bluuebunny/crossref_metadata_2025_split huggingface dataset:
1121. Does Anti-Vaccine Equal Anti-Antibody? Differing Rates of Veteran Acceptance of Monoclonal Antibody Therapies for COVID-19 By Prior Vaccination Status
Authors: Brennan Martha , Shumaker Amy Hirsch , Stiefel Usha 
Published: December 2022

Abstract

Background
We assessed correlation between prior acceptance of COVID-19 vaccination and acceptance of monoclonal antibody (MAb) treatment for mild-to-moderate COVID-19.

Methods
Adult outpatients evaluated for treatment with MAb between August 31st, 2021 and April 23, 2022 in a large tertiary care VA healthcare system were included. MAb therapies administered over the period included casirivimab-imdevimab, sotrovimab, and bebtelovimab. All patients were screened by a small central clinician team with experience discussing COVID therapies under Emergency Use Authorization (EUA). Baseline characteristics, rationale for not offering MAb, and rates of vaccination and acceptance of therapy were recorded. In addition, rates of acceptance for the initial 4 months were compared to rates during the second 4 months of the program, using Chi-square or Fisher’s exact test.

Results
203 patients (mean age 68, 91% male) with early COVID-19 were screened for MAb. 68% were vaccinated. 158 (78%) of those screened were offered MAb. The most common reason MAb was not offered was duration of illness longer than specified by EUA (65%). 112 (71%) patients offered MAb accepted, and 94 (84%) received MAb. Of 106 vaccinated patients offered MAb, 81 (76%) accepted. In contrast, of 52 unvaccinated patients offered MAb, only 31 (60%) accepted (Chi-square p = 0.046). However, when analyzed over time, unvaccinated patients were significantly more likely to accept MAb during the second 4 months of the program (7/7 patients, 100%) than during the first 4 months of the program (24/45 patients, 53%, Fisher’s exact p = 0.033). This disparity was not seen in vaccinated patients, who accepted MAb at a rate of 73% during the first half of the program, and 88% during the second half (Chi-square p = 0.19).

Conclusion
Vaccinated patients were significantly more likely to accept MAb therapy for COVID-19 than unvaccinated patients, suggesting that willingness to accept COVID-19 vaccination predicts willingness to accept other COVID-19 therapeutics. However, disparity in acceptance rates in our population is significantly attenuating over time, suggesting a “late-adopter,” phenomenon that has implications for continued efforts to encourage therapeutics and vaccines for COVID-19.

Disclosures
All Authors: No reported disclosures.
1124. Effect of High-Dose versus Standard-Dose Dexamethasone on Mortality Among Mechanically Ventilated COVID-19 Patients
Authors: Kale-Pradhan Pramodini , Pacitto Regina , Krumm Lauren , Hejnar Anna , Giuliano Christopher , Johnson Leonard B 
Published: December 2022

Abstract

Background
Anti-inflammatory agents like dexamethasone (DEX) have become a mainstay of treatment for COVID-19. Despite randomized trials demonstrating that a 6 mg daily dose of DEX improved patient outcomes in hospitalized COVID-19 patients receiving oxygen, clinicians often prescribe higher doses of corticosteroids without evidence to support this practice. The purpose of this study was to compare outcomes of ventilated COVID-19 patients who received standard dose (SD) versus high dose (HD) DEX.

Methods
This was a multi-site, retrospective, observational study of ventilated COVID-19-positive patients who received at least three days of DEX between June 1, 2020 and January 31, 2022. Sample size was calculated based on a 3:1 high:standard-dose prescribing pattern ratio. The primary outcome of this study was the association between mortality and SD (&lt;6mg daily) versus HD ( &gt;10mg daily) DEX in ventilated COVID-19 patients. Secondary outcomes included average blood glucose (BG), number of BG readings above 200, incidence of bacterial nosocomial infection, ventilator-free days, length of stay (LOS) and ICU LOS.

Results
Of 322 patients screened, 110 were excluded primarily for average daily DEX dose of &gt; 6 to ≤ 10mg. Of the 212 included patients, 53 (25%) received SD DEX and 159 (75%) received HD DEX. Data demonstrate no significant effect of DEX dose on mortality, number of BG readings &gt; 200, incidence of nosocomial infections, LOS, or ventilator-free days (p &gt;0.05). After controlling for confounding factors no difference in mortality persisted (OR 1.45 95% CI 0.66- 3.20). Average daily BG and ICU LOS were significantly greater in the HD group compared to the SD group (p = 0.003, p = 0.019 respectively).

