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BackgroundAcute kidney injury (AKI) is associated with mortality in patients hospitalized with COVID-19, however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied. MethodsElectronic health record data were obtained from 53 health systems in the United States (US) in the National COVID Cohort Collaborative (N3C). We selected hospitalized adults diagnosed with COVID-19 between March 6th, 2020, and January 6th, 2022. AKI was determined with serum creatinine (SCr) and diagnosis codes. Time were divided into 16-weeks (P1-6) periods and geographical regions into Northeast, Midwest, South, and West. Multivariable models were used to analyze the risk factors for AKI or mortality. ResultsOut of a total cohort of 306,061, 126,478 (41.0 %) patients had AKI. Among these, 17.9% lacked a diagnosis code but had AKI based on the change in SCr. Similar to patients coded for AKI, these patients had higher mortality compared to those without AKI. The incidence of AKI was highest in P1 (49.3%), reduced in P2 (40.6%), and relatively stable thereafter. Compared to the Midwest, the Northeast, South, and West had higher adjusted AKI incidence in P1, subsequently, the South and West regions continued to have the highest relative incidence. In multivariable models, AKI defined by either SCr or diagnostic code, and the severity of AKI was associated with mortality. ConclusionsUncoded cases of COVID-19-associated AKI are common and associated with mortality. The incidence and distribution of COVID-19-associated AKI have changed since the first wave of the pandemic in the US.
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The presence of SARS-CoV-2 mutants, including the emerging variant B.1.1.7, has raised great concerns in terms of pathogenesis, transmission, and immune escape. Characterizing SARS-CoV-2 mutations, evolution, and effects on infectivity and pathogenicity is crucial to the design of antibody therapies and surveillance strategies. Here we analyzed 454,443 SARS-CoV-2 spike genes/proteins and 14,427 whole-genome sequences. We demonstrated that the early variant B.1.1.7 may not have evolved spontaneously in the United Kingdom or within human populations. Our extensive analyses suggested that Canidae, Mustelidae or Felidae, especially the Canidae family (for example, dog) could be a possible host of the direct progenitor of variant B.1.1.7. An alternative hypothesis is that the variant was simply yet to be sampled. Notably, the SARS-CoV-2 whole genome represents a large number of potential co-mutations with very strong statistical significances (p value
ABSTRACT
The current COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of confirmed cases and thousands of deaths globally. Extensive efforts and progress have been made to develop effective and safe vaccines against COVID-19. A primary target of these vaccines is the SARS-CoV-2 spike (S) protein, and many studies utilized structural vaccinology techniques to either stabilize the protein or fix the receptor-binding domain at certain states. In this study, we extended an evolutionary protein design algorithm, EvoDesign, to create thousands of stable S protein variants without perturbing the surface conformation and B cell epitopes of the S protein. We then evaluated the mutated S protein candidates based on predicted MHC-II T cell promiscuous epitopes as well as the epitopes similarity to human peptides. The presented strategy aims to improve the S proteins immunogenicity and antigenicity by inducing stronger CD4 T cell response while maintaining the proteins native structure and function. The top EvoDesign S protein candidate (Design-10705) recovered 31 out of 32 MHC-II T cell promiscuous epitopes in the native S protein, in which two epitopes were present in all seven human coronaviruses. This newly designed S protein also introduced nine new MHC-II T cell promiscuous epitopes and showed high structural similarity to its native conformation. The proposed structural vaccinology method provides an avenue to rationally design the antigens structure with increased immunogenicity, which could be applied to the rational design of new COVID-19 vaccine candidates.
