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COVID-19 quarantine provides the largest intervention data of myopia progression in schoolchildren. We found grade is an important risk factor, and COVID-19-induced modifications of student’s online time and outdoor activity time sufficiently change myopia progression.

Simultaneous measurement of multiple modalities in single-cell analysis, represented by CITE-seq, is a promising approach to link transcriptional changes to cellular phenotype and function, requiring new computational methods to define cellular subtypes and states based on multiple data types. Here, we design a flexible single-cell multimodal analysis framework, called CITEMO, to integrate the transcriptome and antibody-derived tags (ADT) data to capture cell heterogeneity from the multi omics perspective. CITEMO uses Principal Component Analysis (PCA) to obtain a low-dimensional representation of the transcriptome and ADT, respectively, and then employs PCA again to integrate these low-dimensional multimodal data for downstream analysis. To investigate the effectiveness of the CITEMO framework, we apply CITEMO to analyse the cell subtypes of Cord Blood Mononuclear Cells (CBMC) samples. Results show that the CITEMO framework can comprehensively analyse single-cell multimodal samples and accurately identify cell subtypes. Besides, we find some specific immune cells that co-express multiple ADT markers. To better describe the co-expression phenomenon, we introduce the co-expression entropy to measure the heterogeneous distribution of the ADT combinations. To further validate the robustness of the CITEMO framework, we analyse Human Bone Marrow Cell (HBMC) samples and identify different states of the same cell type. CITEMO has an excellent performance in identifying cell subtypes and states for multimodal omics data. We suggest that the flexible design idea of CITEMO can be an inspiration for other single-cell multimodal tasks. The complete source code and dataset of the CITEMO framework can be obtained from https://github.com/studentiz/CITEMO.

BackgroundUnderstanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown.MethodsWe constructed a powerful computational framework to characterize the host genetics-influenced immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets (N = 606,534 cells).ResultsWe found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly-expressed genetics-risk genes increased with the severity of COVID-19. Three cell-subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were specifically expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significant up-regulated genes including S100A12, S100A8, S100A9, and IFITM1 confer higher risk to the cytokine storms among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality of multiple immunologic features, including elevation of proliferation, migration, and chemotaxis. Moreover, we observed a prominent increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues, and elevated interactions with epithelial cells could contribute to enhance the resident to lung airway for against COVID-19 infection.ConclusionsWe uncover a major genetics-modulated immunological shift between mild and severe infection, including an increase in up-regulated genetic-risk genes, excessive secreted inflammatory cytokines, and functional immune cell subsets contributing high risk to severity, which provides novel insights in parsing the host genetics-influenced immune cells for severe COVID-19.

Background Understanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown. Methods We constructed a computational framework to characterize the host genetics that influence immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets containing healthy controls and patients with mild, moderate, and severe symptom (N = 606,534 cells). We collected 10 predefined gene sets including inflammatory and cytokine genes to calculate cell state score for evaluating the immunological features of individual immune cells. Results We found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly expressed genes increased with the severity of COVID-19. Three cell subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were highly expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significantly up-regulated genes, including S100A12, S100A8, S100A9, and IFITM1, confer higher risk to the dysregulated immune response among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality including elevation of proliferation, migration, and chemotaxis. Moreover, we observed an increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues. The enhanced interactions of CXCR6+ memory CD8+T cells with epithelial cells facilitate the recruitment of this specific population of T cells to airways, promoting CD8+T cell-mediated immunity against COVID-19 infection. Conclusions We uncover a major genetics-modulated immunological shift between mild and severe infection, including an elevated expression of genetics-risk genes, increase in inflammatory cytokines, and of functional immune cell subsets aggravating disease severity, which provides novel insights into parsing the host genetic determinants that influence peripheral immune cells in severe COVID-19.

