Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

BACKGROUND: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. OBJECTIVES: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. METHODS: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. RESULTS: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. CONCLUSIONS: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.

Working with service users and our local community to co-design an inclusive and person-centred hospice day service

BackgroundWith an ageing population the need for palliative care services is set to rise.1Whilst there is no clear definition of palliative care day services, traditionally they offer a range of physical, psychosocial and spiritual services to enhance quality of life.2 However the Covid19 pandemic has presented challenges whilst also highlighting opportunities for innovation in many areas of palliative care, including day services.3 There is currently limited evidence to suggest what service users want from a palliative care day service, and as we emerge from the pandemic there is a unique opportunity to develop a new place-based service in our locality.Aim(s)To identify areas for improvement in our hospice day services and to understand how the service can become more inclusive and person centred.MethodsAs part of the re-development of our hospice day service we have created an electronic questionnaire. This was developed by day service staff with the input of therapy, senior management and research teams. The questionnaire is designed for hospice service users (patients and carers) and non-service users (people from our local community), and looks to identify what our day services should offer in terms of activities and accessibility.ResultsWe received thirty-two responses, the majority (n=17) from people living with a terminal illness. Participants highlighted a number of areas for improvement. Using the survey results we are working to adapt our services to provide a more inclusive and accessible hospice day service.ConclusionsWhen considering the re-development of a service it is important to consider the needs of the current service user and the local community. The results of this questionnaire have helped us to begin co-designing a more inclusive and person-centred approach to day services, which we hope will suit the needs of those using the service both now and in the future.ReferencesWorld Health Organization, 2018. Palliative care fact sheet. Geneva: WHO.Hasson F, Jordan J, McKibben L. et al. Challenges for palliative care day services: a focus group study. BMC Palliat Care 2021;20:11. https://doi.org/10.1186/s12904-020-00699-7Dunleavy L, Preston N, Bajwah S, Bradshaw A, Cripps R, Fraser LK, Maddocks M, Hocaoglu M, Murtagh FE, Oluyase AO, Sleeman KE, Higginson IJ, Walshe C. ‘Necessity is the mother of invention': Specialist palliative care service innovation and practice change in response to COVID-19. Results from a multinational survey (CovPall). Palliat Med. 2021 May;35(5):814–829. doi: 10.1177/02692163211000660. Epub 2021 Mar 23. PMID: 33754892;PMCID: PMC8114457.

SARS-CoV-2 down-regulates ACE2 through lysosomal degradation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its Spike (S) glycoprotein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry. ACE2 is a critical negative regulator of the renin-angiotensin system and plays a protective role in preventing tissue injury. Expression of ACE2 has been shown to decrease upon infection by SARS-CoV. However, whether SARS-CoV-2 down-regulates ACE2 and the underlying mechanism and biological impact of this down-regulation have not been well defined. Here we show that the SARS-CoV-2 infection down-regulates ACE2 in vivo in an animal model, and in cultured cells in vitro, by inducing clathrin- and AP2-dependent endocytosis, leading to its degradation in the lysosome. SARS-CoV-2 S-treated cells and ACE2 knockdown cells exhibit similar alterations in downstream gene expression, with a pattern indicative of activated cytokine signaling that is associated with respiratory distress and inflammatory diseases often observed in COVID-19 patients. Finally, we have identified a soluble ACE2 fragment with a stronger binding to SARS-CoV-2 S that can efficiently block ACE2 down-regulation and viral infection. Thus, our study suggests that ACE2 down-regulation represents an important mechanism underlying SARS-CoV-2-associated pathology, and blocking this process could be a promising therapeutic strategy.

SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-ß signaling.

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-ß signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-ß signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.

