Uniform consistency for local fitting of time series non-parametric regression allowing for discrete-valued response

Local linear kernel fitting is a popular nonparametric technique for modelling nonlinear time series data. Investigations into it, although extensively made for continuousvalued case, are still rare for the time series that are discrete-valued. In this paper, we propose and develop the uniform consistency of local linear maximum likelihood (LLML) fitting for time series regression allowing response to be discrete-valued under β-mixing dependence condition. Specifically, the uniform consistency of LLML estimators is established under time series conditional exponential family distributions with aid of a beta-mixing empirical process through local estimating equations. The rate of convergence is also provided under mild conditions. Performances of the proposed method are demonstrated by a Monte-Carlo simulation study and an application to COVID-19 data. There is a huge potential for the developed theory contributing to further development of discrete-valued response semiparametric time series models © 2022 American Psychological Association

Pyroptosis in the lung and spleen of patients died from COVID-19

The purpose of this study was to investigate the expression of pyroptosis-related factors (NLRP3, IL-18, NF-kappa B, HMGB-1, and GSDMD) in patients who died of COVID-19. The expression levels of NLRP3, IL-18, NF-kappa B, HMGB-1, and GSDMD in lung and spleen tissues of the COVID-19 group and the control group were detected by tissue immunofluorescence. The control group includes lung tissues and spleen tissues of two patients who died unexpectedly without SARS-CoV-2 infection, and the COVID-19 group includes the lung and spleen tissues of three patients who died of SARS-CoV-2 virus infection. The positive rates of NF-kappa B, NLRP3, IL-18, and GSDMD in the lung tissues from the control group and COVID-19 group were 9.8% vs 73.4% (p = 0.000), 5.5% vs 63.6% (p = 0.000), 24.4% vs 76.2% (p = 0.000), and 17.5% and 46.8% (p = 0.000) respectively. The positive rates of NF-kappa B, NLRP3, IL-18, HMGB-1, and GSDMD in the spleen tissues from the control group and COVID-19 group were 20.6% vs 71.2% (p = 0.000), 18.9% vs 72.0% (p = 0.000), 15.2% vs 64.8% (p = 0.000), 27.6% vs 69.2% (p = 0.000), and 23% and 48.8% (p = 0.000), respectively. The positive rates of SARS-CoV-2 spike protein in the CD68 positive cells of the lung and spleen in the control group and COVID-19 group were 2.5% vs 56.8% (p = 0.000);3.0% vs 64.9% (p = 0.000) respectively. The rates of NF-kappa B positive nuclei in the control group and COVID-19 group were 13.4% vs 51.4% (p = 0.000) in the lung and 38.2% vs 59.3% (p = 0.000) in the spleen. The rates of HMGB-1 positive cytoplasm in the control and the COVID-19 group were 19.7% vs 50.3% (p = 0.000) in the lung and 12.3% vs 45.2% (p = 0.000) in the spleen. The targets of SARS-CoV-2 are the lung and spleen, where increased macrophages could be involved in the up-regulation of pyroptosis-related inflammatory factors such as NF-kappa B, HMGB-1, NLRP3, IL-18, and GSDMD.

The form of global aviation market space in the context of the epidemic

There are many mismatches between international aviation circuit breakers/ maintenance and the stringency index and severity of the outbreak in the origin or destination country in the context of COVID-19. Under the background of the global outbreak of COVID19, in addition to the reasons for the stage of epidemic transmission, prevention-control environment and testing/treatment methods, the underlying impact on the global aviation market its own cannot be ignored. Based on market space theory and market network relationship analysis methods, as well as the international routes, flight volume/frequency/seat capacity and airport operation data of the six major global airline markets for four representative periods from 2019 to 2020, this paper intends to analyze the form of the global aviation market space under the background of the epidemic. The conclusions are as follows. In the process of shrinking the global route network, the original major aviation connections from Western Europe to North America and those from China, Japan to South Korea and the United States have not changed. The developed economies/emerging economies have shown the existence of spatial aggregation. South America has maintained a clear-pointed route to North America and at the same time, a large number of routes to Europe have been cut off. Oceania has increased the use of hub airports in Southeast Asia to maintain routes to Europe and the United States. Market-dependent countries have shown the existence of spatial duality. Aggregate and dual markets highlight the dominant role of the economic landscape. The relatively independent existence of space is strongly influenced by the "regional model", and the aviation market shaping inside and outside the regional alliance is completely different with the European Union, the African Union, and the ASEAN as typical cases. Culturally neighboring countries show the existence of compact connected communities. There are clear manifestations between China-Japan-South Korea, ASEAN to China-Japan-South Korea and Northeast Africa to Arab countries, which are supported by the potential support of cultural and local sensitivity to maintain a high frequency of flights. The above changes in aviation connectivity demonstrate the persistence of inherent aviation value chains and their reinforcing effect on the forms of existence of global aviation market space. It is necessary to explore the economicgeographical implications of the forms of existence of the global aviation market space in depth under the background of the COVID-19 epidemic reinterpret the assertions related to the market space existence forms dominated by globalization in recent years. © 2023, Science Press. All rights reserved.

