The effect of diabetes on surgical versus percutaneous left main revascularization outcomes: a systematic review and meta-analysis.

BACKGROUND: The optimal method of coronary revascularization for diabetes mellitus (DM) patients with left main coronary artery disease (LMCAD) is controversial in the drug-eluting stent (DES) era. METHODS: We performed a systematic review and meta-analysis comparing DES-based percutaneous coronary intervention (PCI) to coronary artery bypass grafting (CABG) for LMCAD in DM patients and tested for effect measure modification (EMM) by diabetes for adverse events. We included all randomized controlled trials (RCTs) and observational studies comparing CABG to DES-based PCI including DM patients with LMCAD published up to March 1, 2021. We completed separate random-effects meta-analyses for four RCTs (4356 patients, mean follow-up of 4.9 years) and six observational studies (9360 patients, mean follow-up of 5.2 years). RESULTS: In RCTs among DM patients, DES-based PCI, compared to CABG, was associated with a 30% increased relative risk (RR) (RR 1.30, 95% CI 1.09-1.56, I2 = 0%), while among non-DM patients, there was a 25% increased relative risk (RR 1.25, 95% CI 1.07-1.44, I2 = 0%) for the composite endpoint of all-cause mortality, myocardial infarction, stroke, and unplanned revascularization (MACCE). There was no evidence of EMM (p-value for interaction = 0.70). The mean weighted SYNTAX score was 25.7. In observational studies, there was no difference between DES-based PCI and CABG for all-cause mortality in patients with DM (RR 1.13, 95% CI 0.91-1.40, I2 = 0%). CONCLUSIONS: CABG was superior to PCI for LMCAD in RCTs in DM patients for MACCE. Heart teams may consider DM as one of the many components in the clinical decision-making process, but may not want to consider DM as a primary deciding factor between DES-based PCI and CABG for LMCAD with low to intermediate anatomical complexity in the other coronary arteries. STUDY REGISTRATION: CRD42021246931 (PROSPERO).

Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection.

Yersinia suppress neutrophil responses by using a type 3 secretion system (T3SS) to inject 6-7 Yersinia effector proteins (Yops) effectors into their cytoplasm. YopH is a tyrosine phosphatase that causes dephosphorylation of the adaptor protein SKAP2, among other targets in neutrophils. SKAP2 functions in reactive oxygen species (ROS) production, phagocytosis, and integrin-mediated migration by neutrophils. Here we identify essential neutrophil functions targeted by YopH, and investigate how the interaction between YopH and SKAP2 influence Yersinia pseudotuberculosis (Yptb) survival in tissues. The growth defect of a ΔyopH mutant was restored in mice defective in the NADPH oxidase complex, demonstrating that YopH is critical for protecting Yptb from ROS during infection. The growth of a ΔyopH mutant was partially restored in Skap2-deficient (Skap2KO) mice compared to wild-type (WT) mice, while induction of neutropenia further enhanced the growth of the ΔyopH mutant in both WT and Skap2KO mice. YopH inhibited both ROS production and degranulation triggered via integrin receptor, G-protein coupled receptor (GPCR), and Fcγ receptor (FcγR) stimulation. SKAP2 was required for integrin receptor and GPCR-mediated ROS production, but dispensable for degranulation under all conditions tested. YopH blocked SKAP2-independent FcγR-stimulated phosphorylation of the proximal signaling proteins Syk, SLP-76, and PLCγ2, and the more distal signaling protein ERK1/2, while only ERK1/2 phosphorylation was dependent on SKAP2 following integrin receptor activation. These findings reveal that YopH prevents activation of both SKAP2-dependent and -independent neutrophilic defenses, uncouple integrin- and GPCR-dependent ROS production from FcγR responses based on their SKAP2 dependency, and show that SKAP2 is not required for degranulation.

SKAP2 is required for defense against K. pneumoniae infection and neutrophil respiratory burst.

Klebsiella pneumoniae is a respiratory, blood, liver, and bladder pathogen of significant clinical concern. We show that the adaptor protein, SKAP2, is required for protection against K. pneumoniae (ATCC 43816) pulmonary infections. Skap2-/- mice had 100-fold higher bacterial burden when compared to wild-type and burden was controlled by SKAP2 expression in innate immune cells. Skap2-/- neutrophils and monocytes were present in infected lungs, and the neutrophils degranulated normally in response to K. pneumoniae infection in mice; however, K. pneumoniae-stimulated reactive oxygen species (ROS) production in vitro was abolished. K. pneumoniae-induced neutrophil ROS response required the activity of SFKs, Syk, Btk, PLCγ2, and PKC. The loss of SKAP2 significantly hindered the K. pneumoniae-induced phosphorylation of SFKs, Syk, and Pyk2 implicating SKAP2 as proximal to their activation in pathogen-signaling pathways. In conclusion, SKAP2-dependent signaling in neutrophils is essential for K. pneumoniae-activated ROS production and for promoting bacterial clearance during infection.

