Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt:Mechanistic and clinical implications

In this article,we provide commentary on the recent article by Zhao et al.We focus on the shifts in the gut microbiota of patients with hepatitis B virus(HBV)-associated cirrhosis/portal hypertension(PH)following transjugular intrahepatic portosystemic shunt(TIPS)and the implications for understanding the mechanisms,diagnosis,and treatment.By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy,the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS,with Morganella species present only in the hepatic encephalopathy group.The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies.Furthermore,the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBVrelated PH.Despite these promising findings,future studies are needed to address limitations,including a small sample size,a relatively short evaluation period for gut microbiota alterations,the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels,and the lack of validation in animal models.In conclusion,Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy,potentially through the intricate gut-liver axis,and has important clinical implications for improving the management of patients with HBV-related PH.

Four-dimensional flow magnetic resonance imaging for noninvasive diagnosis of clinically significant portal hypertension and high-risk gastroesophageal varices in patients with cirrhosis

Introduction:Noninvasive diagnoses of clinically significant portal hypertension(CSPH)and high-risk gastroesophageal varices are clinically relevant but challenging.Four-dimensional(4D)flow magnetic resonance imaging(MRI)provides comprehensive flow information and is a promising alternative.This study evaluated the efficacy of 4D flow MRI as a noninvasive method for diagnosing CSPH and high-risk varices in patients with liver cirrhosis.Methods:This prospective study enrolled consecutive patients diagnosed with liver cirrhosis at a tertiary referral center between October 2020 and March 2021.Each participant underwent abdominal 4D flow MRI.Hemodynamic parameters within the portal vein,including the average and peak flow velocities,normalized flow volume(Q_(normal)),and regurgitant fraction(R%),were extracted and compared between healthy individuals and patients with CSPH and between participants with high-and low-risk varices.Subsequently,these parameters were incorporated into a logistic regression(LR)model refined using L1 regularization and validated using five-fold cross-validation.The diagnostic efficacy was evaluated using receiver operating characteristic(ROC)curves.Results:Eighty-two participants were enrolled(71 patients diagnosed with liver cirrhosis and 11 healthy individuals serving as controls).Among hemodynamic parameters,patients with CSPH exhibited a notable increase in Q_(normal)of 0.66±0.19 ml*m^(2)/[cycle*kg](P=0.001)and an R%of 1.98(2.05)(P=0.002).Similarly,patients with high-risk varices showed a higher Q_(normal)of 0.61±0.15 ml*m^(2)/[cycle*kg](P<0.001)and R%of 1.88(2.81)(P=0.006).ROC analysis revealed an area under the curve(AUC)for Q_(normal)of 0.93 and 0.91 for R%for diagnosing CSPH,while the LR model showcased a superior AUC of 0.95.For high-risk varices,Q_(normal)and R%showed AUC values of 0.75 and 0.70,respectively,whereas the LR model showed a higher AUC of 0.84.Conclusion:As a noninvasive imaging modality,4D flow MRI exhibits considerable potential for the diagnosis of CSPH and high-risk gastroesophageal varices;thus,it may minimize the reliance on invasive procedures in patients with cirrhosis.

宫颈癌调强计划Portal Dosimetry剂量验证中拼接野的应用分析

目的提出一种生成Portal Dosimetry(以下简称PD)分野的拼接野(以下简称PD拼接野)方法,并对宫颈癌计划的PD拼接野进行分析研究。方法选取20例宫颈癌患者的七野调强治疗计划进行研究,治疗计划中每个大野分成1对分野。首先制作仅含分野的PD剂量验证计划,然后使用直线加速器出束执行。通过矩阵拼接和矩阵叠加,分别得到每对PD分野对应的PD拼接野和PD大野。使用PD软件模块,得到PD拼接野和PD大野的伽玛通过率,分别记为Gp和Gd。使用Gm表示每对PD分野的平均伽玛通过率值。对Gp、Gd和Gm进行统计分析和比较研究。结果所有140个射野的Gp、Gd和Gm的值分别为98.78%±0.70%、97.34%±1.25%和98.87%±0.51%。两两比较结果显示,Gp和Gd差异具有统计学意义(P<0.05);Gp和Gm的数据差异较小。对每个PD验证计划,计算所有同一类射野对应的计划验证通过率(Gplan)。对Gplan数据进行统计分析显示,PD拼接野和PD大野差异具有统计学意义(P<0.05),PD拼接野和PD分野的数据差异较小。结论本文提出的PD拼接野概念为评价PD剂量验证结果提供了有益的参考信息。

