Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication.

The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication and for allowing the virus to evade the host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due to PLpro's restricted substrate binding pocket. In this report, we screened a 115 000-compound library for PLpro inhibitors and identified a new pharmacophore, based on a mercapto-pyrimidine fragment that is a reversible covalent inhibitor (RCI) of PLpro and inhibits viral replication in cells. Compound 5 had an IC50 of 5.1 µM for PLpro inhibition and hit optimization yielded a derivative with increased potency (IC50 0.85 µM, 6-fold higher). Activity based profiling of compound 5 demonstrated that it reacts with PLpro cysteines. We show here that compound 5 represents a new class of RCIs, which undergo an addition elimination reaction with cysteines in their target proteins. We further show that their reversibility is catalyzed by exogenous thiols and is dependent on the size of the incoming thiol. In contrast, traditional RCIs are all based upon the Michael addition reaction mechanism and their reversibility is base-catalyzed. We identify a new class of RCIs that introduces a more reactive warhead with a pronounced selectivity profile based on thiol ligand size. This could allow the expansion of RCI modality use towards a larger group of proteins important for human disease.

Building a Covid-19 secure intensive care unit: A human-centred design approach.

Background: The Covid-19 pandemic has highlighted weaknesses in the National Health Service critical care provision including both capacity and infrastructure. Traditionally, healthcare workspaces have failed to fully incorporate Human-Centred Design principles resulting in environments that negatively affect the efficacy of task completion, patient safety and staff wellbeing. In the summer of 2020, we received funds for the urgent construction of a Covid-19 secure critical care facility. The aim of this project was to design a pandemic resilient facility centred around both staff and patient requirements and safety, within the available footprint. Methods: We developed a simulation exercise, underpinned by Human-Centred Design principles, to evaluate intensive care designs through Build Mapping, Tasks Analysis and Qualitative data. Build Mapping involved taping out sections of the design and mocking up with equipment. Task Analysis and qualitative data were collected following task completion. Results: 56 participants completed the build simulation exercise generating 141 design suggestions (69 task related, 56 patient and relative related, 16 staff related). Suggestions translated to 18 multilevel design improvements; five significant structural changes (Macro level) including wall moves and lift size change. Minor improvements were made at a Meso and Micro design level. Critical care design drivers identified included functional drivers (visibility, Covid-19 secure environment, workflow, and task efficiency) and behavioural drivers (learning and development, light, humanising intensive care and design consistency). Conclusion: Success of clinical tasks, infection control, patient safety and staff/patient wellbeing are highly dependent on clinical environments. Primarily, we have improved clinical design by focusing on user requirements. Secondly, we developed a replicable approach to exploring healthcare build plans revealing significant design changes, that may have only been identified once built.

Health Behaviors During the COVID-19 Epidemic: Perspectives From Studying International Coping and Compliance.

Control of the COVID-19 pandemic requires significant changes in people's health behaviors. We offer this multidisciplinary perspective on the extent of compliance with social distancing recommendations and on coping with these measures around the globe in the first months of the pandemic. We present descriptive data from our survey of 17,650 respondents across 18 countries and territories in June 2020. The majority of respondents worried about contracting the virus. Nearly all engaged in at least some preventive behaviors, particularly handwashing, mask wearing, and avoiding social events. Most reported that it would be difficult to continue these behaviors for more than a few months, and about half reported feeling more anxious since the start of the pandemic. Commonly reported coping behaviors included news consumption, watching television, and sleeping. Our cross-national study highlights areas for developing and implementing health behavior interventions in the global fight to stop the spread of COVID-19.

The Use of Wearable Pulse Oximeters in the Prompt Detection of Hypoxemia and During Movement: Diagnostic Accuracy Study.

