Metabolic reprogramming of the inflammatory response in the nervous system:the crossover between inflammation and metabolism

Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.

Solar hydrogen production from electrochemical ammonia splitting powered by a single perovskite solar cell

For carbon-free electrochemical fuel formation,the electrochemical cell must be powered by renewable energy.Obtaining solar-powered H_(2) fuel from water typically requires multiple photovoltaic cells and/or junctions to drive the water splitting reaction.Because of the lower thermodynamic requirements to oxidize ammonia compared to water,solar cells with smaller open circuit voltages can provide the required potential for ammonia splitting.In this work,a single perovskite solar cell with an open-circuit potential of 1.08 V is coupled to a 2-electrode electrochemical cell employing hybrid electroanodes functionalized with Ru-based molecular catalysts.The device is active for more than 30 min,producing N_(2) and H_(2) in a 1:2.9 ratio with 89%faradaic efficiency with no external applied bias.This work illustrates that hydrogen production from ammonia can be driven by conventional semiconductors.

Small molecules to target tau amyloid aggregation

Protein aggregation has been linked with many neurodegenerative diseases,such as Alzheimer’s disease(AD)or Parkinson’s disease.AD belongs to a group of heterogeneous and incurable neurodegenerative disorders collectively known as tauopathies.They comprise frontotemporal dementia,Pick’s disease,or corticobasal degeneration,among others.The symptomatology varies with the specific tau protein variant involved and the affected brain region or cell type.However,they share a common neuropathological hallmark-the formation of proteinaceous deposits named neurofibrillary tangles.Neurofibrillary tangles,primarily composed of aggregated tau(Zhang et al.,2022),disrupt normal neuronal functions,leading to cell death and cognitive decline.

Design and redesign journey of a drug for transthyretin amyloidosis

The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).

Incidence of cystoid macular edema after Descemet's stripping automated endothelial keratoplasty

AIM： To determine the incidence of cystoid macular edema（CME） after Descemet＇s stripping automated endothelial keratoplasty（DSAEK）.METHODS： This study included all consecutive patients operated in a Spanish tertiary reference hospital over a period of four years. A total of 55 eyes from 47 patients matched the selection criteria. CME was diagnosed clinically at the slit-lamp and confirmed by optical coherence tomography. RESULTS： Six cases of CME were diagnosed postoperatively, which represented an incidence of 11%. Three patients had previously undergone DSAEK alone（7%; 3/41） and the other three, DSAEK combined with phacoemulsification（21%; 3/14）. Five out of six patients with CME responded to standard therapy.CONCLUSION： CME is a possible complication after DSAEK and can be treated with standard therapy. CME appears more frequently when DSAEK is combined with phacoemulsification and posterior chamber（PC） intraocular lens（IOL） implantation. Intraoperative damage to the corneal endothelial cells might play a role in the pathogenesis of CME. As long as the causes remain unclear, we recommend administering prophylaxis when risk factors are present or when combined surgery is planned.

Automated Synthesis of Wideband Bandpass Filters Based on Slow-Wave EBG Structures

This paper is focused on the automated synthesis of wideband bandpass filters operating at microwave frequencies and based on electromagnetic bandgap(EBG)structures.The classical counterpart of such filter consists of a combination of transmission line sections and shunt-connected grounded stubs placed at equidistant positions.By replacing the transmission line sections with capacitively-loaded lines(a kind of EBG-based lines)exhibiting the same phase shift at the lower cutoff frequency and the same characteristic(actually Bloch)impedance,filter size is reduced and the spurious pass bands can be efficiently suppressed.In practice,the loading capacitances are implemented by means of patches,in order to achieve a fully planar filter implementation.The presence of the patches reduces the effective phase velocity of the capacitively-loaded lines,thus providing a slow-wave effect useful for filter miniaturization.Moreover,due to periodicity,such EBG-based lines exhibit wide stop bands,which are used for spurious suppression.Even though such EBGbased filters were previously reported by some of the authors,a systematic synthesis method was not applied for filter design.In this paper,the main aim is to demonstrate the potential of aggressive space mapping(ASM)for that purpose,and it will be shown that such filters can be automatically synthesized.

Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

BACKGROUND Dermatologic adverse events(DAEs)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent received.The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic treatment.As is the case in other conditions,individual genetic variants may partially explain a higher risk of DAEs.AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.METHODS We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(AE)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAEs:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,respectively.The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).RESULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of DAEs.Thereafter,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAEs(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,ECOG-PS,diabetes and AHT.The value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of DAE development.CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2(rs4762)gene variant.If validated in other anti-oncogenic treatments,it might be considered a good prognosis marker.

LL-37 and CsgC exemplify the crosstalk between anti-amyloid, antimicrobial, and anti-biofilm protein activities

Protein misfolding and aggregation into amyloid fibrils is the main pathological hallmark of neurodegenerative diseases,including Alzheimer’s,Parkinson’s,Huntington’s,and prion diseases(Chiti and Dobson,2017).These insoluble fibrillar deposits possess a common structure characterized by a cross-β-sheet conformation in which β-strands run transversely to the fiber axis and form an intermolecular network of hydrogen bonds.

Growth plasticity of conifers did not avoid declining resilience to soil and atmospheric droughts during the 20th century

Background:Plasticity in response to environmental drivers can help trees cope with droughts.However,our understanding of the importance of plasticity and physiological adjustments in trees under global change is limited.Methods:We used the International Tree-Ring Data Bank(ITRDB)to examine 20th century growth responses in conifer trees during(resistance)and following(resilience)years of severe soil and atmospheric droughts occurring in isolation or as compound events.Growth resilience indices were calculated using observed growth divided by expected growth to avoid spurious correlations,in which the expected values were obtained by the autoregressive moving average(ARIMA)model.We used high atmospheric vapour pressure deficit(VPD)to select years of atmospheric drought and low annual values of the Standardized Precipitation-Evapotranspiration Index(SPEI)to select years with soil drought.We acquired the sensitivities(i.e.,the slopes of the relationships)by fitting the resilience indices as a function of environmental drivers,and assessed how these sensitivities changed over time for different types of drought events using linear mixed models.We also checked whether plasticity in growth responses was sufficient to prevent long-term trends of growth reductions during or after severe droughts.We acknowledge that by focusing on the response of surviving trees from the ITRDB we are potentially biasing our results towards higher resilience,as stand level responses(e.g.,mortality)may result in lowered competition after the disturbance event.Results:Sensitivities of resilience to VPD and SPEI changed throughout the 20th century,with the directions of these changes often reversing in the second half of the century.For the 1961–2010 period,changing sensitivities had positive effects on resilience,especially following years of high-VPD and compound events,avoiding growth losses that would have occurred if sensitivities had remained constant.Despite sensitivity changes,resilience was still lower at the end of the 20th century compared to the beginning of the century.Conclusions:Future adjustments to low-SPEI and high-VPD events are likely to continue to compensate for the trends in climate only partially,leading to further generalized reductions in tree growth of conifers.An improved understanding of these plastic adjustments and their limits,as well as potential compensatory processes at the stand level,is needed to project forest responses to climate change.

Depolarizing metrics in the biomedical field:Vision enhancement and classification of biological tissues

Polarimetry encompasses a collection of optical techniques broadly used in a variety of fields.Nowadays,such techniques have provided their suitability in the biomedical field through the study of the polarimetric response of biological samples(retardance,dichroism and depolarization)by measuring certain polarimetric observables.One of these features,depolarization,is mainly produced by scattering on samples,which is a predominant efiect in turbid media as biological tissues.In turn,retardance and dichroic efiects are produced by tissue anisotropies and can lead to depolarization too.Since depolarization is a predominant efiect in tissue samples,we focus on studying difierent depolarization metrics for biomedical applications.We report the suitability of a set of depolarizing observables,the indices of polarimetric purity(IPPs),for biological tissue inspection.We review some results where we demonstrate that IPPs lead to better performance than the depolarization index,which is a well-established and commonly used depolarization observable in the literature.We also provide how IPPs are able to significantly enhance contrast between difierent tissue structures and even to reveal structures hidden by using standard intensity images.Finally,we also explore the classificatory potential of IPPs and other depolarizing observables for the discrimination of difierent tissues obtained from ex vivo chicken samples(muscle,tendon,myotendinous junction and bone),reaching accurate models for tissue classification.

