Liver transplantation is the primary therapeutic intervention for end-stage liver disease.However,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.The clinical ...Liver transplantation is the primary therapeutic intervention for end-stage liver disease.However,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.The clinical manifestations associated with early arterial complications following liver transplantation are often non-specific.Without timely intervention,these complications can result in graft fai-lure or patient mortality.Therefore,early diagnosis and the formulation of an op-timal treatment plan are imperative.Ultrasound examination remains the pre-dominant imaging modality for detecting complications post liver transplan-tation.This article comprehensively reviews common causes and clinical present-ations of early hepatic artery complications in the post-transplantation period and delineates abnormal sonographic findings for accurate diagnosis of these con-ditions.Overall,ultrasound offers the advantages of convenience,safety,effect-iveness,and non-invasiveness.It enables real-time,dynamic,and precise evalua-tion,making it the preferred diagnostic method for post-liver transplantation assessments.INTRODUCTION Liver transplantation stands as the primary therapeutic approach for end-stage liver disease.Continuous advancements in surgical techniques and the application of novel immunosuppressive agents contribute to ongoing improvements in the success rate and overall survival in patients undergoing liver transplantation procedures.Despite these advan-cements,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.During the early stages following liver transplantation(within the first 30 d),proper hepatic artery function is crucial for hepatic arterial blood flow.During later stages,collateral circulation,including arteries such as the phrenic artery,right gastric artery,and gastroduodenal artery,becomes important for maintaining hepatic blood supply.It is now understood that the establishment of effective collateral circulation is pivotal for determining the prognosis of hepatic artery complic-ations.The clinical manifestations of these complications are closely linked to factors such as timing,severity,and the specific type of onset.Insufficient hepatic arterial blood flow can lead to abnormal liver function,hepatic infarction,and the formation of hepatic abscesses.Additionally,since the hepatic artery is the sole blood supply to the biliary tract,hepatic artery-related ischemia may result in biliary stricture,obstruction,and the formation of bile ducts.Ultrasound examination remains the primary imaging modality for diagnosing complications post liver transplantation.This article comprehensively reviews common causes and clinical presentations of early hepatic artery complications in the post-transplantation period and outlines abnormal sonographic findings for accurately diagnosing these conditions.NORMAL HEPATIC ARTERY During the intraoperative phase,an ultrasound examination is typically conducted to evaluate the hepatic artery anas-tomosis.The normal internal diameter of the hepatic artery typically ranges from 2 to 5 mm.Two strong echo points are typically identified near the anastomosis.To assess blood flow dynamics,peak systolic velocity,end-diastolic velocity,and resistance index are measured at the donor and recipient sides of the anastomosis following angle correction.Anastomotic stenosis presence and severity can be evaluated by comparing the velocity at the anastomotic site with that at the recipient side.Postoperatively,direct visualization of the anastomosis site through gray ultrasound scans is often challenging.The surgical approach has a significant impact on the proper hepatic artery’s position,resulting in a lower overall success rate of continuous visualization.Color Doppler ultrasound is primarily employed to trace the artery’s path,and spectral measurements are taken at the brightest position of the Color Doppler blood flow signal,primarily used to identify the presence of high-speed turbulence.Hepatic artery spectrum examination plays a crucial role,as a favorable arterial spectral waveform and appropriate hepatic artery flow velocity typically indicate a successful anastomosis,even in cases where the hepatic artery anastomosis cannot be directly visualized by ultrasound.The hepatic artery runs alongside the portal vein,often selected as a reference due to its larger inner diameter.A normal hepatic artery spectrum displays a regular pulsation pattern with a rapid rise in systole and a slow decline in diastole.Parameters for assessing hepatic artery resistance include a resistance index between 0.5 to 0.8 and an artery systolic acceleration of less than 80 ms.Instantaneous increases in the resistance index(RI>0.8)often occur within 2 d after surgery,followed by a subsequent return to normal hepatic arterial parameters.It has been established that the maximum blood flow velocity during systole in the hepatic artery should not exceed 200 cm/s[1].展开更多
Objective To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy.Methods After retrospectively screening the data of 742 patient...Objective To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy.Methods After retrospectively screening the data of 742 patients between January 2007 and July 2020,50 patients aged 13 to 39 years with Enneking stage II disease were included in the study.Serum lipid levels,including total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),lipoprotein-α[Lp(a)],and apolipoprotein A1,B,and E(ApoA1,ApoB,and ApoE),and clinicopathological characteristics were collected before and after neoadjuvant chemotherapy.Results The mean levels of TC,TG,and ApoB were significantly increased following neoadjuvant chemotherapy(16%,38%,and 20%,respectively,vs.pretreatment values;P<0.01).The mean levels of LDL-C and ApoE were also 19%and 16%higher,respectively(P<0.05).No correlation was found between the pretreatment lipid profile and the histologic response to chemotherapy.An increase in Lp(a)was strongly correlated with the Ki-67 index(R=0.31,P=0.023).Moreover,a trend toward longer disease-free survival(DFS)was observed in patients with decreased TG and increased LDL-C following chemotherapy,although this difference was not statistically significant(P=0.23 and P=0.24,respectively).Conclusion Significant elevations in serum lipids were observed after neoadjuvant chemotherapy in patients with localized osteosarcoma.There was no prognostic significance of pretreatment serum lipid levels on histologic response to neoadjuvant chemotherapy.The scale of increase in serum Lp(a)might have a potential prognostic role in osteosarcoma.Patients with increased LDL-C or reduced TG after chemotherapy seem to exhibit a trend toward favorable DFS.展开更多
