Structural Insights of the SARS-CoV-2 Nucleocapsid Protein: Implications for the Inner-workings of Rapid Antigen Tests

The nucleocapsid (N) protein is an abundant component of SARS-CoV-2 and a key analyte for lateral-flow rapid antigen tests. Here, we present new structural insights for the SARS-CoV-2 N protein using cryo-electron microscopy (EM) and molecular modeling tools. Epitope mapping based on structural data supported host-immune interactions in the C-terminal portion of the protein, while other regions revealed protein-protein interaction sites. Complementary modeling results suggested that N protein structures from known variants of concern (VOC) are nearly 100% conserved at specific antibody-binding sites. Collectively, these results suggest that rapid tests that target the nucleocapsid C-terminal domain should have similar accuracy across all VOCs. In addition, our combined structural modeling workflow may guide the design of immune therapies to counter viral processes as we plan for future variants and pandemics.

COVID-19 Crisis Timeline: The Warning and the Surge

After an initial warning, an infectious health crisis, especially a viral one, can surge rapidly from a small outbreak to an overwhelming epidemic or even a pandemic. A surge usually consists of a rapid escalation phase, a peak phase, and a slow de-escalation phase. A surge may include an increase of all categories of patients, emergency room visits, in-patient admissions, and critically ill patients with multi-organ failure requiring ventilation, hemodialysis, and other intensive care measures. There is an accumulative effect of the rapid successive waves of patients admitted into the hospital, with a severe strain on the human and material resources of the hospital. In many health crises, as with the COVID-19 pandemic, the majority of the patients are hospitalized for a long time. Such a long hospitalization slows down the recovery from the crisis significantly. There is a disruptive effect of a health crisis on regular hospital functions and services, such as elective surgery, ambulatory clinics, and care and follow-up of patients with diseases other than the cause of the infectious crisis. This disruption may result in worsening of chronic diseases, such as diabetes, asthma, mental illnesses, and others. It may also result in delay in diagnosis and treatment of various types of cancers and later presentation of cancers at higher stages. Consequently, the disruption places special requirements for resumption of regular services after the crisis and an additional substantial burden on hospital capabilities. This chapter describes the initial COVID-19 crisis at SBH Health System in the Bronx, New York, USA, and shows its unfolding surge over time alongside an overview of the response. While the COVID-19 crisis has unique characteristics, many lessons learned from this crisis can be applied to other crises, especially infectious pandemics. © SBH Health System 2022.

Wastewater surveillance could serve as a pandemic early warning system for COVID‐19 and beyond

Wastewater‐based surveillance can be used as an early warning system to identify COVID‐19 outbreaks because the viral load can be observed in sewage before it is clinically verified. Wastewater surveillance of SARS‐CoV‐2 can trace the transmission dynamics of infection in communities when using the scale of a wastewater diversion and treatment system. Using this early detection method can help protect human health and mitigate socio‐economic losses. It can help quantify the epidemiological data of a given population in real‐time and circumvent the need for other epidemiological indicators. There are challenges in using this technique in areas with underdeveloped sewerage infrastructure. It is especially the case in developing nations where uniform protocols for viral detection are lacking, and wastewater is heterogeneous because of environmental and operational conditions. This article explains the need for and importance of wastewater‐based surveillance for SARS‐CoV‐2. It lays out the most recent methodological approaches for detecting SARS‐CoV‐2 in municipal wastewater and outlines the main challenges associated with wastewater‐based epidemiology (WBE). The article includes a case study of surveillance work across India to demonstrate how a developing nation manages research and locational challenges. The socio‐economic, ethical, and policy dimensions of WBE for SARS‐CoV‐2 are also discussed.This article is categorized under: Engineering Water > Water, Health, and Sanitation Engineering Water > Sustainable Engineering of Water Engineering Water > Methods [ FROM AUTHOR] Copyright of WIRES Water is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Community consensus on core open science practices to monitor in biomedicine.

