Clinical efficacy of nirmatrelvir and ritonavir combination for treating diabetic patients with COVID-19.

The aim of this study was to investigate the clinical efficacy of a combination of nirmatrelvir and ritonavir (NMV-r) for treating COVID-19 in patients with diabetes mellitus (DM). This retrospective cohort study used the TriNetX research network to identify adult diabetic patients with COVID-19 between January 1, 2020, and December 31, 2022. Propensity score matching was used to match patients who received NMV-r (NMV-r group) with those who did not receive NMV-r (control group). The primary outcome was all-cause hospitalization or death during the 30-day follow-up period. Two cohorts comprising 13 822 patients with balanced baseline characteristics were created using propensity score matching. During the follow-up period, the NMV-r group had a lower risk of all-cause hospitalization or death than the control group (1.4% [n = 193] vs. 3.1% [n = 434]; hazard ratio [HR], 0.497; 95% confidence interval [CI], 0.420-0.589). Compared with the control group, the NMV-r group also had a lower risk of all-cause hospitalization (HR, 0.606; 95% CI, 0.508-0.723) and all-cause mortality (HR, 0.076; 95% CI, 0.033-0.175). This lower risk was consistently observed in almost all subgroup analyses, which examined sex (male: 0.520 [0.401-0.675]; female: 0.586 [0.465-0.739]), age (age 18-64 years: 0.767 [0.601-0.980]; ≥65 years: 0.394 [0.308-0.505]), level of HbA1c (<7.5%: 0.490 [0.401-0.599]; ≥7.5%: 0.655 [0.441-0.972]), unvaccinated (0.466 [0.362-0.599]), type 1 DM (0.453 [0.286-0.718]) and type 2 DM (0.430 [0.361-0.511]). NMV-r can help reduce the risk of all-cause hospitalization or death in nonhospitalized patients with DM and COVID-19.

Comparative analysis of epidemiological trends of COVID-19 in Shanghai and New York City

ObjectiveTo assess the effects of countermeasures against coronavirus disease 2019 (COVID-19) in Shanghai from March to May 2022 in comparison with epidemiological trend of COVID-19 in New York City. MethodsDaily confirmed cases, asymptomatic SARS-CoV-2 carriers, and daily deaths were obtained in the Shanghai Municipal Health Commission and the Center for Disease Control and Prevention (CDC) of the United States. Descriptive study was conducted by using these data. ResultsFrom March 1 to May 17, the number of daily asymptomatic SARS-CoV-2 infections in Shanghai was up to 58 times as large as that of daily confirmed cases;however, the number of daily confirmed cases in Shanghai was generally less than that in New York in the same time period. At the peak of the COVID-19 epidemic, the growth of daily attack rate in Shanghai was significantly lower than that in New York (P < 0.05). Moreover, the number of daily death was evidently less than that in New York. In addition, the vaccination rate in the elderly (aged 60 years) in Shanghai was evidently lower than that in New York (aged 65 years). ConclusionThe COVID-19 epidemics in Shanghai from March to May 2022 and in New York after December 2021 were both caused by the Omicron variant. Compared with the Delta variant, the Omicron variant has stronger replication ability and infectivity, resulting in challenges to the containment of the epidemic in metropolis such as Shanghai and New York City. The epidemic in New York City remained crucial due to absence of effective countermeasures, while that in Shanghai has been effectively contained with strict countermeasures. The prevention and control strategies may be adjusted along with the continual evolution of SARS-CoV-2 and increasing trend of imported COVID-19 cases.

Entangling of Peptide Nanofibers Reduces the Invasiveness of SARS-CoV-2.

The viral spike (S) protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) receptors on the host cells, facilitating its entry and infection. Here, functionalized nanofibers targeting the S protein with peptide sequences of IRQFFKK, WVHFYHK and NSGGSVH, which are screened from a high-throughput one-bead one-compound screening strategy, are designed and prepared. The flexible nanofibers support multiple binding sites and efficiently entangle SARS-CoV-2, forming a nanofibrous network that blocks the interaction between the S protein of SARS-CoV-2 and the ACE2 on host cells, and efficiently reduce the invasiveness of SARS-CoV-2. In summary, nanofibers entangling represents a smart nanomedicine for the prevention of SARS-CoV-2.

Title: Serious COVID-19 may have a causal relationship with myocardial injury: A Mendelian randomization study.

