The Scuppernong River Project, Volume 1: Explorations of Tyrrell County Maritime History

PAST Foundation, UNC Coastal Studies Institute, East Carolina Universit

AK002, a Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody that Induces Antibody-Dependent Cell-Mediated Cytotoxicity against Human Eosinophils and Inhibits Mast Cell-Mediated Anaphylaxis in Mice

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. METHODS: The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. RESULTS: AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. CONCLUSION: AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition

AK002, a Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody that Induces Antibody-Dependent Cell-Mediated Cytotoxicity against Human Eosinophils and Inhibits Mast Cell-Mediated Anaphylaxis in Mice.

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. METHODS: The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. RESULTS: AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. CONCLUSION: AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition

Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation*

The economic implications of sedative choice in the management of patients receiving mechanical ventilation are unclear because of differences in costs and clinical outcomes associated with specific sedatives. Therefore, we aimed to determine the cost-effectiveness of the most commonly used sedatives prescribed for mechanically ventilated critically ill patients

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort

International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats:The REVEAL Study

Background: Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. Hypothesis/Objectives: Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). Animals: One thousand seven hundred and thirty client-owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). Methods: Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long-term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. Results: During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean \ub1 standard deviation, 1.3 \ub1 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9-15 years. Conclusions and Clinical Importance: Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019 : a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dosespecific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in countryreported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. Findings By 2019, global coverage of third-dose DTP (DTP3; 81.6% [95% uncertainty interval 80.4-82 .7]) more than doubled from levels estimated in 1980 (39.9% [37.5-42.1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38.5% [35.4-41.3] in 1980 to 83.6% [82.3-84.8] in 2019). Third- dose polio vaccine (Pol3) coverage also increased, from 42.6% (41.4-44.1) in 1980 to 79.8% (78.4-81.1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56.8 million (52.6-60. 9) to 14.5 million (13.4-15.9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. Interpretation After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens