Cooperativity and induced oligomerisation control the interaction of SARS- CoV-2 with its cellular receptor and patient-derived antibodies (preprint)

Viral entry is mediated by oligomeric proteins on the virus and cell surfaces. The association is therefore open to multivalent interactions between these proteins, yet such recognition is typically rationalised as affinity between monomeric equivalents. As a result, assessment of the thermodynamic mechanisms that control viral entry has been limited. Here, we use mass photometry to overcome the analytical challenges consequent to multivalency. Examining the interaction between the spike protein of SARS-CoV-2 and the ACE2 receptor, we find that ACE2 induces oligomerisation of spike in a variant- dependent fashion. We also demonstrate that patient-derived antibodies use induced-oligomerisation as a primary inhibition mechanism or to enhance the effects of receptor-site blocking. Our results reveal that naive affinity measurements are poor predictors of potency, and introduce a novel antibody-based inhibition mechanism for oligomeric targets.

Exploring Plastic-Management Policy in China: Status, Challenges and Policy Insights

Plastic pollution is recognized as one of the most urgent global environmental concerns. China is the top producer and consumer of plastics and creates the most plastic waste globally. To evaluate policy options to control plastic pollution in China, we first reviewed the relevant policies and action plans in place. Then, we examined plastic-material flows and changes at the national level based on officially published data to evaluate the current situation and efficacy of policies at the macro-level. Results showed that 2016, the start of the 13th Five-Year Plan, was a pivotal year in the history of China's plastic policies tackling plastic issues nationally and internationally. Since 2016, the growth trend in the production and consumption of plastic products has slowed and the recycling rate has risen, surpassing 30% in 2021. To further tackle plastic pollution, key suggestions with important policy implications were provided, covering better integration of policies, the combined management of vertical–horizontal governance, tracking-system implementation, the introduction of a quality-certification system, the development of behaviour-based consumer-oriented solutions, the promotion of stakeholder collaboration, and the need for appropriate post-COVID-19 policies.

HLA-B evolutionary divergence is associated with poor outcomes after SARS-CoV-2 infection

Objectives Human leukocyte antigens (HLA) are highly diverse transmembrane proteins that present viral peptides to T cells and launch pathogen-specific immune responses. We aim to investigate the correlation between HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of SARS-CoV-2 infection in a cohort from the St. Louis Metropolitan area. Methods We enrolled adult patients with SARS-CoV-2 infection confirmed by RT-PCR who were hospitalized at two tertiary hospitals in St. Louis between March and July 2020. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HLA alleles were assigned based on key-exon sequences (G group) and limited to the 2-field resolution. HED was calculated by Grantham distance, which considers the difference in composition, polarity, and molecular volume between each pair of amino acids from maternal and paternal HLA. The HED score was obtained for HLA class I (HLA-A, -B, and -C) genotypes using the HLAdivR package in R. Clinical data were collected retrospectively from electronic medical records. A poor outcome was defined as an admission to the intensive care unit (ICU), a need for mechanical ventilation, or death. A favorable outcome was defined as the absence of the above poor outcomes. Results A total of 234 patients were enrolled in this study, 96 being females (41%). The median age and BMI were 66 years old and 28.30 kg/m2, respectively. African Americans comprised 71.4% of the cohort. Only 19 patients (8.1%) presented with no comorbidity;the rest had one or more comorbidities, with cardiovascular diseases being the most common. A total of 137 (58.5%) patients had poor outcomes from SARS-CoV-2 infection, while 97 (41.5%) patients had a favorable outcome. We detected a significant association between higher HLA-B HED and favorable outcomes, with each 1-point increase in HLA-B HED associated with 8% increased probability for the composite endpoint (OR 1.08, 95% CI=1.01-1.16, P = 0.04). The HED scores calculated for HLA-A or HLA-C were not significantly different between patients with favorable or poor outcomes. In a multivariate logistic regression analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). Conclusion Our study shows a significant correlation between lower HLA-B HED scores and poor outcomes after SARS-CoV-2 infection. This finding suggests that maximizing the presentation of diverse SARS-CoV-2 peptides by HLA-B alleles may improve the clearance of SARS-CoV-2. Further studies are warranted to understand the functional and mechanistic implications of this finding.

