The role of 'non-knowledge' in crisis policymaking: a proposal and agenda for future research

Background: Recent complex and cross-boundary policy problems, such as climate change, pandemics, and financial crises, have recentred debates about state capacity, democratic discontent and the 'crisis of expertise'. These problems are contested and open to redefinition, misunderstanding, spin, and deception, challenging the ability of policymakers to locate, discriminate, comprehend, and respond to competing sources of knowledge and expertise. We argue that 'non-knowledge' is an under-explored aspect of responses to major policy crises. Key points: While discussed in recent work in sociology and other social sciences, non-knowledge has been given less explicit attention in policy studies, and is not fully captured by orthodox understandings of knowledge and evidence use. We outline three main forms of non-knowledge that challenge public agencies: amnesia, ignorance and misinformation. In each case, 'non-knowledge' is not simply the absence of policy-relevant knowledge. Amnesia refers to what is forgotten, reinvented or 'unlearned', while claims of ignorance involve obscuring or casting aside of relevant knowledge that could (or even should) be available. To be misinformed is to actively believe false or misleading information. In each instance, non-knowledge may have strategic value for policy actors or aid the pursuit of self-interest. Conclusions and implications: We demonstrate the relevance of non-knowledge through a brief case study, emerging from the inquiry into the COVID-19 hotel quarantine programme in the Australian state of Victoria. We argue that both amnesia and 'practical' forms of ignorance contributed to failures during the early part of the programme. © Policy Press 2023.

Convalescent human IgG, but not IgM, from COVID-19 survivors confers dose-dependent protection against SARS-CoV-2 replication and disease in hamsters.

Introduction: Antibody therapeutic strategies have served an important role during the COVID-19 pandemic, even as their effectiveness has waned with the emergence of escape variants. Here we sought to determine the concentration of convalescent immunoglobulin required to protect against disease from SARS-CoV-2 in a Syrian golden hamster model. Methods: Total IgG and IgM were isolated from plasma of SARS-CoV-2 convalescent donors. Dose titrations of IgG and IgM were infused into hamsters 1 day prior to challenge with SARS-CoV-2 Wuhan-1. Results: The IgM preparation was found to have ~25-fold greater neutralization potency than IgG. IgG infusion protected hamsters from disease in a dose-dependent manner, with detectable serum neutralizing titers correlating with protection. Despite a higher in vitro neutralizing potency, IgM failed to protect against disease when transferred into hamsters. Discussion: This study adds to the growing body of literature that demonstrates neutralizing IgG antibodies are important for protection from SARS-CoV-2 disease, and confirms that polyclonal IgG in sera can be an effective preventative strategy if the neutralizing titers are sufficiently high. In the context of new variants, against which existing vaccines or monoclonal antibodies have reduced efficacy, sera from individuals who have recovered from infection with the emerging variant may potentially remain an efficacious tool.

The effect of the SARS-CoV-2 pandemic on suspected cancer referrals at a regional head and neck unit

The novel coronavirus SARS-CoV-2, initially identified in late 2019 as a small case cluster, has rapidly become a global pandemic. Government restrictions, closure of primary care services, interruption of cancer screening programmes, and fear of contracting the virus have demonstrably led to a reduction in referrals for suspected cancer and delays to treatment across the United Kingdom. A retrospective analysis was carried out on suspected cancer referrals to the maxillofacial service at Aberdeen Royal Infirmary during the 12 months from March 2020, and compared with the 12 months prior. Suspected cancer referrals reduced by 38.6% (p < 0.001) during this period, with a reduction in the percentage referred by General Dental Practitioners. Further analysis shows a proportionate reduction in squamous cell carcinoma diagnoses, with other diagnoses remaining stable. Time from referral to first appointment, biopsy, and treatment showed no change. Stage at diagnosis and treatment modality was also unaffected. Assuming no change to the incidence of head and neck malignancies, over a third of new malignancies may have been undiagnosed during the 12 months from March 2020. Evidence for the impact of the pandemic is likely to become apparent as services return to pre-pandemic levels and these patients begin to present.Copyright © 2021 The Authors

Probable vertical transmission of Alpha variant of concern (B.1.1.7) with evidence of SARS-CoV-2 infection in the syncytiotrophoblast, a case report.

