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Children with autism commonly suffer from comorbid functional gastrointestinal disorders (FGID) and anxiety. The raised prevalence of both conditions in autism suggests complex reciprocal relationships, which are seldom explored in non-treatment-seeking FGID. The relationships between subtypes of FGID and anxiety are also unclear. This study recruited boys with autism and age-matched typically developing (TD) boys, aged 4-11 years, who were not actively seeking help for gastrointestinal problems. Their parents completed the Rome IV Diagnostic Questionnaires for Pediatric FGID. Four groups of children with and without autism/FGID were identified and compared on their anxiety level using the Spence children's anxiety scale. In 69 boys with autism and 69 age-matched TD boys, FGID were identified in 22 and 16 boys, respectively. ANCOVA demonstrated a significant interaction effect of autism and FGID on anxiety (F[1, 129] = 5.43, p = 0.021), while conditional logistic regression identified an interaction effect of autism and anxiety on the odds of FGID (OR 1.038, 95% CI 1.002-1.075, p = 0.038). Explorative post hoc analysis showed higher anxiety in functional nausea and vomiting disorder (p = 0.033) and functional abdominal pain disorder (p = 0.029) among boys with autism than TD boys with the same respective subtypes of FGID. In summary, among prepubertal boys with autism, the presence of FGID that are non-treatment-seeking in nature, has a significantly stronger association with higher levels of anxiety than TD boys. The strength of association may be more prominent in subtypes of FGID. Possible pathomechanisms including the underlying microbiota spectra and inflammatory paths should be explored in future studies. LAY SUMMARY: Anxiety and gastrointestinal problems are common symptoms in autism. Given that gut health could be linked to emotions, their association in young boys with autism was studied. The presence of nausea vomiting, or abdominal pain were associated with raised anxiety among boys with autism, yet this was not observed in typically developing boys. This suggests that anxiety among autistic children could be partly explained by the presence of FGID.

Androgen deprivation therapy (ADT), either by medical or surgical castration, is the backbone for standard treatment of locally advanced or metastatic prostate cancer, yet it is also associated with various metabolic and cardiovascular complications. Recent evidence have shown that obesity, insulin resistance, or metabolic disturbances can be associated with changes in the gut microbiome, while animal studies also show that castration is associated with changes in the gut microbiome. This study aims to investigate whether the fecal microbiota in prostate cancer patients who had undergone prostatectomy or ADT are different, and explore changes in phylogeny and pathways that may lead to side effects from ADT. A total of 86 prostate cancer patients (56 patients on ADT and 30 patients with prostatectomy) were recruited. The fecal microbiota was analyzed by the 16S rRNA gene for alpha- and beta-diversities by QIIME2, as well as the predicted metabolic pathways by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2. The alpha-diversity was significantly lower in the ADT group. The beta-diversity was significantly different between the groups, in which Ruminococcus gnavus and Bacteroides spp were having higher relative abundance in the ADT group, whereas Lachnospira and Roseburia were reduced. The Firmicutes-to-Bacteroidetes ratio is noted to be lower in the ADT group as well. The functional pathway prediction showed that the biosynthesis of lipopolysaccharide (endotoxin) and propanoate was enriched in the ADT as well as the energy cycle pathways. This study is limited by the cross-sectional design and the clinical heterogeneity. There is a significant difference in gut microbiome between prostate cancer patients on ADT and prostatectomy. We theorize that this difference may contribute to the development of metabolic complications from ADT. Further longitudinal studies are awaited.

BackgroundThere were limited data on the risk of post-polypectomy bleeding (PPB) in patients on direct oral anticoagulants (DOAC). We aimed to evaluate the PPB and thromboembolic risks among DOAC and warfarin users in a population-based cohort.MethodsWe performed a territory-wide retrospective cohort study involving patients in Hong Kong from 2012 to 2020. Patients who received an oral anticoagulant and had undergone colonoscopy with polypectomy were identified. Propensity-score models with inverse probability of treatment weighting were developed for the warfarin-DOAC and between-DOAC comparisons. The primary outcome was clinically significant delayed PPB, defined as repeat colonoscopy requiring haemostasis within 30 days. The secondary outcomes were 30-day blood transfusion requirement and new thromboembolic event.ResultsApixaban was associated with lower PPB risk than warfarin (adjusted HR (aHR) 0.39, 95% CI 0.24 to 0.63, pFor thromboembolic events, apixaban was associated with lower risk than warfarin (aHR 0.22, 95% CI 0.11 to 0.45, pConclusionsApixaban was associated with a significantly lower risk of PPB and thromboembolism than warfarin, dabigatran and rivaroxaban, particularly in older patients with right-sided polyps.

The Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is believed to share similar characteristics with SARS in 2003 and Mediterranean East Respiratory Syndrome (MERS) in 2012. We hypothesized that countries with previous exposure to SARS and MERS were significantly more likely to have fewer cases and deaths from coronavirus disease 2019 (COVID-19). We retrieved the incidence of COVID-19 per 100,000 population within 30 days since the first confirmed case was reported from the 2019 Novel COVID-19 data repository by the Johns Hopkins Centre for Systems Science and Engineering for 94 countries. The association between previous exposure to SARS and/or MERS and the 30-day COVID-19 incidence rate was examined by multivariable linear regression analysis, whilst controlling for potential confounders including the INFORM COVID-19 Risk Index, Testing Policies, Democracy Index, Scientific Citation Index, Gross Domestic Product (GDP), Human Development Index (HDI) and the population density of each country. We found that countries with previous exposure to SARS and/or MERS epidemics were significantly more likely to have lower incidence of COVID-19 (β coefficient - 225.6, 95% C.I. - 415.8,- 35.4, p = 0.021). However, countries being classified as having "full democracy" using Democracy Index had higher incidence of COVID-19 (reference: authoritarian regime; β coefficient 425.0, 95% C.I. 98.0, 752.0, p = 0.011). This implies that previous exposure to global epidemics and Democracy Index for a country are associated its performance in response to COVID-19. We recommend future studies should evaluate the impact of various pandemic control strategies at individual, community, and policy levels on mitigation of the disease.

Coronavirus disease 2019 (COVID-19) is affecting millions of patients worldwide. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family Coronaviridae, with 80% genomic similarities to SARS-CoV. Lymphopenia was commonly seen in infected patients and has a correlation to disease severity. Thrombocytopenia, coagulation abnormalities, and disseminated intravascular coagulation were observed in COVID-19 patients, especially those with critical illness and non-survivors. This pandemic has caused disruption in communities and hospital services, as well as straining blood product supply, affecting chemotherapy treatment and haematopoietic stem cell transplantation schedule. In this article, we review the haematological manifestations of the disease and its implication on the management of patients with haematological disorders.

Background Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. Results Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. Conclusion Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria.

