Altered immune response to vaccination in patients with plasma cell premalignancy

Introduction Patients with hematological malignancies, including multiple myeloma (MM), experience suboptimal responses to SARS-CoV-2 vaccination. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) are precursors to MM and exhibit altered immune cell composition and function. The SARS-CoV-2 pandemic and the subsequent population-wide vaccination represent an opportunity to study the real-life immune response to a common antigen. Here, we present updated results from the IMPACT study, a study we launched in November 2020 to characterize the effect of plasma cell premalignancy on response to SARS-CoV2 vaccination (vx). Methods We performed: (i) ELISA for SARS-CoV-2-specific antibodies on 1,887 peripheral blood (PB) samples (237 healthy donors (HD), and 550 MGUS, 947 SMM, and 153 MM patients) drawn preand post-vx;(ii) single-cell RNA, T cell receptor (TCR), and B cell receptor (BCR) sequencing (10x Genomics) on 224 PB samples (26 HD, and 20 MGUS, 48 SMM, and 24 MM patients) drawn preand post-vx;(iii) plasma cytokine profiling (Olink) on 106 PB samples (32 HD, and 38 MGUS and 36 SMM patients) drawn pre- and post-vx;and (iv) bulk TCR sequencing (Adaptive Biotechnologies) on 8 PB samples from 4 patients (2 MGUS, 2 SMM) drawn pre- and post-vx. Results Patients with MGUS and SMM achieved comparable antibody titers to HD two months post-vx. However, patient titers waned significantly faster, and 4 months post-vx we observed significantly lower titers in both MGUS (Wilcoxon rank-sum, p=0.030) and SMM (p=0.010). These results indicate impaired humoral immune response in patients with MGUS and SMM.At baseline, the TCR repertoire was significantly less diverse in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.039), while no significant difference was observed in the BCR repertoire (p=0.095). Interestingly, a significant increase in TCR repertoire diversity was observed post-vx in patients with SMM (paired t-test, p=0.014), indicating rare T cell clone recruitment in response to vaccination. In both HD and patients, recruited clones showed upregulation of genes associated with CD4+ naive and memory T cells, suggesting preservation of the T cell response in SMM, which was confirmed by bulk TCR-sequencing in 4 patients.Lastly, by cytokine profiling, we observed a defect in IL-1beta and IL-18 induction post-vx in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.047 and p=0.015, respectively), two key monocyte-derived mediators of acute inflammation, suggesting an altered innate immune response as well. Conclusion Taken together, our findings highlight that despite the absence of clinical manifestations, plasma cell premalignancy is associated with defects in both innate and adaptive immune responses. Therefore, patients with plasma cell premalignancy may require adjusted vaccination strategies for optimal immunization.

Research on sentiment classification algorithm for Corona Virus Disease 2019 Weibo text

Since the outbreak of Corona Virus Disease 2019, it has had a significant impact on people's lives. In order to help the government grasp the social opinion and do more scientific and practical propaganda and public opinion guidance for prevention and control, and to fully reflect people's attitude toward the epidemic and provide data support for government departments to release epidemic prevention measures. This paper uses Corona Virus Disease 2019-related Weibo comments as the research object and analyzes their sentiment using deep learning algorithms. The number of characters in Weibo comments is usually less than 140, which belongs to the category of short texts. Due to the use of few words, random user language, and irregular grammar, these texts have poor performance in text separation and word vector expression, adversely affecting sentiment classification. In order to solve this problem, this paper constructs the BERT-DPCNN model for sentiment analysis of epidemic short texts, which can not only extract the sentence-level text dependencies but also effectively avoid the problem of gradient disappearance of deep neural networks. The experiments show that the BERT-DPCNN model has the best effect and is of great value for the sentiment classification of short epidemic text. © 2022 IEEE.

