 294 were included for analysis. Use of the SNAP was associated with a statistically significant reduction in LoS of -8.8 hours (95% CI -12.6 to -2.0), and a reduced risk of anaphylactoid reaction (Number Needed to Treat=10). CONCLUSION: In this retrospective study, use of the SNAP reduced the duration of inpatient admissions and rate of anaphylactoid reactions.

A new pandemic and an old epidemic: The impact of COVID-19 and gun violence as measured by years of potential life lost in a US city.

BACKGROUND: The COVID-19 pandemic has altered daily life on a global scale and has resulted in significant mortality with >985,000 lives lost in the United States alone. Superimposed on the COVID-19 pandemic has been a concurrent worsening of longstanding urban gun violence. We sought to evaluate the impact attributable to these 2 major public health issues on the greater Louisville region as determined by years of potential life lost. METHODS: Using the Collaborative Jefferson County Firearm Injury Database, all firearm injuries from January 1, 2011 to December 31, 2021 were examined. The COVID-19 data was compiled from the Louisville Metro Department of Public Health and Wellness. Pre-COVID (March 1, 2019-February 29, 2020) and COVID (March 1, 2020-February 28, 2021) time intervals were examined. The demographics, outcomes data, and years of potential life lost were determined for the groups, and injury locations were geocoded. RESULTS: From 2011 to 2021, there were 6,043 firearm injuries in Jefferson County, Kentucky. During the COVID time interval, there were 4,574 years of potential life lost due to the SARS-CoV-2 virus and 9,722 years of potential life lost due to all-cause gun violence. In the pre-COVID time interval, there were 5,723 years of potential life lost due to all-cause gun violence. CONCLUSION: In Louisville, greater years of potential life lost were attributable to firearm fatalities than the SARS-CoV-2 virus. Given the impact of COVID-19, the robust response has been proportionate and appropriate. The lack of response to firearm injury and fatality is striking in comparison. Additional resources to combat the sequelae of gun violence are needed.

Tackling Challenging Data Integrity Topics in 2020: Update on Good Clinical Practice Perspectives from the US FDA and MHRA UK.

With the globalization of clinical trials, regulators have increased collaboration to evaluate the adequacy of clinical trial conduct and to optimize regulatory oversight. The 2020 joint Good Clinical Practice (GCP) symposium of the US Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency provided the agencies' perspectives on the challenges in ensuring data quality in novel clinical trial designs and the importance of the management and documentation of protocol deviations, sponsor oversight of clinical trials, and use of electronic source data, including electronic health records. This paper summarizes considerations of both agencies on these topics, along with case examples. This paper touches upon considerations when using real-world data to support regulatory decisions. It also discusses the impact of the coronavirus disease 2019 (COVID-19) pandemic on clinical trial conduct and underscores the importance of well-designed, resilient, and adaptable systems for GCP compliance and data integrity.

Telemedicine Can Support Measurable and High-Quality Epilepsy Care During the COVID-19 Pandemic.

Routine outpatient epilepsy care has shifted from in-person to telemedicine visits in response to safety concerns posed by the coronavirus disease 2019 (COVID-19) pandemic. But whether telemedicine can support and maintain standardized documentation of high-quality epilepsy care remains unknown. In response, the authors conducted a quality improvement study at a level 4 epilepsy center between January 20, 2019, and May 31, 2020. Weekly average completion proportion of standardized documentation used by a team of neurologists for adult patients for the diagnosis of epilepsy, seizure classification, and frequency were analyzed. By December 15, 2019, a 94% average weekly completion proportion of standardized epilepsy care documentation was achieved that was maintained through May 31, 2020. Moreover, during the period of predominately telemedicine encounters in response to the pandemic, the completion proportion was 90%. This study indicates that high completion of standardized documentation of seizure-related information can be sustained during telemedicine appointments for routine outpatient epilepsy care at a level 4 epilepsy center.

Successful heart transplantation in a patient who recovered from COVID-19.

Coronavirus disease-2019 has created unprecedented challenges for society, and specifically the medical community. While the pandemic continues to unfold, the transplant community has had to pivot to keep recipients, donors, and institutional transplant teams safe given the unique circumstances inherent to solid organ transplantation.

Virtual academic detailing (e-Detailing): A vital tool during the COVID-19 pandemic.

As the coronavirus disease (COVID-19) pandemic continues its course in 2020, telehealth technology provides opportunities to connect patients and providers. Health policies have been amended to allow easy access to virtual health care, highlighting the field's dynamic ability to adapt to a public health crisis. Academic detailing, a peer-to-peer collaborative outreach designed to improve clinical decision-making, has traditionally relied on in-person encounters for effectiveness. A growth in the adoption of telehealth technology translates to increases in academic detailing reach for providers unable to meet with academic detailers in person. The U.S. Department of Veterans Affairs (VA) has used academic detailing to promote and reinforce evidence-based practices and has encouraged more virtual academic detailing (e-Detailing). Moreover, VA academic detailers are primarily clinical pharmacy specialists who provide clinical services and education and have made meaningful contributions to improving health care at VA. Amid the COVID-19 pandemic and physical isolation orders, VA academic detailers have continued to meet with providers to disseminate critical health care information in a timely fashion by using video-based telehealth. When working through the adoption of virtual technology for the delivery of medical care, providers may need time and nontraditional delivery of "evidence" before eliciting signals for change. Academic detailers are well suited for this role and can develop plans to help address provider discomfort surrounding the use of telehealth technology. By using e-Detailing as a method for both familiarizing and normalizing health professionals with video-based telehealth technology, pharmacists are uniquely poised to deliver consultation and direct-care services. Moreover, academic detailing pharmacists are ambassadors of change, serving an important role navigating the evolution of health care in response to emergent public health crises and helping define the norms of care delivery to follow.