BACKGROUND: Commercially available wearable (ambulatory) pulse oximeters have been recommended as a method for managing patients at risk of physiological deterioration, such as active patients with COVID-19 disease receiving care in hospital isolation rooms; however, their reliability in usual hospital settings is not known. OBJECTIVE: We report the performance of wearable pulse oximeters in a simulated clinical setting when challenged by motion and low levels of arterial blood oxygen saturation (SaO2). METHODS: The performance of 1 wrist-worn (Wavelet) and 3 finger-worn (CheckMe O2+, AP-20, and WristOx2 3150) wearable, wireless transmission-mode pulse oximeters was evaluated. For this, 7 motion tasks were performed: at rest, sit-to-stand, tapping, rubbing, drinking, turning pages, and using a tablet. Hypoxia exposure followed, in which inspired gases were adjusted to achieve decreasing SaO2 levels at 100%, 95%, 90%, 87%, 85%, 83%, and 80%. Peripheral oxygen saturation (SpO2) estimates were compared with simultaneous SaO2 samples to calculate the root-mean-square error (RMSE). The area under the receiver operating characteristic curve was used to analyze the detection of hypoxemia (ie, SaO2<90%). RESULTS: SpO2 estimates matching 215 SaO2 samples in both study phases, from 33 participants, were analyzed. Tapping, rubbing, turning pages, and using a tablet degraded SpO2 estimation (RMSE>4% for at least 1 device). All finger-worn pulse oximeters detected hypoxemia, with an overall sensitivity of ≥0.87 and specificity of ≥0.80, comparable to that of the Philips MX450 pulse oximeter. CONCLUSIONS: The SpO2 accuracy of wearable finger-worn pulse oximeters was within that required by the International Organization for Standardization guidelines. Performance was degraded by motion, but all pulse oximeters could detect hypoxemia. Our findings support the use of wearable, wireless transmission-mode pulse oximeters to detect the onset of clinical deterioration in hospital settings. TRIAL REGISTRATION: ISRCTN Registry 61535692; http://www.isrctn.com/ISRCTN61535692. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-034404.

British Columbia CARMA-CHIWOS Collaboration (BCC3): protocol for a community-collaborative cohort study examining healthy ageing with and for women living with HIV.

INTRODUCTION: Women living with HIV (WLWH) experience accelerated ageing and an increased risk of age-associated diseases earlier in life, compared with women without HIV. This is likely due to a combination of viral factors, gender differences, hormonal imbalance and psychosocial and structural conditions. This interdisciplinary cohort study aims to understand how biological, clinical and sociostructural determinants of health interact to modulate healthy ageing in WLWH. METHODS AND ANALYSIS: The British Columbia Children and Women: AntiRetroviral therapy and Markers of Aging-Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CARMA-CHIWOS) Collaboration (BCC3) study will enrol WLWH (n=350) and sociodemographically matched HIV-negative women (n=350) living in British Columbia. A subset of BCC3 participants will be past participants of CARMA, n≥1000 women and children living with and without HIV, 2008-2018 and/or CHIWOS, n=1422 WLWH, 2013-2018. Over two study visits, we will collect biological specimens for virus serologies, hormones and biological markers as well as administer a survey capturing demographic and sociostructural-behavioural factors. Sociodemographics, comorbidities, number and type of chronic/latent viral infections and hormonal irregularities will be compared between the two groups. Their association with biological markers and psychostructural and sociostructural factors will be investigated through multivariable regression and structural equation modelling. Retrospective longitudinal analyses will be conducted on data from past CARMA/CHIWOS participants. As BCC3 aims to follow participants as they age, this protocol will focus on the first study visits. ETHICS AND DISSEMINATION: This study has been approved by the University of British Columbia Children's and Women's Research Ethics Board (H19-00896). Results will be shared in peer-reviewed journals, conferences and at community events as well as at www.hivhearme.ca and @HIV_HEAR_me. WLWH are involved in study design, survey creation, participant recruitment, data collection and knowledge translation. A Community Advisory Board will advise the research team throughout the study.

Social policy as an integral component of pandemic response: Learning from COVID-19 in Brazil, Germany, India and the United States.

