Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV (preprint)

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4+ T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV-negative participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were 'rescued' after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV-negative participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral 'blips' in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4+ T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

Thyrotoxicosis after COVID-19 Infection with a Delay in Graves' Disease Antibody Positivity.

Background and Objective. Mounting evidence implicates COVID-19 as a cause of thyroid dysfunction, including thyrotoxicosis due to both thyroiditis and Graves' disease (GD). In this report, we present a case of thyrotoxicosis following COVID-19 infection that was ultimately found to represent GD with significantly delayed diagnostic serum antibody positivity. Case Report. A 65-year-old woman with a history of uncomplicated COVID-19 infection one month prior, presented to the Emergency Department with exertional dyspnea and palpitations, and was found to be in atrial fibrillation with rapid ventricular response (AF with RVR). Labs showed subclinical hyperthyroidism and the patient was started on a beta-blocker and methimazole. One month later, thyroid-stimulating immunoglobulin (TSI) resulted negative and thyroid function tests had normalized. The clinical picture suggested thyroiditis, and methimazole was stopped. One month later, the patient again presented in AF with RVR, with labs showing overt biochemical thyrotoxicosis. Antibodies were re-tested, and the thyrotropin receptor antibody (TRAb) and TSI resulted positive, confirming GD. Discussion. Most notable in this case is the feature of delayed GD antibody positivity: the diagnostic immunoassay for GD resulted negative one and two months after infection, but was ultimately positive three months after infection. To the authors' knowledge, this represents the longest delayed antibody positivity reported to date, amongst cases of new-onset GD following COVID. Conclusion. The clinical course of GD following COVID-19 infection is highly variable. This case underscores the need for vigilance in monitoring for delayed GD antibody positivity due to the important therapeutic implications of distinguishing thyroiditis from GD.

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins.

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

Regional peak flow as a novel approach to assess regional pulmonary mechanics by electrical impedance tomography: an observational validation study.

Background: Spontaneous breathing efforts during mechanical ventilation are a widely accepted weaning approach for acute respiratory distress syndrome (ARDS) patients. These efforts can be too vigorous, possibly inflicting lung and diaphragm damage. Higher positive end expiratory pressure (PEEP) levels can be used to lower the magnitude of vigorous breathing efforts. Nevertheless, PEEP titrating tools are lacking in spontaneous mechanical ventilation (SMV). Therefore, the aim is to develop an electrical impedance tomography (EIT) algorithm for quantifying regional lung mechanics independent from a stable plateau pressure phase based on regional peak flow (RPF) by EIT, which is hypothetically applicable in SMV and to validate this algorithm in patients on controlled mechanical ventilation (CMV). Methods: The RPF algorithm quantifies a cumulative overdistension (ODRPF) and collapse (CLRPF) rate and is validated in a prospective cohort of mechanically ventilated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients on CMV. ODRPF and CLRPF are compared with compliance-based cumulative overdistension (ODP500) and collapse (CLP500) rates from the Pulmovista 500 EIT device at multiple PEEP levels (PEEP 10 cmH2O to PEEP 24 cmH2O) in EIT measurements from CMV patients by linear mixed models, Bland-Altman analysis and intraclass correlation coefficient (ICC). Results: Seventy-eight patients were included. Linear mixed models revealed an association between ODRPF and ODP500 of 1.02 (0.98-1.07, P<0.001) and between CLRPF and CLP500 of 0.93 (0.80-1.05, P<0.001). ICC values ranged from 0.78 to 0.86 (P<0.001) for ODRPF and ODP500 and from 0.70 to 0.85 (P<0.001) for CLRPF and CLP500 (PEEP 10 to PEEP 24). The mean bias between ODRPF and ODP500 in these PEEP levels ranged from 0.80% to 4.19% and from -1.31% to 0.13% between CLRPF and CLP500. Conclusions: A RPF approach for quantifying regional lung mechanics showed a moderate to good agreement in coronavirus disease 2019 (COVID-19) related ARDS patients on CMV compared to the compliance-based approach. This, in addition to being independent of a plateau pressure phase, indicates that the RPF approach is a valid method to explore for quantifying regional lung mechanics in SMV.

Biomarkers of alveolar epithelial injury and endothelial dysfunction are associated with scores of pulmonary edema in invasively ventilated patients.

