Ocular manifestations of COVID-19 infection: A retrospective study (preprint)

Introduction: Corona Virus Disease 2019 (COVID-19) swept the world rapidly to become the world’s first major public health problem. SARS-CoV-2’s receptors are expressed in multiple tissues throughout the body and can cause multiple organ damage when engaged by the virus. We collected and classified the clinical ocular manifestations of individuals infected with the SARS-CoV-2 during the pandemic and analyzed them to gain an understanding of the ocular manifestations of COVID-19. Methods: We conducted a retrospective study to collect the demographic characteristics, the SARS-CoV-2 infection signs and symptoms, and specifically, the ocular manifestations of the individuals with COVID-19. We used SPSS for all statistical analyses, to calculate the incidence of COVID-19 ocular manifestations and to analyze the possible associations between those and sex, age, and clinical manifestations of COVID-19. Results: Of the 452 records reviewed, 134 didn’t pass any tests to confirm COVID-19, so this group did not participate in the analysis. Of the remaining 318 reviewed records, 147 (46.2%, n=318) belonged to men and 171 (53.8%, n=318) to women. The most common systemic symptoms were cough, expectoration, chills, fever, and fatigue. In addition, we found women to be more likely than men to experience cough, expectoration, nasal congestion, runny nose, sore throat, hoarseness, low back pain, taste changes, and arthralgia. The overall incidence ofCOVID-19 eye manifestations was 26.7% (n=318) and the most common symptoms were eyeball pain, decreased vision , eye itching or foreign body sensation, and photophobia or tearing. Women were more likely than men to experience eyeball pain and orbital pain. We found sex and the prolonged screen time usage to be associated with COVID-19 ocular manifestations, whereas age, BMI, history of eye disease, basic diseases, types of COVID-19, vaccination status, and vaccination time were not associated with the presence of ocular manifestations. Conclusion: COVID-19 ocular manifestations are common, and the main ones include eyeball pain and decreased vision. The variables associated with eye discomfort are sex and the  prolonged screen time usage. Other variables such as age, BMI, underlying diseases, and type of COVID-19 were not associated with the occurrence of ocular symptoms in COVID-19.

Efficacy and safety of Lianhua Qingwen capsules combined with standard of care in the treatment of adult patients with mild to moderate COVID-19 (FLOSAN): protocol for a randomized, double-blind, international multicenter clinical trial.

Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).

Designer DNA NanoGripper (preprint)

DNA has shown great biocompatibility, programmable mechanical properties, and structural addressability at the nanometer scale, making it a versatile material for building high precision nanorobotics for biomedical applications. Herein, we present design principle, synthesis, and characterization of a DNA nanorobotic hand, called the "NanoGripper", that contains a palm and four bendable fingers as inspired by human hands, bird claws, and bacteriophages evolved in nature. Each NanoGripper finger has three phalanges connected by two flexible and rotatable joints that are bendable in response to binding to other entities. Functions of the NanoGripper have been enabled and driven by the interactions between moieties attached to the fingers and their binding partners. We showcase that the NanoGripper can be engineered to interact with and capture various objects with different dimensions, including gold nanoparticles, gold NanoUrchins, and SARS-CoV-2 virions. When carrying multiple DNA aptamer nanoswitches programmed to generate fluorescent signal enhanced on a photonic crystal platform, the NanoGripper functions as a sensitive viral biosensor that detects intact SARS-CoV-2 virions in human saliva with a limit of detection of ~ 100 copies/mL, providing RT-PCR equivalent sensitivity. Additionally, we use confocal microscopy to visualize how the NanoGripper-aptamer complex can effectively block viral entry into the host cells, indicating the viral inhibition. In summary, we report the design, synthesis, and characterization of a complex nanomachine that can be readily tailored for specific applications. The study highlights a path toward novel, feasible, and efficient solutions for the diagnosis and therapy of other diseases such as HIV and influenza.

