我们应用多性状GWAS模型结合GERD(78 707例;288 734个对照)和遗传相关性状，包括教育程度、抑郁和体重指数。我们还使用多性状分析来识别BE风险位点。23andMe重复了最高命中数(462 753例GERD, 24 099例BE, 1 484 025例对照组)。我们还将GERD基因座分为肥胖驱动型和抑郁驱动型两个亚组。研究人员对这些亚组进行了研究，以确定它们与组织特异性基因表达以及严重食管疾病(BE和/或食管腺癌，EA)风险的关系。

我们鉴定出88个与GERD相关的位点，经过多次测试校正后，其中59个位点在23andMe中复制。我们的BE分析确定了7个新的位点。此外，我们发现只有肥胖驱动的GERD位点(而不是抑郁驱动的位点)与食管组织中富集的基因相关，并成功预测BE/EA。

我们的多性状模型识别了许多新的GERD和BE风险位点。 We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

一名51岁男性来我们胃肠科就诊，主诉腹胀和打嗝。他的病史有显著的糖尿病和甲状腺乳头状癌的甲状腺切除术。他报告偶尔有胃灼热，但否认有任何腹痛、排便习惯改变、体重减轻或恶性肿瘤家族史。他的一个孩子患有自闭症。体检注意到足部有无症状的皮肤颜色病变(figure 1A)，但其他均为阴性。上消化道内镜示食管(figure 1B)大量白色斑块，胃(figure 1C)和十二指肠可见多发小息肉。结肠镜检查发现大量息肉分布在整个结肠(图1D)，回肠末端有多个息肉。胃、十二指肠和结肠的活检结果均与增生性息肉一致(figure 1E)。

你的诊断是什么?

验证通过反流监测诊断胃食管反流病(GORD)的Lyon共识标准。< / p > < /秒>Design

Manual review of impedance-pH tracings from patients with proton pump inhibitor (PPI)-dependent heartburn, evaluated off PPI. Acid exposure time (AET) thresholds defined by the Lyon Consensus and impedance parameters were investigated, namely, total refluxes (TRs), postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI).

The study included 488 patients, 178 (36%) with normal (<4%) AET, 89 (18%) with inconclusive (4%–6%) AET and 221 (45%) with abnormal (>6%) AET, alongside with 70 healthy controls. At receiver operating characteristic analysis, area under curve was 0.89, 0.95 and 0.89 for TRs, PSPW index and MNBI, respectively, and threshold values were 40, 50% and 2000 ; the 4% physiological AET threshold defined by the Lyon Consensus showed 100% specificity but 63% sensitivity. The thresholds defined for impedance parameters were validated against AET by means of ordered logistic regression, being in concordance with the 4% AET threshold (OR 2.5 for TRs, 18.9 for PSPW index and 5.7 for MNBI). TRs positivity and concordant PSPW index/MNBI positivity were found in 80%–90% of patients in the abnormal AET group, in 73%–74% of cases in the inconclusive AET group and in 28%–40% of cases in the group with normal AET.

Our results show the overall validity of the Lyon Consensus approach to GORD diagnosis. Adding evaluation of impedance parameters, namely, TRs, PSPW index and MNBI to AET appraisal, substantially improves the diagnostic yield of reflux monitoring.

化生源于对损伤做出反应的分化细胞类型，被认为是许多癌症的前体。损伤后的修复性化生黏膜中存在异质细胞系，包括小凹细胞、增殖细胞和spasmolytic polypeptide- transcription metaplasia (SPEM)细胞，SPEM是一种关键的化生细胞群。分泌酶原的主细胞是胃粘膜中的长寿细胞，被认为是SPEM细胞的起源;然而，一种相互矛盾的范式提出了峡部祖细胞作为SPEM的起源。< / p > < /秒>Design

Gastric intrinsic factor (GIF) is a stomach tissue-specific gene and exhibits protein expression unique to mature mouse chief cells. We generated a novel chief cell-specific driver mouse allele, GIF-rtTA. GIF-GFP reporter mice were used to validate specificity of GIF-rtTA driver in chief cells. GIF-Cre-RnTnG mice were used to perform lineage tracing during homoeostasis and acute metaplasia development. L635 treatment was used to induce acute mucosal injury and coimmunofluorescence staining was performed for various gastric lineage markers.

We demonstrated that mature chief cells, rather than isthmal progenitor cells, serve as the predominant origin of SPEM cells during the metaplastic process after acute mucosal injury. Furthermore, we observed long-term label-retaining chief cells at 1 year after the GFP labelling in chief cells. However, only a very small subset of the long-term label-retaining chief cells displayed the reprogramming ability in homoeostasis. In contrast, we identified chief cell-originating SPEM cells as contributing to lineages within foveolar cell hyperplasia in response to the acute mucosal injury.

Our study provides pivotal evidence for cell plasticity and lineage contributions from differentiated gastric chief cells during acute metaplasia development.