Purpose: Chromosomal instability (CIN) is a common phenomenon in colorectal cancer, but its role and underlying cause remain unknown. We have identified that mitotic regulator microtubule-associated protein 9 (MAP9) is a critical regulator of CIN in colorectal cancer. We thus studied the effect of MAP9 loss on colorectal cancer in Map9-knockout mice and in cell lines. Experimental Design: We generated colon epithelial–specific Map9-knockout mice and evaluated colorectal cancer development. Effect of Map9 knockout on colorectal cancer progression was determined in chemical or ApcMin/+-induced colorectal cancer. Molecular mechanism of MAP9 was determined using spectral karyotyping, microtubule assays, and whole-genome sequencing (WGS). Clinical significance of MAP9 was examined in 141 patients with CRC. Results: Spontaneous colonic tumors (9.1%) were developed in colon epithelium–specific Map9-knockout mice at 17 months, but none was observed in wild-type littermates. Map9 deletion accelerated colorectal cancer formation both in ApcMin/+ mice and azoxymethane-treated mice, and reduced survival in ApcMin/+ mice. Mechanistically, MAP9 stabilized microtubules and mediated mitotic spindle assembly. MAP9 also maintained the spindle pole integrity and protected K-fiber from depolymerization at spindle poles. MAP9 loss induced severe mitosis failure, chromosome segregation errors, and aneuploidy, leading to transformation of normal colon epithelial cells. WGS confirmed enhanced CIN in intestinal tumors from Map9 knockout ApcMin/+ mice. In patients with colorectal cancer, MAP9 was frequently silenced and its downregulation was associated with poor survival. Conclusions: MAP9 is a microtubule stabilizer that contributes to spindle stability and inhibits colorectal tumorigenesis, supporting the role of MAP9 as a tumor suppressor for preventing CIN in colorectal cancer.

Previous decades have witnessed a change in the epidemiology of Clostridium difficile infections. This study aimed to determine temporal trends in the incidence of C difficile infection across geographic regions.An initial search of the relevant literature was conducted from date inception to October 2018 without language restriction. We estimated the pooled incidences using logit transformation, weighted by inverse variance. The Joinpoint Regression Analysis Program was used to explore its temporal trend.Globally, the estimated incidence of C difficile infection increased from 6.60 per 10,000 patient-days in 1997 to 13.8 per 10,000 patient-days in 2004. Thereafter, a significant downward trend was observed, at -8.75% annually until 2015. From 2005 to 2015, the incidences in most European countries decreased at a rate between 1.97% and 4.11% per annum, except in France, where an increasing incidence was observed (β = 0.16; P.001). The incidences have stabilized in North America over the same period; however, in Asia, the incidence increased significantly from 2006 to 2014 (annualized percentage change = 14.4%; P.001). The increase was greatest in Western Asian countries, including Turkey and Israel (β0.10; P.004).This study revealed rapid changes in the incidence of C difficile infection. This meta-analysis should inform the allocation of resources for controlling C difficile infection and future surveillance efforts in countries where epidemiologic information on C difficile infection remains sparse.

Background: Viral infections of the respiratory tract represent a major global health concern. Co-infection with bacteria may contribute to severe disease and increased mortality in patients. Nevertheless, viral-bacterial co-infection patterns and their clinical outcomes have not been well characterized to date. This study aimed to evaluate the clinical features and outcomes of patients with viral-bacterial respiratory tract co-infections.Methods: We included 19,361 patients with respiratory infection due to respiratory viruses [influenza A and B, respiratory syncytial virus (RSV), parainfluenza] and/or bacteria in four tertiary hospitals in Hong Kong from 2013 to 2017 using a large territory-wide healthcare database. All microbiological tests were conducted within 48 h of hospital admission. Four etiological groups were included: (1) viral infection alone; (2) bacterial infection alone; (3) laboratory-confirmed viral-bacterial co-infection and (4) clinically suspected viral-bacterial co-infection who were tested positive for respiratory virus and negative for bacteria but had received at least four days of antibiotics. Clinical features and outcomes were recorded for laboratory-confirmed viral-bacterial co-infection patients compared to other three groups as control. The primary outcome was 30-day mortality. Secondary outcomes were intensive care unit (ICU) admission and length of hospital stay. Propensity score matching estimated by binary logistic regression was used to adjust for the potential bias that may affect the association between outcomes and covariates.Findings: Among 15,906 patients with respiratory viral infection, there were 8451 (53.1%) clinically suspected and 1,087 (6.8%) laboratory-confirmed viral-bacterial co-infection. Among all the bacterial species, Haemophilus influenzae (226/1,087, 20.8%), Pseudomonas aeruginosa (180/1087, 16.6%) and Streptococcus pneumoniae (123/1087, 11.3%) were the three most common bacterial pathogens in the laboratory-confirmed co-infection group. Respiratory viruses co-infected with non-pneumococcal streptococci or methicillin-resistant Staphylococcus aureus was associated with the highest death rate [9/30 (30%) and 13/48 (27.1%), respectively] in this cohort. Compared with other infection groups, patients with laboratory-confirmed co-infection had higher ICU admission rate (p < 0.001) and mortality rate at 30 days (p = 0.028), and these results persisted after adjustment for potential confounders using propensity score matching. Furthermore, patients with laboratory-confirmed co-infection had significantly higher mortality compared to patients with bacterial infection alone.Interpretation: In our cohort, bacterial co-infection is common in hospitalized patients with viral respiratory tract infection and is associated with higher ICU admission rate and mortality. Therefore, active surveillance for bacterial co-infection and early antibiotic treatment may be required to improve outcomes in patients with respiratory viral infection.

Colorectal cancer (CRC) is a common cancer globally. It is a complex disease influenced by genetic and environmental factors. Early studies on familial cases have identified major genes involved in CRC, such as proto-oncogenes KRAS, PIK3CA and BRAF, and tumour-suppressor genes APC and TP53. These genes have provided valuable insight into the molecular pathogenesis of CRC, and some have made ways to clinical utility to help diagnose cancer syndromes, prognosticate oncological outcomes and predict treatment responses. While these genetic factors are important, recent studies have suggested contribution of microorganisms to colorectal carcinogenesis. Observational studies, animal experiments and translational works have identified several microorganisms as potential carcinogenic bacteria, such as Fusobacterium nucleatum and Peptostreptococcus anaerobius. With the advent of sequencing technology and bioinformatics, more genomic and metagenomic factors are being uncovered as important players in CRC carcinogenesis. This article aims to review recent genomic and metagenomic discoveries relating to CRC.

Impaired autophagic degradation of intracellular lipids is causally linked to the development of non‐alcoholic steatohepatitis (NASH). Pharmacological agents that can restore hepatic autophagic flux could therefore have therapeutic potentials for this increasingly prevalent disease. Herein, we investigated the effects of polydatin, a natural precursor of resveratrol, in a murine nutritional model of NASH and a cell line model of steatosis. Results showed that oral administration of polydatin protected against hepatic lipid accumulation and alleviated inflammation and hepatocyte damage in db/db mice fed methionine‐choline deficient diet. Polydatin also alleviated palmitic acid‐induced lipid accumulation in cultured hepatocytes. In both models, polydatin restored lysosomal function and autophagic flux that were impaired by NASH or steatosis. Mechanistically, polydatin inhibited mTOR signalling and up‐regulated the expression and activity of TFEB, a known master regulator of lysosomal function. In conclusion, polydatin ameliorated NASH through restoring autophagic flux. The polydatin‐regulated autophagy was associated with inhibition of mTOR pathway and restoration of lysosomal function by TFEB. Our study provided affirmative preclinical evidence to inform future clinical trials for examining the potential anti‐NASH effect of polydatin in humans.