Arrhythmic syncope: From diagnosis to management

Syncope is a concerning symptom that affects a large proportion of patients.It can be related to a heterogeneous group of pathologies ranging from trivial causes to diseases with a high risk of sudden death.However,benign causes are the most frequent,and identifying high-risk patients with potentially severe etiologies is crucial to establish an accurate diagnosis,initiate effective therapy,and alter the prognosis.The term cardiac syncope refers to those episodes where the cause of the cerebral hypoperfusion is directly related to a cardiac disorder,while arrhythmic syncope is cardiac syncope specifically due to rhythm disorders.Indeed,arrhythmias are the most common cause of cardiac syncope.Both bradyarrhythmia and tachyarrhythmia can cause a sudden decrease in cardiac output and produce syncope.In this review,we summarized the main guidelines in the management of patients with syncope of presumed arrhythmic origin.Therefore,we presented a thorough approach to syncope work-up through different tests depending on the clinical characteristics of the patients,risk stratification,and the management of syncope in different scenarios such as structural heart disease and channelopathies.

内建电场辅助光催化甲烷干重整的研究进展

甲烷(CH_(4))和二氧化碳(CO_(2))是导致全球变暖的两种主要温室气体.甲烷干重整技术能够同时消耗两种温室气体并制备氢气(H2)和一氧化碳(CO),是减少温室效应的理想策略之一.CH_(4)和CO_(2)在热力学上具有很高的稳定性,所以活化CH_(4)和CO_(2)需要克服较高的能垒,导致传统的甲烷干重整技术总是需要高热能来触发该反应发生.光催化技术的发展为在温和条件下启动甲烷干重整反应提供了更多的可能.然而,由于光激发载流子之间的快速重组,光催化效率仍然较低,难以满足工业需求.研究人员发现,通过构建内置电场增强电荷载流子的分离和转移动力学是解决上述问题的可靠策略.本文首先介绍了甲烷干重整的反应机理和用于甲烷干重整的工业热催化材料.随后,总结了光催化甲烷干重整的优点和潜在的光催化材料,重点介绍了两类催化剂:(1)由铁电效应产生的永久自发极化进而构筑的内建电场的光催化剂.由于自发极化引起的电场,基于铁电材料的光催化剂在促进电荷转移方面显示出较大潜力.(2)由异质结结构在界面处引发内建电场的光催化剂.基于两种具有合适能带结构的半导体构建Ⅱ型异质结也是一种有效方法,由于交错间隙结构,在界面处形成内置电场,导致不同半导体分别进行氧化和还原过程.此外,Z型载流子转移机制可以保留具有更强还原能力的电子和更强氧化能力的空穴,将较低氧化还原能力的光生载流子重组,从而通过界面电场促进光催化甲烷干重整过程.(3)局域表面等离激元共振(LSPR)效应引发内建热电场的光催化剂.金属纳米颗粒在可见-近红外(Vis-NIR)光的照射下会产生共振现象,将会导致金属中的电子结构不连续,从而构建局部电场.因此,LSPR效应在提高光(热)催化甲烷干重整效率方面具有巨大潜力.随着光催化甲烷干重整技术的发展,人们对理解反应机理或阐明光催化剂中特定组分在反应中的作用提出了更多要求,导致原位表征技术和理论计算受到了极大的关注.最后,介绍了先进的原位表征和理论计算在该领域应用的主要进展,并预测了原位表征在光催化甲烷干重整领域的潜在功能,为从事该领域且处于起步阶段的年轻研究者提供了一定参考.虽然在光催化甲烷干重整领域已经取得了许多突破和进展,但仍存在一些挑战需要克服.根据已有的研究结果,本文总结了内建电场辅助光催化甲烷干重整领域的主要面临挑战,并提出了应对这些挑战的可行性策略,为未来对该领域进行更深入的研究提供借鉴.