BACKGROUND: Pulmonary edema is a central hallmark of Acute Respiratory Distress Syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to permeability but their differential contribution to pulmonary edema development remains understudied. METHODS: Plasma levels of surfactant protein-D (SP-D), soluble receptor for advanced glycation end products (sRAGE) and angiopoietin-2 (Ang-2) were measured in a prospective, multicenter cohort of invasively ventilated patients. Pulmonary edema was quantified using the radiographic assessment of lung edema (RALE) and global lung ultrasound (LUS) score. Variables were collected within 48 hours after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. RESULTS: In 362 patients, higher SP-D, sRAGE and Ang-2 concentrations were significantly associated with higher RALE and global LUS scores. After stratification by ARDS subgroups (pulmonary, non-pulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, while sRAGE and Ang-2 showed less consistent associations throughout the subgroups. In a multivariable analysis, SP-D levels were most strongly associated with pulmonary edema when combined with sRAGE (RALE score: ßSP-D = 6.79 units/log10 pg/mL, ßsRAGE = 3.84 units/log10 pg/mL, R2 = 0.23; global LUS score: ßSP-D = 3.28 units/log10 pg/mL, ßsRAGE = 2.06 units/log10 pg/mL, R2 = 0.086), while Ang-2 did not further improve the model. CONCLUSION: Biomarkers of epithelial injury and endothelial dysfunction were associated with pulmonary edema in invasively ventilated patients. SP-D and sRAGE showed the strongest association, suggesting that epithelial injury may form a final common pathway in the alveolar-capillary barrier dysfunction underlying pulmonary edema.

Prognostic Value of the Radiographic Assessment of Lung Edema Score in Mechanically Ventilated ICU Patients.

INTRODUCTION: The Radiographic Assessment of Lung Edema (RALE) score provides a semi-quantitative measure of pulmonary edema. In patients with acute respiratory distress syndrome (ARDS), the RALE score is associated with mortality. In mechanically ventilated patients in the intensive care unit (ICU) with respiratory failure not due to ARDS, a variable degree of lung edema is observed as well. We aimed to evaluate the prognostic value of RALE in mechanically ventilated ICU patients. METHODS: Secondary analysis of patients enrolled in the 'Diagnosis of Acute Respiratory Distress Syndrome' (DARTS) project with an available chest X-ray (CXR) at baseline. Where present, additional CXRs at day 1 were analysed. The primary endpoint was 30-day mortality. Outcomes were also stratified for ARDS subgroups (no ARDS, non-COVID-ARDS and COVID-ARDS). RESULTS: 422 patients were included, of which 84 had an additional CXR the following day. Baseline RALE scores were not associated with 30-day mortality in the entire cohort (OR: 1.01, 95% CI: 0.98-1.03, p = 0.66), nor in subgroups of ARDS patients. Early changes in RALE score (baseline to day 1) were only associated with mortality in a subgroup of ARDS patients (OR: 1.21, 95% CI: 1.02-1.51, p = 0.04), after correcting for other known prognostic factors. CONCLUSIONS: The prognostic value of the RALE score cannot be extended to mechanically ventilated ICU patients in general. Only in ARDS patients, early changes in RALE score were associated with mortality.

Predicting COVID-19 prognosis in the ICU remained challenging: external validation in a multinational regional cohort.

OBJECTIVES: Many prediction models for coronavirus disease 2019 (COVID-19) have been developed. External validation is mandatory before implementation in the intensive care unit (ICU). We selected and validated prognostic models in the Euregio Intensive Care COVID (EICC) cohort. STUDY DESIGN AND SETTING: In this multinational cohort study, routine data from COVID-19 patients admitted to ICUs within the Euregio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, outcomes, and reporting. Furthermore, general ICU scores were assessed. Discrimination was assessed by area under the receiver operating characteristic curves (AUCs) and calibration by calibration-in-the-large and calibration plots. A random-effects meta-analysis was used to pool results. RESULTS: 551 patients were admitted. Mean age was 65.4 ± 11.2 years, 29% were female, and ICU mortality was 36%. Nine out of 238 published models were externally validated. Pooled AUCs were between 0.53 and 0.70 and calibration-in-the-large between -9% and 6%. Calibration plots showed generally poor but, for the 4C Mortality score and Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) score, moderate calibration. CONCLUSION: Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimination and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision-making.