SARS-CoV-2 spike protein enhanced thrombosis is inhibited by tipiracil in mice

Background: COVID-19 is accompanied by excessive systemic thrombotic events, but the mechanism is unknown. All major COVID-19 vaccines were associated with thrombosis. Thymidine phosphorylase (TYMP) plays an important role in platelet activation, thrombosis, and inflammation. TYMP expression is significantly increased in COVID-19 patients. Aim(s): To test the hypothesis that TYMP mediates SARS-CoV-2 spike protein (SP)-enhanced thrombosis. Method(s): Transfection of plasmid encoding SP or the receptor-binding domain (RBD) with human ACE2 was conducted in COS-7 cells. BEAS-2B cells were treated with SP or RBD containing COS-7 cell lysates, and TYMP expression and activation of NF-kappaB were examined. K18-hACE2 transgenic (ACE2-TG) mice were intraperitoneally treated with SP or RBD containing COS-7 cells lysates, and thrombosis was assessed three days later using the FeCl3 injury-induced carotid artery thrombosis model. Result(s): SP and RBD led to ACE2 shedding, significantly increased TYMP expression, and NF-kappaB activation in BEAS-2B cells. In comparison to wildtype mice, ACE2-TG mice are anti-thrombotic and had significantly prolonged thrombosis time. Treating ACE2-TG mice with COS-7 cells transfected with empty plasmid did not affect the thrombosis. However, treating the ACE2-TG mice with SP-or RBD-containing COS-7 cell lysates dramatically enhanced thrombosis and significantly shortened time to occlusive thrombi formation. SP is more powerful than RBD in enhancing thrombosis. SP-enhanced thrombosis was dramatically inhibited by simultaneously feeding the mice with 1 mg/kg of tipiracil. TYMP is expressed in human type II alveolar epithelial cells and bronchial epithelium. By using the MGH Emergency Department COVID-19 Cohort with Olink Proteomics TYMP data and Receiver Operating Characteristic analysis, we found TYMP is a sensitive and specific marker in diagnosing COVID-19 (AUC 0.8721, p < 0.0001). Conclusion(s): SARS-CoV-2 SP and RBD are pro-inflammatory and pro-thrombotic. SP/RBD-induced thrombosis is inhibited by tipiracil, a TYMP inhibitor. TYMP is a sensitive marker for COVID-19 diagnosis. Targeting TYMP could be a novel effective treatment for COVID-19.

Humoral SARS-CoV-2 response in asymptomatic precursor plasma cell dyscrasia patients: IMPACT study results

Introduction: Patients with hematologic malignancies, including multiple myeloma (MM), experience worse SARS-CoV-2 infection outcomes and sub-optimal vaccine responses. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precede MM and affect ∼5% of individuals age >=50. We previously showed that individuals with MGUS and SMM exhibit immune dysregulation. Here, we investigate the immune response to SARS-CoV-2 vaccination in these asymptomatic but potentially immunocompromised individuals. Methods: The IMPACT study (IRB #20-332) is a prospective study at Dana-Farber Cancer Institute in collaboration with MMRF, which enrolled individuals nationwide with a diagnosed plasma cell dyscrasia and healthy individuals. As of October 2021, 3,005 individuals completed a questionnaire regarding prior infection or vaccination. We obtained 1,350 blood samples from 628 participants and analyzed anti-SARS-CoV-2 IgG antibody titer by ELISA. Results: 2,771 (92%) participants were fully vaccinated (2 doses BNT162b2 or mRNA-1273;1 dose Ad26.COV2.s), 269 (9%) had received a 3rd mRNA vaccine dose, and 234 (8%) were unvaccinated. 1,387 (46%) and 1,093 (36%) participants received mRNA vaccines (BNT162b2 and mRNA-1273), and 139 (5%) participants received an adenovirus vector vaccine (Ad26.COV2.S). 34 (1%) individuals reported SARS-CoV-2 infection after full vaccination. We measured antibody titers in 201 MGUS, 223 SMM, 40 smoldering Waldenstrom macroglobulinemia (SWM), 64 MM, and 100 healthy controls. Multiple linear regression model estimated the association between various clinical variables and post-vaccination antibody titers. As previously reported, having MM was associated with low antibody titer (p < 0.001). Of note, having SMM, regardless of risk stratification by 2/20/20 criteria, was also associated with low antibody titers, indicating that even low-risk SMM patients have a poor response to vaccination. MGUS and SWM diagnoses were not significantly associated with antibody titers. Additionally, male sex (p < 0.010), elapsed time after vaccination (p < 0.001), and BNT162b2 vaccine (p < 0.001) were associated with low antibody titers. SARS-CoV-2 infection prior to vaccination was associated with high antibody titers. We identified 25 patients (6 MGUS, 10 SMM, 2 SWM, 7 MM) who submitted blood samples after both the 2nd and 3rd dose. In these patients we observed a significant increase in antibody titer after a 3rd dose (p = 0.002). We also observed that antibody titers of patients after a 3rd dose (13 MGUS, 12 SMM, 2 SWM, 31 MM) were comparable to that of healthy individuals after a 2nd dose (p = 0.833). Conclusion: Our data indicates that suboptimal response to SARS-CoV-2 does not only occur with MM and cancer patients receiving therapy but also in precursor asymptomatic patients including low-risk SMM.

