BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

Gut microbial communities are likely remodeled in tandem with accumulated physiological decline during aging, yet there is limited understanding of gut microbiome variation in advanced age. Here, we performed a metagenomics-based enterotype analysis in a geographically homogeneous cohort of 367 enrolled Chinese individuals between the ages of 60 and 94 years, with the goal of characterizing the gut microbiome of elderly individuals and identifying factors linked to enterotype variations. In addition to two adult-like enterotypes dominated by Bacteroides (ET-Bacteroides) and Prevotella (ET-Prevotella), we identified a novel enterotype dominated by Escherichia (ET-Escherichia), whose prevalence increased in advanced age. Our data demonstrated that age explained more of the variance in the gut microbiome than previously identified factors such as type 2 diabetes mellitus (T2DM) or diet. We characterized the distinct taxonomic and functional profiles of ET-Escherichia, and found the strongest cohesion and highest robustness of the microbial co-occurrence network in this enterotype, as well as the lowest species diversity. In addition, we carried out a series of correlation analyses and co-abundance network analyses, which showed that several factors were likely linked to the overabundance of Escherichia members, including advanced age, vegetable intake, and fruit intake. Overall, our data revealed an enterotype variation characterized by Escherichia enrichment in the elderly population. Considering the different age distribution of each enterotype, these findings provide new insights into the changes that occur in the gut microbiome with age and highlight the importance of microbiome-based stratification of elderly individuals.
Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Bacteroides ; China ; Diabetes Mellitus, Type 2/microbiology* ; Escherichia coli/classification* ; Gastrointestinal Microbiome/genetics* ; Metagenomics ; East Asian People

OBJECTIVE: Paridis Rhizoma (Chonglou in Chinese), a traditional Chinese herbal medicine, has been shown have strong anti-tumor effects. Paris saponin VII (PSVII), an active constituent isolated from Paridis Rhizoma, was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study. Here, we aimed to elucidate the anti-pancreatic ductal adenocarcinoma (PDAC) effect of PSVII and the underlying mechanism. METHODS: Cell viability was determined by CCK-8, colony formation, and cell migration assays. Cell apoptosis and reactive oxygen species (ROS) production were measured by flow cytometry with annexin V/propidine iodide (Annexin V/PI) and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. Pyroptosis was evaluated by morphological features, Hoechst 33342/PI staining assay, and release of lactate dehydrogenase (LDH). JC-1 fluorescent dye was employed to measure mitochondrial membrane potential. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the levels of proteins or mRNAs. The effect in vivo was assessed by a xenograft tumor model. RESULTS: PSVII inhibited the viability of PDAC cells (BxPC-3, PANC-1, and Capan-2 cells) and induced gasdermin E (GSDME) cleavage, as well as the simultaneous cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP). Knockdown of GSDME shifted PSVII-induced pyroptosis to apoptosis. Additionally, the effect of PSVII was significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone (Z-DEVD-FMK), on the induction of GSDME-dependent pyroptosis. PSVII also elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells. The ROS scavenger N-acetyl cysteine (NAC) suppressed the release of LDH and inhibited Caspase-9, Caspase-3, and GSDME cleavage in PDAC cells, ultimately reversing PSVII-induced pyroptosis. Furthermore, in a xenograft tumor model, PSVII markedly suppressed the growth of PDAC tumors and induced pyroptosis. CONCLUSION These results demonstrated that PSVII exerts therapeutic effects through Caspase-3/GSDME-dependent pyroptosis and may constitute a novel strategy for preventing chemotherapeutic resistance in patients with PDAC in the future.