Developing an open access toolkit to support the implementation of journal clubs in hospices

BackgroundResearch is essential to improving outcomes for patients with life-threatening illness and it is vital that hospices are at the centre of this (Payne, Preston, Turner et al, 2013). Journal clubs have been identified as a way of sharing evidence amongst hospice teams, developing staff research skills and contributing to hospice research culture but they are not widespread in hospices, with barriers often encountered in their development and sustainability (Turner & Payne, 2019. Eur J Palliat Care. 19:34).AimsThis project aims to develop a toolkit to support hospices in establishing and sustaining multidisciplinary journal clubs.MethodsAt Marie Curie Hospice, Liverpool, a new model of journal club was implemented in January 2019 with a focus on promoting reflection of the relevance of research to clinical practice (Steele, Stanley & Nwosu, 2019. BMJ Support Palliat Care. 9:A50). Attendance, and contributions to presenting, come from across the multidisciplinary team and palliative care service sites in the locality. A toolkit to allow this to be replicated was developed by the research team, informed by participant feedback and the successes and challenges of setting up the journal club from scratch then surviving, growing and thriving in a semi-virtual model despite the COVID-19 pandemic (Stanley, Nwosu & Finney, 2021. BMJ Support Palliat Care. 11:A4).ResultsThe toolkit consists of a practical guide to both setting up and running the journal club, with flexibility to be individualised to diverse hospices across the UK. In addition, it includes resources such as presenter templates and certificates. The toolkit is being piloted in two palliative care centres so that facilitators and barriers to its use can be identified.ConclusionsThis work will lead to the development of a freely available toolkit that any hospice can use to support their implementation of a journal club, thus promoting a research culture and evidence-based practice.

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells.

SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.

Rapid detection of SARS-CoV-2 RNA in saliva via Cas13.

Rapid nucleic acid testing is central to infectious disease surveillance. Here, we report an assay for rapid COVID-19 testing and its implementation in a prototype microfluidic device. The assay, which we named DISCoVER (for diagnostics with coronavirus enzymatic reporting), involves extraction-free sample lysis via shelf-stable and low-cost reagents, multiplexed isothermal RNA amplification followed by T7 transcription, and Cas13-mediated cleavage of a quenched fluorophore. The device consists of a single-use gravity-driven microfluidic cartridge inserted into a compact instrument for automated running of the assay and readout of fluorescence within 60 min. DISCoVER can detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in saliva with a sensitivity of 40 copies µl-1, and was 94% sensitive and 100% specific when validated (against quantitative PCR) using total RNA extracted from 63 nasal-swab samples (33 SARS-CoV-2-positive, with cycle-threshold values of 13-35). The device correctly identified all tested clinical saliva samples (10 SARS-CoV-2-positive out of 13, with cycle-threshold values of 23-31). Rapid point-of-care nucleic acid testing may broaden the use of molecular diagnostics.

An intranasal ASO therapeutic targeting SARS-CoV-2.

The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identify an LNA ASO binding to the 5' leader sequence of SARS-CoV-2 that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the COVID-19 mouse model potently suppresses viral replication (>80-fold) in the lungs of infected mice. We find that the LNA ASO is efficacious in countering all SARS-CoV-2 "variants of concern" tested both in vitro and in vivo. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce or prevent transmission and decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences and could be stockpiled for future coronavirus pandemics.

Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.

Broad-spectrum CRISPR-mediated inhibition of SARS-CoV-2 variants and endemic coronaviruses in vitro.

A major challenge in coronavirus vaccination and treatment is to counteract rapid viral evolution and mutations. Here we demonstrate that CRISPR-Cas13d offers a broad-spectrum antiviral (BSA) to inhibit many SARS-CoV-2 variants and diverse human coronavirus strains with >99% reduction of the viral titer. We show that Cas13d-mediated coronavirus inhibition is dependent on the crRNA cellular spatial colocalization with Cas13d and target viral RNA. Cas13d can significantly enhance the therapeutic effects of diverse small molecule drugs against coronaviruses for prophylaxis or treatment purposes, and the best combination reduced viral titer by over four orders of magnitude. Using lipid nanoparticle-mediated RNA delivery, we demonstrate that the Cas13d system can effectively treat infection from multiple variants of coronavirus, including Omicron SARS-CoV-2, in human primary airway epithelium air-liquid interface (ALI) cultures. Our study establishes CRISPR-Cas13 as a BSA which is highly complementary to existing vaccination and antiviral treatment strategies.