Background:The natural history of chronic HBV infection is typically characterized by four stages:the immune tolerance period,the immune clearance period,the immune control period,and the immune escape period.These st...Background:The natural history of chronic HBV infection is typically characterized by four stages:the immune tolerance period,the immune clearance period,the immune control period,and the immune escape period.These stages are associated with the distribution of HBcAg in liver cells;however,this relationship remains a topic of broad debate within the field of liver disease.To objectively and quantitatively measure the intracellular distribution of HBcAg,this paper aims to design a method referred to as the“layered evaluation method”and to examine its validation.Methods:The distribution of HBcAg in liver cells is assessed using Image Pro Plus image processing software,along with calculations of cytoplasmic and nuclear positive staining rates.Results:The findings indicate that the highest proportion of patients exhibited a positive cytoplasmic expression rate ranging from 0-2.5%.More than 40% of the total sample was categorized within the 0-2.5% positive nuclear expression range.The HBcAg cytoplasmic positive staining rates were classified into five levels:a cytoplasmic HBcAg positive staining rate of less than 0.05% is designated as level 0,indicating negative expression;a staining rate between 0.05% and 5% is classified as level 1;a rate from 5% to less than 10% is classified as level 2;a rate from 10% to less than 20% is classified as level 3;and a nuclear positivity rate exceeding 20% is classified as level 4.Conclusion:The inflammatory activity grade in these patients was positively correlated with the cytoplasmic distribution of HBcAg.Furthermore,the nuclear distribution rate of HBcAg was significantly higher in the G3 group compared to the other groups.展开更多
Objective Here we aimed to investigate the difference in clinical characteristics and outcomes between pediatric and adult patients with COVID-19.Methods A total of 333 consecutive patients with laboratory-confirmed S...Objective Here we aimed to investigate the difference in clinical characteristics and outcomes between pediatric and adult patients with COVID-19.Methods A total of 333 consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated in the departments of Internal medicine of Shenzhen Third People’s Hospital from January 11 th to February 10 th,2020 were included.The data were obtained from electronic medical records.The epidemiological data,clinical characteristics,length of hospital stays,and outcomes of pediatric and adult patients were compared.Results Compared with adult patients,pediatric patients had a shorter time of symptom onset to hospitalization than adults[median time,1(IQR,1.0-1.0)d vs.3(IQR,2.0-6.0)d,P<0.001],milder or fewer symptoms,less severe chest CT findings.The clinical severity classification of children was less severe than adults.Up to 15 th March,the end of the follow-up,33(100%)children and 292(97.3%)adult patients had been discharged from hospital.Only 2(0.7%)adult patients died,with an overall case mortality of 0.6%.The median length of hospital stay of pediatric patients was shorter than that of adult patients[19(95%CI:16.6-21.4)d vs.21(95%CI:19.9-22.1)d,P=0.024].Conclusion Pediatric patients with COVID-19 had milder or less clinical symptoms,less evident pulmonary imaging changes,better prognosis,and shorter length of hospital stay.展开更多
Dear Editor,Unlike previous outbreaks of the mpox(previously known as monkeypox),which were localized in Africa and resulted in small numbers of infections due to limited human-to-human transmission,the current outbre...Dear Editor,Unlike previous outbreaks of the mpox(previously known as monkeypox),which were localized in Africa and resulted in small numbers of infections due to limited human-to-human transmission,the current outbreak beginning in May 2022,has spread rapidly primarily through human-to-human transmission in non-endemic countries(Gong et al.,2022).As of 27 Sep 2023,115 countries and regions have reported cases of mpox to the World Health Organization(WHO),bringing the total number of confirmed cases to 90,618 including 125 deaths.Although the number of new cases has decreased in most WHO regions in the second half of 2022,the curves reveal a long outbreak tail in different subregions of the Americas.More worrying,106 mpox cases were reported in the mainland of China in June 2023.展开更多
Aims:Surveys and research on the applications of the hepatic venous pressure gradient(HVPG)are important for understanding the current status and future development of this technology in China.This article aimed to in...Aims:Surveys and research on the applications of the hepatic venous pressure gradient(HVPG)are important for understanding the current status and future development of this technology in China.This article aimed to investigate the status of hepatic venous pressure gradient measurement in China in 2022.Methods:We investigated the overall status of HVPG technology in China-including hospital distribution,hospital level,annual number of cases,catheters used,average cost,indications,and current challenges by using online questionnaire.By counting the number and percentages of cases of these results,we hope to clarify the current status of HVPG measurements in China.Results:According to the survey,85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces.A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022,of which 2813 cases(56.4%)were measured alone.The average cost of HVPG measurement was 5646.8±2327.9 CNY.Of the clinical teams who performed the measurements(sometimes multiple per hospital),94.3%(82/87)used the balloon method,and the majority of the teams(72.4%,63/87)used embolectomy catheters.Conclusions:This survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this technology.It is still necessary to continue promoting and popularizing this technology in the future.展开更多
Objective To evaluate multidrug resistant loop-mediated isothermal amplification(MDR-LAMP)assay for the early diagnosis of multidrug-resistant tuberculosis and to compare the mutation patterns associated with the rpoB...Objective To evaluate multidrug resistant loop-mediated isothermal amplification(MDR-LAMP)assay for the early diagnosis of multidrug-resistant tuberculosis and to compare the mutation patterns associated with the rpoB,katG,and inhA genes at the Chinese Center for Disease Control and Prevention.Methods MDR-LAMP assay was evaluated using 100 Mycobacterium tuberculosis(Mtb)isolates obtained from the National Reference Laboratory for Tuberculosis in China.Phenotypic resistance to isoniazid and rifampicin and whole-genome sequencing served as reference standards.Results The sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)of MDR-LAMP were 85.5%,93.6%,96.7%,and 74.4%for the detection of resistance to isoniazid and rifampicin,respectively,and 80.5%,92.3%,98.6%,and 41.4%for the detection of Mtb cultured from smear-positive sputum samples,respectively.When DNA sequencing was used as the reference standard,the sensitivity,specificity,PPV,and NPV of MDR-LAMP were 93.1%,92.3%,97.2%,and 82.8%for the detection of katG and inhA gene mutations,respectively,and 89.1%,88.9%,93.4%,and 81.1%for the detection of rpoB gene mutation,respectively.Conclusion MDR-LAMP is a rapid and accessible assay for the laboratory identification of rifampicin and isoniazid resistance of Mtb isolates.展开更多
