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.

Global burden of cirrhosis and other chronic liver diseases due to nonalcoholic fatty liver disease,1990-2019

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)has become the leading cause of cirrhosis and other chronic liver diseases(COCLDs).AIM To conduct a comprehensive and comparable updated analysis of the global,regional,and national burden of COCLDs due to NAFLD in 204 countries and territories from 1990 and 2019 by age,sex,and sociodemographic index.METHODS Data on COCLDs due to NAFLD were collected from the Global Burden of Diseases,Injuries,and Risk Factors Study 2019.Numbers and age-standardized prevalence,death,and disability-adjusted life years(DALYs)were estimated through a systematic analysis of modelled data from the Global Burden of Diseases,Injuries,and Risk Factors Study 2019.The estimated annual percentage change was used to determine the burden trend.RESULTS In 2019,the global age-standardized prevalence rate of COCLDs due to NAFLD was 15022.90 per 100000 population[95%uncertainty interval(UI):13493.19-16764.24],which increased by 24.51%(22.63%to 26.08%)from 1990,with an estimated annual percentage change of 0.78(95%confidence interval:0.74-0.82).In the same year,however,the age-standardized death rate and age-standardized DALYs per 100000 population were 1.66(95%UI:1.20-2.17)and 43.69(95%UI:31.28-58.38),respectively.North Africa and the Middle East had the highest prevalence rates of COCLDs due to NAFLD.The death rate increased with age up to the 95+age group for both sexes.Males had higher numbers of prevalence,death rate,and DALYs than females across all age groups before the 65-69 age group.The sociodemographic index was negatively correlated with the age-standardized DALYs.CONCLUSION Globally,the age-standardized prevalence rate has increased during the past three decades.However,the agestandardized death rate and age-standardized DALYs decreased.There is geographical variation in the burden of COCLDs due to NAFLD.It is strongly recommended to improve the data quality of COCLDs due to NAFLD across all countries and regions to facilitate better monitoring of the burden of COCLDs due to NAFLD.

Postoperative morbidity adversely impacts oncological prognosis after curative resection for hilar cholangiocarcinoma

BACKGROUND Postoperative morbidity after curative resection for hilar cholangiocarcinoma(HCCA)is common;however,whether it has an impact on oncological prognosis is unknown.AIM To evaluate the influence of postoperative morbidity on tumor recurrence and mortality after curative resection for HCCA.METHODS Patients with recently diagnosed HCCA who had undergone curative resection between January 2010 and December 2017 at The First Affiliated Hospital of Army Medical University in China were enrolled.The independent risk factors for morbidity in the 30 d after surgery were investigated,and links between postoperative morbidity and patient characteristics and outcomes were assessed.Postoperative morbidities were divided into five grades based on the Clavien-Dindo classification,and major morbidities were defined as Clavien-Dindo≥3.Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for recurrence-free survival(RFS)and overall survival(OS).RESULTS Postoperative morbidity occurred in 146 out of 239 patients(61.1%).Multivariate logistic regression revealed that cirrhosis, intraoperative blood loss > 500 mL, diabetes mellitus,and obesity were independent risk factors. Postoperative morbidity was associated with decreasedOS and RFS (OS: 18.0 mo vs 31.0 mo, respectively, P = 0.003;RFS: 16.0 mo vs 26.0 mo, respectively,P = 0.002). Multivariate Cox regression analysis indicated that postoperative morbidity wasindependently associated with decreased OS [hazard ratios (HR): 1.557, 95% confidence interval(CI): 1.119-2.167, P = 0.009] and RFS (HR: 1.535, 95%CI: 1.117-2.108, P = 0.008). Moreover, majormorbidity was independently associated with decreased OS (HR: 2.175;95%CI: 1.470-3.216, P <0.001) and RFS (HR: 2.054;95%CI: 1.400-3.014, P < 0.001) after curative resection for HCCA.CONCLUSIONPostoperative morbidity (especially major morbidity) may be an independent risk factor forunfavorable prognosis in HCCA patients following curative resection.

