Biochemical analysis of SARS-CoV-2 Nsp13 helicase implicated in COVID-19 and factors that regulate its catalytic functions.

Replication of the 30-kilobase genome of SARS-CoV-2, responsible for COVID-19, is a key step in the coronavirus life cycle that requires a set of virally encoded nonstructural proteins such as the highly conserved Nsp13 helicase. However, the features that contribute to catalytic properties of Nsp13 are not well established. Here, we biochemically characterized the purified recombinant SARS-CoV-2 Nsp13 helicase protein, focusing on its catalytic functions, nucleic acid substrate specificity, nucleotide/metal cofactor requirements, and displacement of proteins from RNA molecules proposed to be important for its proofreading role during coronavirus replication. We determined that Nsp13 preferentially interacts with single-stranded DNA compared with single-stranded RNA to unwind a partial duplex helicase substrate. We present evidence for functional cooperativity as a function of Nsp13 concentration, which suggests that oligomerization is important for optimal activity. In addition, under single-turnover conditions, Nsp13 unwound partial duplex RNA substrates of increasing double-stranded regions (16-30 base pairs) with similar efficiency, suggesting the enzyme unwinds processively in this range. We also show Nsp13-catalyzed RNA unwinding is abolished by a site-specific neutralizing linkage in the sugar-phosphate backbone, demonstrating continuity in the helicase-translocating strand is essential for unwinding the partial duplex substrate. Taken together, we demonstrate for the first time that coronavirus helicase Nsp13 disrupts a high-affinity RNA-protein interaction in a unidirectional and ATP-dependent manner. Furthermore, sensitivity of Nsp13 catalytic functions to Mg2+ concentration suggests a regulatory mechanism for ATP hydrolysis, duplex unwinding, and RNA protein remodeling, processes implicated in SARS-CoV-2 replication and proofreading.

Association of mobile health (mHealth) use with health status and COVID-19-related concerns by people with mobility impairments.

PURPOSE: Mobile health (mHealth) technology has increased dramatically in the wake of the pandemic. Less research has focused on people with mobility impairing (PMI) disabilities. This study determined the prevalence of mHealth use among PMI adults during the COVID-19 escalation and examines demographic, health and COVID-19 concerns correlates. METHODS: PMI adults (N = 304) completed an online survey investigating mHealth use and COVID-19 concerns related to food access in June of 2020. Smartphone and mHealth use were measured with an adapted version of the survey used in the Pew Internet & American Life project. Descriptive and multivariable analyses were conducted to determine associations of demographics, health status, and COVID-19 concerns with mHealth use. About two-thirds (N = 201) of the sample were mHealth users (owned a smartphone and engaged in health-promoting behaviors with the smartphone; e.g., sought online information, tracked health behaviors, used patient portals). RESULTS: Having hypertension was associated with higher mHealth use, and having higher COVID-19 concerns about food access was associated with higher mHealth use. Those who used mHealth were also more engaged with smartphone apps for communication, services, and entertainment. Only the association between educational attainment and mHealth use remained significant after adjusting for other covariates in multivariable logistic regression models. DISCUSSION: PMIs continue to need support in the use of mHealth technology to help maximize access to potentially important tools for rehabilitation and health management. There is a need to continue to investigate mHealth and its applications for people with disabilities.Implications for RehabilitationMany people with mobility impairing disabilities may be missing opportunities for mHealth rehabilitation and healthcare.COVID-19 has widened existing gaps in access and use of mHealth technology among people with mobility impairing disabilities.Focused education is needed to help people with disabilities exploit the full range of services of their smartphones to increase access to care, social connectivity, and other important goods and services to enhance rehabilitation and health management.

Establishment of CORONET, COVID-19 Risk in Oncology Evaluation Tool, to Identify Patients With Cancer at Low Versus High Risk of Severe Complications of COVID-19 Disease On Presentation to Hospital.

PURPOSE: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET). METHODS: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O2) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort. RESULTS: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation. CONCLUSION: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer.

Preschoolers' parent and teacher/director perceptions of returning to early childcare education during the COVID-19 pandemic.