A class of anomalous diffusion epidemic models based on CTRW and distributed delay

In recent years, the epidemic model with anomalous diffusion has gained popularity in the literature. However, when introducing anomalous diffusion into epidemic models, they frequently lack physical explanation, in contrast to the traditional reaction-diffusion epidemic models. The point of this paper is to guarantee that anomalous diffusion systems on infectious disease spreading remain physically reasonable. Specifically, based on the continuous-time random walk (CTRW), starting from two stochastic processes of the waiting time and the step length, time-fractional space-fractional diffusion, time-fractional reaction-diffusion and fractional-order diffusion can all be naturally introduced into the SIR (S: susceptible, I: infectious and R: recovered) epidemic models, respectively. The three models mentioned above can also be applied to create SIR epidemic models with generalized distributed time delays. Distributed time delay systems can also be reduced to existing models, such as the standard SIR model, the fractional infectivity model and others, within the proper bounds. Meanwhile, as an application of the above stochastic modeling method, the physical meaning of anomalous diffusion is also considered by taking the SEIR (E: exposed) epidemic model as an example. Similar methods can be used to build other types of epidemic models, including SIVRS (V: vaccine), SIQRS (Q: quarantined) and others. Finally, this paper describes the transmission of infectious disease in space using the real data of COVID-19. © 2023 World Scientific Publishing Company.

Characteristics of Inpatient Deaths During the COVID-19 Pandemic at a Comprehensive Cancer Center (Sci214)

Outcomes: 1. Apply the knowledge about how the COVID-19 pandemic has impacted the care of patients with serious illness into daily practice. 2. Summarize current research findings in hospice and palliative care and describe its relevance to the care and treatment of patients with serious illness. Context: The urgency of the COVID-19 pandemic has brought forth an increased focus on palliative care involvement and advance care planning discussions around end-of-life preferences;however, few outcomes have been reported to date. The objective of this study was to compare characteristics of patients with advanced cancer during their terminal admission at a tertiary care comprehensive cancer center before and after the onset of the COVID-19 pandemic. Method(s): A random sample of 250 inpatient deaths from April 1, 2019 to July 31, 2019 was compared to a random sample of 250 inpatient deaths from April 1, 2020 to July 31. Sociodemographic and clinical characteristics, timing of palliative care referral, timing of DNR order, location of death, and pre-admission Out-of-Hospital DNR documentation were included. Result(s): Timing of DNR orders occurred earlier (2.9 days vs. 1.7 days prior to death, p=0.024), while the frequency of DNR orders before death did not change (94% vs. 90%, p=0.25). Palliative care referrals increased (68% vs. 60%, p=0.062) and occurred earlier (3.5 days vs. 2.5 days prior to death, p=0.037). Overall length of stay increased (9.4 days vs. 7 days, p=0.048). 36% of inpatient deaths occurred in ICU and 36% in the PCU, compared to 48% and 29% prior to the COVID-19 pandemic, respectively (p=0.01). Conclusion(s): DNR orders occurred significantly earlier after the onset of the COVID-19 pandemic, indicating a shift in early and intentional conversations with patients with advanced cancer at the time of their terminal admission. Earlier palliative care referrals and significantly fewer ICU deaths also suggest an improvement in quality end-of-life care. These findings highlight encouraging changes that have occurred as a response to the COVID-19 pandemic and may have future implications for timely integration of palliative care. Further research is needed to understand how to maintain and expand on such progress.Copyright © 2023

A COVID-19 detection method based on self-supervised learning and transfer learning