Gap junctions are hexagonal arrays of protein molecules in the plasma membrane and were first described in Mauthner cell synapses of goldfish. They form pathways for coupling between cells, allowing passive, electrotonic spread of ions and also passage of larger molecules such as amino acids and nucleotides. They are expressed in both excitable and non-excitable tissues. Each gap junction is made of two connexons, which are hexameric proteins of the connexin subunit. In this review, the roles that connexins play in gastrointestinal motility, the mechanisms of altered connexin expression leading to inflammatory bowel disease, gastrointestinal infections, and gastrointestinal symptoms in autistic spectrum disorder are discussed in detail.

BACKGROUND Faecal microbiota transplantation (FMT) is effective for Clostridium difficile infections (CDI) refractory to standard treatment and is being studied in other diseases. AIM To evaluate donor characteristics, procedures and clinical outcomes of FMT. METHODS We systematically reviewed FMT studies published up to 29 August 2018 using MEDLINE (R) and EMBASE and identified clinical studies with FMT donor information. We reported data on donor characteristics, screening criteria, administration, clinical outcomes and adverse events. RESULTS Among 5267 reports, 239 full-text articles were screened and 168 articles were included. FMT was performed commonly for CDI (n = 108) and inflammatory bowel disease (IBD) (n = 31). We reported characteristics of 1513 donors [58% male; mean age, 34.3 years; mean body mass index, 21.6]. Donors in Asia were younger than the West (mean age 30.7 vs 32.9, P = 0.00075). Less than 50% of studies screened donors for transmittable pathogens. Final cure rate for CDI was 95.6% (95% confidence interval [CI], 93.9%-97.1%) and final remission rates for ulcerative colitis (UC) and Crohn's disease (CD) were 39.6% (95% CI, 25.4%-54.6%) and 47.5% (95% CI, 29.4%-65.8%), respectively. Cure rates in CDI and final remission rates for CD and UC were comparable across all routes of FMT administration. Overall adverse event incidence was

Fecal microbiome transplant (FMT) has gained popularity over the past few years, given its success in treating several gastrointestinal diseases. At the same time, microbial populations in the gut have been shown to have more physiological effects than we expected as “habitants” of the gut. The imbalance in the gut microbiome or dysbiosis, particularly when there are excessive harmful pathogens, can trigger not just infections but can also result in the development of common diseases, such as cancer and cardiometabolic diseases. By using FMT technology, the dysbiosis of the gut microbiome in patients can be resolved by administering fecal materials from a healthy donor. The current review summarizes the history and current uses of FMT before suggesting potential ideas for its high-quality application in clinical settings.

Tumor suppressor genes (TSGs) exhibit distinct evolutionary features. We speculated that TSG promoters could have evolved specific features that facilitate their tumor-suppressing functions. We found that the promoter CpG dinucleotide frequencies of TSGs are significantly higher than that of non-cancer genes across vertebrate genomes, and positively correlated with gene expression across tissue types. The promoter CpG dinucleotide frequencies of all genes gradually increase with gene age, for which young TSGs have been subject to a stronger evolutionary pressure. Transcription-related features, namely chromatin accessibility, methylation and ZNF263-, SP1-, E2F4- and SP2-binding elements, are associated with gene expression. Moreover, higher promoter CpG dinucleotide frequencies and chromatin accessibility are positively associated with the ability of TSGs to resist downregulation during tumorigenesis. These results were successfully validated with independent datasets. In conclusion, TSGs evolved specific promoter features that optimized cancer resistance through achieving high expression in normal tissues and resistance to downregulation during tumorigenesis.

Objectives Guillain‐Barré syndrome (GBS) results from autoimmune attack on the peripheral nerves, causing sensory, motor and autonomic abnormalities. Emerging evidence suggests that there might be an association between COVID‐19 and GBS. Nevertheless, the underlying pathophysiological mechanism remains unclear. Materials and Methods We performed bioinformatic analyses to delineate the potential genetic crosstalk between COVID‐19 and GBS. Results COVID‐19 and GBS were associated with a similar subset of immune/inflammation regulatory genes, including TNF, CSF2, IL2RA, IL1B, IL4, IL6 and IL10. Protein‐protein interaction network analysis revealed that the combined gene set showed an increased connectivity as compared to COVID‐19 or GBS alone, particularly the potentiated interactions with CD86, IL23A, IL27, ISG20, PTGS2, HLA‐DRB1, HLA‐DQB1 and ITGAM, and these genes are related to Th17 cell differentiation. Transcriptome analysis of peripheral blood mononuclear cells from patients with COVID‐19 and GBS further demonstrated the activation of interleukin‐17 signalling in both conditions. Conclusions Augmented Th17 cell differentiation and cytokine response was identified in both COVID‐19 and GBS. PBMC transcriptome analysis also suggested the pivotal involvement of Th17 signalling pathway. In conclusion, our data suggested aberrant Th17 cell differentiation as a possible mechanism by which COVID‐19 can increase the risk of GBS., Functional protein‐protein association networks of (A) COVID‐19– and (B) GBS‐related genes were analyzed by STRING. Genes associated with the two disease entities (COVID‐19, disease id: C000657245, version 4, N.PMIDs ≥ 4; GBS, disease id: C0018378, Gene‐Disease Association Score ≥ 0.02) were retrieved from DisGeNET, a knowledge platform for disease genomics. Only highly confident interactions derived from ‘Experiments’, ‘Databases’, ‘Co‐expression’ and ‘Co‐occurrence’ with the minimum required interaction score of 0.900 were shown. The Markov cluster (MLC) algorithm with an inflation parameter of 3 was used for network clustering.

