Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes.

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

Professionalism-training in undergraduate medical education in a multi-cultural, multi-ethnic setting in the Gulf Region: an exploration of reflective essays.

BACKGROUND: Despite the established need to prioritize professionalism-training in developing future physicians, very few medical programs in the Gulf Region embed in their curricula discrete contextualized courses aimed at developing the corresponding competencies, while fostering self-directed learning. This study aims at exploring the perception of undergraduate medical students in a multi-cultural, multi-ethnic setting regarding their understanding of, and personal experience with professionalism through their engagement with the content of an innovative curriculum-based professionalism course, offered at a Medical School in Dubai, United Arab Emirates. METHODS: The study used a qualitative phenomenological research design. Out of 33 students, 29 students had submitted reflective essays. The content of these essays was inductively analyzed following a six-step framework for conducting thematic analysis. The framework's steps include familiarizing oneself with the data, generating initial codes, searching for themes, reviewing themes, defining and naming themes, and producing the report. FINDINGS: The inductive qualitative analysis generated the Professionalism Learning Journey model. This conceptual model includes four interconnected themes: Awareness, Acknowledgement, Realization, and Application. The generated model depicts the trajectory that the learners appear to experience while they are engaging with the content of the course. CONCLUSION: Integrating a professionalism-training course into an undergraduate medical curriculum is likely to be positively appraised by the learners. It raises their awareness, enables them to value the subject matter and the sophistication of its application, and empowers them to put into practice the taught principles, on an individual basis and collectively. This is especially true when the course is entrenched in constructivism experiential learning theory and designed to foster self-directed learning. The introduced conceptual model, in conjunction with the innovative professionalism-training course curriculum, can serve as a template for other competencies and other schools.

Bereavement, Memorial Attendance, and Mental Health During the COVID-19 Pandemic: Longitudinal Results from the Nurses' Health Study.

BACKGROUND: Mortality increased during the COVID-19 pandemic. Many bereaved individuals were not able to gather to memorialize their loved ones, yet it is unknown if this contributed to worsening mental health. OBJECTIVE: Examine the association of bereavement in the early part of the COVID-19 pandemic with subsequent psychological distress and the role of memorial attendance in reducing psychological distress among the bereaved. DESIGN, SETTINGS, SUBJECTS: In May 2020, 39,564 older females from the Nurses' Health Study II enrolled in a longitudinal COVID-19 substudy (meanage = 65.2 years, SD = 4.5). METHODS: Linear regression analyses estimated associations of bereavement reported between March and October, 2020 with subsequent psychological distress between January and October 2021, adjusting for sociodemographic and prepandemic depression symptoms. Secondary models examined associations between memorial attendance and psychological distress. RESULTS: Bereavement during the early part of the COVID-19 pandemic was associated with higher psychological distress (adjusted ß = 0.21, 95% CI: 0.15, 0.26) assessed over the next year. Among the bereaved, memorial attendance was associated with lower psychological distress (in-person: adjusted ß = -0.41, 95% CI: -0.53, -0.29; online: adjusted ß = -0.24, 95% CI: -0.46, --0.02). CONCLUSION: Attending memorials was associated with lower subsequent psychological distress among bereaved older females.

Clinical learning environments across two different healthcare settings using the undergraduate clinical education environment measure.

BACKGROUND: The clinical placements of our medical students are almost equally distributed across private and public sectors. This study aims to assess medical students' perceptions of their Clinical learning Environment (CLE) across these two different healthcare settings, using the Undergraduate Clinical Education Environment Measure (UCEEM). METHODS: 76 undergraduate medical students (Year 5 and 6), were invited to participate. Data were collected using an online UCEEM with additional questions related to demographics and case load exposure. The UCEEM consists of two overarching domains of experiential learning and social participation, with four subdomains of learning opportunities, preparedness, workplace interaction, and inclusion. RESULTS: 38 questionnaires were received. Of 225 responses to the individual UCEEM items, 51 (22.6%) scored a mean of ≥ 4 (range 4-4.5, representing strong areas), 31 (13.7%) scored a mean of ≤ 3 (range 2.1-3, needing attention) and 143 (63.6%) scored a mean of 3.1-3.9 (areas that could be improved). The majority (63%) of the case load exposure responses scored a mean of ≥ 4 (range 4-4.5). Compared to the private sittings, there is a significant reduction in total UCEEM (p = 0.008), preparedness for student entry (p = 0.003), and overarching dimension of social participation (p = 0.000) scores for the public sector. Similarly, both workplace interaction patterns and student inclusion and equal treatment scored significantly lower for the public sector (p = 0.000 and p = 0.011 respectively). Two out of three case load exposure items scored significantly higher for the public sector (p = 0.000). DISCUSSION: The students' CLE perceptions were generally positive. The lower UCEEM ratings in the public sector items were related to student entry preparedness, workplace interactions, student inclusiveness and workforce equity of treatment. In contrast the students were exposed to more variety and larger number of patients in the public sector. These differences indicated some significantly different learning environments between the two sectors.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