Automatic Sleep Staging Using BiRNN with Data Augmentation and Label Redirection

Sleep staging has always been a hot topic in the field of sleep medicine, and it is the cornerstone of research on sleep problems. At present, sleep staging heavily relies on manual interpretation, which is a time-consuming and laborious task with subjective interpretation factors. In this paper, we propose an automatic sleep stage classification model based on the Bidirectional Recurrent Neural Network (BiRNN) with data bundling augmentation and label redirection for accurate sleep staging. Through extensive analysis, we discovered that the incorrect classification labels are primarily concentrated in the transition and nonrapid eye movement stage I (N1). Therefore, our model utilizes a sliding window input to enhance data bundling and an attention mechanism to improve feature enhancement after label redirection. This approach focuses on mining latent features during the N1 and transition periods, which can further improve the network model's classification performance. We evaluated on multiple public datasets and achieved an overall accuracy rate of 87.3%, with the highest accuracy rate reaching 93.5%. Additionally, the network model's macro F1 score reached 82.5%. Finally, we used the optimal network model to study the impact of different EEG channels on the accuracy of each sleep stage.

Dynamic associations between the respiratory tract and gut antibiotic resistome of patients with COVID-19 and its prediction power for disease severity.

The antibiotic resistome is the collection of all antibiotic resistance genes (ARGs) present in an individual. Whether an individual's susceptibility to infection and the eventual severity of coronavirus disease 2019 (COVID-19) is influenced by their respiratory tract antibiotic resistome is unknown. Additionally, whether a relationship exists between the respiratory tract and gut ARGs composition has not been fully explored. We recruited 66 patients with COVID-19 at three disease stages (admission, progression, and recovery) and conducted a metagenome sequencing analysis of 143 sputum and 97 fecal samples obtained from them. Respiratory tract, gut metagenomes, and peripheral blood mononuclear cell (PBMC) transcriptomes are analyzed to compare the gut and respiratory tract ARGs of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between ARGs and immune response. Among the respiratory tract ARGs, we found that Aminoglycoside, Multidrug, and Vancomycin are increased in ICU patients compared with nICU patients. In the gut, we found that Multidrug, Vancomycin, and Fosmidomycin were increased in ICU patients. We discovered that the relative abundances of Multidrug were significantly correlated with clinical indices, and there was a significantly positive correlation between ARGs and microbiota in the respiratory tract and gut. We found that immune-related pathways in PBMC were enhanced, and they were correlated with Multidrug, Vancomycin, and Tetracycline ARGs. Based on the ARG types, we built a respiratory tract-gut ARG combined random-forest classifier to distinguish ICU COVID-19 patients from nICU patients with an AUC of 0.969. Cumulatively, our findings provide some of the first insights into the dynamic alterations of respiratory tract and gut antibiotic resistome in the progression of COVID-19 and disease severity. They also provide a better understanding of how this disease affects different cohorts of patients. As such, these findings should contribute to better diagnosis and treatment scenarios.

Nursing workforce allocation in the intensive care units of COVID-19-designated hospitals: A nationwide cross-sectional survey in China.

AIM: To explore the nursing workforce allocation in intensive care units (ICUs) of COVID-19-designated hospitals during the epidemic peak in China. DESIGN: A nationwide cross-sectional online survey. METHODS: A total of 37 head nurses and 262 frontline nurses in 37 ICUs of COVID-19-designated tertiary hospitals located in 22 cities of China were surveyed. The self-reported human resource allocation questionnaire was used to assess the nursing workforce allocation. RESULTS: The average patient-to-nurse ratio was 1.89 ± 1.14, and the median working hours per shift was 5 h. The top four majors of front-line nurses in ICUs were respiratory (31.30%), lemology (27.86%), intensive care (21.76%) and emergency (17.18%). We also found that a smaller average patient-to-nurse ratio (odds ratio [OR]: 0.328, 95% CI: 0.108, 1.000), longer average weekly rest time per person (OR: 0.193, 95% CI: 0.051, 0.729) and larger proportion of 6-9 working years (OR: 0.002, 95% CI: 0.001, 1.121) decreased the occurrence of nursing adverse events.

Generation of SARS-CoV-2 escape mutations by monoclonal antibody therapy.

COVID-19 patients at risk of severe disease may be treated with neutralising monoclonal antibodies (mAbs). To minimise virus escape from neutralisation these are administered as combinations e.g. casirivimab+imdevimab or, for antibodies targeting relatively conserved regions, individually e.g. sotrovimab. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to detect emerging drug resistance in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the antibody epitopes and for casirivimab+imdevimab multiple mutations are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.

Social anxiety and depression symptoms in Chinese left-behind children after the lifting of COVID-19 lockdown: A network analysis.