Portal vein thrombosis:Insight into physiopathology,diagnosis,and treatment

Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis, but might also occur in absence of an overt liver disease. Several causes, either local or systemic, might play an important role in PVT pathogenesis. Frequently, more than one risk factor could be identified; however, occasionally no single factor is discernable. Clinical examination, laboratory investigations, and imaging are helpful to provide a quick diagnosis, as prompt treatment might greatly affect a patient's outcome. In this review, we analyze the physiopathological mechanisms of PVT development, together with the hemodynamic and functional alterations related to this condition. Moreover, we describe the principal factors most frequently involved in PVT development and the recent knowledge concerning diagnostic and therapeutic procedures. Finally, we analyze the implications of PVT in the setting of liver transplantation and its possible influence on patients' future prognoses.

Portal hypertension and gastrointestinal bleeding:Diagnosis,prevention and management

Bleeding from esophageal varices is a life threatening complication of portal hypertension.Primary prevention of bleeding in patients at risk for a first bleeding episode is therefore a major goal.Medical prophylaxis consists of non-selective beta-blockers like propranolol or carvedilol.Variceal endoscopic band ligation is equally effective but procedure related morbidity is a drawback of the method.Therapy of acute bleeding is based on three strategies:vasopressor drugs like terlipressin,antibiotics and endoscopic therapy.In refractory bleeding,self-expandable stents offer an option for bridging to definite treatments like transjugular intrahepatic portosystemic shunt(TIPS).Treatment of bleeding from gastric varices depends on vasopressor drugs and on injection of varices with cyanoacrylate.Strategies for primary or secondary prevention are based on non-selective beta-blockers but data from large clinical trials is lacking.Therapy of refractory bleeding relies on shuntprocedures like TIPS.Bleeding from ectopic varices,portal hypertensive gastropathy and gastric antral vascular ectasia-syndrome is less common.Possible medical and endoscopic treatment options are discussed.

Reliability in endoscopic diagnosis of portal hypertensive gastropathy

AIM: To analyze reliability among endoscopists in diagnosing portal hypertensive gastropathy (PHG) and to determine which criteria from the most utilized classifications are the most suitable. METHODS: From January to July 2009, in an academic quaternary referral center at Santa Casa of S o Paulo Endoscopy Service, Brazil, we performed this singlecenter prospective study. In this period, we included 100 patients, including 50 sequential patients who had portal hypertension of various etiologies; who were previously diagnosed based on clinical, laboratory and imaging exams; and who presented with esophageal varices. In addition, our study included 50 sequentialpatients who had dyspeptic symptoms and were referred for upper digestive endoscopy without portal hypertension. All subjects underwent upper digestive endoscopy, and the images of the exam were digitally recorded. Five endoscopists with more than 15 years of experience answered an electronic questionnaire, which included endoscopic criteria from the 3 most commonly used Portal Hypertensive Gastropathy classifications (McCormack, NIEC and Baveno) and the presence of elevated or flat antral erosive gastritis. All five endosco- pists were blinded to the patients' clinical information, and all images of varices were deliberately excluded for the analysis. RESULTS: The three most common etiologies of portal hypertension were schistosomiasis (36%), alcoholic cirrhosis (20%) and viral cirrhosis (14%). Of the 50 patients with portal hypertension, 84% were Child A, 12% were Child B, 4% were Child C, 64% exhibited previous variceal bleeding and 66% were previously endoscopic treated. The endoscopic parameters, presence or absence of mosaic-like pattern, red point lesions and cherry-red spots were associated with high inter-observer reliability and high specificity for diagnosing Portal Hypertensive Gastropathy. Sensitivity, specificity and reliability for the diagnosis of PHG (%) were as follows: mosaic-like pattern (100; 92.21; High); fine pink speckling (56; 76.62; Unsatisfactory); superficial reddening (69.57; 66.23; Unsatisfactory); red-point lesions (47.83; 90.91; High); cherry-red spots (39.13; 96.10; High); isolated red marks (43.48; 88.31; High); and confluent red marks (21.74; 100; Unsatisfactory). Antral elevated erosive gastritis exhibited high reliability and high specificity with respect to the presence of portal hypertension (92%) and the diagnosis of portal hypertensive gastropathy (88.31%). CONCLUSION: The most suitable endoscopic criteria for the diagnosis of PHG were mosaic-like pattern, redpoint lesions and cherry-red spots with no subdivisions,which were associated with a high rate of inter-observer reliability.

