Dependency Structures in Differentially Coded Cardiovascular Time Series

Objectives. This paper analyses temporal dependency in the time series recorded from aging rats, the healthy ones and those with early developed hypertension. The aim is to explore effects of age and hypertension on mutual sample relationship along the time axis. Methods. A copula method is applied to raw and to differentially coded signals. The latter ones were additionally binary encoded for a joint conditional entropy application. The signals were recorded from freely moving male Wistar rats and from spontaneous hypertensive rats, aged 3 months and 12 months. Results. The highest level of comonotonic behavior of pulse interval with respect to systolic blood pressure is observed at time lags τ=0, 3, and 4, while a strong counter-monotonic behavior occurs at time lags τ=1 and 2. Conclusion. Dynamic range of aging rats is considerably reduced in hypertensive groups. Conditional entropy of systolic blood pressure signal, compared to unconditional, shows an increased level of discrepancy, except for a time lag 1, where the equality is preserved in spite of the memory of differential coder. The antiparallel streams play an important role at single beat time lag

Copula as a dynamic measure of cardiovascular signal interactions

Objectives: Copula is a tool for measuring linear and non-linear interactions between two or more time series. The aim of this paper is to prove that a copula approach can accurately capture and visualize the spatial and temporal fluctuations in dependency structures of cardiovascular signals, and to outline the application possibilities. Methods: The method for measuring the level of interaction between systolic blood pressure and the corresponding pulse interval is validated statistically and pharmacologically. The time series are recorded from the freely moving male Wistar rats equipped with radio-telemetry device for blood pressure recording, before and after administration of autonomic blockers scopolamine, atenolol, prazosin and hexamethonium. Implicit (Gaussian and t) and explicit (Clayton, Frank and Gumbel) copulas were calculated and compared to the conventional bivariate methods (Kendal, Pearson, Spearman and classical correlation). Further statistical validation was done using artificially generated surrogate data. A window sliding procedure for dynamic monitoring the signals' coupling strength is implemented. Results: Under the baseline physiological conditions, SBP-PI dependency is significant for time lags 0 s-4 s. Hexamethonium completely abolished the dependency, scopolamine abolished it for time lags 0 s-2 s, atenolol first slightly increased, than for lags greater than 2 s decreased the dependency and prazosin had no effect. Isospectral and isodistributional surrogate data tests confirm that copulas successfully notify the absence of dependency as well. Conclusion: Copula approach accurately captures the temporal fluctuations in dependency structures of SBP and PI, simultaneously enabling a visualization of dependency levels within the particular signal zones. An analysis showed that copulas are more sensitive than the conventional statistical measures, with Frank copula exhibiting the best characterization of SBP and PI dependency

Voronoi Decomposition of Cardiovascular Dependency Structures in Different Ambient Conditions: An Entropy Study

This paper proposes a method that maps the coupling strength of an arbitrary number of signals D, D >= 2, into a single time series. It is motivated by the inability of multiscale entropy to jointly analyze more than two signals. The coupling strength is determined using the copula density defined over a [0 1](D) copula domain. The copula domain is decomposed into the Voronoi regions, with volumes inversely proportional to the dependency level (coupling strength) of the observed joint signals. A stream of dependency levels, ordered in time, creates a new time series that shows the fluctuation of the signals' coupling strength along the time axis. The composite multiscale entropy (CMSE) is then applied to three signals, systolic blood pressure (SBP), pulse interval (PI), and body temperature (t(B)), simultaneously recorded from rats exposed to different ambient temperatures (t(A)). The obtained results are consistent with the results from the classical studies, and the method itself offers more levels of freedom than the classical analysis

On entropy of probability integral transformed time series

Abstract The goal of this paper is to investigate the changes of entropy estimates when the amplitude distribution of the time series is equalized using the probability integral transformation. The data we analyzed were with known properties—pseudo-random signals with known distributions, mutually coupled using statistical or deterministic methods that include generators of statistically dependent distributions, linear and non-linear transforms, and deterministic chaos. The signal pairs were coupled using a correlation coefficient ranging from zero to one. The dependence of the signal samples is achieved by moving average filter and non-linear equations. The applied coupling methods are checked using statistical tests for correlation. The changes in signal regularity are checked by a multifractal spectrum. The probability integral transformation is then applied to cardiovascular time series—systolic blood pressure and pulse interval—acquired from the laboratory animals and represented the results of entropy estimations. We derived an expression for the reference value of entropy in the probability integral transformed signals. We also experimentally evaluated the reliability of entropy estimates concerning the matching probabilities

Estimating demand pressures arising from need for social services for older people

