Development of a model based on the age-adjusted Charlson comorbidity index to predict survival for resected perihilar cholangiocarcinoma

BACKGROUND Perihilar cholangiocarcinoma(pCCA)has a poor prognosis and urgently needs a better predictive method.The predictive value of the age-adjusted Charlson comorbidity index(ACCI)for the long-term prognosis of patients with multiple malignancies was recently reported.However,pCCA is one of the most surgically difficult gastrointestinal tumors with the poorest prognosis,and the value of the ACCI for the prognosis of pCCA patients after curative resection is unclear.AIM To evaluate the prognostic value of the ACCI and to design an online clinical model for pCCA patients.METHODS Consecutive pCCA patients after curative resection between 2010 and 2019 were enrolled from a multicenter database.The patients were randomly assigned 3:1 to training and validation cohorts.In the training and validation cohorts,all patients were divided into low-,moderate-,and high-ACCI groups.Kaplan-Meier curves were used to determine the impact of the ACCI on overall survival(OS)for pCCA patients,and multivariate Cox regression analysis was used to determine the independent risk factors affecting OS.An online clinical model based on the ACCI was developed and validated.The concordance index(C-index),calibration curve,and receiver operating characteristic(ROC)curve were used to evaluate the predictive performance and fit of this model.RESULTS A total of 325 patients were included.There were 244 patients in the training cohort and 81 patients in the validation cohort.In the training cohort,116,91 and 37 patients were classified into the low-,moderate-and high-ACCI groups.The Kaplan-Meier curves showed that patients in the moderate-and high-ACCI groups had worse survival rates than those in the low-ACCI group.Multivariable analysis revealed that moderate and high ACCI scores were independently associated with OS in pCCA patients after curative resection.In addition,an online clinical model was developed that had ideal C-indexes of 0.725 and 0.675 for predicting OS in the training and validation cohorts.The calibration curve and ROC curve indicated that the model had a good fit and prediction performance.CONCLUSION A high ACCI score may predict poor long-term survival in pCCA patients after curative resection.High-risk patients screened by the ACCI-based model should be given more clinical attention in terms of the management of comorbidities and postoperative follow-up.

Association between gene polymorphisms of vitamin D receptor and pulmonary tuberculosis susceptibility:a meta-analysis

Background:The vitamin D receptor(VDR) gene is a primary candidate gene for tuberculosis susceptibility,but results of previous studies are somewhat contradictory and underpowered.Thus,it is essential to further explore the association between VDR gene polymorphisms and risk of pulmonary tuberculosis(PTB).Methods:A systematic review and meta-analysis about the association between FokI,TaqI,ApaI and BsmI polymorphisms and PTB susceptibility was conducted.Statistical Package for Social Science(Version 13.0) and Review Manager(Version 4.2,The Cochrane Collaboration) were used to analyze the data reported in studies.Results:A total of 13 studies with 2 262 cases and 2 833 controls were involved in the FokI polymorphism,and the results showed FokI polymorphism was associated with PTB susceptibility(allele f vs F:OR=1.12,95% CI=[1.02,1.23];the additive effect model ff vs FF:OR=1.40,95%CI=[1.10,1.77];the recessive genetic model ff vs Ff+FF:OR=1.39,95%CI=[1.12,1.71]).No significant associations were observed between TaqI(15 studies with 3 031 cases and 3 132 controls),ApaI(7 studies with 1 495 cases and 1 922 controls),BsmI(6 studies with 919 cases and 1 250 controls) variants and PTB susceptibility.Conclusion:We found variant FokI polymorphism of VDR gene may play a risky role in PTB development,and the genetic model was presumed to be recessive.

