Systematic Review with Meta-Analysis: Fecal Microbiota Transplantation for Severe or Fulminant Clostridioides difficile.

BACKGROUND: Severe and fulminant Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality. While fecal microbiota transplantation (FMT) has proved to be a highly effective treatment for recurrent CDI, its efficacy in severe or fulminant CDI remains uncertain. AIMS: To perform a systematic review with meta-analysis evaluating clinical outcomes and safety of FMT in severe and fulminant CDI. METHODS: A systemic review with meta-analysis was performed through comprehensive search of Embase, Medline (Ovid), trial registers, and conference abstracts through January 2020. Studies on FMT in severe and fulminant CDI were included. Meta-analysis was done with random effects models given heterogeneity to estimate rates of cure, mortality, and colectomy. Publication bias was assessed using Egger's test. RESULTS: Sixteen studies comprised of one randomized controlled trial, four cohort studies, and eleven case series were analyzed. In total, 676 patients underwent FMT for severe or fulminant CDI. The overall rate of clinical cure after single FMT was 61.3% (95% CI 43.2-78.0%) with 10.9% (95% CI 0.2-30.2%) of patients experiencing major adverse events. The overall pooled colectomy rate after FMT was 8.2% (95% CI 0.1-23.7%) with a pooled all-cause mortality rate after FMT of 15.6% (95% CI 7.8-25.0%). CONCLUSION: Low-quality data support the use of fecal microbiota transplantation in patients with severe and fulminant Clostridioides difficile infection.

Oral Fecal Microbiota Transplant Capsules Are Safe and Effective for Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis.

GOALS: We performed a systematic review with meta-analysis to examine the efficacy and safety of oral fecal microbiota transplantation (FMT) capsules for recurrent Clostridioides difficile infection (rCDI). BACKGROUND: FMT through colonoscopy is established as effective and safe in treating multiple recurrences of CDI, but consensus has not been established on delivery through oral capsules. STUDY: A systematic literature search was performed with multiple databases including MEDLINE and EMBASE to identify original studies including at least 10 patients that investigated the role of oral FMT capsules to treat rCDI. Cure rates were pooled by a random effects model and publication bias was assessed with the Egger test. Secondary analyses assessed for differences between capsule preparation (frozen vs. lyophilized stool) and delivery modality (capsule vs. colonoscopy). RESULTS: Fifteen studies (12 case series and 3 randomized controlled trials) encompassing 763 patients were identified for inclusion. Significant variability existed in baseline patient characteristics and protocols. Meta-analysis of proportions showed efficacy of oral FMT capsules to be 0.821 (95% confidence interval: 0.762-0.874). No evidence for publication bias was found (P=0.51). Secondary analyses did not find significant differences in efficacy. Fourteen adverse events leading to death or hospitalization were noted, none of which were attributed to FMT. CONCLUSIONS: Oral FMT capsules for rCDI are promising because of ease of administration and noninvasive delivery. We found an overall efficacy of 82.1% with a low rate of serious adverse events. Further studies are needed to optimize protocols and outcomes.

Ginseng metabolite protopanaxadiol interferes with lipid metabolism and induces endoplasmic reticulum stress and p53 activation to promote cancer cell death.

Protopanaxadiol (PPD), a ginseng metabolite generated by the gut bacteria, was shown to induce colorectal cancer cell death and enhance the anticancer effect of chemotherapeutic agent 5-FU. However, the mechanism by which PPD promotes cancer cell death is not clear. In this manuscript, we showed that PPD activated p53 and endoplasmic reticulum (ER) stress and induced expression of BH3-only proteins Puma and Noxa to promote cell death. Induction of Puma by PPD was p53-dependent, whereas induction of Noxa was p53-independent. On the other hand, PPD also induced prosurvival mechanisms including autophagy and expression of Bcl2 family apoptosis regulator Mcl-1. Inhibition of autophagy or knockdown of Mcl-1 significantly enhanced PPD-induced cell death. Interestingly, PPD inhibited expression of genes involved in fatty acid and cholesterol biosynthesis and induced synergistic cancer cell death with fatty acid synthase inhibitor cerulenin. As PPD-induced ER stress was not significantly affected by inhibition of new protein synthesis, we suggest PPD may induce ER stress directly through causing lipid disequilibrium.

Error-checking intraoperative arterial line blood pressures.

Electronic medical records now store a wealth of intraoperative hemodynamic data. However, analysis of such data is plagued by artifacts related to the monitoring environment. Here, we present an algorithm for automated identification of artifacts and replacement using interpolation of arterial line blood pressures. After IRB approval, minute-by-minute digital recordings of systolic, diastolic, and mean arterial pressures (MAP) obtained during anesthesia care were analyzed using predetermined metrics to identify values anomalous from adjacent neighbors. Anomalous data points were then replaced with linear interpolation of neighbors. The algorithm was then validated against manual artifact identification in 54 anesthesia records and 41,384 arterial line measurements. To assess the algorithm's effect on data analysis, we calculated the percent of time spent with MAP below 55 mmHg and above 100 mmHg for both raw and conditioned datasets. Manual review of the dataset identified 1.23% of all pressure readings as artifactual. When compared to manual review, the algorithm identified artifacts with 87.0% sensitivity and 99.4% specificity. The average difference between manual review and algorithm in identifying the start of arterial line monitoring was 0.17, and 2.1 min for the end of monitoring. Application of the algorithm decreased the percent of time below 55 mmHg from 4.3 to 2.0% (2.1% with manual review) and time above 100 mmHg from 8.8 to 7.3% (7.3% manual). This algorithm's performance was comparable to manual review by a human anesthesiologist and reduced the incidence of abnormal MAP values identified using a sample analysis tool.