Non-pharmacological management for chemotherapy-induced nausea and vomiting in patients with cancer:a scoping review

Objective:This review aimed to map and summarize published studies that tested non-pharmacological management for chemotherapyinduced nausea and vomiting(CINV).Methods:We searched for eligible studies in 5 electronic databases and screened the retrieved studies using the inclusion and exclusion criteria.Data were then collated according to the types of interventions,measurement tool,and outcomes.Results:The search yielded 2343 records,of which 11 were included.Four categories of non-pharmacological CINV management were made;manipulative and body-based therapy(n=5 studies);mind–body therapy(n=3 studies);biologically based practice(n=1 study),and energy therapy(n=2 studies).Seven different scales were used to measure CINV.Nine studies repor ted improvement in CINV.Conclusions:This scoping review demonstrates the breadth of non-pharmacological management to address CINV.Various types of CINV scales were used to measure CINV severity.The management and scale can be utilized to improve nursing care,par ticularly in cancer care.

鳄鱼上颚的形貌曲面拟合及其偏差分析

为了研究鳄鱼上颚的形貌特征对其结构特性的影响并将其应用于仿生设计,需对鳄鱼上颚的曲面进行提取并研究.运用逆向工程技术对鳄鱼头骨进行三维重构,并结合多项式拟合方法分别建立按照生物形貌特征划分的三个曲面的数学模型,将三个数学模型的数据进行合并后与生物模型进行偏差对比.结果表明,三个数学模型拟合方程拟合后的确定系数值均接近于1,且其标准偏差在可接受范围内.复杂生物曲面模型可转化为多个数学模型,再将多个数学模型的数据合并后转化为完整的模型,可为鳄鱼头骨的力学特性研究及工程仿生设计提供依据.

实时经支气管超声引导针吸活检在肺癌分期中的应用

线性经支气管超声引导针吸活检(endobronchial ultrasound-guided transbronchial needle aspiration,EBUS-TBNA)是新引进的技术,它是实时超声下可视淋巴结的针吸活检。尽管有研究显示,其为肺癌纵隔分期的有效方法,但全世界多数机构并未应用该技术。本报道旨在分享我们应用EBUS-TBNA的经验,并对相关文献做一简要概述。我们对有关该技术的已有文献进行综述,并特别介绍了我们应用该技术方面的经验。EBUS-TBNA用以探查肺癌患者的转移性纵隔淋巴结和/或肺门淋巴结是有效且安全的。在其它病理状态下,其亦为有效的诊断方法。

Neurodegeneration:An early event of diabetic retinopathy

Diabetic retinopathy(DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia.However,retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination.In other words,retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR.Therefore,the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR.Elevated levels of glutamate and the overexpression of the renin-angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina.Among neuroprotective factors,pigment epithelial derived factor,somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review.Nevertheless,it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye.New strategies,based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors,are currently being tested in experimental models and in clinical pilot studies.Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.

Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018.A large amount of evidence supports the amyloid cascade hypothesis,which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles,and these aggregates lead to inflammation,synaptic impairment,neuronal loss,and thus to cognitive decline and behavioral abnormalities.The poor correlation found between cognitive decline and amyloid plaques,have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer’s disease.The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and,although amyloid-beta may initiate the cascade of events,tau impairment is likely the effector molecule of neurodegeneration.Recently,it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and,more importantly,that downregulation of tau partially reverses transcriptional perturbations.Despite mounting evidence points to an interplay between amyloid-beta and tau,some factors could independently affect both pathologies.Thus,the dual pathway hypothesis,which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed.Among others,the immune system seems to be strongly involved in amyloid-beta and tau pathologies.Other factors,as the apolipoprotein Eε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation.Interestingly,amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials.Likewise,it has been shown that tau-immunotherapy also reduces amyloid-beta levels.Thus,even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy,combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer’s disease.