The Chinese version of Posttraumatic Growth and Depreciation Inventory-Expanded version (PTGDI-X) for cancer survivors.

Many patients with cancer report positive changes often referred to as posttraumatic growth (PTG). Some of these self-reported PTG may represent maladaptive illusions created by individuals to cope with the illness. A recently established Posttraumatic Growth and Depreciation Inventory - Expanded version (PTGDI-X) includes both PTG and posttraumatic depreciation (PTD) items. This inventory may provide a more balanced picture of the phenomenological world of cancer survivors. We examined the Chinese version of the PTGDI-X's applicability to cancer patients, and how PTG and PTD were related to posttraumatic stress symptoms. Two hundred sixty-five cancer survivors in Taiwan completed the Chinese version of the PTGDI-X, along with the PTSD Checklist for the DSM-5 to measure posttraumatic stress disorder (PTSD) symptoms. Confirmatory factor analysis showed that the factor structure of the PTGDI-X established in a multi-national study fit our data from cancer patients modestly well. The PTD score had a significant and positive correlation with PTSD symptoms, whereas the PTG and PTSD showed a significant curvilinear relationship in the form of an inverted U-shape. This study's results indicate that PTG and PTD are separated constructs with differential relationships with cancer outcomes. The Chinese version of the PTGDI-X is a viable instrument for psycho-oncological research. The PTD scores can provide useful information to guide cognitive interventions to reduce distorted cognitions. In contrast, the PTG scores can provide further information on the phenomenological world of cancer survivors. In this study, clinical implications and future studies were considered.

Motivational interviewing for caries prevention in adolescents: a randomized controlled trial.

OBJECTIVE: The objective of this study is to investigate the effectiveness of motivational interviewing (MI) in changing health behaviors (snack and toothbrushing) and preventing dental caries among adolescents. METHODS: Five hundred and twelve adolescents with unfavorable caries-related behaviors ("snacking three times or more a day" and/or "toothbrushing less often than twice a day") were randomly assigned to three groups. Group I received prevailing health education (oral health talks and pamphlets). Participants in group II joined a one-on-one face-to-face MI session. In group III, a patient communication tool (Cariogram) was incorporated to facilitate the MI process. At baseline and 24 months post-intervention, a self-administered questionnaire gathered information of participants' sociodemographic characteristics and oral health self-efficacy and behaviors. Their oral hygiene and tooth status were assessed by a blinded examiner. RESULTS: After 24 months, 460 (89.8%) participants were followed up. Compared with group I, (i) restriction of frequent snacking was more likely in group II [OR (95% CI): 3.91 (1.48-10.33)] and group III [OR (95% CI): 6.33 (2.46-16.27)], whereas group III tended to adopt the behavior of toothbrushing twice a day [OR (95% CI): 4.80 (1.79-12.85)]; (ii) no significant between-group difference in plaque score reduction was found (p > 0.05); and (iii) groups II and III developed fewer cavitated teeth (△DICDASII 3-6MFT) [ß (95% CI): - 0.19 (- 0.37, - 0.01) and - 0.20 (- 0.38, - 0.02), respectively], whereas increment of total carious lesions (△DICDASII 1-6MFT) was lower in group III [ß (95% CI): - 0.63 (- 1.24, - 0.02)]. CONCLUSION: MI outperformed prevailing health education in improving oral health behaviors and preventing dental caries among adolescents. CLINICAL RELEVANCE: Incorporating MI into dental care for caries-prone adolescents contributes to optimal health outcomes. TRIAL REGISTRATION: HKUCTR-1852 ( http://www.hkuctr.com/ ) (Hong Kong, 2013).

Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis.

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

Intestinal Virome in Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.

Discovery of a ZIP7 inhibitor from a Notch pathway screen.

The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.

Aluminum-Hydride-Catalyzed Hydroboration of Carbon Dioxide.