The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates （NHPs）, causing severe hemorrhagic fevers with high fatali...The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates （NHPs）, causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.展开更多
Advances in nanotechnology have opened new frontiers in the diagnosis and treatment of cancer.Nanoparticle-based technology improves the precision of tumor diagnosis when combined with imaging,as well as the accuracy ...Advances in nanotechnology have opened new frontiers in the diagnosis and treatment of cancer.Nanoparticle-based technology improves the precision of tumor diagnosis when combined with imaging,as well as the accuracy of drug target delivery,with fewer side effects.Optimized nanosystems have demonstrated advantages in many fields,including enhanced specificity of detection,reduced toxicity of drugs,enhanced effect of contrast agents,and advanced diagnosis and therapy of gastrointestinal(GI)cancers.In this review,we summarize the current nanotechnologies in diagnosis and treatment of GI cancers.The development of nanotechnology will lead to personalized approaches for early diagnosis and treatment of GI cancers.展开更多
Objectives To investigate the clinical features of tuberculosis(TB)-associated immune reconstitution inflammatory syndrome(TB-IRIS) in patients co-infected with HIV/TB or latent infection during highly active antiretr...Objectives To investigate the clinical features of tuberculosis(TB)-associated immune reconstitution inflammatory syndrome(TB-IRIS) in patients co-infected with HIV/TB or latent infection during highly active antiretroviral therapy(HAART).Methods HIV-infected patients treated in the Third People's Hospital of Shenzhen, China between March 2012 and March 2013 were recruited, and divided into 3 groups: 1) HIV/TB co-infection group(n = 50), 2) HIV/MTB latent infection group(n = 50), and 3) HIV infection group(n = 50), with 12-month follow-up. Patients in the HIV/TB co-infection group were treated with HAART 2 weeks after TB therapy. Patients were assessed at different time-points.Results The incidence and mortality rates of TB-IRIS were 40% and 10% in the HIV/TB co-infected patients, and 2%(and no mortality) in the HIV/MTB group. The HIV infected group did not display TB-IRIS or death. About 95% HIV/TB co-infected patients were 20-39 years old when TB-IRIS occurred, and 65% of the patients developed TB-IRIS 2 weeks after HAART. For the co-infection group, those with TB-IRIS(20/20, 100%) had fever, with a significantly higher incidence than those who did not develop TB-IRIS(6.7%, 2/30, P < 0.05). The patients with TB-IRIS in co-infection group displayed markedly higher clinical biochemical markers, acute phase reactants, increased CD4+ cell counts, and 2 log10-decreases of HIV RNA loads, compared with the patients not presenting with TB-IRIS(P < 0.05). Conclusion HIV/TB co-infected patients presented with a high-risk of developing TB-IRIS during HAART treatment. Early diagnosis and treatment could decrease mortality rates in TB-IRIS.展开更多
BACKGROUND The widespread coronavirus disease 2019(COVID-19)has led to high morbidity and mortality.Therefore,early risk identification of critically ill patients remains crucial.AIM To develop predictive rules at the...BACKGROUND The widespread coronavirus disease 2019(COVID-19)has led to high morbidity and mortality.Therefore,early risk identification of critically ill patients remains crucial.AIM To develop predictive rules at the time of admission to identify COVID-19 patients who might require intensive care unit(ICU)care.METHODS This retrospective study included a total of 361 patients with confirmed COVID-19 by reverse transcription-polymerase chain reaction between January 19,2020,and March 14,2020 in Shenzhen Third People’s Hospital.Multivariate logistic regression was applied to develop the predictive model.The performance of the predictive model was externally validated and evaluated based on a dataset involving 126 patients from the Wuhan Asia General Hospital between December 2019 and March 2020,by area under the receiver operating curve(AUROC),goodness-of-fit and the performance matrix including the sensitivity,specificity,and precision.A nomogram was also used to visualize the model.RESULTS Among the patients in the derivation and validation datasets,38 and 9 participants(10.5%and 2.54%,respectively)developed severe COVID-19,respectively.In univariate analysis,21 parameters such as age,sex(male),smoker,body mass index(BMI),time from onset to admission(>5 d),asthenia,dry cough,expectoration,shortness of breath,asthenia,and Rox index<18(pulse oxygen saturation,SpO2)/(FiO2×respiratory rate,RR)showed positive correlations with severe COVID-19.In multivariate logistic regression analysis,only six parameters including BMI[odds ratio(OR)3.939;95%confidence interval(CI):1.409-11.015;P=0.009],time from onset to admission(≥5 d)(OR 7.107;95%CI:1.449-34.849;P=0.016),fever(OR 6.794;95%CI:1.401-32.951;P=0.017),Charlson index(OR 2.917;95%CI:1.279-6.654;P=0.011),PaO2/FiO2 ratio(OR 17.570;95%CI:1.117-276.383;P=0.041),and neutrophil/lymphocyte ratio(OR 3.574;95%CI:1.048-12.191;P=0.042)were found to be independent predictors of COVID-19.These factors were found to be significant risk factors for severe patients confirmed with COVID-19.The AUROC was 0.941(95%CI:0.901-0.981)and 0.936(95%CI:0.886-0.987)in both datasets.The calibration properties were good.CONCLUSION The proposed predictive model had great potential in severity prediction of COVID-19 in the ICU.It assisted the ICU clinicians in making timely decisions for the target population.展开更多
Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis s...Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals.展开更多
