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The high transmission rate of COVID-19 and the number of populations whose commute or recreational activities span across multiple counties/cities on a daily basis warrant serious attention to outbreaks in nearby areas beyond the administrative boundaries of counties/cities. We respond to these challenges by developing models using space-time cluster analysis to identify the hot spots and creating a dashboard that provides interactive visualizations of the results. The models use a Getis-Ord Gi statistic to identify clusters based on county-level daily confirmed cases, and Mann-Kendall tests combined with an adapted rule-based process to classify the type of the clusters. The space-time cluster analysis clearly displays the developing trends in the disease transmission patterns. The dashboard supports state- and county-level queries and expandable information. The dashboard displays the statistically tested spatiotemporal trends of COVID-19 breakout in concise and straightforward graphics. © 2023 Taylor and Francis Group, LLC.
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The CT images of lungs of COVID-19 patients have distinct pathological features, segmenting the lesion area accurately by the method of deep learning, which is of great significance for the diagnosis and treatment of COVID-19 patients. Instance segmentation has higher sensitivity and can output the Bounding Boxes of the lesion region, however, the traditional instance segmentation method is weak in the segmentation of small lesions, and there is still room for improvement in the segmentation accuracy. We propose a instance segmentation network which is called as Semantic R-CNN. Firstly, a semantic segmentation branch is added on the basis of Mask-RCNN, and utilizing the image processing tool Skimage in Python to label the connected domain for the result of semantic segmentation, extracting the rectangular boundaries of connected domain and using them as Proposals, which will replace the Regional Proposal Network in the instance segmentation. Secondly, the Atrous Spatial Pyramid Pooling is introduced into the Feature Pyramid Network, then improving the feature fusion method in FPN. Finally, the cascade method is introduced into the detection branch of the network to optimize the Proposals. Segmentation experiments were carried out on the pathological lesion segmentation data set of CC-CCII, the average accuracy of the semantic segmentation is 40.56mAP, and compared with the Mask-RCNN, it has improved by 9.98mAP. After fusing the results of semantic segmentation and instance segmentation, the Dice coefficient is 80.7%, the sensitivity is 85.8%, and compared with the Inf-Net, it has increased by 1.6% and 8.06% respectively. The proposed network has improved the segmentation accuracy and reduced the false-negatives. © 2022 ACM.
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Introduction: Calciphylaxis, otherwise known as calcium uremic arteriolopathy, is defined as calcium deposition around blood vessels in skin and fat tissue which occurs in 1-4% of patients with end-stage renal disease (ESRD). Calcium deposition in the esophagus is extremely rare;to date, there have been only 4 cases reported worldwide. We report the fifth case of esophageal mucosal calcinosis occurring in a young male with ESRD. Case Description/Methods: A 37-year-old Thai man with ESRD on peritoneal dialysis since 2005 presented with generalized weakness and odynophagia due to oral ulcers, resulting in poor PO intake. He denied drinking alcohol, illicit drug use, or smoking. On exam his abdomen was soft, non-distended, non-tender, without any guarding. Past medical history included hypertension and COVID-19 in January 2022. Laboratory tests revealed neutropenia and pancytopenia, hyperphosphatemia, and hypocalcemia. EGD revealed distal esophageal esophagitis and hemorrhagic erosive gastropathy. Biopsy showed ulcerative esophagitis with dystrophic calcification, consistent with esophageal mucosal calcinosis .No intestinal metaplasia was noted. Immunohistochemistry was negative for CMV, HSV1, and HSV2. The patient was treated with pantoprazole 40mg IV every 12 hours, Magic Mouthwash 5ml qid, and Carafate 10mg qid. He was transferred to a cancer center where he had a bone marrow biopsy formed which was negative. His symptoms resolved and the patient was discharged to home (Figure). Discussion(s): Esophageal mucosal calcinosis is extremely rare. It is due to a combination of factors involving acidosis and the phenotypic differentiation (and apoptosis) of vascular smooth muscle cells (VSMC) into chondrocytes or osteoblast-like cells. These changes, along with the passive accumulation of calcium and phosphate, induce calcification. Acidosis is well-known to promote inflammation of the arterial walls, releasing cytokines that induce vascular calcification. The benefits of treatment with sodium thiosulfate remain unclear. An ample collection of cases should help devise standardized treatment options and establish management guidelines for this condition.
