1.Percutaneous coronary intervention vs . medical therapy in patients on dialysis with coronary artery disease in China.
Enmin XIE ; Yaxin WU ; Zixiang YE ; Yong HE ; Hesong ZENG ; Jianfang LUO ; Mulei CHEN ; Wenyue PANG ; Yanmin XU ; Chuanyu GAO ; Xiaogang GUO ; Lin CAI ; Qingwei JI ; Yining YANG ; Di WU ; Yiqiang YUAN ; Jing WAN ; Yuliang MA ; Jun ZHANG ; Zhimin DU ; Qing YANG ; Jinsong CHENG ; Chunhua DING ; Xiang MA ; Chunlin YIN ; Zeyuan FAN ; Qiang TANG ; Yue LI ; Lihua SUN ; Chengzhi LU ; Jufang CHI ; Zhuhua YAO ; Yanxiang GAO ; Changan YU ; Jingyi REN ; Jingang ZHENG
Chinese Medical Journal 2025;138(3):301-310
BACKGROUND:
The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China.
METHODS:
This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences.
RESULTS:
Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n = 278] vs . 43.7% [ n = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses.
CONCLUSION
This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans
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Percutaneous Coronary Intervention/methods*
;
Male
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Female
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Coronary Artery Disease/drug therapy*
;
Retrospective Studies
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Renal Dialysis/methods*
;
Middle Aged
;
Aged
;
China
;
Proportional Hazards Models
;
Treatment Outcome
2.Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients
Jinlin HOU ; Edward GANE ; Rozalina BALABANSKA ; Wenhong ZHANG ; Jiming ZHANG ; Tien Huey LIM ; Qing XIE ; Chau-Ting YEH ; Sheng-Shun YANG ; Xieer LIANG ; Piyawat KOMOLMIT ; Apinya LEERAPUN ; Zenghui XUE ; Ethan CHEN ; Yuchen ZHANG ; Qiaoqiao XIE ; Ting-Tsung CHANG ; Tsung-Hui HU ; Seng Gee LIM ; Wan-Long CHUANG ; Barbara LEGGETT ; Qingyan BO ; Xue ZHOU ; Miriam TRIYATNI ; Wen ZHANG ; Man-Fung YUEN
Clinical and Molecular Hepatology 2024;30(2):191-205
Background/Aims:
Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients.
Methods:
This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks.
Results:
68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported.
Conclusions
48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.
3.The distribution of blood pressure and associated factors of the elderly with type 2 diabetes in Jiangsu Province.
Jia Hui LIU ; Han Kun XIE ; Jian SU ; Zheng ZHU ; En Chun PAN ; Yan LU ; Fu Ping WAN ; Qing Yang YAN ; Ning ZHANG ; Shu Jun GU ; Ming WU ; Jin Yi ZHOU ; Chong SHEN
Chinese Journal of Preventive Medicine 2023;57(5):614-625
Objective: To investigate the distribution of blood pressure and analyze the associated factors of blood pressure of the elderly with type 2 diabetes in Jiangsu Province. Methods: The elderly over 60 years old participants with type 2 diabetes in the communities of Huai'an City and Changshu City, Jiangsu Province were selected in this study. They were divided into two groups: taking antihypertensive drugs and not taking antihypertensive drugs. The demographic characteristics, such as age and sex, and relevant factors were collected by questionnaire. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by physical examination. The percentile of SBP and DBP in each age group of men and women were described. The kernel density estimation curve was used to show the blood pressure distribution. The trend of blood pressure with age was fitted by locally weighted regression. The logistic regression model was used to analyze relevant factors of blood pressure. Results: A total of 12 949 participants were included in this study, including 7 775 patients in the antihypertensive drug group and 5 174 patients in the group without antihypertensive drugs. The SBP of participants was concentrated at 140-160 mmHg, and their DBP was concentrated at 75-85 mmHg. There were significant differences in the distribution of blood pressure among the subgroups of body mass index (BMI) and rural areas whether taking antihypertensive drugs and not. For participants aged under 80 years old, the SBP showed an increasing trend with age and the DBP showed a decreasing trend with age. Age, BMI ≥24 kg/m2, fasting blood glucose ≥7.0 mmol/L, living in rural areas and no smoking were influencing factors of the elevated SBP; BMI ≥24 kg/m2, male, living in rural areas, no smoking, drinking alcohol and not receiving drug hypoglycemic treatment were influencing factors of the elevated DBP. Conclusion: The SBP of older diabetic adults in Jiangsu Province is at a high level, and the distribution of blood pressure is significantly different between men and women in taking antihypertensive drugs group. The SBP presents a rising trend and the DBP is decreasing at the age of 60-80 years. The blood pressure level of this population are mainly affected by age, BMI, urban and rural areas, smoking.