Since the global outbreak of COVID-19, the epidemic has had a great impact on people's lives and the world economy. Diagnosis of COVID-19 using deep learning has become increasingly important due to the inefficiency of traditional RT-PCR test. However, training deep neural networks requires a large amount of manually labeled data, and collecting a large number of COVID-19 CT images is difficult. To address this issue, we explore the effect of Pretext-Invariant Representation Learning (PIRL) using unlabeled datasets to pre-train the network on classification results. In addition, we also explore the prediction effect of PIRL combined with transfer learning (TF). According to the experimental results, applying the TF-PIRL prediction model constructed in this paper to COVID-19 diagnosis, the accuracy and AUC are 0.7734 and 0.8556 respectively, which outperform the network training from scratch, transfer learning-based network training and PIRL-based network training. © 2022 IEEE.

Deconstruction of COVID-19 transmission network and its epidemic analysis in a suburban village of Shijiazhuang in China

In January 2021, the COVID-19 outbreak in Xiaoguozhuang Village of Shijiazhuang, the first COVID-19 public health emergency in the rural areas of China. Based on the individual trajectory data in 14 days of 941 confirmed cases, taking the transmission network structural analysis and the epidemic transmission dynamics analysis as the methods, the COVID-19 transmission network from the three aspects is deconstructed: epidemic points formation, types of outputs, and regional expansion evolution. Compared with the COVID-19 transmission network of Beijing Xinfadi Market and Dalian Kaiyang Seafood Company, the conclusions are as follows: (1) The numbers of epidemic points and types are large. In the approximate exposure time, new epidemic points will be formed simultaneously with the central city under the background of rapid urbanization. Still, high community activity leads to the formation of co-exposure to epidemic points;short distance "pendulum moves" leading to more extensive individual trajectory density, and finally resulting in the risk of temporary exposure of epidemic points. (2) It has the significant individual-individual contact infection characteristic and output chain relationship characteristic. The secondary outputs of the rural areas are due to the multigenerational family transmission, which is not seen in the urban cities. (3) Compared with the regional expansion of urban cities, the rural areas are manifested by a longer transmission period, caused by the long occult time of outbreaks and the relatively high relative risk of symptomatic confirmed cases in the rural areas. Finally, three suggestions are put forward, enlarging the management space from the terminal areas to adjacent areas around airports, and then implementing delay management on the overflow personnel based on time shift due to carrying the virus from potential epidemic points and buffering isolation area according to the range of risk changes. The deconstruction network of public health emergencies is a beneficial exploration and will provide a basis for improving the resilience of public health networks in rural areas. © 2022, Science Press. All rights reserved.

Lipolysis is accompanied by immune microenvironment remodeling in adipose tissue of obesity with different exercise intensity.

OBJECTIVE: Obesity and overweight are risk factors for chronic disease worldwide. The purpose of this study was to compare the transcriptome of exercise-induced fat mobilization in obese people, and to explore the effect of different exercise intensity on the correlation of immune microenvironment remodeling and lipolysis in adipose tissue. MATERIALS AND METHODS: Microarray datasets of adipose tissue before and after exercise were downloaded from the Gene Expression Omnibus. Then, we used gene-enrichment analysis and PPI-network construction to elucidate the function and enrichment pathways of the differentially expressed genes (DEGs) and to identify the central genes. A network of protein-protein interactions was obtained using STRING and visualized with Cytoscape. RESULTS: A total of 929 DEGs were identified between 40 pre-exercise (BX) samples and 65 post-exercise (AX) samples from GSE58559, GSE116801, and GSE43471. Among these DEGs, adipose tissue-expressed genes were duly recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that DEGs were mostly enriched in lipid metabolism. Studies have found that mitogen-activated protein kinase (MAPK) signaling pathway and forkhead box O (FOXO) signaling pathway are up-regulated, while Ribosome, coronavirus disease (COVID-19) and IGF-1 gene are down-regulated. Although we found the up-regulated genes that noted IL-1 among others, and the down-regulated gene was IL-34. The increase of inflammatory factors leads to changes in cellular immune microenvironment, and high-intensity exercise leads to increased expression of inflammatory factors in adipose tissue, leading to inflammatory responses. CONCLUSIONS: Exercise at different intensities leads to the degradation of adipose and is accompanied by changes in the immune microenvironment within adipose tissue. High intensity exercise can cause the imbalance of immune microenvironment of adipose tissue while causing fat degradation. Therefore, moderate intensity and below exercise is the best way for the general population to reduce fat and weight.

