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Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibited PLpro with k inact /K I = 10,000 M - 1 s - 1 , achieved sub-microM EC 50 values against three SARS-CoV-2 variants in mammalian cell lines, and did not inhibit a panel of human deubiquitinases at > 30 microM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validated our design strategy and established the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.
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BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.
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Dementia , Malus , Aged , Cost-Benefit Analysis , Humans , Life Style , Quality of Life , Single-Blind Method , Tea , TechnologyABSTRACT
This book offers an extensive look into the ways living through the COVID-19 pandemic has deepened our understanding of the crises people experience in their relationships with work. Leading experts explore burnout as an occupational phenomenon that arises through mismatches between workplace and individuals on the day-to-day patterns in work life. By disrupting where, when, and how people worked, pandemic measures upset the delicate balances in place regarding core areas of work life. Chapters examine the profound implications of social distancing on the quality and frequency of social encounters among colleagues, with management, and with clientele. The book covers a variety of occupational groups such as those in the healthcare and education sectors, and demonstrates the advantages and strains that come with working from home. The authors also consider the broader social context of working through the pandemic regarding risks and rewards for essential workers. By focusing on changes in organisational structures, policies, and practices, this book looks at effective ways forward in both recovering from this pandemic and preparing for further workplace disruptions. A wide audience of students and researchers in psychology, management, business, healthcare, and social sciences, as well as policy makers in government and professional organisations, will benefit from this detailed insight into the ways COVID-19 has affected contemporary work attitudes and practices. © 2023 selection and editorial matter, Michael P. Leiter and Cary L. Cooper. All rights reserved.
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Background: Autologous hematopoietic stem cell transplantation (aHSCT) is an effective and safe treatment resulting in suppression of disease activity and delay of disease progression in patients with highly active relapsing remitting multiple sclerosis (RRMS) who failed first line disease modifying treatments (DMT) (Burt et al. 2019). However, its safety and effectiveness compared to high efficacy DMTs remains undetermined. Around 4-14% RRMS patients present with an aggressive clinical course (Lacobaeus et al. 2020). There is no unanimous definition of aggressive MS but rapidly evolving severe MS (RES-MS) is defined as patients with >=2 disabling relapses in 1 year, and >=1 gadoliniumenhancing lesions or a significant increase in T2 lesion load on brain magnetic resonance imaging (MRI). High efficacy DMTs are usually a first line treatment to prevent long term disability (Laffaldano et al. 2021). In a retrospective study Das et al. (2021) demonstrated no evidence of disease activity in 100% of patients with treatment naive aggressive RRMS treated with aHSCT. Method(s): Star-MS, ISRCTN88667898, is a multicentre parallelgroup rater-blinded randomised controlled trial of aHSCT versus high efficacy DMT (alemtuzumab, cladribine, ocrelizumab and ofatumumab) of 198 RRMS patients in the United Kingdom. aHSCT is delivered using non-myeloablative conditioning with a cyclophosphamide/anti-thymocyte globulin regimen followed by an unselected autologous graft. Eligibility was based on clinical practice at the time the trial was conceived in 2019 and included patients with >=2 relapses, or 1 relapse and evidence of MRI disease activity >3 months before or after its onset, in the last 12 months despite use of a DMT (but not a comparator DMT). Star-MS opened recruitment in September 2021 following an 18 month delay due to COVID. Changes to clinical practice, namely early use of high efficacy treatment, no longer aligned with trial design, reducing the pool of eligible patients, resulting in slower than expected recruitment. Trial protocol was revised to include active RRMS, defined as >=1 relapse or evidence of MRI disease activity in last 12 months use of a DMT, or RES-MS in treatment naive patients. Here we describe the positive impact of utilising adaptations to study design to keep clinical trials aligned with clinical practice. Conclusion(s): Clinical trials must be responsive to changing clinical practice to ensure success and relevance to the target patient population.
