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Butcher Fog posted an update 6 months, 1 week ago
SUMMARYGram-negative bacteremia is a devastating public health threat, with high mortality in vulnerable populations and significant costs to the global economy. Concerningly, rates of both Gram-negative bacteremia and antimicrobial resistance in the causative species are increasing. Gram-negative bacteremia develops in three phases. First, bacteria invade or colonize initial sites of infection. Second, bacteria overcome host barriers, such as immune responses, and disseminate from initial body sites to the bloodstream. Third, bacteria adapt to survive in the blood and blood-filtering organs. Selleck Silmitasertib To develop new therapies, it is critical to define species-specific and multispecies fitness factors required for bacteremia in model systems that are relevant to human infection. A small subset of species is responsible for the majority of Gram-negative bacteremia cases, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii The few bacteremia fitness factors identified in these prominent Gram-negative species demonstrate shared and unique pathogenic mechanisms at each phase of bacteremia progression. Capsule production, adhesins, and metabolic flexibility are common mediators, whereas only some species utilize toxins. This review provides an overview of Gram-negative bacteremia, compares animal models for bacteremia, and discusses prevalent Gram-negative bacteremia species.Herpesviruses are ubiquitous pathogens that establish lifelong, latent infections in their host. Spontaneous reactivation of herpesviruses is often asymptomatic or clinically manageable in healthy individuals, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with multiple proliferative cardiovascular and post-transplant diseases. Herpesviruses encode viral G protein-coupled receptors (vGPCRs) that alter the host cell by hijacking cellular pathways and play important roles in the viral life cycle and these different disease settings. In this review, we discuss the pharmacological and signaling properties of these vGPCRs, their role in the viral life cycle, and their contribution in different diseases. Because of their prominent role, vGPCRs have emerged as promising drug targets, and the potential of vGPCR-targeting therapeutics is being explored. Overall, these vGPCRs can be considered as attractive targets moving forward in the development of antiviral, cancer, and/or cardiovascular disease treatments. SIGNIFICANCE STATEMENT In the last decade, herpesvirus-encoded G protein-coupled receptors (GPCRs) have emerged as interesting drug targets with the growing understanding of their critical role in the viral life cycle and in different disease settings. This review presents the pharmacological properties of these viral receptors, their role in the viral life cycle and different diseases, and the emergence of therapeutics targeting viral GPCRs.MHC class I molecules play an important role in adaptive immune responses against intracellular pathogens. These molecules are highly polymorphic, and many allotypes have been characterized. In a transplantation setting, a mismatch between MHC allotypes may initiate an alloimmune response. Rhesus macaques (Macaca mulatta, Mamu) are valuable as a preclinical model species in transplantation research as well as to evaluate the safety and efficacy of vaccine candidates. In both lines of research, the availability of nonhuman primate MHC-reactive mAbs may enable in vitro monitoring and detection of presence of particular Mamu molecules. In this study, we screened a collection of thoroughly characterized HLA class I-specific human mAbs for cross-reactivity with rhesus macaque MHC class I allotypes. Two mAbs, OK4F9 and OK4F10, recognize an epitope that is defined by isoleucine (I) at amino acid position 142 that is present on the Indian rhesus macaque Mamu-B*00801 allotype, which is an allotype known to be associated with elite control of SIV replication. The reactive pattern of a third mAb, MUS4H4, is more complex and includes an epitope shared on Mamu-A2*0501 and -B*00101-encoded Ags. This is the first description, to our knowledge, of human HLA-reactive mAbs that can recognize Mamu allotypes, and these can be useful tools for in vitro monitoring the presence of the relevant allelic products. Moreover, OK4F9 and OK4F10 can be powerful mAbs for application in SIV-related research.Chimeric Ag receptor (CAR) T cell therapy has shown astonishing potency in treating a variety of hematological malignancies in recent years. Along with this lifesaving potential comes the life-threatening toxicities of cytokine release syndrome (CRS) and neurotoxicity. This work seeks to consolidate biomarker candidates with the potential to predict the severity of CRS and neurotoxicity in patients receiving CD19-targeted CAR T cell therapy. In this systematic review, 33 clinical trials were evaluated for biomarkers that can predict the severity of posttreatment CRS and neurotoxicity. CRS and neurotoxicity occurred in 73.4 and 37% of the reviewed patients, respectively. Identified biomarker candidates included tumor burden, platelet count, C-reactive protein, ferritin, IFN-γ, IL-2, IL-6, IL-8, IL-10, IL-15, and TGF-β. Combinatorial algorithms based on cytokine levels and clinical parameters show excellent promise in predicting CAR-T-cell-therapy-associated toxicities, with improved accuracy over the component biomarkers.In the course of the COVID-19 pandemic, it has become clear that primary healthcare systems play a critical role in clinical care, such as patient screening, triage, physical and psychological support and also in promoting good community advice and awareness in coordination with secondary healthcare and preventive care. Because of the role of social and environmental factors in COVID-19 transmission and burden of disease, it is essential to ensure that there is adequate coordination of population-based health services and public health interventions. The COVID-19 pandemic has shown the primary and community healthcare (P&CHC) system’s weaknesses worldwide. In many instances, P&CHC played only a minor role, the emphasis being on hospital and intensive care beds. This was compounded by political failures, in supporting local community resilience. Placing community building, social cohesion and resilience at the forefront of dealing with the COVID-19 crisis can help align solutions that provide a vision of ‘planetary health’.
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