Mechanistic study of the transmission pattern of the SARS-CoV-2 omicron variant.

The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID-19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike-angiotensin-converting enzyme-2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse-grained model. Our study extended beyond the receptor-binding domain (RBD) of spike trimer through comprehensive modeling of the full-length spike trimer rather than just the RBD. Our free-energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full-length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

Age-period-cohort analysis of incidence, mortality and disability-adjusted life years of esophageal cancer in global, regional and national regions from 1990 to 2019.

OBJECTIVE: In view of the high incidence and mortality of esophageal cancer, the latest statistical data on the disease burden of esophageal cancer can provide strategies for cancer screening, early detection and treatment, and help to rationally allocate health resources. This study provides an analysis of the global disease burden and risk factors of esophageal cancer from 1990 to 2019. METHODS: Using the 2019 Global Burden of Disease, Injury and Risk Factor (GBD) data, we present the incidence, mortality and disability-adjusted life years (DALY) of esophageal cancer in 21 regions and 204 countries and different sociodemographic index (SDI) regions from 1990 to 2019. The age-period-cohort model was used to estimate the age, period, and cohort trend of esophageal cancer in different SDI regions. The estimated proportion of DALY attributable to each risk factor from 1990 to 2019. RESULTS: From 1990 to 2019, the number of new cases of esophageal cancer, the number of deaths and DALY increased by 67.07%, 55.97% and 42.13%, respectively, but age standardized incidence rate (ASIR), age standardized mortality rate (ASMR) and age standardized DALY rate (ASDR) decreased by 19.28%, 25.32% and 88.22%, respectively. Overall, the results of the age-period-cohort model showed that the incidence, mortality, and DALY rates in countries and regions with higher SDI levels showed a downward trend over time and with the passage of time. Conversely, there were no significant changes in incidence and mortality in countries and regions with low SDI levels. In the past 30 years, the incidence and death of esophageal cancer in the world has gradually changed to people over 80 years old, but the population aged 60-79 still accounts for the largest proportion. The global DALY in esophageal cancer is mainly attributable to smoking, followed by alcohol consumption and occupational exposure. CONCLUSIONS: Although ASIR, ASMR and ASDR have decreased significantly, esophageal cancer is still the main factor causing the disease burden worldwide. Public health administrators in low SDI and low-middle SDI countries are high-risk areas for esophageal cancer, and preventive control measures should be implemented to raise awareness, screening, and treatment of esophageal cancer in these areas. Tobacco and alcohol control and reduction of occupational hazards are key steps in reducing the burden of esophageal cancer.

Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration.

Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P = 0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P = 0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.

Benefit of Early Initiation of Neuraminidase Inhibitor Treatment to Hospitalized Patients With Avian Influenza A(H7N9) Virus.

Background: The significance of early neuraminidase inhibitor (NAI) therapy for treating influenza A(H7N9) is currently unknown. Methods: The duration of viral shedding was monitored by reverse-transcription polymerase chain reaction after patients with confirmed H7N9 infection were admitted to the First Affiliated Hospital, Zhejiang University, during April 2013-April 2017. Indices such as the length of hospitalization and mortality were collected, and the correlation between the time of administration of NAI and the severity of disease was systematically analyzed. Results: One hundred sixty patients with confirmed H7N9 infection were divided into 3 groups according to NAI starting time. Three of 20 (15%) patients for whom NAI was administered within 2 days died compared with 12 of 52 (23.1%) patients who received treatment within 2-5 days and 33 of 88 (37.5%) patients who were treated after 5 days (P < .05). The median durations of viral shedding from NAI therapy initiation was 4.5 days (interquartile range [IQR], 3-9 days) for patients who took antiviral medication within 2 days, which was significantly different from that for patients who took medication within 2-5 days (7.5 days [IQR, 4.25-12.75 days]) or after 5 days (7 days [IQR, 5-10 days]) (P < .05). We found that the duration of viral shedding from NAI therapy was the shortest in spring 2013 (5.5 days) and the longest in winter-spring 2016-2017 (8.5 days) (P < .05), showing a prolonged trend. Conclusions: Early NAI therapy within 2 days of illness shortened the duration of viral shedding and improved survival in patients with H7N9 viral infection.

Improved Survival of Patients with ST-Segment Elevation Myocardial Infarction 3-6 Hours After Symptom Onset Is Associated with Inter-Hospital Transfer for Primary Percutaneous Coronary Intervention (PCI) at a Large Regional ST-Segment Elevation Myocardial Infarction (STEMI) Program vs. In-Hospital Thrombolysis in a Community Hospital.