BACKGROUND: Early Care and Education (ECE) sites are critical hubs for social, emotional, and physical learning development of preschool children (ages 3-5). The COVID-19 pandemic has impacted ECE enrollment and participation; until June 2022, preschool children in the US were ineligible for COVID-19 vaccines. It is critical to identify perceptions of teachers/directors and parents to enhance safe return-to-school efforts. METHODS: Focus groups (n = 7; 22 participants) were conducted with ECE teachers/directors throughout Arizona to examine perceptions of COVID-19 testing for families and staff at ECE sites, and current and possible COVID-19 mitigation strategies during Summer 2021. Preschool parents from underserved families in Phoenix (n = 41) completed a brief survey on their perceptions of benefits of ECE for themselves and their children, thoughts on COVID-19 mitigation strategies, and timing for safe return to school during Spring 2021. Focus groups were transcribed and analyzed for themes using constant comparison. RESULTS: There were 4 focus group themes: 1) perceptions of saliva-based COVID-19 testing, 2) logistical strategies for COVID-19 testing at ECE sites; 3) successes and challenges with current COVID-19 mitigation strategies; 4) ideas to support improved COVID-19 mitigation, including outdoor gardening. Parents rated peace of mind about the child's education as the most important benefit for themselves of in-person ECE (74.6%), and social development for children as the most important benefit for their children (54.4%). Over 40% of parents reported it would not be safe to send children back until 2022. CONCLUSIONS: COVID-19 continues to impact attendance at ECE sites, despite parents reporting key benefits to attending ECE sites. Teachers/directors supported COVID-19 mitigation strategies including saliva-based testing and gardening education to improve safe return to schools.

Evaluating experiences, usability and patient satisfaction with telehealth for tertiary outpatient physiotherapy services during COVID-19: A mixed-methods study.

INTRODUCTION: In response to the COVID-19 pandemic, telehealth has been rapidly implemented in outpatient services worldwide. However, little is known about the experiences of telehealth in a tertiary outpatient physiotherapy setting. OBJECTIVE: 1) describe the experience of physiotherapists and patients who utilized telehealth services in a tertiary health facility; and 2) identify the challenges and opportunities of physiotherapy service provision via telehealth in a tertiary health facility. METHODS: A mixed-methods approach was undertaken in the physiotherapy outpatient department between June and October 2020. Patients utilizing telehealth services were invited to complete a purposely designed survey. Physiotherapists completed the Telehealth Usability Questionnaire (TUQ) and provided open-ended responses. Descriptive analysis of quantitative data was completed and thematic analysis was used for qualitative data. RESULTS: Patients reported positive experiences with telehealth, with 93% finding it easy to use and 90% satisfied with the time it took to get an appointment. Scores on the TUQ by physiotherapists were highest for usefulness with a mean (SD) score of 6.02 (1.09), while lower scores were seen for reliability with a score of 3.24 (1.48). Five broad themes were identified: 1) connecting with patients during a pandemic; 2) keeping treatment on track; 3) unprepared for the technology challenges; 4) telehealth - not quite the real thing; and 5) better resources to facilitate moving forwards.While the overall patient experience was high, physiotherapist's satisfaction with telehealth was more varied. Additional work may be needed to improve the technical and logistical aspects of telehealth to support ongoing use in physiotherapy clinical practice.

Fragmented world, connected community: Success factors of the first online EACH summer school for early-career researchers

Overall, the 2021 EACH Summer School for early-career researchers was a masterclass - not only in research but also in holding a successful online event. Although there were some concerns beforehand about downsides of online events, the Summer School managed to connect, teach, and inspire its participants in ways they did not anticipate. Shaping a comfortable atmosphere and having a varying program that included both formal and social activities was key. From wider accessibility came breadth of experience and perspective. From interactive icebreakers and informal chats came a supportive research network. Despite screens, we created a successful work environment and shared tips and tools for academic strategy, survival, and support. The 2021 Summer School was an illustration of just how much can be achieved despite restrictions. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

Patient engagement in melanoma research: from bench to bedside.

Advances in research have transformed the management of melanoma in the past decade. In parallel, patient advocacy has gained traction, and funders are increasingly prioritizing patient and public involvement. Here we discuss the ways in which patients and the public can be engaged in different stages of the research process, from developing, prioritizing and refining the research question to preclinical studies and clinical trials, then finally to ongoing research in the clinic. We discuss the challenges and opportunities that exist at each stage in order to ensure that a representative population of patients and the public contribute to melanoma research both now and in the future.

Still striding toward social justice? Redirecting physical activity research in a post-COVID-19 world.

The COVID-19 crisis and parallel Black Lives Matter movement have amplified longstanding systemic injustices among people of color (POC). POC have been differentially affected by COVID-19, reflecting the disproportionate burden of ongoing chronic health challenges associated with socioeconomic inequalities and unhealthy behaviors, including a lack of physical activity. Clear and well-established benefits link daily physical activity to health and well-being-physical, mental, and existential. Despite these benefits, POC face additional barriers to participation. Thus, increasing physical activity among POC requires additional considerations so that POC can receive the same opportunities to safely participate in physical activity as Americans who are White. Framed within the Ecologic Model of Physical Activity, this commentary briefly describes health disparities in COVID-19, physical activity, and chronic disease experienced by POC; outlines underlying putative mechanisms that connect these disparities; and offers potential solutions to reduce these disparities. As behavioral medicine leaders, we advocate that solutions must redirect the focus of behavioral research toward community-informed and systems solutions.

