Optimal Timing of Antiretroviral Therapy Initiation in Acquired Immunodeficiency Syndrome-Associated Toxoplasmic Encephalitis:A Prospective Observational Multicenter Study in China

Background:Toxoplasmic encephalitis(TE)is the most frequent cause of expansive brain lesions among patients with acquired immunodeficiency syndrome(AIDS).However,the optimal timing of antiretroviral therapy(ART)initiation in these patients remains controversial.This study aims to investigate the differences in outcomes of ART initiation at different times,in order to help clarify the treatment timing of AIDS-associated TE.Methods:This multicenter prospective observational study included 87 patients recruited from 11 research centers in China(from March 2019 to December 2022).Of the patients,38 were assigned to the early ART group(initiating ART within 2 weeks after anti-Toxoplasma treatment initiation),and the remaining 49 patients received deferred ART(initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation).The main outcomes includedmortality and emergence of immune reconstitution inflammatory syndrome(IRIS).Human immunodeficiency virus(HIV)-1 viral load and CD4^(+)T-cell counts at weeks 24 and 48 were observed.Results:The number of deaths(1 vs.5,P=0.225)and incidence of IRIS(2.6%vs.0,P=0.437)were not significantly different between the early and deferred ART groups at week 48.Early ART initiation did not contribute significantly to HIV-1 viral load control(<50 copies/mL,n=8 vs.n=3 at week 24,P=0.142;n=7 vs.n=7 atweek 48,P=1.000).The median CD4^(+)T-cell counts between the two groups were not significantly different,either at week 24(155 vs.91 cells/mm^(3),P=0.837)or atweek 48(181 vs.146 cells/mm^(3),P=0.219).Conclusion:In patients with AIDS-associated TE,early ART initiation was not significantly different from deferred ART initiation in terms of incidence of mortality,IRIS,and HIV virological and immunological outcomes.Trial registration:This study was registered(registration number:ChiCTR1900021195)as one of 12 clinical trials under the title of a general project at the Chinese Clinical Trial Registry(chictr.gov)on February 1,2019.Enrollment for this study began inMarch 2019.

Metformin may be a viable adjunctive therapeutic option to potentially enhance immune reconstitution in HIV-positive immunological non-responders

Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immunological non-responders(INRs),who exhibit dramatically low CD4^(+)T-cell counts despite the use of effective antiretroviral therapy,with long-term inhibition of viral replication.In this review,we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response,and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART.We found that immune cell exhaustion,combined with chronic inflammation and the HIV-associated dysbiosis syndrome,may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery.Interestingly,we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion,chronic inflammation,and HIV-associated gut dysbiosis syndrome,mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery.In light of evidence discussed in this review,it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution.The approach described herein may represent a promising area of therapeutic intervention,aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.

Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor

According to the World Health Organization(WHO)newly updated situation report on March 18th,2020,the coronavirus disease 2019(COVID-19)pandemic has confirmed 191,127 cases and claimed 7807 deaths worldwide.1 The etiological agent of COVID-19 has been identified as a novel coronavirus,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),belonging to Sarbecovirus subgenus(genus Betacoronavirus,family Coronaviridae)and showing 79.6 and 96.2%sequence identity in nucleotide to SARS-CoV and a bat coronavirus(BatCoV RaTG13),respectively.2–4 Like SARS-CoV infection,a substantial fraction of COVID-19 patients exhibits severe respiratory symptoms and has to be hospitalized in intensive care unit.5–8 Although the mortality rate of COVID-19 is significantly lower than that of SARS-CoV infection,SARS-CoV-2 shows much higher human-to-human transmission rate,rapidly leading to a global pandemic declared by WHO on March 11th,2020.