BACKGROUND This study sought to compare the 30-day and 1-year survival of patients diagnosed with ST-segment elevation myocardial infarction (STEMI), whose symptom onset to in-hospital first medical contact (IHFMC) was 3-6 h, who received either in-hospital thrombolysis (IHT) in the nearest county hospital or direct transfer to a larger hospital in Henan province, China for primary percutaneous coronary intervention (PPCI). MATERIAL AND METHODS Patients were allocated into 2 groups: one group received IHT in the local county hospital, whereas the other group were transferred to the PCI centers to receive PPCI. Patient demographic data, baseline characteristics, and time between different stages of patient contact to the initiation of treatment for IHT or PPCI were recorded for analysis. RESULTS No significant difference was identified between the 2 groups with the baseline characteristics and demographic data. The all-cause mortality was not significantly different between the IHT and PPCI group at 30 days (13.0% vs. 9.9%, p=0.386). However, a significant difference in mortality between the IHT and PPCI group was observed at 1 year (23.4% vs. 14.1%, p=0.035). Inter-hospital transfer time for PPCI tended to be the independent predictor for survival (OR: 4.4 CI 95%: 1.9-14.5, p 0.001). Overall, the patients undergoing PPCI in inter-hospital transfer had a higher survival rates for 1 year compared with patients receiving IHT. CONCLUSIONS Despite the delay associated with inter-hospital transfer for PPCI, patients with STEMI 3-6 h after symptom onset have improved survival with PPCI over patients treated locally with IHT.

Neutrophil-to-Lymphocyte Ratio Predicts the Severity of Incarcerated Groin Hernia.

BACKGROUND The incarceration of a segment of bowel within a groin hernia can result in intestinal strangulation if hernia treatment is delayed. Once intestinal strangulation occurs, a bowel resection may be required, and there is an overall increased risk for postoperative complications. The aim of this study was to identify biomarkers to predict the severity of an incarcerated groin hernia. MATERIAL AND METHODS We retrospectively evaluated the records of 95 patients with incarcerated groin hernias who underwent emergency surgical correction of the hernias. The need for a bowel resection was regarded as an indicator of severity in incarcerated groin hernia patients. The patients were divided into 2 groups: patients with bowel resection surgery and patients without bowel resection surgery. RESULTS We discovered that leukocyte count (leukocyte count ≥10×10³/mm³), neutrophil-to-lymphocyte ratio (NLR, NLR ≥11.5), presentation of bowel obstruction, and duration of incarceration (duration of incarceration ≥26 h) were significantly associated with bowel resection in incarcerated groin hernia patients by using the chi-square test. Factors such as leukocyte count, NLR, presentation of bowel obstruction, and duration of incarceration were analyzed using multivariate logistic regression analysis. We found that NLR, presentation of bowel obstruction, and duration of incarceration were independently and significantly related to bowel resection in incarcerated groin hernia patients. CONCLUSIONS An elevated NLR can serve as a biomarker for the prediction of severity of incarcerated groin hernias. Additionally, incarcerated groin hernia patients who present with bowel obstruction or with duration of intestinal incarceration longer than 26 h have an increased risk for bowel resection.

Enteropathogens in children less than 5 years of age with acute diarrhea: a 5-year surveillance study in the Southeast Coast of China.

BACKGROUND: Diarrhea is the second most common cause of death among children less than 5 years of age worldwide. The etiological agents of diarrhea in the southeast coastal area of China were studied from July 2009 to December 2014. METHODS: A total of the 2318 patients were enrolled in this study and examined for the presence of viruses, bacteria, and parasites. Multiplex real-time PCR was used for the detection of diarrheagenic Escherichia.coli (DEC). DEC strains were tested for susceptibility to a panel of 20 antibiotics using the Kirby-Bauer disc-diffusion method. RESULTS: Of the 2318 children with diarrhea, 962 (41.5 %) were positive for at least one pathogen. Rotavirus, human calicivirus (HucV), and DEC were predominant, with detection rates of 19.1 % (443), 17.7 % (411), and 7.6 % (177), respectively. The prevalences of various pathogens in patients of different ages and in different seasons were not the same. The resistance rates of 177 strains of DEC to ampicillin, tetracycline, and cefazolin were 93.2 %, 60.0 %, and 57.7 %, respectively. CONCLUSIONS: Rotavirus, HucV, and DEC were the main pathogens associated with diarrhea in Zhejiang, China. DEC possessed high levels of antibiotic resistance. Increased monitoring of etiological agents of diarrhea is necessary.

