Rapid evaluation of COVID-19 vaccine effectiveness against symptomatic infection with SARS-CoV-2 variants by analysis of genetic distance.

Timely evaluation of the protective effects of Coronavirus Disease 2019 (COVID-19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is urgently needed to inform pandemic control planning. Based on 78 vaccine efficacy or effectiveness (VE) data from 49 studies and 1,984,241 SARS-CoV-2 sequences collected from 31 regions, we analyzed the relationship between genetic distance (GD) of circulating viruses against the vaccine strain and VE against symptomatic infection. We found that the GD of the receptor-binding domain of the SARS-CoV-2 spike protein is highly predictive of vaccine protection and accounted for 86.3% (P = 0.038) of the VE change in a vaccine platform-based mixed-effects model and 87.9% (P = 0.006) in a manufacturer-based model. We applied the VE-GD model to predict protection mediated by existing vaccines against new genetic variants and validated the results by published real-world and clinical trial data, finding high concordance of predicted VE with observed VE. We estimated the VE against the Delta variant to be 82.8% (95% prediction interval: 68.7-96.0) using the mRNA vaccine platform, closely matching the reported VE of 83.0% from an observational study. Among the four sublineages of Omicron, the predicted VE varied between 11.9% and 33.3%, with the highest VE predicted against BA.1 and the lowest against BA.2, using the mRNA vaccine platform. The VE-GD framework enables predictions of vaccine protection in real time and offers a rapid evaluation method against novel variants that may inform vaccine deployment and public health responses.

SARS-CoV-2 targets the lysosome to mediate airway inflammatory cell death.

As the coronavirus disease 2019 (COVID-19) pandemic continues to wreak havoc, researchers around the globe are working together to understand how the responsible agent - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages the respiratory system and other organs. Macroautophagy/autophagy is an innate immune response against viral infection and is known to be manipulated by positive-strand RNA viruses, including SARS-CoV-2. Nevertheless, the link between autophagic subversion and cell death or inflammation in COVID-19 remains unclear. Emerging evidence suggests that SARS-CoV-2 could trigger pyroptosis, a form of inflammatory programmed cell death characterized by the activation of inflammasomes and CASP1 (caspase 1) and the formation of transmembrane pores by GSDMD (gasdermin D). In this connection, autophagic flux impairment is a known activator of inflammasomes. This prompted us to investigate if SARS-CoV-2 could target autophagy to induce inflammasome-dependent pyroptosis in lung epithelial cells.Abbreviations: ATP6AP1: ATPase H+ transporting accessory protein 1; CASP1: caspase 1; COVID-19: coronavirus disease 2019; GSDMD: gasdermin D; IL1B: interleukin 1 beta; IL18: interleukin 18; KRT 18: keratin 18; NLRP3: NLR family pyrin domain containing 3; NOD: nucleotide oligomerization domain; NSP6: non-structural protein 6; TFEB: transcription factor EB; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

Impact of COVID-19 on pornography use: Evidence from big data analyses.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has led to radical changes in social distancing awareness and affected social relationships. Owing to large-scale lockdown, home quarantine and social distancing requirements, it was anticipated that sexual activities would be severely impacted. However, retrospective self-report studies showed that pornography use and autoerotism increased during the pandemic. AIM: This study used big-data databases available on the Internet to investigate factors that modulated pornography use during the pandemic. METHODS: Daily relative search volume (RSV) data from Google Trends for the period from 24 February 2020 to 13 July 2020 were extracted. Pornhub traffic data were extracted from the Pornhub Insights website, for the period from 24 February 2020 to 13 July 2020. The parameter was defined as 'percent change in traffic compared to an average day in 2019'. The number of daily new cases of COVID-19 was extracted from the database on Our World in Data. OUTCOME MEASURES: The normality of the data was examined using the Shapiro-Wilk test. All variables included in this study were non-normally distributed. Therefore, non-parametric tests or parametric tests with bootstrapping were adopted where appropriate. RESULTS: According to Google Trends, the RSV for 'pornography' increased after late March 2020, which is close to the date when the World Health Organization declared COVID-19 a global pandemic. The number of daily new cases of COVID-19 was positively correlated with the traffic of Pornhub, a popular pornography website, and the RSV for 'pornography'. Moderation analysis demonstrated a significant main effect of daily new cases of COVID-19 and the RSV for 'social distancing' in predicting Pornhub traffic/RSV for 'pornography'. Furthermore, the RSV for 'social distancing' significantly moderated the relationship between daily new cases and Pornhub traffic/RSV for 'pornography'. A stronger COVID-pornography use association was observed with increased social distancing awareness. CONCLUSION: Increased pornography consumption during the pandemic was observed, and it was associated with the severity of the pandemic. Social distancing awareness could be a key factor influencing interest in and use of pornography. Further studies on the changes in sexual desire and birth-rate control are worthwhile because long-term public health may be affected by the changes in sexual behaviour during the pandemic.

SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1.

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1ß/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.