ObjectiveTo investigate the clinical features of patients with acute-on-chronic liver failure （ACLF）， and to construct a risk scoring table that can accurately predict the prognosis of patients in the early stage. MethodsA retrospective analysis was performed for the clinical data of 502 patients with ACLF who were admitted to Tangdu Hospital， Air Force Medical University， from January 1， 2010 to December 31， 2020 （training set）， and the influencing factors for 28-day mortality rate were identified. The 69 ACLF patients who were admitted to Tangdu Hospital， Air Force Medical University， from January 1 to December 31， 2021 were enrolled as the validation set. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. A univariate Cox regression analysis was used to obtain the early warning indicators associated with the 28-day prognosis of ACLF patients， and variance inflation factors were used to assess multicollinearity among predictors； a multivariate Cox regression analysis was used to construct a risk model for ACLF prognosis （mortality）. A risk scoring table for ACLF prognosis （mortality） was developed based on regression coefficients （β） from the model equation and weight assignments in the nomogram. Internal validation and comparison were performed for the risk model for ACLF prognosis （mortality）， the scoring table for ACLF prognosis （mortality）， and other scoring models （Child-Turcotte-Pugh ［CTP］ score， Model for End-Stage Liver Disease ［MELD］ score， MELD combined with serum sodium concentration ［MELD-Na］ score， and integrated MELD ［iMELD］ score） in the training set， while external validation and comprehensive evaluation of the scoring table and the other scoring models were performed in the validation set. The Nagelkerke’s R² test and the Hosmer-Lemeshow test were used to assess the degree of fitting of the risk model for ACLF prognosis （mortality）， the scoring table for ACLF prognosis （mortality）， and other scoring models， and fitting curves were plotted. C-index was used to assess the discriminatory ability of the scoring table for ACLF prognosis （mortality） and the other scoring models， and the Z-test was used for comparison of C-index between different models. The decision curve analysis was used to compare the clinical benefits of the scoring table for ACLF prognosis （mortality） and the other scoring models. ResultsThe multivariate Cox regression analysis showed that age （hazard ratio ［HR］=1.027， 95% confidence interval ［CI］： 1.015 — 1.039， P<0.001）， hepatic encephalopathy grade （grade 1： HR=2.928， 95%CI： 1.463 — 5.858， P=0.002； grade 2： HR=3.811， 95%CI： 2.078 — 6.988， P<0.001； grade 3： HR=3.916， 95%CI： 1.917 — 8.001， P<0.001； grade 4： HR=6.966， 95%CI： 4.559 — 10.644， P<0.001）， an increase in total bilirubin （TBil） by ≥17.1 μmol/L per day （HR=1.771， 95%CI： 1.248 — 2.513， P=0.001）， creatinine （HR=1.005， 95%CI： 1.004 — 1.006， P<0.001）， neutrophil count （HR=1.092， 95%CI： 1.060 — 1.126， P<0.001）， and international normalized ratio （HR=1.298， 95%CI： 1.187 — 1.418， P<0.001） were independent risk factors associated with the 28-day mortality rate of ACLF patients， and a risk scoring table was constructed for ACLF prognosis （mortality）. The Nagelkerke’s R² test showed that the risk scoring table for ACLF prognosis （mortality） had an R² value of 0.599 in the training set and 0.722 in the validation set， which were higher than the R² values of CTP， MELD， MELD-Na， and iMELD scores. The Hosmer-Lemeshow test showed that the risk scoring table for ACLF prognosis （mortality） had a P value of 0.280 in the training set and 0.788 in the validation set. The C-index analysis showed that the scoring table had a higher C-index than the other scoring models in the validation set （all P<0.001）， as well as a higher C-index than CTP score in the training set （P<0.001）. The decision curve analysis showed that the risk scoring table for ACLF prognosis （mortality） had higher clinical net benefits than the other scoring models. ConclusionCompared with other scoring models currently used in clinical practice， the novel risk scoring table for ACLF prognosis （mortality） constructed based on the six predictive factors of age， hepatic encephalopathy grade， an increase in TBil by ≥17.1 μmol/L per day， creatinine， neutrophil count， and international normalized ratio has a relatively high value in predicting the 28-day prognosis of ACLF patients.

Objective : To explore the risk factors of prognosis in patients with severe community-acquired pneumonia(SCAP) in different age groups. Methods : A multi-center and prospective study was conducted at 11 teaching hospitals in China from December 2017 to October 2021. Patients who met the criteria were assigned to the elderly group(≥65 years) and the non-elderly group(18-64 years) to demonstrate the clinical characteristics of SCAP. Patients were divided into survival group and death group according to whether they died in hospital, to determine the risk factors associated with mortality by multivariate logistic regression analysis. Results: A total of 170 patients with SCAP were included in the study. The age of SCAP was 20-93(65.75±15.23) years old, and the proportion of SCAP in the elderly was 58.82%(100/170). In-hospital mortality of non-elderly SCAP was 24.3%(17/70), and the in-hospital mortality of elderly SCAP was 28%(28/100). Compared with non-elderly group, patients in elderly group had higher severity score and more complications on admission, but the symptoms of fever and respiratory rate at admission were less obvious. In multivariable logistic regression analysis, the factors significantly associated with in-hospital mortality of non-elderly SCAP were pneumonia severity index(PSI) score(P=0.016,OR=1.022, 95%CI1.004-1.041) and invasive mechanical ventilation(P=0.037,OR=4.543, 95%CI1.092-18.898) on admission, and the risk factors associated with in-hospital mortality in elderly SCAP were sequential organ failure assessment(SOFA) score(P=0.006,OR=1.240, 95%CI1.063-1.446) and combined with coronary artery disease on admission(P=0.037,OR=2.834, 95%CI1.066-7.534). Conclusion In-hospital mortality for SCAP is high. PSI score and invasive mechanical ventilation are risk factors for in-hospital mortality of non-elderly patients with SCAP, and SOFA score and combined with coronary artery disease on admission are risk factors for in-hospital mortality of elderly patients with SCAP.

