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Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARβ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARβ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARβ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions.

Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/μL) received 2 doses of ChAdOx1 nCoV-19 (AZD1222) 4–6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that, 6 months after vaccination, the majority of measurable immune responses were greater than prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.

The influence of arterial and ventricular parameters on the main fiducial pressure points and index during systole has been investigated using a mix of in silico and in vivo data. Notably, an index, QIx, based entirely on ventricular ejection patterns has been developed and its potential in describing the augmentation pressure index, AIx, has been investigated and compared against the reflection coefficient Г. In a group of hypertensive patients (n = 156) and in healthy volunteers whose physiology was modulated via administration of vasoactive drugs (n = 13), QIx was found to be more correlated to AIx than Г (coefficient of determination, R2 = 0.71 vs R2 = 0.53 in the normotensive group; R2 = 0.52 vs R2 = 0.37 in the hypertensive group). This trend was confirmed by a LASSO analysis on in vivo data (standardised coefficient, β = 0.42 vs β = 0.22, p < 0.001 in both cases) and also observed in an in silicosensitivity analysis on a reduced 7-artery model of the upper aortic arch (for variations between –25% and +25% of QIx and Г from baseline values, AIx varied between −245% and +193%, −194% and +191% respectively) (Figure 1). All analyses were also concordant for the main determinants of the first systolic shoulder P1 and augmentation pressure AP: pulse wave velocity (β = 0.74, p < 0.001) and peak flow velocity (β = 0.41, p < 0.001) are the main determinants of P1 while reflection waves (β = 0.34, p < 0.001) and stroke volume (β = 0.37, p < 0.001) mainly define AP (Figure 1). These results further strengthen the case that ventricular dynamics is at least as important as arterial stiffening in raised pulse pressure. Figure 1

We examined the ability of a simple reduced model comprising a proximal characteristic impedance linked to a Windkessel element to accurately predict central Pulse Pressure (PP) from aortic blood flow, verified that parameters of the model corresponded to physical properties, and applied the model to examine PP dependence on cardiac and vascular properties. PP obtained from the reduced model was compared with theoretical values obtained in silico and measured values in vivo. Theoretical values were obtained using a distributed multisegment model in a population of virtual (computed) subjects in which cardiovascular properties were varied over the pathophysiological range (n = 3,095). In vivo measurements were in normotensive subjects during modulation of physiology with vasoactive drugs (n = 13) and in hypertensive subjects (n = 156). Central PP derived from the reduced model agreed with theoretical values (mean difference ±SD, −0.09 ± 1.96 mmHg) and with measured values (means differences −1.95 ± 3.74 and −1.18 ± 3.67 mmHg for normotensive and hypertensive subjects, respectively). Parameters extracted from the reduced model agreed closely with theoretical and measured physical properties. Central PP was seen to be determined mainly by total arterial compliance (inversely associated with central arterial stiffness) and ventricular dynamics: the blood volume ejected by the ventricle into the aorta up to time of peak pressure and blood flow into the aorta (corresponding to the rate of ventricular ejection) up to this point. Increased flow and volume accounted for 20.1 mmHg (52%) of the 39.0 mmHg difference in PP between the upper and lower tertiles of the hypertensive subjects 1.

Purpose: Hypertension, the single biggest killer worldwide1, arises mainly as a result of an increase in central pulse pressure (PP)2, yet haemodynamic basis of that increase is still disputed. We examined the ability of a simple “reduced” model comprising a proximal characteristic impedance linked to a Windkessel element to accurately predict PP from aortic blood flow and applied the model to examine PP dependence on cardiac and vascular properties. Method: PP obtained from the model was compared with theoretical values obtained in silico and in vivo. Theoretical values were obtained using a distributed multi-segment model in a population of “virtual” subjects (n = 3,095) in which cardiovascular properties were varied over the pathophysiological range. In vivo measurements were in normotensive subject (n = 13) during modulation of physiology with vasoactive drugs with divergent actions on cardiac and cascular properties and in hypertensive subjects (n = 156). Results: PP derived from the model agreed with theoretical values (mean difference SD, −0.09±1.96 mmHg) and with measured values (−1.95±3.74 and −1.18±3.67 mmHg for normotensive and hypertensive subjects respectively). Parameters extracted from the model agreed closely with theoretical and measured physical properties. PP was seen to be determined mainly by total arterial compliance (inversely associated with arterial stiffness) and ventricular dynamics: the volume of blood ejected up to time of pulse pressure and the rate of ventricular ejection up to this point. Conclusion: Increased flow and/or volume accounted for 20.1 mmHg (52%) of the 39.0 mmHg difference in pulse pressure between the upper and lower tertiles of the hypertensive subjects.