Lysosome activation in peripheral blood mononuclear cells and prognostic significance of circulating LC3B in COVID-19.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.

Bioinformatic analyses suggest augmented interleukin-17 signaling as the mechanism of COVID-19-associated herpes zoster.

Herpes zoster results from latent varicella zoster virus reactivation in the dorsal root ganglia, causing blistering rash along the dermatomal distribution and post-herpetic neuralgia. Increasing studies indicated that there may be a correlation between herpes zoster and COVID-19. Nevertheless, the detailed pathophysiological mechanism is still unclear. We used bioinformatic analyses to study the potential genetic crosstalk between herpes zoster and COVID-19. COVID-19 and herpes zoster were associated with a similar subset of genes involved in "cytokine-cytokine receptor interaction," "Jak-STAT signaling pathway," and "IL-17 signaling pathway," including TNF, IL10, ESR1, INFG, HLA-A, CRP, STAT3, IL6, IL7, and IL17A. Protein-protein interaction network assay showed that the combined gene set indicated a raised connectivity as compared to herpes zoster or COVID-19 alone, particularly the potentiated interactions with APOE, ARSA, CCR2, CCR5, CXCL13, EGFR, GAL, GP2, HLA-B, HLA-DRB1, IL5, TECTA, and THBS1, and these genes are related to "cytokine-cytokine receptor interaction". Augmented Th17 cell differentiation and the resulting enhanced IL-17 signaling were identified in both COVID-19 and herpes zoster. Our data suggested aberrant interleukin-17 signaling as one possible mechanism through which COVID-19 could raise the risk of herpes zoster.

Development of a multivariable prediction model for severe COVID-19 disease: a population-based study from Hong Kong.

Recent studies have reported numerous predictors for adverse outcomes in COVID-19 disease. However, there have been few simple clinical risk scores available for prompt risk stratification. The objective is to develop a simple risk score for predicting severe COVID-19 disease using territory-wide data based on simple clinical and laboratory variables. Consecutive patients admitted to Hong Kong's public hospitals between 1 January and 22 August 2020 and diagnosed with COVID-19, as confirmed by RT-PCR, were included. The primary outcome was composite intensive care unit admission, need for intubation or death with follow-up until 8 September 2020. An external independent cohort from Wuhan was used for model validation. COVID-19 testing was performed in 237,493 patients and 4442 patients (median age 44.8 years old, 95% confidence interval (CI): [28.9, 60.8]); 50% males) were tested positive. Of these, 209 patients (4.8%) met the primary outcome. A risk score including the following components was derived from Cox regression: gender, age, diabetes mellitus, hypertension, atrial fibrillation, heart failure, ischemic heart disease, peripheral vascular disease, stroke, dementia, liver diseases, gastrointestinal bleeding, cancer, increases in neutrophil count, potassium, urea, creatinine, aspartate transaminase, alanine transaminase, bilirubin, D-dimer, high sensitive troponin-I, lactate dehydrogenase, activated partial thromboplastin time, prothrombin time, and C-reactive protein, as well as decreases in lymphocyte count, platelet, hematocrit, albumin, sodium, low-density lipoprotein, high-density lipoprotein, cholesterol, glucose, and base excess. The model based on test results taken on the day of admission demonstrated an excellent predictive value. Incorporation of test results on successive time points did not further improve risk prediction. The derived score system was evaluated with out-of-sample five-cross-validation (AUC: 0.86, 95% CI: 0.82-0.91) and external validation (N = 202, AUC: 0.89, 95% CI: 0.85-0.93). A simple clinical score accurately predicted severe COVID-19 disease, even without including symptoms, blood pressure or oxygen status on presentation, or chest radiograph results.

Miller Fisher syndrome associated with COVID-19: an up-to-date systematic review.

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Miller Fisher syndrome (MFS) have been reported. We want to summarize the main features of patients with MFS and COVID-19. A PubMed search was performed on 8 October to identify references reporting cases with MFS associated with COVID-19 from the first report of COVID-19 to 8 October 2020 using the following keywords: "Miller Fisher syndrome" AND "COVID-19" OR "SARS-CoV-2". A systematic review from the first report of coronavirus disease 2019 (COVID-19) to 8 October 2020 revealed 7 cases with Miller Fisher syndrome (MFS) associated with COVID-19. The 7 cases came from 5 countries but most of these patients were from Europe (85.7%), especially Spain. There are 5 cases of MFS diagnosed after the laboratory confirmation of SARS-CoV-2 infection. The mean onset time of MFS-associated neurological symptoms was 14.75 days after the diagnosis of COVID-19. However, the two remaining cases presented initially with MFS-associated neurological symptoms followed by the diagnosis of COVID-19. The most common symptoms of COVID-19-associated MFS were perioral paresthesias (57.1%), ataxia (57.1%), blurred vision (42.9), ophthalmoplegia (42.9), and generalized areflexia (42.9). However, more cohort and case-control studies are required to establish the epidemiological linkage.