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The concept of single-valued neutrosophic sets (SVNSs) is considered as an attractive tool for dealing with highly ambiguous and uncertain information. The correlation coefficient of SVNSs acts as an important measure in the single-valued neutrosophic set theory and it has been applied in various fields, such as the pattern recognition, medical diagnosis, decision-making and also clustering analysis. To alleviate the weakness of the existing correlation coefficients, a novel statistical correlation coefficient is put forward to measure the degree of correlation between two SVNSs. This statistical correlation coefficient is developed based on the variance and covariance of SVNSs and its value is between −1 and 1. When solving the multicriteria decision making problems, the criteria show different weight values. To consider the weight information of multiple criteria, the weighted statistical correlation coefficient is developed for SVNSs. Afterwards, two numerical examples are given to show the effectiveness of the proposed statistical correlation coefficient in the pattern recognition, which can accurately classify unknown patterns into known patterns. Finally, the feasibility and practicability of the proposed correlation coefficient formula are illustrated by a practical multiple attribute decision making problem of traditional Chinese medicine diagnosis. The comparative results show that the proposed correlation coefficient formula is rational and effective. © 2023 the Author(s), licensee AIMS Press.
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Objective To explore the application of ultrasound-guided arterial line placement in severe patients with COVID-19. Methods From February to April 2020, we retrospectively collected and analyzed the clinical data of critical patients with COVID-19 with an indwelling peripheral arterial catheter treated by the medical team of Peking Union Medical College Hospital. Patients with ultrasound-guided peripheral arterial catheterization were taken as the study group, while patients whose arterial catheter was placed by traditional palpation were taken as the control group. The puncture condition and complication rate were compared between the two groups. Results A total of 60 severe patients with COVID-19 who met the inclusion and exclusion criteria were enrolled in this study. There were 30 cases in the study group and 30 cases in the control group. In the study group, the success rate of the first catheterization of the peripheral artery (63.3% vs. 26.7%) and the total puncture success rate [(79.43+/- 25.79)% vs. (53.07+/-30.21)%] were higher than those in the control group (all P < 0.05), the puncture times(1.43+/-0.56 vs. 2.50+/-1.28) were less than those of the control group (P < 0.05). The rates of 24-hour disuse (6.7% vs. 30.0%), local hematoma (10.0% vs. 36.7%), occlusion, and tortuous (3.3% vs. 40.0%) in the study group were lower than those in the control group (all P < 0.05). Conclusion Under the three-level protection, ultrasound-guided arterial catheter placement for severe patients with COVID-19 can improve the success rate of catheter placement, reduce puncture times, and reduce the incidence of complications.Copyright © 2021, Peking Union Medical College Hospital. All rights reserved.
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Alternative medicine (AM) is one of the medical fields that use more natural and traditional therapies for disease diagnosis and treatment, in which traditional Chinese medicine (TCM) now has been recognized as one of the main approaches of AM. As a clinical and evidencedriven discipline with long histories, AM is also heavily relied on in the utilization of big healthcare and therapeutic data for improving the capability of diagnosis and treatment. In particular, artificial intelligence (AI) has been widely adopted in AM to deliver more practical and feasible intelligent solutions for clinical operations since 1970s. This chapter summarizes the main approaches, related typical applications, and future directions of AI in AM to give related researchers a brief useful reference. We find that although AM has not been widely used in clinical practice internationally, the AI studies showed abundant experiences and technique trials in expert system, machine learning, data mining, knowledge graph, and deep learning. In addition, various types of data, such as bibliographic literatures, electronic medical records, and images were used in the related AI tasks and studies. Furthermore, during this COVID-19 pandemic era, we have witnessed the clinical effectiveness of TCM for COVID-19 treatment, which mostly was detected by real-world data mining applications. This indicates the potential opportunity of the booming of AI research and applications in various aspects (e.g., effective clinical therapy discovery and network pharmacology of AM drugs) in AM fields. © Springer Nature Switzerland AG 2022.