Introduction: Definitive vertical transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been rarely reported. We present a case of a third trimester pregnancy with fetal distress necessitating cesarean section that demonstrated maternal, placental, and infant infection with the SARS-CoV-2 Alpha variant/B.1.1.7. Methods: CDC's Influenza SARS-CoV-2 Multiplex RT-PCR Assay was used to test for SARS-CoV-2 in a maternal NP swab, maternal plasma, infant NP swab, and formalin-fixed paraffin-embedded (FFPE) placental tissue specimens. Whole genome sequencing (WGS) was performed on maternal plasma, infant, and placental specimens to determine the SARS-CoV-2 genotype. Histopathological evaluation, SARS-CoV-2 immunohistochemistry testing (IHC), and electron microscopy (EM) analysis were performed on placenta, umbilical cord, and membrane FFPE blocks. Results: All specimens tested positive for SARS-CoV-2 by RT-PCR. WGS further revealed identical SARS-CoV-2 sequences from clade 20I/501Y.V1 (lineage Alpha/B.1.1.7) in maternal plasma, infant, and placental specimens. Histopathologic evaluation of the placenta showed histiocytic and neutrophilic intervillositis with fibrin deposition and trophoblast necrosis with positive SARS-CoV-2 immunostaining in the syncytiotrophoblast and electron microscopy evidence of coronavirus. Discussion: These findings suggest vertical transmission of SARS-CoV-2, supported by clinical course timing, identical SARS-CoV-2 genotypes from maternal, placental, and infant samples, and IHC and EM evidence of placental infection. However, determination of the timing or distinction between prepartum and peripartum SARS-CoV-2 transmission remains unclear.

Nirmatrelvir plus ritonavir in COVID-19: a profile of its use.

Oral nirmatrelvir plus ritonavir (Paxlovid™) is an effective treatment option for coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nirmatrelvir inhibits the main protease of SARS-CoV-2, with ritonavir acting as a pharmacokinetic booster. In the phase II/III EPIC-HR trial, nirmatrelvir plus ritonavir reduced the risk of progression to severe COVID-19 in symptomatic, unvaccinated, non-hospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease. The incidence of COVID-19-related hospitalization or death through day 28 was significantly lower with nirmatrelvir plus ritonavir than with placebo. The efficacy of nirmatrelvir plus ritonavir has also been demonstrated in the real-world setting. Nirmatrelvir plus ritonavir is generally well tolerated, with most adverse events being of mild or moderate severity. Supplementary Information: The online version contains supplementary material available at 10.1007/s40267-022-00971-1.

Probable vertical transmission of Alpha variant of concern (B.1.1.7) with evidence of SARS-CoV-2 infection in the syncytiotrophoblast, a case report

Introduction Definitive vertical transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been rarely reported. We present a case of a third trimester pregnancy with fetal distress necessitating cesarean section that demonstrated maternal, placental, and infant infection with the SARS-CoV-2 Alpha variant/B.1.1.7. Methods CDC's Influenza SARS-CoV-2 Multiplex RT-PCR Assay was used to test for SARS-CoV-2 in a maternal NP swab, maternal plasma, infant NP swab, and formalin-fixed paraffin-embedded (FFPE) placental tissue specimens. Whole genome sequencing (WGS) was performed on maternal plasma, infant, and placental specimens to determine the SARS-CoV-2 genotype. Histopathological evaluation, SARS-CoV-2 immunohistochemistry testing (IHC), and electron microscopy (EM) analysis were performed on placenta, umbilical cord, and membrane FFPE blocks. Results All specimens tested positive for SARS-CoV-2 by RT-PCR. WGS further revealed identical SARS-CoV-2 sequences from clade 20I/501Y.V1 (lineage Alpha/B.1.1.7) in maternal plasma, infant, and placental specimens. Histopathologic evaluation of the placenta showed histiocytic and neutrophilic intervillositis with fibrin deposition and trophoblast necrosis with positive SARS-CoV-2 immunostaining in the syncytiotrophoblast and electron microscopy evidence of coronavirus. Discussion These findings suggest vertical transmission of SARS-CoV-2, supported by clinical course timing, identical SARS-CoV-2 genotypes from maternal, placental, and infant samples, and IHC and EM evidence of placental infection. However, determination of the timing or distinction between prepartum and peripartum SARS-CoV-2 transmission remains unclear.