The state of open science needs to be monitored to track changes over time and identify areas to create interventions to drive improvements. In order to monitor open science practices, they first need to be well defined and operationalized. To reach consensus on what open science practices to monitor at biomedical research institutions, we conducted a modified 3-round Delphi study. Participants were research administrators, researchers, specialists in dedicated open science roles, and librarians. In rounds 1 and 2, participants completed an online survey evaluating a set of potential open science practices, and for round 3, we hosted two half-day virtual meetings to discuss and vote on items that had not reached consensus. Ultimately, participants reached consensus on 19 open science practices. This core set of open science practices will form the foundation for institutional dashboards and may also be of value for the development of policy, education, and interventions.

Coping during the COVID-19 pandemic among young adults experiencing homelessness and unstable housing: A qualitative study.

BACKGROUND: Young adults experiencing homelessness (YAEH) experience more stressors compared to housed peers, yet little is known about the impact of the COVID-19 pandemic on these youth. The purpose of this qualitative study was to explore how YAEH perceived the pandemic's impact on their well-being and coping. METHODS: YAEH were recruited from those participating in an HIV prevention study. Semi-structured interviews were conducted and analysis was guided by Lazarus and Folkman's transactional theory of stress and coping. RESULTS: Four major themes were identified from interviews with 40 youth: (1) ongoing harms, (2) COVID-19 as a stressor, (3) mental health impacts, and (4) coping strategies. Participants described unmet basic needs, emotions of frustration and anxiety, and several coping strategies including substance use. CONCLUSION: Many YAEH reported experiencing continued challenges that were compounded by the stressors related to the COVID-19 pandemic. Special considerations are needed to address pandemic-related exacerbations of mental health symptoms and substance use among YAEH.

Treating Children with Hcv Close to Home through a Virtual National Multidisciplinary Network

Background and Aims Hepatitis C virus (HCV) infection is a major global health problem in adults & children. The recent efficacy of Direct Acting Anti-viral therapy (DAA) has cure rates of 99% in adults and adolescents. These drugs were licensed for children 3-12 yrs during the recent coronavirus pandemic. To ensure equitable access, safe & convenient supply during lockdown, we established a virtual national treatment pathway for children with HCV in England & evaluated its feasibility, efficacy & treatment outcomes. Method A paediatric Multidisciplinary Team Operational Delivery Network (pMDT ODN), supported by NHS England (NHSE), was established with relevant paediatric specialists to provide a single point of contact for referrals & information. Referral & treatment protocols were agreed for HCV therapy approved by MHRA & EMA. On referral the pMDT ODN agreed the most appropriate DAA therapy based on clinical presentation & patient preferences, including ability to swallow tablets. Treatment was prescribed in association with the local paediatrician & pharmacist, without the need for children & families to travel to national centres. All children were eligible for NHS funded therapy;referral centres were approved by the pMDT ODN to dispense medication;funding was reimbursed via a national NHSE agreement. Demographic & clinical data, treatment outcomes & SVR 12 were collected. Feedback on feasibility & satisfaction on the pathway was sought from referrers. Results In the first 6 months, 34 children were referred;30- England;4 - Wales;median (range) age 10 (3.9 - 14.5) yrs;15M;19F: Most were genotype type 1 (17) & 3 (12);2 (1);4(4). Co-morbidities included: obesity (2);cardiac anomaly (1);Cystic Fibrosis (1);Juvenile Arthritis (1). No child had cirrhosis. DAA therapy prescribed: Harvoni (21);Epclusa (11);Maviret (2) .27/34 could swallow tablets;3/7 received training to swallow tablets;4/7 are awaiting release of granules.11/27 have completed treatment and cleared virus;of these 7/11 to date achieved SVR 12. 30 children requiring DAA granule formulation are awaiting referral and treatment. Referrers found the virtual process easy to access, valuing opportunity to discuss their patient's therapy with the MDT & many found it educational. There were difficulties in providing the medication through the local pharmacy. However there are manufacturing delays in providing granule formulations because suppliers focused on treatments for COVID, leading to delays in referring and treating children unable to swallow tablets. Conclusion The National HCV pMDT ODN delivers high quality treatment & equity of access for children & young people, 3- 18 yrs with HCV in England, ensuring they receive care close to home with 100% cure rates.