BACKGROUND: Returning to social life after the lifting of COVID-19 lockdown may increase risk of social anxiety, which is highly co-morbid with depression. However, few studies have reported the association between them. AIMS: To explore the complex relationship between social anxiety and depression symptoms in left-behind children after the lifting of the COVID-19 lockdown. METHODS: A cross-sectional survey was conducted 6 months after the lockdown removal. A total of 3,107 left-behind children completed the survey with a mean age of 13.33 and a response rate of 87.77%. Depression and social anxiety severity were assessed by the DSM-5 Patient Health Questionnaire for Adolescents and the DSM-5 Social Anxiety Disorder Questionnaire, respectively. The symptom-level association between the two disorders was examined using network analysis. RESULTS: After the lifting of COVID-19 lockdown, the prevalence of depression and social anxiety in left-behind children was 19.57% and 12.36%, respectively, with a co-morbidity rate of 8.98%. Network analysis showed that "Social tension" and "Social avoidance" had the greatest expected influence; "Humiliation" and "Motor" were bridge symptom nodes in the network. The directed acyclic graph indicated that "Social fright" was at the upstream of all symptoms. CONCLUSION: Attention should be paid to social anxiety symptoms in left-behind children after the lifting of COVID-19 lockdown. Prevention and intervention measures should be taken promptly to reduce the comorbidity of social anxiety and depression symptoms in the left-behind children after the lifting of lockdown.

A new uncertain multi-objective programming model with chance-entropy constraint for advertising promotion.

The COVID-19 outbreak has forced people to stay at home to prevent the spread of the virus. In this case, social media platforms have become the main communication venue for people. Online sales platforms have also become the main field for people's daily consumption. So, how to make full use of social media to carry out online advertising promotion, and then achieve better marketing, is one of the core issues that the marketing industry must pay attention to and solve. Therefore, this study takes the advertiser as the decision-maker, maximizes the number of full playing, likes, comments and forwarding, and minimizes the cost of advertising promotion as the decision-making goals, and Key Opinion Leader (KOL) selection as the decision vector. Based on this, a multi-objective uncertain programming model of advertising promotion is constructed. Among them, the chance-entropy constraint is proposed by combining the entropy constraint and the chance constraint. In addition, the multi-objective uncertain programming model is transformed into a clear single-objective model through mathematical derivation and linear weighting of the model. Finally, the practicability and effectiveness of the model are verified by numerical simulation, and decision-making suggestions for advertising promotion are put forward.

Association between Covid-19 vaccination and incidence of type 1 diabetes in China: Evidence from 14.14 million registered residents between 2007 and 2021.

AIMS: Reports have suggested that COVID-19 vaccination may cause Type 1 diabetes (T1D), particularly fulminant T1D (FT1D). This study aimed to investigate the incidence of T1D in a general population of China, where>90% of the people have received three injections of inactivated SARS-Cov-2 vaccines in 2021. METHODS: A population-based registry of T1D was performed using data from the Beijing Municipal Health Commission Information Center. Annual incidence rates were calculated by age group and gender, and annual percentage changes were assessed using Joinpoint regression. RESULTS: The study included 14.14 million registered residents, and 7,697 people with newly diagnosed T1D were identified from 2007 to 2021. T1D incidence increased from 2.77 in 2007 to 3.84 per 100,000 persons in 2021. However, T1D incidence was stable from 2019 to 2021, and the incidence rate did not increase when people were vaccinated in January-December 2021. The incidence of FT1D did not increase from 2015 to 2021. CONCLUSIONS: The findings suggest that COVID-19 vaccination did not increase the onset of T1D or have a significant impact on T1D pathogenesis, at least not on a large scale.

Potential of conserved antigenic sites in development of universal SARS-like coronavirus vaccines.

Given pandemic risks of zoonotic SARS-CoV-2 variants and other SARS-like coronaviruses in the future, it is valuable to perform studies on conserved antigenic sites to design universal SARS-like coronavirus vaccines. By using antibodies obtained from convalescent COVID-19 patients, we succeeded in functional comparison of conserved antigenic sites at multiple aspects with each other, and even with SARS-CoV-2 unique antigenic sites, which promotes the cognition of process of humoral immune response to the conserved antigenic sites. The conserved antigenic sites between SARS-CoV-2 and SARS-CoV can effectively induce affinity maturation of cross-binding antibodies, finally resulting in broadly neutralizing antibodies against multiple variants of concern, which provides an important basis for universal vaccine design, however they are subdominant, putatively due to their lower accessibility relative to SARS-CoV-2 unique antigenic sites. Furthermore, we preliminarily design RBDs to improve the immunogenicity of these conserved antigenic sites. Our study focusing on conserved antigenic sites provides insights for promoting the development of universal SARS-like coronavirus vaccines, thereby enhancing our pandemic preparedness.

