Heterogenous treatment effects: secrets for a reliable treat-to-target trial?

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Pulsations as a Driver for LBV Variability

Among the most spectacular variable stars are the Luminous Blue Variables (LBVs), which can show three types of variability. The LBV phase of evolution is poorly understood, and the driving mechanisms for the variability are not known. The most common type of variability, the S Dor instability, occurs on timescales of tens of years. During an S Dor outburst, the visual magnitude of the star increases, while the bolometric magnitude stays approximately constant. In this work, we investigate pulsation as a possible trigger for the S Dor type outbursts. We calculate the pulsations of envelope models using a nonlinear hydrodynamics code including a time-dependent convection treatment. We initialize the pulsation in the hydrodynamic model based on linear non-adiabatic calculations. Pulsation properties for a full grid of models from 20 to 85 M$_{\odot}$ were calculated, and in this paper we focus on the few models that show either long-period pulsations or outburst-like behaviour, with photospheric radial velocities reaching 70-80 km/s. At the present time, our models cannot follow mass loss, so once the outburst event begins, our simulations are terminated. Our results show that pulsations alone are not able to drive enough surface expansion to eject the outer layers. However, the outbursts and long-period pulsations discussed here produce large variations in effective temperature and luminosity, which are expected to produce large variations in the radiatively driven mass-loss rates.Comment: 9 pages, 10 figures, accepted for publication in MNRA

Perivascular adipose tissue inflammation in vascular disease

Perivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. In vascular pathologies, perivascular adipose tissue increases in volume and becomes dysfunctional, with altered cellular composition and molecular characteristics. PVAT dysfunction is characterized by its inflammatory character, oxidative stress, diminished production of vaso-protective adipocyte-derived relaxing factors and increased production of paracrine factors such as resistin, leptin, cytokines (IL-6 and TNF-α) and chemokines [RANTES (CCL5) and MCP-1 (CCL2)]. These adipocyte-derived factors initiate and orchestrate inflammatory cell infiltration including primarily T cells, macrophages, dendritic cells, B cells and NK cells. Protective factors such as adiponectin can reduce NADPH oxidase superoxide production and increase NO bioavailability in the vessel wall, while inflammation (e.g. IFN-γ or IL-17) induces vascular oxidases and eNOS dysfunction in the endothelium, vascular smooth muscle cells and adventitial fibroblasts. All of these events link the dysfunctional perivascular fat to vascular dysfunction. These mechanisms are important in the context of a number of cardiovascular disorders including atherosclerosis, hypertension, diabetes and obesity. Inflammatory changes in PVAT's molecular and cellular responses are uniquely different from classical visceral or subcutaneous adipose tissue or from adventitia, emphasizing the unique structural and functional features of this adipose tissue compartment. Therefore, it is essential to develop techniques for monitoring the characteristics of PVAT and assessing its inflammation. This will lead to a better understanding of the early stages of vascular pathologies and the development of new therapeutic strategies focusing on perivascular adipose tissue

Epigenetics and immunometabolism in diabetes and aging

Significance: A strong relationship between hyperglycemia, impaired insulin pathway and cardiovascular disease in type 2 diabetes (T2D) is linked to oxidative stress and inflammation. Immunometabolic pathways link these pathogenic processes and pose important potential therapeutic targets. Recent Advances: The link between immunity and metabolism is bi-directional and includes the role of inflammation in the pathogenesis of metabolic disorders such as T2D, obesity, metabolic syndrome and hypertension as well as the role of metabolic factors in regulation of immune cell functions. Low-grade inflammation, oxidative stress, balance between superoxide and nitric oxide, and the infiltration of macrophages, T cells, B cells in insulin-sensitive tissues, leads to metabolic impairment and accelerated ageing. Critical Issues: Inflammatory infiltrate and altered immune cell phenotype precede development of metabolic disorders. Inflammatory changes are tightly linked to alterations in metabolic status and energy expenditure and are controlled by epigenetic mechanisms. Future directions: A better comprehension of these mechanistic insights is of utmost importance to identify novel molecular targets. Here, we describe a complex scenario of epigenetic changes and immunometabolism linking to diabetes and aging-associated vascular disease