A C57BL/6 Mouse Model of SARS-CoV-2 Infection Recapitulates Age- and Sex-Based Differences in Human COVID-19 Disease and Recovery.

We present a comprehensive analysis of SARS-CoV-2 infection and recovery using wild type C57BL/6 mice and a mouse-adapted virus, and we demonstrate that this is an ideal model of infection and recovery that phenocopies acute human disease arising from the ancestral SARS-CoV-2. Disease severity and infection kinetics are age- and sex-dependent, as has been reported for humans, with older mice and males in particular exhibiting decreased viral clearance and increased mortality. We identified key parallels with human pathology, including intense virus positivity in bronchial epithelial cells, wide-spread alveolar involvement, recruitment of immune cells to the infected lungs, and acute bronchial epithelial cell death. Moreover, older animals experienced increased virus persistence, delayed dispersal of immune cells into lung parenchyma, and morphologic evidence of tissue damage and inflammation. Parallel analysis of SCID mice revealed that the adaptive immune response was not required for recovery from COVID disease symptoms nor early phase clearance of virus but was required for efficient clearance of virus at later stages of infection. Finally, transcriptional analyses indicated that induction and duration of key innate immune gene programs may explain differences in age-dependent disease severity. Importantly, these data demonstrate that SARS-CoV-2-mediated disease in C57BL/6 mice phenocopies human disease across ages and establishes a platform for future therapeutic and genetic screens for not just SARS-CoV-2 but also novel coronaviruses that have yet to emerge.

Detection of Infectious SARS-CoV-2 in Specimens with High CT Values Is More Common for Omicron than for Delta Variants

Background. Although not validated, cycle threshold (Ct) values from real-time (r)RT-PCR are sometimes used as a proxy for infectiousness to inform public health decision-making. A better understanding of variant-specific viral dynamics, including RNA and infectious virus relationships, is needed to clarify implications for diagnostics and transmission. Methods. Non-hospitalized SARS-CoV-2-infected individuals were recruited <= 5 days post-onset and self-collected nasal swabs daily for two weeks. Sequencing was used to determine variant, an in-house quantitative rRT-PCR targeting N gene was used to produce Ct values and determine RNA load, and cytopathic effect was used to assess the presence or absence of infectious virus (binary outcome). We used a Ct threshold of 30 to define high-Ct (Ct > 30) or low-Ct (Ct <= 30) specimens and assessed the percentage of RNA-positive specimens that had infectious virus;variantspecific percentages were compared by chi2 test. Results. We included 113 and 200 RNA-positive specimens from 18 and 28 Omicron- and Delta-infected participants, respectively;timing of RNA-positive specimen collection was similar in both groups (median = 8d post-onset). Maximum observed RNA levels occurred at median of 5 days post-onset for both variants but were lower for participants with Omicron vs Delta [mean RNA copies/mL = 105.2 vs 107.9]. Despite lower RNA levels, infectious virus was frequently detected for both variants [Omicron: median duration = 4.5d;Delta: median = 6d;p = 0.13]. Omicron specimens with infectious virus had higher Cts vs Delta specimens [mean Ct = 29.9 vs 23.2, p < 0.001]. In high-Ct specimens (Ct > 30;Table), the percentage of specimens with infectious virus was typically higher for Omicron vs Delta, and was significantly higher in adults [27.3% vs 9.5%]. In low-Ct specimens (Ct <= 30), the percentage with infectious virus was similar or higher for Omicron vs Delta, and was significantly higher in children [87.5% vs 53.8%] and in those unvaccinated [94.1% vs 47.4%]. Conclusion. CDC does not recommend the use of Ct values as a proxy for infectiousness. These data further highlight that Ct values may not provide a reliable or consistent proxy for infectiousness across variants.

