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Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism. 在多项研究中对肠道-肝脏-脂肪轴进行的多组学研究揭示了肠道微生物群和抗病毒反应与全身葡萄糖代谢之间的一致联系。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-07 DOI: 10.1136/gutjnl-2024-332602
Anna Castells-Nobau, José Maria Moreno-Navarrete, Lisset de la Vega-Correa, Irene Puig, Massimo Federici, Jiuwen Sun, Remy Burcelin, Laurence Guzylack-Piriou, Pierre Gourdy, Laurent Cazals, María Arnoriaga-Rodríguez, Gema Frühbeck, Luisa Maria Seoane, José López-Miranda, Francisco J Tinahones, Carlos Dieguez, Marc-Emmanuel Dumas, Vicente Pérez-Brocal, Andrés Moya, Nikolaos Perakakis, Geltrude Mingrone, Stefan Bornstein, Jose Ignacio Rodriguez Hermosa, Ernesto Castro, Jose Manuel Fernández-Real, Jordi Mayneris-Perxachs

Background: The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.

Objective: To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.

Design: Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).

Results: Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes.

Conclusion: These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.

背景:微生物群正在成为胰岛素抵抗和肥胖症易感性的关键因素:微生物群正在成为导致胰岛素抵抗和肥胖的关键因素:了解肠道微生物群与多种组织的胰岛素敏感性之间的相互作用:设计:在六项研究中采用多组学和多组织综合方法,将优生血糖钳夹测量(六项研究中的四项采用了这种方法)与葡萄糖代谢和胰岛素抵抗的其他测量方法(糖化血红蛋白(HbA1c)和空腹血糖)相结合:结果:在四项研究(ADIPOINST,n=15;IRONMET,n=121;FLORINASH,n=67;FLOROMIDIA,n=24)中,蛋白质细菌门的几个属和种始终与胰岛素敏感性呈负相关。空肠、回肠和结肠的转录组分析显示,T 细胞相关特征与胰岛素敏感性呈正相关。回肠和结肠中的蛋白质细菌与 HbA1c 呈正相关,但与 T 细胞数量呈负相关。空肠脱氧胆酸与胰岛素敏感性呈负相关。皮下脂肪组织(ADIPOMIT,n=740)和内脏脂肪组织(VAT)(ADIPOINST,n=29)的转录组学揭示了分别与 HbA1c 和胰岛素敏感性相关的 T 细胞相关特征。VAT 蛋白细菌与胰岛素敏感性呈负相关。ADIPOINST 和 FLORINASH 研究中的多组学和多组织整合将粪便蛋白细菌与空肠和肝脏脱氧胆酸以及空肠、VAT 和肝脏转录组特征联系起来,这些特征涉及肌动蛋白细胞骨架、胰岛素和 T 细胞信号传导。空腹血糖与干扰素诱导的基因以及肠道和增值血管中的抗病毒反应密切相关。在黑腹果蝇中进行的研究验证了这些与人类胰岛素敏感性相关的变化:这些数据全面揭示了微生物组-肠道-脂肪肝轴及其对全身胰岛素作用的影响,提出了潜在的治疗目标。
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引用次数: 0
Potential microbial effects on microsatellite instability possibly drive divergence in colorectal cancer immunotherapy responses among different anatomical subsites. 微生物对微卫星不稳定性的潜在影响可能导致不同解剖亚位点的结直肠癌免疫疗法反应出现差异。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-05 DOI: 10.1136/gutjnl-2024-334008
Ruize Qu, Zhipeng Zhang, Wei Fu
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引用次数: 0
Quest for HBV functional cure: what have we learnt from silencing RNAs? 寻求 HBV 功能性治愈:我们从沉默 RNA 中学到了什么?
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-05 DOI: 10.1136/gutjnl-2024-333763
Norah Terrault, Anna S Lok
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引用次数: 0
TPX2 serves as a novel target for expanding the utility of PARPi in pancreatic cancer through conferring synthetic lethality. TPX2 是一个新靶点,可通过赋予合成致死率来扩大 PARPi 在胰腺癌中的应用。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-05 DOI: 10.1136/gutjnl-2024-332782
Mingming Xiao, Rong Tang, Haoqi Pan, Jing Yang, Xuhui Tong, He Xu, Yanmei Guo, Yalan Lei, Di Wu, Yubin Lei, Yamei Han, Zhilong Ma, Wei Wang, Jin Xu, Xianjun Yu, Si Shi

Background: PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.

