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The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated (Cas) systems have recently received notable attention for their applications in nucleic acid detection. Despite many attempts, the majority of current CRISPR‐based biosensors in infectious respiratory disease diagnostic applications still require target preamplifications. This study reports a new biosensor for amplification‐free nucleic acid detection via harnessing the trans‐cleavage mechanism of Cas13a and ultrasensitive graphene field‐effect transistors (gFETs). CRISPR Cas13a‐gFET achieves the detection of SARS‐CoV‐2 and respiratory syncytial virus (RSV) genome down to 1 attomolar without target preamplifications. Additionally, we validate the detection performance using clinical SARS‐CoV‐2 samples, including those with low viral loads (Ct value >30). Overall, these findings establish our CRISPR Cas13a‐gFET among the most sensitive amplification‐free nucleic acid diagnostic platforms to date.
ABSTRACT
Nucleic acid detection plays a critical role in medical diagnostics, environmental monitoring, and food safety. In their Research Article (e202203826), Xue Gao, Yi Zhang and co‐workers developed a new biosensor for amplification‐free nucleic acid detection via harnessing the trans‐cleavage mechanism of Cas13a and ultrasensitive graphene field‐effect transistors (gFETs). The illustration shows the Cas13a‐mediated RNA trans‐cleavage on a gFET surface for sensor signal transduction.
ABSTRACT
Der Nachweis von Nukleinsäuren spielt eine wichtige Rolle in der medizinischen Diagnostik, der Umweltüberwachung und der Lebensmittelsicherheit. In ihrem Forschungsartikel (e202203826) entwickelten Xue Gao, Yi Zhang und Mitarbeiter einen neuen Biosensor für den amplifikationsfreien Nukleinsäurenachweis, indem sie den trans‐Spaltungsmechanismus von Cas13a und ultrasensitive Graphen‐Feldeffekttransistoren (gFETs) nutzten. Die Abbildung zeigt die Cas13a‐vermittelte RNA‐trans‐Spaltung auf der gFET‐Oberfläche für die Sensorsignalübertragung.
ABSTRACT
Der Nachweis von Nukleinsäuren spielt eine wichtige Rolle in der medizinischen Diagnostik, der Umweltüberwachung und der Lebensmittelsicherheit. In ihrem Forschungsartikel (DOI: 10.1002/ange.202203826) entwickelten Xue Gao, Yi Zhang und Mitarbeiter einen neuen Biosensor für den amplifikationsfreien Nukleinsäurenachweis, indem sie den trans-Spaltungsmechanismus von Cas13a und ultrasensitive Graphen-Feldeffekttransistoren (gFETs) nutzten. Die Abbildung zeigt die Cas13a-vermittelte RNA-trans-Spaltung auf der gFET-Oberfläche für die Sensorsignalübertragung.
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Objective: To assess the global epidemic of Coronavirus disease 2019(COVID-19) in October 2021 and the risk of importation.
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The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented worldwide health crisis. Many previous research studies have found and investigated its links with one or some natural or human environmental factors. However, a review on the relationship between COVID-19 incidence and both the natural and human environment is still lacking. This review summarizes the inter-correlation between COVID-19 incidence and environmental factors. Based on keyword searching, we reviewed 99 relevant peer-reviewed articles and other research literature published since January 2020. This review is focused on three main findings. One, we found that individual environmental factors have impacts on COVID-19 incidence, but with spatial heterogeneity and uncertainty. Two, environmental factors exert interactive effects on COVID-19 incidence. In particular, the interactions of natural factors can affect COVID-19 transmission in micro- and macro- ways by impacting SARS-CoV-2 survival, as well as human mobility and behaviors. Three, the impact of COVID-19 incidence on the environment lies in the fact that COVID-19-induced lockdowns caused air quality improvement, wildlife shifts and socio-economic depression. The additional value of this review is that we recommend future research perspectives and adaptation strategies regarding the interactions of the environment and COVID-19. Future research should be extended to cover both the effects of the environment on the COVID-19 pandemic and COVID-19-induced impacts on the environment. Future adaptation strategies should focus on sustainable environmental and public policy responses.
