Mark R. Thomas

The design of microphone arrays yielding constant directivity over wide bandwidths produces a tradeoff between narrow element spacing for aliasing performance at high frequencies, and wide spacing for white noise gain performance at low frequencies. In the design of spherical microphone arrays, free-space cardioid microphones allow embedding of spheres at multiple radii, providing constant directivity over wider bandwidths. The physical size of the microphone capsules and cabling limits the practical lower bound on sphere radius and consequentially how high the resulting aliasing frequency can be pushed. This paper proposes an inverted cardioid topology in which the main lobes on the inner sphere capsules face radially inward, instead of outward, allowing denser packing of elements. Practical measurements on a dual-sphere design, targeting third-order soundfield capture, investigate the self-shadowing behavior and show near constant modal beamformer directivity between 400 Hz and 8 kHz.

New antithrombotic medications with less effect on haemostasis are needed for the long-term treatment of acute coronary syndromes (ACS). The platelet receptor glycoprotein VI (GPVI) is critical in atherothrombosis, mediating platelet activation at atherosclerotic plaque. The inhibition of spleen tyrosine kinase (Syk) has been shown to block GPVI-mediated platelet function. The aim of our study was to investigate if the Syk inhibitor fostamatinib could be repurposed as an antiplatelet drug, either alone or in combination with conventional antiplatelet therapy. The effect of the active metabolite of fostamatinib (R406) was assessed on platelet activation and function induced by atherosclerotic plaque and a range of agonists in the presence and absence of the commonly used antiplatelet agents aspirin and ticagrelor. The effects were determined ex vivo using blood from healthy volunteers and aspirin- and ticagrelor-treated patients with ACS. Fostamatinib was also assessed in murine models of thrombosis. R406 mildly inhibited platelet responses induced by atherosclerotic plaque homogenate, likely due to GPVI inhibition. The anti-GPVI effects of R406 were amplified by the commonly-used antiplatelet medications aspirin and ticagrelor; however, the effects of R406 were concentration-dependent and diminished in the presence of plasma proteins, which may explain why fostamatinib did not significantly inhibit thrombosis in murine models. For the first time, we demonstrate that the Syk inhibitor R406 provides mild inhibition of platelet responses induced by atherosclerotic plaque and that this is mildly amplified by aspirin and ticagrelor.

Understanding the pathways involved in the formation and stability of the core and shell regions of a platelet-rich arterial thrombus may result in new ways to treat arterial thrombosis. The distinguishing feature between these two regions is the absence of fibrin in the shell which indicates that in vitro flow-based assays over thrombogenic surfaces, in the absence of coagulation, can be used to resemble this region. In this study, we have investigated the contribution of Syk tyrosine kinase in the stability of platelet aggregates (or thrombi) formed on collagen or atherosclerotic plaque homogenate at arterial shear (1000 s⁻¹). We show that post-perfusion of the Syk inhibitor PRT-060318 over preformed thrombi on both surfaces enhances thrombus breakdown and platelet detachment. The resulting loss of thrombus stability led to a reduction in thrombus contractile score which could be detected as early as 3 min after perfusion of the Syk inhibitor. A similar loss of thrombus stability was observed with ticagrelor and indomethacin, inhibitors of platelet adenosine diphosphate (ADP) receptor and thromboxane A₂ (TxA₂), respectively, and in the presence of the Src inhibitor, dasatinib. In contrast, the Btk inhibitor, ibrutinib, causes only a minor decrease in thrombus contractile score. Weak thrombus breakdown is also seen with the blocking GPVI nanobody, Nb21, which indicates, at best, a minor contribution of collagen to the stability of the platelet aggregate. These results show that Syk regulates thrombus stability in the absence of fibrin in human platelets under flow and provide evidence that this involves pathways additional to activation of GPVI by collagen.