Changes of human immunodeficiency virus (HIV) burden globally and in China over three decades: a secondary analysis of global HIV statistics

Background: A more comprehensive understanding of the trends of incidence, prevalence, and mortality in human immunodeficiency virus (HIV), and their complex interrelationships, may provide important evidence for decision-making related to HIV prevention and control. The variances in these indices between different population groups, genders, and ages are critical to decipher evolving patterns of the HIV epidemic in specific populations.Methods: A secondary analysis of relevant data was conducted using data extracted from the Global Burden of Disease study of 2019. HIV/acquired immune deficiency syndrome (AIDS) incidence, prevalence, AIDS-related mortality, and mortality-to-prevalence ratio (MPR) for annual percentage change, average annual percentage change (AAPC), and corresponding 95% confidence intervals (CIs) were calculated using joinpoint regression statistical analysis.Results: The AAPC of HIV/AIDS incidence, prevalence, AIDS-related mortality rate, and MPR were -1.4 (95% CI: -1.6, -1.2), 4.1 (95% CI: 4.0, 4.3), 2.0 (95% CI: 1.7, 2.3), and -2.1 (95% CI: -2.3, -1.8) between 1990 and 2019 globally, and were 3.5 (95% CI: 2.2, 4.8), 6.9 (95% CI: 6.8, 7.0), 8.1 (95% CI: 7.1, 9.1), and 1.2 (95% CI: 0.1, 2.3) in China during the same period. In terms of differences in the preceding indicators by gender, we observed a similar pattern of trends for male and female genders both globally and in China during the entire study period. Each specific age group exhibits a distinct pattern in terms of incidence, prevalence, mortality rate, and MPR both globally and in China.Conclusions: Prevalence and mortality rates of HIV/AIDS have increased between 1990 and 2019 globally and in China. While the incidence rate and MPR have declined globally over the past three decades, these two indicators are observed to present an increasing trend in China. There is a high HIV burden among young and middle-aged adults globally;however, the elderly have a high HIV burden in China. HIV screening at older age should be scaled up, and patients with advanced HIV disease should be provided early with additional care and health resources.

Establishment and evaluation of an overlap extension polymerase chain reaction technique for rapid and efficient detection of drug-resistance in Mycobacterium tuberculosis

Background:Rapid and accurate detection of drug resistance inMycobacterium tuberculosis is critical for effective control of tuberculosis(TB).Herein,we established a novel,low cost strategy having high accuracy and speed for the detection ofM.tuberculosis drug resistance,using gene splicing by overlap extension PCR(SOE PCR).Methods:The SOE PCR assay and Sanger sequencing are designed and constructed to detect mutations of rpoB,embB,katG,andinhA promoter,which have been considered as the major contributors to rifampicin(RFP),isoniazid(INH),and ethambutol(EMB)resistance inM.tuberculosis.One hundred and eightM.tuberculosis isolates came from mycobacterial cultures of TB cases at Chongqing Public Health Medical Center in China from December 2018 to April 2019,of which 56 isolates were tested with the GeneXpert MTB/RIF assay.Performance evaluation of the SOE PCR technique was compared with traditional mycobacterial culture and drug susceptibility testing(DST)or GeneXpert MTB/RIF among these isolates.Kappa identity test was used to analyze the consistency of the different diagnostic methods.Results:We found that the mutations of S531L,S315T and M306V were most prevalent for RFP,INH and EMB resistance,respectively,in the 108 M.tuberculosis isolates.Compared with phenotypic DST,the sensitivity and specificity of the SOE PCR assay for resistance detection were 100.00% and 88.00% for RFP,94.64% and 94.23% for INH,and 68.97% and 79.75% for EMB,respectively.Compared with the GeneXpert MTB/RIF,the SOE PCR method was completely consistent with results of the GeneXpert MTB/RIF,with a concordance of 100% for resistance to RFP.Conclusions:In present study,a novel SOE PCR diagnostic method was successfully developed for the accurate detection ofM.tuberculosis drug resistance.Our results using this method have a high consistency with that of traditional phenotypic DST or GeneXpert MTB/RIF,and SOE PCR testing in clinical isolates can also be conducted rapidly and simultaneously for detection of drug resistance to RFP,EMB,and INH.

The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity

The adaptive immunity that protects patients from coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is not well characterized.In particular,the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses,but the underlying mechanisms remain unknown;meanwhile,the protective immunity that guide the recovery of these asymptomatic patients is elusive.Here,we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity(mild,n=10,moderate,n=32,severe,n=12)and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center(GC)B cell responses that result in robust and prolonged humoral immunity,assessed by GC response indicators including follicular helper T(TFH)cell and memory B cell responses as well as serum CXCL13 levels.Alternatively,these patients mounted potent virus-specific TH1 and CD8+T cell responses.In sharp contrast,patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses;however,the virus-specific TH1 and CD8+T cells were minimally induced in these patients.These results,therefore,uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity,providing important insights into rational design of effective COVID-19 vaccines.