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Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ~50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-{lambda} and Tnf-) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19 , Heredodegenerative Disorders, Nervous System , Central Nervous System InfectionsABSTRACT
Objective: To observe distribution of traditional Chinese medicine(TCM) patterns and changes of peripheral blood cell count and chest imaging in mild and moderate COVID-19 patients.
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We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average ~1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.
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Summary We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average ∼1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.
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Objective: To investigate the epidemiological characteristics of dermatosis in Medicssent to aid treatment in Hubei province from Hainan province during the prevention and control of COVID-19 epidemic, so as to provide reference for clinical medical staff to take reasonable and effective preventive measures.
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Background: To investigate the CT changes of different clinical types of COVID-19 pneumonia. Methods: : This retrospective study included 50 patients with COVID-19 from 16 January 2020 to 25 February 2020. We analyzed the clinical characteristics, CT characteristics and the pneumonia involvement of the patients between the moderate group and the severe and critical group, and the dynamic changes of severity with the CT follow-up time. Results: : There were differences in the CT severity score of the right lung in the initial CT, and total CT severity score in the initial and follow-up CT between the moderate group and the severe and critical group (all p <0.05). There was a quadratic relationship between total CT severity score and CT follow-up time in the severe and critical group (r 2 =0.137, p=0.008), the total CT severity score peaked at the second follow-up CT. There was no correlation between total CT severity score and CT follow-up time in the moderate group (p >0.05). There were no differences in the occurrence rate of CT characteristics in the initial CT between the two groups (all p >0.05). There were differences in the occurrence rate of ground-glass opacity and crazy-paving pattern in the second follow-up CT, and pleural thickening or adhesion in the third follow-up CT between the two groups (all p <0.05). Conclusions: : The CT changes of COVID-19 pneumonia with different severity were different, and the extent of pneumonia involvement by CT can help to assess the severity of COVID-19 pneumonia rather than the initial CT characteristics.
Subject(s)
Coronavirus Infections , Pneumonia , COVID-19ABSTRACT
Background: The rapid spread of coronavirus disease 2019 (COVID-19) revealed significant constraints in critical care capacity. In anticipation of subsequent waves, reliable prediction of disease severity is essential for critical care capacity management and may enable earlier targeted interventions to improve patient outcomes. The purpose of this study is to develop and externally validate a prognostic model/clinical tool for predicting COVID-19 critical disease at presentation to medical care. Methods: This is a retrospective study of a prognostic model for the prediction of COVID-19 critical disease where critical disease was defined as ICU admission, ventilation, and/or death. The derivation cohort was used to develop a multivariable logistic regression model. Covariates included patient comorbidities, presenting vital signs, and laboratory values. Model performance was assessed on the validation cohort by concordance statistics. The model was developed with consecutive patients with COVID-19 who presented to University of California Irvine Medical Center in Orange County, California. External validation was performed with a random sample of patients with COVID-19 at Emory Healthcare in Atlanta, Georgia. Results: Of a total 3208 patients tested in the derivation cohort, 9% (299/3028) were positive for COVID-19. Clinical data including past medical history and presenting laboratory values were available for 29% (87/299) of patients (median age, 48 years [range, 21-88 years]; 64% [36/55] male). The most common comorbidities included obesity (37%, 31/87), hypertension (37%, 32/87), and diabetes (24%, 24/87). Critical disease was present in 24% (21/87). After backward stepwise selection, the following factors were associated with greatest increased risk of critical disease: number of comorbidities, body mass index, respiratory rate, white blood cell count, % lymphocytes, serum creatinine, lactate dehydrogenase, high sensitivity troponin I, ferritin, procalcitonin, and C-reactive protein. Of a total of 40 patients in the validation cohort (median age, 60 years [range, 27-88 years]; 55% [22/40] male), critical disease was present in 65% (26/40). Model discrimination in the validation cohort was high (concordance statistic: 0.94, 95% confidence interval 0.87-1.01). A web-based tool was developed to enable clinicians to input patient data and view likelihood of critical disease. Conclusions and Relevance: We present a model which accurately predicted COVID-19 critical disease risk using comorbidities and presenting vital signs and laboratory values, on derivation and validation cohorts from two different institutions. If further validated on additional cohorts of patients, this model/clinical tool may provide useful prognostication of critical care needs.