Background and aim: Gastrointestinal manifestations of the coronavirus disease 2019 (COVID-19) pandemic may mimic irritable bowel syndrome (IBS), and social distancing measures may affect IBS patients negatively. We aimed to study the impact of COVID-19 on respondents with self-reported IBS. Methods: We conducted an anonymized survey from May to June 2020 in 33 countries. Knowledge, attitudes, and practices on personal hygiene and social distancing as well as psychological impact of COVID-19 were assessed. Statistical analysis was performed to determine differences in well-being and compliance to social distancing measures between respondents with and without self-reported IBS. Factors associated with improvement or worsening of IBS symptoms were evaluated. Results: Out of 2704 respondents, 2024 (74.9%) did not have IBS, 305 (11.3%) had self-reported IBS, and 374 (13.8%) did not know what IBS was. Self-reported IBS respondents reported significantly worse emotional, social, and psychological well-being compared with non-IBS respondents and were less compliant to social distancing measures (28.2% vs 35.3%, P = 0.029); 61.6% reported no change, 26.6% reported improvement, and 11.8% reported worsening IBS symptoms. Higher proportion of respondents with no change in IBS symptoms were willing to practice social distancing indefinitely versus those who deteriorated (74.9% vs 51.4%, P = 0.016). In multivariate analysis, willingness to continue social distancing for another 2-3 weeks (vs longer period) was significantly associated with higher odds of worsening IBS. Conclusion: Our study showed that self-reported IBS respondents had worse well-being and compliance to social distancing measures than non-IBS respondents. Future research will focus on occupational stress and dietary changes during COVID-19 that may influence IBS.

OBJECTIVES: To assess the risk of coronavirus transmission to healthcare workers performing aerosol-generating procedures and the potential benefits of personal protective equipment during these procedures. DATA SOURCES: MEDLINE, EMBASE, and Cochrane CENTRAL were searched using a combination of related MeSH terms and keywords. STUDY SELECTION: Cohort studies and case controls investigating common anesthetic and critical care aerosol-generating procedures and transmission of severe acute respiratory syndrome coronavirus 1, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus 2 to healthcare workers were included for quantitative analysis. DATA EXTRACTION: Qualitative and quantitative data on the transmission of severe acute respiratory syndrome coronavirus 1, severe acute respiratory syndrome coronavirus 2, and Middle East respiratory syndrome coronavirus to healthcare workers via aerosol-generating procedures in anesthesia and critical care were collected independently. The Risk Of Bias In Non-randomized Studies - of Interventions tool was used to assess the risk of bias of included studies. DATA SYNTHESIS: Seventeen studies out of 2,676 yielded records were included for meta-analyses. Endotracheal intubation (odds ratio, 6.69, 95% CI, 3.81-11.72; p < 0.001), noninvasive ventilation (odds ratio, 3.65; 95% CI, 1.86-7.19; p < 0.001), and administration of nebulized medications (odds ratio, 10.03; 95% CI, 1.98-50.69; p = 0.005) were found to increase the odds of healthcare workers contracting severe acute respiratory syndrome coronavirus 1 or severe acute respiratory syndrome coronavirus 2. The use of N95 masks (odds ratio, 0.11; 95% CI, 0.03-0.39; p < 0.001), gowns (odds ratio, 0.59; 95% CI, 0.48-0.73; p < 0.001), and gloves (odds ratio, 0.39; 95% CI, 0.29-0.53; p < 0.001) were found to be significantly protective of healthcare workers from contracting severe acute respiratory syndrome coronavirus 1 or severe acute respiratory syndrome coronavirus 2. CONCLUSIONS: Specific aerosol-generating procedures are high risk for the transmission of severe acute respiratory syndrome coronavirus 1 and severe acute respiratory syndrome coronavirus 2 from patients to healthcare workers. Personal protective equipment reduce the odds of contracting severe acute respiratory syndrome coronavirus 1 and severe acute respiratory syndrome coronavirus 2.

Objectives We examined if the WHO International Health Regulations (IHR) capacities were associated with better COVID-19 pandemic control. Design Observational study. Setting Population-based study of 114 countries. Participants General population. Main outcome measures For each country, we extracted: (1) the maximum rate of COVID-19 incidence increase per 100,000 population over any 5-day moving average period since the first 100 confirmed cases; (2) the maximum 14-day cumulative incidence rate since the first case; (3) the incidence and mortality within 30 days since the first case and first COVID-19-related death, respectively. We retrieved the 13 country-specific International Health Regulations capacities and constructed linear regression models to examine whether these capacities were associated with COVID-19 incidence and mortality, controlling for the Human Development Index, Gross Domestic Product, the population density, the Global Health Security index, prior exposure to SARS/MERS and Stringency Index. Results Countries with higher International Health Regulations score were significantly more likely to have lower incidence (β coefficient −24, 95% CI −35 to −13) and mortality (β coefficient −1.7, 95% CI −2.5 to −1.0) per 100,000 population within 30 days since the first COVID-19 diagnosis. A similar association was found for the other incidence outcomes. Analysis using different regression models controlling for various confounders showed a similarly significant association. Conclusions The International Health Regulations score was significantly associated with reduction in rate of incidence and mortality of COVID-19. These findings inform design of pandemic control strategies, and validated the International Health Regulations capacities as important metrics for countries that warrant evaluation and improvement of their health security capabilities.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome–lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration

Colorectal cancer (CRC), prostate cancer (PC) and breast cancer (BC) are among the most common cancers worldwide with well-established screening strategies. We aim to investigate the effectiveness and compliance of a one-stop screening service for CRC, PC and BC. Asymptomatic subjects aged 50–75 years were invited. Eligible subjects were offered fecal immunochemical test (FIT) for CRC screening. Serum prostate specific antigen (PSA) and Prostate Health Index (PHI) were offered for male PC screening and mammogram (MMG) for female BC screening as a one-stop service. Colonoscopy was offered to FIT+ subjects, prostate biopsy to PSA/PHI+ (PSA>10/PHI≥35) males and breast biopsy to MMG+ (Breast Imaging-Reporting and Data System, BI-RADS≥4) females. From August 2018 to April 2020, 3165 subjects were recruited. All participants (1372 men and 1793 women) were willing to accept FIT for CRC screening, and PSA/PHI test or MMG as second cancer screening. 102 subjects diagnosed advanced neoplasms after colonoscopy. Thirty-three males diagnosed PC after prostate biopsy and 15 females diagnosed BC after breast biopsy. No major complication reported in first tier screening tests. Subjects who were willing to undergo CRC screening were highly likely to accept other cancer screening when offered in a one-stop program. In conclusion, the effectiveness and compliance of a one-stop service for CRC, PC, and BC screening among asymptomatic subjects were high. Future studies should be conducted to test various ways of integrating cancer screening programs.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04034953.

Colorectal cancer (CRC) is a heterogeneous disease with different gene expression patterns. There are two major colorectal carcinogenesis pathways: conventional adenoma-carcinoma pathway and alternative serrated neoplasia pathway. Apart from the conventional pathway that is typically initiated by characteristic APC mutation and chromosomal instability, the serrated neoplasia pathway is mainly characterized by mutations of BRAF or KRAS, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Despite the malignant potential of serrated lesions, they can be easily overlooked during endoscopy screening and even in pathological assessment due to its anatomical location, morphology, and histological features. It has been shown that environmental factors especially the gut microbial composition play a key role in CRC pathogenesis. Thus, the preferential localization of serrated lesions in specific intestine areas suggest that niche-specific microbiota composition might intertwined with host genetic perturbations during the development of serrated lesions. Although serrated lesions and conventional adenomas are biologically different, most studies have focused on conventional adenomas, while the pathophysiology and role of microorganisms in the development of serrated lesions remain elusive. In this review, we discuss on the role of gut microbiota in the serrated neoplasia pathway of colorectal carcinogenesis and its specific clinical and molecular features, and summarize the potential mechanisms involved.