Development and Application of an Insulated Isothermal RT-PCR for On-site Detecting Nebovirus

Nebovirus (NeV) is an emerge diarrhea-causing virus in calves, the aim of this study is to establish an insulated isothermal RT-PCR(iiRT-PCR) for detecting NeV on field. Based on the RdRp sequences of NeV in GenBank database, a pair of primers and a fluorescent TaqMan probe were designed and synthesized. After optimizing the react system and condition, the iiRT-PCR method for detection of NeV was established. The iiRT-PCR assay could amplify specific fragment of NeV, without amplification of irrelevant pathogens, including bovine coronavirus, bovine norovirus, bovine rotavirus, bovine viral diarrhea virus, bovine torovirus, bovine Cryptosporidium parvum, bovine Eimeria. The intra- and inter-coefficients of variation were 3.07%-3.12% and 2.45%-3.01%, respectively, and the detection limit of viral nucleic acid of the assay was 5.38 copies•μL-1. One hundred and one calf diarrhea samples, collected from Hongyuan County, Ruoergai Prefecture, Xichang City, Liangshan Yi Autonomous Prefecture and Langzhong City in Sichuan Province during 2020-2021, were used to detect NeV, and 64.36% samples were detected as NeV positive. The study established an iiRT-PCR method for NeV detection with good specificity and reproducible as well as high sensitivity. Moreover, combined with the premixed detection reagent and PetNAD nucleic acid extraction kit, this assay could be used to NeV detect on-site, and only 1 hour from nucleic acid extraction to result report, which contribute to the fast detection for NeV.

Suggestions and thoughts on the reform of China’s public health system during COVID-19

This paper analyzed many problems in the construction of China′s public health system exposed in the process of prevention and control of novel coronavirus′s epidemic situation. Conscientiously studying the spirit of the two sessions, combined with the national conditions of our country, this paper put forward several specific reform suggestions on the legal system construction of the public health system, the improvement of the institutional system, the training direction of public health personnel, the public health service system, the information construction and the construction of the health emergency system, to made a preliminary exploration on the further improvement of the emergency response mechanism of major epidemic situations. © 2021, Publication Centre of Anhui Medical University. All rights reserved.

[Brief introduction of population medicine and value-based healthcare].

Three healthcare revolutions and four medical paradigm shifts have had a profound impact on the development of healthcare system, which has greatly improved human health, however, the COVID-19 pandemic has exposed hidden dangers and problems in the construction of the healthcare system. In this paper, we made a brief introduction of population medicine and value-based healthcare for the purpose of suggesting new ideas and directions for the future development of healthcare system.

Targeting thymidine phosphorylase may be a novel therapy for covid-19

Background : Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), is a human respiratory disease. Hitherto, there is no effective treatment has been established. Patients with cardiovascular or diabetes comorbidities are a high-risk cohort. COVID-19 is accompanied by excessive systemic thrombotic events, but the mechanism is not yet known. Our recent studies found that thymidine phosphorylase (TYMP) plays an important role in platelet activation, thrombosis, and TYMP expression is increased in obese and diabetic patients. Aims : To test the hypothesis that TYMP participates in the host response to SARS-CoV-2. Methods : By co-transfection of SARS-CoV-2 spike protein (SP) and human ACE2 into Cos-7 cells, we examined how SP regulates ACE2 and TYMP expression. By using data provided by the MGH (Massachusetts General Hospital) Emergency Department COVID-19 Cohort with Olink Proteomics we analyzed the correlation between plasma TYMP and the severity of COVID-19. Results : Overexpression of S protein or its receptor-binding domain led to ACE2 shedding into a different size. S protein also increased TYMP expression in Cos-7 cells. In comparing to COVID-19 negative patients, plasma TYMP in COVID-19 patients was significantly increased in a severity-dependent manner. The increase of plasma TYMP was earlier than the increase of C creative protein, a predictive factor for inflammation and future risk of cardiovascular events. The increase of TYMP is positively associated with plasma D-dimer and lactate dehydrogenase, the presence of pulmonary symptoms, as well as IFN-γ and IFN-λ, especially IFN-λ. We also found that TYMP is highly expressed in mouse asthmatic lungs and human type II alveolar epithelial cells and bronchial epithelium, which mediate SARS-CoV-2 entry. Conclusions : TYMP is positively correlated with COVID-19 acuity and COVID-19-associated thrombotic event, inflammation, and organ damages. TYMP could be an acuity marker for COVID-19 diagnosis. Targeting TYMP could be a novel effective medicine for COVID-19.

