Intrahepatic microbes govern liver immunity by programming NKT cells.

The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity.

Persistent viremia in an immunocompetent patient with inherited chromosomally integrated HHV-6B.

Human herpesvirus-6 (HHV-6), the virus which causes roseola, has traditionally been associated with benign and self-limited childhood illness. However, HHV-6 establishes lifelong latency and can reactivate in immunocompromised adult patients. In about 1% of cases, it integrates into the human genome as inherited chromosomally integrated HHV-6 (iciHHV-6). We report the case of a 70-year-old man presenting with altered mental status and agitation. His infectious workup revealed a cerebrospinal fluid sample positive for HHV-6 with virus detectable in the blood as well. He was subsequently treated with ganciclovir. HHV-6 viremia (DNAemia) persisted, and the antiviral medications were switched to foscarnet under the assumption of treatment failure due to drug resistance. After several admissions to the hospital for the same complaint, and after noticing that DNAemia persisted despite adequate treatment for HHV-6, infectious disease specialists ordered testing for chromosomally integrated virus. Test results confirmed the presence of iciHHV-6, explaining his consistently elevated serum viral load. Primary HHV-6 infection in adults causes a transient increase in viral load with resolution and clearance after a few weeks while iciHHV-6 is characterized by persistent detection of viral DNA at a high copy number. Individuals with iciHHV-6 can develop HHV-6 disease and are at increased risk for active viral replication when treated with immunosuppressive medications, but only mRNA testing, which is not widely available can differentiate between latent and active infection. This makes the decision to treat challenging in this patient population. When faced with a positive HHV-6 DNA result in the setting of equivocal symptoms, clinicians should consider the possibility of chromosomally integrated virus rather than drug-resistant virus in order to reduce exposure to potentially toxic antiviral medications.

When Variants Collide: An Unusual Presentation of Metastatic Gastric Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm.

Gastrointestinal neuroendocrine neoplasms were recently reclassified into the 2019 World Health Organization schema into well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Among these, gastric MiNENs are exceedingly rare and often metastasize quickly without diagnostic clues. We present a refractory gastric MiNEN with unique presenting features. This case highlights the clinical spectrum of these tumors, the importance of accurate histochemical interpretation, and clinical management in the absence of formalized guidelines. Future therapies looking at novel targets and palliative symptom relief are needed.

Effect of Vitamin D Supplementation on the Incidence of Diabetes Mellitus.

CONTEXT: The effect of vitamin D supplementation on the risk of type 2 diabetes mellitus (T2DM) remains controversial because most randomized controlled trials (RCTs) have been small or have reported low doses of vitamin D. OBJECTIVE: To conduct a meta-analysis of RCTs testing vitamin D supplementation in the prevention of T2DM. DATA SOURCES: Database search of PubMed/MEDLINE, EMBASE, and the Cochrane Library was performed by 2 reviewers from inception through September 15, 2019. STUDY SELECTION: We included RCTs that reported the effect of vitamin D supplementation for at least 1 year on T2DM prevention. DATA EXTRACTION: Two independent reviewers extracted the data. The risk ratios (RRs) and 95% confidence intervals (CIs) were reported. Primary outcome of the meta-analysis was the incidence of T2DM. DATA SYNTHESIS: Nine RCTs were included (43 559 participants). The mean age (standard deviation) was 63.5 (6.7) years. The RR for vitamin D compared with placebo was 0.96 (95% CI, 0.90-1.03); P = 0.30. In trials testing moderate to high doses of supplementation (≥1000 IU/day), all conducted among participants with prediabetes, the RR for vitamin D compared with placebo was 0.88 (95% CI, 0.79-0.99). In contrast, the trials testing lower doses, which were conducted in general population samples, showed no risk reduction (RR, 1.02; 95% CI, 0.94-1.10; P, interaction by dose = 0.04). CONCLUSION: In patients with prediabetes, vitamin D supplementation at moderate to high doses (≥1000 IU/day), significantly reduced the incidence risk of T2DM, compared with placebo.