It is easy but mistaken to think that public health emergency measures and social policy can be separated. This paper compares the experiences of Brazil, Germany, India and the United States during their 2020 responses to the COVID-19 pandemic to show that social policies such as unemployment insurance, flat payments and short-time work are crucial to the effectiveness of non-pharmaceutical interventions as well as to their political sustainability. Broadly, public health measures that constrain economic activity will only be effective and sustainable if paired with social policy measures that enable people to comply without sacrificing their livelihoods and economic wellbeing. Tough public health policies and generous social policies taken together proved a success in Germany. Generous social policies uncoupled from strong public health interventions, in Brazil and the US during the summer of 2020, enabled lockdown compliance but failed to halt the pandemic, while tough public health measures without social policy support rapidly collapsed in India. In the COVID-19 and future pandemics, public health theory and practice should recognise the importance of social policy to the immediate effectiveness of public health policy as well as to the long-term social and economic impact of pandemics.

Transplant of SARS-CoV-2-infected Living Donor Liver: Case Report.

Given the high community prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), transplant programs will encounter SARS-CoV-2 infections in living donors or recipients in the perioperative period. There is limited data on SARS-CoV-2 viremia and organotropism beyond the respiratory tract to inform the risk of transplant transmission of SARS-CoV-2. We report a case of a living donor liver transplant recipient who received a right lobe graft from a living donor with symptomatic PCR-confirmed SARS-CoV-2 infection 3 d following donation. The donor was successfully treated with remdesivir, dexamethasone, and coronavirus disease 2019 (COVID-19) convalescent plasma. No viral transmission was identified, and both donor and recipient had excellent postoperative outcomes.

Understanding Vaccine Hesitancy in the Context of COVID-19: The Role of Trust and Confidence in a Seventeen-Country Survey.

Objectives: An effective vaccine to SARS-CoV-2 cannot be successfully deployed if a significant number of people worldwide are unwilling to accept it. We investigated the relationship between trust in scientists and medical professionals and perceptions of vaccine safety and effectiveness. We also build on past studies by exploring the relationship between confidence in global health organizations and vaccine hesitancy. Methods: We conducted an online survey in seventeen countries/territories across five world regions between May -June 2020. We assessed the relationship between COVID19 vaccine hesitancy, confidence in public health organizations, and trust in key experts and leaders. Results: Our findings strongly suggest that confidence in the World Health Organization combined with trust in domestic scientists and healthcare professionals is a strong driver of vaccine acceptance across multiple countries/territories. Conclusion: We find that hesitancy is widespread, and uptake would be insufficient to achieve herd immunity. There is widespread confidence in how public health organizations have responded to the current pandemic and this is related to vaccine acceptance. Our results also highlight the important role of trust in health care providers and scientists in reducing COVID19 vaccine hesitancy.

Perspectives in the study of the political economy of COVID-19 vaccine regulation.

Vaccines against SARS-CoV-2 continue to be developed at an astonishingly quick speed and the early ones, like Pfizer and Moderna, have been shown to be more effective than many public health scientists had dared to hope. As COVID-19 vaccine research continues to progress, the world's eyes are turning toward medicine regulators. COVID-19 vaccines need to be authorized for use in each country in which the pharmaceutical industry intends to commercialize its product. This results in a patchwork of regulations that can influence the speed at which products are launched and the standards that govern them. In this research forum article, we discuss several key questions about COVID-19 vaccine regulations that should shape research on the next stage of the pandemic response. We call for a research agenda that looks into the political economy of pharmaceutical regulation, particularly from a comparative perspective, including Global South countries.

COVID-19 in Russia: Should we expect a novel response to the novel coronavirus?

Russia provides an important case study in its COVID-19 response by a country that has one of the largest epidemics, increasingly authoritarian government policies, and important domestic and international political influence. In this article, we describe and explain Russia's public health and social policy responses to COVID-19 - earlier in the pandemic when the concern was the border with China, to later when there were confirmed cases in all regions in the country. In the past, Russia has served as an interesting case for exploring global health politics and infectious diseases. Thus, we position our analysis of the COVID-19 response through a reflection on infectious disease control in the Soviet Union and contemporary Russia. We explore the following: government control, contention with official statistics, (dis-)information, (mis-)trust, and vulnerabilities of medical care workers. We also discuss how Russia is reinforcing its role in global health during the pandemic, for example through vaccine development and foreign humanitarian aid. We situate our analysis in the historical, political, and social contexts to help explain Russia's response to the novel coronavirus pandemic.