在对三个CD临床试验方案(n=350例患者，基线SES-CD和ge;3例确诊溃疡)，数据汇总并随机分为70%的训练队列和30%的测试队列。MM-SES-CD采用logistic回归模型确定的各参数权重进行设计，ER为1年(SES-CD <3)为因变量。使用最大约登指数确定ER低概率和高概率的切点评分，并在测试队列中验证。< / p > < /秒>Results

Baseline ulcer size, extent of ulceration and presence of non-passable strictures had the strongest association with 1-year ER as compared with affected surface area, with differential weighting of individual parameters across disease segments being observed during logistic regression. The MM-SES-CD was generated using this weighted regression model and demonstrated strong discrimination for ER in the training dataset (area under the receiver operator curve (AUC) 0.83, 95% CI 0.78 to 0.94) and in the testing dataset (AUC 0.82, 95% CI 0.77 to 0.92). In comparison to the MM-SES-CD scoring model, the original SES-CD score lacks accuracy (AUC 0.60, 95% CI 0.55 to 0.65) for predicting the achievement of ER.

We developed and internally validated the MM-SES-CD as an endoscopic severity assessment tool to predict one-year ER in patients with CD on active therapy.

评估瑞典活检证实的乳糜泻(CD)的发病率，并检查随时间推移十二指肠/空肠粘膜正常活检的发病率，作为CD意识和调查的代表。

基于1990–2015年基于活检报告的全国性人群队列研究，显示十二指肠/空肠的绒毛萎缩(VA)或黏膜正常。< / p > < /秒>Results

We identified 44 771 individuals (63% females) with a biopsy report specifying VA and 412 279 (62% females) with a biopsy report indicating normal mucosa (without a prior biopsy indicating VA). The median age at diagnosis of CD was 28 years. The mean age-standardised incidence rate during the study period was 19.0 per 100 000 person-years (95% CI 17.3 to 20.8). The incidence reached a peak in 1994 for both sexes and a second higher peak in 2002–2003 for females and in 2006 for males. The lifetime risk of developing CD was 1.8% (2.3% in females and 1.4% in males).

Prior to 2015, there was a parallel rise in rates for biopsies showing normal duodenal/jejunal mucosa.

In Sweden, the incidence of CD increased until 2002–2003 in females and until 2006 in males. Since then, the incidence of CD has declined despite increasing duodenal/jejunal biopsies, suggesting that increased awareness and investigation are unlikely to elevate the incidence of the disease in Sweden. Across a lifetime, 1 in 44 females and 1 in 72 males are expected to be diagnosed with CD in Sweden, indicating a relatively high societal burden of disease.

Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.

Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host–microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

肠道菌群在调节宿主免疫反应中起关键作用。我们进行了一项前瞻性观察性研究，以检查已接种灭活疫苗(CoronaVac;或mRNA疫苗(BNT162b2;BioNTech;Comirnaty)。< / p > < /秒>Design

We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA.

We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05).

Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.

We searched the medical literature through to 2 April 2021 to identify RCTs of a low FODMAP diet in IBS. Efficacy was judged using dichotomous assessment of improvement in global IBS symptoms or improvement in individual IBS symptoms, including abdominal pain, abdominal bloating or distension, and bowel habit. Data were pooled using a random effects model, with efficacy reported as pooled relative risks (RRs) with 95% CIs, and interventions ranked according to their P-score.

We identified 13 eligible RCTs (944 patients). Based on failure to achieve an improvement in global IBS symptoms, a low FODMAP diet ranked first vs habitual diet (RR of symptoms not improving=0.67; 95% CI 0.48 to 0.91, P-score=0.99), and was superior to all other interventions. Low FODMAP diet ranked first for abdominal pain severity, abdominal bloating or distension severity and bowel habit, although for the latter it was not superior to any other intervention. A low FODMAP diet was superior to British Dietetic Association (BDA)/National Institute for Health and Care Excellence (NICE) dietary advice for abdominal bloating or distension (RR=0.72; 95% CI 0.55 to 0.94). BDA/NICE dietary advice was not superior to any other intervention in any analysis.

In a network analysis, low FODMAP diet ranked first for all endpoints studied. However, most trials were based in secondary or tertiary care and did not study effects of FODMAP reintroduction and personalisation on symptoms.

无梗锯齿状病变(SSLs)在各个年龄段都很常见，但BRAF突变型癌症主要发生在老年人中。异常DNA甲基化在年轻患者的SSL中并不常见。在这里，我们询问衰老和DNA甲基化在SSL启动和进展中的作用。< / p > < /秒>Design

We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.

Inducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.

SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.

尽管在影像学和病理评价方面取得了重大进展，但早期鉴别良恶性胆道狭窄仍然具有挑战性。内窥镜逆行胰胆管造影术(ERCP)用于检查胆道狭窄，收集胆汁。我们测试了胆细胞游离DNA (cfDNA)的下一代测序(NGS)突变分析的诊断潜力。< / p > < /秒>Design

A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay.

An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut.

Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.

