Institutional trust is a distinct construct related to vaccine hesitancy and refusal.

BACKGROUND: Vaccine hesitancy is driven by a heterogeneous and changing set of psychological, social and historical phenomena, requiring multidisciplinary approaches to its study and intervention. Past research has brought to light instances of both interpersonal and institutional trust playing an important role in vaccine uptake. However, no comprehensive study to date has specifically assessed the relative importance of these two categories of trust as they relate to vaccine behaviors and attitudes. METHODS: In this paper, we examine the relationship between interpersonal and institutional trust and four measures related to COVID-19 vaccine hesitancy and one measure related to general vaccine hesitancy. We hypothesize that, across measures, individuals with vaccine hesitant attitudes and behaviors have lower trust-especially in institutions-than those who are not hesitant. We test this hypothesis in a sample of 1541 Canadians. RESULTS: A deficit in both interpersonal and institutional trust was associated with higher levels of vaccine hesitant attitudes and behaviors. However, institutional trust was significantly lower than interpersonal trust in those with high hesitancy scores, suggesting that the two types of trust can be thought of as distinct constructs in the context of vaccine hesitancy. CONCLUSIONS: Based on our findings, we suggest that diminished institutional trust plays a crucial role in vaccine hesitancy. We propose that this may contribute to a tendency to instead place trust in interpersonally propagated belief systems, which may be more strongly misaligned with mainstream evidence and thus support vaccine hesitancy attitudes. We offer strategies rooted in these observations for creating public health messages designed to enhance vaccine uptake.

X-ray Nanoimaging of Crystal Defects in Single Grains of Solid-State Electrolyte Li7-3xAlxLa3Zr2O12.

All-solid-state lithium batteries promise significant improvements in energy density and safety over traditional liquid electrolyte batteries. The Al-doped Li7La3Zr2O12 (LLZO) solid-state electrolyte shows excellent potential given its high ionic conductivity and good thermal, chemical, and electrochemical stability. Nevertheless, further improvements on electrochemical and mechanical properties of LLZO call for an in-depth understanding of its local microstructure. Here, we employ Bragg coherent diffractive imaging to investigate the atomic displacements inside single grains of LLZO with various Al-doping concentrations, resulting in cubic, tetragonal, and cubic-tetragonal mixed structures. We observe coexisting domains of different crystallographic orientations in the tetragonal structure. We further show that Al doping leads to crystal defects such as dislocations and phase boundaries in the mixed- and cubic-phase grain. This study addresses the effect of Al doping on the nanoscale structure within individual grains of LLZO, which is informative for the future development of solid-state batteries.

Combined Blockade of TNF-α and IL-17A Alleviates Progression of Collagen-Induced Arthritis without Causing Serious Infections in Mice.

The cytokines TNF-α and IL-17A are elevated in a variety of autoimmune diseases, including rheumatoid arthritis. Both cytokines are targets of several biologic drugs used in the clinic, but unfortunately many patients are refractory to these therapies. IL-17A and TNF-α are known to mediate signaling synergistically to drive expression of inflammatory genes. Hence, combined blockade of TNF-α and IL-17A represents an attractive treatment strategy in autoimmune settings where monotherapy is not fully effective. However, a major concern with this approach is the potential predisposition to opportunistic infections that might outweigh any clinical benefits. Accordingly, we examined the impact of individual versus combined neutralization of TNF-α and IL-17A in a mouse model of rheumatoid arthritis (collagen-induced arthritis) and the concomitant susceptibility to infections that are likely to manifest as side effects of blocking these cytokines (oral candidiasis or tuberculosis). Our findings indicate that combined neutralization of TNF-α and IL-17A was considerably more effective than monotherapy in improving collagen-induced arthritis disease even when administered at a minimally efficacious dose. Encouragingly, however, dual cytokine blockade did not cooperatively impair antimicrobial host defenses, as mice given combined IL-17A and TNF-α neutralization displayed infectious profiles and humoral responses comparable to mice given high doses of individual anti-TNF-α or anti-IL-17A mAbs. These data support the idea that combined neutralization of TNF-α and IL-17A for refractory autoimmunity is likely to be associated with acceptable and manageable risks of opportunistic infections associated with these cytokines.

A justification of health policy federalism.