Detection of a novel avian influenza A (H7N9) virus in humans by multiplex one-step real-time RT-PCR assay.

BACKGROUND: A novel avian influenza A (H7N9) virus emerged in eastern China in February 2013. 413 confirmed human cases, including 157 deaths, have been recorded as of July 31, 2014. METHODS: Clinical specimens, including throat swabs, sputum or tracheal aspirates, etc., were obtained from patients exhibiting influenza-like illness (ILIs), especially from those having pneumonia and a history of occupational exposure to poultry and wild birds. RNA was extracted from these samples and a multiplex one-step real-time RT-PCR assay was developed to specifically detect the influenza A virus (FluA). PCR primers targeted the conserved M and Rnase P (RP) genes, as well as the hemagglutinin and neuraminidase genes of the H7N9 virus. RESULTS: The multiplex assay specifically detected the avian H7N9 virus, and no cross-reaction with other common respiratory pathogens was observed. The detection limit of the assay was approximately 0.05 50% tissue culture infective doses (TCID50), or 100 copies per reaction. Positive detection of the H7N9 virus in sputum/tracheal aspirates was higher than in throat swabs during the surveillance of patients with ILIs. Additionally, detection of the matrix (M) and Rnase P genes aided in the determination of the novel avian H7N9 virus and ensured the quality of the clinical samples. CONCLUSIONS: These results demonstrate that the multiplex assay detected the novel avian H7N9 virus with high specificity and sensitivity, which is essential for the early diagnosis and treatment of infected patients.

Reperfusion times of ST-Segment elevation myocardial infarction in hospitals.

OBJECTIVE: To investigate the reperfusion time in patients with ST-segment elevation myocardial infarction (STEMI) in Henan Province, China, and discuss the strategies for shortening that period. METHODS: The reperfusion times of 1556 STEMI cases in 30 hospitals in Henan Province were analyzed from January 2008 to August 2012, including 736 cases from provincial hospitals, 462 cases from municipal hospitals and 358 cases from country hospitals. The following data: Time period 1 (from symptom onset to first medical contact), Time period 2 (from first medical contact to diagnosis), Time period 3 (from the diagnosis to providing consent), Time period 4 (from the time of providing consent to the beginning of treatment) and Time period 5 (from the beginning of treatment to the patency) were recorded and analyzed. RESULTS: In patients receiving primary percutaneous coronary intervention, the door-to-balloon time of provincial hospitals and municipal hospitals was 172±13 minutes and 251±14 minutes, respectively. The hospitals at both levels had a delay comparison of 90 minutes largely caused by the delay in the time for obtaining consent. In patients receiving thrombolysis treatment, the door-to-needle times of provincial hospitals, municipal hospitals and country hospitals were 86±7, 91±7 and 123±11 minutes, respectively. The hospitals at all levels had delays lasting more than 30 minutes, which was mainly attributed to the delay in the time for providing consent. Compared with the time required by the guidelines, the reperfusion time of patients with STEMI in China is evidently delayed. In terms of China's national conditions, the door-to-balloon time is too general. Therefore, we suggest refining this time as the first medical contact-diagnosis time, consent provision time, therapy preparation time and the start of therapy balloon time. CONCLUSION: Compared to the time required by the guidelines, the reperfusion time of patients with STEMI in China was obviously greater. In terms of China's national conditions, the door to balloon time is not applicable. So it is suggested to refine it as the first medical contact-diagnosis time, providing consent time, therapy prepare time and the start of therapy - balloon time.

Identification of ground spilled oil of buried pipeline based on laser absorption spectroscopy: Numerical investigation and experimental verification.

The ground diffusion characteristics of buried oil pipeline after leakage and the laser optical transmission mechanism of surface oil film are the basis of spectral detection technology. Based on the computational fluid dynamics to solve the diffusion equation of multiphase flow in porous media, the leakage law of oil under different soil porosity is analyzed in two dimensions: surface diffusion diameter and oil film thickness. TracePro optical simulation is used to study the absorption and reflection patterns of laser at the oil-gas interface, and validation experiments are carried out based on the tunable diode laser absorption spectroscopy method. The results show that oil is easily accumulated on the ground surface with larger soil porosity and in the depressions of the ground surface. When the oil film thickness is greater than 2 mm, the laser cannot transmit the oil layer and the received light intensity is only provided by the mirror reflection at the oil-gas interface. The mechanism of laser detection of oil leaks is the spectral absorption of volatile alkane gases in the upper layer of the oil film by a laser of a specific wavelength.

Dynamic associations between the respiratory tract and gut antibiotic resistome of patients with COVID-19 and its prediction power for disease severity.