Adult
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Aged
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Humans
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Male
;
Female
;
Middle Aged
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Aged, 80 and over
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Blood Pressure/physiology*
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Diabetes Mellitus, Type 2/epidemiology*
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Antihypertensive Agents/therapeutic use*
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Smoking
;
Body Mass Index
;
Hypertension/epidemiology*
4.Potential biomarkers for diagnosis and disease evaluation of idiopathic pulmonary fibrosis.
Qing WANG ; Zhaoliang XIE ; Nansheng WAN ; Lei YANG ; Zhixian JIN ; Fang JIN ; Zhaoming HUANG ; Min CHEN ; Huiming WANG ; Jing FENG
Chinese Medical Journal 2023;136(11):1278-1290
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.
Humans
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Idiopathic Pulmonary Fibrosis/diagnosis*
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Biomarkers
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Lung Diseases, Interstitial
;
Lung
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Bronchoalveolar Lavage Fluid
;
Disease Progression
;
Prognosis
5.The status and influencing factors of presenteeism among clinical nurses: a systematic review.
Wan Ying NI ; Jia Lin WANG ; Jie YUN ; Wan Qing XIE ; Chun MA ; Si Hui SU
Chinese Journal of Industrial Hygiene and Occupational Diseases 2023;41(4):286-293
Objective: To systematically review the status and factors influencing presenteeism among clinical nurses. Methods: In December 2021, CNKI, CBM, Wanfang, VIP, Web of Science, PubMed, Embase, The Cochrane Library, CINAHL, PsyclNFO and other databases were electronically searched to cross sectional studies on the current situation and factors influencing the occurrence of presenteeism among clinical nurses. The search terms mainly included presenteeism, sick at work, Stanford Presenteeism Scale, nurse, level, risk factor, influence, et al. And the search time was from the establishment of the database to November 30, 2021. Literature screening, data extraction and evaluation of the risk of bias in the included literature were done independently by two researchers, and meta-analysis was performed using Stata 15.1 software. Results: A total of 29 studies involving 13 535 clinical nurses were included.The results of the meta-analysis showed that the score of presenteeism was 17.99 [95% CI (17.02-18.95), P =0.000]. Subgroup analysis showed that presenteeism scores were higher in articles published before 2020 (ES=19.28, 95%CI: 18.41-20.15, P=0.000) and in the group of nurses aged 36 to 40 years (ES=19.27, 95%CI: 17.35~21.19, P=0.000), female (ES= 17.04, 95%CI: 14.70-19.39, P=0.000), secondary school education (ES=21.01, 95%CI: 17.76-24.26, P= 0.007), married (ES=17.49, 95%CI: 15.13-19.85, P=0.000), working for 5 to 10 years (ES=17.78, 95%CI: 16.54-19.02, P=0.000), contract (ES=17.05, 95%CI: 15.23-18.87, P=0.000), working in pediatrics (ES= 16.65, 95% CI: 15.31-17.99, P=0.000) and European region (ES =21.21, 95% CI: 20.50-21.93, P=0.000) . Conclusion: Current evidence suggests that clinical nurses are at high risk of presenteeism, which is affected by variety of factors. The managers should pay attention to the physical and mental health of nurses, identify high-risk factors as early as possible and take measures to reduce the occurrence of presenteeism and improve the quality of nursing.
Humans
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Female
;
Child
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Presenteeism
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Cross-Sectional Studies
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Mental Health
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PubMed
;
Nurses
6.Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.
Yue GAO ; Chun-Jie LIU ; Hua-Yi LI ; Xiao-Ming XIONG ; Gui-Ling LI ; Sjors G J G IN 'T VELD ; Guang-Yao CAI ; Gui-Yan XIE ; Shao-Qing ZENG ; Yuan WU ; Jian-Hua CHI ; Jia-Hao LIU ; Qiong ZHANG ; Xiao-Fei JIAO ; Lin-Li SHI ; Wan-Rong LU ; Wei-Guo LV ; Xing-Sheng YANG ; Jurgen M J PIEK ; Cornelis D DE KROON ; C A R LOK ; Anna SUPERNAT ; Sylwia ŁAPIŃSKA-SZUMCZYK ; Anna ŁOJKOWSKA ; Anna J ŻACZEK ; Jacek JASSEM ; Bakhos A TANNOUS ; Nik SOL ; Edward POST ; Myron G BEST ; Bei-Hua KONG ; Xing XIE ; Ding MA ; Thomas WURDINGER ; An-Yuan GUO ; Qing-Lei GAO
Protein & Cell 2023;14(6):579-590
Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans
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Female
;
Blood Platelets/pathology*
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Biomarkers, Tumor/genetics*
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Ovarian Neoplasms/pathology*
;
China
7.Establishment of leukemia cell model with inducible AML1-ETO expression and its effect on fatty acid metabolism in leukemia cells.