BACKGROUND:A pathophysiological feature of septic organ failure is endothelial dysfunction in sepsis(EDS).The physiological and pathological mechanism of sepsis is considered to be vascular leakage caused by endothelial dysfunction.These pathological changes lead to systemic organ injury.However,an analysis using bibliometric methods has not yet been conducted in the field of EDS.This study was conducted to provide an overview of knowledge structure and research trends in the field of EDS. METHODS:Based on previous research,a literature search was performed in the Web of Science Core Collection(WoSCC)for publications associated with EDS published between the year 2003 and 2023.Various types of data from the publications,such as citation frequency,authorship,keywords and highly cited articles,were extracted.The"Create Citation Report"feature in the WoSCC was employed to calculate the Hirsch index(h-index)and average citations per item(ACI)of authors,institutions,and countries.To conduct bibliometric and visualization analyses,three bibliometric tools were used,including R-bibliometrix,CiteSpace(co-citation analysis of references),and VOSviewer(co-authorship analysis of institutions,co-authorship analysis of authors,co-occurrence analysis of keywords). RESULTS:After excluding invalid records,the study finaly included 4,536 publications with 135,386 citations.Most of these publications originated in the USA,China,Germany,Canada,and Japan.Harvard University emerged as the most prolific institution,while professor Jong-Sup Bae and his research team at Kyungpook National University emerged as authors with the greatest influence.The"protein C","tissue factor","thrombin","glycocalyx","acute kidney injury","syndecan-1"and"biomarker"were identified as prominent areas of research.Future research may focus on molecular mechanisms(such as as vascular endothelial[VE]-cadherin regulation)and therapeutic interventions to enhance endothelial repair and function. CONCLUSION:Our findings show a growing interest in EDS research.Key areas for future research include signaling pathways,molecular mechanisms,endothelial repair,and interactions between endothelial cells and other cell types in sepsis.

[Abstract]Objective To explore the predictive value of plaque characteristic index based on coronary CT angiography(CCTA)for disease-specific myocardial ischemia in stable coronary artery disease(CAD).Methods 90 stable CAD patients admitted to Zhongshan Hospital,Fudan University from October 2020 to March 2022 were prospectively enrolled,including 135 target vessels with stenosis degree ranging from 30%to 90%.All participants sequentially underwent CCTA,ICA,and fractional flow reserve(FFR)measurement within 2 weeks.Based on the presence or absence of significant hemodynamic stenosis,all patients were divided into myocardial ischemic population(FFR≤0.8,n=30)and non ischemic population(FFR＞0.8,n= 60),135 target blood vessels were divided into a disease-specific myocardial ischemia group(FFR≤0.8,n=36)and a non disease-specific myocardial ischemia group(FFR＞0.8,n=99).Univariate and subsequent forward stepwise multivariate logistic regression analyses were used to assess independent predictors of myocardial ischemia,and CCTA-derived plaque characteristics index logistic regression model was created.Receiver operating characteristic(ROC)analysis was used to analyze the diagnostic performance of CCTA-derived plaque characteristics index on detecting myocardial ischemia.Results There were no significant differences in age,body mass index,gender,cardiovascular risk factors,and medication between myocardial ischemia population and non-ischemia population.Compared with the non-lesion-specific ischemia group,plaque length,plaque area,percent area stenosis,total atheroma volume,vessel volume and lipid rich volume,positive remodeling and napkin-ring signs were significantly higher in lesion-specific group,while minimum luminal area(MLA)was significantly lower.MLA(OR=0.303,95%CI 0.178-0.517,P＜0.001)and total atheroma volume(TAV,OR=1.006,95%CI 1.002-1.010,P=0.003)were found to be the significant independent predictors of myocardial ischemia.The regression equation of CCTA-derived plaque characteristic index for predicting probability was P=1/[1+e-(-1.194 41×MLA+0.006 058×TAV+0.600 912)].The area under the ROC curve(AUC)of CCTA-derived plaque characteristic index on detecting myocardial ischemia was 0.879(95%CI 0.811-0.928),and the overall diagnostic accuracy,sensitivity,specificity,PPV and NPV were 80.0%,83.3%,78.8%,58.8%,and 92.9%,respectively.Conclusions CCTA-derived plaque characteristic index performs well in diagnosing lesion-specific myocardial ischemia,showing its great clinical application prospect.