我们旨在确定遗传易感高危个体胰腺癌监测的长期收益。< / p > < /秒>Design

From 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.

366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1–32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).

The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

We performed bulk RNA sequencing of HCC tissue as well as flow cytometry and single-cell RNA sequencing of enriched ILCs from non-tumour liver, margin and tumour core derived from 48 patients with HCC. Simultaneous measurement of protein and RNA expression at the single-cell level (AbSeq) identified precise signatures of ILC subgroups. In vitro culturing of ILCs was used to validate findings from in silico analysis. Analysis of RNA-sequencing data from large HCC cohorts allowed stratification and survival analysis based on transcriptomic signatures.

RNA sequencing of tumour, non-tumour and margin identified tumour-dependent gradients, which were associated with poor survival and control of ILC plasticity. Single-cell RNA sequencing and flow cytometry of ILCs from HCC livers identified natural killer (NK)-like cells in the non-tumour tissue, losing their cytotoxic profile as they transitioned into tumour ILC1 and NK-like-ILC3 cells. Tumour ILC composition was mediated by cytokine gradients that directed ILC plasticity towards activated tumour ILC2s. This was liver-specific and not seen in ILCs from peripheral blood mononuclear cells. Patients with high ILC2/ILC1 ratio expressed interleukin-33 in the tumour that promoted ILC2 generation, which was associated with better survival.

Our results suggest that the tumour cytokine milieu controls ILC composition and HCC outcome. Specific changes of cytokines modify ILC composition in the tumour by inducing plasticity and alter ILC function.

A highly multiplexed imaging mass cytometry (IMC) panel was designed to simultaneously quantify 36 biomarkers of tissues from 134 patients with HCC and 7 healthy donors to generate 562 highly multiplexed histology images at single-cell resolution. Different function units were defined by topological analysis of TME. CN relevant to the patients’ prognosis was identified as specific target for HCC therapy. Transgenic mouse models were used to validate the novel immunotherapy target for HCC.

Three major types of intratumour areas with distinct distribution patterns of tumorous, stromal and immune cells were identified. 22 cellular metaclusters and 16 CN were defined. CN composed of various types of cells formed regional function units and the regional immunity was regulated reversely by resident Kupffer cells and infiltrating macrophages with protumour and antitumour function, respectively. Depletion of Kupffer cells in mouse liver largely enhances the T cell response, reduces liver tumour growth and sensitises the tumour response to antiprogrammed cell death protein-1 treatment.

Our findings reveal for the first time the various topological function units of HCC TME, which also presents the largest depository of pathological landscape for HCC. This work highlights the potential of Kupffer cell-specific targeting rather than overall myeloid cell blocking as a novel immunotherapy for HCC treatment.

确定免疫衰竭(慢性肝衰竭的标志之一)的组成部分对于我们理解肝硬化并发症至关重要。各种抑制CD4⁺ T细胞已被证实为系统免疫激活的有效抑制剂。在这里，我们建立了表达人白细胞抗原G (HLA-G)的抑制性CD4⁺ T细胞亚群在急性肝硬化失代偿(AD)患者中的存在、调节和作用机制。< / p > < /秒>Design

Flow cytometry was used to determine the proportion and immunophenotype of CD4⁺HLA-G⁺ T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4⁺HLA-G⁺ cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways.

Patients with AD were distinguished by an expansion of a CD4⁺HLA-G⁺CTLA-4⁺IL-35⁺ immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G⁺ phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines.

We have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.

代谢产物改变对肝细胞癌(HCC)的致瘤性很重要。我们对HCC患者和健康肝供者门静脉血液中的代谢产物变化进行了综合代谢组学分析，并与肝组织和粪便样本中的代谢产物变化进行了比较。< / p > < /秒>Design

Serum (portal and central vein), liver tissue (HCC tumour and adjacent non-tumour, normal liver) and stool samples were collected from 102 subjects (52 HCC patients and 50 healthy controls) in the discovery cohort; and 100 subjects (50 HCC patients and 50 healthy controls) in an independent validation cohort. Untargeted metabolomic profiling was performed using high-performance liquid chromatography-mass spectrometry. The function of candidate metabolites was validated in hepatocyte cell lines.

Detailed metabolomic evaluation showed distinct clusters of metabolites in serum, liver tissue and stool samples from patients with HCC and control individuals (p<0.001). HCC patients had significantly higher levels of portal vein serum and HCC tissue metabolites of DL-3-phenyllactic acid, L-tryptophan, glycocholic acid and 1-methylnicotinamide than healthy controls, which were associated with impaired liver function and poor survival. On the other hand, HCC patients had lower levels of linoleic acid and phenol in portal vein and stool samples than healthy controls. Linoleic acid and phenol significantly inhibited HCC proliferation, inferring their anti-HCC function as protective metabolites.

The integrative metabolome analysis of serum, tissue and stool metabolites revealed unreported metabolic alterations in HCC patients. In portal vein, we identified elevated and depleted metabolites signifying that they might play a role in HCC development.