Conclusion
There is no association between HD DEX and mortality among ventilated COVID-19 patients compared to SD DEX. Moreover, HD DEX is associated with detrimental effects such as prolonged ICU LOS and higher average daily BG. This study supports the use of SD DEX in ventilated COVID-19 patients.

Disclosures
All Authors: No reported disclosures.
1134. Lenzilumab Treatment in COVID-19 Pneumonia Reduces Circulating Cytokines and Markers of Systemic Inflammation
Authors: Chappell Dale , Kilcoyne Adrian , Cerasoli Frank , Lukas John , Durrant Cameron , Temesgen Zelalem , Polk Christopher , Baker Jason , Marconi Vincent 
Published: December 2022

Abstract

Background
Coronavirus disease 2019 (COVID-19) results from SARS-CoV-2-induced hyperinflammatory immune response, orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF increases interleukin-6 (IL-6) levels, ultimately leading to increased C-reactive protein (CRP). The LIVE-AIR trial demonstrated that lenzilumab, the GM-CSF neutralizing antibody, improved the likelihood of survival without invasive mechanical ventilation (IMV) in hospitalized COVID-19 patients requiring supplemental oxygen but not IMV. This sub-analysis correlated levels of cytokines before and after lenzilumab treatment.

Methods
LIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial (NCT04351152). Patients hospitalized with COVID-19 pneumonia, requiring only supplemental oxygen, were randomized to receive lenzilumab (1800 mg in three equally divided doses of 600 mg, q8h) or placebo IV infusion, in addition to standard of care which included remdesivir and corticosteroids. Blood taken at baseline (BL) and subsequent to treatment through day 10 (D10) were obtained and analyzed by high sensitivity enzyme immunoassay for GM-CSF, IL-6, and CRP.

Results
Baseline IL-6 levels (Loge-transformed for all cytokines and biomarkers) were linearly correlated with higher baseline GM-CSF levels (slope=0.60, p&lt; 0.001). Baseline CRP levels were linearly correlated with higher baseline IL-6 levels (slope=0.29, p &lt; 0.001). GM-CSF levels decreased with lenzilumab treatment on day 1 (D1) which persisted through D10 (Table). In contrast, GM-CSF increased with placebo treatment. IL-6 levels decreased only with lenzilumab treatment. CRP following lenzilumab or placebo treatment decreased on D1 to similar levels and further decreased on D10 only with lenzilumab treatment.
Cytokine Levels Associated with Lenzilumab Treatment

Conclusion
Lenzilumab decreased GM-CSF as well as downstream cytokines and systemic biomarkers of inflammation during the hyperinflammatory immune response of COVD-19.

Disclosures
Dale Chappell, MD, MBA, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Adrian Kilcoyne, MD, Humanigen, Inc: Employee Frank Cerasoli, PhD, Humanigen, Inc: Advisor/Consultant John Lukas, PhD, Humanigen, Inc: Advisor/Consultant Cameron Durrant, MD, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Zelalem Temesgen, MD, Gilead: unrestricted educational grant (to the institution)|Humanigen, Inc: Grant/Research Support|Merck: unrestricted educational grant (to the institution)|ViiV: Advisor/Consultant Christopher Polk, MD, Gilead: Advisor/Consultant Jason Baker, MD, Gilead: Grant/Research Support|Humanigen, Inc: Grant/Research Support Vincent Marconi, MD, Gilead: Grant/Research Support.
1141. Phase 3 Trial (in progress) of the SYK Inhibitor Fostamatinib in Patients Hospitalized with COVID-19: Protocol and Study Implementation Updates
Authors: Yan Lucy , Mallat Ziad , Lobo Suzana Margareth , Malik Anuj , Dummer Wolfgang 
Published: December 2022