A Photonic Resonator Interferometric Scattering Microscope for Label-free Detection of Nanometer-Scale Objects with Digital Precision in Point-of-Use Environments (preprint)

Label-free detection and digital counting of nanometer-scaled objects such as nanoparticles, viruses, extracellular vesicles, and protein molecules enable a wide range of applications in cancer diagnostics, pathogen detection, and life science research. The contrast of interferometric scattering microscopy is amplified through a photonic crystal surface, upon which scattered light from an object combines with illumination from a monochromatic plane wave source. The use of a photonic crystal substrate for interference scattering microscopy results in reduced requirements for high-intensity lasers or oil-immersion objectives, thus opening a pathway toward instruments that are more suitable for environments outside the optics laboratory. Here, we report the design, implementation, and characterization of a compact Photonic Resonator Interferometric Scattering Microscope (PRISM) designed for point-of-use environments and applications. The instrument incorporates two innovative elements that facilitate operation on a desktop in ordinary laboratory environments by users that do not have optics expertise. First, because scattering microscopes are extremely sensitive to vibration, we incorporated an inexpensive but effective solution of suspending the main components of the instrument from a rigid metal framework using elastic bands, resulting in an average of 28.7 dBV reduction in vibration amplitude compared to an office desk. Second, an automated focusing module based on the principle of total internal reflection maintains the stability of image contrast over time and spatial position, facilitating automated data collection. In this work, we characterize the performance of the instrument by measuring the contrast from gold nanoparticles with diameters in the 10-40 nm range and by observing various biological analytes, including HIV virus, SARS-CoV-2 virus, exosomes, and ferritin protein.

Parenting stress in lockdown: The role of changes in Children's routines and Parents' relationship with live‐in grandparents

Objectives Background Method Results Conclusion This study examined parenting stress in relation to changes in preschool‐aged children's routines and change in relationship quality between parents and live‐in grandparents caused by the lockdown.The Chinese city of Wuhan was the first city in the world to enforce a strict citywide lockdown to curtail the spread of Covid‐19. The 76‐day (1/23–4/8/2020) lockdown affected about 13 million of Wuhan's residents, many of whom were families with young children.Survey data were collected from 130 parents in Wuhan on parenting stress, children's routines in learning, play/exercise, screen exposure and sleep before, during and after the lockdown.The lockdown led to a significant decrease in the amount of time that the children spent daily in playing/exercise and learning, but a significant increase in nighttime sleep and screen exposure. Hierarchical linear regression analyses showed that controlling for other variables, the following significantly predicted parenting stress: decrease in learning time, parent–grandparent relationship deterioration, and the interaction between decrease in learning time and parent–grandparent relationship improvement.Minimizing loss of learning time and preventing parent–grandparent relationship deterioration could help reduce parenting stress during the lockdown. [ FROM AUTHOR] Copyright of Journal of Marriage & Family 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.)

Net-shaped DNA nanostructure designed for rapid/sensitive detection and potential inhibition of SARS-CoV-2 virus (preprint)

We present a net-shaped DNA nanostructure (called "DNA Net" herein) design strategy for selective recognition and high-affinity capture of the intact SARS-CoV-2 virions through spatial pattern-matching and multivalent interactions between the aptamers (targeting wild type spike-RBD) positioned on the DNA Net and the trimeric spike glycoproteins displayed on the viral outer surface. Carrying a designer nanoswitch, the DNA Net-aptamers releases fluorescent signal upon virus binding that is easily read by a hand-held fluorimeter for a rapid (in 10 mins), simple (mix-and-read), sensitive (PCR equivalent), room temperature compatible, and inexpensive (~ $1.26/test) COVID-19 test assay. The DNA Net-aptamers also impede authentic wild-type SARS-CoV-2 infection in cell culture with a near 1,000-fold enhancement of the monomeric aptamer. Furthermore, our DNA Net design principle and strategy can be customized to tackle other life-threatening and economically influential viruses like influenza and HIV, whose surfaces carry class-I viral envelope glycoproteins like the SARS-CoV-2 spikes in trimeric forms.