Background: A recent study has shown that the central pressure waveform could be determined by a very small set of parameters accounting for the physical properties of the heart and the arteries [1]. Particularly, main pressure features like first systolic shoulder (P1) and systolic (P2) pressures were estimated accurately. Methods: By combining a numerical virtual population (n=3,325) similar to [2] and experimental data acquired from a pressure/Doppler flow velocity transducer place in the ascending aorta in 18 patients (meanSD: age 63±11 yr, aortic BP 136±23/73±13 mmHg) at the time of cardiac catheterization, we assessed the accuracy of those predictions for magP1 (P1-DBP) and P2 using respectively a water hammer [3] and a 3-element Windkessel models [4]. Contributions of the heart and arterial properties to these estimates though respectively blood velocity, volume and pulse wave velocity, compliance, resistance were then derived from the theoretical models used. Results: P1 and P2 estimates agreed well with theoretical pressure both in the numerical dataset (mean+//0-SD difference, 1.1±3.2 mmHg and -1.6±3.1 mmHg respectively) and the clinical cohort (mean+//0-SD difference, -2.4±5.5 mmHg and 1.9±6.5 mmHg respectively). The ratio arterial-to-heart contribution has been shown to be fairly constant as magP1 was increasing. Conclusions: Arteries and heart contribute as much to rise in P1. More clinical data are being collected to quantify the contributions of the heart and arteries to P2.

Backward traveling waves, an important determinant of central haemodynamics, are usually regarded as being due to reflections from discontinuities in the arterial tree. However, consideration of a single tube model of the arterial with a single site of reflection shows that a backward pressure wave may be generated by elastic recoil of large arteries, in which case the magnitude of the backward wave is proportional to that of the forward wave. A 55-segment 1-D model of the arterial which allows reflection as a continuum along the arterial tree and, for a given prescribed aortic flow, generates physiological aortic pulse waveforms was used to examine the relation of the backward to forward pressure waves in 4107 “virtual subjects” with arterial parameters spanning the physiological range. Backward pressure wave was closely correlated with the forward wave (R = 0.931, P < 0.001). Clinical data was obtained by carotid tonometry and aortic Doppler sonography during modulation of cardiovascular function in healthy volunteers (n = 13, age 46.5 ± 10.1 years with inotropic, vasopressor and vasodilator drugs (dobutamine, norepinephrine phentolamine and nitroglycerin). The magnitude of backward pressure was highly correlated with forward pressure over a range 5–15 mmHg (R = 0.824, P < 0.001) with a constant ratio of backward to forward wave magnitude except during treatment with nitroglycerin, a vasodilator known to be highly selective for large muscular arteries. These numerical and experimental data suggest that backward pressure waves can be generated by elastic recoil of large arteries independent of pressure wave reflection and this effect dominates in human physiology.

Introduction: Nitroglycerin (NTG) has a particularly marked action to reduce augmentation pressure (cAP), attributed to a reduction in timing or amplitude of pressure wave reflection. However, a recent study suggests that cAP is determined in large part by ventricular contraction/relaxation dynamics. We examined whether the reduction in cAP induced by NTG is associated with a change in left ventricular (LV) systolic function. Methods: We estimated myocardial wall stress from transthoracic echocardiographic imaging of the LV and LV pressure estimated from carotid tonometry during systole. Eighteen subjects aged 43.0±11.9 (mean ± SD) years were studied before and 7-12 min after NTG (400 μg sublingually). Carotid pressure calibrated by mean and diastolic blood pressure was used to calculate time-varying LV wall stress from endocardial and epicardial volumes obtained from wall tracking analysis. Tissue Doppler Imaging (TDI) S wave (a measure of LV systolic function) was measured at the basal mitral annulus from an echocardiographic 4-chamber view. Results: NTG decreased cAP from 16.3±3.6 to 4.5±2.9mmHg (means±SEM, P