A class of anomalous diffusion epidemic models based on CTRW and distributed delay

In recent years, the epidemic model with anomalous diffusion has gained popularity in the literature. However, when introducing anomalous diffusion into epidemic models, they frequently lack physical explanation, in contrast to the traditional reaction-diffusion epidemic models. The point of this paper is to guarantee that anomalous diffusion systems on infectious disease spreading remain physically reasonable. Specifically, based on the continuous-time random walk (CTRW), starting from two stochastic processes of the waiting time and the step length, time-fractional space-fractional diffusion, time-fractional reaction-diffusion and fractional-order diffusion can all be naturally introduced into the SIR (S: susceptible, I: infectious and R: recovered) epidemic models, respectively. The three models mentioned above can also be applied to create SIR epidemic models with generalized distributed time delays. Distributed time delay systems can also be reduced to existing models, such as the standard SIR model, the fractional infectivity model and others, within the proper bounds. Meanwhile, as an application of the above stochastic modeling method, the physical meaning of anomalous diffusion is also considered by taking the SEIR (E: exposed) epidemic model as an example. Similar methods can be used to build other types of epidemic models, including SIVRS (V: vaccine), SIQRS (Q: quarantined) and others. Finally, this paper describes the transmission of infectious disease in space using the real data of COVID-19.

REGIONAL VARIATION IN COVID-19 MITIGATION PRACTICES AMONG HOME- AND COMMUNITY-BASED LONG-TERM CARE PROVIDERS

Residential care communities (RCC) and adult day services centers (ADSC) were greatly impacted by COVID-19. As state-regulated home- and community-based care settings (HCBSs), they experienced changing regulations, outbreaks among care recipients and staff, and new challenges to safely provide services. Using a nationally representative sample of over 11,600 RCCs and census of nearly 5,500 ADSCs from the 2020 National Post-acute and Long-term Care Study, this study examined the prevalence and regional variation (p<.05) of practices to mitigate COVID-19. Preliminary data show that most RCCs (87%) and ADSCs (72%) screened for symptoms. Most RCCs limited communal activities (83%) and ADSCs reduced hours or temporarily closed (73%). More RCCs used video telemedicine than audio-only (40% vs 34%) to assess, diagnose, or treat users. However, more ADSCs used audio-only than video telemedicine (25% vs 17%). Over 80% of all providers always or sometimes imposed in-person restrictions on family, visitors, volunteers, and non-essential services providers. More ADSCs in the Midwest (82%) and South (80%) screened symptoms than Northeast (68%) and more ADSCs in the Midwest (85%) limited hours/temporarily closed than Northeast (72%). More RCCs in the Midwest (43%) and South (41%) used video telemedicine than Northeast (36%);however, a lower percentage of ADSCs in the Midwest (9%) and South (12%) used video telemedicine than Northeast (25%). Results show a variety of experiences in the first year of the COVID-19 pandemic among these two HCBSs. Practices to mitigate COVID-19 while continuing to provide needed services were common, with some differences across settings and US regions.

Smoking products suppress type I IFN during SARS-CoV-2 infection

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which can lead to the development severe pneumonia. While some hospital data shows a positive correlation between smoking and severe pneumonia, more molecular-level mechanisms need to be determined. The previous study investigates the mechanism of the negative effect of smoking on anti-viral infection on Type I interferons (IFNs). Research has shown that Type I IFNs play an important role in defending against SARS-Cov-2. Here, we want to investigate smoking components' effects on SARS-CoV-2 at the molecular level in vitro and give some ideas on the correlation between smoking and syndrome. © The Authors, published by EDP Sciences.

Immune inhibitory receptor LILRB2 enhances SARS-CoV-2 spike protein-mediated immune inflammation