Objective: There is a significant unmet clinical need to broaden the utility of PARPi.

Design: RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.

Results: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both in vitro and in vivo. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.

Conclusions: Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.

背景:PARP抑制剂(PARPi)已被授权用于携带致病性种系BRCA1/2突变的转移性胰腺癌患者的维持治疗。然而,BRCA1/2 基因突变在胰腺癌中非常罕见:扩大 PARPi 的应用范围还有大量临床需求未得到满足:设计:进行RNA测序以筛选对PARPi敏感的潜在靶点。在患者来源异种移植(PDX)、异种移植和患者来源类器官模型中验证了合成致死效应。通过LC-MS/MS、共免疫沉淀、激光微照射、免疫荧光、同源重组(HR)或非同源末端连接(NHEJ)报告系统、原位邻接试验和活细胞延时成像分析等方法探讨了其机制:结果:爪蟾驱动蛋白样蛋白 2(TPX2)的靶向蛋白是一个可利用的漏洞。在对 PARPi 敏感的 PDX 模型中,TPX2 被下调,抑制 TPX2 可使 PARPi 在体外和体内合成致死。从机理上讲,TPX2以依赖细胞周期的方式发挥作用。在S/G2期,ATM介导的TPX2 S634磷酸化促进BRCA1被招募到双链断裂(DSB)处进行HR修复,而非磷酸化的TPX2则与53BP1相互作用,将其招募到NHEJ中。磷酸化和非磷酸化 TPX2 之间的平衡决定了 DSB 修复途径的选择。在有丝分裂过程中,TPX2 磷酸化会增强极光 A 的活性,促进有丝分裂进程和染色体稳定性。用细胞穿透肽靶向 TPX2 S634 磷酸化会导致基因组不稳定和有丝分裂灾难,并增强 PARPi 的敏感性。此外,抑制TPX2或S634磷酸化与吉西他滨联合使用可进一步提高胰腺癌对PARPi的敏感性:我们的研究结果揭示了TPX2在控制DNA DSB修复途径选择和有丝分裂进程中的双重功能意义,为胰腺癌患者提供了一种潜在的PARPi治疗策略。
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引用次数: 0
Effectiveness of mailed outreach and patient navigation to promote HCC screening process completion: a multicentre pragmatic randomised clinical trial. 促进完成 HCC 筛查流程的邮寄宣传和患者指导的有效性:一项多中心实用随机临床试验。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-05 DOI: 10.1136/gutjnl-2024-332508
Amit G Singal, Manasa Narasimman, Darine Daher, Sruthi Yekkaluri, Yan Liu, MinJae Lee, Vanessa Cerda, Aisha Khan, Karim Seif El Dahan, Jennifer Kramer, Purva Gopal, Caitlin Murphy, Ruben Hernaez

Background: Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis.

Methods: Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses.

Results: All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage.

Conclusion: Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions.

Trial registration number: NCT02582918.