Invasive and non-invasive diagnosis of cirrhosis and portal hypertension

With advances in the management and treatment of advanced liver disease,including the use of antiviral therapy,a simple,one stage description for advanced fibrotic liver disease has become inadequate.Although refining the diagnosis of cirrhosis to reflect disease heterogeneity is essential,current diagnostic tests have not kept pace with the progression of this new paradigm.Liver biopsy and hepatic venous pressure gradient measurement are the gold standards for the estimation of hepatic fibrosis and portal hypertension(PHT),respectively,and they have diagnostic and prognostic value.However,they are invasive and,as such,cannot be used repeatedly in clinical practice.The ideal noninvasive test should be safe,easy to perform,inexpensive,reproducible as well as to give numerical and accurate results in real time.It should be predictive of long term outcomes related with fibrosis and PHT to allow prognostic stratification.Recently,many types of noninvasive alternative tests have been developed and are under investigation.In particular,imaging and ultrasound based tests,such as transient elastography,have shown promising results.Although most of these noninvasive tests effectively identify severe fibrosis and PHT,the methods available for diagnosing moderate disease status are still insufficient,and further investigation is essential to predict outcomes and individualize therapy in this field.

Diagnostic challenges in non-cirrhotic portal hypertension-porto sinusoidal vascular disease

Non-cirrhotic portal hypertension consists of a group of diseases characterized by signs and complications of portal hypertension,which differ from cirrhosis through histological alterations,hemodynamic characterization and,clinical outcome.Because of the similarities in clinical presentation and imaging signs,frequently these patients,and particularly those with porto-sinusoidal vascular disease(PSVD),are misdiagnosed as having liver cirrhosis and thus raising difficulties in their diagnosis.The most challenging differentiation to be considered is between PSVD and cirrhosis and,although not pathognomonic,liver biopsy is still the standard of diagnosis.Although they still require extended validation before being broadly used,new non-invasive methods for the diagnosis of porto-sinusoidal vascular disease,like transient elastography,contrast-enhanced ultrasound or metabolomic profiling,have shown promising results.Another issue is the differentiation between PSVD and chronic extrahepatic portal vein obstruction,especially now when it is known that 40%of patients suffering from PSVD develop portal vein thrombosis.In this particular case,once the portal vein thrombosis occurred,the diagnosis of PSVD is impossible according to the current guidelines.Moreover,so far,the differentiation between PSVD and sinusoidal obstruction syndrome has not been clear so far in particular circumstances.In this review we highlighted the diagnostic challenges regarding the PSVD,as well as the current techniques used in the evaluation of these patients.

Nodular regenerative hyperplasia:Evolving concepts on underdiagnosed cause of portal hypertension

Nodular regenerative hyperplasia(NRH)is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules.NRH may lead to the development of non-cirrhotic portal hypertension.There are no published systematic population studies on NRH and our current knowledge is limited to case reports and case series.NRH may develop via autoimmune,hematological,infectious,neoplastic,or drug-related causes.The disease is usually asymptomatic,slowly or nonprogressive unless complications of portal hypertension develop.Accurate diagnosis is made by histopathology,which demonstrates diffuse micronodular transformation without fibrous septa.Lack of perinuclear collagen tissue distinguishes NRH from typical regenerative nodules in the cirrhotic liver.While the initial treatment is to address the underlying disease,ultimately the therapy is directed to the management of portal hypertension.The prognosis of NRH depends on both the severity of the underlying illness and the prevention of secondary complications of portal hypertension.In this review we detail the epidemiology,pathogenesis,diagnosis,management,and prognosis of NRH.

