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1.
Journal of Asian Public Policy ; : 1-15, 2022.
Article in English | Taylor & Francis | ID: covidwho-1927232
4.
J Virol ; 96(3): e0082621, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1691430

ABSTRACT

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.


Subject(s)
Adenovirus Infections, Human/metabolism , Adenovirus Infections, Human/virology , Adenoviruses, Human/classification , Adenoviruses, Human/physiology , Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism , Host-Pathogen Interactions , Membrane Cofactor Protein/metabolism , Adenoviruses, Human/ultrastructure , Animals , Biomarkers , Blood Cell Count , CHO Cells , Cell Line , Coxsackie and Adenovirus Receptor-Like Membrane Protein/chemistry , Cricetulus , Disease Models, Animal , Gene Expression , Humans , Membrane Cofactor Protein/chemistry , Membrane Cofactor Protein/genetics , Mice, Transgenic , Models, Biological , Models, Molecular , Mutagenesis , Protein Binding , Protein Conformation , Serogroup , Sialic Acids/metabolism , Sialic Acids/pharmacology , Structure-Activity Relationship
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321375

ABSTRACT

At the onset of the COVID-19 pandemic, hospitals were in dire need of data-driven analytics to provide support for critical, expensive, and challenging decisions. Yet, the majority of analytics being developed were targeted toward state- and national-level policy decisions, with little availability of actionable information to support tactical and operational decision making and execution at the hospital level. To fill this gap, we developed a multi-method framework leveraging a parsimonious design philosophy that allows for rapid deployment of high-impact predictive and prescriptive analytics in a time-sensitive, dynamic, limited data environment such as a novel pandemic. Our framework integrates disease progression models tailored to data availability during different stages of the pandemic with a stochastic network model of patient movements among units within individual hospitals to forecast time-varying patient workload and demand for critical resources. Both components employ adaptive tuning to account for hospital-dependent, time-varying parameters that provide consistently accurate predictions as changes in system dynamics are learned over time. The product of this research is a workload prediction and decision support framework customized to individual hospital that specifically targets actionable information based on hospital needs. Yet, by design, our framework is portable across hospital data-systems and easily implementable for expeditious expansion. This work was contextually grounded in close collaboration with IU Health, the largest health system in Indiana with 18 hospitals serving over 1 million residents. Since April 2020, we have implemented our framework to support decisions from operational to strategic made by multiple departments at IU Health as well as the executive leadership team during the course of the COVID-19 pandemic.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311774

ABSTRACT

This book is a collection of essays from scholars at Singapore Management University School of Law analysing the challenges and implications of COVID-19 from the perspective of different areas of law, including private law, corporate law, insolvency law, data protection, financial laws, public law, privacy law, commercial law, constitutional law, law and technology, and dispute resolution. It also analyses how the COVID-19 pandemic will affect the judicial system, the study of law, and the future of the legal profession. Beyond considerations of the pandemic’s influence on law and legal service delivery the authors consider how law can help facilitate the orderly transition to a sustainable future – the new normal.

7.
Alzheimers Dement (N Y) ; 7(1): e12141, 2021.
Article in English | MEDLINE | ID: covidwho-1669647

ABSTRACT

INTRODUCTION: The SINGER pilot randomized controlled trial aims to examine the feasibility and acceptability of the Finnish Geriatric Intervention Study (FINGER) multi-domain lifestyle interventions compared to Singaporean adaptations. METHODS: Seventy elderly participants were recruited and randomized into FINGER (n = 36) or SINGER (n = 34) interventions; involving physical exercise, cognitive training, diet, and vascular risk factors management, for 6 months. RESULTS: Both intervention groups were equally feasible and acceptable with participants completing at least 80% of the interventions. Body strength improved in both groups (Pupper body = .04, P lower body = .06, P core = .05). More participants in the SINGER group attained good blood pressure control at month-6 compared to FINGER (41% vs 19%; P = .06). DISCUSSION: This study is the first to compare the feasibility of multi-domain interventions adapted to local culture with the FINGER interventions. The findings will be utilized for a larger study to provide evidence for the efficacy of multi-domain lifestyle interventions in preventing cognitive decline.

8.
Production and Operations Management ; n/a(n/a), 2021.
Article in English | Wiley | ID: covidwho-1583457

ABSTRACT

At the onset of the COVID-19 pandemic, hospitals were in dire need of data-driven analytics to provide support for critical, expensive, and complex decisions. Yet, the majority of analytics being developed were targeted at state- and national-level policy decisions, with little availability of actionable information to support tactical and operational decision making and execution at the hospital level. To fill this gap, we developed a multi-method framework leveraging a parsimonious design philosophy that allows for rapid deployment of high-impact predictive and prescriptive analytics in a time-sensitive, dynamic, data-limited environment, such as a novel pandemic. The product of this research is a workload prediction and decision support tool to provide mission-critical, actionable information for individual hospitals. Our framework forecasts time-varying patient workload and demand for critical resources by integrating disease progression models, tailored to data availability during different stages of the pandemic, with a stochastic network model of patient movements among units within individual hospitals. Both components employ adaptive tuning to account for hospital-dependent, time-varying parameters that provide consistently accurate predictions by dynamically learning the impact of latent changes in system dynamics. Our decision support system is designed to be portable and easily implementable across hospital data systems for expeditious expansion and deployment. This work was contextually grounded in close collaboration with IU Health, the largest health system in Indiana, which has 18 hospitals serving over one million residents. Our initial prototype was implemented in April 2020 and has supported managerial decisions, from the operational to the strategic, across multiple functionalities at IU  Health. This article is protected by copyright. All rights reserved