Effect of oxygenation modalities among patients with postoperative respiratory failure: a pairwise and network meta-analysis of randomized controlled trials.

BACKGROUND: Postoperative respiratory failure is associated with increased perioperative complications. Our aim is to compare outcomes between non-invasive ventilation (NIV), high-flow nasal cannula (HFNC), and standard oxygen in patients at high-risk for or with established postoperative respiratory failure. METHODS: Electronic databases including PubMed, Embase, and the Cochrane Library were reviewed from inception to September 2019. We included only randomized controlled trials (RCTs) that compared NIV, HFNC, and standard oxygen in patients at high risk for or with established postoperative respiratory failure. We performed a Bayesian network meta-analysis to calculate the odds ratio (OR) and Bayesian 95% credible intervals (CrIs). RESULTS: Nine RCTs representing 1865 patients were included (the mean age was 61.6 ± 10.2 and 64.4% were males). In comparison with standard oxygen, NIV was associated with a significant reduction in intubation rate (OR 0.23; 95% Cr.I. 0.10-0.46), mortality (OR 0.45; 95% Cr.I. 0.27-0.71), and intensive care unit (ICU)-acquired infections (OR 0.43, 95% Cr.I. 0.25-0.70). Compared to standard oxygen, HFNC was associated with a significant reduction in intubation rate (OR 0.28, 95% Cr.I. 0.08-0.76) and ICU-acquired infections (OR 0.41; 95% Cr.I. 0.20-0.80), but not mortality (OR 0.58; 95% Cr.I. 0.26-1.22). There were no significant differences between HFNC and NIV regarding different outcomes. In a subgroup analysis, we observed a mortality benefit with NIV over standard oxygen in patients undergoing cardiothoracic surgeries but not in abdominal surgeries. Furthermore, in comparison with standard oxygen, NIV and HFNC were associated with lower intubation rates following cardiothoracic surgeries while only NIV reduced the intubation rates following abdominal surgeries. CONCLUSIONS: Among patients with post-operative respiratory failure, HFNC and NIV were associated with significantly reduced rates of intubation and ICU-acquired infections compared with standard oxygen. Moreover, NIV was associated with reduced mortality in comparison with standard oxygen.

Aspirin Efficacy in Primary Prevention: A Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: The role of aspirin as a means of primary prevention remains controversial. AIM: We have conducted a meta-analysis of all randomized controlled trials (RCTs) to evaluate the role of aspirin in primary prevention. METHODS: Literature search was performed via PubMed, Embase, and the Cochrane Library for all related RCTs. All-cause mortality was the primary endpoint. Secondary endpoints included major adverse cardiovascular events (MACE), myocardial infarction (MI), cardiovascular mortality, cerebrovascular events, and bleeding events. We used a random effects model to report the risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Our analysis included 17 RCTs (164,862 patients; 83,309 received aspirin and 81,744 received placebo). Our study did not demonstrate any significant reduction in all-cause mortality for patients treated with aspirin when compared with placebo (RR 0.97; 95% CI 0.93-1.01; P = 0.13). Sensitivity analysis performed by excluding healthy elderly (≥ 65) showed significant reductions in all-cause mortality in the aspirin-treated patients (RR 0.94; 95% CI 0.90-0.99; P = 0.01). There were no significant differences between both groups regarding cardiovascular mortality and cerebrovascular events (P > 0.05). However, aspirin-treated patients significantly reduced MACE and MI events (RR 0.89; 95% CI 0.85-0.93; P < 0.001 and RR 0.88; 95% CI 0.78-0.98; P = 0.02, respectively), respectively. However, aspirin was associated with a significantly higher incidence of bleeding, including major bleeding and intracranial bleeding (P < 0.001). CONCLUSIONS: Aspirin use in primary prevention has resulted in a lower incidence of MACE and MI without significantly effecting cerebrovascular events. However, aspirin was associated with a higher bleeding risk. Use of aspirin as a means of primary prevention should be thoroughly discussed with patients and pursued based on the risk of cardiovascular disease while also considering bleeding risk.