Diagnosis and treatment of portal biliopathy

Background: Portal biliopathy producing intrahepa- tic and extrahepatic biliary ductai abnormalities from portal hypertension, particularly with extrahepatic portal vein obstruction (EHPVO) is common. A majority of these patients are asymptomatic, but oc- casionally there is symptomatic biliary obstruction, and cholangitis and choledocholithiasis. Objective: To explore the principles of diagnosis and treatment of portal biliopathy. Data sources: To review the literature of portal bili- opathy. Conclusions: Endoscopic sphincterotomy, stone ex- traction and supportive drainage could effectively re- lieve cholangitis when jaundice is associated with common bile duct stones. Definitive decompressive portal-system vein shunting operation and choledo- cho-jejunostomy are sometimes required when biliary obstruction is recurrent and progressive.

Ultrasound-guided fine needle aspiration biopsy in differential diagnosis of portal vein tumor thrombosis

BACKGROUND: Portal vein tumor thrombosis(PVTT) is a serious complication and a major metastatic way of hepa- tocellular carcinoma (HCC). But portal vein benign throm- bosis(PVBT) always appears in patients with hepatocirrho- sis, and PVTT should be differentiated from PVBT. The aim of this study was to probe the value of ultrasound- guided fine needle aspiration biopsy in differential diagnosis of PVTT. METHODS: Twenty-two HCC patients with portal vein thrombosis and 8 hepatocirrhosis patients with portal vein thrombosis were studied by ultrasound-guided fine needle aspiration biopsy. Twelve portal vein thrombosis filling portal vein embranchment of the 30 portal vein thrombosis patients were examined by 18G automatic biopsy. The positive rates of aspiration biopsy cytology and histology were calculated and compared with those of automatic biopsy. RESULTS: The positive rates of fine needle aspiration biop- sy cytology and histology were 93.3% (28/30) and 90.0% (27/30), respectively. They were not different markedly from that of automatic biopsy 91.7% (11/12). In aspira- tion biopsy of 22 HCC patients with PVTT, HCC cellular was found in 19 portal vein thrombosis patients (86.4%) by cytology examination and in 18 portal vein thrombosis patients (81.8%) by histology examination. In total, 20 tumor thrombi were detected. The other two were diag- nosed as benign thrombosis. No HCC cell and/or tissue was observed in 8 patients with hepatocirrhosis associated with portal vein thrombosis. CONCLUSIONS: Ultrasound-guided fine needle biopsy in detecting PVTT shows a high positive rate and is of diag- nostic value. The positive rate is not apparently different from that of automatic biopsy. Hence the case that fails to be diagnosed by color Doppler flow imaging ( CDFI) and pulsed Doppler can be detected early by ultrasound-guided fine needle aspiration biopsy.

Diagnosis and surgical treatment of giant splenic artery aneurysms with portal hypertension; report of 4 cases

BACKGROUND:Giant splenic artery aneurysm (GSAA) is a rare but clinically relevant disease. Its importance lies in potential rupture and hemorrhage. Early diagnosis and treatment before rupture of GSAA are crucial to GSAA pa- tients especially to GSAA patients with portal hypertension (PHT). METHODS: Four patients of GSAA with PHT treated at our hospital from December 1999 to September 2001 were retrospectively reviewed. RESULTS: GSAA was found in all patients with digital sub- stracted angiography ( DSA) and/or magnetic resonance angiography (MRA) before operation. Resection of GSAA and treatment of PHT were carried out successfully with no perioperative mortality. CONCLUSIONS: Patients with GSAA are apt to have PHT or segmental PHT because of suppression of the splenic vein or formation of aneurysm-portal vein fistula. Opera- tion should be focused on GSAA, and PHT complica- tions.