Wan Qing XIE ; Xue YANG ; Run Xia GU ; Zheng TIAN ; Hai Yan XING ; Ke Jing TANG ; Qing RAO ; Shao Wei QIU ; Min WANG ; Jian Xiang WANG
Chinese Journal of Hematology 2023;44(5):366-372
Objective: To investigate the effect of the AML1-ETO (AE) fusion gene on the biological function of U937 leukemia cells by establishing a leukemia cell model that induces AE fusion gene expression. Methods: The doxycycline (Dox) -dependent expression of the AE fusion gene in the U937 cell line (U937-AE) were established using a lentivirus vector system. The Cell Counting Kit 8 methods, including the PI and sidanilide induction, were used to detect cell proliferation, cell cycle-induced differentiation assays, respectively. The effect of the AE fusion gene on the biological function of U937-AE cells was preliminarily explored using transcriptome sequencing and metabonomic sequencing. Results: ①The Dox-dependent Tet-on regulatory system was successfully constructed to regulate the stable AE fusion gene expression in U937-AE cells. ②Cell proliferation slowed down and the cell proliferation rate with AE expression (3.47±0.07) was lower than AE non-expression (3.86 ± 0.05) after inducing the AE fusion gene expression for 24 h (P<0.05). The proportion of cells in the G(0)/G(1) phase in the cell cycle increased, with AE expression [ (63.45±3.10) %) ] was higher than AE non-expression [ (41.36± 9.56) %] (P<0.05). The proportion of cells expressing CD13 and CD14 decreased with the expression of AE. The AE negative group is significantly higher than the AE positive group (P<0.05). ③The enrichment analysis of the transcriptome sequencing gene set revealed significantly enriched quiescence, nuclear factor kappa-light-chain-enhancer of activated B cells, interferon-α/γ, and other inflammatory response and immune regulation signals after AE expression. ④Disorder of fatty acid metabolism of U937-AE cells occurred under the influence of AE. The concentration of the medium and short-chain fatty acid acylcarnitine metabolites decreased in cells with AE expressing, propionyl L-carnitine, wherein those with AE expression (0.46±0.13) were lower than those with AE non-expression (1.00±0.27) (P<0.05). The metabolite concentration of some long-chain fatty acid acylcarnitine increased in cells with AE expressing tetradecanoyl carnitine, wherein those with AE expression (1.26±0.01) were higher than those with AE non-expression (1.00±0.05) (P<0.05) . Conclusion: This study successfully established a leukemia cell model that can induce AE expression. The AE expression blocked the cell cycle and inhibited cell differentiation. The gene sets related to the inflammatory reactions was significantly enriched in U937-AE cells that express AE, and fatty acid metabolism was disordered.
Humans
;
U937 Cells
;
RUNX1 Translocation Partner 1 Protein
;
Leukemia/genetics*
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Core Binding Factor Alpha 2 Subunit/genetics*
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Oncogene Proteins, Fusion/genetics*
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Leukemia, Myeloid, Acute/genetics*
8.Analysis on the industry characteristics of newly diagnosed occupational pneumoconiosis in Foshan City, 2007-2021
XU Zhi heng SU Shi biao TAN Qiang CHEN Wan xia DENG Na LI Hong li XIE Ying qing
China Occupational Medicine 2022;52(04):435-
Abstract: Objective
To analyze the industry characteristics of new occupational pneumoconiosis in Foshan from 2007 to
Methods
2021. The data of new cases of occupational pneumoconiosis in Foshan City from 2007 to 2021 were obtained from
“ ” , “
the China Disease Prevention and Control Information System subsystem the Occupational Disease and Health Hazardous
”, Results
Factors Monitoring Information System and the industry characteristics of the cases were analyzed. From 2007 to
, , ( )
2021 there were 886 new cases of occupational pneumoconiosis in Foshan mainly include silicosis 68.3% in males
( ), ( )
94.2% and stage Ⅰ pneumoconiosis cases 75.9% . The median age of cases at the time of diagnosed disease was 47 years
,
old and the median working age of dust exposure was 11.2 years. The enterprises where all cases are located involve eight top
, ; , -
industry categories of which manufacturing industry accounted for 97.6% and 30 major industry categories of which non
( ) ,
metallic mineral products industry was the highest 60.5% . There were 554 sporadic cases and 332 cluster cases and the
, , Conclusion
industries were mainly non-metallic mineral products accounting for 55.0% and 69.6% respectively.