Klebsiella pneumoniae is a type of bacteria that can cause life-threatening infections ­ including pneumonia, blood stream infections, and urinary tract infections ­ in hospitalized patients. These infections can be difficult to treat because some K. pneumoniae are resistant to antibiotics. The bacteria are normally found in the human intestine, and they do not usually cause infections in healthy people. This implies that healthy people's immune systems are better able to fend off K. pneumoniae infections; learning how could help scientists develop new ways to treat or prevent infections in hospitalized patients. In healthy people, a type of immune cell called neutrophils are the first line of defense against bacterial infections. Several different proteins are needed to activate neutrophils, including a protein called SKAP2. But the role of this protein in fighting K. pneumoniae infections is not clear. To find out what role SKAP2 plays in the defense against pneumonia caused by K. pneumoniae, Nguyen et al. compared infections in mice with and without the protein. Mice lacking SKAP2 in their white blood cells had more bacteria in their lungs than normal mice. The experiments showed that neutrophils from mice with SKAP2 produce a burst of chemicals called "reactive oxygen species", which can kill bacteria. But neutrophils without the protein do not. Without SKAP2, several proteins that help produce reactive oxygen species do not work. Understanding the role of SKAP2 in fighting infections may help scientists better understand the immune system. This could help clinicians to treat conditions that cause it to be hyperactive or ineffective. More studies are needed to determine if SKAP2 works the same way in human neutrophils and if it works against all types of K. pneumoniae. If it does, then scientists might be able use this information to develop therapies that help the immune system fight infections.

Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target.

Antibiotic resistance is a major public health threat that has stimulated the scientific community to search for nontraditional therapeutic targets. Because virulence, but not the growth, of many Gram-negative bacterial pathogens depends on the multicomponent type three secretion system injectisome (T3SSi), the T3SSi has been an attractive target for identifying small molecules, peptides, and monoclonal antibodies that inhibit its function to render the pathogen avirulent. While many small-molecule lead compounds have been identified in whole-cell-based high-throughput screens (HTSs), only a few protein targets of these compounds are known; such knowledge is an important step to developing more potent and specific inhibitors. Evaluation of the efficacy of compounds in animal studies is ongoing. Some efforts involving the development of antibodies and vaccines that target the T3SSi are further along and include an antibody that is currently in phase II clinical trials. Continued research into these antivirulence therapies, used alone or in combination with traditional antibiotics, requires combined efforts from both pharmaceutical companies and academic labs.

Pre-colonization with the commensal fungus Candida albicans reduces murine susceptibility to Clostridium difficile infection.

Clostridium difficile is a major nosocomial pathogen responsible for close to half a million infections and 27,000 deaths annually in the U.S. Preceding antibiotic treatment is a major risk factor for C. difficile infection (CDI) leading to recognition that commensal microbes play a key role in resistance to CDI. Current antibiotic treatment of CDI is only partially successful due to a high rate of relapse. As a result, there is interest in understanding the effects of microbes on CDI susceptibility to support treatment of patients with probiotic microbes or entire microbial communities (e.g., fecal microbiota transplantation). The results reported here demonstrate that colonization with the human commensal fungus Candida albicans protects against lethal CDI in a murine model. Colonization with C. albicans did not increase the colonization resistance of the host. Rather, our findings showed that one effect of C. albicans colonization was to enhance a protective immune response. Mice pre-colonized with C. albicans expressed higher levels of IL-17A in infected tissue following C. difficile challenge compared to mice that were not colonized with C. albicans. Administration of cytokine IL-17A was demonstrated to be protective against lethal murine CDI in mice not colonized with C. albicans. C. albicans colonization was associated with changes in the abundance of some bacterial components of the gut microbiota. Therefore, C. albicans colonization altered the gut ecosystem, enhancing survival after C. difficile challenge. These findings demonstrate a new, beneficial role for C. albicans gut colonization.

A 3D intestinal tissue model supports Clostridioides difficile germination, colonization, toxin production and epithelial damage.

Endospore-forming Clostridioides difficile is a causative agent of antibiotic-induced diarrhea, a major nosocomial infection. Studies of its interactions with mammalian tissues have been hampered by the fact that C. difficile requires anaerobic conditions to survive after spore germination. We recently developed a bioengineered 3D human intestinal tissue model and found that low O2 conditions are produced in the lumen of these tissues. Here, we compared the ability of C. difficile spores to germinate, produce toxin and cause tissue damage in our bioengineered 3D tissue model versus in a 2D transwell model in which human cells form a polarized monolayer. 3D tissue models or 2D polarized monolayers on transwell filters were challenged with the non-toxin producing C. difficile CCUG 37787 serotype X (ATCC 43603) and the toxin producing UK1 C. difficile spores in the presence of the germinant, taurocholate. Spores germinated in both the 3D tissue model as well as the 2D transwell system, however toxin activity was significantly higher in the 3D tissue models compared to the 2D transwells. Moreover, the epithelium damage in the 3D tissue model was significantly more severe than in 2D transwells and damage correlated significantly with the level of toxin activity detected but not with the amount of germinated spores. Combined, these results show that the bioengineered 3D tissue model provides a powerful system with which to study early events leading to toxin production and tissue damage of C. difficile with mammalian cells under anaerobic conditions. Furthermore, these systems may be useful for examining the effects of microbiota, novel drugs and other potential therapeutics directed towards C. difficile infections.

Prevalence and antimicrobial resistance pattern of bacterial meningitis in Egypt.

Infectious diseases are the leading cause of morbidity and mortality in the developing world. In Egypt bacterial diseases constitute a great burden, with several particular bacteria sustaining the leading role of multiple serious infections. This article addresses profound bacterial agents causing a wide array of infections including but not limited to pneumonia and meningitis. The epidemiology of such infectious diseases and the prevalence of Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae are reviewed in the context of bacterial meningitis. We address prevalent serotypes in Egypt, antimicrobial resistance patterns and efficacy of vaccines to emphasize the importance of periodic surveillance for appropriate preventive and treatment strategies.