An epidemiological study of resistant tuberculosis in Chongqing,China

Background The epidemiological characteristics of drug-resistant tuberculosis(DR-TB)is fundamental to improving the prevention and control of DR-TB.Mutations in katG315 is thought to be the most predictive molecule markers for Isoniazid(INH)resistance in Mycobacterium tuberculosis(MTB).However,mutations to these genes have not been thoroughly studied in China,and epidemiological evidence of their expression levels are especially lacking in the southwest of China,which has a high TB burden within the population.Methods MTB isolates were obtained from patients with active pulmonary tuberculosis at the TB dispensary and Chest hospital in Chongqing city between June 2003 and June 2006.Proportion methods were used to test the sensitivity to INH,RFP,SM and EMB of cultured MTB.A total of 100 MTB isolates were also randomly selected for analysis of the molecular mutation spectrum of katG by DNA sequencing.Results Totally 1 089 MTB isolates that completed positive sputum cultures and evaluated for their sensitivity to the four first-line drugs among 2 777 patients with TB.The prevalence of DR-TB and multi-drug resistant tuberculosis(MDR-TB)were 27.7%(302/1089)and 7.3%(79/1089),respectively.The resistance to anti-TB drugs was found to be highest for SM(16·3%)and INH(14·0%).There was also a significant increase in the prevalence of resistance to RFP and EMB(P<0.01),and an increase in MDR-TB between June 2003 and June 2004 and between July 2005 and June 2006.The total mutation rate of katG315 was 75·5%(37/49)in INH-resistant MTB,and mutation sites included S315T,S315N and S315I with mutation rates of 81·1%(30/37),13·5%(5/37)and 5·4%(2/37),respectively. No katG315 mutants were found in any of the 48 INH-sensitive MTB.Our preliminary diagnostic results suggest that mutations in katG315 may potentially serve as molecular markers that can be used to diagnose the resistance to anti-TB drug of INH.Conclusion In the Chongqing,DR-TB and MDR-TB are increasing,and are becoming key problems for tuberculosis control.The use of katG315 mutations as potential molecule markers for drug resistance to INH may help improve patient treatment and decrease the spread of the disease.

Modeling the Long-term Antibody Response and Duration of Immune Protection Induced by an Inactivated,Preservative-free Hepatitis A Vaccine(Healive)in Children

Objective Long-term seroprotection via the hepatitis A vaccine is essential for the prevention of disease from the hepatitis A virus(HAV).Due to documented difficulties during decade-long follow-ups after receiving vaccines,statistical-modeling approaches have been applied to predict the duration of immune protection.Methods Based on five-year follow-up data from a randomized positive-controlled trial among Chinese children(1–8 years old)following a 0,6 months vaccination schedule,a power-law model accounting for the kinetics of B-cell turnover,as well as a modified power-law model considering a memory-B-cell subpopulation,were fitted to predict the long-term immune responses induced by HAV vaccination(Healive or Havrix).Anti-HAV levels of each individual and seroconversion rates up to 30 years after vaccination were predicted.Results A total of 375 participants who completed the two-dose vaccination were included in the analysis.Both models predicted that,over a life-long period,participants vaccinated with Healive would have close but slightly higher antibody titers than those of participants vaccinated with Havrix.Additionally,consistent with previous studies,more than 90%of participants were predicted to maintain seroconversion for at least 30 years.Moreover,the modified power-law model predicted that the antibody titers would reach a plateau level after nearly 15 years post-vaccination.Conclusions Based on the results of our modeling,Healive may adequately induce long-term immune responses following a 0,6 months vaccination schedule in children via induction of memory B cells to provide stable and durable immune protection.

Bioequivalence Assessment of Topical Ophthalmic Drugs Using Sparse Sampling Pharmacokinetics Data

In the development of eye drop medications,difficulty in sampling is a major challenge[1].Drug concentrations in the aqueous humor(AH)can only be measured when the eye is undergoing surgery,such as cataract replacement.Sampling from tears may significantly reduce the amount of medication remaining in the eye.Owing to limitations caused by sampling difficulty,the concentration–time profile for each subject is generally unattainable when estimating the pharmacokinetics parameters for topical ophthalmic drugs.Instead,each subject can be sampled at one of several prespecified sampling times.