Abstract

Background
Immune dysregulation associated with COVID-19 includes immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Fig 1). Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, was approved for immune thrombocytopenia (ITP) in 2018, and the Phase 3 trials showed a lower than expected rate of thrombosis.1 Clinical studies showed a reduction in IL-6 in patients with rheumatoid arthritis.2 The active metabolite of fostamatinib (R406) protected against LPS-induced acute lung injury and thrombosis in mice3,4 and reduced MUC1 in a mouse model of ALI.5 Fostamatinib demonstrated abrogation of the hyperimmune response caused by anti-spike IgG,6 including reduction in hyperactivation of platelets7 and NETosis in neutrophils8 in in vitro studies using plasma from patients with severe COVID-19.
A phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo (all received standard of care [SOC]) in 59 hospitalized patients with COVID-19 and demonstrated reduction in mortality, ordinal scale scores, and number of days in the intensive care unit (ICU) as well as meeting the primary endpoint of safety.9 A phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19 is underway. Figure 1.Mechanism of Disease (COVID-19) and Role of SYK inhibition

Methods
A Phase 3, randomized, double-blind, placebo-controlled, adaptive design, multi-center study (NCT04629703) is underway to evaluate fostamatinib in 308 adult patients hospitalized with COVID-19 and on oxygen without intubation (Fig 2). Patients will receive fostamatinib 150 mg BID or placebo for 14 days; both arms receive SOC. At baseline, the clinical status score (8-point ordinal scale) had to be 5 or 6. Patients ≥ 65 years had to have ≥ 1 risk factor for severe disease and adults &lt; 65 had to have ≥ 3. The primary outcome is days on oxygen (Day 1 to 29). Other endpoints include change in clinical status score, days in the ICU, time to hospital discharge, all-cause mortality, oxygen-free status and safety. Fostamatinib is investigational for COVID-19.

Results
Blinded data from this trial in progress are as of 2 December 2021. See Fig 3.

Conclusion
Final results of this Phase 3 trial are anticipated in 2022.

Disclosures
Lucy Yan, MD, PhD, Rigel Pharmaceuticals: Employee|Rigel Pharmaceuticals: Stocks/Bonds Ziad Mallat, MD, PhD, Rigel Pharmaceuticals: Advisor/Consultant Suzana Margareth Lobo, MD, PhD, Rigel Pharmaceuticals: Grant/Research Support Anuj Malik, MD, MS, Rigel Pharmaceuticals: Grant/Research Support Wolfgang Dummer, MD, PhD, Rigel Pharmaceuticals: Employee|Rigel Pharmaceuticals: Stocks/Bonds.
1162. A data-driven approach to predict plasma leakage using explainable machine learning
Authors: Marandi Ramtin Zargari , Leung Preston , Sigera Chathurani , Murray Daniel Dawson , Weeratunga Praveen , Fernando Deepika , Rodrigo Chaturaka , Rajapakse Senaka , MacPherson Cameron 
Published: December 2022

Abstract

Background
Dengue could cause complications with an estimated 10,000 deaths per annum. It mostly affects low- and middle-income countries such as Sri Lanka with limited healthcare resources to handle seasonal outbreaks. A third of dengue patients usually have a critical phase characterized by plasma leakage with increased risk of life-threatening complications. A data-driven approach was required to find early predictors of plasma leakage that are usually available in routine care from a resource limited setting, as means of triaging patients for hospital admission.

Methods
We utilized a prospective cohort (The Colombo dengue study in Sri Lanka) that recruits patients meeting the clinical case definition of dengue fever. The cohort includes 4,781 instances of clinical signs, symptoms, and in-hospital laboratory tests from N=877 patients (60.3% patients infected by Dengue) recorded in first four days of fever. By excluding incomplete patient instances, the data was randomly split to a development set (N=378) and a test set (N=144). From the development set, five most informative features were identified using the minimum description length (MDL) algorithm. Logistic regression was used to create a prediction model using the development set. Shapley analysis was used to explain the model on the test set extracting the extent by which each predictor contributed to the predictions.

Results
The MDL algorithm revealed that hemoglobin (HGB), hematocrit (HCT), aspartate aminotransferase (AST), age, and gender to be the most informative predictors of plasma leakage. The logistic regression model predicted plasma leakage with (AUC = 0.76) on the test set (Fig 1). The HGB appeared to contribute the most to the predictions with the higher values associated with higher predicted risk of plasma leakage and vice versa (Fig 2).
Figure 2 SHAP decision plot for the logistic regression model on the test set. The features are sorted from top to bottom by their mean absolute SHAP values (higher interpreted as more contributing). Feature values are normalised to [0 1] by the min-max normalisation method and colour-coded (grey points are missing values), outliers were squished to the range using Hampel filter. For gender, male is indicated by red and female by blue. The colour of each line is the same as the value of the feature connected to in downwards direction.