ObjectiveThe impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM).DesignIn this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24.ResultsProportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (pBifidobacterium and Lactobacillus compared with FMT alone (pConclusionRepeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients’ microbiota and improvement in lipid profile and liver stiffness.Trial registration numberNCT03127696.

Background Earlier studies suggest that probiotics have protective effects in the prevention of respiratory tract infections (RTIs). Whether such benefits apply to RTIs of viral origin and mechanisms supporting the effect remain unclear. Aim To determine the role of gut microbiota modulation on clinical and laboratory outcomes of viral RTIs. Methods We conducted a systematic review of articles published in Embase and MEDLINE through 20 April 2020 to identify studies reporting the effect of gut microbiota modulation on viral RTIs in clinical studies and animal models. The incidence of viral RTIs, clinical manifestations, viral load and immunological outcomes was evaluated. Results We included 58 studies (9 randomized controlled trials; 49 animal studies). Six of eight clinical trials consisting of 726 patients showed that probiotics administration was associated with a reduced risk of viral RTIs. Most commonly used probiotics were Lactobacillus followed by Bifidobacterium and Lactococcus. In animal models, treatment with probiotics before viral challenge had beneficial effects against influenza virus infection by improving infection-induced survival (20/22 studies), mitigating symptoms (21/21 studies) and decreasing viral load (23/25 studies). Probiotics and commensal gut microbiota exerted their beneficial effects through strengthening host immunity. Conclusion Modulation of gut microbiota represents a promising approach against viral RTIs via host innate and adaptive immunity regulation. Further research should focus on next generation probiotics specific to viral types in prevention and treatment of emerging viral RTIs. Supplementary Information The online version contains supplementary material available at 10.1007/s00394-021-02519-x.

Background GABA-deficit characterizes depression (MDD), which is highly comorbid with Functional Dyspepsia (FD). We examined brain GABA concentrations and resting activities in post-prandial distress subtype FD (FD-PDS) patients with and without MDD. Methods 24 female age/education-matched FD-PDS with comorbid MDD (FD-PDS-MDD), non-depressed FD-PDS, and healthy controls each were compared on GABA concentrations, resting fMRI (fALFF) in bilateral pregenual anterior cingulate (pgACC), left dorsolateral prefrontal cortex (DLPFC), insula, and somatosensory cortex (SSC). Results FD-PDS-MDD patients had mild though elevated depressive symptoms. FD-PDS patients had generally mild dyspeptic symptoms. No significant between-group differences in GABA or fALFF were found. No significant correlations were found between GABA and depressive/dyspeptic symptoms after Bonferroni correction. In patients, GABA correlated positively with left insula fALFF (r = 0.38, Bonferroni-corrected p = .03). Conclusion We did not find altered GABA concentrations or brain resting activity in FD-PDS or its MDD comorbidity. The neurochemical link between MDD and FD remains elusive.

Background & Aims Proteus spp, Gram-negative facultative anaerobic bacilli, have recently been associated with Crohn's disease (CD) recurrence after intestinal resection. We investigated the genomic and functional role of Proteus as a gut pathogen in CD. Methods Proteus spp abundance was assessed by ure gene–specific polymerase chain in 54 pairs of fecal samples and 101 intestinal biopsies from patients with CD and healthy controls. The adherence, invasion, and intracellular presence of 2 distinct isolates of Proteus mirabilis in epithelial cells were evaluated using immunofluorescence and electron microscopy. Intracellular gene expression profiles and regulated pathways were analyzed by RNA sequencing and KEGG pathway analysis. Biologic functions of 2 isolates of P mirabilis were determined by in vitro cell culture, and in vivo using conventional mice and germ-free mice. Results Proteus spp were significantly more prevalent and abundant in fecal samples and colonic tissue of patients with CD than controls. A greater abundance of the genus Fusobacterium and a lesser abundance of the genus Faecalibacterium were seen in patients with CD with a high Proteus spp abundance. All 24 Proteus monoclones isolated from patients with CD belonged to members of P mirabilis lineages and 2 isolates, recovered from stool or mucosa, were used in further studies. Mice gavaged with either P mirabilis strain had more severe colonic inflammation. Co-culture of the isolates with epithelial cell lines showed bacterial adherence, invasion, increased production of pro-inflammatory cytokines IL-18 and IL-1α, and cell necrosis. Both isolates induced key pro-inflammatory pathways, including NOD-like receptor signaling, Jak-STAT signaling, and MAPK signaling, and induced pro-inflammatory genes and activated inflammation-related pathways in gnotobiotic mice. Conclusions P mirabilis in the gut is associated with CD and can induce inflammation in cells and animal models of colitis. P mirabilis can act as a pathobiont and play a crucial role in the pathogenesis of CD.

From its beginning in December 2019, the coronavirus disease 2019 outbreak has spread globally from Wuhan and is now declared a pandemic by the World Health Organization. The sheer scale and severity of this pandemic is unprecedented in the modern era. Although primarily a respiratory tract infection transmitted by direct contact and droplets, during aerosol-generating procedures, there is a possibility of airborne transmission. In addition, emerging evidence suggests possible fecal-oral spread of the virus. Clinical departments that perform endoscopy are faced with daunting challenges during this pandemic. To date, multiple position statements and guidelines have been issued by various professional organizations to recommend practices in endoscopic procedures. This article aims to summarize and discuss available evidence for these practices, to provide guidance for endoscopy to enhance patient safety, avoid nosocomial outbreaks, protect healthcare personnel, and ensure rational use of personal protective equipment. Responses adapted to national recommendations and local infection control guidelines and tailored to the availability of medical resources are imminently needed to fight the coronavirus disease 2019 pandemic.

The novel coronavirus disease is currently causing a major pandemic. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the Betacoronavirus genus that also includes the SARS-CoV and Middle East respiratory syndrome coronavirus. While patients typically present with fever and a respiratory illness, some patients also report gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain. Studies have identified the SARS-CoV-2 RNA in stool specimens of infected patients, and its viral receptor angiotensin converting enzyme 2 was found to be highly expressed in gastrointestinal epithelial cells. These suggest that SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract. This has important implications to the disease management, transmission, and infection control. In this article, we review the important gastrointestinal aspects of the disease.