Research on nutrigenomics has accumulated sufficient data in the past two decades that have dem on strated phe no types of single n ucleotide polymorphisms (SNPs) betwee n healthy and micronutrient-deficient populatio...Research on nutrigenomics has accumulated sufficient data in the past two decades that have dem on strated phe no types of single n ucleotide polymorphisms (SNPs) betwee n healthy and micronutrient-deficient populations. For instance, Zhang et al. showed that the genes MTHFR C677T, MTRR A66G, and MTR A2756G were the genetic factors resp on sible for low absorptio n and bioavailability of vitamins such as folate, B6/ and B12. It has also been reported that these nutrients are closely associated with the prevale nee of neural tube defects in newborn infants。展开更多
The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previo...The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice （MARV/Ang-MA）, with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate （NHP） model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs （MARV/Ang- GA）. Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1x10-1 TCID50 （median tissue culture infective dose）. Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.展开更多
Objective Various immune cells in patients with CHB have been demonstrated to play critical roles in HBV infection.The goal of this study is to observe changes in Thl7,Treg,Thl and B lymphocytes from peripheral blood ...Objective Various immune cells in patients with CHB have been demonstrated to play critical roles in HBV infection.The goal of this study is to observe changes in Thl7,Treg,Thl and B lymphocytes from peripheral blood and to evaluate immune status of CHB patients undergoing antiviral treatment.Methods Total of 49 CHB patients,19 asymptomatic carriers and 29 healthy donors were included in our present study.The frequencies of peripheral Thl7 cells(CD3^+CD4^+IL-17^+Tcells),Treg cells(CD3^+CD4^+CD25^+CD127^- T cells),Th1 cells(CD3^+CD4^+IFN^-γ T cells) and B lymphocytes in chronic hepatitis B(CHB) were analyzed by flow cytometry.Results The frequency of Th17 cells increased after treatment for 6 months,but there was no statistically significant difference of IL-17 expression between baseline and 6 months after treatment.The frequencies of Treg cells,momory B cells and total CD19^+B cells decreased after antiviral treatment.The frequencies of Thl cells and plasma cells increased after antiviral treatment.Conclusions This study highlights that the reestablishment of immune function during antiviral treatment in CHB patients,which caused by the antiviral drugs or the patients themselves.CHB patients may exhibit varied responses to these antiviral drugs.It is essential to supplement immune therapy during the antiviral treatment,but Th17 may play a limited role in inflammation during antiviral treatment,targeting Th17 therapy may not be useful for CHB treatment.More time and more experiments are critical to explain it.展开更多
1|INTRODUCTION Accurate pathogenic testing is essential for early diag-nosis and precise treatment of COVID‐19,and correct specimen collection and handling is vital for accurate diagnosis[1].With the continuing mutat...1|INTRODUCTION Accurate pathogenic testing is essential for early diag-nosis and precise treatment of COVID‐19,and correct specimen collection and handling is vital for accurate diagnosis[1].With the continuing mutations,the pathogenicity of Severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)has gradually decreased,so the management of COVID‐19 in China has been down-graded to Class B(http://www.nhc.gov.cn).Infections with different SARS‐CoV‐2 variants produce variable clinical manifestations,and the types of specimens vary accordingly[2].The purpose of developing this guideline was to standardize the process of specimen collection and handling for microbiological testing from patients with confirmed or suspected COVID‐19 to avoid incorrect diagnosis and treatment.展开更多
Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in th...Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.展开更多
The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SA...The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.展开更多
Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.Th...Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.展开更多
Since the first reported case of monkeypox in the UK in May 2022,there has been an upward trend in monkeypox cases and a global outbreak.However,reports of severe cases are relatively limited.In this study,we report a...Since the first reported case of monkeypox in the UK in May 2022,there has been an upward trend in monkeypox cases and a global outbreak.However,reports of severe cases are relatively limited.In this study,we report a case of severe monkeypox in a patient with HIV.The patient presented with skin lesions that started on his face and around the penis and persisted for several months.Throughout the course of the disease,he received systematic symp-tomatic supportive treatment,topical remedies,and special care for the rash.He also underwent cidofovir antiviral therapy and smallpox‐vaccinated healthy population‐derived plasma therapy in succession,with the condition ultimately showing improvement after plasma treatment.After more than 3 months of hospitalization,he fully recovered.To the best of our knowledge,this is the first reported use of smallpox‐vaccinated healthy population‐derived plasma in the treatment of severe monkeypox cases.展开更多
基金Supported by the Shenzhen Science and Technology R&D Fund,No.JCYJ20220530163011026and Shenzhen Third People’s Hospital,No.G2022008 and No.G2021008。
文摘Liver transplantation is the primary therapeutic intervention for end-stage liver disease.However,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.The clinical manifestations associated with early arterial complications following liver transplantation are often non-specific.Without timely intervention,these complications can result in graft fai-lure or patient mortality.Therefore,early diagnosis and the formulation of an op-timal treatment plan are imperative.Ultrasound examination remains the pre-dominant imaging modality for detecting complications post liver transplan-tation.This article comprehensively reviews common causes and clinical present-ations of early hepatic artery complications in the post-transplantation period and delineates abnormal sonographic findings for accurate diagnosis of these con-ditions.Overall,ultrasound offers the advantages of convenience,safety,effect-iveness,and non-invasiveness.It enables real-time,dynamic,and precise evalua-tion,making it the preferred diagnostic method for post-liver transplantation assessments.INTRODUCTION Liver transplantation stands as the primary therapeutic approach for end-stage liver disease.Continuous advancements in surgical techniques and the application of novel immunosuppressive agents contribute to ongoing improvements in the success rate and overall survival in patients undergoing liver transplantation procedures.Despite these advan-cements,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.During the early stages following liver transplantation(within