Translational research : the journal of laboratory and clinical medicine
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Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. ⋯ In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.
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The sexually transmitted infection gonorrhea, caused by the Gram-negative bacterium Neisseria gonorrhoeae, can cause urethritis, cervicitis, and systemic disease, among other manifestations. N. gonorrhoeae has rapidly rising incidence along with increasing levels of antibiotic resistance to a broad range of drugs including first-line treatments. The rise in resistance has led to fears of untreatable gonorrhea causing substantial disease globally. ⋯ Second, vaccine development, long an important goal, is advancing. Third, new diagnostics promise rapid detection of antibiotic resistance and a shift from empiric to tailored treatment. The deployment of these new tools for addressing the challenge of antibiotic resistance will require careful consideration to provide optimal care for all patients while extending the lifespan of treatment regimens.
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The global burden of bacterial infections is rising due to increasing resistance to the majority of first-line antibiotics, rendering these drugs ineffective against several clinically important pathogens. Limited transport of antibiotics into cells compounds this problem for gram-negative bacteria that exhibit prominent intracellular lifecycles. Furthermore, poor bioavailability of antibiotics in infected tissues necessitates higher doses and longer treatment regimens to treat resistant infections. ⋯ However, in vivo therapeutic efficacy of HDTs is reliant on adequate bioavailability. Particle-based formulations demonstrate the potential to enable targeted drug delivery, enhance cellular uptake, and increase drug concentration in the host cell of HDTs. This review selected HDTs for clinically important pathogens, identifies formulation strategies that can improve their therapeutic efficacy and offers insights toward further development of HDTs for bacterial infections.
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The current tuberculosis (TB) predicament poses numerous challenges and therefore every incremental scientific work and all positive socio-political engagements, are steps taken in the right direction to eradicate TB. Progression of the late stage TB-drug pipeline into the clinics is an immediate deliverable of this global effort. ⋯ It includes a status check of the current TB-drug pipeline with a focus on the associated biology, emerging targets, and their promising chemical inhibitors. Potential synergies and/or gaps within or across different chemotherapeutic strategies are systematically reviewed as well.
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While antibiotics are a key infrastructure underpinning modern medicine, evolution will continue to undermine their effectiveness, requiring continuous investment to sustain antibiotic effectiveness. The antibiotic R&D ecosystem is in peril, moving towards collapse. Key stakeholders have identified pull incentives such as Market Entry Rewards or subscription models as the key long-term solution. ⋯ Bridging solutions are required from private actors in the interim. This article explores potential solutions led by private actors, including (1) traditional for-profit companies; (2) non-profit enterprises; and (3) public benefit corporations with lower profit expectations, akin to a public utility. All face similar commercial struggles, but nonprofits and public benefit corporations can accept lower profit expectations and might be more politically attractive recipients of pull incentives.