背景:肝细胞癌(HCC)因癌症治疗过程中的失败而备受困扰,导致晚期诊断率和死亡率居高不下。我们评估了邮寄外展邀请函加患者导航对促进肝硬化患者完成 HCC 筛查流程的有效性:2018年4月至2021年9月期间,我们在美国三个医疗系统的肝硬化患者中开展了一项多中心实用随机临床试验,比较了HCC筛查的邮寄外展加患者导航(1436人)与基于就诊筛查的常规护理(1436人)。我们的主要结果是在 36 个月内完成筛查过程,次要结果是筛查覆盖的时间比例(PTC)。所有患者均纳入意向筛查分析:所有 2872 名参与者(中位年龄 61.3 岁;32.3% 为女性)均纳入了意向筛查分析。在随机接受外展治疗的患者中,6.6%(95% CI:5.3% 至 7.9%)的患者完成了筛查过程;在随机接受常规治疗的患者中,3.3%(95% CI:2.4% 至 4.3%)的患者完成了筛查过程(OR 2.05,95% CI:1.44 至 2.92)。在年龄、性别、种族和民族、Child-Turcotte-Pugh 等级和医疗系统等大多数亚群中,干预措施提高了 HCC 筛查流程的完成率。外展治疗组的 PTC 也明显高于常规治疗组(平均 37.5% vs 28.2%;RR 1.33,95% CI:1.31 至 1.35)。尽管筛查使用不足,但两组中的大多数 HCC 都在早期阶段被发现:结论:与常规护理相比,邮寄外展加导航服务大大提高了肝硬化患者HCC筛查过程的完成率,在大多数受检亚组中效果一致。然而,两组患者的筛查完成率仍未达到最佳水平,这说明有必要采取更深入的干预措施:试验注册号:NCT02582918。
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引用次数: 0
Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma 药理激活 STAT1-GSDME 热解回路可加强肝细胞癌的表观遗传免疫疗法
IF 24.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-01 DOI: 10.1136/gutjnl-2024-332281
Yalin Tu, Haoran Wu, Chengpeng Zhong, Yan Liu, Zhewen Xiong, Siyun Chen, Jing Wang, Patrick Pak-Chun Wong, Weiqin Yang, Zhixian Liang, Jiahuan Lu, Shufen Chen, Lingyun Zhang, Yu Feng, Willis Wai-Yiu Si-Tou, Baoyi Yin, Yingnan Lin, Jianxin Liang, Liying Liang, Joaquim S L Vong, Weida Ren, Tsz Tung Kwong, Howard Leung, Ka Fai To, Stephanie Ma, Man Tong, Hanyong Sun, Qiang Xia, Jingying Zhou, David Kerr, Nick La Thangue, Joseph J Y Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng
Background Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. Objective We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). Design We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial ([NCT03419481][1]) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. Results HCC patients showing higher HDAC1 / 2 / 3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Conclusion Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance ([NCT05873244][2]). Data are available on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom
背景 基因组筛选发现了免疫检查点阻断疗法(ICB)难治性肿瘤中干扰素-γ(IFNγ)通路的缺陷。然而,人们对该通路的非突变调控和治疗开发的可逆性仍然知之甚少。目的 我们旨在确定与ICB耐药相关的可药物组蛋白去乙酰化酶(HDACs),并为肝细胞癌(HCC)患者开发一种易于转化的联合治疗方法。设计 我们通过单细胞 RNA 测序将 pembrolizumab 试验([NCT03419481][1])中 HCC 患者的预后结果与肿瘤细胞中所有 HDAC 同工酶的表达相关联。我们利用免疫图谱分析、单细胞多组学和染色质免疫沉淀测序,并通过基因修饰和共培养系统验证,研究了选择性 HDAC 抑制剂在 4 种抗 ICB 正位和自发模型中的疗效和作用机制。结果 HDAC1 / 2 / 3 表达较高的 HCC 患者表现出 IFNγ 信号不足,接受 ICB 治疗后存活率较低。选择性 I 类 HDAC 抑制剂 CXD101 的瞬时治疗可使 HDAC1/2/3 高表达的肿瘤对 ICB 疗法重新敏感,从而产生依赖 CD8+T 细胞的抗肿瘤和记忆 T 细胞反应。从机理上讲,CXD101与ICB协同作用,通过增强染色质可及性和IFNγ响应基因的H3K27超乙酰化,刺激STAT1驱动的抗肿瘤免疫。IFNγ+GZMB+细胞毒性淋巴细胞的瘤内招募进一步促进了CXD101诱导的Gasdermin E(GSDME)的裂解,从而以STAT1依赖性的方式触发了热休克。值得注意的是,GSDME 的缺失模拟了 STAT1 基因敲除,通过挫败热蛋白和 IFNγ 反应,取消了 CXD101-ICB 联合疗法的抗肿瘤疗效和生存益处。结论 我们的免疫表观遗传学策略利用 IFNγ 介导的网络来增强癌症-免疫循环,揭示了 STAT1-GSDME 自强化热解回路,为正在进行的应对 ICB 抗药性的 II 期试验提供了机理基础 ([NCT05873244][2])。如有合理要求,可提供相关数据。[1]:/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]:/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom
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引用次数: 0
Correction: Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation 更正:人类和实验性肝硬化患者炎症小体激活的不同易导致急性-慢性肝衰竭,无论之前是否有失代偿现象
IF 24.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-11-01 DOI: 10.1136/gutjnl-2019-320170corr1
BMJ Publishing Group Ltd and British Society of Gastroenterology
Monteiro S, Grandt J, Uschner FE, et al . Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous …
Monteiro S, Grandt J, Uschner FE, et al .炎症小体的不同激活易导致既往有或既往无急性慢性肝衰竭的人类和实验性肝硬化...
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引用次数: 0