the first 30 d),proper hepatic artery function is crucial for hepatic arterial blood flow.During later stages,collateral circulation,including arteries such as the phrenic artery,right gastric artery,and gastroduodenal artery,becomes important for maintaining hepatic blood supply.It is now understood that the establishment of effective collateral circulation is pivotal for determining the prognosis of hepatic artery complic-ations.The clinical manifestations of these complications are closely linked to factors such as timing,severity,and the specific type of onset.Insufficient hepatic arterial blood flow can lead to abnormal liver function,hepatic infarction,and the formation of hepatic abscesses.Additionally,since the hepatic artery is the sole blood supply to the biliary tract,hepatic artery-related ischemia may result in biliary stricture,obstruction,and the formation of bile ducts.Ultrasound examination remains the primary imaging modality for diagnosing complications post liver transplantation.This article comprehensively reviews common causes and clinical presentations of early hepatic artery complications in the post-transplantation period and outlines abnormal sonographic findings for accurately diagnosing these conditions.NORMAL HEPATIC ARTERY During the intraoperative phase,an ultrasound examination is typically conducted to evaluate the hepatic artery anas-tomosis.The normal internal diameter of the hepatic artery typically ranges from 2 to 5 mm.Two strong echo points are typically identified near the anastomosis.To assess blood flow dynamics,peak systolic velocity,end-diastolic velocity,and resistance index are measured at the donor and recipient sides of the anastomosis following angle correction.Anastomotic stenosis presence and severity can be evaluated by comparing the velocity at the anastomotic site with that at the recipient side.Postoperatively,direct visualization of the anastomosis site through gray ultrasound scans is often challenging.The surgical approach has a significant impact on the proper hepatic artery’s position,resulting in a lower overall success rate of continuous visualization.Color Doppler ultrasound is primarily employed to trace the artery’s path,and spectral measurements are taken at the brightest position of the Color Doppler blood flow signal,primarily used to identify the presence of high-speed turbulence.Hepatic artery spectrum examination plays a crucial role,as a favorable arterial spectral waveform and appropriate hepatic artery flow velocity typically indicate a successful anastomosis,even in cases where the hepatic artery anastomosis cannot be directly visualized by ultrasound.The hepatic artery runs alongside the portal vein,often selected as a reference due to its larger inner diameter.A normal hepatic artery spectrum displays a regular pulsation pattern with a rapid rise in systole and a slow decline in diastole.Parameters for assessing hepatic artery resistance include a resistance index between 0.5 to 0.8 and an artery systolic acceleration of less than 80 ms.Instantaneous increases in the resistance index(RI>0.8)often occur within 2 d after surgery,followed by a subsequent return to normal hepatic arterial parameters.It has been established that the maximum blood flow velocity during systole in the hepatic artery should not exceed 200 cm/s[1].
基金supported by China Medicine Education Association(CMEA)(No.2020KTS012)the National Natural Science Foundation of China(NSFC)(No.82002962 and No.81900189).
文摘Objective To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy.Methods After retrospectively screening the data of 742 patients between January 2007 and July 2020,50 patients aged 13 to 39 years with Enneking stage II disease were included in the study.Serum lipid levels,including total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),lipoprotein-α[Lp(a)],and apolipoprotein A1,B,and E(ApoA1,ApoB,and ApoE),and clinicopathological characteristics were collected before and after neoadjuvant chemotherapy.Results The mean levels of TC,TG,and ApoB were significantly increased following neoadjuvant chemotherapy(16%,38%,and 20%,respectively,vs.pretreatment values;P<0.01).The mean levels of LDL-C and ApoE were also 19%and 16%higher,respectively(P<0.05).No correlation was found between the pretreatment lipid profile and the histologic response to chemotherapy.An increase in Lp(a)was strongly correlated with the Ki-67 index(R=0.31,P=0.023).Moreover,a trend toward longer disease-free survival(DFS)was observed in patients with decreased TG and increased LDL-C following chemotherapy,although this difference was not statistically significant(P=0.23 and P=0.24,respectively).Conclusion Significant elevations in serum lipids were observed after neoadjuvant chemotherapy in patients with localized osteosarcoma.There was no prognostic significance of pretreatment serum lipid levels on histologic response to neoadjuvant chemotherapy.The scale of increase in serum Lp(a)might have a potential prognostic role in osteosarcoma.Patients with increased LDL-C or reduced TG after chemotherapy seem to exhibit a trend toward favorable DFS.
文摘Background:The natural history of chronic HBV infection is typically characterized by four stages:the immune tolerance period,the immune clearance period,the immune control period,and the immune escape period.These stages are associated with the distribution of HBcAg in liver cells;however,this relationship remains a topic of broad debate within the field of liver disease.To objectively and quantitatively measure the intracellular distribution of HBcAg,this paper aims to design a method referred to as the“layered evaluation method”and to examine its validation.Methods:The distribution of HBcAg in liver cells is assessed using Image Pro Plus image processing software,along with calculations of cytoplasmic and nuclear positive staining rates.Results:The findings indicate that the highest proportion of patients exhibited a positive cytoplasmic expression rate ranging from 0-2.5%.More than 40% of the total sample was categorized within the 0-2.5% positive nuclear expression range.The HBcAg cytoplasmic positive staining rates were classified into five levels:a cytoplasmic HBcAg positive staining rate of less than 0.05% is designated as level 0,indicating negative expression;a staining rate between 0.05% and 5% is classified as level 1;a rate from 5% to less than 10% is classified as level 2;a rate from 10% to less than 20% is classified as level 3;and a nuclear positivity rate exceeding 20% is classified as level 4.Conclusion:The inflammatory activity grade in these patients was positively correlated with the cytoplasmic distribution of HBcAg.Furthermore,the nuclear distribution rate of HBcAg was significantly higher in the G3 group compared to the other groups.