Successful clozapine re-challenge following myocarditis.

OBJECTIVE: To explore the evidence around clozapine re-challenge following myocarditis. CONCLUSION: This case adds to the 17 cases of clozapine re-challenge following myocarditis, of which 71% were successful (12 cases). This demonstrates that re-challenge could be performed safely and effectively in the context of clozapine-induced myocarditis, if accompanied by a strict and rigorous monitoring protocol.

Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK.

Ginseng is one of the most commonly used herbs that is believed to have a variety of biological activities, including reducing blood sugar and cholesterol levels, anti-cancer, and anti-diabetes activities. However, little is known about the molecular mechanisms involved. In this study, we showed that protopanaxadiol (PPD), a metabolite of the protopanaxadiol group ginsenosides that are the major pharmacological constituents of ginsengs, significantly altered the expression of genes involved in metabolism, elevated Sestrin2 (Sesn2) expression, activated AMPK, and induced autophagy. Using CRISPR/CAS9-mediated gene editing and shRNA-mediated gene silencing, we demonstrated that Sesn2 is required for PPD-induced AMPK activation and autophagy. Interestingly, we showed that PPD-induced Sesn2 expression is mediated redundantly by the GCN2/ATF4 amino acid-sensing pathway and the PERK/ATF4 endoplasmic reticulum (ER) stress pathway. Our results suggest that ginseng metabolite PPD modulates the metabolism of amino acids and lipids, leading to the activation of the stress-sensing kinases GCN2 and PERK to induce Sesn2 expression, which promotes AMPK activation, autophagy, and metabolic health.

The current status of human laryngeal transplantation in 2017: A state of the field review.

OBJECTIVES: Human laryngeal allotransplantation has long been contemplated as a surgical option following laryngectomy, but there is a paucity of information regarding the indications, surgical procedure, and patient outcomes. Our objectives were to identify all human laryngeal allotransplants that have been undertaken and reported in the English literature and to evaluate the success of the procedure. DATA SOURCES: MEDLINE, Embase, Current Index to Nursing and Allied Health Literature, Web of Science and Scopus, and the Gray literature. REVIEW METHODS: A comprehensive search strategy was undertaken across multiple databases. Inclusion criteria were case reports of patients who had undergone human laryngeal allotransplantation. Information regarding indications, operative techniques, complications, graft viability, and functional outcomes were extracted. RESULTS: A total of 5,961 articles, following removal of duplicates, matched the search criteria and were screened, with five case reports relating to two patients, ultimately fulfilling the entry criteria. CONCLUSIONS: Two laryngeal transplants have been reported in the medical literature. Although both patients report improved quality of life relating to their ability to communicate with voice, further research is necessary to shape our understanding of this complicated operation, its indications, and its functional outcomes. Laryngoscope, 127:1861-1868, 2017.

Integrative radiogenomic profiling of squamous cell lung cancer.

Radiotherapy is one of the mainstays of anticancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is still not well defined. Here, we report the development of a high-throughput platform for measuring radiation survival in vitro and its validation in comparison with conventional clonogenic radiation survival analysis. We combined results from this high-throughput assay with genomic parameters in cell lines from squamous cell lung carcinoma, which is standardly treated by radiotherapy, to identify parameters that predict radiation sensitivity. We showed that activation of NFE2L2, a frequent event in lung squamous cancers, confers radiation resistance. An expression-based, in silico screen nominated inhibitors of phosphoinositide 3-kinase (PI3K) as NFE2L2 antagonists. We showed that the selective PI3K inhibitor, NVP-BKM120, both decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1-mutant cells to radiation. We then combined results from this high-throughput assay with single-sample gene set enrichment analysis of gene expression data. The resulting analysis identified pathways implicated in cell survival, genotoxic stress, detoxification, and innate and adaptive immunity as key correlates of radiation sensitivity. The integrative and high-throughput methods shown here for large-scale profiling of radiation survival and genomic features of solid-tumor-derived cell lines should facilitate tumor radiogenomics and the discovery of genotype-selective radiation sensitizers and protective agents.

Specific killing of Rb mutant cancer cells by inactivating TSC2.

The retinoblastoma (Rb) tumor suppressor is often inactivated in cancers. To identify genes that can be used to specifically target such cancers, we carried out a genetic screen in Drosophila. We identified gig (fly TSC2) and found that inactivation of rbf (fly Rb) and gig synergistically induced cell death. Interestingly, inactivation of TSC2 specifically kills Rb mutant cancer cells under stress conditions, which is correlated with an inhibition of tumor growth. We show that cancer cell killing induced by concomitant inactivation of Rb and TSC2 is mediated by increased cellular stress, including oxidative stress. Inactivation of TSC2 and Rb synergistically induce oxidative stress via increased protein synthesis, inhibited de novo lipid synthesis, and decreased reactive oxygen species scavenger enzyme SOD2 induction.