A SARS-CoV-2-Related Virus from Malayan Pangolin Causes Lung Infection without Severe Disease in Human ACE2-Transgenic Mice.

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the most severe emerging infectious disease in the current century. The discovery of SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins in South Asian countries indicates that SARS-CoV-2 likely originated from wildlife. To date, two SARSr-CoV-2 strains have been isolated from pangolins seized in Guangxi and Guangdong by the customs agency of China, respectively. However, it remains unclear whether these viruses cause disease in animal models and whether they pose a transmission risk to humans. In this study, we investigated the biological features of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans, pangolins, civets, bats, pigs, and mice for cell entry and infect cell lines derived from humans, monkeys, bats, minks, and pigs. The virus could infect three mouse models but showed limited pathogenicity, with mild peribronchial and perivascular inflammatory cell infiltration observed in lungs. Our results suggest that this SARSr-CoV-2 virus from pangolins has the potential for interspecies infection, but its pathogenicity is mild in mice. Future surveillance among these wildlife hosts of SARSr-CoV-2 is needed to monitor variants that may have higher pathogenicity and higher spillover risk. IMPORTANCE SARS-CoV-2, which likely spilled over from wildlife, is the third highly pathogenic human coronavirus. Being highly transmissible, it is perpetuating a pandemic and continuously posing a severe threat to global public health. Several SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins have been identified since the SARS-CoV-2 outbreak. It is therefore important to assess their potential of crossing species barriers for better understanding of their risk of future emergence. In this work, we investigated the biological features and pathogenicity of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin, named MpCoV-GX. We found that MpCoV-GX can utilize ACE2 from 7 species for cell entry and infect cell lines derived from a variety of mammalian species. MpCoV-GX can infect mice expressing human ACE2 without causing severe disease. These findings suggest the potential of cross-species transmission of MpCoV-GX, and highlight the need of further surveillance of SARSr-CoV-2 in pangolins and other potential animal hosts.

Efficacy and Safety of Upadacitinib Induction Therapy in Patients With Moderately to Severely Active Crohn’s Disease: Results From a Randomized Phase 3 U-EXCEL Study

Introduction: Eligible patients(N=526) with moderate to severe active Crohn’s Disease(CD), defined as average daily stool frequency(SF)≥4 and/or abdominal pain score(APS)≥2, and a Simple Endoscopic Score for CD(SES-CD) (excluding the narrowing component subscore) ≥6(≥4 for subjects with isolated ileal disease). PBO % [95% CI] h Co-Primary Endpoints Clinical remission, wk 12  Per CDAI a  Per SF/APS b 29.1 [22.4, 35.8] 22.2 [16.0, 28.3] 49.5 [44.2, 54.8] 50.7 [45.5, 56.0] 20.8 [12.7, 28.8]** 28.7 [20.9, 36.4]** Endoscopic response c , wk 12 13.1 [8.1, 18.0] 45.5 [40.3, 50.8] 33.0 [26.2, 39.9]** Key Secondary Endpoints Clinical Remission, wk 4  Per CDAI a  Per SF/APS b 26.7 [20.2, 33.3] 14.8 [9.5, 20.0] 37.1 [32.1, 42.2] 35.7 [30.7, 40.7] 10.8 [2.9, 18.6]* 21.2 [14.3, 28.2]** Corticosteroid-free clinical remission, wk 12  per CDAI d  per SF/APS d (N=64) 15.7 [6.8, 24.7] 12.5 [4.4, 20.6] (N=126) 42.9 [34.2, 51.5] 44.4 [35.8, 53.1] 27.7 [15.7, 39.8]** 32.6 [21.5, 43.7]** Clinical Response CR-100 e  Week 2  Week 12 20.4 [14.4, 26.5] 37.3 [30.1, 44.5] 32.2 [27.3, 37.1] 56.6 [51.4, 61.8] 11.7 [4.2, 19.2]* 19.8 [11.3, 28.4]** Endoscopic remission f , wk 12 7.4 [3.5, 11.3] 28.9 [24.2, 33.7] 21.8 [15.8, 27.8]** Patient randomization was stratified by baseline corticosteroid use, endoscopic disease severity, and the number of previously failed biologics. All patients within this dataset were included here within the ITT population. a Clinical remission per CDAI = per US, CDAI < 150. b Clinical remission per SF/APS = per EU, average daily SF ≤ 2.8 and average daily APS ≤ 1.0 and both not greater than baseline c Endoscopic response = decrease in SES-CD > 50% from baseline (or for subjects with a baseline SES-CD of 4, at least a 2-point reduction from baseline), as scored by a central reviewer. d Corticosteroid-free clinical remission = discontinuation of corticosteroid use and achievement of clinical remission per CDAI or SF/APS at wk 12 among patients on corticosteroids at baseline. e Clinical response-100 = decrease of ≥ 100 points in CDAI from baseline. f Endoscopic remission = SES-CD ≤ 4, at least a 2-point reduction versus baseline and no subscore >1 in any individual variable, as scored by a central reviewer. g Results are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). h 95% CI for adjusted difference and p-value are calculated according to the Cochran-Mantel-Haenszel (CMH) test adjusted for randomization strata. **P ≤ .0001 or *P ≤ .01 vs PBO;Average daily abdominal pain score, APS;Coronavirus disease 2019, COVID-19;Confidence Interval, CI;Crohn’s Disease Activity Index, CDAI;Simple Endoscopic Score for CD, SES-CD, Placebo, PBO;Once daily, QD;average daily very soft/liquid stool frequency, SF;Upadacitinib, UPA.