Spatio-temporal evolution and influencing factors of COVID-19 epidemic in Zhejiang Province

The global outbreak of novel Coronavirus Disease (COVID-19) epidemic has seriously endangered people's health and hindered rapid economic development. Geographic analysis of spatial and temporal transmission patterns in key regions can help prevent and control the epidemic. This paper takes Zhejiang province as the research area. With the help of POI data, the methods such as textual analysis, mathematical statistics, and spatial regression analysis are used to analyze the socio-demographic characteristics of confirmed cases and the spatio-temporal evolution of the epidemic, and then analyze its influencing factors. The results show that: (1) The age distribution of confirmed cases spanned a wide range, showing normal distribution of "large in the middle and small at both ends." (2) The epidemic period is divided into five stages: the initial period, the outbreak period, the steady decline period, the internal stable period, and the oversea input period. The interval between the onset time and announcing a confirmed case was mostly 0-6 d, and the time interval of non-local cases is longer than that of local cases, and the onset of most of the non-local cases occur on the day the patients leave their original place. There was no significant gender difference in the proportion of daily incidence, and the proportion of age had stage features. (3) The spatial distribution aligned in the direction of "Southeast-Northwest", the evolution trend developed from "single place distribution" to "multi-area cluster cases" and then to "key input" evolution, with "high-high" "high-low" clustering characteristics;The migration path of confirmed cases presented an obvious core-edge structure, and the first significant flow was from the center of Wuhan. (4) By analyzing the factors affecting the distribution of the epidemic,it is found that the ratio of the elderly population, per capita GDP, the proportion of the tertiary industry, the number of industries above the scale, and the distance from Wuhan were the dominant factors. Finally, several suggestions on targeted prevention and control measures are made, and the weaknesses of the study and future directions of efforts are pointed out.

Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study.

BACKGROUND: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. METHODS: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. RESULTS: Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown ß-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. CONCLUSION: A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.

Pharmacodynamic Study of QingFei Paidu Decoction in the Treatment of Acute Respiratory Distress Syndrome Caused by Coronavirus Disease-2019 (COVID-19) (preprint)

Background: The outbreak of the Coronavirus Disease-2019 (COVID-19) has threatened the public health of the world, and may eventually lead to acute respiratory impoverishment syndrome (ARDS). ARDS is a clinical syndrome caused by intrapulmonary or extrapulmonary reasons, which has complex pathogenesis and high mortality rate, it’s also one of the important factors in death from the 2019 novel coronavirus (2019-nCoV) epidemic. It has been reported that traditional Chinese medicine (TCM) can exert a good effect in the process of treatment. The present study aimed to observe the protective effects of TCM formula Qingfei Paidu Decoction (QFPD) on ARDS rats and explore the pharmacodynamic mechanism of the compound. Methods: 24 male rats were randomly divided into 4 groups (n=6), blank control group, model group, QFPD group (18.6g·kg-1·d-1) and dexamethasone group (2mg·kg-1·d-1). Blank control group rats were given saline, whereas other groups were injected with oleic acid (OA) and lipopolysaccharide (LPS) successively to establish ARDS model, and observed the behavioral performance of rats after model building. The morphological changes of lung tissue under optical microscope were observed; rat lung index (LI) and lung permeability index (LPI) were measured; blood PH, partial arterial oxygen pressure (PaO2, mmHg), partial arterial carbon dioxide pressure (PaCO2, mmHg), arterial oxygen saturation (SaO2) were measured by blood gas analyzer; the levels of tumor necrosis factor-α (TNF-α), interleukin (IL-1β, IL-6, IL-8, IL-10), thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α), kerbs von lungren 6 antigen (KL-6), C-reactive protein (CRP), and the expression of superoxide dismutase (SOD) were measured via test kit.Results: Compared with the model group, the two treatment groups could improve the respiratory and lung injury in rats, and could restore the expression levels of thromboxane, various cytokines and protein to varying degrees.Conclusions: QFPD and dexamethasone have protective effects on ARDS rats induced by jointly injecting OA and LPS, and QFPD has the better effect in between. These may be related to reducing the expression levels of IL-1β, IL-6, IL-8, TNF-α, CRP, TXB2, KL-6, and increasing the contents of IL-10, 6Keto-PGF1a and SOD vitality in the body.

Association of menopausal status with COVID-19 outcomes: a propensity score matching analysis.