A secondary analysis examining the performance of the State Optimism Measure (SOM) compared to the Life Orientation Test-Revised (LOT-R) in measuring optimism over time.

Objective: Optimism is an important factor impacting health and human functioning. Originally conceptualized as a trait, increasing evidence indicates that optimism can change over time and could be an intervention target. Measures are needed that can capture changes in optimism.Design: In this secondary analysis, we compared the performance of a newly developed state measure, the State Optimism Measure (SOM), to the widely used trait measure, the Life Orientation Test-Revised (LOT-R), in detecting changes over time during a disruptive life event: the onset of the COVID-19 pandemic in the United States.Main Outcome Measures: Participants (n = 81) were nondaily smokers participating in a smoking cessation intervention, who completed the SOM and LOT-R before and after the initial COVID-19 outbreak.Results: Optimism declined from pre- to post-COVID-19 outbreak, as assessed by both scales (LOT-R: p=.0147,gav=0.23; SOM: p<.0001,gav=0.56). The change detected was greater when measured by the SOM (p<.0001). Changes in optimism were correlated with concurrent changes in perceived stress, positive affect, and negative affect.Conclusion: Our results suggest that the SOM has a greater sensitivity to detect within-person changes in optimism than the LOT-R and highlight the SOM's utility for longitudinal studies assessing changes in optimism.

Biobehavioral Implications of Covid-19 for Transplantation and Cellular Therapy Recipients

A growing body of literature has emphasized the importance of biobehavioral processes – defined as the interaction of behavior, psychology, socioenvironmental factors, and biological processes – for clinical outcomes among transplantation and cellular therapy (TCT) patients. TCT recipients are especially vulnerable to distress associated with pandemic conditions and represent a notably immunocompromised group at greater risk for SARS-CoV-2 infection with substantially worse outcomes. The summation of both the immunologic and psychologic vulnerability of TCT patients renders them particularly susceptible to adverse biobehavioral sequelae associated with the Covid-19 pandemic. Stress and adverse psychosocial factors alter neural and endocrine pathways through sympathetic nervous system and hypothalamic-pituitary-adrenal axis signaling that ultimately affect gene regulation in immune cells. Reciprocally, global inflammation and immune dysregulation related to TCT contribute to dysregulation of neuroendocrine and central nervous system function, resulting in the symptom profile of depression, fatigue, sleep disturbance, and cognitive dysfunction. In this article, we draw upon literature on immunology, psychology, neuroscience, hematology and oncology, Covid-19 pathophysiology, and TCT processes to discuss how they may intersect to influence TCT outcomes, with the goal of providing an overview of the significance of biobehavioral factors in understanding the relationship between Covid-19 and TCT, now and for the future. We discuss the roles of depression, anxiety, fatigue, sleep, social isolation and loneliness, and neurocognitive impairment, as well as specific implications for sub-populations of interest, including pediatrics, caregivers, and TCT donors. Finally, we address protective psychological processes that may optimize biobehavioral outcomes affected by Covid-19.

COVID-19 Impact on Smokers Participating in Smoking Cessation Trials: The Experience of Nondaily Smokers Participating in a Smartphone App Study.