基金supported by the National Clinical Research Center for Infectious DiseasesFunds for the Construction of Key Medical Disciplines in Shenzhen and the Sanming Project of Medicine in Shenzhen[SZSM201612014]。
文摘Objective Here we aimed to investigate the difference in clinical characteristics and outcomes between pediatric and adult patients with COVID-19.Methods A total of 333 consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated in the departments of Internal medicine of Shenzhen Third People’s Hospital from January 11 th to February 10 th,2020 were included.The data were obtained from electronic medical records.The epidemiological data,clinical characteristics,length of hospital stays,and outcomes of pediatric and adult patients were compared.Results Compared with adult patients,pediatric patients had a shorter time of symptom onset to hospitalization than adults[median time,1(IQR,1.0-1.0)d vs.3(IQR,2.0-6.0)d,P<0.001],milder or fewer symptoms,less severe chest CT findings.The clinical severity classification of children was less severe than adults.Up to 15 th March,the end of the follow-up,33(100%)children and 292(97.3%)adult patients had been discharged from hospital.Only 2(0.7%)adult patients died,with an overall case mortality of 0.6%.The median length of hospital stay of pediatric patients was shorter than that of adult patients[19(95%CI:16.6-21.4)d vs.21(95%CI:19.9-22.1)d,P=0.024].Conclusion Pediatric patients with COVID-19 had milder or less clinical symptoms,less evident pulmonary imaging changes,better prognosis,and shorter length of hospital stay.
基金supported by the National Key Plan for Scientific R&D of China(2021YFC2301900)the National Science Fund for Distinguished Young Scholars(82025022)+2 种基金Guangdong Science and Technology Plan Project,Construction of high-level biosafety laboratories(2021B1212030010)Shenzhen Science and Technology Program(ZDSYS20210623091810030)Shenzhen Medical Research Funds(B2302052).
文摘Dear Editor,Unlike previous outbreaks of the mpox(previously known as monkeypox),which were localized in Africa and resulted in small numbers of infections due to limited human-to-human transmission,the current outbreak beginning in May 2022,has spread rapidly primarily through human-to-human transmission in non-endemic countries(Gong et al.,2022).As of 27 Sep 2023,115 countries and regions have reported cases of mpox to the World Health Organization(WHO),bringing the total number of confirmed cases to 90,618 including 125 deaths.Although the number of new cases has decreased in most WHO regions in the second half of 2022,the curves reveal a long outbreak tail in different subregions of the Americas.More worrying,106 mpox cases were reported in the mainland of China in June 2023.
文摘Aims:Surveys and research on the applications of the hepatic venous pressure gradient(HVPG)are important for understanding the current status and future development of this technology in China.This article aimed to investigate the status of hepatic venous pressure gradient measurement in China in 2022.Methods:We investigated the overall status of HVPG technology in China-including hospital distribution,hospital level,annual number of cases,catheters used,average cost,indications,and current challenges by using online questionnaire.By counting the number and percentages of cases of these results,we hope to clarify the current status of HVPG measurements in China.Results:According to the survey,85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces.A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022,of which 2813 cases(56.4%)were measured alone.The average cost of HVPG measurement was 5646.8±2327.9 CNY.Of the clinical teams who performed the measurements(sometimes multiple per hospital),94.3%(82/87)used the balloon method,and the majority of the teams(72.4%,63/87)used embolectomy catheters.Conclusions:This survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this technology.It is still necessary to continue promoting and popularizing this technology in the future.
基金the Chinese Center for Disease Control and Prevention project[59911905 and 59911916].
文摘Objective To evaluate multidrug resistant loop-mediated isothermal amplification(MDR-LAMP)assay for the early diagnosis of multidrug-resistant tuberculosis and to compare the mutation patterns associated with the rpoB,katG,and inhA genes at the Chinese Center for Disease Control and Prevention.Methods MDR-LAMP assay was evaluated using 100 Mycobacterium tuberculosis(Mtb)isolates obtained from the National Reference Laboratory for Tuberculosis in China.Phenotypic resistance to isoniazid and rifampicin and whole-genome sequencing served as reference standards.Results The sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)of MDR-LAMP were 85.5%,93.6%,96.7%,and 74.4%for the detection of resistance to isoniazid and rifampicin,respectively,and 80.5%,92.3%,98.6%,and 41.4%for the detection of Mtb cultured from smear-positive sputum samples,respectively.When DNA sequencing was used as the reference standard,the sensitivity,specificity,PPV,and NPV of MDR-LAMP were 93.1%,92.3%,97.2%,and 82.8%for the detection of katG and inhA gene mutations,respectively,and 89.1%,88.9%,93.4%,and 81.1%for the detection of rpoB gene mutation,respectively.Conclusion MDR-LAMP is a rapid and accessible assay for the laboratory identification of rifampicin and isoniazid resistance of Mtb isolates.
基金supported by the Public Health Agency of Canada(PHAC)partially supported by the NIH and CIHR grants to X.G.Qiu(U19 AI109762-1 and CIHR-IER-143487,respectively)+1 种基金the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates （NHPs）, causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.
基金Supported by the Nanshan District Science and Technology Plan Project,No.2020048 Generalthe Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties,No.SZGSP010.
文摘Advances in nanotechnology have opened new frontiers in the diagnosis and treatment of cancer.Nanoparticle-based technology improves the precision of tumor diagnosis when combined with imaging,as well as the accuracy of drug target delivery,with fewer side effects.Optimized nanosystems have demonstrated advantages in many fields,including enhanced specificity of detection,reduced toxicity of drugs,enhanced effect of contrast agents,and advanced diagnosis and therapy of gastrointestinal(GI)cancers.In this review,we summarize the current nanotechnologies in diagnosis and treatment of GI cancers.The development of nanotechnology will lead to personalized approaches for early diagnosis and treatment of GI cancers.