Aims: Natriuretic peptides are routinely quantified to diagnose heart failure (HF). Their concentrations are also elevated in atrial fibrillation (AF). To clarify their interpretation, we measured natriuretic peptides in unselected patients with cardiovascular conditions and related their concentrations to AF and HF status and to outcomes. Methods and results: Consecutive patients with cardiovascular conditions presenting to a large teaching hospital (median age 70 [IQR 60–78] years, 40% women) underwent clinical assessment, 7-day ECG-monitoring, and echocardiography to diagnose AF and HF. N-terminal pro B-type natriuretic peptide (NT-proBNP) was centrally quantified. Clinical characteristics and NT-proBNP concentrations were related to HF hospitalization or cardiovascular death. Follow-up data was available in 1611/1616 patients (99.7%) and analysis performed at 2.5 years. Based on a literature review, four NT-proBNP groups were defined (<300pg/ml, 300–999pg/ml, 1000–1999pg/ml and ≥2000pg/ml). Multivariate Cox proportional hazards analysis of the composite outcome against AF and HF phenotype groups. This was adjusted for confounding factors including age, sex, race, body mass index, hypertension, diabetes, coronary artery disease, severe valvular heart disease, left bundle branch block, hyponatraemia, urea, haemoglobin, estimated glomerular filtration rate, NT-proBNP, medical treatment with ACE inhibitors or angiotensin receptor blockers, beta-blockers, diuretic (thiazide or loop diuretics), and anticoagulants (novel oral anticoagulant or vitamin K antagonist). Cox proportional hazards analysis adjusted for confounding variables for the composite outcome against baseline NT-proBNP concentration ranges was also performed in each patient group based on AF and HF status. HF hospitalization or cardiovascular death increased from patients with neither AF nor HF (36/488, 3.2/100 person-years), to 55/353 (7.1/100 person-years) in patients with AF only, 91/366 (12.1/100 person-years) in patients with HF only, and, 128/404 (17.7/100 person-years) in patients with AF plus HF (p<0.001). Higher NT-proBNP concentrations predicted the outcome in patients with AF only (C-statistic 0.82 [95% CI 0.77 to 0.86], p-value<0.001) and in other phenotype groups (C statistic in AF plus HF 0.66 [95% CI 0.61 to 0.70], p-value<0.001)). Sensitivity analyses confirmed these findings. Conclusion: Elevated NT-proBNP concentrations predict future HF events in patients with AF irrespective of the presence of HF. In line with previous studies in HF, an NT-proBNP threshold of 1000 pg/ml is useful to identify high-risk patients with AF whether or not they are diagnosed with HF at the time of assessment. Pending external validation, these findings encourage the routine quantification of NT-proBNP in the initial assessment of patients with AF. Funding Acknowledgement: Type of funding sources: Public grant(s) – EU funding. Main funding source(s): 1) This study was partially supported by European Union BigData@Heart and 2) CATCH ME (Characterising Afib by Translating its Causes into Health Modifiers in the Elderly)

GPVI is the major signalling receptor for collagen on platelets. We have raised 54 nanobodies (Nb), grouped into 33 structural classes based on their complementary determining region 3 (CDR3) loops, against recombinant GPVI-Fc (dimeric GPVI) and have characterised their ability to bind recombinant GPVI, resting and activated platelets, and to inhibit platelet activation by collagen. Nanobodies from six different binding classes showed the strongest binding to recombinant GPVI-Fc suggesting that there was not a single dominant class. The most potent three, Nb2, 21 and 35, inhibited collagen-induced platelet aggregation with nanomolar IC50 values and inhibited platelet aggregation under flow. The binding K_D of the most potent Nb, Nb2, against recombinant monomeric and dimeric GPVI was 0.6 and 0.7 nM, respectively. The crystal structure of monomeric GPVI in complex with Nb2 revealed a binding epitope adjacent to the CRP binding groove within the D1 domain. In addition, a novel conformation of GPVI involving a domain swap between the D2 domains was observed. The domain swap is facilitated by the outward extension of the C-C' loop which forms the domain swap hinge. The functional significance of this conformation was tested by truncating the hinge region so that the domain swap cannot occur. Nb2 was still able to displace collagen and CRP binding to the mutant, but signalling was abolished in a cell-based NFAT-reporter assay. This demonstrates that the C-C' loop region is important for GPVI signalling but not ligand binding and suggests the domain-swapped structure may represent an active GPVI conformation.

Microphone array calibration is required to accurately capture the information in an audio source recording. Existing calibration methods require expensive hardware and setup procedures to compute filters for correcting microphone responses. Typically, such methods struggle to extend measurement accuracy to low frequencies. As a result, the error due to microphone gain mismatch propagates to all the modes in the spherical harmonic domain representation of a signal. Several existing algorithms use modal representation of sound and error propagation in modes fundamentally limits the performance of such algorithms. A method for reducing the error propagation in modes by correcting the mismatched microphone gains is proposed, where RAndom PerturbatIons for Diffuse-field (RAPID) is used to design filters for correcting the mismatch. Experimental results show that the directivity pattern of a calibrated spherical microphone array using RAPID provides up to 6dB improvement in the front back factor.