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The SARS-CoV-2 infected cases and the caused mortalities have been surging since the COVID-19 pandemic. Viral mutations emerge during the virus circulating in the population, which is shaping the viral infectivity and pathogenicity. Here we extensively analyzed 6698 SARS-CoV-2 whole genome sequences with specific sample collection dates in NCBI database. We found that four mutations, i.e., 5UTR_c-241-t, NSP3_c-3037-t, NSP12_c-14408-t, and S_a-23403-g, became the dominant variants and each of them represented nearly 100% of all virus sequences since the middle May, 2020. Notably, we found that co-occurrence rates of three significant multi-site co-mutational patterns, i.e., (i) S_a-23403-g, NSP12_c-14408-t, 5UTR_c-241-t, NSP3_c-3037-t, and ORF3a_c-25563-t; (ii) ORF8_t-28144-c, NSP4_c-8782-t, NSP14_c-18060-t, NSP13_a-17858-g, and NSP13_c-17747-t; and (iii) N_g-28881-a, N_g-28882-a, and N_g-28883-c, reached 66%, 90%, and nearly 100% of recent sequences, respectively. Moreover, we found significant decrease of CpG dinucleotide at positions 241(c)-242(g) in the 5UTR during the evolution, which was verified as a potential target of human zinc finger antiviral protein (ZAP). The four dominant mutations, three significant multi-site co-mutations, and the potential escape mutation of ZAP-target in 5UTR region contribute to the rapid evolution of SARS-CoV-2 virus in the population, thus shaping the viral infectivity and pathogenicity. This study provides valuable clues and frameworks to dissect the viral replication and virus-host interactions for designing effective therapeutics. One Sentence SummaryFour dominant mutations, three significant multi-site co-mutations, and 5UTR CpG escape contribute to the rapid evolution of SARS-CoV-2 virus.
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To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane protein, have been tested for vaccine development against SARS and MERS. We further used the Vaxign reverse vaccinology tool and the newly developed Vaxign-ML machine learning tool to predict COVID-19 vaccine candidates. The N protein was found to be conserved in the more pathogenic strains (SARS/MERS/COVID-19), but not in the other human coronaviruses that mostly cause mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10) were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and linear B-cell epitopes localized in specific locations and functional domains of the protein. Our predicted vaccine targets provide new strategies for effective and safe COVID-19 vaccine development.
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Objective To evaluate the efficacy of pivot-regulating manipulations applied in traditional Chinese medicine (TCM) clinical nursing for infantile anorexia based on the meridian and acupoint theory. Methods One hundred and twenty children with anorexia were randomly divided into trial group and control group , 60 cases in each group. The control group was given spine-pinching therapy based on the conventional nursing care. The trial group was given pivot-regulating manipulations based on the conventional nursing care , and the pivot-regulating manipulations covered manipulating spleen -stomach meridian , regulating Neibagua, kneading Banmen, kneading abdomen, manipulating acupoints of Zhongwan, Tianshu and Zusanli, and pinching spine according to the deficiency-excess differentiation, once every other day and 3 times constituting one course of treatment. After treatment for 2 courses, the clinical efficacy of the two groups was evaluated. The changes in TCM symptom scores and physical examination indexes of body height, body mass, head circumference, chest circumference, height-for-age (HT/A), weight-for-age (WT/A) in the two groups were observed before and after treatment. Results(1) Five cases(3 differentiated into excess syndrome and 2 into deficiency syndrome) of the trial group dropped out and quitted from the trial, and 6 cases of the control group dropped out and quitted from the trial. (2) After two courses of treatment, the total effective rate of the trial group was 94.55％, and that of the control group was 87.04％, the difference being significant (P < 0.05). (3) After treatment, the scores of appetite and food-intake amount, complexion and lip color, water intake, restlessness, and urination as well as TCM symptom scores in both groups were improved; the WT/A of the trial group was also improved (P < 0.05 compared with those before treatment). The trial group had better effect on improving the scores of appetite and food-intake amount, complexion and lip color, and restlessness as well as TCM symptom scores than the control group (P < 0.05 or P < 0.001). The trial group also showed better effect on improving body mass, body height, head circumference, and HT/A than the control group(P<0.05). Conclusion As a nursing method based on the meridian and acupoint theory as well as syndrome differentiation and treatment, pivot-regulating manipulations are effective for the treatment of infantile anorexia by quickly starting an effect and obviously relieving the symptoms.