Single-use scopes may reduce various environmental impacts of gastroscopy in some situations but probably not in routine practice of endoscopy units. 在某些情况下,一次性使用的胃镜可能会减少胃镜检查对环境的各种影响,但在内窥镜检查室的常规操作中可能不会。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-30 DOI: 10.1136/gutjnl-2024-334018
Mathieu Pioche, Guillaume Vidal, Madj Ben Rejeb, Rémi Collin, Jérémie Jacques
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引用次数: 0
Evolution of the use, effectiveness and safety of bismuth-containing quadruple therapy for Helicobacter pylori infection between 2013 and 2021: results from the European registry on H. pylori management (Hp-EuReg) 2013年至2021年期间治疗幽门螺杆菌感染的含铋四联疗法的使用情况、有效性和安全性的演变:欧洲幽门螺杆菌管理登记处(Hp-EuReg)的结果
IF 24.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-26 DOI: 10.1136/gutjnl-2024-332804
Llum Olmedo, Xavier Calvet, Emili Gené, Dmitry S Bordin, Irina Voynovan, M. Castro-Fernandez, Manuel Pabón-Carrasco, Alma Keco-Huerga, Ángeles Perez-Aisa, Alfredo J Lucendo, Luís Rodrigo, Aiman S Sarsenbaeva, Igor B Khlinov, Galyna Fadieienko, Oleg Zaytsev, Ángel Lanas, Samuel J Martínez-Domínguez, Enrique Alfaro, Laimas Jonaitis, Óscar Núñez, Rinaldo Pellicano, Luis Hernández, Oleksiy Gridnyev, Juozas Kupcinskas, Antonio Gasbarrini, Doron Boltin, Yaron Niv, Gülüstan Babayeva, Ricardo Marcos-Pinto, Bojan Tepes, Marino Venerito, Veronika Papp, Frode Lerang, Mārcis Leja, Perminder S Phull, Wojciech Marlicz, Michael Doulberis, Sinead M Smith, Vladimir Milivojevic, Lumir Kunovsky, Antonio Mestrovic, Tamara Matysiak-Budnik, Halis Simsek, Anna Cano-Català, Ignasi Puig, Leticia Moreira, Pablo Parra, Olga P Nyssen, Francis Megraud, Colm O'Morain, Javier P Gisbert
Background Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating Helicobacter pylori infection even in areas of high bacterial antibiotic resistance. Objective To describe the time trends of use, effectiveness and safety of BQT in Europe using the European Registry on Helicobacter pylori Management (Hp-EuReg). Design Patients registered in the Hp-EuReg from 2013 to 2021 who had received BQT were included. The regimens prescribed, the number of eradication attempts, effectiveness, adherence and safety were analysed. The effectiveness was assessed by modified intention to treat (mITT). Time-trend and multivariate analyses were performed to determine variables that predicted treatment success. Results Of the 49 690 patients included in the Hp-EuReg, 15 582 (31%) had received BQT. BQT use increased from 8.6% of all treatments in 2013 to 39% in 2021. Single-capsule BQT—containing bismuth, metronidazole and tetracycline—plus a PPI (single-capsule BQT, ScBQT) was the most frequent treatment mode (43%). Schemes that obtained an effectiveness above 90% were the 10-day ScBQT and 14-day BQT using tetracycline plus metronidazole, or amoxicillin plus either clarithromycin or metronidazole. Only ScBQT achieved above 90% cure rates in all the geographical areas studied. Using the ScBQT scheme, adherence, the use of standard or high-dose PPIs, 14-day prescriptions and the use of BQT as first-line treatment were significantly associated with higher mITT effectiveness. Conclusion The use of BQT increased notably in Europe over the study period. A 10-day ScBQT was the scheme that most consistently achieved optimal effectiveness. Trial registration number [NCT02328131][1]. All data relevant to the study are included in the article or uploaded as online supplemental information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02328131&atom=%2Fgutjnl%2Fearly%2F2024%2F10%2F25%2Fgutjnl-2024-332804.atom