This study describes the first use of a bis(phosphoranyl)methanido aluminum hydride, [ClC(PPh2NMes)2AlH2] (2, Mes = Me3C6H2), for the catalytic hydroboration of CO2. Complex 2 was synthesized by the reaction of a lithium carbenoid [Li(Cl)C(PPh2NMes)2] with 2 equiv of AlH3·NEtMe2 in toluene at -78 °C. 2 (10 mol %) was able to catalyze the reduction of CO2 with HBpin in C6D6 at 110 °C for 2 days to afford a mixture of methoxyborane [MeOBpin] (3a; yield: 78%, TOF: 0.16 h-1) and bis(boryl)oxide [pinBOBpin] (3b). When more potent [BH3·SMe2] was used instead of HBpin, the catalytic reaction was extremely pure, resulting in the formation of trimethyl borate [B(OMe)3] (3e) [catalytic loading: 1 mol % (10 mol %); reaction time: 60 min (5 min); yield: 97.6% (>99%); TOF: 292.8 h-1 (356.4 h-1)] and B2O3 (3f). Mechanistic studies show that the Al-H bond in complex 2 activated CO2 to form [ClC(PPh2NMes)2Al(H){OC(O)H}] (4), which was subsequently reacted with BH3·SMe2 to form 3e and 3f, along with the regeneration of complex 2. Complex 2 also shows good catalytic activity toward the hydroboration of carbonyl, nitrile, and alkyne derivatives.

Mucin Secretion in Cystic Fibrosis: A Systematic Review.

BACKGROUND: Mucus protects the epithelium against invaders and toxic materials. Sticky and thick mucus is characteristic of CF. OBJECTIVE: The aim of this systematic review is to characterize the specific mucins secreted in the lung and intestinal tract of CF patients. METHODS: A systematic literature search was conducted up to December 31, 2019. The following terms were used: "cystic fibrosis" AND "mucin." Case-control studies comparing mucin expression in CF patients to healthy controls were included. RESULTS: We found 741 eligible studies, 694 studies were rejected because they were performed in animals and not in full text, and 32 studies were excluded being editorials, duplications, review articles, meta-analysis, or not in English. Fifteen studies were eligible for our study, including 150 CF patients compared to 82 healthy controls, all fulfilled the inclusion criteria. The main mucin types expressed in the sinus submucosal glands, sputum, tracheobronchial surface epithelium, and lung submucosal glands were MUC5AC and MUC5B. Increase in the number of sinusoidal submucosal glands and expression of MUC5B was found in CF patients, but no such difference from healthy controls was found for the number of goblet cells in the surface epithelium nor in the expression of -MUC5AC. The opposite was found in the tracheobronchial surface epithelium and in the lungs. CONCLUSIONS: Increased expression of MUC5AC in the surface epithelium and of MUC5B in the subepithelial glands may be the result of higher secretion rate of mucin into the lumen of the respiratory tract, causing mucus plaque, infection, and inflammation.

A gp130-Src-YAP module links inflammation to epithelial regeneration.

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Coping profiles predict long-term anxiety trajectory in breast cancer survivors.

This study examined the long-term trajectory patterns of anxiety in breast cancer survivors and identified its predicting variables, especially the type of coping profile. Eighty-one patients who completed all four questionnaires from the 10-year study were included in the analysis. Anxiety scores from the Hospital Anxiety and Depression Scale were used in latent class growth analysis to chart the anxiety trajectory of cancer survivors. Demographic variables, clinical variables, depression level, and coping profiles (adaptive versus maladaptive) were used as predictors. Our study identified a two-class model of long-term anxiety trajectory among breast cancer survivors, with a resistant group (85.2%) and a distress group (14.8%). Demographic and clinical variables were not associated with anxiety trajectory paths. On the other hand, maladaptive coping characterized by higher scores in helplessness/hopelessness, cognitive avoidance, and anxious preoccupation, and lower scores in fighting spirit and fatalism in the Mini-MAC was a significant predictor of distressed anxiety. Coping profiles identified using the Mini-MAC were predictive of long-term anxiety trajectory among breast cancer survivors in our survey. Early interventions on coping with cancer could reduce long-term anxiety problems.

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

Cognitive vulnerabilities to anxiety symptoms among Chinese adolescents: A 3-year longitudinal study.