Changes in the Dog's and Cat's Behaviors, as Reported by the Owners, before and during the Lockdown in China.

Considering the effects that the COVID-19 pandemic had and still has on human psychological health, it is expected that it might also affect household dogs' and cats' welfare. The current study explores the behavioral changes in dogs and cats before (BL) and during the lockdown (DL), as reported by their owners in China. Besides demographic parameters, variables related to the daily management of dogs and cats were analyzed in relation to behavioral problems, stress-related behaviors, and anxiety-related behaviors before and during the lockdown. A total of 261 questionnaires were collected. In general, behavioral problems and stress-related behaviors in dogs (p < 0.001) and cats (p < 0.001) decreased DL compared to BL, while anxiety-related behaviors in cats did not show any differences between the two periods considered. On the other hand, anxiety-related behaviors were more frequent in dogs DL (36.3%) compared to BL (35%), which were associated with reduced frequency of play activities with the owners (p = 0.016) and altered sleeping habits (p < 0.01). During the lockdown, dogs' and cats' daily routines and management (feeding and sleeping habits, dogs' walks, dogs' and cats' play activities, litter box management, and cats' lifestyle) experienced changes, but they were not associated with any behavioral issues. On the other hand, the behavioral issues considered for dogs and cats were more frequent BL, which were influenced by the daily management of the pets. The current study showed how critical the attention the owners can provide to the pets could be, to improve their companion animals' welfare. Therefore, it is important to provide pet owners with behavioral management support both during particularly difficult periods such as a lockdown and during regular daily routines.

Pulmonary pathophysiology development of COVID-19 assessed by serial Electrical Impedance Tomography in the MaastrICCht cohort.

Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1-3 after intubation, 66 from day 4-6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO2/FiO2-ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (p = 0.017) and PEEP was 11.8 (SD 2.8) cmH2O vs. 11.3 (SD 3.4) cmH2O, (p = 0.475), for ICU survivors and non-survivors. At day 1-3, compliance was ~ 55 mL/cmH2O vs. ~ 45 mL/cmH2O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12-13 cmH2O. At day 4-6 compliance changed to ~ 50 mL/cmH2O vs. ~ 38 mL/cmH2O. At day 7 and beyond, compliance was ~ 38 mL/cmH2O with the intersection at a PEEP of ~ 9 cmH2O vs. ~ 25 mL/cmH2O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH2O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups.

The Awesome Power of Human Genetics of Infectious Disease.

Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and susceptibility to infectious diseases. GWA studies enabled the identification of many common variants associated with small shifts in susceptibility to infectious diseases. This is exemplified by multiple loci associated with leprosy, malaria, HIV, tuberculosis, and coronavirus disease 2019 (COVID-19), which illuminate genetic architecture and implicate pathways underlying pathophysiology. Despite these successes, most of the heritability of infectious diseases remains to be explained. As the field advances, current limitations may be overcome by applying methodological innovations such as cellular GWA studies and phenome-wide association (PheWA) studies as well as by improving methodological rigor with more precise case definitions, deeper phenotyping, increased cohort diversity, and functional validation of candidate loci in the laboratory or human challenge studies.

The Pandemic Consumer Response: A Stockpiling Perspective and Shopping Channel Preferences

Covid-19 has changed consumer behaviour, probably forever. Initial consumer stockpiling led to stockouts, threat and uncertainty for consumers. To overcome shortages, consumers expanded their use of channels and many consumers started buying online for the first time. In this paper, we aim to address important research gaps related to consumer behaviour during the pandemic and especially stockpiling. Our paper starts by presenting the findings of our pre-study, which used social media to elicit or confirm potential constructs for our quantitative models. These constructs complemented the protection motivations theory to explain stockpiling behaviour, forming the basis for study 1, the stockpiling preparation stage and study 2, the effects of the Covid-19 pandemic disruptor on customer service logistics and lockdown shopping channel preferences. For studies 1 and 2 we gathered data via a UK online panel-structured questionnaire survey (n = 603). Results confirm that consumer-driven changes to supply chains emanate largely from consumer uncertainty. Lockdown restrictions led to consumers feeling socially excluded, but enhanced consumers' positive attitudes towards shopping online and increased consumers' altruism. In response, consumers stockpiled by visiting physical stores and/or ordering online. Lockdown restrictions led to feelings of social exclusion but, importantly, stockpiling helped to minimize consumer anxiety and fear and even increase wellbeing.

