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Carbapenem resistance, an emerging global health problem, compromises the treatment of infections caused by nosocomial pathogens. Preclinical and clinical trials demonstrate that a new generation of carbapenemases inhibitors, together with the recently approved avibactam, relebactam and vaborbactam, would address this resistance. Our review summarizes the latest developments related to carbapenemase inhibitors synthesized to date, as well as their spectrum of activity and their current stage of development. A particular focus will be on β-lactam/β-lactamase inhibitor combinations that could potentially be used to treat infections caused by carbapenemase-producer pathogens. These new combinations mark a critical step forward the fight against antimicrobial resistance.

Background: Our objective was to identify published models of coordination between entities funding or delivering health services in humanitarian crises, whether the coordination took place during or after the crises.Methods: We included reports describing models of coordination in sufficient detail to allow reproducibility. We also included reports describing implementation of identified models, as case studies. We searched Medline, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and the WHO Global Health Library. We also searched websites of relevant organizations. We followed standard systematic review methodology.Results: Our search captured 14,309 citations. The screening process identified 34 eligible papers describing five models of coordination of delivering health services: the “Cluster Approach” (with 16 case studies), the 4Ws “Who is Where, When, doing What” mapping tool (with four case studies), the “Sphere Project” (with two case studies), the “5x5” model (with one case study), and the “model of information coordination” (with one case study). The 4Ws and the 5x5 focus on coordination of services for mental health, the remaining models do not focus on a specific health topic. The Cluster approach appears to be the most widely used. One case study was a mixed implementation of the Cluster approach and the Sphere model. We identified no model of coordination for funding of health service.Conclusion: This systematic review identified five proposed coordination models that have been implemented by entities funding or delivering health service in humanitarian crises. There is a need to compare the effect of these different models on outcomes such as availability of and access to health services.

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In clear cell renal cell carcinoma, the VHL/HIF axis lays the groundwork for tumorigenesis and is the target of many therapeutic agents. However, HIF activation alone is largely insufficient for kidney tumor development, and the secondary mutations in PBRM1, BAP1, SETD2, KDM5C or other tumor suppressor genes are strong enablers of tumorigenesis. Interestingly, it has been discovered that VHL loss, and subsequent HIF activation, result in ISGF3 upregulation a negative feedback loop mediated by ISGF3, a transcription factor activated by type I interferon, and the secondary mutations in multiple tumor suppressor genes all partially disable this negative feedback loop to facilitate tumor growth. The convergence of so many cancer genes on this pathway suggests that it plays an important role in ccRCC development and maintenance. The tumors with secondary mutations that dampen the negative feedback loop might be exquisitely sensitive to its reactivation, and pharmacological activation of ISGF3 could be an effective method to treat ccRCC patients either alone or in combination with other effective therapies. In this review, we examine the relevance of the type I IFN pathway to ccRCC, synthesize our current knowledge of the ccRCC tumor suppressors in its regulation, and explore how this may impact the future treatment of ccRCC patients.