Assessment of community health needs of Chongqing residents: a qualitative study

Objective: The aim of this preliminary qualitative study was to gain insight into community health needs in order to develop health program for community in Chongqing. Methods: Totally 40 participants were assigned into 6 focus group discussions. All groups were led by local language speakers, and their talking was recorded after gaining informed consent. Transcribed data were coded and subjected to thematic analysis. Results: The main obtained themes were that community health problems were chronic noncommunicable disease, main health service needs included regularly free check-up and health education, and perceived health risk factors were unhealthy lifestyle and behavior as well as environment problems. Conclusion: Our community health needs assessment (CHNA) with FGDs indicate that residents realize the importance of prevention of disease. Our study identifies that primarily community health promotion is one of the priorities of community health service needs, including reorienting health service, health education, guiding behavior or lifestyle, and creating healthy environments. The findings of this study can provide guidance to the development of more effective and pertinent health program in this community.

Gastroduodenal artery disconnection during liver transplantation decreases non-anastomotic stricture incidence

Background:The hepatic artery is the only blood source nourishing the biliary duct and associated with biliary complication after liver transplantation(LT).Gastroduodenal artery(GDA)disconnection increased proper hepatic artery flow.Whether this procedure attenuates biliary non-anastomotic stricture(NAS)is not clear.Methods:A total of 241 patients with LT were retrospectively analyzed.The patients were divided into the GDA disconnection(GDA-)and GDA preservation(GDA+)groups.Propensity score matching(PSM)was administrated to reduce bias.Logistic regression was conducted to analyze risk factors for biliary NAS before and after PSM.Postoperative complications were compared.Kaplan-Meier survival analysis and log-rank tests were performed to compare overall survival.Results:In all,99 patients(41.1%)underwent GDA disconnection,and 49(20.3%)developed NAS.Multivariate logistic regression revealed that GDA preservation(OR=2.24,95%CI:1.11-4.53;P=0.025)and model for end-stage liver disease(MELD)score>15(OR=2.14,95%CI:1.12-4.11;P=0.022)were risk factors for biliary NAS.PSM provided 66 pairs using 1:2 matching method,including 66 GDA disconnection and 99 GDA preservation patients.Multivariate logistic regression after PSM also showed that GDA preservation(OR=3.15,95%CI:1.26-7.89;P=0.014)and MELD score>15(OR=2.41,95%CI:1.08-5.36;P=0.031)were risk factors for NAS.When comparing complications between the two groups,GDA preservation was associated with a higher incidence of biliary NAS before and after PSM(P=0.031 and 0.017,respectively).In contrast,other complications including early allograft dysfunction(P=0.620),small-for-size graft syndrome(P=0.441),abdominal hemorrhage(P=1.000),major complications(Clavien-Dindo grade≥3,P=0.318),and overall survival(P=0.088)were not significantly different between the two groups.Conclusions:GDA disconnection during LT ameliorates biliary NAS incidence and may be recommended for application in clinical practice.

MinK gene G112A polymorphisms and atrial fibrillation:a Meta-analysis

Atrial fibrillation (AF) is the most common arrhythmia with multi-factorial pathogenesis. A number of studies of genetic epidemiology have assessed the association of G112A (G38S) single nucleotide polymorphisms (SNPs) in Mink gene with AF in different populations. However, the results are inconsistent and inconclusive. We performed a Meta-analysis of the association between G112A polymorphisms of MinK gene and AF to estimate the magnitude of the gene effect. Six case-control studies with a combined 854 cases and 1079 controls were summarized. Subgroups in different races were separately analyzed. Heterogeneity and publication bias were also explored. When all groups were pooled, the individuals with G allele had an over 40% higher risk of AF compared with individuals with the A allele. The GG genotype (versus AA genotype) was found to be significant association with increased AF risk. The significant associations were also found in both dominant and recessive genetic model. For subgroup analysis, the results were consistent with above, except that the pooled OR for Chinese population was not significant in a recessive genetic model. In conclusion, G112A polymorphisms in Mink gene may have an important effect on the pathogenesis of AF. This warrants further investigation in large multi-center studies with precise design.