The apportionment of responsibility for health policy within multi-level states should be sensitive to a number of conflicting normative pressures, some of which militate for placing decision-making authority at the higher reaches of policy-making structures, while others would seem to require placing them lower down this structure. The principle of subsidiarity is a structural principle that addresses in a manner that is neutral with respect to these values a way of addressing the conflicting claims of these values. Standard accounts of federalism fare poorly with respect to the criterion of subsidiarity. While central governments are at first glance better equipped to apply such a principle to the issue of the distribution of authority, there are strong empirical grounds for thinking that centralized governments will non-neutrally privilege central authorities in applying the principle. Federal structures that admit of overlapping jurisdictions, and that therefore require that deliberation among federal parties occur as a condition of the problem of the distribution of powers over health care being solved, are most amenable to solving problems of distribution of authority.

Disagreement, Unenforceability, and Harm Reduction.

Talk of harm reduction has expanded horizontally, to apply to an ever-widening range of policy domains, and vertically, becoming part of official legal and political discourse. This expansion calls for philosophical theorization. What is the best way in which to characterize harm reduction? Does it represent a distinctive ethical position? How is it best morally justified, and what are its moral limits? I distinguish two varieties of harm reduction. One of them, technocratic harm reduction, is premised on the fact of non-enforceability of prohibitionist policies. The second, deliberative harm reduction, is premised on the fact of reasonable disagreement, grounded in the fact that reasonable persons disagree about a range of controversial behaviours. I argue that deliberative harm reduction better accounts for some of harm reduction's most attractive features, and provides a plausible way of accounting for harm reductions's justificatory grounds and limits.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

Political legitimacy and research ethics.

In democratic theory, "legitimacy" refers to the set of conditions that must be in place in order for the claims to authority of somebody to be deemed appropriate, and for their claims to compliance to be warranted. Though criteria of legitimacy have been elaborated in the context of democratic states, there is no reason for them not to be drawn up, with appropriate amendments, for other kinds of authority structures. This paper examines the claims to authority made over researchers by international bodies governing research ethics, who exercise their authority by the research ethics guidelines they produce (including recent revisions to the Declaration of Helsinki and CIOMS Guidelines). We argue that discussions of such bodies and sets of guidelines often elide questions of justification and questions of legitimacy, and that the grounds that might allow us to mount a strong case for the latter are at present sorely underdeveloped.

Cytokines: The Good, the Bad, and the Deadly.

Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon ß reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions.

Conscientious refusal and health professionals: does religion make a difference?

Freedom of Conscience and Freedom of Religion should be taken to protect two distinct sets of moral considerations. The former protects the ability of the agent to reflect critically upon the moral and political issues that arise in her society generally, and in her professional life more specifically. The latter protects the individual's ability to achieve secure membership in a set of practices and rituals that have as a moral function to inscribe her life in a temporally extended narrative. Once these grounds are distinguished, it becomes more difficult to grant healthcare professionals' claims to religious exemptions on the basis of the latter than it is on the basis of the former. While both sets of considerations generate 'internal reasons' for rights to accommodation, the relevant 'external' reasons present in the case of claims of moral conscience do not possess analogues in the case of claims of religious conscience. However, the argument applies only to 'irreducibly religious' claims, that is to claims that cannot be translated into moral vocabulary. What's more, there may be reasons to grant the claims of religious persons to exemptions that have to do not with the nature of the claims, but with the beneficial effects that the presence of religious persons may have in the context of the healthcare institutions of multi-faith societies.

Spontaneous Supercrystal Formation During a Strain-Engineered Metal-Insulator Transition.

Mott metal-insulator transitions possess electronic, magnetic, and structural degrees of freedom promising next-generation energy-efficient electronics. A previously unknown, hierarchically ordered, and anisotropic supercrystal state is reported and its intrinsic formation characterized in-situ during a Mott transition in a Ca2RuO4 thin film. Machine learning-assisted X-ray nanodiffraction together with cryogenic electron microscopy reveal multi-scale periodic domain formation at and below the film transition temperature (TFilm ≈ 200-250 K) and a separate anisotropic spatial structure at and above TFilm. Local resistivity measurements imply an intrinsic coupling of the supercrystal orientation to the material's anisotropic conductivity. These findings add a new degree of complexity to the physical understanding of Mott transitions, opening opportunities for designing materials with tunable electronic properties.

Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis.

Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response. Consequently, drug allergies are DHRs for which an immunological mechanism, with antibody and/or T cell, is demonstrated. Despite decades of research, methods to predict the potential for a new chemical entity to cause DHRs or to correctly attribute DHRs to a specific mechanism and a specific molecule are not well-established. This review will focus on allergic reactions induced by systemically administered low-molecular weight drugs with an emphasis on drug- and patient-specific factors that could influence the development of DHRs. Strategies for predicting and diagnosing DHRs, including potential tools based on the current state of the science, will also be discussed.