Identification of Digital Health Priorities for Palliative Care Research: Modified Delphi Study.

BACKGROUND: Developments in digital health have the potential to transform the delivery of health and social care to help citizens manage their health. Currently, there is a lack of consensus about digital health research priorities in palliative care and a lack of theories about how these technologies might improve care outcomes. Therefore, it is important for health care leaders to identify innovations to ensure that an increasingly frail population has appropriate access to palliative care services. Consequently, it is important to articulate research priorities as the first step in determining how finite resources should be allocated to a field saturated with rapidly developing innovation. OBJECTIVE: The aim of this study is to identify research priority areas for digital health in palliative care. METHODS: We selected digital health trends, most relevant to palliative care, from a list of emerging trends reported by a leading institute of quantitative futurists. We conducted 2 rounds of the Delphi questionnaire, followed by a consensus meeting and public engagement workshop to establish a final consensus on research priorities for digital technology in palliative care. We used the views of public representatives to gain their perspectives on the agreed priorities. RESULTS: A total of 103 experts (representing 11 countries) participated in the first Delphi round. Of the 103 experts, 55 (53.3%) participated in the second round. The final consensus meetings were attended by 10.7% (11/103) of the experts. We identified 16 priority areas, which involved many applications of technologies, including care for patients and caregivers, self-management and reporting of diseases, education and training, communication, care coordination, and research methodology. We summarized the priority areas into eight topics: big data, mobile devices, telehealth and telemedicine, virtual reality, artificial intelligence, smart home, biotechnology, and digital legacy. CONCLUSIONS: The priorities identified in this study represent a wide range of important emerging areas in the fields of digital health, personalized medicine, and data science. Human-centered design and robust governance systems should be considered in future research. It is important that the risks of using these technologies in palliative care are properly addressed to ensure that these tools are used meaningfully, wisely, and safely and do not cause unintentional harm.

The B.1.427/1.429 (epsilon) SARS-CoV-2 variants are more virulent than ancestral B.1 (614G) in Syrian hamsters.

As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel SARS-CoV-2 variant designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and it was shown to have enhanced infectivity in vitro and decreased antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both variants exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most marked body weight loss among the 3 variants. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three variants. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the oropharynx but not in the lungs. In multi-virus in-vivo competition experiments, we found that B.1. (614G), epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the nasal cavity, B.1. (614G), gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) and WA-1 variants in hamsters. These results demonstrate enhanced virulence and high relative oropharyngeal replication of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) variant.

How can technology be used to support communication in palliative care beyond the COVID-19 pandemic?

IntroductionThe need for palliative care is expected to increase globally due to a number of socioeconomic factors,1 therefore it is essential for society to use technology better to improve palliative care.2AimsThis project looks to identify learning beyond the COVID19 pandemic in the United Kingdom (UK), highlighting knowledge and skills required to support healthcare professionals to adopt technology to support communication.MethodAn electronic survey was developed consisting of a maximum of 36 multiple choice and free text response questions gathering demographic information and covering three themed areas: Communication within the multidisciplinary team, use of technology for education and using technology to support communication with patients and carers.ResultsThe survey received 234 responses from palliative care healthcare professionals across the UK, with 97% of respondents reporting that they have used technology to support communication more since the beginning of the Covid19 pandemic. Responses have highlighted several benefits of using technology to support communication in these areas, whilst providing greater understanding of the barriers that exist.ConclusionOur work has shown that there is an increasing use of technology to support communication in palliative care. It is essential that organisations acknowledge and adapt to this change in order for healthcare professionals to provide the best possible care by improving access and quality of palliative care services.ImpactThis work highlights areas of improvement needed to allow healthcare professionals to use technology to support communication. If used well, this can improve the scope of palliative care delivery in the future.References Bone AE, Gomes B, Etkind SN, et al. What is the impact of population ageing on the future provision of end-of-life care? Population-based projections of place of death. Palliative Medicine 2017;32(2):329–36. doi:10.1177/0269216317734435 Nwosu AC, Collins B, Mason S. Big data analysis to improve care for people living with serious illness: the potential to use new emerging technology in palliative care. Palliative Medicine 2018;32(1):164–66. doi:10.1177/0269216317726250