Asymptotic inference for moderate deviations from a unit root of nearly unstable INAR(1) processes

The INAR(1) processes with coefficients , where c>0 is a fixed constant and is a deterministic sequence growing to infinity at a slower rate than n, which are often referred to as nearly unstable INAR processes with moderate deviations from a unit root. We consider some basic properties of the processes and obtain the conditional least squares estimation of the coefficient , which converges to a normal distribution at speed . The simulation study provides numerical support for the theoretical results. The practical utility is illustrated in the data sets about liquor offences, claims of short-term disability and COVID-19, respectively.

Evaluation of T cell responses to naturally processed variant SARS-CoV-2 spike antigens in individuals following infection or vaccination

Most existing studies characterising SARS-CoV-2-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of ACE-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19. We show that rVACV expression of SARS-CoV-2 antigen can be used as an alternative to SARS-CoV-2 infection to evaluate T cell responses to naturally processed spike antigens. In addition, rVACV system can be used to evaluate the cross-reactivity of memory T cells to variants of concern (VOCs) and to identify epitope escape mutants. Finally, our data show that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations. Graphical Yin et al. utilize two informative systems for evaluating overall T cell responses to SARS-CoV-2 and variants, enabling greater understanding of T cell responses to the virus, cross-reactivity to viral variants and the differences between vaccine- and infection-induced immunity to SARS-CoV-2, and other emerging viruses in the future.

The Effects of Social Media Communication and e-WOM on Brand Equity: The Moderating Roles of Product Involvement

As brand equity (BE) is a valuable, but intangible, asset of any firm, understanding BE represents a primary task for many organizations. Factors that influence the development of BE are of inordinate academic and practical significance and a source of continuous investigation. While the current literature on social media communication (SMC) and BE provides a wealth of information, our study pioneers the most recent processes of mediation and moderation of electronic word-of-mouth and product involvement (PI) in BE research. Accordingly, the results of this work will likely become one of the key sources of information in sustainable marketing planning and in the development of strategies. To accomplish this goal, we assessed the structural relationships among SMC, electronic word of mouth (e-WOM), PI, and BE. A questionnaire survey was administered concerning consumer brands in China. In this survey, due to the need for social distancing during the COVID-19 pandemic, the questionnaire was distributed and collected via the internet. A total of 369 data sets were analyzed by partial least squares structural equation modeling (PLS-SEM). The results of our investigation reveal that: (a) social media firm- and user-generated content have a positive impact on e-WOM, (b) social media firm- and user-generated content have a positive impact on BE, (c) e-WOM has a positive impact on BE and serves as an intermediary role between SMC and BE, and (d) PI exerts specific moderating effects between SMC and BE.

Working from home and firm resilience to the COVID‐19 pandemic

The COVID‐19 pandemic has disrupted firms' operations. To cope with the crisis, many firms have allowed their employees to work from home (WFH). We examine whether a firm's WFH capacity has increased its resilience during the pandemic. We test the hypotheses using a unique data set that combines listed firms' financial statements, supply chain partners, and job postings on a leading online platform that provides hiring services. We find that imposing COVID‐19 anti‐contagion policies on firms and their suppliers or customers significantly increases their operating revenue volatility, slows their recovery, and has repercussions on their supply chains. WFH enhances firms' resistance capacity by reducing the effect of COVID‐19 on their operating revenue volatility and disruptions to their supply chain partners;however, it also decreases their recovery capacity by extending the time taken to return to normal. Firm attributes, along with workers' occupations, education, and experience, have an impact on the effect of WFH on firm resilience. This study enhances our understanding of shock transmission across supply chains and WFH as a source of firm resilience.

In situ electrospun aloe-nanofiber membrane for chronic wound healing.