The twelve years preceding the introduction of the community care reforms in 1993/4 saw an increased demand for health and social services generated by the increase in numbers of older people (particularly the over 85s) and reflected in the rapid growth of residential and nursing home places over a twelve year period (from 224,000 in 1983 to 427,000 in 1994). While the move into the residential and nursing home sector was partly driven by the perverse incentives offered by social security in the early 1980s, it may also have reflected a real increase in the levels of dependency experienced by older people coming into contact with the services during the period. This has fuelled concern about rising costs. However, there are competing forecasts of how big a burden the costs of care will be. One of the difficulties is in determining how far the burden will fall on statutory services or formal services (provided by either the statutory or independent sectors) and how far the pool of informal carers will be large enough to maintain the level of care which it provides currently. The Institute of Actuaries published an influential paper in 1993 (Nuttall et al, 1993) suggesting that the current cost of informal caring based on a rate of £7 per hour could be estimated at £33.9 billion. The House of Commons Health Committee (1996) took evidence during 1995 and 1996 and concluded that the gloomiest forecasts were unfounded and that radical action was not needed in the immediate future. Nevertheless, whatever the predictions for the medium and long term, concerns have been raised with regard to current capacities to meet demand. The community care changes resulting from the Act were funded by a transfer, Special Transitional Grant (STG), to the local authorities with which to meet their new responsibilities. There has been a continuing debate as to whether the STG and the SSA allocations have been sufficient to enable them to do this. The Association of Directors of Social Services and the Association of Metropolitan Authorities (now subsumed into the Association of Local Government) have repeatedly called for a review of the current funding of community care saying they are unable to meet the full needs of dependent people (Community Care, 1996, 1997a).elderly, social services

The Relationship Between Resilience, Attachment, and Emotional Coping Styles

The construct of resilience has been widely associated with the ability to adequately cope with stressors, which leads to positive long-term health outcomes. Attachment and emotional coping style literatures have both been tentatively linked to resilience, with dismissive and secure attachment styles as well as the repressive coping style positively associated with resilience. However, both avoidantly attached and repressive individuals employ coping strategies that allow them to dissociate from negative emotions, which seems to contradict the stress adaptive quality of resilience. The goal of this study was to explore the theoretical parallel between the attachment and emotional coping styles literature as well as to examine the mediating effect of emotional coping in the relationship between attachment and resilience. A convenience sample of 266 participants (110 men; 156 women) completed online questionnaires regarding attachment, trait anxiety, defensiveness, and resilience. It was expected that attachment behaviors would theoretically coincide with the dimensional characteristics underlying emotional coping styles (defensiveness and trait anxiety) as well as uniquely predict odds of belonging to categories of emotional coping styles; attachment avoidance and anxiety would differentially predict resilience; and emotional coping style dimensions would mediate the relations between attachment behaviors and resilience. Results of regression and path analyses revealed that attachment avoidance was negatively associated with defensiveness and attachment anxiety positively predicted trait anxiety. Both attachment anxiety and avoidance negatively predicted resilience. Exploratory analyses revealed that defensiveness positively predicted resilience whereas trait anxiety negatively predicted resilience. Trait anxiety mediated the relationship between attachment anxiety and resilience. Results suggest that repressive and avoidant individuals display similar coping strategies, but possess unique motivations for employing these strategies. The findings call into question the efficacy of relying on the construct of resilience as an indicator of well-being and it is suggested that health providers implement a physiological stress assessment in conjunction with traditional measures of resilience and well-being

A genome-wide, single-cell analysis of vascular smooth muscle cell plasticity

Vascular smooth muscle cells (VSMCs) possess a remarkable capacity to change phenotype in response to injury or inflammation. In healthy arteries, VSMCs exist in a contractile state, but upon vascular inflammation or injury, they can switch into an activated state, in which they downregulate the contractile differentiation markers and show increased migration, proliferation and secretion of proinflammatory cytokines. This process is termed phenotypic switching and can lead to VSMC accumulation within atherosclerotic plaques. Previous observations of clonal expansion of a small number of VSMCs in atherosclerosis suggested that VSMCs were functionally heterogeneous. I hypothesised that functional heterogeneity of VSMCs in disease may originate from VSMC heterogeneity in healthy arteries. In the first part of this thesis I explored the regional heterogeneity of VSMCs originating from different parts of the mouse aorta, as well as heterogeneity of VSMCs within a vascular bed using single-cell and bulk RNA sequencing. VSMCs originating from the atherosclerosis-prone aortic arch and atherosclerosis-resistant descending thoracic aorta were found to have distinct transcriptional signatures at the single-cell level. Additionally, several disease-relevant genes were observed to be heterogeneously expressed within both vascular beds. In the second chapter I identified and characterised a rare subset of VSMCs expressing Stem cell antigen 1 (SCA1). Single-cell RNA-seq was combined with VSMC-specific lineage tracing to profile gene expression in individual VSMCs from healthy mouse arteries and to compare SCA1-expressing VSMCs to other cells. SCA1-positive VSMCs were heterogeneous, with many of them expressing low levels of contractile VSMC markers. Additionally, a subset of SCA1-positive VSMCs in healthy arteries expressed transcriptional signatures characteristic of activated VSMCs involved in phenotypic switching. In the third chapter I investigated the involvement of SCA1-positive VSMCs in phenotypic switching. SCA1 upregulation was found to mark the process of VSMC phenotypic switching following in vitro culture and in vivo vascular injury. Single-cell RNA-seq profiling of VSMCs in atherosclerosis and following vascular injury showed that Ly6a/Sca1-expressing VSMCs were present and expressed transcriptional signatures similar to activated SCA1-positive cells observed in healthy arteries. Overall the results presented in this thesis highlight the heterogeneous nature of VSMCs in healthy arteries, both regionally and within a vascular bed. I identified a rare subset of SCA1-positive VSMCs with activated transcriptional signatures in healthy arteries. I hypothesised that SCA1-positive VSMCs may be responsible for clonal expansion of VSMCs in atherosclerosis, which would have clinical implications for earlier detection and specific targeting of expanding VSMCs in atherosclerosis in the future. In support of this hypothesis I have shown that Ly6a/Sca1 is upregulated in model systems of VSMC phenotypic switching and that transcriptional signatures of Ly6a/Sca1-expressing VSMCs in mouse atherosclerosis and vascular injury resemble those of healthy activated SCA1-positive VSMCs.BBSRC DTP studentshi