Background: The association of coronavirus disease 2019 (COVID-19) with myocardial injury is not well known. This study explored the association between them using the Mendelian randomization (MR) method. Method: We obtained summary data from genome-wide association studies (GWAS) on myocardial injury and COVID-19 from public databases. Then, as tool variables, we chose single nucleotide polymorphisms associated with susceptibility and COVID-19 severity to investigate the causal relationship of COVID-19 with myocardial injury using inverse-variance weighting (IVW) as the primary approach. Finally, the reliability of the results was evaluated by performing sensitivity analyses. Results: As revealed by the IVW analyses, the seriously hospitalized patients with COVID-19 had causality with myocardial injury, with an ß of 0.14 and 95% confidence interval (CI) of 0.03-0.25 (p = 0.01). The results showed that COVID-19 with severe respiratory symptoms positively affected myocardial injury (ß = 0.11, 95% CI = 0.03-0.19; p = 0.005). Conclusion: According to this study, severe respiratory symptoms and hospitalization due to COVID-19 may increase the risk of myocardial injury.

PF-D-Trimer, a protective SARS-CoV-2 subunit vaccine: immunogenicity and application.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and continues to have a significant impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, which is primarily responsible for the host immune response upon infection. Here we present the preclinical studies of a broadly protective SARS-CoV-2 subunit vaccine developed from our trimer domain platform using the Delta spike protein, from antigen design through purification, vaccine evaluation and manufacturability. The pre-fusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. Immunogenicity studies have shown that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous viral challenge. Neutralizing antibodies induced by this vaccine show cross-reactivity against the ancestral WA1, Delta and several Omicrons, including BA.5.2. The formulated PF-D Trimer is stable for up to six months without refrigeration. The Trimer Domain platform was proven to be a key technology in the rapid production of PF-D-Trimer vaccine and may be crucial to accelerate the development and accessibility of updated versions of SARS-CoV-2 vaccines.

Multiple Perspectives with Online EFL Practicum Technology Learning: Case Study on a Cloud.

This yearlong study describes multiple stakeholders' perspectives of 20 preservice English as Foreign Language (EFL) teachers, 43 elementary school students, 2 online mentors, and a teacher-researcher during a technology professional development practicum on a cloud. The case study provides qualitative and quantitative data from stakeholders concerning technology integration after participating in online project-based EFL instruction. The participating stakeholders encountered affordances and challenges that enhanced their online learning and teaching repertoires and offered nuanced evidence within this online professional development community. The findings call for continuing exploration of online practicums in preservice (language) teacher education and further research documenting complexities of multiple stakeholders' technology professional development.

A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action.

The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors' health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment. Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2-67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3-55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0-37.0), psychiatric symptoms (19.7%, 95% CI 16.1-23.6) mainly depression (18.3%, 95% CI 13.3-23.8) and PTSD (17.9%, 95% CI 11.6-25.3), and neurological symptoms (18.7%, 95% CI 16.2-21.4), such as cognitive deficits (19.7%, 95% CI 8.8-33.4) and memory impairment (17.5%, 95% CI 8.1-29.6). Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery. Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.

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.

Disruption in Blood Pressure Control With the COVID-19 Pandemic: The PCORnet Blood Pressure Control Laboratory.

OBJECTIVE: To explore trends in blood pressure (BP) control before and during the COVID-19 pandemic. PATIENTS AND METHODS: Health systems participating in the National Patient-Centered Clinical Research Network (PCORnet) Blood Pressure Control Laboratory Surveillance System responded to data queries, producing 9 BP control metrics. Averages of the BP control metrics (weighted by numbers of observations in each health system) were calculated and compared between two 1-year measurement periods (January 1, 2019, through December 31, 2019, and January 1, 2020, through December 31, 2020). RESULTS: Among 1,770,547 hypertensive persons in 2019, BP control to <140/<90 mm Hg varied across 24 health systems (range, 46%-74%). Reduced BP control occurred in most health systems with onset of the COVID-19 pandemic; the weighted average BP control was 60.5% in 2019 and 53.3% in 2020. Reductions were also evident for BP control to <130/<80 mm Hg (29.9% in 2019 and 25.4% in 2020) and improvement in BP (reduction of 10 mm Hg in systolic BP or achievement of systolic BP <140 mm Hg; 29.7% in 2019 and 23.8% in 2020). Two BP control process metrics exhibited pandemic-associated disruption: repeat visit in 4 weeks after a visit with uncontrolled hypertension (36.7% in 2019 and 31.7% in 2020) and prescription of fixed-dose combination medications among those with 2 or more drug classes (24.6% in 2019 and 21.5% in 2020). CONCLUSION: BP control decreased substantially during the COVID-19 pandemic, with a corresponding reduction in follow-up health care visits among persons with uncontrolled hypertension. It is unclear whether the observed decline in BP control during the pandemic will contribute to future cardiovascular events.