OBJECTIVE: This study established cognitive vulnerability of anxiety symptoms among high school students. METHOD: A total of 72 grade 9-11 students completed measures on levels of anxiety sensitivity (AS), selective attentional processing, and anxiety symptoms annually between 2016 and 2018. RESULTS: Latent class growth analysis (unconditional model) showed a four-class model: High (stable) (6.94%), low (stable) (11.11%), medium (decreasing) (61.11%), and medium (increasing) (20.83%). The conditioned model controlling for the physical-concerns dimension of AS and negative attentional bias demonstrated that a two-class model consisted of a low anxiety class (n = 59, 81.9%) and a high anxiety class (n = 13, 18.1%) provided the best fit for the data. Negative attentional bias is a significant factor related to the development of anxiety trajectories. CONCLUSION: Attentional bias modification to disengage from negative stimuli may serve as a potential target of intervention to reduce chronic anxiety among high school students.

Relationships between hope and mental health among women in prison.

BACKGROUND: Previous research with non-offenders has linked a higher dispositional cognition of hope to lower levels of psychological symptoms and demonstrated mediating effects of attentional biases on the relationship between hope and psychological symptoms, but this has not been explored among offenders. AIMS: Our aim was to investigate associations between a dispositional cognition of hope and habitual attentional processing styles and distress among women in prison. We hypothesised that higher levels of hope would be associated with more attention to positive information and less to negative information in the surroundings and, in turn, lower levels of depression, anxiety and stress symptoms in women in prison. METHOD: In a cross-sectional study, we recruited consenting women serving a prison sentence who had been referred to psychological services. Participants completed a set of self-rating inventories individually, which scaled their levels of hope, attention to positive and negative information and symptoms of anxiety, stress and depression. RESULTS: Two hundred and three women participated. Their average age was 35.68 years (range 21-67 years). Over half were recidivists (170, 58%). Overall, the higher the level of hope they had, the lower were the ratings of their psychological symptoms. Positive attentional bias was associated with higher hope and lower psychological distress. In contrast, negative attentional bias was related to lower hope and higher psychological distress ratings. In statistical models, both attentional biases appeared to be partial mediators of the relationship between hope and psychological distress. CONCLUSIONS: Our findings among women in prison were consistent with those in non-forensic populations and not previously studied among prisoners. They suggest that it would be worth evaluating interventions to modify attentional styles as they may have value in increasing hope and reducing psychological symptoms and perhaps also harmful behaviours in this vulnerable population.

Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice.

OBJECTIVE: Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease. DESIGN: Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model). RESULTS: In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g-/- mice. CONCLUSION: Ethanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.

No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients With Cirrhosis.

BACKGROUND & AIMS: Screening patients with cirrhosis for hepatocellular carcinoma (HCC) has been recommended. We conducted a matched case-control study within the US Veterans Affairs (VA) health care system to determine whether screening by abdominal ultrasonography (USS) and/or by measuring serum level of α-fetoprotein (AFP) was associated with decreased cancer-related mortality in patients with cirrhosis. METHODS: We defined cases (n = 238) as patients with cirrhosis who died of HCC from January 1, 2013 through August 31, 2015 and had been in VA care with a diagnosis of cirrhosis for at least 4 years before the diagnosis of HCC. We matched each case to 1 control (n = 238), defined as a patient with cirrhosis who did not die of HCC and had been in VA care for at least 4 years before the date of the matched case's HCC diagnosis. Controls were matched to cases by year of cirrhosis diagnosis, race and ethnicity, age, sex, etiology of cirrhosis, Model for End-Stage Liver Disease score, and VA medical center. We identified all USS and serum AFP tests performed within 4 years before the date of HCC diagnosis in cases or the equivalent index date in controls and determined by chart extraction (blinded to case or control status) whether these tests were performed for screening. RESULTS: There were no significant differences between cases and controls in the proportions of patients who underwent screening USS (52.9% vs 54.2%), screening measurement of serum AFP (74.8% vs 73.5%), screening USS or measurement of serum AFP (81.1% vs 79.4%), or screening USS and measurement of serum AFP (46.6% vs 48.3%) within 4 years before the index date, with or without adjusting for potential confounders. There also was no difference in receipt of these screening tests within 1, 2, or 3 years before the index date. CONCLUSIONS: In a matched case-control study of the VA health care system, we found that screening patients with cirrhosis for HCC by USS, measurement of serum AFP, either test, or both tests was not associated with decreased HCC-related mortality. We encourage additional case-control studies to evaluate the efficacy of screening for HCC in other health care systems, in which available records are sufficiently detailed to enable identification of the indication for USS and AFP tests.