Physiopathology of splanchnic vasodilation in portal hypertension

In liver cirrhosis, the circulatory hemodynamic alterations of portal hypertension signifi cantly contribute to many of the clinical manifestations of the disease. In the physiopathology of this vascular alteration, mesen- teric splanchnic vasodilation plays an essential role by initiating the hemodynamic process. Numerous studies performed in cirrhotic patients and animal models have shown that this splanchnic vasodilation is the result of an important increase in local and systemic vasodilators and the presence of a splanchnic vascular hyporesponsiveness to vasoconstrictors. Among the molecules and factors known to be potentially involved in this arterial vasodilation, nitric oxide seems to have a crucial role in the physiopathology of this vascular alteration. However, none of the wide variety of mediators can be described as solely responsible, since this phenomenon is multifactorial in origin. Moreover, angiogenesis and vascular remodeling processes alsoseem to play a role. Finally, the sympathetic nervous system is thought to be involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension, although the nature and extent of its role is not completely understood. In this review, we discuss the different mechanisms known to contribute to this complex phenomenon.

Failed medial patellofemoral ligament reconstruction:Causes and surgical strategies

Patel ar instability is a common clinical problem encountered by orthopedic surgeons specializing in the knee. For patients with chronic lateral patellar instability, the standard surgical approach is to stabilize the patella through a medial patellofemoral ligament(MPFL) reconstruction. Foreseeably, an increasing number of revision surgeries of the reconstructed MPFL will be seen in upcoming years. In this paper, the causes of failed MPFL reconstruction are analyzed:(1) incorrect surgical indication or inappropriate surgical technique/patient selection;(2) a technical error; and(3) an incorrect assessment of the concomitant risk factors for instability. An understanding of the anatomy and biomechanics of the MPFL and cautiousness with the imaging techniques while favoring clinical over radiological findings and the use of common sense to determine the adequate surgical technique for each particular case, are critical to minimizing MPFL surgery failure. Additionally, our approach to dealing with failure after primary MPFL reconstruction is also presented.

Detection of hyper-conserved regions in hepatitis B virus X gene potentially useful for gene therapy

AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in various clinical stages(from chronic infection to cirrhosis and hepatocellular carcinoma, both HBeA g-negative and HBeA g-positive), and infected with HBV genotypes A-F and H. In a serum sample from each patient with viremia > 3.5 log IU/m L, the HBX 5' end region [nucleotide(nt) 1255-1611] was PCRamplified and submitted to next-generation sequencing(NGS). We assessed genotype variants by phylogenetic analysis, and evaluated conservation of this region by calculating the information content of each nucleotide position in a multiple alignment of all unique sequences(haplotypes) obtained by NGS. Conservation at the HBx protein amino acid(aa) level was also analyzed.RESULTS NGS yielded 1333069 sequences from the 27 samples, with a median of 4578 sequences/sample(2487-9279, IQR 2817). In 14/27 patients(51.8%), phylogenetic analysis of viral nucleotide haplotypes showed a complex mixture of genotypic variants. Analysis of the information content in the haplotype multiple alignments detected 2 hyper-conserved nucleotide regions, one in the HBX upstream non-coding region(nt 1255-1286) and the other in the 5' end coding region(nt 1519-1603). This last region coded for a conserved amino acid region(aa 63-76) that partially overlaps a Kunitz-like domain.CONCLUSION Two hyper-conserved regions detected in the HBX 5' end may be of value for targeted gene therapy, regardless of the patients' clinical stage or HBV genotype.