Conclusion
Our results give support to the predictability of plasma leakage in patients suspected of Dengue fever in their first four days of fever onset. The study also underlines the relevance of the machine learning approach to identify the predictors and the practicality of the prediction model as reflected by the prediction performance to triage patients for hospital admission in resource limited settings.

Disclosures
All Authors: No reported disclosures.
Half-hearted Support to Pluralist Curriculum Building: The Case of Religion
Authors: Temperman Jeroen 
Published: December 2022

ABSTRACT
This article makes two claims, one explanatory, one normative. The former aims at explaining why pluralist religion teaching, be it teaching in the style advocated by the OSCE Toledo Guiding Principles on Teaching about Religions and Beliefs in Public Schools or other forms of pluralist religion teaching or religious literacy teaching, has not become an overwhelming success in Europe. To that effect, the article identifies a number of incentives and disincentives contained in (interpretations of) international human rights law that serve to perpetuate confessional teaching models. The normative claim advanced in this article challenges international human rights monitoring bodies’ ‘claw-back-clause’ reading of educational and religious rights of pupils and parental liberties. Specifically, the article concludes that advances in socio-legal science show that opt-outs are no remedy for the risks emanating from confessional religion teaching within public schools—rather, opt-outs are part of the problem.
The Welfare State Begins at Home
Authors: Chettiar Teri 
Published: December 2022

Abstract
Chapter 2 explores how the wartime discovery of widespread emotional “deprivation” in children—and fears attached to its long-term psychological effects—transformed post-WWII British political culture by making it a basic duty of the modern state to ensure citizens’ emotional health. This chapter reveals how concerns about Britain’s future after 1945 became tied to the developmental futures of British children. Alongside its agenda of eliminating poverty and guaranteeing full employment, Britain’s new welfare state was tasked with ensuring that all children be reared within “family-like” environments and given the best possible shot at emotional health. Concern for children’s emotional development framed the government’s approach to adoption, foster care, daycare provision, and children’s in-patient treatment in hospitals. The protection and promotion of family intimacy came to be seen as one of the functions of the new welfare state. This not only helped reinvent the family as first and foremost a set of intimate relationships, it also introduced a new emotional component to the rights and responsibilities of modern democratic citizenship.
Pursuing Connection
Authors: Chettiar Teri 
Published: December 2022

Abstract
This chapter examines the launching of counseling and befriending services by British queer activist organizations at the height Britain’s so-called sexual revolution. Seeking to remedy the many serious social and emotional problems that homosexual, bisexual, and trans populations faced, supporters of homosexual law reform and queer liberation activists alike saw in counseling a promising solution to the harmful psychological effects of social exclusion and internalized homo- and transphobia. However, as this chapter demonstrates, although the meaning and markers of psychological “health” were expanded and revised, many features of Britain’s dominant constellation of sexual values were retained as goals and even internalized by social reformers themselves. This chapter reveals that British counseling aimed at queer people, in its pursuit of resolving the emotional suffering uniquely experienced by sexual minorities, focused on cultivating clients’ psychological capacity to choose and sustain lasting intimate relationships.
The Right to Visit (I)
Authors: Huber Jakob 
Published: December 2022

AbstractThis chapter turns to Kant’s discussion of cosmopolitan right, where the argument from earth dwellership reappears. Starting with the ‘constraining’ dimension of the cosmopolitan right to visit, it makes sense of Kant’s anticolonialism against the background of his grounded cosmopolitanism. The primary systematic question is on which juridical basis Kant can radically curtail the comportment of Western emissaries abroad, denying them in particular a right to force non-state peoples to enter the civil condition, for instance by simply settling in their vicinity. The chapter argues that it is their shared earth dwellership which constrains travellers to cautious offers for interaction and exchange even in the absence of a shared property practice. Construing a regress from the property argument to the more fundamental domain of earth dwellership, I show how Kant is able to conceptualise a distinctly juridical critique of colonialism as wrongful comportment. The chapter thus highlights that Kant’s grounded cosmopolitanism is a cosmopolitanism of self-constraint vis-à-vis distant strangers or unfamiliar forms of collective life and political association.
The Right to Visit (II)
Authors: Huber Jakob 
Published: December 2022