Objective·To explore the possible roles of immune inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) in the immune inflammation after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and provide a potential therapeutic way for the coronavirus disease 2019 (COVID-19). Methods·The supernatants containing the extracellular domain of spike protein (S-ECD) were collected, and the detection of the protein expression and activity in the conditional medium by Western blotting and flow cytometric analysis was followed by. The binding of S-ECD with LILRB2 was measured by co-immunoprecipitation and flow cytometric analysis. The mRNA expression levels of several inflammation genes in a human mononuclear cell line (THP1) or peripheral blood mononuclear cells (PBMC) were measured after spike protein stimulation for 24 h by quantitative RT-PCR. The protein levels of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the conditional medium were examined by enzyme-linked immunosorbent assay (ELISA). The siLILRB2 was transferred into CD33+ myeloid cells purified from human peripheral blood with Lipofectamine 3000 reagents. The knockdown efficiency was detected 24 h after transfection by flow cytometric analysis. The difference in the protein levels of IL-6 between the control cells and LILRB2-knocked-down cells after spike protein treatment was evaluated by ELISA. Results·The study established a transfection system with 293T cells by which the SARSCoV-2 S-ECD could be secreted to supernatants with normal biological activities. The interaction and the binding of spike protein with LILRB2 were evaluated by a co-immunoprecipitation assay and flow cytometric analysis, respectively. The mRNA expression levels of IL-6, IL-8, arginase 1 and IL-2 in THP1 cells were significantly up-regulated 24 h after spike protein treatment compared to the control cells (all P<0.05). Consistently, the mRNA levels of IL-6, transforming growth factor-β (TGF-β), IL-8, IL-10 and IL-β in PBMC were notably increased after spike protein stimulation (all P<0.05). In addition, spike protein could also induce the release of IL-6 and IL-1β in PBMC as measured by ELISA (all P<0.05). More importantly, spike protein was able to increase the secretion of IL-1β and IL-6 by CD33+ myeloid cells 24 h after treatment (both P<0.05). LILRB2-overexpressing THP1 cells produced more IL-6 24 h after treatment with spike protein than the control cells (P<0.05). Two siRNAs could efficiently down-regulate the expression of LILRB2 in CD33+ cells as evaluated by flow cytometric analysis. Consistently, spike protein had no effect on the IL-6 secretion to supernatant from LILRB2-knockdown CD33+ myeloid cells. Conclusion·SARS-CoV-2 can induce cytokine release syndrome by inflammatory factors, such as IL-6 and IL-1β, released by myeloid cells through spike protein binding to LILRB2. © 2022 Editorial Department of Journal of Shanghai Second Medical University. All rights reserved.

A Topological Data Analysis Approach to the COVID-19

Topological data analysis (TDA) has emerged as a method for understanding data clouds by extracting and comparing the structure of datasets. This paper applies one of the TDA instruments available which is called the Mapper algorithm to analyze the COVID-19 data in China. The Mapper graphs generated by the algorithm successfully reflect the development of COVID-19 across China and provide a relatively complete visualization of the pandemic. Experimental results indicate that the proposed method may have the potential to become a robust predictive tool for the spread of the coronavirus. © 2022 IEEE.

CHARACTERISTICS OF INPATIENT DEATH DURING THE COVID-19 PANDEMIC AT A COMPREHENSIVE CANCER CENTER

Introduction The urgency of the COVID-19 pandemic brought forth an increased emphasis on palliative care referrals and advance care planning discussions;however, few outcomes have been reported to date. The primary objective of this study was to compare the timing of DNR order for patients with advanced cancer during their terminal admission before and after the onset of the COVID-19 pandemic. Methods A random sample of 250 inpatient deaths from April 1, 2019 to July 31, 2019 was compared to another 250 inpatient deaths from April 1, 2020 to July 31, 2020. Clinical characteristics, timing and frequency of DNR orders, palliative care referral patterns, and location of death were included. Results Timing of DNR orders occurred earlier (2.9 days vs. 1.7 days prior to death, p=0.024), while the frequency of DNR orders before death did not change (94% vs 90%, p=0.25). Palliative care referrals increased (68% vs. 60%, p=0.062) and occurred earlier (3.5 days vs. 2.5 days prior to death, p=0.037). Overall length of stay increased (9.4 days vs. 7 days, p=0.048). Significantly fewer deaths occurred in the ICU (36% vs. 48%) and more deaths occurred in the Palliative Care Unit (36% vs. 29%). Conclusions During the COVID-19 pandemic, we observed a trend of earlier DNR orders, increased timely palliative care referrals, and fewer ICU deaths, indicating an improvement in quality end-of-life care. These findings may have implications for integration of palliative care. More research is needed to expand on such progress.