Biological Determinants of Post-Acute Sequelae of SARS-CoV-2

Background. The biological determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), defined as the persistence or recurrence of symptoms not explained by an alternative medical diagnosis, are poorly understood. We assessed viral and immunological determinants during acute SARS-CoV-2 infection for an association with PASC at 4 to 8 months. Methods. From September 2020 to February 2022, symptomatic nonhospitalized individuals with laboratory-confirmed SARS-CoV-2 infection were identified within 5 days of symptom onset. We used anterior nasal biospecimens to measure the magnitude and duration of RNA and infectious viral shedding as well as blood samples to measure soluble markers of inflammation during the acute phase (first 28 days post-enrollment). PASC was defined as self-report of 1 or more COVID-19 attributed symptoms between 4 and 8 months after initial illness. We compared virologic and inflammatory markers, GFAP (a marker of neuronal damage) and neutralizing antibody levels from the acute phase between those with and without PASC using Mann-Whitney U tests or repeated measures mixed effects linear models. Results. Among 71 SARS-CoV-2-positive participants with a completed follow-up visit between 4 to 8 months, we included 69 with virologic data and 61 with inflammatory marker data. Median age was 37 (IQR: 29 to 48) Overall, 16/72 (23%) reported at least one qualifying PASC symptom. Report of PASC was associated with >9 days of RNA shedding (p=0.04);all participants stopped RNA shedding by day 20. During acute illness, those with subsequent PASC had increased levels of INF-alpha, INF-gamma, IP-10, IL-10, and MCP-1;these differences were greatest in the early period and normalized over 2 to 3 weeks post-illness onset. Compared to those without PASC, during the acute illness those with PASC had increased levels of GFAP and decreased levels of neutralizing antibodies but these differences were not statistically significant. Conclusion. We found indications that viral and immunological factors during acute illness may be associated with PASC, suggesting acute immunologic response to SARS-CoV-2 may have longer term effects and play a role in PASC. Further understanding of the clinically significance of these observations is needed.

A Telepsychiatry Simulation for Suicide Assessment: Increasing Virtual Mental Health Competency in Health Professional Students

Objectives: Suicide is a global epidemic that claims up to 800,000 lives each year and is the second leading cause of death in young people aged 15-29 years. With the COVID-19 pandemic came increased rates of stress, helplessness, and suicide among adolescents. The increasing popularity of telemedicine opens new doors for identifying patients in distress, decreasing suicide rates, and increasing access to mental health services. Youth and adolescents grew up with electronics and will likely be open to the use of telemedicine in the future. However, it is unknown how prepared learners are for the unique challenges of these new modes of patient interaction. Method(s): We designed a telemedicine simulation for medical and physician assistant students to identify, assess, and appropriately escalate care for a standardized patient (SP) with suicidal ideation. We incorporated didactics on telepsychiatry, a motivational interviewing exercise, and a simulated telemedicine objective structured clinical exam (OSCE). Students completed a participant survey and were evaluated by SPs on their medical knowledge, interpersonal/communication skills, and 8 key telemedicine competencies. Result(s): Forty-four students completed the workshop, and 30 students completed the participant survey. Students were strongest in interpersonal/communication skills and weakest in telemedicine competencies. SPs evaluated telemedicine performance by deeming students "not yet entrustable," "approaching entrustment," or "entrustable" based on their ability to perform a described behavior or task unsupervised. Only 20% of students were entrustable to describe when patient safety was at risk, including when and how to escalate care. Fifty percent correctly interpreted the Patient Health Questionnaire, 59% completed the Columbia Suicide Risk Assessment, and 41% completed a suicide safety plan. Ninety-seven percent of students said that they expect to use telemedicine in their future practice. Conclusion(s): The telepsychiatry OSCE revealed gaps in students' telepsychiatry knowledge, particularly in telemedicine-specific competencies. Future studies are needed to assess the generalizability of our findings, including incorporating adolescent SPs to prepare students for the mental health needs of all ages given increasing rates of suicide in adolescent populations. TVM, S, AC Copyright © 2022