From Mouse Models to Patients: A Comparative Bioinformatic Analysis of HFpEF and HFrEF

Heart failure (HF) represents an immense health burden with currently no curative therapeutic strategies. Study of HF patient heterogeneity has led to the recognition of HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) as distinct syndromes regarding molecular characteristics and clinical presentation. Until the recent past, HFrEF represented the focus of research, reflected in the development of a number of therapeutic strategies. However, the pathophysiological concepts applicable to HFrEF may not be necessarily applicable to HFpEF. HF induces a series of ventricular modeling processes that involve, among others, hallmarks of hypertrophy, fibrosis, inflammation, all of which can be observed to some extent in HFpEF and HFrEF. Thus, by direct comparative analysis between HFpEF and HFrEF, distinctive features can be uncovered, possibly leading to improved pathophysiological understanding and opportunities for therapeutic intervention. Moreover, recent advances in biotechnologies, animal models, and digital infrastructure have enabled large-scale collection of molecular and clinical data, making it possible to conduct a bioinformatic comparative analysis of HFpEF and HFrEF. Here, I first evaluated the field of HF transcriptome research by revisiting published studies and data sets to provide a consensus gene expression reference. I discussed the patient clientele that was captured, revealing that HFpEF patients were not represented. Thus, I applied alternative approaches to study HFpEF. I utilized a mouse surrogate model of HFpEF and analyzed single cell transcriptomics to gain insights into the interstitial tissue remodeling. I contrasted this analysis by comparison of fibroblast activation patterns found in mouse models resembling HFrEF. The human reference was used to further demonstrate similarities between models and patients and a novel possible biomarker for HFpEF was introduced. Mouse models only capture selected aspects of HFpEF but largely fail to imitate the complex multi-factor and multi-organ syndrome present in humans. To account for this complexity, I performed a top-down analysis in HF patients by analyzing phenome-wide comorbidity patterns. I derived clinical insights by contrasting HFpEF and HFrEF patients and their comorbidity profiles. These profiles were then used to predict associated genetic profiles, which could be also recovered in the HFpEF mouse model, providing hypotheses about the molecular links of comorbidity profiles. My work provided novel insights into HFpEF and HFrEF syndromes and exemplified an interdisciplinary bioinformatic approach for a comparative analysis of both syndromes using different data modalities

Older workers' work limitations, vitality and retirement preferences:the differential effects of chronic health conditions

In the last decades, governments across the western world are increasing retirement ages and suspending early work exit routes to sustain their labour force. Resultantly, older workers are working longer than they previously expected. Because the prevalence of chronic health conditions increases with age, older workers may also be combatting many health- and work-related challenges posed by chronic health conditions. In this dissertation, I investigate the heterogeneities in how chronic health conditions affect older workers’ vitality, health-related work limitations and subjective life expectancy, and how these effects drive older workers’ preferences to retire early. Additionally, I study the role of the organization in sustainably supporting older workers with chronic health conditions. The findings demonstrate that chronic health conditions differ widely in how they affect older workers’ health, work and retirement preferences. These effects differ by the type of chronic health condition and whether the chronic health condition was newly diagnosed. The findings also suggest that a psychologically safe organizational climate and flexible working times could promote the healthy ageing of older workers with chronic health conditions at work. Moreover, the results shows that retirement improves the vitality of older workers, more so for manual workers than non-manual workers. Taken together, experiencing chronic health conditions in the years before retirement is detrimental to older workers health, work and functioning. Because future cohorts of older workers will work longer, it is important to develop effective strategies to protect and promote the health and work ability of older workers with chronic health conditions