Alleviating excessive inflammation while accelerating chronic wound healing to prevent wound infection has remained challenging, especially during the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 when patients experienced difficulties with receive appropriate healthcare. We addressed this issue by developing handheld electrospun aloe-nanofiber membranes (ANFMs) with convenient, environmentally friendly properties and a therapeutic capacity for wound closure. Our results showed that ANFMs fabricated with high molecular weight polyvinyl alcohol (PVA) to form fibers during electrospinning had uniform fibrous architecture and a porous structure. Given the value of aloe gel in accelerating wound healing, liquid extracts from ANFMs significantly downregulated the expression of the pro-inflammatory genes, interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), and markedly suppress the generation of reactive oxygen species (ROS) induced by lipopolysaccharide in RAW264.7 macrophages. These results indicated the excellent antioxidant and anti-inflammatory effects of ANFMs. After implantation into a mouse diabetic wound model for 12 days in situ, ANFMs notably expedited chronic wound healing via promoting angiogenesis and enhancing cell viability. Our ANFMs generated by handheld electrospinning in situ healed chronic wounds offer a convenient and promising alternative for patients to heal their own wounds under variable conditions.

HLA-B evolutionary divergence is associated with outcomes after SARS-CoV-2 infection.

We examined the correlation between class I HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of 234 adult inpatients with confirmed SARS-CoV-2 infection. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HED scores for HLA class I (HLA-A, -B, and -C) genotypes were calculated using Grantham's distance. Higher HED scores for HLA-B, but not HLA-A or -C, are significantly associated with a decreased probability of poor outcomes including ICU admission, mechanical ventilation, and death (OR = 0.93; P = 0.04) in the univariate analysis. In the multivariate analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). This finding is consistent with the notion that broader peptide repertoires presented by class I HLA may be beneficial in infection control.

Evolution of long-term vaccine induced and hybrid immunity in healthcare workers after different COVID19 vaccine regimens: a longitudinal cohort study

Background Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS-CoV-2. However, the maintenance of such responses – and hence protection from disease – requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARS-CoV-2 immunity & reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Methods Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. Findings We make three observations: Firstly, the dynamics of humoral and cellular responses differ;binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and boosted T cell responses above the 6-month level post dose 2. Thirdly, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people – a feature maintained until 6 months after the third dose. Conclusions Broadly cross-reactive T cell responses are well maintained over time – especially in those with combined vaccine and infection-induced immunity ("hybrid” immunity) – and may contribute to continued protection against severe disease. Funding Department for Health and Social Care, Medical Research Council Graphical abstract Moore et al. studied antibody and cellular responses to COVID-19 vaccines before and after dose 3. Antibody responses waned, but T cell responses were well maintained. T cells recognised Omicron variants better and for longer than antibodies. Differences due to vaccine regimen and previous infection evened out over time.

Rapid escape of new SARS-CoV-2 Omicron variants from BA.2 directed antibody responses

In November 2021 Omicron BA.1, containing a raft of new spike mutations emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or SARS-CoV-2 infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional RBD amino-acid substitutions compared to BA.2. We describe a panel of 25 potent mAbs generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titre of vaccine or BA.1, BA.2 or BA.4/5 immune serum. Graphical Dijokaite-Guraliuc et al. analyse potently neutralizing antibodies from vaccinated individuals with BA.2 breakthrough infections. The antibodies bind 3 sites on the receptor binding domain, 2 in common with early pandemic antibodies. Mutations in more recent variants map closely to these sites leading to reduced neutralization in all but one mAb.

Crisis communication in the WHO COVID-19 press conferences: A retrospective analysis.

OBJECTIVES: The objective of this study is to investigate, from a longitudinal perspective, how WHO communicated COVID-19 related information to the public through its press conferences during the first two years of the pandemic. METHODS: The transcripts of 195 WHO COVID-19 press conferences held between January 22, 2020 and February 23, 2022 were collected. All transcripts were syntactically parsed to extract highly frequent noun chunks that were potential topics of the press conferences. First-order autoregression models were fit to identify "hot" and "cold" topics. In addition, sentiments and emotions expressed in the transcripts were analyzed using lexicon-based sentiment/emotion analyses. Mann-Kendall tests were performed to capture the possible trends of sentiments and emotions over time. RESULTS: First, eleven "hot" topics were identified. These topics were pertinent to anti-pandemic measures, disease surveillance and development, and vaccine-related issues. Second, no significant trend was captured in sentiments. Last, significant downward trends were found in anticipation, surprise, anger, disgust, and fear. However, no significant trends were found in joy, trust, and sadness. CONCLUSIONS: This retrospective study provided new empirical evidence on how WHO communicated issues pertaining to COVID-19 to the general public through its press conferences. With the help of the study, members of the general public, health organizations, and other stake-holders will be able to better understand the way in which WHO has responded to various critical events during the first two years of the pandemic.