DIAGNOSIS OF FAMILIAL HYPERCHOLESTEROLEMIA: A WORK IN PROGRESS

Therapeutic Area ASCVD/CVD in Special Populations Background An ICD-10 code for Familial Hypercholesterolemia (FH), E78.01, became effective October 2016 following a proposal by the Family Heart Foundation. It differentiated FH from other forms of elevated cholesterol with a goal of increasing assessment of this treatable genetic condition. Prior to E78.01, <1% of FH patients in the US were diagnosed (Nordestgarrd, 2013). This study aims to characterize the current number and percent of FH patients diagnosed with E78.01 in an expansive, real-world US dataset. Methods The Family Heart Database includes 197 million people including 22 million children with diagnostic data from claims who were screened or treated for any form of cardiovascular risk from October 2016 through June 2020. Patients with FH (E78.01) were counted if the diagnostic code was applied for a single in-patient claim or at least twice, >7 days apart, for an out-patient claim. The number of total (diagnosed + undiagnosed) FH patients within the dataset was estimated assuming an occurrence of 1:250 individuals. Results Patients diagnosed with FH using E78.01 has increased substantially since 2016. During 2017 and 2018, use of the code was brisk and likely included previously and newly diagnosed individuals. Diagnosis was reduced dramatically with the onset of the COVID-19 pandemic corresponding with the marked reduction of in-person clinic visits and near halting of preventive care. By June 2020, 246,689 FH patients were diagnosed representing 31.3% of the estimated total (diagnosed + undiagnosed) FH population of 787,886 within the dataset. At the time of E78.01 code assignment, 52% of diagnosed FH patients were female;51% were aged 18 to 65 years, 47% were >65 years;they were Black (8%), Hispanic (5%), White (54%), and Other/Unknown (33%);40% had ASCVD and household income ranged from <$30K (13%) to >$100K (20%). Conclusion The number of patients diagnosed with FH (E78.01) has increased substantially since 2016. Within this large, real-world dataset of Americans, 31.3% of the estimated FH population had been diagnosed as of Jun 2020. However, most FH patients remain undiagnosed, delaying treatment and cascade screening. The rate of diagnosis was also hampered by the COVID-19 pandemic.

Myeloperoxidase-derived hypochlorous acid targets human airway epithelial plasmalogens liberating protein modifying electrophilic 2-chlorofatty aldehydes.

Neutrophil and airway epithelial cell interactions are critical in the inflammatory response to viral infections including respiratory syncytial virus, Sendai virus, and SARS-CoV-2. Airway epithelial cell dysfunction during viral infections is likely mediated by the interaction of virus and recruited neutrophils at the airway epithelial barrier. Neutrophils are key early responders to viral infection. Neutrophil myeloperoxidase catalyzes the conversion of hydrogen peroxide to hypochlorous acid (HOCl). Previous studies have shown HOCl targets host neutrophil and endothelial cell plasmalogen lipids, resulting in the production of the chlorinated lipid, 2-chlorofatty aldehyde (2-ClFALD). We have previously shown that the oxidation product of 2-ClFALD, 2-chlorofatty acid (2-ClFA) is present in bronchoalveolar lavage fluid of Sendai virus-infected mice, which likely results from the attack of the epithelial plasmalogen by neutrophil-derived HOCl. Herein, we demonstrate small airway epithelial cells contain plasmalogens enriched with oleic acid at the sn-2 position unlike endothelial cells which contain arachidonic acid enrichment at the sn-2 position of plasmalogen. We also show neutrophil-derived HOCl targets epithelial cell plasmalogens to produce 2-ClFALD. Further, proteomics and over-representation analysis using the ω-alkyne analog of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDyA) showed cell adhesion molecule binding and cell-cell junction enriched categories similar to that observed previously in endothelial cells. However, in contrast to endothelial cells, proteins in distinct metabolic pathways were enriched with 2-ClFALD modification, particularly pyruvate metabolism was enriched in epithelial cells and mitochondrial pyruvate respiration was reduced. Collectively, these studies demonstrate, for the first time, a novel plasmalogen molecular species distribution in airway epithelial cells that are targeted by myeloperoxidase-derived hypochlorous acid resulting in electrophilic 2-ClFALD, which potentially modifies epithelial physiology by modifying proteins.