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With the acceleration of globalization, the sustained increase of mobility, the intensification of global warming and environmental changes, the transmission of diseases has become more diverse. In recent years, the corona virus disease 2019(COVID-19) has caused huge economic losses and social unrest around the world. A single-discipline has been unable to solve such complex public health problems effectively. The proposal and development of the One Health approach is closely related to the issues on veterinary medicine and zoonoses. One Health focuses on intradisciplinary, multi-sectoral, and cross-fields collaboration at three levels, including local, regional and global levels, to explore the humans-animals-environment interface complexity. In this review, the development process of One Health approach was introduced. The relationship between the One Health and zoonoses, the role of the One Health in the prevention and control of zoonoses, and how to effectively implement the One Health approach in the real world were explored, providing references for research on zoonoses prevention and control, anti-microbial resistance, food safety, and the impact of climate change on health.Copyright © 2022, National Institute of Parasitic Diseases. All rights reserved.
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Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug in development for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor [competitive and time-dependent inhibition (TDI)] and inducer of CYP3A4, prompting evaluation of the clinical relevance of these results in a Ph 1 drug-drug interaction (DDI) study in healthy participants using midazolam (MDZ), a sensitive CYP3A4 substrate as an index drug. Method(s): Two groups of 12 healthy participants were enrolled and received a single dose of 2mg MDZ alone on Day 1. Between Days 3 and 7 inclusive, all participants received oral BEM 550mg twice daily (BID). On day 3 and day 7, Group A received a single dose of 2mg MDZ simultaneously with BEM;Group B on these two days received 2mg MDZ 2h after BEM. Serial plasma samples were obtained and measured for MDZ and 1-OH-MDZ levels. Result(s): A single dose (simultaneous or staggered) of BEM slightly increased the plasma exposure of MDZ (14%-26%). Staggered BEM had less impact (8%-17%) on 1-OH-MDZ than simultaneous dosing (22%-31%). Inhibitory effect of BEM was more pronounced with repeat dosing, consistent with in vitro data showing TDI on CYP3A4. After repeat dosing, simultaneously administered BEM increased plasma MDZ exposure by 83%-98%, without affecting the exposure of 1-OH-MDZ. With repeat dosing, staggered BEM showed less effect on both MDZ and 1-OH-MDZ. There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): BEM is a weak inhibitor (ratio between 1.25 and 2) of CYP3A4. No dose adjustment is needed for drugs that are substrates of CYP3A4 when co-administered with BEM.
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Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.
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The pandemic of Corona Virus Disease 2019 (COVID-19) worldwide has prompted the use One Health concept to solve health problems and improve the public health governance system. Using the Superiority Weakness Opportunity Threats (SWOT) analysis method to analyze the opportunities and challenges brought by the current development of One Health in China. The results show that the current advantage is that the Chinese government attaches great importance to One Health, and Chinese scholars are also actively involved in the development of One Health, but there are still disadvantages of weak foundation and low international influence. At the same time, with the opportunity for more recognition of the concept of One Health in the world, China is facing challenges such as insufficient talent competitiveness and unbalanced development in the development of One Health. In this regard, this paper puts forward the strategies and key research contents for developing One Health in China to provide ideas for promoting the development of One Health in China.Copyright © 2022, National Institute of Parasitic Diseases. All rights reserved.
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One Health is an upgrade and optimization of health concepts, which recognizes the integrated health of the human-animal-environment. It emphasizes the use of interdisciplinary collaboration, multi-sectoral coordination, and multi-organizational One Health approaches to solve scientific questions. The surveillance and early warning system is the basis of public health emergency prevention and control. The COVID-19 pandemic and the emerging infectious disease (EID) have put great challenges on the existing surveillance and early warning systems worldwide. Guided by the concept of One Health, we attempt to build a new pattern of integrated surveillance and early warning system for EID. We will detail the system including the One Health-based organizational structure, zoonotic and environmental science surveillance network, EID reporting process, and support and guarantee from education and policy. The integrated surveillance and early warning system for EID constructed here has practical and application prospects, and will provide guidance for the prevention and control of COVID-19 and the possible EID in the future.Copyright © 2022, National Institute of Parasitic Diseases. All rights reserved.