AbstractThis chapter addresses the permissive aspect of cosmopolitan right, which is concerned with global mobility. I argue that individuals have a right to roam the earth’s surface in their capacity as earth dwellers. As cosmopolitan agents ‘on the move’, they create the conditions for lawful peace among the entire cosmopolitan plurality, including both states and non-state peoples. Earth dwellership thus limits exclusive claims to land or territory to the conditions of global mobility, which is a fundamental precondition for transforming the disjunctive community of original common possession into a juridical community of legal subjects. Both dimensions of the cosmopolitan right to visit are integrated in that they spell out the conditions for realising a cosmopolitan political order in the future under conditions where such an order can neither be brought about nor maintained by force.
Progress, Hope, and the Cosmopolitan State
Authors: Huber Jakob 
Published: December 2022

AbstractApproaching the project of bringing the community of disjunctive possession under law from a perspective of historical time, the chapter zooms in on Kant’s conception of cosmopolitan progress. It distinguishes two dimensions of political progress in Kant, which concern the perfection and the creation of political institutions respectively. These two domains intersect in the idea of a cosmopolitan state, i.e., a state that contributes to cosmopolitan progress by binding itself and its citizens to rightful comportment towards other states and non-state peoples. The path to a global institutional order proceeds via radically reformed states. If we do our part in establishing a condition of peace, we may reasonably hope for the willingness of other states and non-state peoples to reciprocate our efforts, such that the idea of a perpetual peace does not remain an empty wish.
Conclusion
Authors: Huber Jakob 
Published: December 2022

AbstractThe ‘Conclusion’ transcends the book’s primarily exegetical ambition by pointing to some of the ways in which Kant’s grounded cosmopolitanism is of continuing relevance, foregrounding two aspects in particular. On the one hand, the relational (yet practice-independent) nature of Kant’s global thinking contrasts with recent global justice theorising, which remains largely focused on distributive questions. This has implications for a number of normative debates around migration, membership or colonialism. On the other hand, the reflexivity enshrined in what I call the global standpoint provides a novel perspective on the perennial question how to accommodate diversity and difference. Kant’s community of earth dwellers is not a homogenous community of individuals already united in shared principles or institutions, but it is made up of a plurality of perspectives in disjunctive relation. This not only provides a timely reminder against the philosophical impatience that continues to characterise global justice debates, Kant’s focus on cosmopolitan activity within the state also transcends the traditional dichotomy between statism and cosmopolitanism.
Theoretical Framework
Authors: Bobić Ana 
Published: December 2022

Abstract
This chapter sets out the theoretical framework for analysis of the interactions between the Court of Justice and national constitutional/supreme courts. It provides a detailed literature review of constitutional pluralism as it was developed in the context of EU constitutional theory. It briefly presents the development of the general theory of legal pluralism in order to zoom into its application to the context of the European Union. Finally, this chapter presents the main criticisms directed to the theory from its inception and in respect of the most recent rule of law crisis in the EU.
Identity Review
Authors: Bobić Ana 
Published: December 2022

Abstract
This chapter examines the function of the national identity clause enshrined in Article 4(2) TEU and how it has been used by the national level in protecting national constitutional particularities. This head of review gained prominence in recent years as a source for contestation of EU law, and its use in the rule of law backsliding in a number of Member States. In this context, this chapter offers an analysis of the national constitutional jurisprudence and its approach to constitutional identity. In so doing, it presents the wide range of national approaches to safeguarding constitutional identity: the German unconditional take on constitutional identity as a limit to the principle of primacy of EU law; the Polish shift from constructive to destructive use of constitutional identity; and finally other Member States that envisage some identity-based limits to primacy, while at the same time offering a range of reconciliatory options should a conflict arise. The chapter further explores the case law of the Court of Justice, by looking at the different ways in which Article 4(2) TEU has featured in its decisions on free movement. The chapter concludes with suggesting a pluralist interpretation of the national identity clause that would accommodate both national constitutional concerns and the requirements of the principle of primacy of EU law.