基金supported by the National Key Discipline of Clinical Infectious Diseases, the National Key Project of the "12th five-year" Infectious Diseases Program: Generalization and Optimization of Standardized Diagnosis and Treatment of AIDS Patients Complicated with TB (2012ZX10001-003)the Key Program of the Natural Science Foundation of Guangdong Province, China (S2012020010873)the Science and Technology Innovation Foundation of Shenzhen, China (CYJ20120829093552348 and JCYJ20130401164750002)
文摘Objectives To investigate the clinical features of tuberculosis(TB)-associated immune reconstitution inflammatory syndrome(TB-IRIS) in patients co-infected with HIV/TB or latent infection during highly active antiretroviral therapy(HAART).Methods HIV-infected patients treated in the Third People's Hospital of Shenzhen, China between March 2012 and March 2013 were recruited, and divided into 3 groups: 1) HIV/TB co-infection group(n = 50), 2) HIV/MTB latent infection group(n = 50), and 3) HIV infection group(n = 50), with 12-month follow-up. Patients in the HIV/TB co-infection group were treated with HAART 2 weeks after TB therapy. Patients were assessed at different time-points.Results The incidence and mortality rates of TB-IRIS were 40% and 10% in the HIV/TB co-infected patients, and 2%(and no mortality) in the HIV/MTB group. The HIV infected group did not display TB-IRIS or death. About 95% HIV/TB co-infected patients were 20-39 years old when TB-IRIS occurred, and 65% of the patients developed TB-IRIS 2 weeks after HAART. For the co-infection group, those with TB-IRIS(20/20, 100%) had fever, with a significantly higher incidence than those who did not develop TB-IRIS(6.7%, 2/30, P < 0.05). The patients with TB-IRIS in co-infection group displayed markedly higher clinical biochemical markers, acute phase reactants, increased CD4+ cell counts, and 2 log10-decreases of HIV RNA loads, compared with the patients not presenting with TB-IRIS(P < 0.05). Conclusion HIV/TB co-infected patients presented with a high-risk of developing TB-IRIS during HAART treatment. Early diagnosis and treatment could decrease mortality rates in TB-IRIS.
文摘BACKGROUND The widespread coronavirus disease 2019(COVID-19)has led to high morbidity and mortality.Therefore,early risk identification of critically ill patients remains crucial.AIM To develop predictive rules at the time of admission to identify COVID-19 patients who might require intensive care unit(ICU)care.METHODS This retrospective study included a total of 361 patients with confirmed COVID-19 by reverse transcription-polymerase chain reaction between January 19,2020,and March 14,2020 in Shenzhen Third People’s Hospital.Multivariate logistic regression was applied to develop the predictive model.The performance of the predictive model was externally validated and evaluated based on a dataset involving 126 patients from the Wuhan Asia General Hospital between December 2019 and March 2020,by area under the receiver operating curve(AUROC),goodness-of-fit and the performance matrix including the sensitivity,specificity,and precision.A nomogram was also used to visualize the model.RESULTS Among the patients in the derivation and validation datasets,38 and 9 participants(10.5%and 2.54%,respectively)developed severe COVID-19,respectively.In univariate analysis,21 parameters such as age,sex(male),smoker,body mass index(BMI),time from onset to admission(>5 d),asthenia,dry cough,expectoration,shortness of breath,asthenia,and Rox index<18(pulse oxygen saturation,SpO2)/(FiO2×respiratory rate,RR)showed positive correlations with severe COVID-19.In multivariate logistic regression analysis,only six parameters including BMI[odds ratio(OR)3.939;95%confidence interval(CI):1.409-11.015;P=0.009],time from onset to admission(≥5 d)(OR 7.107;95%CI:1.449-34.849;P=0.016),fever(OR 6.794;95%CI:1.401-32.951;P=0.017),Charlson index(OR 2.917;95%CI:1.279-6.654;P=0.011),PaO2/FiO2 ratio(OR 17.570;95%CI:1.117-276.383;P=0.041),and neutrophil/lymphocyte ratio(OR 3.574;95%CI:1.048-12.191;P=0.042)were found to be independent predictors of COVID-19.These factors were found to be significant risk factors for severe patients confirmed with COVID-19.The AUROC was 0.941(95%CI:0.901-0.981)and 0.936(95%CI:0.886-0.987)in both datasets.The calibration properties were good.CONCLUSION The proposed predictive model had great potential in severity prediction of COVID-19 in the ICU.It assisted the ICU clinicians in making timely decisions for the target population.
基金supported by the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)the National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals.
基金supported by Rural compulsory education student nutrition improvement plan-student nutrition and health condition in-depth monitoring and evaluation project [2016-019]
文摘Research on nutrigenomics has accumulated sufficient data in the past two decades that have dem on strated phe no types of single n ucleotide polymorphisms (SNPs) betwee n healthy and micronutrient-deficient populations. For instance, Zhang et al. showed that the genes MTHFR C677T, MTRR A66G, and MTR A2756G were the genetic factors resp on sible for low absorptio n and bioavailability of vitamins such as folate, B6/ and B12. It has also been reported that these nutrients are closely associated with the prevale nee of neural tube defects in newborn infants。
基金supported by the Public Health Agency of Canada(PHAC)partially supported by the NIH and CIHR grants to X.G.Qiu(U19 AI109762-1 and CIHR-IER-143487,respectively)+1 种基金grants from the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice （MARV/Ang-MA）, with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate （NHP） model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs （MARV/Ang- GA）. Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1x10-1 TCID50 （median tissue culture infective dose）. Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.