Improving thromboprophylaxis in children admitted to a quaternary care children's hospital with COVID-19

Background: The incidence of venous thrombo-embolism (VTE) in hospitalized children has increased by 70%-200% over the last 2-decades. Given this increase, many pediatric centers have initiated electronic clinical decision supports (ECDS) to prognosticate VTE risk and recommend appropriate prophylaxis. COVID-19 is a risk factor for VTE, however ECDS algorithms developed before the COVID-19 pandemic may not accurately prognosticate VTE risk in children with COVID-19. Aim(s): To identify areas for improvement of thromboprophylaxis recommendations for children admitted to hospital with COVID-19. Method(s): Inpatients with a positive COVID-19 PCR test on admission (or within 24 h) were identified at a quaternary-care pediatric center between March 1st 2020 and January 20th 2022. The results of the institution's automated thromboprophylaxis recommendations were compared to institutional best practice guidelines for COVID-19 thromboprophylaxis and to the thromboprophylaxis actually received by the patient. Using this data, a quality improvement (QI) initiative to improve adherence to COVID-19 thromboprophylaxis recommendations through ECDS optimization was implemented. This QI study was exempt from ethics approval. Result(s): Of the 375 inpatients with COVID-19 who underwent thromboprophylaxis screening, 43 were excluded as their COVID-19 was performed >24 h after admission and 5 were excluded for having incomplete data. Table 1 shows the characteristics of the final cohort. 179 (54.4%) patients had a D-dimer performed during their admission. The number of patients that met criteria for chemo-prophylaxis via each screening modality is shown in Figure 1. Five inpatients developed VTE;three had VTE symptoms at presentation, two were identified as high-risk for VTE by both the automated and best practice assessments but were not started on chemoprophylaxis due to family preference or a contraindication to anticoagulation. Conclusion(s): Automated thromboprophylaxis recommendations developed prior to the COVID-19 pandemic may not identify COVID-19 patients needing chemoprophylaxis. Existing ECDS tools need to be updated to reflect COVID-19 specific risk factors for VTEs.

Bacillus Calmette-Guerin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers: a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials (preprint)

BACKGROUND: The objective is to determine the impact of the Bacillus Calmette-Guerin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology. METHODS: Planned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively -- with no trial results available -- for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exact e-value logrank test (at level alpha = 0.5% for infections and level alpha = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial. RESULTS: Six trials were included in the primary analysis with 4 433 participants in total. The e-values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40). DISCUSSION: It is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type-I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance. OTHER: No external funding. Preregistered at PROSPERO: CRD42021213069.

Barriers to Long-acting Injectable Antipsychotic Adherence During the COVID-19 Pandemic: Observations From One Site.