Mifepristone as Bridge or Adjunct Therapy in the Management of Challenging Cushing Disease Cases.

Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.

Demographic, health, and economic transitions and the future care burden.

The COVID-19 pandemic has caused millions of infections and deaths worldwide, forced schools to suspend classes, workers to work from home, many to lose their livelihoods, and countless businesses to close. Throughout this crisis, families have had to protect, comfort and care for their children, their elderly and other members. While the pandemic has greatly intensified family care responsibilities for families, unpaid care work has been a primary activity of families even in normal times. This paper estimates the future global need for caregiving, and the burden of that need that typically falls on families, especially women. It takes into account projected demographic shifts, health transitions, and economic changes in order to obtain an aggregate picture of the care need relative to the potential supply of caregiving in low-, middle- and high-income countries. This extensive margin of the future care burden, however, does not capture the weight of that burden unless the quantity and quality of care time per caregiver are taken into account. Adjusting for care time given per caregiver, the paper incorporates data from time-use surveys, illustrating this intensive margin of the care burden in three countries that have very different family and economic contexts-Ghana, Mongolia, and South Korea. Time-use surveys typically do not provide time data for paid care services, so the estimates depend only on the time intensity of family care. With this caveat, the paper estimates that the care need in 2030 would require the equivalent of one-fifth to two-fifths of the paid labor force, assuming 40 weekly workhours. Using the projected 2030 mean wage for care and social service workers to estimate the hypothetical wage bill for these unpaid caregivers if they were paid, we obtain a value equivalent to 16 to 32 percent of GDP in the three countries.

Harm reduction via online platforms for people who use drugs in Russia: a qualitative analysis of web outreach work.

BACKGROUND: Harm reduction services to people who use drugs (PWUD) in Russia are insufficient in terms of quantity, government endorsement, and accessibility. The situation has recently deteriorated even further because of social distancing measures of the COVID-19 pandemic. Several organizations have started to provide some harm reduction services via online platforms by web outreach. However, little is known on how online outreach services are organized and implemented. Drawing on the example of St. Petersburg-based NGO "Humanitarian Action," we explored web outreach work in Telegram instant messenger. METHODS: Our data were comprised of 4 semi-structured interviews with the NGO staff and 301 cases of web outreach work with PWUD. We used thematic analysis to study the process of web outreach, harm reduction service provision, and needs of PWUD. RESULTS: Three stages of the process of web outreach work were identified: clients initiating communication, NGO workers addressing clients' needs, and NGO workers receiving clients' feedback. Communication proceeded in group chat or direct messages. Challenges in addressing clients' needs happened when clients turned for help after hours, sent recorded voice messages, sent unclear messages, and/or were unwilling to transition to telephone communication. All web outreach workers reported receiving only positive feedback on their work. The needs of PWUD were categorized into two major themes, depending on whether they can be addressed fully or partially online. In cases of online only provision of services, web outreach workers helped PWUD treat minor injection drug use complications, obtain verified harm reduction information and receive general psychological support. In instances of partial online services provision, PWUD were assisted in getting treatment of severe injection drug use complications, overdoses, and in accessing offline medical, psychological, social, legal and harm reduction services. CONCLUSIONS: Our research demonstrated that web outreach work is a convenient tool for delivering some harm reduction services to PWUD either partially or completely online and for recruiting new clients (including hard-to-reach PWUD that avoid attending brick-and-mortar facilities). Harm reduction organizations should consider incorporating online harm reduction services into their activities. However, further research is needed to explore relative advantages and disadvantages of online harm reduction services.

Harm reduction via online platforms for people who use drugs in Russia: A qualitative analysis of web outreach work.