SummaryBackgroundHigh prevalence of myopia of adolescent has been a global public health concern. Their risk factors and effective prevention methods for myopia across schoolchildren developmental stages are critically needed but remain uncertain due to the difficulty in implementing intervention measurements under normal life situation. We aimed to study the impact of the COVID-19 quarantine on myopia development among over one-million schoolchildren.MethodsWe designed the ongoing longitudinal project of Myopic Epidemiology and Intervention Study (MEIS) to biannually examine myopia among millions of schoolchildren for ten years in Wenzhou City, Zhejiang Province, China. In the present study, we performed three examinations of myopia in 1,305 elementary and high schools for schoolchildren in June 2019, December 2019 and June 2020. We used the normal period (June-December 2019) and COVID-19 quarantine period (January-June 2020) for comparisons. Myopia was defined as an uncorrected visual acuity of 20/25 or less and a spherical equivalent refraction (SER) of -0.5 diopters (D) or less. High myopia was defined as an SER of -6.0 D or less.FindingsIn June 2019, 1,001,749 students aged 7-18 were eligible for examinations. In the 6-month and 12-month follow-up studies, there were 813,755 eligible students (81.2%) and 768,492 eligible students (76.7%), respectively. Among all students, we found that half-year myopia progression increased approximate 1.5 times from -0.263 D (95% CI, -0.262 to -0.264) during normal period to -0.39 D (95% CI, -0.389 to -0.391) during COVID-19 quarantine (P < 0.001). Multivariate Cox regression analysis identified grade rather than age was significantly associated with myopia (Hazard ratio [HR]: 1.10, 95% CI, 1.08 to 1.13; P < 0.001) and high myopia (HR: 1.40, 95% CI, 1.35 to 1.46; P < 0.001) after adjustment for other factors. The prevalence, progression, and incidence of myopia and high myopia could be categorized into two grade groups: I (grades 1-6) and II (grades 7-12). Specifically, COVID-19 quarantine for 6 months sufficiently increased risk of developing myopia (OR: 1.36, 95% CI, 1.33 to 1.40) or high myopia (OR: 1.30, 95% CI, 1.22 to 1.39) in Grade Group I, but decreased risk of developing myopia (OR: 0.45, 95% CI, 0.43 to 0.48) or high myopia (OR: 0.57, 95% CI, 0.54 to 0.59) in Grade Group II.InterpretationThe finding that behavioral modifications for six months during COVID-19 quarantine sufficiently and grade-specifically modify myopia development offers the largest human behavioral intervention data at the one million scale to identify the grade-specific causal factors and effective prevention methods for guiding the formulation of myopia prevention and control policies.FundingKey Program of National Natural Science Foundation of China; the National Natural Science Foundation of China; Scientific Research Foundation for Talents of Wenzhou Medical University; Key Research and Development Program of Zhejiang Province.Research in contextEvidence before this studyMyopia is the most-common refractive error worldwide. Myopia with younger onset may result in developing high myopia, which is associated with sight-threatening ocular diseases such as maculopathy, retinal detachment, opticneuropathy, glaucoma, retinal atrophy, choroidal neovascularization. In light of the increasing prevalence of myopia and high myopia has been a global public health concern, the impact of COVID-19 lockdown on myopia development has gained substantial attention. We searched PubMed, Google Scholar, and MEDLINE databases for original articles reported between database inception and November 10, 2020, using the following search terms: (coronavirus OR COVID* OR SARS-COV-2 OR lockdown OR quarantine) AND (myopia OR short-sightedness OR refractive error). To date, there was no original study reported to uncover the influence of COVID-19 quarantine on myopia progression.Added value of this studyThis study provides the largest longitudinal intervention data on myopia progression in Chinese schoolchildren covering all grades of schoolchildren at one-million scale. COVID-19 quarantine model uncovers that behavioral modifications for six months may lead to significant increase of overall prevalence of myopia associated with their increased screen times and decreased outdoor activity times. Importantly, their effects on developing myopia or high myopia of students are grade-dependent, which were risk factors for elementary schools period but protective factors for high schools period partly due to reduced school education burden.Implications of all the available evidenceThis one-million schoolchildren myopia survey offers evidence that six months behavioral modifications sufficiently and grade-specifically change the progression of myopia and high myopia. In view of the increased use of electronic devices is an unavoidable trend, effective myopia prevention strategy according to grade among students is urgently needed. Since COVID-19 outbreak is still ongoing and spreading, international collaborate efforts are warranted to uncover the influence of COVID-19 on myopia progression to further substantiate these findings.