Protein-ligand binding affinity prediction with edge awareness and supervised attention.

Accurate prediction of protein-ligand binding affinity is crucial in structure-based drug design but remains some challenges even with recent advances in deep learning: (1) Existing methods neglect the edge information in protein and ligand structure data; (2) current attention mechanisms struggle to capture true binding interactions in the small dataset. Herein, we proposed SEGSA_DTA, a SuperEdge Graph convolution-based and Supervised Attention-based Drug-Target Affinity prediction method, where the super edge graph convolution can comprehensively utilize node and edge information and the multi-supervised attention module can efficiently learn the attention distribution consistent with real protein-ligand interactions. Results on the multiple datasets show that SEGSA_DTA outperforms current state-of-the-art methods. We also applied SEGSA_DTA in repurposing FDA-approved drugs to identify potential coronavirus disease 2019 (COVID-19) treatments. Besides, by using SHapley Additive exPlanations (SHAP), we found that SEGSA_DTA is interpretable and further provides a new quantitative analytical solution for structure-based lead optimization.

Serum miR-21 and miR-148b levels in patients with chronic hepatitis B and their predictive value for liver tissue inflammation grading and fibrosis staging

Objective: The aim of this study was to explore the predictive value of serum microRNAs (miR)-21 and miR-148b for liver histopathological inflammation grading and fibrosis staging in patients with chronic hepatitis B (CHB).

Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study.

Background: While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods: A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1-365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings: Advanced age (HR 2.77, 95%CI 2.53-3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03-4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55-5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14-1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37-0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17-1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20-1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45-1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80-13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10-1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32-1.67) and 365 days (RR 1.54, 95%CI 1.21-1.96) compared to COVID-19 patients with no AKI. Interpretation: COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery. Funding: Authors are supported by various funders, with full details stated in the acknowledgement section.

A triple-RBD-based mucosal vaccine provides broad protection against SARS-CoV-2 variants of concern.

The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.

Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.

The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC50) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC50 ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic.

Lethal Swine Acute Diarrhea Syndrome Coronavirus Infection in Suckling Mice.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a recently emerging bat-borne coronavirus responsible for high mortality rates in piglets. In vitro studies have indicated that SADS-CoV has a wide tissue tropism in different hosts, including humans. However, whether this virus potentially threatens other animals remains unclear. Here, we report the experimental infection of wild-type BALB/c and C57BL/6J suckling mice with SADS-CoV. We found that mice less than 7 days old are susceptible to the virus, which caused notable multitissue infections and damage. The mortality rate was the highest in 2-day-old mice and decreased in older mice. Moreover, a preliminary neuroinflammatory response was observed in 7-day-old SADS-CoV-infected mice. Thus, our results indicate that SADS-CoV has potential pathogenicity in young hosts. IMPORTANCE SADS-CoV, which likely has originated from bat coronaviruses, is highly pathogenic to piglets and poses a threat to the swine industry. Little is known about its potential to disseminate to other animals. No efficient treatment is available, and the quarantine strategy is the only preventive measure. In this study, we demonstrated that SADS-CoV can efficiently replicate in suckling mice younger than 7 days. In contrast to infected piglets, in which intestinal tropism is shown, SADS-CoV caused infection and damage in all murine tissues evaluated in this study. In addition, neuroinflammatory responses were detected in some of the infected mice. Our work provides a preliminary cost-effective model for the screening of antiviral drugs against SADS-CoV infection.

The Glycan-Binding Trait of the Sarbecovirus Spike N-Terminal Domain Reveals an Evolutionary Footprint.

