Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial.

Importance: Elevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.

Objective: To evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.

Design, Setting, And Participants: A multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.

C286, an orally available retinoic acid receptor β agonist drug, regulates multiple pathways to achieve spinal cord injury repair.

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).

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL-286, a novel retinoic acid receptor-β agonist for treatment of spinal cord injury, in male healthy participants.

Aims: KCL-286 is an orally available agonist that activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male healthy volunteers to establish dosing to be used in the SCI patient population.

Durability of ChAdOx1 nCoV-19 vaccination in people living with HIV.

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.

Novel Pressure Wave Separation Analysis for Cardiovascular Function Assessment Highlights Major Role of Aortic Root.

Objective: A novel method was presented to separate the central blood pressure wave (CBPW) into five components with different biophysical and temporal origins. It includes a time-varying emission coefficient ( γ) that quantifies pulse wave generation and reflection at the aortic root.

Methods: The method was applied to normotensive subjects with modulated physiology by inotropic/vasoactive drugs (n = 13), hypertensive subjects (n = 158), and virtual subjects (n = 4,374).

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial.

Background: Data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV.

Methods: In this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18-55 years with HIV were enrolled at two HIV clinics in London, UK.

Identifying Hemodynamic Determinants of Pulse Pressure: A Combined Numerical and Physiological Approach.

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.

Reduced First-Phase Ejection Fraction and Sustained Myocardial Wall Stress in Hypertensive Patients With Diastolic Dysfunction: A Manifestation of Impaired Shortening Deactivation That Links Systolic to Diastolic Dysfunction and Preserves Systolic Ejection Fraction.

Impaired shortening deactivation of cardiac myocytes could sustain myocardial contraction, preserving ejection fraction at the expense of diastolic dysfunction. We examined the relationship between first-phase ejection fraction (EF1), the fraction of left ventricular volume ejected from the start of systole to the time of the first peak in left ventricular pressure (corresponding to the time of maximal ventricular shortening) to the duration of myocardial contraction and diastolic function in patients with hypertension (n=163), and varying degrees of diastolic dysfunction. Left ventricular systolic pressure was estimated by carotid tonometry; time-resolved left ventricular cavity and wall volume were obtained by echocardiography with speckle wall tracking.

Forward and Backward Pressure Waveform Morphology in Hypertension.

We tested the hypothesis that increased pulse wave reflection and altered backward waveform morphology contribute to increased pulse pressure in subjects with higher pulse pressure compared with lower pulse pressure and to actions of vasoactive drugs to increase pulse pressure. We examined the relationship of backward to forward wave morphology in 158 subjects who were evaluated for hypertension (including some normotensive subjects) divided into 3 groups by central pulse pressure: group 1, 33±6.5 mm Hg; group 2, 45±4.

On the impact of modelling assumptions in multi-scale, subject-specific models of aortic haemodynamics.

Simulation of haemodynamics has become increasingly popular within the research community. Irrespective of the modelling approach (zero-dimensional (0D), one-dimensional (1D) or three-dimensional (3D)), in vivo measurements are required to personalize the arterial geometry, material properties and boundary conditions of the computational model. Limitations in in vivo data acquisition often result in insufficient information to determine all model parameters and, hence, arbitrary modelling assumptions.

Microbubbles shunting via a patent foramen ovale impair endothelial function.

Objectives: Exposure to intravascular microbubbles after diving and during medical procedures alters endothelial function. The aim of this study was to investigate whether a patent foramen ovale altered forearm endothelial function by facilitating microbubbles transfer.

Design: Patients attended on two separate visits, at least seven days apart receiving agitated saline or no active intervention in random order.

Noninvasive calculation of the aortic blood pressure waveform from the flow velocity waveform: a proof of concept.

Estimation of aortic and left ventricular (LV) pressure usually requires measurements that are difficult to acquire during the imaging required to obtain concurrent LV dimensions essential for determination of LV mechanical properties. We describe a novel method for deriving aortic pressure from the aortic flow velocity. The target pressure waveform is divided into an early systolic upstroke, determined by the water hammer equation, and a diastolic decay equal to that in the peripheral arterial tree, interposed by a late systolic portion described by a second-order polynomial constrained by conditions of continuity and conservation of mean arterial pressure.

Future Treatment of Hypertension: Shifting the Focus from Blood Pressure Lowering to Arterial Stiffness Modulation?

Isolated systolic hypertension is the commonest form of hypertension from middle age onwards. Achieving target systolic blood pressure (BP) control remains difficult in everyday clinical practice and even under clinical trial conditions. Most antihypertensive medicines were designed to lower peripheral vascular resistance, which was considered the haemodynamic determinant of hypertension; most are effective in reducing steady but not pulsatile components of BP.

Impaired neuronal nitric oxide synthase-mediated vasodilator responses to mental stress in essential hypertension.

Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.

Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures.

Background: Inorganic nitrite dilates small resistance arterioles via hypoxia-facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries.

Dominance of the forward compression wave in determining pulsatile components of blood pressure: similarities between inotropic stimulation and essential hypertension.

Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.

Augmentation pressure is influenced by ventricular contractility/relaxation dynamics: novel mechanism of reduction of pulse pressure by nitrates.

Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively.

Regulation of vascular tone and pulse wave velocity in human muscular conduit arteries: selective effects of nitric oxide donors to dilate muscular arteries relative to resistance vessels.

Arterial tone in muscular conduit arteries may influence pressure wave reflection through changes in diameter and pulse wave velocity. We examined the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, nitroglycerine and nitroprusside, and brain natriuretic peptide were compared with the α-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil, and hydralazine.

Flow-mediated dilation of the radial artery is offset by flow-induced reduction in transmural pressure.

Flow-mediated dilation of the brachial or radial artery in response to transient hyperaemic flow, the most widely used test of endothelial function, is only manifest after flow decays back to baseline. We examined whether this dissociation of flow and diameter might be explained by a reduction in transmural pressure generated by high flow. Studies were performed in healthy subjects 20 to 55 years of age.

Modernising morning report: innovation in teaching and learning.

Background: Over recent years there has been a shift in undergraduate medical education, from predominantly passive, didactic teaching methods to facilitating learning by focusing on the management of common scenarios, through the means of problem- and case-based learning.

Context: Case-based learning and peer-led teaching are often overlooked at postgraduate level, despite the continuing demonstrated success of these methods in fostering independent reasoning and problem-solving skills that are vital for newly qualified doctors to develop. When trying to strike a balance between educational needs and service provision, it is essential to identify and implement efficient, effective approaches to optimise learning opportunities.