背景铋剂四联疗法(BQTs)包括铋剂、一种质子泵抑制剂(PPI)和两种抗生素,即使在细菌对抗生素耐药性较高的地区,该疗法对治疗幽门螺旋杆菌感染也非常有效。目的 利用欧洲幽门螺杆菌管理登记处(Hp-EuReg)描述欧洲使用 BQT 的时间趋势、有效性和安全性。设计 纳入 2013 年至 2021 年在 Hp-EuReg 登记并接受过 BQT 治疗的患者。对处方方案、根除尝试次数、有效性、依从性和安全性进行了分析。疗效通过改良意向治疗(mITT)进行评估。进行了时间趋势和多变量分析,以确定预测治疗成功的变量。结果 在纳入 Hp-EuReg 的 49 690 名患者中,15 582 人(31%)接受了 BQT 治疗。BQT在所有治疗中的使用率从2013年的8.6%增至2021年的39%。含铋剂、甲硝唑和四环素的单胶囊BQT加PPI(单胶囊BQT,ScBQT)是最常见的治疗模式(43%)。有效率超过 90% 的方案是使用四环素加甲硝唑或阿莫西林加克拉霉素或甲硝唑的 10 天 ScBQT 和 14 天 BQT。在研究的所有地区中,只有 ScBQT 的治愈率超过 90%。使用 ScBQT 方案、坚持治疗、使用标准或大剂量 PPIs、14 天处方以及将 BQT 作为一线治疗与较高的 mITT 有效率显著相关。结论 在研究期间,欧洲 BQT 的使用明显增加。为期 10 天的 ScBQT 是最能持续获得最佳疗效的方案。试验注册号[NCT02328131][1]。与该研究相关的所有数据均包含在文章中或作为在线补充信息上传。[1]:/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02328131&atom=%2Fgutjnl%2Fearly%2F2024%2F10%2F25%2Fgutjnl-2024-332804.atom
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引用次数: 0
Safe and successful gut-restricted adsorbent strategy against cirrhosis and acute-on-chronic liver failure 针对肝硬化和急性-慢性肝衰竭的安全、成功的肠道限制吸附策略
IF 24.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-26 DOI: 10.1136/gutjnl-2024-332457
Schalk Willem Van der Merwe, Maite G Fernandez-Barrena
Cirrhosis marks the advanced stage of chronic liver disease characterised by sustained inflammation leading to the loss of hepatocytes and the progression of fibrosis. These structural and functional alterations profoundly impact blood flow within the hepatic microcirculation, potentially culminating in portal hypertension over time. Traditionally, the evolution of cirrhosis has been divided into two clinical phases: An initial asymptomatic stage known as compensated cirrhosis followed by decompensated cirrhosis, marked by the emergence of complications such as ascites, variceal bleeding, hepatic encephalopathy, jaundice, coagulopathy and bacterial infections. Decompensated cirrhosis typically signals a more aggressive disease course with patients susceptible to hepatic and extrahepatic organ dysfunction, complications or necessitating liver transplantation.1 It is imperative to recognise that decompensated cirrhosis transcends hepatic manifestations representing a systemic disorder. Recent observational studies in Europe, including chronic liver failure acute-on-chronic liver failure (CANONIC) and PREDICTing Acute-on-chronic liver failure (PREDICT), have further classified decompensated cirrhosis into non-acute and various forms of acute decompensation, potentially leading to acute-on-chronic liver failure (ACLF). However, the precise factors determining the trajectory towards decompensation in cirrhosis remain elusive. Accumulating evidence suggests that specific preceding events play pivotal roles in this progression. Notably, clinically significant portal hypertension, systemic inflammation and failure of the intestinal barrier leading to bacterial product translocation through the portal circulation are key events interdependently influencing each …
肝硬化是慢性肝病的晚期阶段,其特点是持续的炎症导致肝细胞丧失和纤维化进展。这些结构和功能上的改变对肝脏微循环内的血流产生了深远的影响,随着时间的推移,有可能最终导致门静脉高压。传统上,肝硬化的演变分为两个临床阶段:最初的无症状阶段称为代偿期肝硬化,随后是失代偿期肝硬化,以腹水、静脉曲张出血、肝性脑病、黄疸、凝血功能障碍和细菌感染等并发症的出现为标志。失代偿期肝硬化通常预示着更凶险的病程,患者容易出现肝内外器官功能障碍、并发症或必须进行肝移植。欧洲最近的观察性研究,包括慢性肝功能衰竭急性慢性肝功能衰竭(CANONIC)和急性慢性肝功能衰竭预测(PREDICT),进一步将失代偿期肝硬化分为非急性和各种形式的急性失代偿,可能导致急性慢性肝功能衰竭(ACLF)。然而,决定肝硬化失代偿轨迹的确切因素仍然难以捉摸。越来越多的证据表明,之前发生的特定事件在这一进展过程中起着关键作用。值得注意的是,临床上明显的门静脉高压、全身炎症和肠道屏障失效导致细菌产物通过门静脉循环转运,这些关键事件相互依存,相互影响......
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