Development of a journal club to improve care in a hospice through evidence based practice

BackgroundMany palliative care organisations use journal clubs to support educational development for staff. However, to date, the potential to use journal clubs to directly improve clinical care in hospices (through quality improvement activity) has not been described in the literature.AimsWe describe the development of a multidisciplinary hospice journal club, through which aimed to (1) develop research questions to clinical care problems in the hospice and (2) identify solutions to these problems to improve care delivery.MethodsIn January 2019, we established fortnightly journal club meetings, which provided staff with the opportunity to present hospice-relevant palliative care research. In these meetings, we discussed the main findings, clinical practice implications and future research questions. Initially, the meetings were in-person, but we later hosted these online (via Microsoft Teams) due to the COVID-19 pandemic, which enabled virtual participation. We used the research questions generated to inform future quality improvement work. We asked staff to complete a feedback survey to determine their views of the process.ResultsWe have conducted 30 journal club meetings, which have generated 124 research questions. Thirteen meetings were virtual. We have conducted quality improvement work using these research questions to improve clinical care. Nineteen staff (representing five clinical sites) completed feedback. The feedback was positive, with participants stating that the journal club was educational, clinically relevant and enjoyable. The main problem identified by participants were technological issues relating to participating in the virtual meetings.Conclusion/DiscussionWe have demonstrated how a palliative care journal club can be used to improve clinical care in a hospice. Our experience can be used by other palliative care settings to engage staff in research and improve care for those with serious illness.

Mapping of UV-C dose and SARS-CoV-2 viral inactivation across N95 respirators during decontamination.

During public health crises like the COVID-19 pandemic, ultraviolet-C (UV-C) decontamination of N95 respirators for emergency reuse has been implemented to mitigate shortages. Pathogen photoinactivation efficacy depends critically on UV-C dose, which is distance- and angle-dependent and thus varies substantially across N95 surfaces within a decontamination system. Due to nonuniform and system-dependent UV-C dose distributions, characterizing UV-C dose and resulting pathogen inactivation with sufficient spatial resolution on-N95 is key to designing and validating UV-C decontamination protocols. However, robust quantification of UV-C dose across N95 facepieces presents challenges, as few UV-C measurement tools have sufficient (1) small, flexible form factor, and (2) angular response. To address this gap, we combine optical modeling and quantitative photochromic indicator (PCI) dosimetry with viral inactivation assays to generate high-resolution maps of "on-N95" UV-C dose and concomitant SARS-CoV-2 viral inactivation across N95 facepieces within a commercial decontamination chamber. Using modeling to rapidly identify on-N95 locations of interest, in-situ measurements report a 17.4 ± 5.0-fold dose difference across N95 facepieces in the chamber, yielding 2.9 ± 0.2-log variation in SARS-CoV-2 inactivation. UV-C dose at several on-N95 locations was lower than the lowest-dose locations on the chamber floor, highlighting the importance of on-N95 dose validation. Overall, we integrate optical simulation with in-situ PCI dosimetry to relate UV-C dose and viral inactivation at specific on-N95 locations, establishing a versatile approach to characterize UV-C photoinactivation of pathogens contaminating complex substrates such as N95s.