Current state of endohepatology: Diagnosis and treatment of portal hypertension and its complications with endoscopic ultrasound

The diagnosis and management of cirrhosis and portal hypertension(PH)with its complications including variceal hemorrhage,ascites,and hepatic encephalopathy continues to evolve.Although there are established“standards of care”in liver biopsy and measurement of PH,gastric varices remain an area without a universally accepted therapeutic approach.The concept of“Endo Hepatology”has been used to describe of the applications of endoscopic ultrasound(EUS)to these challenges.EUS-liver biopsy(EUS-LB)offers an alternative to percutaneous and transjuglar liver biopsy without compromising safety or efficacy,and with added advantages including the potential to reduce sampling error by allowing biopsies in both hepatic lobes.Furthermore,EUS-LB can be performed during the same procedure as EUS-guided portal pressure gradient(PPG)measurements,allowing for the collection of valuable diagnostic and prognostic data.EUS-guided PPG measurements provide an appealing alternative to the transjugular approach,with proposed advantages including the ability to directly measure portal vein pressure.In addition,EUS-guided treatment of gastric varices(GV)offers several possible advantages to current therapies.EUS-guided treatment of GV allows detailed assessment of the vascular anatomy,similar efficacy and safety to current therapies,and allows the evaluation of treatment effect through doppler ultrasound visualization.The appropriate selection of patients for these procedures is paramount to ensuring generation of useful clinical data and patient safety.

Diagnosis and management of extrahepatic portal vein aneurysm:a case report

BACKGROUND: Extrahepatic portal vein aneurysm is a rare clinical entity with no more than 50 reported cases in the English literature. This study was to elucidate the procedures used in the diagnosis and management of portal vein aneurysm. METHOD: The clinical data of a patient with extrahepatic portal vein aneurysm were analyzed. RESULTS: Extrahepatic portal vein aneurysm associated with portal hypertension and splenomegaly was diagnosed by color Doppler ultrasonography (US), computed tomography (CT), magnetic resonance angiography (MRA) and angiography (indirect portography). Splenectomy and surgical shunt (splenorenal shunt) were performed. No hepatic encephalopathy and variceal bleeding occurred after the operation except mild pancreatic leakage caused by partial pancreatic tail resection. The patient recovered well. CONCLUSIONS: Extrahepatic portal vein aneurysm can be evaluated by US, CT, MRA, and angiography for optimum conservative or surgical management.

Ultrasound-based elastography for the diagnosis of portal hypertension in cirrhotics

Progressive fibrosis is encountered in almost all chronicliver diseases. Its clinical signs are diagnostic in advanced cirrhosis, but compensated liver cirrhosis is harder to diagnose. Liver biopsy is still considered the reference method for staging the severity of fibrosis, but due to its drawbacks(inter and intra-observer variability, sampling errors, unequal distribution of fibrosis in the liver, and risk of complications and even death), non-invasive methods were developed to assess fibrosis(serologic and elastographic). Elastographic methods can be ultrasound-based or magnetic resonance imaging-based. All ultrasoundbased elastographic methods are valuable for the early diagnosis of cirrhosis, especially transient elastography(TE) and acoustic radiation force impulse(ARFI) elastography, which have similar sensitivities and specificities, although ARFI has better feasibility. TE is a promising method for predicting portal hypertension in cirrhotic patients, but it cannot replace upper digestive endoscopy. The diagnostic accuracy of using ARFI in the liver to predict portal hypertension in cirrhotic patients is debatable, with controversial results in published studies. The accuracy of ARFI elastography may be significantly increased if spleen stiffness is assessed, either alone or in combination with liver stiffness and other parameters. Two-dimensional shearwave elastography, the Elast PQ technique and strain elastography all need to be evaluated as predictors of portal hypertension.

基于TIA Portal的HMI+PLC虚拟仿真探究

文章提出一种在TIA Portal软件上集成人机界面(Human Machine Interface,HMI)和可编程逻辑控制器(ProgrammableLogicController,PLC)进行虚拟仿真的方法。该方法能够在现有的硬件条件下,使学生不受时间、地点等的限制,只需要在计算机上安装TIA PORTAL软件就可以进行虚拟学习,构建控制系统,进行硬件组态、编程、控件组态、仿真运行和程序调试等。最后,以十字路口的交通灯为例,采用基于实际物理设备和基于TIAPORTAL软件虚拟仿真两种方式搭建控制系统,完成项目的设计、组态、编程、调试和运行测试。主要任务是寻找方法构建虚拟网络,将虚拟运行的PLC与HMI设备联系起来,实现虚拟设备之间和软件之间的数据传输,达到与使用实际物理设备效果相同的目的。