9.
Alzheimer's & Dementia ; 17(S10):e057643, 2021.
Article in English | Wiley | ID: covidwho-1589195

ABSTRACT

Background Mandated lockdowns and restricted activity in response to the COVID-19 pandemic has affected our everyday life1. Seniors, in particular, have been affected due to higher morbidity and mortality2. The World-Wide-FINGERS-SARS-CoV-2 survey is part of an international project, consisting of members of the World-Wide FINGERS (WW-FINGERS) Network for dementia risk reduction and prevention3. The study aims to measure the direct and indirect effects of the outbreak in midlife and older age. Preliminary results of this ongoing study is focused on lifestyle changes. Method The survey commenced in September 2020.Participants aged 45 and above were recruited from existing research cohorts, memory clinic patients and community subjects. Sociodemographic factors, health related information, impact on lifestyle and behavior as well as personality factors were collected through three modalities: self-administered online survey, telephone survey and in person with research staff. Result At present, 167 non-demented participants were included in the current preliminary analysis. Majority of the participants were Chinese (83.2%), aged 65 and above (59.3%), male (58.1%), with at least secondary education (80.8%). The survey found that 61.6% of the participants reported decreased contact with friends and relatives, with 22.2% reporting an increase in loneliness. Approximately one-third of the participants reported a decrease in physical activity (35.9%) and an increase in food intake (30.5% in snacking habits;25.1% in fruits consumption). Approximately half of the participants reported increase in usage of internet and digital services to keep in contact with family and friends. Conclusion The COVID-19 pandemic has produced measurable impacts on lifestyle-related behavior of individuals. The decrease in social interaction and increase in loneliness during the pandemic due to government directive, along with concerns of contracting the virus highlight the importance of digital services for and digital literacy in older adults to keep them connected and supported remotely.

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294919

ABSTRACT

ABSTRACT Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against SARS-CoV-2 and HIV-1. Yet, its primary receptor portfolio remains controversial, potentially including sialic acid, CAR, integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned by the inability to co-crystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo . Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domains CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (IM) injection, but not after intranasal (IN) administration. Ad26 transduction was 10-fold lower than Ad5 after intratumoral (IT) injection of CD46-expressing tumors. Ad26 transduction of liver was 1000-fold lower than Ad5 after intravenous (IV) injection. These data demonstrate the use of CD46 by Ad26 under certain situations, but also show that the receptor has little consequence by other routes of administration. Finally, IV injection of high doses of Ad26 into CD46 mice induced release of liver enzymes in the bloodstream and reduced white blood cell counts, but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during COVID-19 vaccination with this serotype of adenovirus. IMPORTANCE Human species D Ad26 is being pursued as a low seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection, and its role in virus biology, vaccine efficacy, and importantly, in vaccine safety.

11.
J Virol ; 96(3): e0082621, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1522911

ABSTRACT

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.


Subject(s)
Adenovirus Infections, Human/metabolism , Adenovirus Infections, Human/virology , Adenoviruses, Human/classification , Adenoviruses, Human/physiology , Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism , Host-Pathogen Interactions , Membrane Cofactor Protein/metabolism , Adenoviruses, Human/ultrastructure , Animals , Biomarkers , Blood Cell Count , CHO Cells , Cell Line , Coxsackie and Adenovirus Receptor-Like Membrane Protein/chemistry , Cricetulus , Disease Models, Animal , Gene Expression , Humans , Membrane Cofactor Protein/chemistry , Membrane Cofactor Protein/genetics , Mice, Transgenic , Models, Biological , Models, Molecular , Mutagenesis , Protein Binding , Protein Conformation , Serogroup , Sialic Acids/metabolism , Sialic Acids/pharmacology , Structure-Activity Relationship
13.
J Virol ; 95(19): e0086221, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1309804

ABSTRACT

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectible human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.


Subject(s)
COVID-19/metabolism , Host Microbial Interactions/physiology , Janus Kinases/metabolism , SARS-CoV-2/metabolism , Cell Line , Gene Expression Regulation , Humans , Immune Evasion , Immunity, Innate , Interferon Type I/metabolism , Janus Kinase 1/metabolism , Myocytes, Cardiac , Receptor, Interferon alpha-beta/metabolism , STAT1 Transcription Factor/metabolism , Signal Transduction , TYK2 Kinase/metabolism , Virus Replication
15.
Nat Microbiol ; 6(1): 73-86, 2021 01.
Article in English | MEDLINE | ID: covidwho-989838

ABSTRACT

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.


Subject(s)
COVID-19/veterinary , Callithrix/immunology , Lung/immunology , Macaca mulatta/immunology , Monkey Diseases/virology , Papio/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Animals , Antibodies, Viral/immunology , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid , COVID-19/diagnostic imaging , COVID-19/immunology , COVID-19/pathology , Female , Humans , Immunity, Cellular/immunology , Immunoglobulin G/immunology , Inflammation/pathology , Lung/virology , Male , Monkey Diseases/immunology , Myeloid Cells/immunology , Viral Load , Virus Shedding
16.
Alzheimers Dement ; 16(11): 1571-1581, 2020 11.
Article in English | MEDLINE | ID: covidwho-713873

ABSTRACT

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.


Subject(s)
Alzheimer Disease/complications , Coronavirus Infections/complications , Dementia/complications , Pneumonia, Viral/complications , Aged , Aged, 80 and over , Alzheimer Disease/therapy , Betacoronavirus , COVID-19 , Coronavirus Infections/therapy , Female , Humans , Male , Pandemics , Pneumonia, Viral/therapy , Risk Factors , SARS-CoV-2
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