Background Harm reduction services to people who use drugs (PWUD) in Russia are insufficient in terms of quantity, government endorsement, and accessibility. The situation has recently deteriorated even further because of social distancing measures of the COVID-19 pandemic. Recently several harm reduction organizations have started to provide some harm reduction services via online platforms by web outreach. However, little is known on how online outreach services are organized and implemented. Drawing on the example of St. Petersburg-based NGO "Humanitarian Action" we explored web outreach work in Telegram instant messenger. Methods 4 semi-structured interviews with the NGO staff and 301 cases of web outreach work with PWUD comprised the dataset. The process of web outreach, service provision to PWUD, and PWUD's needs were thematically analyzed. Results Three stages of the process of web outreach work were determined: clients initiating communication, NGO workers addressing clients' needs, and NGO workers receiving clients' feedback. Communication proceeded either in group chat or in direct messages. Challenges in addressing clients' needs happened when clients turned for help in nighttime, sent recorded voice messages, sent unclear messages, and/or were unwilling to transition to telephone communication. All web outreach workers reported receiving only positive feedback on their work. PWUD's needs were categorized into two major themes, depending on whether they can be addressed fully or partially online. In cases of online only provision of services, web outreach workers helped PWUD treat minor injection drug use complications, obtain verified harm reduction information and receive general psychological support. In instances of partial online services provision, PWUD were assisted in getting treatment of severe injection drug use complications, overdoses, and in accessing offline medical, psychological, social, legal and harm reduction services. Conclusions Our research demonstrated that web outreach work is a convenient tool for delivering some harm reduction services to PWUD either partially or completely online and recruiting new clients (including hard-to-reach PWUD that avoid attending brick-and-mortar facilities). It indicates that harm reduction organizations should consider incorporating online harm reduction services into their activities. However, more research is needed to explore relative advantages and disadvantages of online harm reduction services delivery.

Effects of COVID-19 pandemic on pediatric kidney transplant in the United States.

BACKGROUND: In March 2020, COVID-19 infections began to rise exponentially in the USA, placing substantial burden on the healthcare system. As a result, there was a rapid change in transplant practices and policies, with cessation of most procedures. Our goal was to understand changes to pediatric kidney transplantation (KT) at the national level during the COVID-19 epidemic. METHODS: Using SRTR data, we examined changes in pediatric waitlist registration, waitlist removal or inactivation, and deceased donor and living donor (DDKT/LDKT) events during the start of the disease transmission in the USA compared with the same time the previous year. RESULTS: We saw an initial decrease in DDKT and LDKT by 47% and 82% compared with expected events and then a continual increase, with numbers reaching expected prepandemic levels by May 2020. In the early phase of the pandemic, waitlist inactivation and removals due to death or deteriorating condition rose above expected values by 152% and 189%, respectively. There was a statistically significant decrease in new waitlist additions (IRR 0.49 0.65 0.85) and LDKT (IRR 0.17 0.38 0.84) in states with high vs. low COVID activity. Transplant recipients during the pandemic were more likely to have received a DDKT, but had similar calculated panel-reactive antibody (cPRA) values, waitlist time, and cause of kidney failure as before the pandemic. CONCLUSIONS: The COVID-19 pandemic initially reduced access to kidney transplantation among pediatric patients in the USA but has not had a sustained effect.

The comparative politics of COVID-19: The need to understand government responses.

COVID-19 has created a ramifying public health, economic, and political crisis throughout many countries in the world. While globally the pandemic is at different stages and far from under control in some countries, now is the time for public health researchers and political scientists to start understanding how and why governments responded the way they have, explore how effective these responses appear to be, and what lessons we can draw about effective public health policymaking in preparation of the next wave of COVID-19 or the next infectious disease pandemic. We argue that there will be no way to understand the different responses to COVID-19 and their effects without understanding policy and politics. We propose four key focuses to understand the reasons for COVID-19 responses: social policies to crisis management as well as recovery, regime type (democracy or autocracy), formal political institutions (federalism, presidentialism), and state capacity (control over health care systems and public administration). A research agenda to address the COVID-19 pandemic that takes politics as a serious focus can enable the development of more realistic, sustainable interventions in policies and shape our broader understanding of the politics of public health.