G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction

GTPase-activating SH3 domain-binding protein 2(G3BP2)is a mediator that responds to environmental stresses through stress granule formation and is involved in the progression of chronic diseases.However,no studies have examined the contribution of G3BP2 in the oscillatory shear stress(OSS)-induced endothelial dysfunction.Here we assessed the effects of G3BP2 in endothelial cells(ECs)function and investigated the underlying mechanism.Using shear stress apparatus and partial ligation model,we identified that stress granulerelated genes in ECs could be induced by OSS with RNA-seq,and then confirmed that G3BP2 was highly and specifically expressed in athero-susceptible endothelia in the OSS regions.G3bp2e/eApoee/e mice had significantly decreased atherosclerotic lesions associated with deficiency of G3BP2 in protecting endothelial barrier function,decreasing monocyte adhesion to ECs and inhibiting the proinflammatory cytokine levels.Furthermore,loss of G3BP2 diminished OSS-induced inflammation in ECs by increasing YAP nucleocytoplasmic shuttling and phosphorylation.These data demonstrate that G3BP2 is a critical OSS regulated gene in regulating ECs function and that G3BP2 inhibition in ECs is a promising atheroprotective therapeutic strategy.

The efficacy assessment of convalescent plasma therapy for COVID-19 patients:a multi-center case series

Convalescent plasma(CP)transfusion has been indicated as a promising therapy in the treatment for other emerging viral infections.However,the quality control of CP and individual variation in patients in different studies make it rather difficult to evaluate the efficacy and risk of CP therapy for coronavirus disease 2019(COVID-19).We aimed to explore the potential efficacy of CP therapy,and to assess the possible factors associated with its efficacy.We enrolled eight critical or severe COVID-19 patients from four centers.Each patient was transfused with 200–400mL of CP from seven recovered donors.The primary indicators for clinical efficacy assessment were the changes of clinical symptoms,laboratory parameters,and radiological image after CP transfusion.CP donors had a wide range of antibody levels measured by serology tests which were to some degree correlated with the neutralizing antibody(NAb)level.No adverse events were observed during and after CP transfusion.Following CP transfusion,six out of eight patients showed improved oxygen support status;chest CT indicated varying degrees of absorption of pulmonary lesions in six patients within 8 days;the viral load was decreased to a negative level in five patients who had the previous viremia;other laboratory parameters also tended to improve,including increased lymphocyte counts,decreased C-reactive protein,procalcitonin,and indicators for liver function.The clinical efficacy might be associated with CP transfusion time,transfused dose,and the NAb levels of CP.This study indicated that CP might be a potential therapy for severe patients with COVID-19.

Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19

COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection.It is currently unknown as to the correlation between the magnitude of neutralizing antibody(NAb)responses and the disease severity in COVID-19 patients.In a cohort of 59 recovered patients with disease severity including severe,moderate,mild,and asymptomatic,we observed the positive correlation between serum neutralizing capacity and disease severity,in particular,the highest NAb capacity in sera from the patients with severe disease,while a lack of ability of asymptomatic patients to mount competent NAbs.Furthermore,the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-tomoderate symptoms.These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity,highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.

Synergistic sulfonamides plus clindamycin as an alternative therapeutic regimen for HIV-associated Toxoplasma encephalitis: a randomized controlled trial