Excess Mortality Associated With the COVID-19 Pandemic-Los Angeles County, March-September 2020.

OBJECTIVE: To more comprehensively estimate COVID-19-related mortality in Los Angeles County by determining excess all-cause mortality and pneumonia, influenza, or COVID (PIC) mortality. DESIGN: We reviewed vital statistics data to identify deaths registered in Los Angeles County between March 15, 2020, and August 15, 2020. Deaths with an ICD-10 (International Classification of Diseases, Tenth Revision) code for pneumonia, influenza, or COVID-19 listed as an immediate or underlying cause of death were classified as PIC deaths. Expected deaths were calculated using negative binomial regression. Excess mortality was determined by subtracting the expected from the observed number of weekly deaths. The Department of Public Health conducts surveillance for COVID-19-associated deaths: persons who died of nontraumatic/nonaccidental causes within 60 days of a positive COVID-19 test result were classified as confirmed COVID-19 deaths. Deaths without a reported positive SARS-Cov-2 polymerase chain reaction result were classified as probable COVID-19 deaths if COVID-19 was listed on their death certificate or the death occurred 60 to 90 days of a positive test. We compared excess PIC deaths with the number of confirmed and probable COVID-19 deaths ascertained by surveillance. SETTING: Los Angeles County. PARTICIPANTS: Residents of Los Angeles County who died. MAIN OUTCOME MEASURE: Excess mortality. RESULTS: There were 7208 excess all-cause and 5128 excess PIC deaths during the study period. The Department of Public Health also reported 5160 confirmed and 323 probable COVID-19-associated deaths. CONCLUSIONS: The number of excess PIC deaths estimated by our model was approximately equal to the number of confirmed and probable COVID-19 deaths identified by surveillance. This suggests our surveillance definition for confirmed and probable COVID-19 deaths might be sufficiently sensitive for capturing the true burden of deaths caused directly or indirectly by COVID-19.

Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort.

The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43-4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.

COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.

BACKGROUND: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. METHODS: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. FINDINGS: 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028). INTERPRETATION: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies. FUNDING: University of Birmingham and University of Oxford.

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

BACKGROUND: Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer. METHODS: In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. FINDINGS: From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks. INTERPRETATION: Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. FUNDING: University of Birmingham, University of Oxford.

Head and neck oncology during the COVID-19 pandemic: Reconsidering traditional treatment paradigms in light of new surgical and other multilevel risks.

The COVID-19 pandemic demands reassessment of head and neck oncology treatment paradigms. Head and neck cancer (HNC) patients are generally at high-risk for COVID-19 infection and severe adverse outcomes. Further, there are new, multilevel COVID-19-specific risks to patients, surgeons, health care workers (HCWs), institutions and society. Urgent guidance in the delivery of safe, quality head and neck oncologic care is needed. Novel barriers to safe HNC surgery include: (1) imperfect presurgical screening for COVID-19; (2) prolonged SARS-CoV-2 aerosolization; (3) occurrence of multiple, potentially lengthy, aerosol generating procedures (AGPs) within a single surgery; (4) potential incompatibility of enhanced personal protective equipment (PPE) with routine operative equipment; (5) existential or anticipated PPE shortages. Additionally, novel, COVID-19-specific multilevel risks to HNC patients, HCWs and institutions, and society include: use of immunosuppressive therapy, nosocomial COVID-19 transmission, institutional COVID-19 outbreaks, and, at some locations, societal resource deficiencies requiring health care rationing. Traditional head and neck oncology doctrines require reassessment given the extraordinary COVID-19-specific risks of surgery. Emergent, comprehensive management of these novel, multilevel surgical risks are needed. Until these risks are managed, we temporarily favor nonsurgical therapy over surgery for most mucosal squamous cell carcinomas, wherein surgery and nonsurgical therapy are both first-line options. Where surgery is traditionally preferred, we recommend multidisciplinary evaluation of multilevel surgical-risks, discussion of possible alternative nonsurgical therapies and shared-decision-making with the patient. Where surgery remains indicated, we recommend judicious preoperative planning and development of COVID-19-specific perioperative protocols to maximize the safety and quality of surgical and oncologic care.