It is recommended that patients with acute upper gastrointestinal bleeding undergo endoscopy within 24 hours after gastroenterologic consultation. The role of endoscopy performed within time frames shorter than 24 hours has not been adequately defined.To evaluate whether urgent endoscopy improves outcomes in patients predicted to be at high risk for further bleeding or death, we randomly assigned patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score of 12 or higher (scores range from 0 to 23, with higher scores indicating a higher risk of further bleeding or death) to undergo endoscopy within 6 hours (urgent-endoscopy group) or between 6 and 24 hours (early-endoscopy group) after gastroenterologic consultation. The primary end point was death from any cause within 30 days after randomization.A total of 516 patients were enrolled. The 30-day mortality was 8.9% (23 of 258 patients) in the urgent-endoscopy group and 6.6% (17 of 258) in the early-endoscopy group (difference, 2.3 percentage points; 95% confidence interval [CI], -2.3 to 6.9). Further bleeding within 30 days occurred in 28 patients (10.9%) in the urgent-endoscopy group and in 20 (7.8%) in the early-endoscopy group (difference, 3.1 percentage points; 95% CI, -1.9 to 8.1). Ulcers with active bleeding or visible vessels were found on initial endoscopy in 105 of the 158 patients (66.4%) with peptic ulcers in the urgent-endoscopy group and in 76 of 159 (47.8%) in the early-endoscopy group. Endoscopic hemostatic treatment was administered at initial endoscopy for 155 patients (60.1%) in the urgent-endoscopy group and for 125 (48.4%) in the early-endoscopy group.In patients with acute upper gastrointestinal bleeding who were at high risk for further bleeding or death, endoscopy performed within 6 hours after gastroenterologic consultation was not associated with lower 30-day mortality than endoscopy performed between 6 and 24 hours after consultation. (Funded by the Health and Medical Fund of the Food and Health Bureau, Government of Hong Kong Special Administrative Region; ClinicalTrials.gov number, NCT01675856.).

Changes in the intestinal microbiota have been associated with development and progression of colorectal cancer (CRC). Archaea are stable components of the microbiota, but little is known about their composition or contribution to colorectal carcinogenesis. We analyzed archaea in fecal microbiomes of 2 large cohorts of patients with CRC.We performed shotgun metagenomic analyses of fecal samples from 585 participants (184 patients with CRC, 197 patients with adenomas, and 204 healthy individuals) from discovery (165 individuals) and validation (420 individuals) cohorts. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database.Principal component analysis of archaeomes showed distinct clusters in fecal samples from patients with CRC, patients with adenomas, and control individuals (P.001), indicating an alteration in the composition of enteric archaea during tumorigenesis. Fecal samples from patients with CRC had significant enrichment of halophilic and depletion of methanogenic archaea. The halophilic Natrinema sp. J7-2 increased progressively in samples from control individuals, to patients with adenomas, to patients with CRC. Abundances of 9 archaea species that were enriched in fecal samples from patients with CRC distinguished them from control individuals with areas under the receiver operating characteristic curve of 0.82 in the discovery cohort and 0.83 in the validation cohort. An association between archaea and bacteria diversities was observed in fecal samples from control individuals but not from patients with CRC. Archaea that were enriched in fecal samples from patients with CRC had an extensive mutual association with bacteria that were enriched in the same samples and exclusivity with bacteria that were lost from these samples.Archaeomes of fecal samples from patients with CRC are characterized by enrichment of halophiles and depletion of methanogens. Studies are needed to determine whether associations between specific archaea and bacteria species in samples from patients with CRC contribute to or are a response to colorectal tumorigenesis.

Objectives The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated. Design To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp+/+) and knockout (Cnlp−/−) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. Results The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms. Conclusions Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

Esophageal squamous cell carcinoma (ESCC) is a deadly disease, partly because it is often diagnosed late in disease stage. An accurate early diagnosis by endoscopy could detect advanced carcinoma as well as curable dysplasia and early ESCC. This could save patients from incurable advanced malignancy. Important progress has been made in high-quality endoscopic diagnosis, including magnifying endoscopy, narrowband imaging, and other image enhancement, as well as in techniques in endoscopic resection. These emerging techniques will aid the early diagnosis of ESCC that lead to higher chance of curing the cancer.

Objective Real-world epidemiological data on the risk of tuberculosis (TB) in patients with immune-mediated diseases treated with biologics are scarce in TB endemic areas. We investigated the incidence of TB in a population-based setting and stratified the risk of TB among different biological therapies. Methods We collected medical data from a territory-wide computerized database in Hong Kong. We reported the incidence of TB in patients treated with various classes of biologics, and calculated standardized incidence ratio by comparing with the general population. Subgroup analyses were performed based on disease subtypes and biological drugs. Results Among 2485 subjects with immune-mediated diseases (82.5% rheumatology diseases; 10.6% IBD; 6.9% dermatology diseases), 54 subjects developed active TB during 6921 person-years of follow-up. The mean age (±s.d.) was 43 (14) years, and the median follow-up duration was 24.9 months (interquartile range 4.9–45.0). The overall standardized incidence ratio of TB was 10.91 (95% CI 8.00–13.82), and patients treated with infliximab had a nearly 26 times increased risk of TB compared with the general population (standardized incidence ratio 25.95; 95% CI 17.23–34.67). The risk of TB with TNF inhibitor was higher than with a non-TNF biologic (hazard ratio 4.34; 95% CI 1.31–14.39), while the risk of infliximab was higher than etanercept and adalimumab (hazard ratio: 4.10 and 2.08, respectively). Conclusion The risk of TB is much higher in patients with immune-mediated diseases on biological therapy compared with the general population, and infliximab is associated with the highest risk of TB among the biologics analysed.

ObjectivesBacteriome and virome alterations are associated with colorectal cancer (CRC). Nevertheless, the gut fungal microbiota in CRC remains largely unexplored. We aimed to characterise enteric mycobiome in CRC.DesignFaecal shotgun metagenomic sequences of 184 patients with CRC, 197 patients with adenoma and 204 control subjects from Hong Kong were analysed (discovery cohort: 73 patients with CRC and 92 control subjects; validation cohort: 111 patients with CRC, 197 patients with adenoma and 112 controls from Hong Kong). CRC-associated fungal markers and ecological changes were also validated in additional independent cohorts of 90 patients with CRC, 42 patients with adenoma and 66 control subjects of published repository sequences from Germany and France. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database.ResultsPrincipal component analysis revealed separate clusters for CRC and control (pConclusionsThis study revealed CRC-associated mycobiome dysbiosis characterised by altered fungal composition and ecology, signifying that the gut mycobiome might play a role in CRC.

AIMS Previous trials on the effectiveness of genotype-guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta-analysis of randomized trials comparing genotype-guided to conventional dosing strategies. METHODS PubMed and the Cochrane Library were searched up to 23 October 2017. RESULTS A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype-guided dosing (mean age 63.3 ± 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1 years; 46% male) groups (mean follow-up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype-guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype-guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2 : 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. CONCLUSIONS Genotype-guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident.

