Inflammatory cytokines, high-sensitivity C-reactive protein, and risk of one-year vascular events, death, and poor functional outcome after stroke and transient ischemic attack.

BACKGROUND: Inflammation driven by pro-inflammatory cytokines is a new therapeutic target in coronary disease. Few data exist on the association of key upstream cytokines and post-stroke recurrence. In a prospective cohort study, we investigated the association between pivotal cytokines, high-sensitivity C-reactive protein (hsCRP) and one-year outcomes. METHODS: BIO-STROKETIA is a multi-center prospective cohort study of non-severe ischemic stroke (modified Rankin score ≤ 3) and transient ischemic attack. Controls were patients with transient symptoms attending transient ischemic attack clinics with non-ischemic final diagnosis. Exclusion criteria were severe stroke, infection, and other pro-inflammatory disease; hsCRP and cytokines (interleukin (IL) 6, IL-1ß, IL-8, IL-10, IL-12, interferon-γ (IFN-γ), tumor-necrosis factor-α (TNF-α)) were measured. The primary outcome was one-year recurrent stroke/coronary events (fatal and non-fatal). RESULTS: In this study, 680 patients (439 stroke, 241 transient ischemic attack) and 68 controls were included. IL-6, IL-1ß, IL-8, IFN-γ, TNF-α, and hsCRP were higher in stroke/transient ischemic attack cases (p ≤ 0.01 for all). On multivariable Cox regression, IL-6, IL-8, and hsCRP independently predicted one-year recurrent vascular events (adjusted hazard ratios (aHR) per-quartile increase IL-6 1.31, confidence interval (CI) 1.02-1.68, p = 0.03; IL-8 1.47, CI 1.15-1.89, p = 0.002; hsCRP 1.28, CI 1.01-1.62, p = 0.04). IL-6 (aHR 1.98, CI 1.26-3.14, p = 0.003) and hsCRP (aHR 1.81, CI 1.20-2.74, p = 0.005) independently predicted one-year fatality. IL-6 and hsCRP (adjusted odds ratio per-unit increase 1.02, CI 1.01-1.04) predicted poor functional outcome, with a trend for IL-1ß (p = 0.054). CONCLUSION: Baseline inflammatory cytokines independently predicted late recurrence, supporting a rationale for randomized trials of anti-inflammatory agents for prevention after stroke and suggesting that targeted therapy to high-risk patients with high baseline inflammation may be beneficial.

Interleukin-6, C-reactive protein, fibrinogen, and risk of recurrence after ischaemic stroke: Systematic review and meta-analysis.

BACKGROUND: Recent randomised trials showed benefit for anti-inflammatory therapies in coronary disease but excluded stroke. The prognostic value of blood inflammatory markers after stroke is uncertain and guidelines do not recommend their routine measurement for risk stratification. METHODS: We performed a systematic review and meta-analysis of studies investigating the association of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen and risk of recurrent stroke or major vascular events (MVEs). We searched EMBASE and Ovid Medline until 10/1/19. Random-effects meta-analysis was performed for studies reporting comparable effect measures. RESULTS: Of 2,515 reports identified, 39 met eligibility criteria (IL-6, n = 10; CRP, n = 33; fibrinogen, n = 16). An association with recurrent stroke was reported in 12/26 studies (CRP), 2/11 (fibrinogen) and 3/6 (IL-6). On random-effects meta-analysis of comparable studies, CRP was associated with an increased risk of recurrent stroke [pooled hazard ratio (HR) per 1 standard-deviation (SD) increase in loge-CRP (1.14, 95% CI 1.06-1.22, p < 0.01)] and MVEs (pooled HR 1.21, CI 1.10-1.34, p < 0.01). Fibrinogen was also associated with recurrent stroke (HR 1.26, CI 1.07-1.47, p < 0.01) and MVEs (HR 1.31, 95% CI 1.15-1.49, p < 0.01). Trends were identified for IL-6 for recurrent stroke (HR per 1-SD increase 1.17, CI 0.97-1.41, p = 0.10) and MVEs (HR 1.22, CI 0.96-1.55, p = 0.10). CONCLUSION: Despite evidence suggesting an association between inflammatory markers and post-stroke vascular recurrence, substantial methodological heterogeneity was apparent between studies. Individual-patient pooled analysis and standardisation of methods are needed to determine the prognostic role of blood inflammatory markers and to improve patient selection for randomised trials of inflammatory therapies.

Creation and application of virtual patient cohorts of heart models.

Patient-specific cardiac models are now being used to guide therapies. The increased use of patient-specific cardiac simulations in clinical care will give rise to the development of virtual cohorts of cardiac models. These cohorts will allow cardiac simulations to capture and quantify inter-patient variability. However, the development of virtual cohorts of cardiac models will require the transformation of cardiac modelling from small numbers of bespoke models to robust and rapid workflows that can create large numbers of models. In this review, we describe the state of the art in virtual cohorts of cardiac models, the process of creating virtual cohorts of cardiac models, and how to generate the individual cohort member models, followed by a discussion of the potential and future applications of virtual cohorts of cardiac models. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Predicting left ventricular contractile function via Gaussian process emulation in aortic-banded rats.