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Aim: The COVID-19 pandemic triggered rapid implementation of telehealth (telephone and videoconference) in Australia. Psycho-oncology clinicians report a need for greater guidance on adapting in person psycho-oncology therapies to telehealth. We aimed to establish consensus on elements of psycho-oncology therapy that can be adapted for telehealth for inclusion in an educational resource incorporating clinical practice recommendations. Method(s): Draft recommendations were developed based on existing literature, reviews and guidelines. These were refined using a co-design process involving expert consultation (n = 13) with psychooncology clinicians and researchers. This process identified some uncertainty around key recommendations. A two round Delphi consensus process was conducted to confirm the relative importance and therapeutic appropriateness of content for inclusion in clinical practice recommendations. Participants included psycho-oncology clinicians with telehealth experience. Respondents rated their level of agreement with each statement on a 5-point Likert scale. Consensus was defined as>80%of respondents scoringwithin two points on the Likert scale. Result(s): The co-design approach identified key topics for inclusion in the recommendations: (1) preparation for telehealth (e.g., privacy, security, technical considerations);(2) clinical and cultural considerations (e.g., safety considerations, therapeutic alliance, vulnerable/ underserved communities);(3) adaptations to therapeutic assessment and intervention;(4) specific client considerations (e.g., clients in palliative care). 32 clinicians participated in Delphi Round 1, where thirteen recommendations were presented and consensus reached for nine. Recommendations where consensus was not reached were re-presented in Round 2.We will present the consensus recommendations based on the Delphi. Conclusion and clinical implication: The clinical practice recommendations will provide a robust expert-endorsed educational resource to guide psycho-oncology clinicians tailoring their practice to telehealth. This will support delivery of evidence-based treatments to people living with cancer, increasing the sustainability of, and confidence in, psycho-oncology telehealth.
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Citizen and community science can improve conservation efforts, help people connect with nature, and strengthen online social infrastructure during periods of disturbance. Volunteers for citizen and community science (CCS) projects engage in a variety of activities ranging from in-person group tasks to isolated online tasks. The diversity of available CCS engagement activity types was altered by the COVID-19 pandemic. Our goals were to document the impact of COVID-19 (1) on participation in different types of CCS projects and (2) across a varying landscape of pandemic-associated restrictions. We examined digital trace data from SciStarter.org to examine participation in CCS projects before and during COVID-19. We created a summative index of different COVID-19 restrictions to quantify how daily life in each US state was impacted. We found that during the pandemic, projects in which data collection occurred away from home had fewer joins than other types of projects. This contrasts with pre-pandemic, for which there was no difference in joins among the different project types. Although there was a decrease in joins among away from home projects that occurred during the pandemic, the difference between pre-pandemic and during the pandemic was not statistically significant. There was no difference in joins among the different project types between individuals in states with few COVID-19 restrictions compared with individuals in states with many COVID-19 restrictions. Interviews conducted with project leaders reinforced these findings and provided examples of how projects could be modified to continue generating data and connecting communities. © 2022 The Author(s).
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The home is a place of shelter, a place for family, and for separation from other parts of life, such as work. Global challenges, the most pressing of which are currently the COVID-19 pandemic and climate change has forced extra roles into many homes and will continue to do so in the future. Biodesign integrates living organisms into designed solutions and can offer opportunities for new kinds of technologies to facilitate a transition to the home of the future. Many families have had to learn to work alongside each other, and technology has mediated a transition from standard models of operation for industries. These are the challenges of the 21st century that mandate careful thinking around interactive systems and innovations that support new ways of living and working at home. In this workshop, we will explore opportunities for biodesign interactive systems in the future home. We will bring together a broad group of researchers in HCI, design, and biosciences to build the biodesign community and discuss speculative design futures. The outcome will generate an understanding of the role of interactive biodesign systems at home, as a place with extended functionalities.
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Aims: The COVID-19 pandemic triggered rapid implementation of telephone and videoconference telehealth across Australia. The Psycho-Oncology Cooperative Research Group (PoCoG) investigated the barriers and enablers to wider implementation post pandemic. Psychologists working in oncology face unique challenges such as working with patients experiencing existential issues and report inadequate training in conducting telehealth psychology. This research aimed to address the paucity of evidence available to guide adaption of therapy to telehealth through the development of evidence-based consensus recommendations for Psycho-oncology . Methods : Content for the recommendations was developed based on a review of the psychology and Psycho-Oncology literature and stakeholder feedback through an expert advisory group (n = 14) comprising clinical psychology, Psycho-Oncology and health communication/education experts, guiding the focus of the content. The compilation of recommendations involved an iterative co-design process. Clinical scenarios, self-reflection exercises and clinical guidance were incorporated to facilitate clinical relevance. The relative importance of content topics was assessed based on a Delphi consensus process that is ongoing. Results : The co-design approach identified key recommendations;(1) adaptations to therapeutic techniques, (2) clinical/practical strategies (including worksheets and case studies), (3) communication challenges, (4) maintaining the therapeutic alliance, and (5) managing patient presentations. A national Delphi consensus process involving clinical psychologists working in oncology is ongoing and will guide further refinement of the educational resource. Conclusions : These recommendations fill an identified gap in the literature and provide a robust expert-endorsed document to guide clinicians through telehealth in the Psycho-Oncology field. This will support an increase in sustainability of, and confidence in, Psycho-Oncology telehealth moving forward.