Background Fibroblast growth factor 21 is a signalling protein involved in cell differentiation, morphogenesis, proliferation and metabolism. Recent studies have associated increased levels of FGF21 in the development of cardiovascular diseases, whereas others have reported no significant associations. Therefore, this systematic review and meta-analysis evaluated the value in predicting the risk of cardio-metabolic disorders and mortality. Methods PubMed and EMBASE were searched until 5th September 2017 for studies that evaluated the roles of FGF21 levels in cardio-metabolic disorders. Results A total of 183 and 301 entries were retrieved; 24 studies met the inclusion criteria. Four studies were identified by an additional search. Therefore, 28 studies were included in the final meta-analysis. High FGF21 levels significantly predicted the incidence of coronary artery disease (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.06–1.55; P Conclusion FGF21 significantly predicts the incidence of coronary artery disease, the risks of metabolic syndrome, diabetes mellitus and renal progression in diabetes. It also predicted all-cause and cardiovascular mortality.

Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori-infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacological ablation of autophagy in mouse and cell line models of H. pylori infection. Here, we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidification and the retrograde trafficking of mannose-6-phosphate receptors, both of which are known to positively regulate lysosomal function. We conclude that H. pylori subverts autophagy into a pro-survival mechanism through inhibition of lysosomal clearance of autophagosomes. Disruption of autophagosome formation offers a novel strategy to reduce H. pylori colonization in human stomachs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Toxin B (TcdB) is a major pathogenic factor of Clostridum difficile. However, the mechanism by which TcdB exerts its cytotoxic action in host cells is still not completely known. Herein, we report for the first time that TcdB induced autophagic cell death in cultured human colonocytes. The induction of autophagy was demonstrated by the increased levels of LC3‐II, formation of LC3+ autophagosomes, accumulation of acidic vesicular organelles and reduced levels of the autophagic substrate p62/SQSTM1. TcdB‐induced autophagy was also accompanied by the repression of phosphoinositide 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) complex 1 activity. Functionally, pharmacological inhibition of autophagy by wortmannin or chloroquine or knockdown of autophagy‐related genes Beclin 1, Atg5 and Atg7 attenuated TcdB‐induced cell death in colonocytes. Genetic ablation of Atg5, a gene required for autophagosome formation, also mitigated the cytotoxic effect of TcdB. In conclusion, our study demonstrated that autophagy serves as a pro‐death mechanism mediating the cytotoxic action of TcdB in colonocytes. This discovery suggested that blockade of autophagy might be a novel therapeutic strategy for C. difficile infection.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited myocardial disease characterized by fibro‐fatty replacement of the right ventricular myocardium, and associated with paroxysmal ventricular arrhythmias and sudden cardiac death (SCD). It is currently the second most common cause of SCD after hypertrophic cardiomyopathy in young people

Cross-sectional studies suggest an increasing trend in incidence and relatively low recurrence rates of Clostridium difficile infections in Asia than in Europe and North America. The temporal trend of C. difficile infection in Asia is not completely understood. We conducted a territory-wide population-based observational study to investigate the burden and clinical outcomes in Hong Kong, China, over a 9-year period. A total of 15,753 cases were identified, including 14,402 (91.4%) healthcare-associated cases and 817 (5.1%) community-associated cases. After adjustment for diagnostic test, we found that incidence increased from 15.41 cases/100,000 persons in 2006 to 36.31 cases/100,000 persons in 2014, an annual increase of 26%. This increase was associated with elderly patients, for whom incidence increased 3-fold over the period. Recurrence at 60 days increased from 5.7% in 2006 to 9.1% in 2014 (p

Background and Aims Endoscopic and histological healing are associated with improved clinical outcomes in ulcerative colitis [UC]. We aimed to investigate the predictive value of faecal immunochemical test [FIT] for endoscopic and histological healing in UC. Methods We measured quantitative FIT and faecal calprotectin [FC] in 140 consecutive UC patients who underwent colonoscopy. We assessed the diagnostic accuracy of FIT for predicting endoscopic healing using the Mayo endoscopic subscore [MES 0/1] and for histological healing using the Geboes score [< 2.0] and Nancy index [grade ≤ 1]. The predictive abilities of FIT were compared with those of FC. Results FIT had an area under the curve [AUC] of 0.77 (95% confidence interval [CI] 0.67-0.86, p < 0.001) for endoscopic healing, an AUC of 0.77 [95% CI 0.67-0.86, p < 0.001] using the Geboes score, and 0.77 [95% CI 0.66-0.85, p < 0.001] using the Nancy Index for histological healing. The AUC of FIT was comparable to that of FC for endoscopic healing [p = 0.773] and histological healing [p = 0.767-0.960], and was comparable to colonoscopy for histological healing [p = 0.384-0.673]. FIT < 50 ng/ml predicted endoscopic healing with a sensitivity, specificity, and positive predictive value [PPV] of 72%, 68%, and 82%, respectively, and for histological healing with a sensitivity, specificity, and PPV of 73-75%, 67%, and 78-80%, respectively. Combining FIT with FC led to a higher specificity [90%] for histological healing. Over 85% of patients with FIT < 50 ng/ml and FC < 50 μg/g achieved histological healing. Conclusions FIT is highly sensitive and accurate to predict endoscopic and histological healing in UC. It represents a promising non-invasive tool for monitoring mucosal healing in UC.

BACKGROUND Sepsis is a systemic host response to an infection leading to organ failure. This is associated with dynamic expression of endogenous host defense peptides. Dysregulation of these peptides is associated with septic morbidity and mortality. METHODS We performed a systematic search of articles indexed in Pubmed, ISI Web of Knowledge, EmBase and Scopus database from inception to October 2016. Both preclinical and clinical studies investigating the role of host defense peptides in pathogenesis and as biomarkers for sepsis were included. RESULTS Of the available literatures, cathelicidin, defensin and hepcidin are amongst the best-characterized peptides. These regulate immune response, and crosstalk with pyroptosis and coagulation cascades. The applicability of these peptides as septic biomarkers has been investigated in vitro and in vivo studies. However, numerous studies were based on endotoxemia without an infection, jeopardizing interpretation of the outcomes. Cathelicidin and defensin were frequently reported in adult sepsis while hepcidin in neonatal sepsis. The expression level of these peptides is significantly associated with septic condition. Most of the studies employed a cross-sectional design, precluding the establishment of a temporal relationship between candidate peptide biomarkers and sepsis. CONCLUSIONS Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides.

BACKGROUND AND AIM Colorectal cancer (CRC) incidence is rising among

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Although polypectomy at early stage reduces CRC incidence, 90% of the polyps are small and diminutive, where removal of them poses risks to patients that may outweigh the benefits. Correctly detecting and predicting polyp type during colonoscopy allows endoscopists to resect and discard the tissue without submitting it for histology, saving time, and costs. Nevertheless, human visual observation of early stage polyps varies. Therefore, this paper aims at developing a fully automatic algorithm to detect and classify hyperplastic and adenomatous colorectal polyps. Adenomatous polyps should be removed, whereas distal diminutive hyperplastic polyps are considered clinically insignificant and may be left in situ . A novel transfer learning application is proposed utilizing features learned from big nonmedical datasets with 1.4-2.5 million images using deep convolutional neural network. The endoscopic images we collected for experiment were taken under random lighting conditions, zooming and optical magnification, including 1104 endoscopic nonpolyp images taken under both white-light and narrowband imaging (NBI) endoscopy and 826 NBI endoscopic polyp images, of which 263 images were hyperplasia and 563 were adenoma as confirmed by histology. The proposed method identified polyp images from nonpolyp images in the beginning followed by predicting the polyp histology. When compared with visual inspection by endoscopists, the results of this study show that the proposed method has similar precision (87.3% versus 86.4%) but a higher recall rate (87.6% versus 77.0%) and a higher accuracy (85.9% versus 74.3%). In conclusion, automatic algorithms can assist endoscopists in identifying polyps that are adenomatous but have been incorrectly judged as hyperplasia and, therefore, enable timely resection of these polyps at an early stage before they develop into invasive cancer.

