Parthenolide reveals an allosteric mode to inhibit the deISGylation activity of SARS-CoV­2 papain-like protease.

The coronavirus papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15 (ISG15), which enable it to participate in virus replication and host innate immune pathways. Therefore, PLpro is considered an attractive antiviral drug target. Here, we show that parthenolide, a germacrane sesquiterpene lactone, has SARS-CoV-2 PLpro inhibitory activity. Parthenolide covalently binds to Cys-191 or Cys-194 of the PLpro protein, but not the Cys-111 at the PLpro catalytic site. Mutation of Cys-191 or Cys-194 reduces the activity of PLpro. Molecular docking studies show that parthenolide may also form hydrogen bonds with Lys-192, Thr-193, and Gln-231. Furthermore, parthenolide inhibits the deISGylation but not the deubiquitinating activity of PLpro in vitro. These results reveal that parthenolide inhibits PLpro activity by allosteric regulation.

Effectiveness of Telemedicine Visits in Reducing 30-Day Readmissions Among Patients With Heart Failure During the COVID-19 Pandemic.

Background The COVID-19 pandemic resulted in a rapid implementation of telemedicine into clinical practice. This study examined whether early outpatient follow-up via telemedicine is as effective as in-person visits for reducing 30-day readmissions in patients with heart failure. Methods and Results Using electronic health records from a large health system, we included patients with heart failure living in North Carolina (N=6918) who were hospitalized between March 16, 2020 and March 14, 2021. All-cause readmission within 30 days after discharge was examined using weighted logistic regression models. Overall, 7.6% (N=526) of patients received early telemedicine follow-up, 38.8% (N=2681) received early in-person follow-up, and 53.6% (N=3711) did not receive follow-up within 14 days of discharge. Compared with patients without early follow-up, those who received early follow-up were younger, were more likely to be Medicare beneficiaries, had more comorbidities, and were less likely to live in an disadvantaged neighborhood. Relative to in-person visits, those with telemedicine follow-up were of similar age, sex, and race but with generally fewer comorbidities. Overall, the 30-day readmission rate (19.0%) varied among patients who received telemedicine visits (15.0%), in-person visits (14.0%), or no follow-up (23.1%). After covariate adjustment, patients who received either telemedicine (odds ratio [OR], 0.55; 95% CI, 0.44-0.72) or in-person (OR, 0.52; 95% CI, 0.45-0.60) visits were similarly less likely to be readmitted within 30 days compared with patients with no follow-up. Conclusions During the COVID-19 pandemic, the use of telemedicine visits for early follow-up increased rapidly. Patients with heart failure who received outpatient follow-up either via telemedicine or in-person had better outcomes than those who received no follow-up.

Understanding Barriers to Healthcare Access for Heart Failure Patients during the COVID-19 Pandemic

Early outpatient follow-up within two weeks after hospital discharge is an effective strategy for improving transitions of care in older patients with heart failure (HF). However, implementing timely follow-up care for HF patients has been challenging, especially during the COVID-19 pandemic. This convergent mixed-methods study identified patients’ barriers to accessing care and ascertained their recommendations for addressing these barriers. We enrolled 264 HF patients admitted to the Duke Heart Center between May 2020 and August 2021. A standardized survey and electronic health records (EHR) were used to collect patients’ sociodemographic, psychosocial, behavioral, and clinical data. For patients who reported some difficulty accessing their healthcare (n=30), semi-structured interviews were conducted to understand these barriers. Data were analyzed using rapid analysis techniques. Barriers to accessing care varied across participants, with scheduling an appointment being the most common barrier (12 of the 30 responses). Participants indicated that job-related conflicts, providers’ availability, or COVID-19 contributed most to the difficulty in scheduling an appointment. Some participants experienced more difficulties during the pandemic due to fewer appointments available for non-acute and non-COVID-19 related needs. Transportation was another critical barrier, which was often associated with the participants’ physical functional status. Participants identified the benefits of using telemedicine to address access to care barriers;however, they shared their concerns that telemedicine visits may not be sufficient to assess their HF conditions. Study findings highlight the need for more continual, tailored, and patient-centered interventions to improve access to care in older HF patients.

The Implementation of a Primary Care-Based Integrated Mobile Health Intervention for Stroke Management in Rural China: Mixed-Methods Process Evaluation

Background: There is a lack of evidence concerning the effective implementation of strategies for stroke prevention and management, particularly in resource-limited settings. A primary-care-based integrated mobile health intervention (SINEMA intervention) has been implemented and evaluated via a 1-year-long cluster-randomized controlled trial. This study reports the findings from the trial implementation and process evaluation that investigate the implementation of the intervention and inform factors that may influence the wider implementation of the intervention in the future. Methods: We developed an evaluation framework by employing both the RE-AIM framework and the MRC process evaluation framework to describe the implementation indicators, related enablers and barriers, and illustrate some potential impact pathways that may influence the effectiveness of the intervention in the trial. Quantitative data were collected from surveys and extracted from digital health monitoring systems. In addition, we conducted quarterly in-depth interviews with stakeholders in order to understand barriers and enablers of program implementation and effectiveness. Quantitative data analysis and thematic qualitative data analysis were applied, and the findings were synthesized based on the evaluation framework. Results: The SINEMA intervention was successfully implemented in 25 rural villages, reached 637 patients with stroke in rural Northern China during the 12 months of the trial. Almost 90% of the participants received all follow-up visits per protocol, and about half of the participants received daily voice messages. The majority of the intervention components were adopted by village doctors with some adaptation made. The interaction between human-delivered and technology-enabled components reinforced the program implementation and effectiveness. However, characteristics of the participants, doctor-patient relationships, and the healthcare system context attributed to the variation of program implementation and effectiveness. Conclusion: A comprehensive evaluation of program implementation demonstrates that the SINEMA program was well implemented in rural China. Findings from this research provide additional information for program adaptation, which shed light on the future program scale-up. The study also demonstrates the feasibility of combining RE-AIM and MRC process evaluation frameworks in process and implementation evaluation in trials. Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03185858.

Treatment and Outcomes of Patients With Ischemic Stroke During COVID-19: An Analysis From Get With The Guidelines-Stroke.

[Figure: see text].

Acute Ischemic Stroke in Patients With COVID-19: An Analysis From Get With The Guidelines-Stroke.

[Figure: see text].