OBJECTIVE: Long-acting injectable antipsychotics (LAI-As) are a crucial treatment option for individuals with serious mental illness. However, due to the necessity of in-person administration of LAI-As, pandemics pose unique challenges for continuity of care in the population prescribed these medications. This project investigated the impact of the coronavirus disease 2019 (COVID-19) pandemic on LAI-A adherence at a Veterans Health Administration medical facility in the United States, as well as changes in LAI-A prescribing and administration practices during this period. METHODS: Electronic health records were evaluated for 101 patients prescribed LAI-As. A subset of 13 patients also participated in an interview and rated subjective concerns about pandemic-related barriers to medication adherence. RESULTS: Pandemic-related barriers to LAI-A adherence and/or changes to LAI-A medications were documented in 33% of the patients. Within-subjects comparison of an adherence metric computed from electronic health record data further suggested a somewhat higher incidence of missed or delayed LAI-A doses during the pandemic compared with before the pandemic. In contrast, only 2 of the 13 patients interviewed anticipated that pandemic-related concerns would interfere with medication adherence. CONCLUSIONS: The results of this study suggest that LAI-A access and adherence can be disrupted by pandemics and other public health emergencies but this finding may not generalize to other sites. As patients may not foresee the potential for disruption, psychiatric service providers may need to assist in proactively problem-solving barriers to access. Improved preparedness and additional safeguards against pandemic-related disruptions to LAI-A access and adherence may help mitigate adverse outcomes in the future. Identifying patients at elevated risk for such disruptions may help support these efforts.

A C57BL/6 Mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery (preprint)

We present a comprehensive analysis of SARS-CoV-2 infection and recovery in wild type C57BL/6 mice, demonstrating that this is an ideal model of infection and recovery that accurately phenocopies acute human disease arising from the ancestral SARS-CoV-2. Disease severity and infection kinetics are age- and sex-dependent, as has been reported for humans, with older mice and males in particular exhibiting decreased viral clearance and increased mortality. We identified key parallels with human pathology, including intense virus positivity in bronchial epithelial cells, wide-spread alveolar involvement, recruitment of immune cells to the infected lungs, and acute bronchial epithelial cell death. Moreover, older animals experienced increased virus persistence, delayed dispersal of immune cells into lung parenchyma, and morphologic evidence of tissue damage and inflammation. Parallel analysis of SCID mice revealed that the adaptive immune response was not required for recovery from COVID disease symptoms nor early phase clearance of virus but was required for efficient clearance of virus at later stages of infection. Finally, transcriptional analyses indicated that induction and duration of key innate immune gene programs may explain differences in age-dependent disease severity. Importantly, these data demonstrate that SARS-CoV-2-mediated disease in C57BL/6 mice accurately phenocopies human disease across ages and establishes a platform for future therapeutic and genetic screens for not just SARS-CoV-2 but also novel coronaviruses that have yet to emerge.

Health Coaching Across the Stages of Vaccine Readiness and Action: A Practical Guide for Public Health Nurses

Yet, lack of vaccine uptake puts in peril the goal of controlling the spread ofthe virus, particularly among communities that are at greatest risk of contracting and dying ofthe illness.8 The reasons for the lack of COVID-19 vaccine uptake among some communities in the United States are multifaceted, some of which include concerns about the safety or effectiveness ofthe vaccines, the speed in which the vaccines were developed, misinformation about the vaccines, and systemic barriers affecting community access (i.e., online appointment systems, inadequate transportation, and lack of child care).9,10 For many communities of color, including African American and Latinx individuals, COVID-19 vaccine reluctance is rooted in both historical and contemporary experiences of systemic racism, forced sterilization of Latinx women in California, the Tuskegee Study of Untreated Syphilis in the Negro Male (renamed as the US Public Health Service Syphilis Study at Tuskegee), marginalization, medical distrust, neglect from the scientific and medical communities, poor public health infrastructure, and institutional abandonment.2,3,10 In addition to those reasons, the politicization ofthe vaccine development process and efforts to increase vaccination after the 2020 US presidential election have deepened distrust among some communities. A 2021 Kaiser Family Foundation survey found that 79% of US adults who have not yet been vaccinated say they would likely turn to a trusted nurse, doctor, or other health care provider when deoiding wherher to ger a vaooination.11 As health oare professionals, nurses and other public health workers are often a patient's first clinical contact and are among the most trusted sources of information about the vaccines. Nurses are leading the nation's vaccine administration efforts and, to many, are the most accessible source of information for questions about safety, side effects, and benefits.11,12 To be effective, nurses and other public health workers require an understanding of the reasons that prevent people from getting vaccinated and have practical tools to support people with their decisions regarding if, when, and how they get vaccinated against COVID-19. The relationship between the stages in the framework are cyclical, and individuals can move in either direction at different points in time when exposed to new information tog., negative news reports) or negative experiences (e.g., a family member who had an adverse reaction).