Objectives: To provide initial insight into how the COVID-19 pandemic could affect smoking behaviors and cessation efforts that were underway at its onset. Methods: An additional survey was added to follow-up assessments in an ongoing smoking cessation study for nondaily smokers: a measure of impact of COVID-19 and a subset of previously administered scales measuring smoking, emotional well-being, and alcohol use. Pre-post tests were conducted (84 ± 28 days apart). Results: Participants (81/100 of enrolled; 67% female, 75% white, 10% Hispanic, 37 ± 11 years old) reported experiencing changes regarding work (35% income reduction/loss; 35% remote work) and living situation (15% consolidated residences). Participants reported their motivation to quit smoking "slightly" increased after COVID-19 (p < 0.001), more so in those having achieved 30-day abstinence (p = 0.0045). Worry, fear, and a desire to support the greater good increased (ps < 0.05). Increases in motivation to quit correlated positively with prosocial and wellness changes. Data from pre- to post-COVID-19 onset showed decreases in emotional well-being (increased stress, negative affect, decreased coping, positive affect, all ps < 0.01), but not changes in smoking abstinence (p = 0.65), readiness to quit (p = 0.16), smoking frequency (p = 0.96), or cigarettes per day (p = 0.96). Heavy drinking decreased (p < 0.01). Trying e-cigarettes increased (p = 0.04). Conclusions: Nondaily smokers participating in a smoking cessation study during the COVID-19 pandemic reported worsened emotional well-being without effects on smoking outcomes and said their motivation to quit was slightly increased. Correlations of motivation to quit with prosocial and wellness changes suggest that targeting these constructs may be particularly helpful during a pandemic.

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine Is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model.

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants. Here, we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprising stabilized, pre-fusion spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction in lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.

Detection and identification of coronaviruses in human tissues using electron microscopy.

The identification of viral particles within a tissue specimen requires specific knowledge of viral ultrastructure and replication, as well as a thorough familiarity with normal subcellular organelles. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has underscored how challenging the task of identifying coronavirus by electron microscopy (EM) can be. Numerous articles have been published mischaracterizing common subcellular structures, including clathrin- or coatomer- coated vesicles, multivesicular bodies, and rough endoplasmic reticulum, as coronavirus particles in SARS-CoV-2 positive patient tissue specimens. To counter these misinterpretations, we describe the morphological features of coronaviruses that should be used to differentiate coronavirus particles from subcellular structures. Further, as many of the misidentifications of coronavirus particles have stemmed from attempts to attribute tissue damage to direct infection by SARS-CoV-2, we review articles describing ultrastructural changes observed in specimens from SARS-CoV-2-infected individuals that do not necessarily provide EM evidence of direct viral infection. Ultrastructural changes have been observed in respiratory, cardiac, kidney, and intestinal tissues, highlighting the widespread effects that SARS-CoV-2 infection may have on the body, whether through direct viral infection or mediated by SARS-CoV-2 infection-induced inflammatory and immune processes. HIGHLIGHTS: The identification of coronavirus particles in SARS-CoV-2 positive tissues continues to be a challenging task. This review provides examples of coronavirus ultrastructure to aid in the differentiation of the virus from common cellular structures.

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model (preprint)

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery, which improve vaccination compliance and demonstrate efficacy against emerging variants. Here we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprised of stabilized, pre-fusion Spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction of lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.