The antibiotic resistome is the collection of all antibiotic resistance genes (ARGs) present in an individual. Whether an individual's susceptibility to infection and the eventual severity of coronavirus disease 2019 (COVID-19) is influenced by their respiratory tract antibiotic resistome is unknown. Additionally, whether a relationship exists between the respiratory tract and gut ARGs composition has not been fully explored. We recruited 66 patients with COVID-19 at three disease stages (admission, progression, and recovery) and conducted a metagenome sequencing analysis of 143 sputum and 97 fecal samples obtained from them. Respiratory tract, gut metagenomes, and peripheral blood mononuclear cell (PBMC) transcriptomes are analyzed to compare the gut and respiratory tract ARGs of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between ARGs and immune response. Among the respiratory tract ARGs, we found that Aminoglycoside, Multidrug, and Vancomycin are increased in ICU patients compared with nICU patients. In the gut, we found that Multidrug, Vancomycin, and Fosmidomycin were increased in ICU patients. We discovered that the relative abundances of Multidrug were significantly correlated with clinical indices, and there was a significantly positive correlation between ARGs and microbiota in the respiratory tract and gut. We found that immune-related pathways in PBMC were enhanced, and they were correlated with Multidrug, Vancomycin, and Tetracycline ARGs. Based on the ARG types, we built a respiratory tract-gut ARG combined random-forest classifier to distinguish ICU COVID-19 patients from nICU patients with an AUC of 0.969. Cumulatively, our findings provide some of the first insights into the dynamic alterations of respiratory tract and gut antibiotic resistome in the progression of COVID-19 and disease severity. They also provide a better understanding of how this disease affects different cohorts of patients. As such, these findings should contribute to better diagnosis and treatment scenarios.

ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer.

Platinum resistance accounts for much of the high mortality and morbidity associated with ovarian cancer. Identification of targets with significant clinical translational potential remains an unmet challenge. Through a high-throughput synthetical lethal screening for clinically relevant targets using 290 kinase inhibitors, we identify calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) as a critical vulnerability in cisplatin-resistant ovarian cancer cells. Pharmacologic inhibition of CAMK2G significantly sensitizes ovarian cancer cells to cisplatin treatment in vitro and in vivo. Mechanistically, CAMK2G directly senses ROS, both basal and cisplatin-induced, to control the phosphorylation of ITPKB at serine 174, which directly regulates ITPKB activity to modulate cisplatin-induced ROS stress. Thereby, CAMK2G facilitates the adaptive redox homeostasis upon cisplatin treatment and drives cisplatin resistance. Clinically, upregulation of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in human ovarian cancers. This study reveals a key kinase network consisting of CAMK2G and ITPKB for ROS sense and scavenging in ovarian cancer cells to maintain redox homeostasis, offering a potential strategy for cisplatin resistance treatment.

Dynamic Alterations in the Respiratory Tract Microbiota of Patients with COVID-19 and its Association with Microbiota in the Gut.

The role of respiratory tract microbes and the relationship between respiratory tract and gut microbiomes in coronavirus disease 2019 (COVID-19) remain uncertain. Here, the metagenomes of sputum and fecal samples from 66 patients with COVID-19 at three stages of disease progression are sequenced. Respiratory tract, gut microbiome, and peripheral blood mononuclear cell (PBMC) samples are analyzed to compare the gut and respiratory tract microbiota of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between respiratory tract microbiome and immune response. In the respiratory tract, significantly fewer Streptococcus, Actinomyces, Atopobium, and Bacteroides are found in ICU than in nICU patients, while Enterococcus and Candida increase. In the gut, significantly fewer Bacteroides are found in ICU patients, while Enterococcus increases. Significant positive correlations exist between relative microbiota abundances in the respiratory tract and gut. Defensin-related pathways in PBMCs are enhanced, and respiratory tract Streptococcus is reduced in patients with COVID-19. A respiratory tract-gut microbiota model identifies respiratory tract Streptococcus and Atopobium as the most prominent biomarkers distinguishing between ICU and nICU patients. The findings provide insight into the respiratory tract and gut microbial dynamics during COVID-19 progression, considering disease severity, potentially contributing to diagnosis, and treatment strategies.

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma.

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(-) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

Assessment of the Diagnostic Ability of Four Detection Methods Using Three Sample Types of COVID-19 Patients.