Objective Patients with resolved hepatitis B virus (HBV) infection are at risk of HBV reactivation during treatment for hematological malignancies. We conducted a systematic review and meta-analysis of the data on the efficacy of antiviral prophylaxis for the prevention of HBV reactivation in this group of patients. Methods We conducted a systemic literature search of PubMed including MEDLINE and EMBASE databases to 31 January 2019 to identify studies published in English comparing antiviral prophylaxis with no prophylaxis for HBV reactivation in patients treated for hematological malignancies. The search terms used were ("occult hepatitis B" OR "resolved hepatitis B") AND ("reactivation") AND ("haematological malignancy" OR "hematological malignancy" OR "chemotherapy" OR "immunotherapy" OR "chemoimmunotherapy" OR "lymphoma" OR "leukemia" OR "transplant"). The primary outcome was the reactivation of HBV infection. Pooled estimates of relative risk (RR) were calculated. Results We identified 13 relevant studies including two randomized controlled trials (RCT), one post hoc analysis from RCT and 10 cohort studies. There was a trend towards a lower rate of HBV reactivation using antiviral prophylaxis, but the difference was not significant (RR 0.57, 95% confidence interval [CI] 0.23-1.40, P = 0.22). When limiting the analysis to the three prospective studies of patients receiving anti-CD20 monoclonal antibodies, we found antiviral prophylaxis was associated with a significantly lower risk of HBV reactivation (RR 0.17, 95% CI 0.06-0.49, P = 0.001). Conclusion Antiviral prophylaxis reduced the risk of HBV reactivation in patients receiving anti-CD20 monoclonal antibodies for hematological malignancies but not in a broader group of patients receiving anticancer therapy.

We have designed a deep-learning model, an “Artificial Intelligent Endoscopist (a.k.a. AI-doscopist)”, to localise colonic neoplasia during colonoscopy. This study aims to evaluate the agreement between endoscopists and AI-doscopist for colorectal neoplasm localisation. AI-doscopist was pre-trained by 1.2 million non-medical images and fine-tuned by 291,090 colonoscopy and non-medical images. The colonoscopy images were obtained from six databases, where the colonoscopy images were classified into 13 categories and the polyps’ locations were marked image-by-image by the smallest bounding boxes. Seven categories of non-medical images, which were believed to share some common features with colorectal polyps, were downloaded from an online search engine. Written informed consent were obtained from 144 patients who underwent colonoscopy and their full colonoscopy videos were prospectively recorded for evaluation. A total of 128 suspicious lesions were resected or biopsied for histological confirmation. When evaluated image-by-image on the 144 full colonoscopies, the specificity of AI-doscopist was 93.3%. AI-doscopist were able to localise 124 out of 128 polyps (polyp-based sensitivity = 96.9%). Furthermore, after reviewing the suspected regions highlighted by AI-doscopist in a 102-patient cohort, an endoscopist has high confidence in recognizing four missed polyps in three patients who were not diagnosed with any lesion during their original colonoscopies. In summary, AI-doscopist can localise 96.9% of the polyps resected by the endoscopists. If AI-doscopist were to be used in real-time, it can potentially assist endoscopists in detecting one more patient with polyp in every 20–33 colonoscopies.

Colorectal cancer (CRC) accounts for about 10% of all new cancer cases globally. Located at close proximity to the colorectal epithelium, the gut microbiota comprises a large population of microorganisms that interact with host cells to regulate many physiological processes, such as energy harvest, metabolism and immune response. Sequencing studies have revealed microbial compositional and ecological changes in patients with CRC, whereas functional studies in animal models have pinpointed the roles of several bacteria in colorectal carcinogenesis, including Fusobacterium nucleatum and certain strains of Escherichia coli and Bacteroides fragilis. These findings give new opportunities to take advantage of our knowledge on the gut microbiota for clinical applications, such as gut microbiota analysis as screening, prognostic or predictive biomarkers, or modulating microorganisms to prevent cancer, augment therapies and reduce adverse effects of treatment. This Review aims to provide an overview and discussion of the gut microbiota in colorectal neoplasia, including relevant mechanisms in microbiota-related carcinogenesis, the potential of utilizing the microbiota as CRC biomarkers, and the prospect for modulating the microbiota for CRC prevention or treatment. These scientific findings will pave the way to clinically translate the use of gut microbiota for CRC in the near future.

Autophagy is a conserved intracellular degradation process enclosing the bulk of cytosolic components for lysosomal degradation to maintain cellular homeostasis. Accumulating evidences showed that a specialized form of autophagy, known as xenophagy, could serve as an innate immune response to defend against pathogens invading inside the host cells. Correspondingly, infectious pathogens have developed a variety of strategies to disarm xenophagy, leading to a prolonged and persistent intracellular colonization. In this review, we first summarize the current knowledge about the general mechanisms of intracellular bacterial infections and xenophagy. We then focus on the ongoing battle between these two processes.

Background & Aims Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. Methods The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by β-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. Results Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. β-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and β-galactosidase activity assay. β-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional β-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via β-galactosidase. β-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. Conclusion S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of β-galactosidase.

Objective There is a need for an improved biomarker for colorectal cancer (CRC) and advanced adenoma. We evaluated faecal microbial markers for clinical use in detecting CRC and advanced adenoma. Design We measured relative abundance of Fusobacterium nucleatum ( Fn ), Peptostreptococcus anaerobius ( Pa ) and Parvimonas micra ( Pm ) by quantitative PCR in 309 subjects, including 104 patients with CRC, 103 patients with advanced adenoma and 102 controls. We evaluated the diagnostic performance of these biomarkers with respect to faecal immunochemical test (FIT), and validated the results in an independent cohort of 181 subjects. Results The abundance was higher for all three individual markers in patients with CRC than controls (p Fn in patients with advanced adenoma than controls (p=0.022). The marker Fn , when combined with FIT, showed superior sensitivity (92.3% vs 73.1%, p Conclusions This study identified marker Fn as a valuable marker to improve diagnostic performance of FIT, providing a complementary role to detect lesions missed by FIT alone. This simple approach may improve the clinical utility of the current FIT, and takes one step further towards a non-invasive, potentially more accurate and affordable diagnosis of advanced colorectal neoplasia.