Subject(s)
Critical Illness , Diabetes Mellitus , Obesity , Hypertension , COVID-19ABSTRACT
Background: Recent epidemiological evidence has demonstrated a higher rate of COVID-19 hospitalizations and deaths among minorities. This pattern of race-ethnic disparities emerging throughout the United States raises the question of what social factors may influence spread of a highly transmissible novel coronavirus. The purpose of this study is to describe race-ethnic and socioeconomic disparities associated with COVID-19 in patients in our community in Orange County, California and understand the role of individual-level factors, neighborhood-level factors, and access to care on outcomes. Methods: This is a case-series of COVID-19 patients from the University of California, Irvine (UCI) across six-weeks between 3/12/2020 and 4/22/2020. Note, California's shelter-in-place order began on 3/19/2020. Individual-level factors included race-ethnicity status were recorded. Neighborhood-level factors from census tracts included median household income, mean household size, proportion without a college degree, proportion working from home, and proportion without health insurance were also recorded. Results: A total of 210-patients tested were COVID-19 positive, of which 73.3% (154/210) resided in Orange County. Hispanic/Latinx patients residing in census tracts below the median income demonstrated exponential growth (rate = 55.9%, R2 = 0.9742) during the study period. In addition, there was a significant difference for both race-ethnic (p < 0.001) and income bracket (p = 0.001) distributions prior to and after California's shelter-in-place. In addition, the percentage of individuals residing in neighborhoods with denser households (p = 0.046), lower levels of college graduation (p < 0.001), health insurance coverage (p = 0.01), and ability to work from home (p < 0.001) significantly increased over the same timeframe. Conclusions and Relevance: Our study examines the race-ethnic disparities in Orange County, CA, and highlights vulnerable populations that are at increased risk for contracting COVID-19. Our descriptive case series illustrates that we also need to consider socioeconomic factors, which ultimately set the stage for biological and social disparities.
Subject(s)
COVID-19 , Encephalitis, CaliforniaABSTRACT
Background: The COVID-19 infection has caused 111652 deaths worldwide as of 13 April 2020. Risk factors for fatal outcomes of COVID-19 have varied across studies due to limited samples and have lacked effective qualitative and quantitative measurements. We performed a meta-analysis to evaluate risk factors for fatal outcomes of COVID-19.Methods: Data on demographic, clinic, laboratory findings and complications were extracted. Quantitative and qualitative synthesis was conducted for weighted-mean-difference (WMD) and odds-ratio (OR).Results: A total of 30 studies involving 5741 survivors and 1670 deaths were included. The death cases were significantly older than survivors (WMD=15.36, 95% CI: 12.90-17.82), male and smoking history showed higher risk to develop fatal outcome (OR=3.37, 95% CI: 2.27-5.01; OR=1.37, 95% CI: 1.02-1.83, respectively). The clinical symptoms including dyspnea (OR=4.63, 95% CI: 2.85-7.54), hemoptysis (OR=3.11, 95% CI: 1.26-7.56), malaise (OR=2.44, 95% CI: 1.49-3.97). comorbidities with coronary heart disease (OR=4.36, 95% CI: 1.91-9.97), COPD (OR=3.70, 95% CI: 2.03-6.73) and cardiovascular disease (OR=3.45, 95% CI: 2.54-4.70). Compared to survivors, many laboratory indexes increased in deaths group, including serum ferritin (WMD=741.47, 95% CI: 566.77-916.16), lactate dehydrogenase (WMD=226.86, 95% CI: 177.08-276.64) and myoglobin (WMD=102.58, 95% CI: 65.12-140.04), and the decreased indexes included PaO2/FiO2 (WMD=-71.61, 95% CI: -134.11 to -9.11), platelets (WMD=-41.09, 95% CI: -47.33 to -34.85) and PaO2 (WMD=-26.09, 95% CI: -38.9 to -13.29). Main complications contributed to the fatal outcome included sepsis (OR=184.61, 95% CI: 33.43-1019.42), shock (OR=133.76, 95% CI: 36.86-485.34) and respiratory failure (OR=47.37, 95% CI: 20.65-108.66). Conclusion: The main risk factors associated with fatal outcome of COVID-19 involved male, older age, smoking history, chronic medical conditions including coronary heart disease, COPD and cardiovascular disease, clinical symptoms including dyspnea, hemoptysis and malaise, the increased laboratory indexes including serum ferritin, lactate dehydrogenase and myoglobin, the decreased indexes including PaO2/FiO2, platelets and PaO2, main complications including sepsis, shock and respiratory failure. These factors could be considered in triaging patients and allocating medical resources when such medical resources are scarce, devising improved protocols for patient diagnosis and management, and developing new drugs and other therapies to treat COVID-19 patients.