A chromosome-scale genome assembly of a diploid alfalfa,the progenitor of autotetraploid alfalfa

Alfalfa(Medicago sativa L.)is one of the most important and widely cultivated forage crops.It is commonly used as a vegetable and medicinal herb because of its excellent nutritional quality and significant economic value.Based on Illumina,Nanopore and Hi-C data,we assembled a chromosome-scale assembly of Medicago sativa spp.caerulea(voucher PI464715),the direct diploid progenitor of autotetraploid alfalfa.The assembled genome comprises 793.2 Mb of genomic sequence and 47,202 annotated protein-coding genes.The contig N50 length is 3.86 Mb.This genome is almost twofold larger and contains more annotated protein-coding genes than that of its close relative,Medicago truncatula(420 Mb and 44,623 genes).The more expanded gene families compared with those in M.truncatula and the expansion of repetitive elements rather than whole-genome duplication(i.e.,the two species share the ancestral Papilionoideae whole-genome duplication event)may have contributed to the large genome size of M.sativa spp.caerulea.Comparative and evolutionary analyses revealed that M.sativa spp.caerulea diverged from M.truncatula~5.2 million years ago,and the chromosomal fissions and fusions detected between the two genomes occurred during the divergence of the two species.In addition,we identified 489 resistance(R)genes and 82 and 85 candidate genes involved in the lignin and cellulose biosynthesis pathways,respectively.The near-complete and accurate diploid alfalfa reference genome obtained herein serves as an important complement to the recently assembled autotetraploid alfalfa genome and will provide valuable genomic resources for investigating the genomic architecture of autotetraploid alfalfa as well as for improving breeding strategies in alfalfa.

MRTF-A transactivates COMT gene and decreases the anti-tumor effects of tamoxifen

Myocardin-related transcription factors A (MRTF-A) is a myocardin-related transcription factor that have been found strongly activated CarG box–containing genes through its direct binding to serum response factor (SRF). In the present study, the MRTF-A ex-pression vector was constructed. The MTT assay showed that transfection of MRTF-A could significantly decrease the anti-tumor effect of tamoxifen on MCF-7 breast cancer cells. The bioinformatics analysis found that the CarG element existed in the pro-moter region of COMT gene of many familiar verte-brates, including of human, rhesus macaque, chimpanzee, etc. The results of RT-PCR assay further showed that MRTF-A could enhance the transcrip-tion level of COMT. These results are the first to indicate that COMT might be a target gene which could be regulated by MRTF-A/SRF, and such transactivation event might be involved in the process of tamoxifen resistance.

Nonequilibrium and morphological characterizations of Kelvin-Helmholtz instability in compressible flows

We investigate the effects of viscosity and heat conduction on the onset and growth of Kelvin-Helmholtz instability (KHI) via an efficient discrete Boltzmann model.Technically,two effective approaches are presented to quantitatively analyze and understand the configurations and kinetic processes.One is to determine the thickness of mixing layers through tracking the distributions and evolutions of the thermodynamic nonequilibrium (TNE) measures;the other is to evaluate the growth rate of KHI from the slopes of morphological functionals.Physically,it is found that the time histories of width of mixing layer,TNE intensity,and boundary length show high correlation and attain their maxima simultaneously.The viscosity effects are twofold,stabilize the KHI,and enhance both the local and global TNE intensities.Contrary to the monotonically inhibiting effects of viscosity,the heat conduction effects firstly refrain then enhance the evolution afterwards.The physical reasons are analyzed and presented.

杏仁核-海马环路中GABA_(A)(δ)R功能减退介导应激引发的焦虑

应激刺激引起杏仁核内GABA系统功能失调与其导致精神疾病发病密切相关,但相关的分子与环路机制仍不明确.本研究通过建立慢性社交挫败应激(CSDS)模型,观察慢性应激对基底外侧杏仁核(BLA)内不同投射神经元抑制性电流的影响,并分析相关的功能意义.结果发现,CSDS下调了BLA内投射至腹侧海马(BLA→vHPC)神经元上由GABA_(A)(δ)R介导的紧张性抑制电流,却上调了投射至前背侧终纹床核神经元的紧张性电流.有趣的是,CSDS引起的小鼠焦虑样行为增加仅与BLA→vHPC神经元上下调的紧张性抑制电流明显相关.在BLA→vHPC神经元上过表达GABA_(A)(δ)R可显著缓解应激诱发的焦虑样行为;相反,敲低其表达则可模拟慢性应激诱发的焦虑样行为.综上所述,本研究揭示了慢性应激对杏仁核不同神经元紧张性抑制电流的差异化调控机制并阐明了其功能意义,这些发现有望为应激相关精神疾病的防治提供精准的干预靶点.

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.