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Case Presentation: A 23-year-old previously healthy man presented with progressive dyspnea. Physical examination revealed jugular venous distension and lower extremity edema. Laboratory testing demonstrated elevated B-type natriuretic peptide (193 pg/mL) and normal high sensitivity troponin. Echocardiogram revealed small pericardial effusion, respiratory variation in diastolic flow across the mitral valve, diastolic septal bounce, and annulus reversus (Figure). The differential diagnosis for constrictive pericarditis was broadly considered in the context of a recent febrile illness and frequent travel to Hawaii and Vietnam;we included infectious, autoimmune, and malignant etiologies. Cardiac magnetic resonance imaging revealed thickening and diffuse enhancement in the pericardium as well as ventricular interdependence. Chest CT identified hilar and anterior mediastinal lymphadenopathy. Laboratory testing was positive for QuantiFERON gold and negative for COVID-19, HIV, and ANA. Transbronchial biopsy demonstrated non-necrotizing granulomas with negative acid-fast bacilli smear, culture, and polymerase chain reaction for mycobacterial DNA. Reexamination identified a red-brown plaque on the patient's thigh;biopsy showed granulomatous inflammation and rod-shaped organism with positive FITE staining. A presumed unifying diagnosis was made of extrapulmonary tuberculosis (TB) complicated by constrictive pericarditis. Discussion(s): Despite being a primarily pulmonary disease, systemic involvement can occur with TB with the heart being one of the most common extrapulmonary sites. This case highlights 1) the utility of extra-cardiac diagnostic testing (e.g., dermatologic biopsy) in the diagnosis of constrictive pericarditis, and 2) the diagnostic challenge associated with extrapulmonary TB, particularly paucibacillary disease that requires a detailed social history with "out-of-the-box" thinking.
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The outbreak of the coronavirus disease 2019 (COVID-19) has become the worst public health event in the whole world, threatening the physical and mental health of hundreds of millions of people. However, because of the high survivability of the virus, it is impossible for humans to eliminate viruses completely. For this reason, it is particularly important to strengthen the prevention of the transmission of viruses and monitor the physical status of the crowd. Wireless sensors are a key player in the fight against the current global outbreak of the Covid-19 pandemic, where they are playing an important role in monitoring human health. The Wireless Body Area Network (WBAN) composed of these wireless sensor devices can monitor human health data without interference for a long time, and update the data in almost real time through the Internet of Things (IoT). However, because the data monitored by the devices is relatively large and the transmission distance is long, only transmitting the data to medical centers through the personal devices (PB) cannot get feedback in time. We propose a non-cooperative game-based server placement method, which is named ESP-19 to improve the efficiency of transmission data of wireless sensors. In this paper, experimental tests are conducted based on the distribution of Shanghai Telecom's base stations, and then the performance of ESP-19 is evaluated. The results show that the proposed method in this paper outperforms the comparison method in terms of service delay. © 2022 IEEE.
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We propose multilayer networks in the frequency domain, including the short-term, medium-term, and long-term layers, to investigate the extreme risk connectedness among financial institutions. Using the conditional autoregressive value at risk (CAViaR) tool to measure the extreme risk of financial institutions, we construct extreme risk networks and inter-sector extreme risk networks of 36 Chinese financial institutions through the proposed approach. We observe that the extreme risk connectedness across financial institutions is heterogeneous in the short-, medium-, and long-term. In general, the long-term connectedness among financial institutions rises sharply during times of financial stress, such as the 2015 Chinese stock market turbulence and the 2020 COVID-19 pandemic. Moreover, we note that the insurers are key players in driving the inter-sector extreme risk networks, because the inter-sector systemic importance of insurance institutions is dominant. Finally, our conclusions provide valuable information for regulators to prevent systemic risk. © 2023 Elsevier B.V.