De novo hemorrhagic sporadic cavernous malformation appearance after COVID-19 respiratory infection: illustrative case.

BACKGROUND: Little is known about whether coronavirus disease 2019 (COVID-19) influences cavernous malformation (CM) formation or hemorrhage risk. OBSERVATIONS: The authors present the case of a 31-year-old patient who developed a hemorrhagic, de novo CM in the setting of a developmental venous anomaly within 3 months of COVID-19 respiratory disease. The authors speculate that COVID-19 disease stimulated formation of the CM through TLR4 inflammatory pathways and subsequently led to the hemorrhagic presentation because of hypercoagulability related to the disease. LESSONS: This case raises the possibility that COVID-19 may be a risk factor for de novo development of CMs in predisposed patients.

Treating children with HCV close to home through a virtual national multidisciplinary network

Background and aims: Hepatitis C virus (HCV) infection is a major global health problem in adults & children. The recent efficacy of Direct Acting Anti-viral therapy (DAA) has cure rates of 99% in adults and adolescents. These drugs were licensed for children 3–12 yrs during the recent coronavirus pandemic. To ensure equitable access, safe & convenient supply during lockdown, we established a virtual national treatment pathway for children with HCV in England & evaluated its feasibility, efficacy & treatment outcomes. Method: A paediatric Multidisciplinary Team Operational Delivery Network (pMDT ODN), supported by NHS England (NHSE), was established with relevant paediatric specialists to provide a single point of contact for referrals & information. Referral & treatment protocolswere agreed for HCV therapy approved byMHRA& EMA. On referral the pMDT ODN agreed the most appropriate DAA therapy based on clinical presentation & patient preferences, including ability to swallow tablets. Treatment was prescribed in association with the local paediatrician & pharmacist, without the need for children & families to travel to national centres. All children were eligible for NHS funded therapy;referral centres were approved by the pMDT ODN to dispense medication;funding was reimbursed via a national NHSE agreement. Demographic & clinical data, treatment outcomes & SVR 12 were collected. Feedback on feasibility & satisfaction on the pathway was sought from referrers. Results: In the first 6 months, 34 childrenwere referred;30- England;4-Wales;median (range) age 10 (3.9–14.5) yrs;15M;19F: Most were genotype type 1 (17) & 3 (12);2 (1);4 (4). Co-morbidities included: obesity (2);cardiac anomaly (1);Cystic Fibrosis (1);Juvenile Arthritis (1). No child had cirrhosis. DAA therapy prescribed: Harvoni (21);Epclusa (11);Maviret (2). 27/34 could swallow tablets;3/7 received training to swallowtablets;4/7 are awaiting release of granules.11/27 have completed treatment and cleared virus;of these 7/11 to date achieved SVR 12. 30 children requiring DAA granule formulation are awaiting referral and treatment. Referrers found the virtual process easy to access, valuing opportunity to discuss their patient’s therapy with the MDT & many found it educational. There were difficulties in providing the medication through the local pharmacy. However there are manufacturing delays in providing granule formulations because suppliers focused on treatments for COVID, leading to delays in referring and treating children unable to swallow tablets. Conclusion: The National HCV pMDT ODN delivers high quality treatment & equity of access for children & young people, 3–18 yrs with HCV in England, ensuring they receive care close to home with 100% cure rates.