Anxiety and depression in the post-pandemic era: concerns about viral mutation and re-outbreak.

BACKGROUND: The 2020 coronavirus pandemic (COVID-19) has been raging for more than 20 months, putting significant strain on public health systems around the world. Despite the fact that the pandemic has been effectively managed in certain countries, regional outbreaks and viral mutations continue to pose a threat to people's lives. The likelihood of post-pandemic changes in people's psychological situations warrants more investigation. DESIGN AND PARTICIPANTS: This study was conducted in the context of another outbreak in Zhangjiajie, China, respondents (infected patients, healthy population) were required to complete self-administered questions and standardized questionnaires, including the patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder-7 (GAD-7), and the Brief Illness Perception Questionnaire (BIPQ). MEASURES: We conducted an anonymous questionnaire survey of infected patients (excluding critically ill patients) in the confirmed COVID-19 ward of Zhangjiajie City People's Hospital's East Hospital from August 14 to 24, 2021, and used convenience sampling to survey medical staff and the general public to assess the psychological reactions of different populations during the delta variant outbreak pandemic. Differences in anxiety and depression severity were compared between groups, with logistic regression models constructed to explore potential factors associated with scoring clinical significant levels of depression and/or anxiety. RESULTS: There is no significant difference (p value = 0.228) between anxiety and depression in patients (n = 53), general public (n = 97), medical personnel (n = 103), and support workers (n = 65). Females reported higher scores on the GAD-7 and the BIPQ, reduced communication with family and friends appeared to be a risk factor for clinically significant anxiety and depression. CONCLUSIONS: There were no significant differences in anxiety and depression across populations explored in this study, but females had higher anxiety and illness perception than males, and effective communication may help improve mental health.

Virus Detection: From State-of-the-Art Laboratories to Smartphone-Based Point-of-Care Testing.

Infectious virus outbreaks pose a significant challenge to public healthcare systems. Early and accurate virus diagnosis is critical to prevent the spread of the virus, especially when no specific vaccine or effective medicine is available. In clinics, the most commonly used viral detection methods are molecular techniques that involve the measurement of nucleic acids or proteins biomarkers. However, most clinic-based methods require complex infrastructure and expensive equipment, which are not suitable for low-resource settings. Over the past years, smartphone-based point-of-care testing (POCT) has rapidly emerged as a potential alternative to laboratory-based clinical diagnosis. This review summarizes the latest development of virus detection. First, laboratory-based and POCT-based viral diagnostic techniques are compared, both of which rely on immunosensing and nucleic acid detection. Then, various smartphone-based POCT diagnostic techniques, including optical biosensors, electrochemical biosensors, and other types of biosensors are discussed. Moreover, this review covers the development of smartphone-based POCT diagnostics for various viruses including COVID-19, Ebola, influenza, Zika, HIV, et al. Finally, the prospects and challenges of smartphone-based POCT diagnostics are discussed. It is believed that this review will aid researchers better understand the current challenges and prospects for achieving the ultimate goal of containing disease-causing viruses worldwide.