, -
Occupational pneumoconiosis in Foshan is dominated by silicosis and the key industries are non metallic mineral products.
9.YANG Jun's clinical experience of acupuncture for oculomotor paralysis.
Shan WANG ; You-Bin TANG ; Qing-Ping ZHANG ; Ai-Hong YUAN ; Hong-Yu XIE ; Rong JI ; Wan-Lin ZHANG ; Lin HAO ; Jun YANG
Chinese Acupuncture & Moxibustion 2022;42(6):669-672
Professor YANG Jun's clinical experience of acupuncture and moxibustion for oculomotor paralysis is summarized. Professor YANG Jun pays attention to disease differentiation and syndrome differentiation in the treatment of this disease. According to the characteristics of oculomotor paralysis, "early diagnosis and seeking treatment from the source" is advocated. According to the etiology and pathogenesis, professor YANG divides oculomotor paralysis into three types: the syndrome of wind-evil attacking collaterals, the syndrome of spleen-stomach weakness and the syndrome of qi-deficiency and blood-stasis. As such, the acupoints are selected according to syndrome differentiation, and several different acupuncture methods (pricking needling at eyelids, penetrating needling and lifting eyelids and contralateral- balance needling on the healthy side) are adopted to improve the symptoms of oculomotor paralysis. It is also suggested to use the combination of scalp acupuncture and electroacupuncture to achieve the best dose-effect state. Moreover, local stimulation around the eyes is important to achieve the effects of "qi reaching affected area".
Acupuncture
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Acupuncture Points
;
Acupuncture Therapy
;
Humans
;
Moxibustion
;
Ophthalmoplegia
;
Syndrome
10.Effect of Jianchangbang Braising Method on Formation of Odor of Polygoni Multiflori Radix Based on HS-GC-MS
Tao ZHANG ; Yaling DENG ; Xiyong CHEN ; Xianwen YE ; Minmin LIU ; Yating XIE ; Ying LIU ; Min HUANG ; Quan WAN ; Qing ZHANG ; Fangcheng YAO ; Jinlian ZHANG
Chinese Journal of Experimental Traditional Medical Formulae 2022;28(14):134-141
ObjectiveBy comparing the difference of volatile components of the decoction pieces before and after being processed by braising method of Jianchangbang and steaming method included in the 2020 edition of Chinese Pharmacopoeia, the influence of processing methods on the flavor formation of Polygoni Multiflori Radix (PMR) was compared. MethodHeadspace-gas chromatography-mass spectrometry (HS-GC-MS) was used to detect the volatile components of 30 batches of PMR samples from 3 origins with 3 processing methods. The GC was performed under programmed temperature (starting temperature of 40 ℃, rising to 150 ℃ at 5 ℃·min-1, and then rising to 195 ℃ at 10 ℃·min-1) with high purity helium as carrier gas and the split ratio of 10∶1. Mass spectrometry conditions were electron impact ion source (EI) and the detection range of m/z 50-650, the peak area normalization method was used to calculate the relative mass fraction of each component. The chromaticity values of different processed products were measured by a precision colorimeter, the relationship between chromaticity values and relative contents of volatile components was investigated by OriginPro 2021, principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were performed on the sample data by SIMCA14.1. The differential components of different processed products of PMR were screened according to the principle of variable importance in the projection (VIP) value>1.5, and the material basis of different odor formation of PMR and its processed products was explored. ResultA total of 59 volatile components were identified, among which 34 were raw products, 33 were braised products, and 27 were steamed products. PCA and OPLS-DA results showed that there were significant differences between the three, but there was no significant difference between samples from different origins of the same processing method. Color parameters of a*, b*, E*ab had no significant correlation with contents of volatile components, while L* was negatively correlated with contents of 2-methyl-2-butenal, 2-methyltetrahydrofuran-3-one and 2,3-dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one (P<0.05). The contents of pungent odor components such as caproic acid, nonanoic acid and synthetic camphor decreased after processing, while the contents of sweet flavor components such as 2-methyl-2-butenal, furfural and 5-hydroxymethylfurfural increased after processing, and the contents of furfural, 5-methyl-2-furanmethanol, 5-hydroxymethylfurfural and other aroma components in the braised products were significantly higher than that in the steamed products. ConclusionHS-GC-MS can quickly identify the volatile substance basis that causes the different odors of PMR and its processed products. The effect of processing methods on the odor is greater than that of origin. There is a significant correlation between the color parameter of L* and contents of volatile components, the "raw" taste of PMR may be related to volatile components such as caproic acid, pelargonic acid and synthetic camphor, the "flavor" after processing may be related to the increase of the contents of 2-methyl-2-butenal, furfural, 5-hydroxymethylfurfural, methyl maltol and furfuryl alcohol.

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