Classical Antigen Presenting Cell Activation Correlates with T Cell Immunity and COVID-19 Severity

Background. The initial response of immune cells against respiratory viruses often determines the severity and duration of disease. The early trajectory of the immune response during infection with SARS-CoV-2 remains poorly understood. Dysregulation of innate immune factors that facilitate viral clearance and the adaptive response, such as type I interferons, have been implicated in severe COVID-19. However, collection of biological samples during the first seven days post-symptom onset has posed a logistical challenge, limiting our knowledge surrounding the immune responses that drive protection versus immunopathology. Methods. From March 2020, Military Health System beneficiaries presenting with a positive SARS-CoV-2 test, a COVID-19 like illness, or a high-risk SARS-CoV-2 exposure at nine military medical treatment facilities across the United States were eligible for enrollment in our longitudinal cohort study, which included collection of respiratory sample, sera, plasma, and peripheral blood mononuclear cells (PBMCs). Twenty-five SARS-CoV-2 infected study participants provided samples with in the first seven days of symptom onset, fifteen of whom were hospitalized with COVID-19. We employed multiparameter spectral flow cytometry to comprehensively analyze the early trajectory of the innate and adaptive immune responses. Results. We discovered that early activation of critical antigen presenting cell subsets was impaired upon comparing inpatients with outpatients, correlating with decreased antigen-experienced T cell responses. Specifically, we noted reduced expression of key costimulatory molecules, CD80 and CD86, on conventional dendritic cells that are required for viral antigen-specific T cell priming. Reduction in CD38, a marker of activation was also observed on inpatient dendritic cell subsets. Conclusion. Reduced antigen presenting cell activation and expression of ligands that facilitate T cell engagement may impede the efficient clearance of SARS-CoV-2, coinciding with more severe disease in our cohort. Further analysis of the functional activation of early innate immune responses triggered by SARS-CoV-2 may unveil new immune biomarkers and therapeutic targets to predict and prevent severe disease associated with inadequate T cell immunity.

Association between Insufficient Interleukin-6 (IL-6) Inhibition and Worsening Outcomes in COVID-19 and Idiopathic Multicentric Castleman Disease (iMCD), and a Mathematical Model to Predict Optimal Dosing to Completely Block IL-6 Activity