BACKGROUND: Despite the growing number of studies on the coronavirus disease-19 (COVID-19), little is known about the association of menopausal status with COVID-19 outcomes. MATERIALS AND METHODS: In this retrospective study, we included 336 COVID-19 inpatients between February 15, 2020 and April 30, 2020 at the Taikang Tongji Hospital (Wuhan), China. Electronic medical records including patient demographics, laboratory results, and chest computed tomography (CT) images were reviewed. RESULTS: In total, 300 patients with complete clinical outcomes were included for analysis. The mean age was 65.3 years, and most patients were women (n = 167, 55.7%). Over 50% of patients presented with comorbidities, with hypertension (63.5%) being the most common comorbidity. After propensity score matching, results showed that men had significantly higher odds than premenopausal women for developing severe disease type (23.7% vs. 0%, OR 17.12, 95% CI 1.00-293.60; p = 0.003) and bilateral lung infiltration (86.1% vs. 64.7%, OR 3.39, 95% CI 1.08-10.64; p = 0.04), but not for mortality (2.0% vs. 0%, OR 0.88, 95% CI 0.04-19.12, p = 1.00). However, non-significant difference was observed among men and postmenopausal women in the percentage of severe disease type (32.7% vs. 41.7%, OR 0.68, 95% CI 0.37-1.24, p = 0.21), bilateral lung infiltration (86.1% vs. 91.7%, OR 0.56, 95% CI 0.22-1.47, p = 0.24), and mortality (2.0% vs. 6.0%, OR 0.32, 95% CI 0.06-1.69, p = 0.25). CONCLUSIONS: Men had higher disease severity than premenopausal women, while the differences disappeared between postmenopausal women and men. These findings support aggressive treatment for the poor prognosis of postmenopausal women in clinical practice.

Association of Menopausal Status with COVID-19 outcomes: a Propensity Score-Matching Analysis (preprint)

Background: Despite the growing number of studies on the Coronavirus Disease-19 (COVID-19), little is known about the association of menopausal status with COVID-19 outcomes. Materials: and methods: In this retrospective study, we included 336 COVID-19 in-patients between February 15, 2020 and April 30, 2020 at the Taikang Tongji Hospital (Wuhan), China. Electronic medical records, including patient demographics, laboratory results, and chest computed tomography (CT) images were reviewed. Results: : In total, 300 patients with complete clinical outcomes were included for analysis. The mean age was 65.3 years and most patients were women (n=167, 55.7%). Over 50% of patients presented with comorbidities, with hypertension (63.5%) being the most common comorbidity. After propensity-score matching, results showed that men had significantly higher odds than premenopausal women for developing severe disease type (23.7% vs. 0%, OR 17.12, 95% CI 1.00–293.60; p =0.003) and bilateral lung infiltration (86.1% vs. 64.7%, OR 3.39, 95% CI 1.08–10.64; p = 0.04), but not for mortality (2.0% vs. 0%, OR 0.88, 95% CI 0.04–19.12, p =1.00). However, non-significant difference was observed among men and post-menopause women in the percentage of severe disease type (32.7% vs. 41.7%, OR 0.68, 95% CI 0.37–1.24, p =0.21) and bilateral lung infiltration (86.1% vs. 91.7%, OR 0.56, 95% CI 0.22–1.47, p =0.24), mortality (2.0% vs. 6.0%, OR 0.32, 95% CI 0.06–1.69, p =0.25). Conclusions: : Men had higher disease severity than premenopausal women, while the differences disappeared between postmenopausal women and men. These findings support aggressive treatment for the poor-prognosis of postmenopausal women in clinical practice.

Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2 (preprint)

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies.  Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.    

Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids (preprint)

Summary ParagraphThe SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.

Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids (preprint)

Summary ParagraphThe current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.

Updated diagnosis, treatment and prevention of COVID-19 in children: experts' consensus statement (condensed version of the second edition).

In the early February, 2020, we called up an experts' committee with more than 30 Chinese experts from 11 national medical academic organizations to formulate the first edition of consensus statement on diagnosis, treatment and prevention of coronavirus disease 2019 (COVID-19) in children, which has been published in this journal. With accumulated experiences in the diagnosis and treatment of COVID-19 in children, we have updated the consensus statement and released the second edition recently. The current version in English is a condensed version of the second edition of consensus statement on diagnosis, treatment and prevention of COVID-19 in children. In the current version, diagnosis and treatement criteria have been optimized, and early identification of severe and critical cases is highlighted. The early warning indicators for severe pediatric cases have been summarized which is utmost important for clinical practice. This version of experts consensus will be valuable for better prevention, diagnosis and treatment of COVID-19 in children worldwide.

Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids (preprint)

The current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo- entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.