Subject(s)
Shock , Pulmonary Disease, Chronic Obstructive , Cardiovascular Diseases , Dyspnea , Hemoptysis , Sepsis , Coronary Disease , Death , COVID-19 , Respiratory InsufficiencyABSTRACT
Two notable features have been identified in the SARS-CoV-2 genome: (1) the receptor binding domain of SARS-CoV-2; (2) a unique insertion of twelve nucleotide or four amino acids (PRRA) at the S1 and S2 boundary. For the first feature, the similar RBD identified in SARs-like virus from pangolin suggests the RBD in SARS-CoV-2 may already exist in animal host(s) before it transmitted into human. The left puzzle is the history and function of the insertion at S1/S2 boundary, which is uniquely identified in SARS-CoV-2. In this study, we identified two variants from the first Guangdong SARS-CoV-2 cell strain, with deletion mutations on polybasic cleavage site (PRRAR) and its flank sites. More extensive screening indicates the deletion at the flank sites of PRRAR could be detected in 3 of 68 clinical samples and half of 22 in vitro isolated viral strains. These data indicate (1) the deletion of QTQTN, at the flank of polybasic cleavage site, is likely benefit the SARS-CoV-2 replication or infection in vitro but under strong purification selection in vivo since it is rarely identified in clinical samples; (2) there could be a very efficient mechanism for deleting this region from viral genome as the variants losing 23585-23599 is commonly detected after two rounds of cell passage. The mechanistic explanation for this in vitro adaptation and in vivo purification processes (or reverse) that led to such genomic changes in SARS-CoV-2 requires further work. Nonetheless, this study has provided valuable clues to aid further investigation of spike protein function and virus evolution. The deletion mutation identified in vitro isolation should be also noted for current vaccine development.
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ObjectivesTo investigate the CT changes of different clinical types of COVID-19 pneumonia.MethodsThis retrospective study included 50 confirmed patients with COVID-19 from 16 January 2020 to 25 February 2020. We analyzed the clinical and CT characteristics of the patients between the moderate group and the severe and critical group, and the dynamic changes of severity with the CT follow-up time.ResultsThere were no differences in the occurrence rate of CT characteristics between the moderate group (n=34) and the severe and critical group (n=16) in the initial CT (all p >0.05). There were differences in the CT score of right lung and total CT score at the initial CT between the two groups (all p <0.05). There was a quadratic relationship between total CT score and CT follow-up time in the severe and critical group (r2=0.137, p=0.008), the total CT severity score peaked at the second follow-up CT. There was no correlation between total CT score and CT follow-up time in the moderate group (p >0.05). The total CT score of the severe and critical group was different between the initial and first follow-up, the second and third follow-ups, the third and fourth follow-ups, and the fourth and fifth follow-ups CT (all p<0.05). The total CT score of the moderate group was different between the second and third follow-ups CT (p<0.05).ConclusionsCOVID-19 pneumonia with the severe and critical types progressed rapidly with the greatest severity at the second follow-up CT, and the moderate type was relatively stable.