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Background: It has been widely acknowledged that severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infects host cells via the angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) entry mechanism. However, ACE2 and TMPRSS2 cannot explain the Toll-like receptor driven response of monocytes since there is no ACE2 expressed on monocytes, suggesting alternative receptor(s) on these cells. Here, we report cell surface glucose-regulated protein 78 (csGRP78) which is abundantly expressed on monocytes to function as an alternative receptor for SARS-CoV- 2 internalization. Method(s): Blood from COVID-19 patients and healthy donors were collected for csGRP78 and monocyte activation marker as well as cytokine concentration. In vitro SPR, GST pull-down and Co-IP assay were used to determine interaction between SARS-CoV- 2 spike protein and GRP78. Cytokine mixture of IL-1beta, IL-6, TNF and IFN-gamma were used to stimulated csGRP78 upregulation on human monocytic cell line THP-1. GRP78-overexpressing- THP- 1 was also established. pseudo-typed virus expressing spike protein was used to infect mock or GRP78 over-expressing THP-1 cells. Result(s): Our results show that csGRP78 is upregulated on the monocyte of COVID-19 patients. Moreover, in vitro cell culture experiments revealed that stimulation of wtTHP-1 and GRP78 over-expressing THP-1 with the relevant cytokines IL-1beta, IL-6, TNF and IFN-gamma induces similar csGRP78 and activation marker upregulation on cell surface as found on patients' monocytes. In vitro spike protein and GRP78 interaction tests, confirmed direct binding of spike protein and GRP78. Finally, pseudo-typed virus infection assay showed that virus entered GRP78 over-expressing THP-1 cells but not control THP-1 cells. Conclusion(s): Our results demonstrate that csGRP78 acts as a potential functional receptor for SARS-CoV- 2 spike protein and mediates ACE2 independent SARS-CoV- 2 entry into monocytes. These findings provide insight into role of monocytes in the pathophysiology of COVID-19, and suggest a new therapeutic target candidate for anti-SARS- CoV- 2 treatment.
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The analysis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) gene copy numbers in wastewater samples can provide quantitative information on Coronavirus Disease-19 (COVID-19) cases within a sewer catchment. However, many wastewater-based epidemiology (WBE) studies have neglected virus decay during the wastewater transportation process in sewers while back-calculating COVID-19 prevalence. Among various sewer condition parameters, wastewater temperature and dilution by fresh/saltwater infiltration may result in a significant change to the virus decay, in terms of both infectivity and Ribonucleic Acid (RNA). This paper reviewed the literature to identify and discuss the effects of temperature and water types (i.e., wastewater, freshwater, and seawater) on coronavirus decay based on the decay rate constants that were collected from published papers. To evaluate the importance of virus decay, a sensitivity analysis was then conducted with decay rates of SARS-CoV-2 RNA based on a WBE back-calculation equation. Finally, the decay rates of coronavirus in wastewater were also compared with those of other viruses to further understand the difference among virus species. The decay of SARS-CoV-2 RNA was found to be less impacted by temperature variation than viable coronaviruses. Nevertheless, WBE back-calculation was still sensitive to the RNA decay rates increased by warm wastewater (i.e., over 26 °C), which could lead to a two-times higher relative variance in estimated COVID-19 prevalence, considering the wastewater temperature variation between 4 and 37 °C in a sewer catchment with a 12-h hydraulic retention time. Comparatively, the sensitivity of the WBE estimation to the enveloped SARS-CoV-2 was greater than nonenveloped enteric viruses, which were less easily degradable in wastewater. In addition, wastewater dilution by stormwater inflow and accompanied cold weather might alleviate the decay of coronavirus infectivity, thus increasing the potential risk of COVID-19 transmission through wastewater. Overall, this paper aims to better understand the impact of in-sewer processes on coronavirus decay and its potential implications for WBE. The outcome could quantitatively inform WBE and improve awareness of the increased risk of COVID-19 infection via wastewater during heavy rainfall events. Given the identified scarcity of data available for coronavirus decay in salt water or with chemical additions, future research on the fate of SARS-CoV-2 subjected to chemical dosing for sewer or wastewater treatment plant operations is recommended. © 2023 by the authors.