Current approaches to evaluate the function of cytotoxic T-cells in non-human primates.

Cytotoxic T-lymphocytes (CTL) are a subset of T-cells that play a critical role in protecting against intracellular infections and cancer, and have the ability to identify and kill infected or transformed cells expressing non-self peptides associated with major histocompatibility (MHC) Class I molecules. Conversely, aberrant CTL activity can contribute to immune-related pathology under conditions of overwhelming infection or autoimmunity. Disease-modifying therapeutics can have unintended effects on CTL, and a growing number of therapeutics are intended to either suppress or enhance CTL or their functions. The susceptibility of CTL to unintended effects from common therapeutic modalities underscores the need for a better understanding of the impact that such therapies have on CTL function and the associated safety implications. While there are reliable ways of quantifying CTL, notably via flow cytometric analysis of specific CTL markers, it has been a greater challenge to implement fit-for-purpose methods measuring CTL function in the context of safety studies of therapeutics. This review focuses on methods for measuring CTL responses in the context of drug safety and pharmacology testing, with the goals of informing the reader about current approaches, evaluating their pros and cons, and providing perspectives on the utility of these approaches for safety evaluation.

Navigating the uncertainty: A novel taxonomy of vaccine hesitancy in the context of COVID-19.

Vaccine hesitancy remains a significant and evolving public health challenge. The COVID-19 pandemic has created a unique decision context with significant uncertainty caused by the novelty of the disease being targeted, unfamiliarity with the vaccines being offered, misinformation, and strong handed government measures. In an effort to extend our understanding of vaccine hesitancy to the high uncertainty decision environment presented by COVID-19, we present a novel taxonomy of the determinants of vaccine hesitancy, based on an inductive analysis of qualitative data gathered during the COVID-19 pandemic. We report on focus group data from a purposive sample of 18 Canadians with varying sociodemographic characteristics and COVID-19 vaccination attitudes. An inductive thematic analysis of this data reveals eight core themes related to vaccine hesitancy: values, trust, social environment, personal anecdotes, environmental fluctuation, prior knowledge, perceived risk & systems of care. We explore these core themes as well as 25 sub-themes, contrasting them with previous models of vaccine hesitancy and suggesting potential strategies for public health professionals.

From scary places to therapeutic landscapes: Voices from the community of people living with schizophrenia.

This article discusses how people living with schizophrenia experience, understand, and respond to their urban environment. Our study relies on experiential photo-voice data gathered with a sample of six people diagnosed with schizophrenia and living in non-institutional settings in Montréal, Canada, to identify how individuals in this community perceive the urban landscape. We adopt a therapeutic landscapes' framework that explores the urban fabric at three levels: physical, social, and symbolic. Research participants identified both health-denying and health-enhancing places within ordinary urban landscapes. Landscapes identified as health-denying are characterized by environmental stressors and loss of control, with construction sites an example highlighted by participants. Healing and restorative landscapes, as identified by participants, were physically attractive or quiet, socially safe and welcoming, and symbolically affirmative of one's identity, all factors worthy of further study. The findings are also policy-relevant: they suggest that people living with schizophrenia and their clinicians can develop strategies to make health-enhancing uses of urban landscapes; and that urban policies and practices can foster urban environments conducive to enhanced health and well-being, both for the community of people living with schizophrenia and the wider population of urban dwellers.

In Situ Nanoscale Dynamics Imaging in a Proton-Conducting Solid Oxide for Protonic Ceramic Fuel Cells.

Hydrogen fuel cells and electrolyzers operating below 600 °C, ideally below 400 °C, are essential components in the clean energy transition. Yttrium-doped barium zirconate BaZr0.8 Y0.2 O3-d (BZY) has attracted a lot of attention as a proton-conducting solid oxide for electrochemical devices due to its high chemical stability and proton conductivity in the desired temperature range. Grain interfaces and topological defects modulate bulk proton conductivity and hydration, especially at low temperatures. Therefore, understanding the nanoscale crystal structure dynamics in situ is crucial to achieving high proton transport, material stability, and extending the operating range of proton-conducting solid oxides. Here, Bragg coherent X-ray diffractive imaging is applied to investigate in situ and in 3D nanoscale dynamics in BZY during hydration over 40 h at 200 °C, in the low-temperature range. An unexpected activity of topological defects and subsequent cracking is found on a nanoscale covered by the macroscale stability. The rearrangements in structure correlate with emergent regions of different lattice constants, suggesting heterogeneous hydration. The results highlight the extent and impact of nanoscale processes in proton-conducting solid oxides, informing future development of low-temperature protonic ceramic electrochemical cells.