Background: Viral nucleic acid detection is considered the gold standard for the diagnosis of coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 infection. However, unsuitable sample types and laboratory detection kits/methods lead to misdiagnosis, which delays the prevention and control of the pandemic. Methods: We compared four nucleic acid detection methods [two kinds of reverse transcription polymerase chain reactions (RT-PCR A: ORF1ab and N testing; RT-PCRB: only ORF1ab testing), reverse transcription recombinase aided amplification (RT-RAA) and droplet digital RT-PCR (dd-RT-PCR)] using 404 samples of 72 hospitalized COVID-19 patients, including oropharyngeal swab (OPS), nasopharyngeal swabs (NPS) and saliva after deep cough, to evaluate the best sample type and method for SARS-CoV-2 detection. Results: Among the four methods, dd-RT-PCR exhibited the highest positivity rate (93.0%), followed by RT-PCR B (91.2%) and RT-RAA (91.2%), while the positivity rate of RT-PCR A was only 71.9%. The viral load in OPS [24.90 copies/test (IQR 15.58-129.85)] was significantly lower than that in saliva [292.30 copies/test (IQR 20.20-8628.55)] and NPS [274.40 copies/test (IQR 33.10-2836.45)]. In addition, if OPS samples were tested alone by RT-PCR A, only 21.4% of the COVID-19 patients would be considered positive. The accuracy of all methods reached nearly 100% when saliva and NPS samples from the same patient were tested simultaneously. Conclusions: SARS-CoV-2 nucleic acid detection methods should be fully evaluated before use. High-positivity rate methods such as RT-RAA and dd-RT-PCR should be considered when possible. Furthermore, saliva after deep cough and NPS can greatly improve the accuracy of the diagnosis, and testing OPS alone is not recommended.

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity.

Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies in vivo. Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8+ T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8+ T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer.

Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension.

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

Hock-a-loogie saliva as a diagnostic specimen for SARS-CoV-2 by a PCR-based assay: A diagnostic validity study.

To clarify the effect of different respiratory sample types on SARS-CoV-2 detection, we collected throat swabs, nasal swabs and hock-a-loogie saliva or sputum, and compared their detection rates and viral loads. The detection rates of sputum (95.65%, 22/23) and hock-a-loogie saliva (88.09%, 37/42) were significantly higher than those in throat swabs (41.54%, 27/65) and nasal swabs (72.31%, 47/65) (P < 0.001). The Ct Values of sputum, hock-a-loogie saliva and nasal swabs were significantly higher than that in throat swabs, whereas no significant difference was observed between sputum and saliva samples. Hock-a-loogie saliva are reliable sample types that can be used to detect SARS-CoV-2, and worthy of clinical promotion.

Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.

OBJECTIVE: To evaluate viral loads at different stages of disease progression in patients infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first four months of the epidemic in Zhejiang province, China. DESIGN: Retrospective cohort study. SETTING: A designated hospital for patients with covid-19 in Zhejiang province, China. PARTICIPANTS: 96 consecutively admitted patients with laboratory confirmed SARS-CoV-2 infection: 22 with mild disease and 74 with severe disease. Data were collected from 19 January 2020 to 20 March 2020. MAIN OUTCOME MEASURES: Ribonucleic acid (RNA) viral load measured in respiratory, stool, serum, and urine samples. Cycle threshold values, a measure of nucleic acid concentration, were plotted onto the standard curve constructed on the basis of the standard product. Epidemiological, clinical, and laboratory characteristics and treatment and outcomes data were obtained through data collection forms from electronic medical records, and the relation between clinical data and disease severity was analysed. RESULTS: 3497 respiratory, stool, serum, and urine samples were collected from patients after admission and evaluated for SARS-CoV-2 RNA viral load. Infection was confirmed in all patients by testing sputum and saliva samples. RNA was detected in the stool of 55 (59%) patients and in the serum of 39 (41%) patients. The urine sample from one patient was positive for SARS-CoV-2. The median duration of virus in stool (22 days, interquartile range 17-31 days) was significantly longer than in respiratory (18 days, 13-29 days; P=0.02) and serum samples (16 days, 11-21 days; P<0.001). The median duration of virus in the respiratory samples of patients with severe disease (21 days, 14-30 days) was significantly longer than in patients with mild disease (14 days, 10-21 days; P=0.04). In the mild group, the viral loads peaked in respiratory samples in the second week from disease onset, whereas viral load continued to be high during the third week in the severe group. Virus duration was longer in patients older than 60 years and in male patients. CONCLUSION: The duration of SARS-CoV-2 is significantly longer in stool samples than in respiratory and serum samples, highlighting the need to strengthen the management of stool samples in the prevention and control of the epidemic, and the virus persists longer with higher load and peaks later in the respiratory tissue of patients with severe disease.