Dysregulated inflammatory responses are characterized by inappropriate levels of inflammatory markers, speed of generation, degree, and major site of production, such as a vital organ. COVID-19 severity and mortality are strongly associated with interleukin (IL)-6 levels. High IL-6 levels are also observed in idiopathic Multicentric Castleman Disease (iMCD). Previously, we developed the first anti-IL-6 monoclonal antibody (mAb) treatments and showed that C-reactive protein (CRP) production could be fully controlled by IL-6 in humans. Using mathematical modeling, with CRP as an IL-6 surrogate marker, we predicted the ability of an anti-IL-6 mAb to block plasma IL-6 activity and showed IL-6 inhibition was dependent on the extent of whole-body IL-6 production. We postulate that in patients (pts) in whom IL-6 concentration at the site of inflammation is higher than in the plasma, full blockade of plasma IL-6 activity, shown by complete CRP inhibition, is the minimum requirement to achieve clinical efficacy. CRP inhibition with tocilizumab (TCZ) in pts with COVID-19. We identified 35 published studies evaluating the efficacy or potential role of anti-IL-6 therapy in pts with severe COVID-19. Surprisingly, only one (Luo et al. J Med Virol 2020;92:814) reported dynamics of CRP reduction for individual patients throughout treatment. We fitted a hypothetical curve of CRP reduction required to completely block IL-6, based on the half-life of CRP, and added data points of CRP serum levels from pts treated with anti-IL-6 receptor (IL-6R) therapy, TCZ, in this study. Complete reduction of CRP was not achieved in all patients: 3 pts who died had CRP levels ≥12.8 mg/l. Of 2 pts whose disease worsened, CRP levels were 93.5 mg/l and 6.3 mg/l. However, pts whose condition stabilized (n=9), or whose symptoms improved (n=1), had CRP levels close to the theoretical curve that is likely required to fully block IL-6 (CRP levels ≤5.0 mg/l). Half of these pts had been given repeated doses of TCZ. Siltuximab (SIL) treatment (NCT01024036 trial) for pts with iMCD. To assess the impact of baseline CRP levels on response to anti-IL-6 therapy, SIL, patients were divided into low and high CRP groups based on a baseline CRP level threshold of 40 mg/l (corresponding to ~40 pg/ml of IL-6;Fig 1). In patients with low baseline CRP levels (<40 mg/l;n=35), CRP levels were significantly reduced with SIL treatment on day 8 (n=26;P=0.0003) and day 15 (n=22;P=0.0043) post-dosing. In patients with high baseline CRP levels (>40 mg/l;n=17), CRP levels were significantly reduced on day 8 (n=17;P<0.0001) and day 15 (n=15;P<0.0001) post-dosing (Fig 1). A significant increase in CRP levels from day 8 to day 15 was observed in these patients (P=0.0120);this increase was not observed in patients with low baseline CRP levels (P=0.243;Fig 1). There was a negative correlation between maximum CRP and hemoglobin change (P<0.001). Inhibition of IL-6 activity by anti-IL-6 (SIL 700 mg) and anti-IL-6R (TCZ 800 mg) as monotherapy, intensified, or combined therapy. To evaluate the effect of therapy on IL-6 activity, our algorithm modeled inhibition of IL-6-(IL-6R/soluble IL-6R)-gp130 transducer complexes. This serves as a proxy for IL-6 bioactivity and accounts for the buffering capacity of gp130, which can be overwhelmed in inflammatory situations with high IL-6 concentrations. Due to uncertainty over the concentration of mAbs in alveoli relative to plasma, we modeled the effects of SIL and TCZ at local concentrations of 100%, 10%, and 1% (Fig 2) of those in plasma. Our model demonstrated that anti-IL-6 was associated with stronger inhibition of CRP than anti-IL-6R. However, only the association of both anti-IL-6 and anti-IL-6R mAbs was associated with a total blockade of CRP, which is probably necessary when IL-6 levels are associated with high risk to the patient. Different administration schedules to intensify anti-IL-6 therapy were modeled, including the repeated or combined use of anti-IL-6 and anti-IL-6R mAbs. The results form a basis to optimize treatment trategies to avoid the cytokine storm in several diseases, including cancer, iMCD, and autoimmune disorders. The feasibility of the theoretically defined approaches needs to be evaluated, particularly the potential side-effect profile for a combined treatment approach. In conclusion, in clinical practice, IL-6 inhibition should be individualized based on pathophysiology and regular CRP monitoring. [Formula presented] Disclosures: Rossi: E-SANA Inc: Other: Co-founder of E-SANA Inc;EUSA Pharma: Consultancy;LEO Pharma: Consultancy;NPO Petrovax Pharm: Consultancy. Levon: E-SANA Inc: Other: Co-founder of E-SANA Inc. Kanhai: EUSA Pharma: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;Pfizer: Other: Study drug for clinical trial of sirolimus. OffLabel Disclosure: Siltuximab is approved for the treatment of iMCD. Tocilizumab is approved for the treatment of Rheumatoid arthritis, Giant cell arteritis, Cytokine release syndrome, Systemic juvenile idiopathic arthritis and Polyarticular juvenile idiopathic arthritis. Combination therapy using Siltuximab and Tocilizumab has not yet been approved.

Integrative analyses identify genes and their functional consequences underlying COVID-19 hospitalization

Recent emergence of SARS-Cov-2 has resulted in unprecedented spread of COVID-19 exhibiting wide variability in individuals’ symptoms. Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of the role of host genetic variation and the molecular mechanisms including the knowledge of genes and pathways that contribute to COVID-19. Previous research to understand the mechanisms underlying severe COVID-19 outcomes have focused on lung- and brain-related pathologies. Here, we integrated a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identified 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. These genes converge on cytokine-cytokine and the JAK-STAT signaling pathways. We functionally characterized the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (BioVU;n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicated these findings in the African-American cohort here in BioVU and found concordant results. This study highlights putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

POSB242 Telemedicine Use During Year 2020 of the COVID-19 Pandemic in Older US Medicare Beneficiaries

