Challenges to the Development of the Next Generation of Self-Reporting Cardiovascular Implantable Medical Devices.

Cardiovascular disease (CVD) is a group of heart and vasculature conditions which are the leading form of mortality worldwide. Blood vessels can become narrowed, restricting blood flow, and drive the majority of hearts attacks and strokes. Reactive surgical interventions are frequently required; including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Despite successful opening of vessels and restoration of blood flow, often in-stent restenosis (ISR) and graft failure can still occur, resulting in subsequent patient morbidity and mortality. A new generation of cardiovascular implants that have sensors and real-time monitoring capabilities are being developed to combat ISR and graft failure. Self-reporting stent/graft technology could enable precision medicine-based and predictive healthcare by detecting the earliest features of disease, even before symptoms occur. Bringing an implantable medical device with wireless electronic sensing capabilities to market is complex and often obstructive undertaking. This critical review analyses the obstacles that need to be overcome for self-reporting stents/grafts to be developed and provide a precision-medicine based healthcare for cardiovascular patients. Here we assess the latest research and technological advancement in the field, the current devices; including smart cardiovascular implantable biosensors and associated wireless data and power transfer solutions. We include an evaluation of devices that have reached clinical trials and the market potential for their end-user implementation.

Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria.

One-third of the world's population is estimated to be latently infected with Mycobacterium tuberculosis. This reservoir of bacteria is largely resistant to antimicrobial treatment that often only targets actively replicating mycobacteria, with current treatment for latent infection revolving around inhibiting the resuscitation event rather than preventing or treating latent infection. As a result, antimicrobials that target latent infection often have little to no activity in vivo. Here we report a method of in vitro analysis of physiologically relevant non-replicating persistence (NRP) utilizing cholesterol as the sole carbon source, alongside hypoxia as a driver of Mycobacterium bovis BCG into the NRP state. Using the minimal cholesterol media NRP assay, we observed an increased state of in vitro resistance to front-line anti-tubercular compounds. However, following a phenotypic screen of an approved-drug library, we identified dapsone as a bactericidal active molecule against cholesterol-dependent NRP M. bovis BCG. Through an overexpression trial of probable antimicrobial target enzymes, we further identified FolP2, a non-functional dihydropteroate synthase homologue, as the likely target of dapsone under cholesterol-NRP due to a significant increase in bacterial resistance when overexpressed. These results highlight the possible reason for little in vivo activity seen for current front-line anti-NRP drugs, and we introduce a new methodology for future drug screening as well as a potential role for dapsone inclusion within the current treatment regime.

Microfluidics as a Novel Technique for Tuberculosis: From Diagnostics to Drug Discovery.

Tuberculosis (TB) remains a global healthcare crisis, with an estimated 5.8 million new cases and 1.5 million deaths in 2020. TB is caused by infection with the major human pathogen Mycobacterium tuberculosis, which is difficult to rapidly diagnose and treat. There is an urgent need for new methods of diagnosis, sufficient in vitro models that capably mimic all physiological conditions of the infection, and high-throughput drug screening platforms. Microfluidic-based techniques provide single-cell analysis which reduces experimental time and the cost of reagents, and have been extremely useful for gaining insight into monitoring microorganisms. This review outlines the field of microfluidics and discusses the use of this novel technique so far in M. tuberculosis diagnostics, research methods, and drug discovery platforms. The practices of microfluidics have promising future applications for diagnosing and treating TB.