Cardiac contraction is the result of integrated cellular, tissue and organ function. Biophysical in silico cardiac models offer a systematic approach for studying these multi-scale interactions. The computational cost of such models is high, due to their multi-parametric and nonlinear nature. This has so far made it difficult to perform model fitting and prevented global sensitivity analysis (GSA) studies. We propose a machine learning approach based on Gaussian process emulation of model simulations using probabilistic surrogate models, which enables model parameter inference via a Bayesian history matching (HM) technique and GSA on whole-organ mechanics. This framework is applied to model healthy and aortic-banded hypertensive rats, a commonly used animal model of heart failure disease. The obtained probabilistic surrogate models accurately predicted the left ventricular pump function (R2 = 0.92 for ejection fraction). The HM technique allowed us to fit both the control and diseased virtual bi-ventricular rat heart models to magnetic resonance imaging and literature data, with model outputs from the constrained parameter space falling within 2 SD of the respective experimental values. The GSA identified Troponin C and cross-bridge kinetics as key parameters in determining both systolic and diastolic ventricular function. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Interaction of Broadband Access and Education Levels in Determining the Rate of Emergency Medical Admissions.

Background We examined the effect of broadband access, educational status and their interaction on local population health. Methods We calculated the annual admission incidence rates for each small area population unit within our hospital catchment, relating quintiles of broadband access to two groups a) full time education to primary level (less than or equal to 15 years) and b) full time education to tertiary level (>18 years). Univariate and multivariable risk estimates were calculated, using truncated Poisson regression. Results 82,368 admissions in 44,628 patients were included. Broadband access was a linear predictor of the admission incidence rate with decreases from Q1 (least access) 50.8 (95%CI 30.2 to 71.4) to Q5 (highest access) 17.9 (95%CI 13.4 to 22.4). Areas with greater numbers educated only to primary level were more influenced by broadband access. Conclusion Broadband access is a predictor of the emergency medical admission rate; this effect is modulated by the baseline education level.

Influence of social deprivation, overcrowding and family structure on emergency medical admission rates.

BACKGROUND: Patients from deprived backgrounds have a higher in-patient mortality following emergency medical admission. AIM: To evaluate the influence of Deprivation Index, overcrowding and family structure on hospital admission rates. DESIGN: Retrospective cohort study. METHODS: All emergency medical admissions from 2002 to 2013 were evaluated. Based on address, each patient was allocated to an electoral division, whose small area population statistics were available from census data. Patients were categorized by quintile of Deprivation Index, overcrowding and family structure, and these were evaluated against hospital admission rate, calculated as rate/1000 population. Univariate and multivariable risk estimates (Odds Ratios or Incidence Rate Ratios) were calculated, using logistic or zero truncated Poisson regression as appropriate. RESULTS: There were 66 861 admissions in 36 214 patients over the 12-year study period. Deprivation Index quintile independently predicted the admission rate, with rates of Q1 12.0 (95% CI 11.8-12.2), Q2 19.5 (95% CI 19.3-19.6), Q3 33.7 (95% CI 33.3-34.0), Q4 31.4 (95% CI 31.2-31.6) and Q5 38.1 (95% CI 37.7-38.5). Similarly the proportions of families with children <15 years old, was an independent predictor of the admission rate with rates of Q1 20.8 (95% CI 20.4-21.1), Q2 23.0 (95% CI 22.7-23.3), Q3 32.2 (95% CI 31.9-32.5), Q4 32.4 (95% CI 32.2-32.7) and Q5 37.2 (95% CI 36.6-37.8). The proportion of families with children ≥15-years old was also predictive but quintile of overcrowding was only predictive in the univarate model. CONCLUSION: Deprivation Index and family structure strongly predict emergency medical hospital admission rates.

Social deprivation and the rate of emergency medical admission for older persons.

BACKGROUND: Deprivation Status increases the annual admission incidence of emergency medical admissions; the extent to which deprivation influences the admission of older persons is less well known. AIM: To examine whether deprivation within a hospital catchment area influences emergency medical admissions for the elderly population. DESIGN: The relationship between Deprivation Status, Dependency Ratio (population proportion of non-working age (<15 or ≥65 years) and age for all emergency admissions (82 368 episodes of 44 628 patients), over a 13-year period, were examined and ranked by quintile. METHODS: Univariate and multi-variable risk estimates (incidence rate ratios) were calculated, using truncated Poisson regression. RESULTS: The Dependency Ratio and the Deprivation index independently predicted the annual incidence rate of medical emergencies; however, when calculated for older persons, the corresponding incidence rate ratios showed a falling trend with increasing Deprivation Status-Q2 0.51 (95% confidence interval [CI]: 0.50, 0.52), Q3 0.59 (95% CI: 0.58, 0.60), Q4 0.51 (95% CI: 0.50, 0.52) and Q5 0.37 (95% CI: 0.36, 0.38). Thus, with increasing Deprivation Status, the proportion of total admission from the ≥65-year cohort fell substantially. CONCLUSION: The admission incidence rate for emergency medical patients is strongly influenced by the catchment area Deprivation Status. However, because of its greater impact on the younger population, increasing deprivation alters the ratio of younger to older persons as a proportion of total emergency admissions.

