Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing

Rationale and design of BISTRO: a randomized controlled trial to determine whether bioimpedance spectroscopy guided fluid management maintains residual kidney function in incident haemodialysis patients

Background: Preserved residual kidney function (RKF) and normal fluid status are associated with better patient outcomes in incident haemodialysis patients. The objective of this trial is to determine whether using bioimpedance technology in prescribing the optimal post-dialysis weight can reduce the rate of decline of RKF and potentially improve patient outcomes. Methods/Design: 516 patients commencing haemodialysis, aged >18 with RKF of > 3 ml/min/1.73 m2 or a urine volume >500 ml per day or per the shorter inter-dialytic period will be consented and enrolled into a pragmatic, open label, randomized controlled trial. The intervention is incorporation of bioimpedance spectroscopy (BI) determination of normally hydrated weight to set a post-dialysis target weight that limits volume depletion, compared to current standard practice. Clinicians and participants will be blinded to BI measures in the control group and a standardized record capturing management of fluid status will be used in all participants. Primary outcome is preservation of residual kidney function assessed as time to anuria (≤100 ml/day or ≤200 ml urine volume in the short inter-dialytic period). A sample size of 516 was based upon a cumulative incidence of 30% anuria in the control group and 20% in the treatment group and 11% competing risks (death, transplantation) over 10 months, with up to 2 years follow-up. Secondary outcomes include rate of decline in small solute clearance, significant adverse events, hospitalization, loss of vascular access, cardiovascular events and interventions, dialysis efficacy and safety, dialysis-related symptoms and quality of life. Economic evaluation will be carried out to determine the cost-effectiveness of the intervention. Analyses will be adjusted for patient characteristics and dialysis unit practice patterns relevant to fluid management. Discussion: This trial will establish the added value of undertaking BI measures to support clinical management of fluid status and establish the relationship between fluid status and preservation of residual kidney function in incident haemodialysis patients. Trial registration: ISCCTN Number: 11342007, completed 26/04/2016; NIHR Portfolio number: CPMS31766; Sponsor: Keele University Keywords: Fluid status, Body composition, Residual kidney function, Haemodialysis, Bioimpedance, Fluid management, Health economic

Foreground modelling via Gaussian process regression: An application to HERA data

The key challenge in the observation of the redshifted 21-cm signal from cosmic reionization is its separation from the much brighter foreground emission. Such separation relies on the different spectral properties of the two components, although, in real life, the foreground intrinsic spectrum is often corrupted by the instrumental response, inducing systematic effects that can further jeopardize the measurement of the 21-cm signal. In this paper, we use Gaussian Process Regression to model both foreground emission and instrumental systematics in $\sim 2$ hours of data from the Hydrogen Epoch of Reionization Array. We find that a simple co-variance model with three components matches the data well, giving a residual power spectrum with white noise properties. These consist of an "intrinsic" and instrumentally corrupted component with a coherence-scale of 20 MHz and 2.4 MHz respectively (dominating the line of sight power spectrum over scales $k_{\parallel} \le 0.2$ h cMpc$^{-1}$) and a baseline dependent periodic signal with a period of $\sim 1$ MHz (dominating over $k_{\parallel} \sim 0.4 - 0.8$h cMpc$^{-1}$) which should be distinguishable from the 21-cm EoR signal whose typical coherence-scales is $\sim 0.8$ MHz

Foreground modelling via Gaussian process regression: An application to HERA data

The key challenge in the observation of the redshifted 21-cm signal from cosmic reionization is its separation from the much brighter foreground emission. Such separation relies on the different spectral properties of the two components, although, in real life, the foreground intrinsic spectrum is often corrupted by the instrumental response, inducing systematic effects that can further jeopardize the measurement of the 21-cm signal. In this paper, we use Gaussian Process Regression to model both foreground emission and instrumental systematics in $\sim 2$ hours of data from the Hydrogen Epoch of Reionization Array. We find that a simple co-variance model with three components matches the data well, giving a residual power spectrum with white noise properties. These consist of an "intrinsic" and instrumentally corrupted component with a coherence-scale of 20 MHz and 2.4 MHz respectively (dominating the line of sight power spectrum over scales $k_{\parallel} \le 0.2$ h cMpc$^{-1}$) and a baseline dependent periodic signal with a period of $\sim 1$ MHz (dominating over $k_{\parallel} \sim 0.4 - 0.8$h cMpc$^{-1}$) which should be distinguishable from the 21-cm EoR signal whose typical coherence-scales is $\sim 0.8$ MHz

Coronary microvascular resistance: methods for its quantification in humans

Coronary microvascular dysfunction is a topic that has recently gained considerable interest in the medical community owing to the growing awareness that microvascular dysfunction occurs in a number of myocardial disease states and has important prognostic implications. With this growing awareness, comes the desire to accurately assess the functional capacity of the coronary microcirculation for diagnostic purposes as well as to monitor the effects of therapeutic interventions that are targeted at reversing the extent of coronary microvascular dysfunction. Measurements of coronary microvascular resistance play a pivotal role in achieving that goal and several invasive and noninvasive methods have been developed for its quantification. This review is intended to provide an update pertaining to the methodology of these different imaging techniques, including the discussion of their strengths and weaknesses