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Background: Anti-tumour necrosis factor drugs such as infliximab are associated with attenuated antibody responses after COVID-19 vaccination It is unknown how infliximab impacts vaccine-induced serological responses against highly transmissible Omicron variants, which possess the ability to evade host immunity and are now the dominating variants causing current waves of infection Methods: In this prospective, multicentre, observational cohort study we investigated neutralising antibody responses against SARS-CoV-2 wild-type and Omicron BA.1 and BA.4/5 variants after three doses of COVID-19 vaccination in 1288 patients with IBD without prior COVID-19 infection, who were established on either infliximab (n=871) or vedolizumab (n=417). Cox proportional hazards models were constructed to investigate the risk of breakthrough infection in relation to neutralising antibody titres Results: Following three doses of COVID-19 vaccine, neutralising titre NT50 (half-inhibitory neutralising titre) was significantly diminished in patients treated with infliximab as compared to patients treated with vedolizumab, against wild-type, BA.1 and BA.4/5 variants (Fig 1). Patients with Crohn's disease showed lower antibody NT50 compared to patients with ulcerative colitis against wild-type strain and BA.4/5 (Fig 2). Older age and thiopurine were independently associated with lower NT50 against wild-type strain and BA.4/5 (Fig 2). Non-white ethnicity was associated with higher NT50 compared to white ethnicity against wild-type strain, BA.1 and BA.4/5 (Fig 2). Breakthrough infection was significantly more frequent in patients treated with infliximab compared to patients treated with vedolizumab (Fig 3). Cox proportional hazards models of time to breakthrough infection after the third dose showed infliximab treatment to be associated with a higher hazard risk (HR) of 1.71 (95% CI [1.08 to 2.71], p=0.022) compared to vedolizumab (Fig 4). Higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and a longer time to breakthrough infection (HR 0.87 [0.79 to 0.95] p=0.0028) (Fig 4) Conclusion(s): Following a third COVID-19 vaccine dose, patients established on infliximab treatment have significantly lower neutralising titres against SARS-CoV-2, which were especially low against Omicron variants. Increased breakthrough infection in infliximab recipients was associated with lower neutralising antibody titres against BA.4/5. These data underline the importance of continued COVID-19 vaccination programs, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy may be reduced.
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Background: Patients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants. Method(s): We prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine and IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARSCoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age. Result(s): Heterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants;GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT and BA.4/5 (P<0.05). Conclusion(s): A third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against the currently dominant variant BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants. .
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The physics output of modern experimental HEP collaborations hinges not only on the quality of its software but also on the ability of the collaborators to make the best possible use of it. With the COVID-19 pandemic making in-person training impossible, the training paradigm at Belle II was shifted from periodic workshops towards guided self-study. To that end, the study material was rebuilt from scratch as a series of modular and hands-on lessons tightly integrated with the software documentation using Sphinx. Each lesson contains multiple exercises that are supplemented with hints and complete solutions. Rather than duplicating information, students are systematically taught to work with the technical reference documentation to find the important sections for themselves. Unit tests ensure that all examples work with different software versions, and feedback buttons make it easy to submit comments for improvements. © Published under licence by IOP Publishing Ltd.
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It has been widely acknowledged that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells via the angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) entry mechanism. However, ACE2 and TMPRSS2 cannot explain the Toll-like receptor driven response of monocytes since there is no ACE2 expressed on monocytes, suggesting alternative receptor(s) on these cells. Here, we report cell surface glucose-regulated protein 78 (csGRP78) which is abundantly expressed on monocytes to function as an alternative receptor for SARS-CoV-2 internalization. Our results show that csGRP78 is upregulated on the monocyte of COVID-19 patients. Moreover, in vitro cell culture experiments revealed that GRP78 over-expressing THP-1 cells and stimulation of wtTHP-1 cells with the relevant cytokines IL-1beta, IL-6, TNF and IFN-gamma induces similar csGRP78 and activation marker upregulation on cell surface as found on patients' monocytes. In vitro spike protein and GRP78 interaction tests (SPR assay, GST-pull down and Co-IP), confirmed direct binding of spike protein and GRP78. Finally, pseudo-typed virus expressing spike protein was used to infect mock or GRP78 over-expressing THP-1 cells. We found that pseudo-typed virus entered GRP78 over-expressing THP-1 cells but not control THP-1 cells. Our results demonstrate that csGRP78 acts as a potential functional receptor for SARS-CoV-2 spike protein and mediates ACE2 independent SARS-CoV-2 entry into monocytes. These findings provide insight into role of monocytes in the pathophysiology of COVID-19, and suggest a new therapeutic target candidate for anti-SARS-CoV2 treatment.