Histopathology and localization of SARS-CoV-2 and its host cell entry receptor ACE2 in tissues from naturally infected US-farmed mink (Neovison vison).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory disease in mink similar to human COVID-19. We characterized the pathological findings in 72 mink from US farms with SARS-CoV-2 outbreaks, localized SARS-CoV-2 and its host cellular receptor angiotensin-converting enzyme 2 (ACE2) in mink respiratory tissues, and evaluated the utility of various test methods and specimens for SARS-CoV-2 detection in necropsy tissues. Of SARS-CoV-2-positive animals found dead, 74% had bronchiolitis and diffuse alveolar damage (DAD). Of euthanized SARS-CoV-2-positive animals, 72% had only mild interstitial pneumonia or minimal nonspecific lung changes (congestion, edema, macrophages); similar findings were seen in SARS-CoV-2-negative animals. Suppurative rhinitis, lymphocytic perivascular inflammation in the lungs, and lymphocytic infiltrates in other tissues were common in both SARS-CoV-2-positive and SARS-CoV-2-negative animals. In formalin-fixed paraffin-embedded (FFPE) upper respiratory tract (URT) specimens, conventional reverse transcription-polymerase chain reaction (cRT-PCR) was more sensitive than in situ hybridization (ISH) or immunohistochemistry (IHC) for detection of SARS-CoV-2. FFPE lung specimens yielded less detection of virus than FFPE URT specimens by all test methods. By IHC and ISH, virus localized extensively to epithelial cells in the nasal turbinates, and prominently within intact epithelium; olfactory mucosa was mostly spared. The SARS-CoV-2 receptor ACE2 was extensively detected by IHC within turbinate epithelium, with decreased detection in lower respiratory tract epithelium and alveolar macrophages. This study expands on the knowledge of the pathology and pathogenesis of natural SARS-CoV-2 infection in mink and supports their further investigation as a potential animal model of SARS-CoV-2 infection in humans.

A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 µg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.

To vax or not to vax: Predictors of anti-vax attitudes and COVID-19 vaccine hesitancy prior to widespread vaccine availability.

The novel coronavirus (COVID-19) is a highly contagious disease responsible for millions of deaths worldwide. Effective vaccines against COVID-19 are now available, however, an extreme form of vaccine hesitancy known as anti-vax attitudes challenge vaccine acceptance and distribution efforts. To understand these anti-vax attitudes and their associated psychological characteristics, we examined several predictors of vaccine hesitancy for COVID-19 and anti-vax attitudes generally. We surveyed 1004 adults (M = 47.0 years, SD = 17.1 years, range 18-98 years) in September-October 2020 across the United States (51% female, 49% male; 76.5% White, 23.5% non-White), prior to widespread availability of the COVID-19 vaccines. Attitudes toward vaccinations were influenced by a variety of factors, especially political attitudes. We should therefore anticipate and attempt to mitigate these challenges to achieving widespread vaccination to reduce the spread of COVID-19 and other communicable diseases.

Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques.

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Postpyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage fluid. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage fluid following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that postpyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques. IMPORTANCE SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution, and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however, no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here, we report that oral administration of live SARS-CoV-2 in nonhuman primates may offer prophylactic benefits, but the formulation and route of administration will require further optimization.

Life Interrupted: Family Routines Buffer Stress during the COVID-19 Pandemic.

Adoption of certain behavioral and social routines that organize and structure the home environment may help families navigate the challenges presented by the COVID-19 pandemic. The current cross-sectional study aimed to assess family routines prior to and during the COVID-19 pandemic and examine associations with individual and family well-being. Using a national sample, 300 caregivers of children ages 6-18 were surveyed using Amazon Mechanical Turk platform during the first three months of COVID-19 pandemic in the United States. Caregivers reported on family demographics, COVID-19-related stress, engagement in family routines (prior to and during the COVID-19 pandemic), stress mindset, self-efficacy, and family resiliency. Overall, families reported engaging in fewer routines during the COVID-19 pandemic compared to prior to the pandemic. COVID-19-related stress was highest in low-income families, families of healthcare workers, and among caregivers who had experienced the COVID-19 virus. Moreover, COVID-19-related stress was negatively related to self-efficacy, positively related to an enhancing stress mindset, and negatively related to family resilience. Engagement in family routines buffered relations between COVID-19-related stress and family resilience, such that COVID-19-related stress was not associated with lower family resilience among families that engaged in high levels of family routines. Results suggest that family routines were challenging to maintain in the context of the COVID-19 pandemic, but were associated with better individual and family well-being during this period of acute health, economic, and social stress.