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Background/AimsThe COVID-19 pandemic has had profound effects on the health of theglobal population both directly, via the sequelae of the infection, andindirectly, including the relative neglect of chronic disease management. Together the International Osteoporosis Federation and NationalOsteoporosis Foundation sought to ascertain the impact on osteoporosis management.MethodsQuestionnaires were electronically circulated to a sample of membersof both learned bodies and included information regarding the locationand specialty of respondents, current extent of face to faceconsultations, alterations in osteoporosis risk assessment, telemedicine experience, alterations to medication ascertainment and delivery, and electronic health record (EHR) utilisation. Responses werecollected, quantitative data analysed, and qualitative data assessedfor recurring themes.ResultsResponses were received from 209 healthcare workers from 53countries, including 28% from Europe, 24% from North America, 19%from the Asia Pacific region, 17% from the Middle East, and 12% fromLatin America. Most respondents were physicians (85%) withphysician assistants, physical therapists and nurses/nurse practitioners represented in the sample. The main three specialtiesrepresented included rheumatology (40%), endocrinology (22%) andorthopaedics (15%).In terms of the type of patient contact, 33% ofrespondents conducted telephone consultations and 21% videoconsultations. Bone mineral density assessment by dual-energy xray absorptiometry (DXA) usage was affected with only 29% able toobtain a scan as recommended. The majority of clinicians (60%) hadsystems in place to identify patients receiving subcutaneous orintravenous medication, and 43% of clinicians reported difficulty inarranging appropriate osteoporosis medications during the COVID-19crisis.ConclusionTo conclude through surveying a global sample of osteoporosishealthcare professionals, we have observed an increase in telemedicine consultations, delays in DXA scanning, interrupted supply ofmedications and reductions in intravenous medication delivery.
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Aim: To deliver a person-centred intervention aiming to achieve significant weight loss and potential remission of type 2 diabetes in a real-world community setting, using a similar model to the DiRECT trial. The programme adapts a holistic multidisciplinary approach with a combination of nutrition, psychology and exercise education support for long-term behaviour change and self-management, as well as enabling system savings. Method: 23 patients (68% BAME, 53% male) with type 2 diabetes participated in the 24-week programme with final visit in December 2020. After initial assessment, participants underwent 12 weeks of total diet replacement (TDR) using 800 kilocalorie daily supplementation, followed by food reintroduction. Culturally sensitive diet and lifestyle support was provided by regular phone calls along with 26 e-learning modules. Results: Mean weight loss after TDR was 13.5 kg (range 5-29 kg) at week 24. 88% of patients at week 24 were not on medication. 81% on diabetic medication at baseline no longer required any diabetic medication;13% were prescribed a lower dose and 6% were still on the same dose. 36% were no longer prescribed any blood pressure medication. Mean HbA1c decreased by 14 mmol/mol at week 24 but was only available for 11 participants due to covid-19 pandemic. There was self-reported improvement in participants' quality of life. Conclusion: The pilot results are in line with findings from DiRECT. System-wide financial benefit was achieved through de-prescribing of diabetes medication. These results are being used to inform and deliver a TDR service as part of NHS England's type 2 diabetes remission programme.
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Introduction Frailty and multimorbidity have been suggested as risk factors for severe COVID-19 disease. We therefore investigated whether frailty and multimorbidity were associated with risk of hospitalisation with COVID-19 in the UK Biobank. Method 502,640 participants aged 40–69 years at baseline (54–79 years at COVID-19 testing) were recruited across UK 2006–10. A modified assessment of frailty using Fried’s classification was generated from baseline data. COVID-19 test results (England) were available 16/03/2020–01/06/2020, mostly taken in hospital settings. Logistic regression was used to discern associations between frailty, multimorbidity and COVID-19 diagnoses, adjusting for sex, age, BMI, ethnicity, education, smoking and number of comorbidity groupings, comparing COVID-19 positive, COVID-19 negative and non-tested groups. Results 4,510 participants were tested for COVID-19 (positive = 1,326, negative = 3,184). 497,996 participants were not tested. Compared to the non-tested group, after adjustment, COVID-19 positive participants were more likely to be frail (OR = 1.4 [95%CI = 1.1, 1.8]), report slow walking speed (OR = 1.3 [1.1, 1.6]), report two or more falls in the past year (OR = 1.3 [1.0, 1.5]) and be multimorbid (≥4 comorbidity groupings vs 0–1: OR = 1.9 [1.5, 2.3]). However, similar strength of associations were apparent when comparing COVID-19 negative and non-tested groups. Furthermore, frailty and multimorbidity were not associated with COVID-19 diagnoses, when comparing COVID-19 positive and COVID-19 negative participants. Conclusions Frailty and multimorbidity do not appear to aid risk stratification, in terms of a positive versus negative results of COVID-19 testing. Investigation of the prognostic value of these markers for adverse clinical sequelae following COVID-19 disease is urgently needed.