基金funded in full by Natural Science Foundation of China(Grant number:30872238)
文摘Objective Various immune cells in patients with CHB have been demonstrated to play critical roles in HBV infection.The goal of this study is to observe changes in Thl7,Treg,Thl and B lymphocytes from peripheral blood and to evaluate immune status of CHB patients undergoing antiviral treatment.Methods Total of 49 CHB patients,19 asymptomatic carriers and 29 healthy donors were included in our present study.The frequencies of peripheral Thl7 cells(CD3^+CD4^+IL-17^+Tcells),Treg cells(CD3^+CD4^+CD25^+CD127^- T cells),Th1 cells(CD3^+CD4^+IFN^-γ T cells) and B lymphocytes in chronic hepatitis B(CHB) were analyzed by flow cytometry.Results The frequency of Th17 cells increased after treatment for 6 months,but there was no statistically significant difference of IL-17 expression between baseline and 6 months after treatment.The frequencies of Treg cells,momory B cells and total CD19^+B cells decreased after antiviral treatment.The frequencies of Thl cells and plasma cells increased after antiviral treatment.Conclusions This study highlights that the reestablishment of immune function during antiviral treatment in CHB patients,which caused by the antiviral drugs or the patients themselves.CHB patients may exhibit varied responses to these antiviral drugs.It is essential to supplement immune therapy during the antiviral treatment,but Th17 may play a limited role in inflammation during antiviral treatment,targeting Th17 therapy may not be useful for CHB treatment.More time and more experiments are critical to explain it.
基金Special Support Fund of Shenzhen for Introduced High‐Level Medical Team,Grant/Award Number:SZSM201412005Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2020A1515010586Science and Technology program of Shenzhen,Grant/Award Number:JCYJ20190809144005609。
文摘1|INTRODUCTION Accurate pathogenic testing is essential for early diag-nosis and precise treatment of COVID‐19,and correct specimen collection and handling is vital for accurate diagnosis[1].With the continuing mutations,the pathogenicity of Severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)has gradually decreased,so the management of COVID‐19 in China has been down-graded to Class B(http://www.nhc.gov.cn).Infections with different SARS‐CoV‐2 variants produce variable clinical manifestations,and the types of specimens vary accordingly[2].The purpose of developing this guideline was to standardize the process of specimen collection and handling for microbiological testing from patients with confirmed or suspected COVID‐19 to avoid incorrect diagnosis and treatment.
基金supported by the National Natural Science Foundation of China (Nos.82130105 to H.L.,82121005 to H.L.,92169112 to S.J.,82041036 to L.L.,T2225002 to M.Z.,82002142 to S.X.,82341093 to F.B.,and 32200131 to Y.Z.)the National Program on Key Research Project of China (2021YFC2300703 to L.L.)+4 种基金National Key R&D Program of China (2022YFC0868900 and 2021YFC0864900 to H.L.,2021YFC2300700 to L.Z.)Shanghai Municipal Science and Technology Major Project,Shanghai Science and Technology Development Funds (20QA1406400 to F.B.)Lingang Laboratory (LG202101-01-07 to H.Y.,LG202103-04-03 to W.D.)Youth Innovation Promotion Association CAS (2023296 to S.Z)the Science and Technology Commission of Shanghai Municipality (YDZX20213100001556 to H.Y.).
文摘Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.
基金supported by grants from Shenzhen Science and Technology Program(Grant No.JCYJ20220530163206015,China)National Key Research and Development Program of China(Grant No.2021YFA0910900)+4 种基金Shenzhen Science and Technology Program(Grant No.JCYJ20220818103017036,China)the National Science Fund for Distinguished Young Scholars(Grant No.82025022,China)Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110033,China)Guangdong Science and Technology Plan Project,construction of high-level biosafety laboratories(Grant No.2021B1212030010,China)Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110033,China).
文摘The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
基金supported by grants from the National Key Research and Development Program of China (No.2021YFC2301404)the National Natural Science Foundation of China (Nos.81991491,82272305,and 32170942)+4 种基金Fujian Natural Science Foundation (No.2020J06007)the Industry-University-Research Project of Xiamen (No.2022CXY0106)the Fundamental Research Funds for the Central Universities (Nos.20720220006 and 20720220004)National Postdoctoral Science Foundation of China (No.2021M712659)CAMS Innovation Fund for Medical Sciences (No.2019RU022).
文摘Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.
基金Science and Technology Research Projects of Shenzhen,Grant/Award Number:JSGG20220606141001003National Key Research and Development Program of China,Grant/Award Number:2022YFC2304403,2022YFC2304404+2 种基金National Natural Science Foundation of China,Grant/Award Number:81971915,82272318Shenzhen Fund for Guangdong Provincial High‐level Clinical Key Specialties,Grant/Award Number:No.SZGSP011Shenzhen Fund for Guangdong Provincial High‐level Clinical Key Specialties(No.SZGSP011)。
文摘Since the first reported case of monkeypox in the UK in May 2022,there has been an upward trend in monkeypox cases and a global outbreak.However,reports of severe cases are relatively limited.In this study,we report a case of severe monkeypox in a patient with HIV.The patient presented with skin lesions that started on his face and around the penis and persisted for several months.Throughout the course of the disease,he received systematic symp-tomatic supportive treatment,topical remedies,and special care for the rash.He also underwent cidofovir antiviral therapy and smallpox‐vaccinated healthy population‐derived plasma therapy in succession,with the condition ultimately showing improvement after plasma treatment.After more than 3 months of hospitalization,he fully recovered.To the best of our knowledge,this is the first reported use of smallpox‐vaccinated healthy population‐derived plasma in the treatment of severe monkeypox cases.