The spike protein on sarbecovirus virions contains two external, protruding domains: an N-terminal domain (NTD) with unclear function and a C-terminal domain (CTD) that binds the host receptor, allowing for viral entry and infection. While the CTD is well studied for therapeutic interventions, the role of the NTD is far less well understood for many coronaviruses. Here, we demonstrate that the spike NTD from SARS-CoV-2 and other sarbecoviruses binds to unidentified glycans in vitro similarly to other members of the Coronaviridae family. We also show that these spike NTD (S-NTD) proteins adhere to Calu3 cells, a human lung cell line, although the biological relevance of this is unclear. In contrast to what has been shown for Middle East respiratory syndrome coronavirus (MERS-CoV), which attaches sialic acids during cell entry, sialic acids present on Calu3 cells inhibited sarbecovirus infection. Therefore, while sarbecoviruses can interact with cell surface glycans similarly to other coronaviruses, their reliance on glycans for entry is different from that of other respiratory coronaviruses, suggesting sarbecoviruses and MERS-CoV have adapted to different cell types, tissues, or hosts during their divergent evolution. Our findings provide important clues for further exploring the biological functions of sarbecovirus glycan binding and adds to our growing understanding of the complex forces that shape coronavirus spike evolution. IMPORTANCE Spike N-terminal domains (S-NTD) of sarbecoviruses are highly diverse; however, their function remains largely understudied compared with the receptor-binding domains (RBD). Here, we show that sarbecovirus S-NTD can be phylogenetically clustered into five clades and exhibit various levels of glycan binding in vitro. We also show that, unlike some coronaviruses, including MERS-CoV, sialic acids present on the surface of Calu3, a human lung cell culture, inhibit SARS-CoV-2 and other sarbecoviruses. These results suggest that while glycan binding might be an ancestral trait conserved across different coronavirus families, the functional outcome during infection can vary, reflecting divergent viral evolution. Our results expand our knowledge on the biological functions of the S-NTD across diverse sarbecoviruses and provide insight on the evolutionary history of coronavirus spike.

Connections between Various Disorders: Combination Pattern Mining Using Apriori Algorithm Based on Diagnosis Information from Electronic Medical Records

Objective. Short-term or long-term connections between different diseases have not been fully acknowledged. This study was aimed at exploring the network association pattern between disorders that occurred in the same individual by using the association rule mining technique. Methods. Raw data were extracted from the large-scale electronic medical record database of the affiliated hospital of Xuzhou Medical University. 1551732 pieces of diagnosis information from 144207 patients were collected from 2015 to 2020. Clinic diagnoses were categorized according to “International Classification of Diseases, 10th revision”. The Apriori algorithm was used to explore the association patterns among those diagnoses. Results. 12889 rules were generated after running the algorithm at first. After threshold filtering and manual examination, 110 disease combinations (support≥0.001, confidence≥60%, lift>1) with strong association strength were obtained eventually. Association rules about the circulatory system and metabolic diseases accounted for a significant part of the results. Conclusion. This research elucidated the network associations between disorders from different body systems in the same individual and demonstrated the usefulness of the Apriori algorithm in comorbidity or multimorbidity studies. The mined combinations will be helpful in improving prevention strategies, early identification of high-risk populations, and reducing mortality.

Novel sarbecovirus bispecific neutralizing antibodies with exceptional breadth and potency against currently circulating SARS-CoV-2 variants and sarbecoviruses.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) has aroused concerns over their increased infectivity and transmissibility, as well as decreased sensitivity to SARS-CoV-2-neutralizing antibodies (NAbs) and the current coronavirus disease 2019 (COVID-19) vaccines. Such exigencies call for the development of pan-sarbecovirus vaccines or inhibitors to combat the circulating SARS-CoV-2 NAb-escape variants and other sarbecoviruses. In this study, we isolated a broadly NAb against sarbecoviruses named GW01 from a donor who recovered from COVID-19. Cryo-EM structure and competition assay revealed that GW01 targets a highly conserved epitope in a wide spectrum of different sarbecoviruses. However, we found that GW01, the well-known sarbecovirus NAb S309, and the potent SARS-CoV-2 NAbs CC12.1 and REGN10989 only neutralize about 90% of the 56 tested currently circulating variants of SARS-CoV-2 including Omicron. Therefore, to improve efficacy, we engineered an IgG-like bispecific antibody GW01-REGN10989 (G9) consisting of single-chain antibody fragments (scFv) of GW01 and REGN10989. We found that G9 could neutralize 100% of NAb-escape mutants (23 out of 23), including Omicron variant, with a geometric mean (GM) 50% inhibitory concentration of 8.8 ng/mL. G9 showed prophylactic and therapeutic effects against SARS-CoV-2 infection of both the lung and brain in hACE2-transgenic mice. Site-directed mutagenesis analyses revealed that GW01 and REGN10989 bind to the receptor-binding domain in different epitopes and from different directions. Since G9 targets the epitopes for both GW01 and REGN10989, it was effective against variants with resistance to GW01 or REGN10989 alone and other NAb-escape variants. Therefore, this novel bispecific antibody, G9, is a strong candidate for the treatment and prevention of infection by SARS-CoV-2, NAb-escape variants, and other sarbecoviruses that may cause future emerging or re-emerging coronavirus diseases.