One-year Outcomes after Discharge from Noncardiac Surgery and Association between Predischarge Complications and Death after Discharge: Analysis of the VISION Prospective Cohort Study.

BACKGROUND: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery. METHODS: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis. RESULTS: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr). CONCLUSIONS: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge.

Blood microbial signatures associated with mortality in patients with sepsis: A pilot study.

Sepsis is a life-threatening illness caused by the dysregulated host response to infection. Nevertheless, our current knowledge of the microbial landscape in the blood of septic patients is still limited. Next-generation sequencing (NGS) is a sensitive method to quantitatively characterize microbiomes at various sites of the human body. In this study, we analyzed the blood microbial DNA of 22 adult patients with sepsis and 3 healthy subjects. The presence of non-human DNA was identified in both healthy and septic subjects. Septic patients had a markedly altered microbial DNA profile compared to healthy subjects over α- and ß-diversity. Unexpectedly, the patients could be further divided into two subgroups (C1 and C2) based on ß-diversity analysis. C1 patients showed much higher bacteria, viruses, fungi, and archaea abundance, and a higher level of α-diversity (Chao1, Observed and Shannon index) than both C2 patients and healthy subjects. The most striking difference was seen in the case of Streptomyces violaceusniger, Phenylobacterium sp. HYN0004, Caulobacter flavus, Streptomyces sp. 11-1-2, and Phenylobacterium zucineum, the abundance of which was the highest in the C1 group. Notably, C1 patients had a significantly poorer outcome than C2 patients. Moreover, by analyzing the patterns of microbe-microbe interactions in healthy and septic subjects, we revealed that C1 and C2 patients exhibited distinct co-occurrence and co-exclusion relationships. Together, our study uncovered two distinct microbial signatures in the blood of septic patients. Compositional and ecological analysis of blood microbial DNA may thus be useful in predicting mortality of septic patients.

Dual RNA sequencing of Helicobacter pylori and host cell transcriptomes reveals ontologically distinct host-pathogen interaction.

Helicobacter pylori is a highly successful pathogen that poses a substantial threat to human health. However, the dynamic interaction between H. pylori and the human gastric epithelium has not been fully investigated. In this study, using dual RNA sequencing technology, we characterized a cytotoxin-associated gene A (cagA)-modulated bacterial adaption strategy by enhancing the expression of ATP-binding cassette transporter-related genes, metQ and HP_0888, upon coculturing with human gastric epithelial cells. We observed a general repression of electron transport-associated genes by cagA, leading to the activation of oxidative phosphorylation. Temporal profiling of host mRNA signatures revealed the downregulation of multiple splicing regulators due to bacterial infection, resulting in aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. Moreover, we demonstrated a protective effect of gastric H. pylori colonization against chronic dextran sulfate sodium (DSS)-induced colitis. Mechanistically, we identified a cluster of propionic and butyric acid-producing bacteria, Muribaculaceae, selectively enriched in the colons of H. pylori-pre-colonized mice, which may contribute to the restoration of intestinal barrier function damaged by DSS treatment. Collectively, this study presents the first dual-transcriptome analysis of H. pylori during its dynamic interaction with gastric epithelial cells and provides new insights into strategies through which H. pylori promotes infection and pathogenesis in the human gastric epithelium. IMPORTANCE: Simultaneous profiling of the dynamic interaction between Helicobacter pylori and the human gastric epithelium represents a novel strategy for identifying regulatory responses that drive pathogenesis. This study presents the first dual-transcriptome analysis of H. pylori when cocultured with gastric epithelial cells, revealing a bacterial adaptation strategy and a general repression of electron transportation-associated genes, both of which were modulated by cytotoxin-associated gene A (cagA). Temporal profiling of host mRNA signatures dissected the aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. We demonstrated a protective effect of gastric H. pylori colonization against chronic DSS-induced colitis through both in vitro and in vivo experiments. These findings significantly enhance our understanding of how H. pylori promotes infection and pathogenesis in the human gastric epithelium and provide evidence to identify targets for antimicrobial therapies.

FOXP4 is a Direct YAP1 Target that Promotes Gastric Cancer Stemness and Drives Metastasis.

The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer (GC). As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. Here, we identified a vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired GC spheroid formation and reduced stemness marker expression, while FOXP4 upregulation potentiated cancer cell stemness. RNA-seq analysis revealed SOX12 as downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small molecule screen identified 42-(2-Tetrazolyl)rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed GC tumor growth and enhanced the efficacy of 5-FU chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in GC regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for GC.