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication.Meplazumab is a humanized anti-CD147 IgG_(2) monoclonal antibody,which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019(COVID-19)patients.Here,we conducted a randomized,double-blinded,placebo-controlled phase 1 trial to evaluate the safety,tolerability,and pharmacokinetics of meplazumab in healthy subjects,and an open-labeled,concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients.In phase 1 study,59 subjects were enrolled and assigned to eight cohorts,and no serious treatment-emergent adverse event(TEAE)or TEAE grade≥3 was observed.The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics.No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort.The biodistribution study indicated that meplazumab reached lung tissue and maintained>14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32.In the exploratory phase 2 study,17 COVID-19 patients were enrolled,and 11 hospitalized patients were involved as concurrent control.The meplazumab treatment significantly improved the discharged(P=0.005)and case severity(P=0.021),and reduced the time to virus negative(P=0.045)in comparison to the control group.These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

Meplazumab in hospitalized adults with severe COVID-19(DEFLECT):a multicenter,seamless phase 2/3,randomized,third-party double-blind clinical trial

Meplazumab,a humanized CD147 antibody,has shown favourable safety and efficacy in our previous clinical studies.In DEFLECT(NCT04586153),167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo.Meplazumab at 0.12 mg/kg,compared to the placebo group,showed clinical benefits in significantly reducing mortality by 83.6%(2.4%vs.14.6%,p=0.0150),increasing the proportion of patients alive and discharged without supplemental oxygen(82.9%vs.70.7%,p=0.0337)and increasing the proportion of patients who achieved sustained clinical improvement(41.5%vs.31.7%).The response rate in the 0.2 mg/kg group was relatively increased by 16.0%compared with the placebo group(53.7%vs.46.3%).Meplazumab also reduced the viral loads and multiple cytokine levels.Compare with the placebo group,the 0.3 mg/kg significantly increased the virus negative rate by 40.6%(p=0.0363)and reduced IL-8 level(p=0.0460);the 0.2 mg/kg increased the negative conversion rate by 36.9%,and reduced IL-4(p=0.0365)and IL-8 levels(p=0.0484).In this study,the adverse events occurred at a comparable rate across the four groups,with no unexpected safety findings observed.In conclusion,meplazumab promoted COVID-19 convalescence and reduced mortality,viral load,and cytokine levels in severe COVID-19 population with good safety profile.

Anatomical hepatectomy for achieving textbook outcome for perihilar cholangiocarcinoma treated with curative-intent resection: A multicenter study

Background and aim:The textbook outcome(TO)is a comprehensive measure that is superior to individual measures for analysis of surgical quality of care.Anatomical hepatectomy(AH)is beneficial in terms of short-term outcomes in patients undergoing resection.This study was performed to investigate the association between AH and achieving the TO for patients with perihilar cholangiocarcinoma(pCCA)treated with curative-intent resection.Methods:This study involved patients who underwent curative-intent resection for newly diagnosed pCCA from January 2013 to January 2018 at three hospitals in China.All patients were divided into two groups according to the type of hepatectomy:the AH group and non-AH group.The incidence and distribution of achieving the TO were compared between the two groups.Univariable and multivariable logistic regression analyses were used to identify independently predictive factors associated with achieving the TO in patients with pCCA.Results:In total,333 patients were enrolled[AH group,225(67.6%);non-AH group,108(32.4%)].The incidence of achieving the TO in all patients was 24.3%,and the incidence was significantly higher in the AH than non-AH group(30.7%vs.11.1%,respectively).Multivariable analysis revealed that AH,total bilirubin concentration of<34μmol/L,maximum tumor size of<3 cm,no macrovascular invasion,and no lymph node metastasis were independently associated with a higher incidence of achieving the TO.Conclusions:The TO was achieved in approximately one-fourth of patients with pCCA who underwent curative-intent resection.The use of AH was more conducive to achieving the TO in patients with pCCA.