Practical considerations for Ultraviolet-C radiation mediated decontamination of N95 respirator against SARS-CoV-2 virus.

Decontaminating N95 respirators for reuse could mitigate shortages during the COVID-19 pandemic. Although the United States Center for Disease Control has identified Ultraviolet-C irradiation as one of the most promising methods for N95 decontamination, very few studies have evaluated the efficacy of Ultraviolet-C for SARS-CoV-2 inactivation. In addition, most decontamination studies are performed using mask coupons that do not recapitulate the complexity of whole masks. We sought to directly evaluate the efficacy of Ultraviolet-C mediated inactivation of SARS-CoV-2 on N95 respirators. To that end we created a portable UV-C light-emitting diode disinfection chamber and tested decontamination of SARS-CoV-2 at different sites on two models of N95 respirator. We found that decontamination efficacy depends on mask model, material and location of the contamination on the mask. Our results emphasize the need for caution when interpreting efficacy data of UV-C decontamination methods.

SARS-CoV-2 nucleocapsid protein forms condensates with viral genomic RNA.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a pandemic that seriously threatens global health. SARS-CoV-2 propagates by packaging its RNA genome into membrane enclosures in host cells. The packaging of the viral genome into the nascent virion is mediated by the nucleocapsid (N) protein, but the underlying mechanism remains unclear. Here, we show that the N protein forms biomolecular condensates with viral genomic RNA both in vitro and in mammalian cells. While the N protein forms spherical assemblies with homopolymeric RNA substrates that do not form base pairing interactions, it forms asymmetric condensates with viral RNA strands. Cross-linking mass spectrometry (CLMS) identified a region that drives interactions between N proteins in condensates, and deletion of this region disrupts phase separation. We also identified small molecules that alter the size and shape of N protein condensates and inhibit the proliferation of SARS-CoV-2 in infected cells. These results suggest that the N protein may utilize biomolecular condensation to package the SARS-CoV-2 RNA genome into a viral particle.

Screening a Library of FDA-Approved and Bioactive Compounds for Antiviral Activity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 168 million cases and 3.4 million deaths to date, while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here, we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19.

90 Evaluating the use of digital communication technology in a hospital specialist palliative care team during the COVID-19 pandemic

BackgroundHealthcare professionals’ use of technology-enabled communication has increased during the COVID19 pandemic, due to social distancing restrictions. Currently, there is little published data about the experience of specialist palliative care teams using this technology, or how these tools can help to support care beyond the pandemic. This project aimed to evaluate the implementation of digital communication technology, in a hospital specialist palliative care team, during the COVID-19 pandemic.MethodDuring the months of September and October 2020, an online survey was distributed to staff in the specialist palliative care team at the Royal Liverpool University Hospitals. The following information was collected: purpose, scope, location of use of technological tools, barriers, and future opportunities.ResultsThe survey was completed by 14 healthcare professionals. Microsoft Teams and Zoom were the most commonly used tools, with team updates (n= 14, 100%), multidisciplinary team meetings (n=14, 100%), education (n=12, 85.7%) and cross-site working (n=9, 64.3%) identified as the most common reasons for use. All participants used the tools on-site (n=14, 100%) with some also connecting at home (n=8, 57.1%) or at an alternative work location (n=2, 14.3%). Twelve (85.7%) reported that meetings were abandoned due to technical barriers. These barriers included: problems with logging in (n=12, 85.7%), connectivity issues (n=12, 85.7%), video/audio quality (n=8, 57.1%) and lack of training (n=8, 57.1%). Identified opportunities included the potential to use technology to support integrated palliative care, by improving communication between hospital and community teams and education. These findings have been used to identify local practice recommendations.ConclusionTechnology has the potential to improve specialist palliative care delivery;however, it is important to identify, and address, several issues (technical, process, and training) in order to overcome barriers to adoption in clinical practice.