Epigenetics and immunometabolism in diabetes and aging

Significance: A strong relationship between hyperglycemia, impaired insulin pathway, and cardiovascular disease in type 2 diabetes (T2D) is linked to oxidative stress and inflammation. Immunometabolic pathways link these pathogenic processes and pose important potential therapeutic targets. Recent Advances: The link between immunity and metabolism is bidirectional and includes the role of inflammation in the pathogenesis of metabolic disorders such as T2D, obesity, metabolic syndrome, and hypertension and the role of metabolic factors in regulation of immune cell functions. Low-grade inflammation, oxidative stress, balance between superoxide and nitric oxide, and the infiltration of macrophages, T cells, and B cells in insulin-sensitive tissues lead to metabolic impairment and accelerated aging. Critical Issues: Inflammatory infiltrate and altered immune cell phenotype precede development of metabolic disorders. Inflammatory changes are tightly linked to alterations in metabolic status and energy expenditure and are controlled by epigenetic mechanisms. Future Directions: A better comprehension of these mechanistic insights is of utmost importance to identify novel molecular targets. In this study, we describe a complex scenario of epigenetic changes and immunometabolism linking to diabetes and aging-associated vascular disease. © Tomasz J

Unexpected series of regular frequency spacing of delta Scuti stars in the non-asymptotic regime -- I. The methodology

A sequence search method was developed to search regular frequency spacing in delta Scuti stars by visual inspection and algorithmic search. We searched for sequences of quasi-equally spaced frequencies, containing at least four members per sequence, in 90 delta Scuti stars observed by CoRoT. We found an unexpectedly large number of independent series of regular frequency spacing in 77 delta Scuti stars (from 1 to 8 sequences) in the non-asymptotic regime. We introduce the sequence search method presenting the sequences and echelle diagram of CoRoT 102675756 and the structure of the algorithmic search. Four sequences (echelle ridges) were found in the 5-21 d^{-1} region, where the pairs of the sequences are shifted (between 0.5-0.59 d^{-1}) by twice the value of the estimated rotational splitting frequency (0.269 d^{-1}). The general conclusions for the whole sample are also presented in this paper. The statistics of the spacings derived by the sequence search method, by FT and that of the shifts are also compared. In many stars, more than one almost equally valid spacing appeared. The model frequencies of FG Vir and their rotationally split components were used to reveal a possible explanation that one spacing is the large separation, while the other is a sum of the large separation and the rotational frequency. In CoRoT 102675756, the two spacings (2.249 and 1.977 d^{-1}) agree better with the sum of a possible 1.710 d^{-1} large separation and two or one times, respectively, the value of the rotational frequency.Comment: 12 pages, 10 figures, accepted for publication in Ap

Endothelial function assessment in atherosclerosis: Comparison of brachial artery flow‑mediated vasodilation and peripheral arterial tonometry

INTRODUCTION Endothelial dysfunction, characterized by the loss of nitric oxide bioavailability, is a key element in the pathogenesis of atherosclerosis and an important prognostic factor in cardiovascular diseases. Therefore, the development of reliable, safe, and noninvasive methods of endothelial function assessment is important for their use in cardiovascular risk stratification. Brachial artery flow‑mediated dilation (FMD) is widely used in research but technical difficulties and problems with calibration between laboratories limit its clinical use. Reactive hyperemia–peripheral artery tonometry (RH‑PAT, EndoPAT) has been developed as a simpler, cheaper, and potentially more reproducible method. OBJECTIVES We aimed to investigate associations between RH‑PAT and FMD in relation to atherosclerotic risk factor profile. PATIENTS AND METHODS The study involved 80 subjects (52 men, 28 women) aged 43.6 ±14.8 years, with moderate‑to‑low cardiovascular risk (mean SCORE, 2.2% ±2%), in whom FMD, RH‑PAT, and intima–media thickness (IMT) were determined. RESULTS The reactive hyperemia index (RHI) measured by RH‑PAT correlated with FMD (r = 0.35, P <0.01). However, no significant correlation was observed between RHI and IMT, SCORE, or the number of classical atherosclerotic risk factors (hypertension, smoking, diabetes, hypercholesterolemia), while FMD was significantly correlated with IMT (r = –0.53, P <0.001), risk factors (r = –0.55, P <0.05), and SCORE (r = –0.4, P <0.05). CONCLUSIONS Despite its technical requirements, FMD is a more sensitive method than RH‑PAT in evaluating the effect of classical atherosclerotic risk factors on vascular endothelial function. Microvasculature response during RH‑PAT needs to be further studied, including the assessment of nonendothelial factors that may affect the measurements, before RH‑PAT becomes the universal tool for the evaluation of the endothelial cells