Circular RNA vaccines against SARS-CoV-2 and emerging variants.

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNARBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2.

Genome-wide CRISPR activation screen identifies candidate receptors for SARS-CoV-2 entry.

The outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has created a global health crisis. SARS-CoV-2 infects varieties of tissues where the known receptor ACE2 is low or almost absent, suggesting the existence of alternative viral entry pathways. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection. Beyond known host proteins, i.e., ACE2, TMPRSS2, and NRP1, we identified multiple host components, among which LDLRAD3, TMEM30A, and CLEC4G were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike's N-terminal domain (NTD). Their essential and physiological roles have been confirmed in either neuron or liver cells. In particular, LDLRAD3 and CLEC4G mediate SARS-CoV-2 entry and infection in an ACE2-independent fashion. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of COVID-19 countermeasures.

Retinal toxicity caused by hydroxychloroquine in patients with systemic lupus erythematosus: A case report.

RATIONALE: Hydroxychloroquine has excellent anti-inflammatory and immunomodulatory effects as one of the antimalarial drugs. In particular, hydroxychloroquine was once widely used as a treatment for the new coronavirus pneumonia epidemic in 2020. Retinopathy caused by hydroxychloroquine is normally irreversible, but little attention has been paid to it. PATIENT CONCERNS: A 38-year-old young Chinese woman was taking oral hydroxychloroquine 400 mg daily to control lupus disease activity for six years after the diagnosis of systemic lupus erythematosus (SLE). She did not have any history of eye disease and was admitted to the hospital with a sudden blurring of both eyes. DIAGNOSES: The diagnosis of retinal macular degeneration caused by hydroxychloroquine was made after excluding other interfering diseases based on the patient's long-term use of hydroxychloroquine and the results of the eye examination. INTERVENTIONS: The patient was discontinued from hydroxychloroquine. To control the recurrence of SLE, she was given intravenous methylprednisolone, oral tacrolimus and mycophenolate. Meanwhile, she was asked to take extra care of her eyes and to come to the hospital every three months to have her vision checked. OUTCOMES: The patient's blurred vision improved one week later. Three months later, her vision examination showed no further decline (0.4 in the right eye and 0.6 in the left eye). Meanwhile, the SLE disease activity index (SLEDAI) decreased from six points to five points currently. LESSONS: Retinopathy caused by hydroxychloroquine is irreversible and there is no particularly effective treatment. Discontinuation of hydroxychloroquine, better daily eye protection, and regular vision checks are the keys to preventing retinopathy. Although hydroxychloroquine causing retinal toxicity was mentioned several years ago, the rate and severity of retinal toxicity require further research. How to get more patients to take care of their eyes requires continuous and increased education by doctors.

Analysis and consideration of registration information of global coronavirus disease 2019 clinical study

Objective: To analyze the registration characteristics of registered clinical research, and find the potential scientific and feasibility problems of clinical research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing reference for the good management of follow-up research registration. Methods: The key words of coronavirus disease 2019 (COVID-19) were identified and retrieved from Chinese Clinical Trial Registry and ClinicalTrials website. The registration characteristics of ethical status, number of recruits, total time, number of groups, intervention, study endpoint type, withdrawal, randomized controlled trial (RCT), stage, registration type, provinces distribution and patients' condition were summarized. IBM SPSS 22.0 software was used to analyze the above characteristics. Results: A total of 400 registered clinical studies were collected. Among them, 59 studies were not ethically approved, 15 studies were withdrawn, and stages of 303 studies were unclear. The differences of the three registration characteristics on the two official websites were statistically significant (all P<0.05). Fourteen studies recruited more than 1 000 people, the total time of 189 studies exceeded 6 months, and the number of groups in 22 studies exceeded 4 groups. There was no significant difference in the three registration characteristics on the two official websites. Only 15 studies were industry-sponsored trial. Most registered clinical studies were distributed in Hubei Province. Conclusion: The awareness of Chinese investigator initiating trial registration has increased. However, by collating and analyzing the registration information, it is found that the study design is not rigorous, so it is necessary to strengthen the registration quality management and study design methodological demonstration.