Provision of palliative and end-of-life care in UK care homes during the COVID-19 pandemic: A mixed methods observational study with implications for policy.

Introduction: Little consideration has been given to how the provision of palliative and end-of-life care in care homes was affected by COVID-19. The aims of this study were to: (i) investigate the response of UK care homes in meeting the rapidly increasing need for palliative and end-of-life care during the COVID-19 pandemic and (ii) propose policy recommendations for strengthening the provision of palliative and end-of-life care within care homes. Materials and methods: A mixed methods observational study was conducted, which incorporated (i) an online cross-sectional survey of UK care homes and (ii) qualitative interviews with care home practitioners. Participants for the survey were recruited between April and September 2021. Survey participants indicating availability to participate in an interview were recruited using a purposive sampling approach between June and October 2021. Data were integrated through analytic triangulation in which we sought areas of convergence, divergence, and complementarity. Results: There were 107 responses to the survey and 27 interviews. We found that (i) relationship-centered care is crucial to high-quality palliative and end-of-life care within care homes, but this was disrupted during the pandemic. (ii) Care homes' ability to maintain high-quality relationship-centered care required key "pillars" being in place: integration with external healthcare systems, digital inclusion, and a supported workforce. Inequities within the care home sector meant that in some services these pillars were compromised, and relationship-centered care suffered. (iii) The provision of relationship-centered care was undermined by care home staff feeling that their efforts and expertise in delivering palliative and end-of-life care often went unrecognized/undervalued. Conclusion: Relationship-centered care is a key component of high-quality palliative and end-of-life care in care homes, but this was disrupted during the COVID-19 pandemic. We identify key policy priorities to equip care homes with the resources, capacity, and expertise needed to deliver palliative and end-of-life care: (i) integration within health and social care systems, (ii) digital inclusivity, (iii) workforce development, (iv) support for care home managers, and (v) addressing (dis)parities of esteem. These policy recommendations inform, extend, and align with policies and initiatives within the UK and internationally.

Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

Which children and young people are at higher risk of severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: A systematic review and individual patient meta-analysis.

BACKGROUND: We aimed to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in hospitalised children and young people (CYP), within a systematic review and individual patient meta-analysis. METHODS: We searched Pubmed, European PMC, Medline and Embase for case series and cohort studies published between 1st January 2020 and 21st May 2021 which included all CYP admitted to hospital with ≥ 30 CYP with SARS-CoV-2 or ≥ 5 CYP with PIMS-TS or MIS-C. Eligible studies contained (1) details of age, sex, ethnicity or co-morbidities, and (2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted groupings of co-morbidities were eligible for narrative review. We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI).PROSPERO: CRD42021235338. FINDINGS: 83 studies were included, 57 (21,549 patients) in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years (reference group), infants (aged <1 year) had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)).The number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a step-wise fashion. Compared with CYP without comorbidity, odds ratios for critical care admission were: 1.49 (1.45-1.53) for 1 comorbidity; 2.58 (2.41-2.75) for 2 comorbidities; 2.97 (2.04-4.32) for ≥3 comorbidities. Corresponding odds ratios for death were: 2.15 (1.98-2.34) for 1 comorbidity; 4.63 (4.54-4.74) for 2 comorbidities and 4.98 (3.78-6.65) for ≥3 comorbidities. Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities. IPD analysis demonstrated that, compared to children without co-morbidity, the risk difference of admission to critical care was increased in those with 1 comorbidity by 3.61% (1.87-5.36); 2 comorbidities by 9.26% (4.87-13.65); ≥3 comorbidities 10.83% (4.39-17.28), and for death: 1 comorbidity 1.50% (0.00-3.10); 2 comorbidities 4.40% (-0.10-8.80) and ≥3 co-morbidities 4.70 (0.50-8.90). INTERPRETATION: Hospitalised CYP at greatest vulnerability of severe disease or death with SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions. FUNDING: RH is in receipt of a fellowship from Kidney Research UK (grant no. TF_010_20171124). JW is in receipt of a Medical Research Council Fellowship (Grant No. MR/R00160X/1). LF is in receipt of funding from Martin House Children's Hospice (there is no specific grant number for this). RV is in receipt of a grant from the National Institute of Health Research to support this work (grant no NIHR202322). Funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.

Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic year.