Objectives: This study aimed to assess telemedicine utilization patterns offered by health providers and used by older Medicare beneficiaries during the coronavirus pandemic. Methods: The Medicare Current Beneficiary Survey (MCBS) supplemental COVID-19 survey -for Fall 2020 was used to identify Medicare beneficiaries (≥ 65 years) with a regular place for medical care and offered telemedicine during the pandemic. Major outcomes: prevalence for whether telemedicine was offered before and during the pandemic, telemedicine use, and digital access to telemedicine. Demographic factors associated with telemedicine use were identified using logistic regression. Results: The study sample included 4380 eligible older individuals (weighted sample: approximates 26.8 million US Medicare beneficiaries (≥ 65 years). Of those 42.9% made telemedicine visits during the pandemic. Approximately 60% of the telemedicine visits were made via telephone call only. Telemedicine was offered to 18% of Medicare beneficiaries before the pandemic vs. 64% during year 2020 of the pandemic. Both voice and video calls were offered to 45% of the respondents before the pandemic vs. 60.2% during the pandemic. Among telemedicine users, 57.2%, 28.3%, and 14.5% used voice calls, video calls, and both voice and video calls for appointments, respectively. Variations in overall telemedicine use were observed by sex, race, region. Beneficiaries with chronic condition numbering 2 to 3 or ≥ 4 were 38% or 119% more likely to use telemedicine. Individuals 65-74 years, female, in a metropolitan area, with higher income were more likely to make video visits. Experience of telecommunication via internet influenced telemedicine use significantly. Conclusions: Telemedicine offered to older Medicare beneficiaries increased dramatically during the coronavirus pandemic. Less than half of the beneficiaries made telemedicine visits. Demographic disparities were different in overall telemedicine use and type of telemedicine use.

Vascular thrombosis and vasculitis in the gastrointestinal tract are associated with poor prognosis in patients with COVID-19

Aim: To report pathologic findings in the gastrointestinal (GI) tract of coronavirus disease 2019 (COVID-19) patients. Material and Methods: we evaluated clinical and GI tract histologic findings in six COVID-19 patients that presented with GI symptoms like diarrhea, and abdominal pain. This study includes surgical resection specimens from five patients and two sets of biopsy specimens from one patient. Results: Idiopathic inflammatory bowel disease was considered in three of six cases based on clinical, radiologic, and endoscopic presentation. Histologically, the enteric mucosa had a spectrum of histologic changes, including active enteritis, chronic active enteritis, and transmural necrosis. Extensive thrombi in vessels and/or vasculitis were identified in three out of the six cases. The presence of extensive vascular thrombi is associated with poor prognosis, and the three patients deceased in a short period of time (ranges from 7-67 days, median 14 days) after admission for GI symptoms. Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) RNA was detected in bowel tissue of one case. The other three patients recovered and were discharged and free of GI symptoms (follow-up period ranges from 235 days to 270 days, median 237 days). Conclusion: COVID-19 associated enteritis may mimic Crohn's disease clinically, radiologically and endoscopically, and these two entities can be differentiated by pathologic findings. COVID-19 patients with GI symptoms may warrant a workup to evaluate for pathologic changes, as the presence of vasculitis and microthrombi may predict poor clinical outcome.

Impact of sample pooling strategy on 2019-nCoV RNA detection results

Objective: To evaluate the impact of sample pooling strategy on 2019-nCoV RNA detection results. Methods: Ten negative swabs were stored in 6 ml virus transport medium, mixed thoroughly and diluted 1:2 and 1:10. Inactivated 2019-nCoV culture medium was added to simulate pooling samples: 10 pooling samples, 5 pooling samples and 1 swab sample. Extraction and amplification were made using three nucleic acid extraction reagents a, b, and c with different extraction methods and systems, as well as five 2019-nCoV detection reagents A-E with various template loading volumes and sensitivities respectively. Results: For the same sample, the Ct values of extracted templates a were 2.10±0.47 and 3.46±0.62 earlier than extracted templates b and c. For samples with identical amplifying, the Ct valves of N and ORF1ab gene of A reagent were 1.16±0.48 and 2.36±0.54 earlier than that of reagent B. Adding nucleic acid of 10 negative swabs to the amplification system lagged the Ct values of reagent A by about 1.36±0.32 Ct, while Ct values of reagent B were not affected. Extracted by regent a, a lag of 1.66±0.39 Ct on average was observed in C, D, and E reagents in detecting pooling samples of ten swabs as compared with one swab sample. When extracting 400 copies/ml pooling samples of ten swabs by reagent a, N gene could be detected by reagents C and E, but not by reagent D. Conclusion: Large amount of extraneous DNA is introduced by sample pooling, which could interfere the effiency of extraction and amplification. Strategies of using extraction reagents with large loading volume and high effiency, together with amplification reagents with large template volume and low limit of detection are helpful for ensuring detection sensitivity of pooling samples, and greatly reducing the risk of false negative results.