Non-cirrhotic portal hypertension with large regenerative nodules: A diagnostic challenge

Non-cirrhotic portal hypertension is a poorly understood condition characterized by portal hypertension in the absence of conventional hepatic cirrhosis and described in association with blood coagulation disorders, myeloproliferative and immunological diseases and with exposure to toxic drugs. Very recently, precise classification criteria have been proposed in order to define four distinct subcategories. The present case highlights how the clinical presentation, the confounding results from imaging studies, and the difficulties in the histological evaluation often render cases of non-cirrhotic portal hypertension a real diagnostic challenge. It also underscores the classification problems which can be faced once this diagnosis is performed. Indeed, the different subcategories proposed result from the prevalent subtypes in a spectrum of hepatic regenerative responses to a variety of injuries determining microcirculatory dis-turbances. More flexibility in classification should derive from this etiopathogenic background.

Experience on Diagnosis and Treatment of Strangulated Intestinal Obstruction Caused by Mesentery Vein Thrombosis on Account of Portal Hypertension

In the present study, to investigate diagnosis and treatment of strangulated intestinal obstruction caused by mesentery vein thrombosis on account of portal hypertension, the data in twelve patients with this disease from 1998 to 2008 were analyzed. All patients presented abdominal pain and vomiting and were confirmed strangulated intestinal obstruction caused by mesentery thrombosis with operation. In this group, nine patients underwent part of small intestine excision, and three patients underwent open-closed operation because of the whole small intestine necrosis caused by intensive mesentery thrombosis. Five patients died after operation. The diagnosis of strangulated intestinal obstruction caused by mesentery thrombosis was difficult because of the slow disease processes and severe outcomes. It is necessary to take some measures to get over the dangers duration after operation.

Diagnosis and management of arterioportal fistula occurring after percutaneous transhepatic portal vein cannula-assisted TIPS

To the Editor:Transjugularintrahepaticportosystemicshunt(TIPS)isusuallyconsideredthechoiceformanagingcomplicationsofportal hypertensionsuchasrefractoryascites,esophagogastricvariceal bleedingandrecurrentbleedinguncontrolledwithfirstline treatment.Inrecentyears,TIPShasbeensuccessfullyusedto treat Budd-Chiari syndrome, hepatic hydrothorax, and portal vein thrombosis.One of the key steps during TIPS is the portal vein puncture.

Intrahepatic portal venous systems in adult patients with cavernous transformation of portal vein: Imaging features and a new classification

Background: Cavernous transformation of the portal vein(CTPV) due to portal vein obstruction is a rare vascular anomaly defined as the formation of multiple collateral vessels in the hepatic hilum. This study aimed to investigate the imaging features of intrahepatic portal vein in adult patients with CTPV and establish the relationship between the manifestations of intrahepatic portal vein and the progression of CTPV. Methods: We retrospectively analyzed 14 CTPV patients in Beijing Tsinghua Changgung Hospital. All patients underwent both direct portal venography(DPV) and computed tomography angiography(CTA) to reveal the manifestations of the portal venous system. The vessels measured included the left portal vein(LPV), right portal vein(RPV), main portal vein(MPV) and the portal vein bifurcation(PVB). Results: Nine males and 5 females, with a median age of 40.5 years, were included in the study. No significant difference was found in the diameters of the LPV or RPV measured by DPV and CTA. The visualization in terms of LPV, RPV and PVB measured by DPV was higher than that by CTA. There was a significant association between LPV/RPV and PVB/MPV in term of visibility revealed with DPV( P = 0.01), while this association was not observed with CTA. According to the imaging features of the portal vein measured by DPV, CTPV was classified into three categories to facilitate the diagnosis and treatment. Conclusions: DPV was more accurate than CTA for revealing the course of the intrahepatic portal vein in patients with CTPV. The classification of CTPV, that originated from the imaging features of the portal vein revealed by DPV, may provide a new perspective for the diagnosis and treatment of CTPV.