Identifying which children and young people (CYP) are most vulnerable to serious infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important to guide protective interventions. To address this question, we used data for all hospitalizations in England among 0-17 year olds from 1 February 2019 to 31 January 2021. We examined how sociodemographic factors and comorbidities might be risk factors for pediatric intensive care unit (PICU) admission among hospitalizations due to the following causes: Coronavirus Disease 2019 (COVID-19) and pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the first pandemic year (2020-2021); hospitalizations due to all other non-traumatic causes in 2020-2021; hospitalizations due to all non-traumatic causes in 2019-2020; and hospitalizations due to influenza in 2019-2020. Risk of PICU admission and death from COVID-19 or PIMS-TS in CYP was very low. We identified 6,338 hospitalizations with COVID-19, of which 259 were admitted to a PICU and eight CYP died. We identified 712 hospitalizations with PIMS-TS, of which 312 were admitted to a PICU and fewer than five CYP died. Hospitalizations with COVID-19 and PIMS-TS were more common among males, older CYP, those from socioeconomically deprived neighborhoods and those who were of non-White ethnicity (Black, Asian, Mixed or Other). The odds of PICU admission were increased in CYP younger than 1 month old and decreased among 15-17 year olds compared to 1-4 year olds with COVID-19; increased in older CYP and females with PIMS-TS; and increased for Black compared to White ethnicity in patients with COVID-19 and PIMS-TS. Odds of PICU admission in COVID-19 were increased for CYP with comorbidities and highest for CYP with multiple medical problems. Increases in odds of PICU admission associated with different comorbidities in COVID-19 showed a similar pattern to other causes of hospitalization examined and, thus, likely reflect background vulnerabilities. These findings identify distinct risk factors associated with PICU admission among CYP with COVID-19 or PIMS-TS that might aid treatment and prevention strategies.

Deaths in children and young people in England after SARS-CoV-2 infection during the first pandemic year.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rarely fatal in children and young people (CYP, <18 years old), but quantifying the risk of death is challenging because CYP are often infected with SARS-CoV-2 exhibiting no or minimal symptoms. To distinguish between CYP who died as a result of SARS-CoV-2 infection and those who died of another cause but were coincidentally infected with the virus, we undertook a clinical review of all CYP deaths with a positive SARS-CoV-2 test from March 2020 to February 2021. The predominant SARS-CoV-2 variants were wild-type and Alpha. Here we show that, of 12,023,568 CYP living in England, 3,105 died, including 61 who were positive for SARS-CoV-2. Of these deaths, 25 were due to SARS-CoV-2 infection (mortality rate, two per million), including 22 due to coronavirus disease 2019-the clinical disease associated with SARS-CoV-2 infection-and 3 were due to pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. In total, 99.995% of CYP with a positive SARS-CoV-2 test survived. CYP older than 10 years, Asian and Black ethnic backgrounds and comorbidities were over-represented in SARS-CoV-2-related deaths compared with other CYP deaths. These results are important for guiding decisions on shielding and vaccinating children. New variants might have different mortality risks and should be evaluated in a similar way.

Care home staff experiences of palliative and end-of-life care in care homes during COVID-19

BackgroundCOVID-19 has had a devastating impact on care homes, their residents and staff. Over 37,000 UK care home residents have died from COVID-19;many more have experienced symptoms and distress (Scobie, 2021). There has been very limited examination of palliative and end-of-life care in care homes during COVID-19, or strategies to improve this.AimsTo examine the experiences of care homes in England of providing palliative and end-of-life care during the COVID-19 pandemic and make recommendations for policy.MethodsOnline survey (in REDCap) of care home staff with leadership responsibilities, identified through established networks. The survey included structured data and free-text comments on COVID-19 outbreaks, experiences of symptom assessment and control, and impact on workforce. The primary outcome was staff self-efficacy to provide palliative and end-of-life care (Phillips, Salamonson, Davidson, 2011).ResultsInterim analysis of 66 respondents found that most staff felt confident to provide palliative care, as measured by the self-efficacy scale (median 3.75, range 1-4 ). 51% (33/65) of respondents identified issues with staff shortages during the pandemic;38% (24/64) experienced changes in staff responsibilities;18% (12/65) experienced challenges in recognising that residents may be dying. 18% (12/65) of care homes did not allow visitors at the end-of-life, and 39% (25/64) experienced difficulties in accessing help from other services. 51% (33/65) experienced challenges in providing bereavement support to relatives. Free-text comments identified staff shortages and exhaustion, and lack of support from other healthcare services, as barriers to good care.ConclusionThis is the first national survey to explore provision of palliative and end-of-life care in care homes during the COVID-19 pandemic. The results will be used to inform policy to ensure high-quality provision of palliative and end-of-life care during future pandemics.

TMEM41B is a host factor required for the replication of diverse coronaviruses including SARS-CoV-2.

Antiviral therapeutics are a front-line defense against virally induced diseases. Because viruses frequently mutate to escape direct inhibition of viral proteins, there is interest in targeting the host proteins that the virus must co-opt to complete its replication cycle. However, a detailed understanding of the interactions between the virus and the host cell is necessary in order to facilitate development of host-directed therapeutics. As a first step, we performed a genome-wide loss of function screen using the alphacoronavirus HCoV-229E to better define the interactions between coronaviruses and host factors. We report the identification and validation of an ER-resident host protein, TMEM41B, as an essential host factor for not only HCoV-229E but also genetically distinct coronaviruses including the pandemic betacoronavirus SARS-CoV-2. We show that the protein is required at an early, but post-receptor engagement, stage of the viral lifecycle. Further, mechanistic studies revealed that although the protein was not enriched at replication complexes, it likely contributes to viral replication complex formation via mobilization of cholesterol and other lipids to facilitate host membrane expansion and curvature. Continued study of TMEM41B and the development of approaches to prevent its function may lead to broad spectrum anti-coronavirus therapeutics.