Background: The preferred therapeutic regimen for Toxoplasma encephalitis (TE) is a combination of pyrimethamine and sulfadiazine, and trimethoprim-sulfamethoxazole (TMP-SMX) plus azithromycin is the widespread alternative therapeutic regimen. The synergistic sulfonamides tablet contains TMP, sulfadiazine, and SMX and hypothetically could be used for TE treatment. This study aimed to compare the efficacy and safety of synergistic sulfonamides plus clindamycin (regimen B) with TMP-SMX plus azithromycin (regimen A) for the treatment of human immunodeficiency virus (HIV) associated TE.Methods: This was an open-labeled, multi-center randomized controlled trial recruited from 11 centers. Each recruited patient was randomly assigned to receive regimen A or regimen B for at least 6 weeks. The overall response was evaluated by assessment of the clinical response of TE-associated clinical features and the radiological response of TE-associated radiological findings. The overall response rate, clinical response rate, radiological response rate, and adverse events were assessed at 2, 6, and 12 weeks. Death events were compared between the two regimens at 6, 12, and 24 weeks.Results: A total of 91 acquired immunodeficiency syndrome (AIDS)/TE patients were included in the final analysis (44 in regimen Avs. 47 in regimen B). The overall response rate, which refers to the combined clinical and radiological response, was 18.2% (8/44) for regimen A and 21.3 % (10/47) for regimen B at week 6. The results of clinical response showed that, in comparison with regimen A, regimen B may perform better with regards to its effect on the relief of clinical manifestations (50.0% [22/44]vs. 70.2% [33/47],P = 0.049). However, no significant differences in radiological response, mortality events, and adverse events were found between the two regimens at week 6.Conclusions: Synergistic sulfonamides plus clindamycin, as a novel treatment regimen, showed no significantly different efficacy and comparable safety in comparison with the TMP-SMX plus azithromycin regimen. In addition, the regimen containing synergistic sulfonamides may exhibit advantages in terms of clinical symptom alleviation.Trial Registration: ChiCTR.org.cn, ChiCTR1900021195.

Three Cases Infected with Avian Influenza A(H5N6)Virus-Chongqing Municipality,China,January-September,2021

Summary What is already known about this topic?The World Health Organization(WHO)has reported a total of 48 cases by October 15,2021.The continuous genomic reassortments of H5N6 and other subtype avian influenza viruses(AIVs)pose a long-term threat to public health and the poultry industry.What is added by this report?Three new cases of H5N6 that occurred from January to September 2021 in Chongqing Municipality,China were reported in this study.Epidemiological information of the three cases showed raising poultry and visiting live poultry market contributed to these infections,and there was no evidence of human-to-human transmission of H5N6 currently but a potential spatial cluster.An increase of H5N6 cases was recorded in the area.What are the implications for public health practice?In case of unexplained pneumonia or severe respiratory infection,the patients’epidemiological history of contact with poultry or live poultry markets(LPMs)may be an important interrogation to help diagnose.Extensive and long-term surveillance of avian influenza viruses in LPMs is essential.

Fungal Translocation Marker in People Living with HIV Needing Treatment for Onychomycosis: A Protocol for the Prospective Pilot Study

Increased microbial translocation and chronic immune activation are two critical problems for people living with HIV(PLWH)in the antiretroviral therapy(ART)era.Compared with numerous studies on bacterial microbiomic communities,there are only a limited number of studies focusing on fungal microbiomic composition and products in PLWH.This study protocol is used to evaluate the changes in bacterial and fungal microbiome populations induced by terbinafine treatment,which is an antifungal agent widely used amongst PLWH.Twenty-two PLWH on a stable ART regimen for more than six months,who require treatment for onychomycosis,will be recruited.The participants will be followed-up for a 12-week treatment period(oral terbinafine 250mg daily)and another 12-weeks of terbinafine discontinuation.Plasma and fecal samples will be collected before and after terbinafine treatment,and for 12weeks after the discontinuation of terbinafine.Plasma gut injury and microbial translocation biomarker assays,in addition to testing for gut microbiome composition,will be undertaken.With this pilot study,we will perform formal sample size calculations and test study feasibility for a possible full-scale study.

Effects of COVID-19 pandemic on human fertility:A scientometric and visualized evaluation

CovID-19,also known as coronavirus disease 2019,is a novel coronavirus disease with high infectivity,strong heterogeneity,and long incubation period(generally 3-14 days).Its main symptoms and signs include fever,dry cough,nasal congestion,fatigue,disorientation,lymphopenia,and dyspnea.The short-term and long-term impacts of covID-19 on human health,particularly its effects on human reproduction and offspring development,continue to receive significant concerns,as they may lead to potential sequelae for several decades or even centuries.