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins (preprint)

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T-cells. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

Changes in Youth Mental Health, Psychological Wellbeing, and Substance Use During the COVID-19 Pandemic: A Rapid Review.

Since the onset of the COVID-19 pandemic, researchers around the world have made efforts to assess its impact on youth mental health; however, the breadth of this topic has impeded a clear assessment of pandemic outcomes. This study aimed to address this gap by reviewing changes in youth (age ≤ 25) mental health, psychological wellbeing, substance use, and the use or delivery of relevant services during the pandemic. PubMed and Embase were searched in May 2021 to conduct a rapid review of the literature. The results encompass 156 primary publications and are reported using a narrative synthesis. Studies of mental health (n = 122) and psychological wellbeing (n = 28) generally indicated poor outcomes in many settings. Publications regarding substance use (n = 41) noted overall declines or unchanged patterns. Studies of service delivery (n = 12) indicated a generally positive reception for helplines and telehealth, although some youth experienced difficulties accessing services. The findings indicate negative impacts of the pandemic on youth mental health, with mixed results for substance use. Services must support marginalized youth who lack access to telehealth. Supplementary Information: The online version contains supplementary material available at 10.1007/s40894-022-00185-6.

Changes in Youth Mental Health, Psychological Wellbeing, and Substance Use During the COVID-19 Pandemic: A Rapid Review

Since the onset of the COVID-19 pandemic, researchers around the world have made efforts to assess its impact on youth mental health;however, the breadth of this topic has impeded a clear assessment of pandemic outcomes. This study aimed to address this gap by reviewing changes in youth (age ≤ 25) mental health, psychological wellbeing, substance use, and the use or delivery of relevant services during the pandemic. PubMed and Embase were searched in May 2021 to conduct a rapid review of the literature. The results encompass 156 primary publications and are reported using a narrative synthesis. Studies of mental health (n = 122) and psychological wellbeing (n = 28) generally indicated poor outcomes in many settings. Publications regarding substance use (n = 41) noted overall declines or unchanged patterns. Studies of service delivery (n = 12) indicated a generally positive reception for helplines and telehealth, although some youth experienced difficulties accessing services. The findings indicate negative impacts of the pandemic on youth mental health, with mixed results for substance use. Services must support marginalized youth who lack access to telehealth. Supplementary Information The online version contains supplementary material available at 10.1007/s40894-022-00185-6.

Turnover intention and coronaphobia among frontline nurses during the second surge of COVID-19: The mediating role of social support and coping skills.

BACKGROUND: Turnover among frontline health care workers, particularly nurses, reached an alarming rate during the COVID-19 pandemic. This turnover has been attributed, in part, to excessive fear of the virus (a condition called coronaphobia). Studies have not yet been conducted examining whether social support and coping skills could act as buffers between coronaphobia and the intention to leave. AIM: To examine the relationship between coronaphobia and frontline nurses' organisational and professional turnover intention and to assess whether social support and coping skills can buffer this relationship. METHODS: A correlational research design was used to collect responses through an online questionnaire from a convenience sample of 687 frontline nurses from the Central Philippines. Data were analyzed using descriptive (mean, standard deviation and percentages) and inferential statistics (t test, Pearson r correlation coefficient, ANOVA and multiple linear regression). RESULTS: More than half of the frontline nurses experienced coronaphobia, while 25.8% reported a desire to leave their job and 20.7% reported a desire to leave their profession. Coronaphobia had direct significant effects on nurses' organisational (ß = .424, p < .001) and professional turnover intention (ß = .316, p < .001). Social support and coping skills partially mediated the relationship between organisational (ß = .365, p < .001; ß = .362, p < .001) and professional turnover intention (ß = .279, p < .001; ß = .289, p < .001). CONCLUSION: Frontline nurses who experienced coronaphobia were more likely to quit their job and the nursing profession. Increasing nurses' social support and enhancing their coping skills reduced the negative effects of coronaphobia, resulting in improved nurse retention. IMPLICATIONS FOR NURSING MANAGEMENT: Institutional approaches to reduce coronaphobia and turnover intention during the pandemic can be facilitated by improving social support through innovative approaches (e.g., use of technology and social media) and equipping nurses with positive coping skills through coping skills training and other empirically based coping skill-building interventions.