The role of anticoagulation in venous thromboembolism primary prophylaxis in patients with malignancy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with cancer. As such, we conducted a meta-analysis of randomized controlled trials (RCTs) that evaluated anticoagulants as primary prophylaxis against VTE in cancer patients. METHODS: Pubmed/MEDLINE, Embase, and the Cochrane Library were screened for all RCTs that used anticoagulation therapy in cancer patients for primary prevention of VTE. The primary outcomes were VTE events. Secondary outcomes included all-cause mortality, VTE-related mortality and major bleeding. A random effects model was used to report the risk ratios (RR) with 95% confidence intervals (CIs), and odds ratios (ORs) with Bayesian 95% credible intervals for both direct and network meta-analyses, respectively. RESULTS: Twenty-four RCTs were included totaling 13,338 patients (7197 received anticoagulation and 6141 received placebo). The mean age ranged between 54.6 and 68.1 years, with 50.5% male. Compared with placebo, low-molecular-weight heparin (LMWH) or direct Xa inhibitors were associated with lower VTE events (RR 0.58; 95%CI 0.48-0.69, P < 0.001) and (RR 0.39; 95%CI 0.24-0.63, p < 0.001), respectively. LMWH was associated with decreased VTE and all-cause mortality when compared with placebo (P < 0.05). Regarding safety outcomes, LMWH and direct Xa inhibitors were not associated with increased risks of major bleeding (P > 0.05) when compared with placebo. Results regarding VTE events and major bleeding were consistent in both lung and pancreatic cancers. CONCLUSIONS: Both LMWH and direct Xa inhibitors were associated with a lower VTE events compared with placebo. However, this potentially protective effect must be balanced against the possible increased risk of bleeding for some patients.

The role of vitamin D supplementation for primary prevention of cancer: meta-analysis of randomized controlled trials.

Background: In the USA cancer is the second leading cause of mortality, as such, primary prevention of cancer is a major public health concern. Vitamin D supplementation has been studied as a primary prevention method for multiple diseases including cardiovascular disease, osteoporosis, diabetes mellitus and cancer. The role of Vitamin D as primary prevention of cancer is still controversial. With fast emergence of large randomized controlled trials (RCTs) in that regards, we aimed to evaluate the efficacy of Vitamin D supplementation as primary prophylaxis for cancer. Methods: A comprehensive electronic database search was conducted for all RCTs where comparison of Vitamin D supplementation versus placebo for the prevention of any type of disease with at least 3 years of Vitamin D supplementation was used and where cancer incidence or mortality was reported. The primary outcome was cancer-related mortality and cancer incidence. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up. Results: We included 10 RCTs with 79,055 total patients, mean age of 68.07 years, a female percentage of 78.02% and a minimum follow-up of 4 years and more. Vitamin D was associated with significant reduction of cancer-related mortality compared with placebo (RR 0.87; 95% CI: 0.79-0.96; P = 0.05: I2 = 0%). Compared with placebo, Vitamin D was not associated with significant reduction of cancer incidence (RR: 0.96; 95% CI: 0.86-1.07; P = 0.46; I2 = 31%). Conclusion: With inclusion of studies, which did not primarily examine vitamin D for the purpose of preventing cancer or reducing cancer mortality our meta-analysis highlights that the use of vitamin D supplementation for primary prevention of cancer is encouraged as it does possibly decrease cancer-related mortality once cancer is diagnosed; however, it has no role or effect on cancer incidence.

Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma.

The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-ß, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103- DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.

Macrophages in Nonalcoholic Steatohepatitis: Friend or Foe?

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease that is characterised by steatosis, chronic inflammation, and hepatocellular injury with or without fibrosis. The role and activation of macrophages in the pathogenesis of NASH is complex and is being studied for possible therapeutic options to help the millions of people diagnosed with the disease. The purpose of this review is to discuss the pathogenesis of NASH through the activation and role of Kupffer cells and other macrophages in causing inflammation and progression of NASH. Furthermore, this review aims to outline some of the current therapeutic options targeting the pathogenesis of NASH.