Objective:To assess the clinical features and CT diagnostic characteristics of Branchio-Oto-Renal or Branchio-Oto Syndrome .Methods:The temporal CT findings and clinical features observations of 13 patients with Branchio-Oto-Renal Syndrome (BORS) or Branchio-Oto Syndrome(BOS) confirmed by genetic testing were retrospectively analyzed. There were 8 males and 5 females, aged from 1 to 39 years, with a median age of 9 years, in which 3 pairs (6 cases) were parent-child relationship.Results:All of 13 cases had hearing loss and preauricular fistula, 11 cases accompanied by 2nd branchial fistulas. There were 20 ears of mixed hearing loss, 3 ears of sensorineural hearing loss, and 2 ears of conductive hearing loss. The mutation point of gene testing was located in EYA1 in 12 cases and SIX1 in 1 case. Twenty ears showed gradually narrowing of the diameter of basal turn, with hypoplasia in the second turn and aplasia in apical turn. There were irregular wall of vestibule and horizontal semicircular canal in 10 ears,widened vestibular in 7 ears, and vestibular fusion with horizontal semicircular canal in 3 ears. Three ears had an enlarged vestibular aqueduct, 8 ears showed enlargement of internal auditory canal. Seventeen ears had adhesion of malleolus to tympanic cavity. Six ears could not measured the incudostapedial joint angle by reason of tympanic inflammatory cover, 3 ears could not show incudostapedial joint, and 8 ears showed the incudostapedial joint angle more than 122°. Six ears showed poor oval window, and 1 ear had poor round window. Eighteen ears showed distended eustachian tube, and accompanied by tympanic or mastoiditis in 11 ears. Anterolateral shift of tympanum was found in 22 ears, 17 ears had low middle cranial fossa, and 3 ears had stenotic external auditory canal. Conclusions:Cochlear dysplasia, ossicular chain malformation and distended eustachian tube comprise the characteristic CT signs of BOS/BORS, which possesses versatile and complex CT findings. Temporal CT can accurately assess the important structures such as cochlea, ossicles, vestibule, semicircular canal, vestibular aqueduct and internal auditory canal. Combing with the clinical characteristics of bilateral, mixed hearing loss, preauricular fistula and branchial fistula can provide valuable information for early diagnosis and treatment.

Objective:To compare the clinical outcomes of anterolateral femoral interregional flap with turbocharge technique and traditional anterolateral femoral flap in repair of large limb wounds.Methods:Clinical data of 38 patients with large limb surface wound(11 cm×39 cm-16 cm×65 cm)admitted to the Sir Run Run Shaw Hospital,Zhejiang University School of Medicine from May 2018 to May 2022 were retrospectively analyzed.Eighteen patients were treated by anterolateral thigh perforator flap combined with superficial circumflex iliac artery flap(ALTP-SCIAP)with turbocharge technique(interregional flap group);while 20 patients were treated with unilateral or bilateral anterolateral femoral flaps,combined with skin grafting if necessary(traditional anterolateral femoral flap group).The survival of skin flap,repair of donor area,complications and patient satisfaction were compared between the two groups.Results:In interregional flap group,18 flaps were harvested and transplanted,the flap width,length and the viable area were(9.9±2.0)cm,(44.2±3.5)cm and(343.2±79.9)cm2,respectively.In traditional anterolateral femoral flap group,29 flaps were harvested and transplanted,the flap width,length and the viable area were(11.0±2.8)cm,(21.7±3.2)cm and(186.4±49.2)cm2,respectively.There were significant differences in the flap length and the viable area between the two groups(t=22.365 and 8.345,both P<0.05).In the interregional flap group,the donor site of flap was closed by direct suture in 11 flaps,by skin retractor assisted suture in 6 flaps,and by skin grafting in one flap.In traditional anterolateral femoral flap group,the donor site of flap was closed by direct suture in 12 flaps,by skin retractor assisted suture in 11 flaps,and by skin grafting in 6 flaps.The skin graft rates of the two groups were 5.6%(1/18)and 20.7%(6/29),respectively(χ2=2.007,P>0.05).The interregional flap group had lower postoperative complications rate(5.6%vs.35.0%,χ2=4.942,P<0.05)and higher patient satisfaction rate(94.4%vs.70.0%,χ2=4.448,P<0.05)than traditional anterolateral femoral flap group.Conclusion:Compared with the traditional anterolateral femoral flap,the anterolateral femoral interregional flap with turbocharge technique has a larger flap area,most of the donor areas of the flap can be sutured directly without skin grafting and with less complications and a higher patient satisfaction rate.