Clinical characteristics of several patients with coronavirus disease 2019 in Lanzhou City

Objective: To investigate and summarize the clinical and imaging features of a few patients with coronavirus disease 2019 (COVID-19) in Lanzhou City. Methods: We carried out a retrospective analysis of the epidemiological data, laboratory results and clinical imaging features of eight hospitalized patients with confirmed COVID-19 in The First Hospital of Lanzhou University from January 23 to February 23, 2020. Results: The sex ratio (men to women) of the 8 patients was 5: 3 while their age ranged from 24 to 57 years old. The incubation period was 1-10 days. Of the 8 patients, 7(87.5%) had COVID-19 brought in from other places in China and 1(12.5%) was a secondary infection case. The main clinical manifestations included cough in 6 cases (75%), fever in 4 cases (50%), expectoration in 3 cases (37.5%), and fatigue in 2 cases (25%). All the 8 cases indicated abnormal manifestations in blood routine examinations, 4 cases (50%) decreased in WBC, 7 cases (87.5%) decreased in Lym count, 5 cases (62.5%) increased in LDH, 1 case (12.5%) increased in CK, 1 case(12.5%) increased in CK-MB, 4 cases (50%) increased in CRP, 2 cases (25%) increased in PCT, and 1 case (12.5%) increased in D-dimer. Of the 2 patients examined by chest digital radiography (DR), one DR finding was not typical and the other one suggested increased bilateral lung markings. Six patients were examined by HRCT, of whom four (50%) showed multiple ground glass opacities on both lobes and two (25%) showed multiple ground glass opacities only on the right lobe;none of the 6 imaging findings suggested pleural effusion. Six patients were discharged from hospital after being cured and 1 patient still underwent treatment. Conclusion: Most of these 8 patients had COVID-19 imported from outside the city, and the patients were relatively young with few underlying diseases. Their major symptoms were fever, cough, and expectoration. All of them exhibited abnormal findings in blood routine examinations;half of them suggested increased CRP while a few ones showed abnormal CK and Ddimer values. The imaging manifestations of most patients were multiple ground glass opacities near the peripheral pleura.

[Preliminary study of the relationship between novel coronavirus pneumonia and liver function damage: a multicenter study].

Objective: To analyze the clinical characteristics of cases of novel coronavirus pneumonia and a preliminary study to explore the relationship between different clinical classification and liver damage. Methods: Consecutively confirmed novel coronavirus infection cases admitted to seven designated hospitals during January 23, 2020 to February 8, 2020 were included. Clinical classification (mild, moderate, severe, and critical) was carried out according to the diagnosis and treatment program of novel coronavirus pneumonia (Trial Fifth Edition) issued by the National Health Commission. The research data were analyzed using SPSS19.0 statistical software. Quantitative data were expressed as median (interquartile range), and qualitative data were expressed as frequency and rate. Results: 32 confirmed cases that met the inclusion criteria were included. 28 cases were of mild or moderate type (87.50%), and four cases (12.50%) of severe or critical type. Four cases (12.5%) were combined with one underlying disease (bronchial asthma, coronary heart disease, malignant tumor, chronic kidney disease), and one case (3.13%) was simultaneously combined with high blood pressure and malignant tumor. The results of laboratory examination showed that the alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBil) for entire cohort were 26.98 (16.88 ~ 46.09) U/L and 24.75 (18.71 ~ 31.79) U/L, 39.00 (36.20 ~ 44.20) g/L and 16.40 (11.34 ~ 21.15) µmol/L, respectively. ALT, AST, ALB and TBil of the mild or moderate subgroups were 22.75 (16.31 ~ 37.25) U/L, 23.63 (18.71 ~ 26.50) U/L, 39.70 (36.50 ~ 46.10) g/L, and 15.95 (11.34 ~ 20.83) µmol/L, respectively. ALT, AST, ALB and TBil of the severe or critical subgroups were 60.25 (40.88 ~ 68.90) U/L, 37.00 (20.88 ~ 64.45) U/L, 35.75 (28.68 ~ 42.00) g/L, and 20.50 (11.28 ~ 25.00) µmol/L, respectively. Conclusion: The results of this multicenter retrospective study suggests that novel coronavirus pneumonia combined with liver damage is more likely to be caused by adverse drug reactions and systemic inflammation in severe patients receiving medical treatment. Therefore, liver function monitoring and evaluation should be strengthened during the treatment of such patients.