Components of the Risk Instrument for Screening in the Community (RISC) that Correlate with Public Health Nurses' Perception of Risk.

BACKGROUND: Functional decline and frailty are common in community-dwelling older adults, leading to an increased risk of adverse outcomes. OBJECTIVE: To examine the factors that public health nurses perceive to cause risk of three adverse outcomes: institutionalisation, hospitalisation, and death, in older adults, using the Risk Instrument for Screening in the Community (RISC). DESIGN: A quantitative, correlational, descriptive design was used. SETTING AND PARTICIPANTS: A sample of 803 community-dwellers, aged over 65 years receiving regular follow-up by public health nurses. Procedure and Measurements: Public health nurses (n=15) scored the RISC and the Clinical Frailty Scale (CFS) on patients in their caseload. We examined and compared correlations between the severity of concern and ability of the caregiver network to manage these concerns with public health nurses' perception of risk of the three defined adverse outcomes. RESULTS: In total, 782 RISC scores were available. Concern was higher for the medical state domain (686/782,88%) compared with the mental state (306/782,39%) and activities of daily living (595/782,76%) domains. Concern was rated as severe for only a small percentage of patients. Perceived risk of institutionalisation had the strongest correlation with concern over patients mental state,(r=0.53), while risk of hospitalisation,(r=0.53) and death,(r=0.40) correlated most strongly with concern over the medical state. Weaker correlations were found for the other domains and RISC scores. The CFS most strongly correlated with the ADL domain,(r=0.78). CONCLUSION: Although the prevalence of concern was high, it was mostly rated as mild. Perceived risk of institutionalisation correlated most with concern over the ability of caregiver networks to manage patients' mental state, while risk of hospitalisation and death correlated with patients' medical state. The findings suggest the importance of including an assessment of the caregiver network when examining community-dwelling older adults. Validation of the RISC and public health nurses' ratings are now required.

Deprivation as an outcome determinant in emergency medical admissions.

BACKGROUND: Deprivation in the general population predicts mortality. We have investigated its relevance to an acute medical admission, using a database of all emergency admissions to St James' Hospital, Dublin, over a 10-year period (2002-11). METHODS: All emergency admissions, based on geocoding of residence, were allocated to a Small Area Health Research Unit division, with a corresponding deprivation index. We then examined this index as a univariate (unadjusted) and independent (adjusted) predictor of 30-day in-hospital mortality. RESULTS: The 30-day in-hospital mortality, over the 10-year period, was higher for those in the upper half of the deprivation distribution (9.6 vs. 8.6%; P = 0.002). Indeed, there was a stepwise increase in 30-day mortality over the quintiles of deprivation from 7.3% (Quintile 1) to 8.8, 10.0, 10.0 and 9.3%, respectively. Univariate logistic regression of the deprivation indices (quintiles) against outcome showed an increased risk (P = 0.002) of a 30-day death with odds ratios (ORs), respectively (compared with lowest deprivation quintile) of 1.39 [95% confidence intervals (CI) 1.21, 1.58], 1.47 (95% CI 1.29, 1.68), 1.44 (95% CI 1.26, 1.64) and 1.39 (95% CI 1.22, 1.59). The deprivation index was an independent predictor of outcome in a model when adjusted for illness severity and co-morbidity. The fully adjusted OR for a 30-day death was increased by 31% (P = 0.001) for patients in the upper half of the deprivation index distribution (OR 1.35; 95% CI 1.23, 1.48; P < 0.001). CONCLUSION: Deprivation, independent of co-morbidity or acute illness severity, is an independent predictor of 30-day mortality in acute medical admissions.

Increased resting metabolic rate and lipid oxidation in exercise-trained individuals: evidence for a role of beta-adrenergic stimulation.

This study investigated the contribution of beta-adrenergic stimulation to the increase in resting metabolic rate (RMR) and lipid oxidation observed in exercise-trained individuals. Nine trained and eight sedentary men were subjected to two testing sessions, during which these variables were measured before and for 3 h after the oral administration of propranolol or placebo. As expected, RMR and lipid oxidation were significantly higher in the trained subjects before the administration of propranolol and throughout the placebo test in comparison with sedentary controls. A significant decrease in RMR and lipid oxidation was induced by propranolol in the trained subjects, whereas no change was observed in the untrained group, and this effect of propranolol was sufficient to abolish the difference between the two groups at baseline and under the placebo condition. Propranolol also induced a significant reduction in heart rate and systolic blood pressure, but the response was comparable in the two groups. In conclusion, the results of this study show that beta-adrenergic stimulation is involved in the increase in RMR and lipid oxidation observed in highly trained individuals. Moreover, the absence of a training-propranolol interaction effect on heart rate and systolic blood pressure suggests the existence of some dissociation between the metabolic and cardiovascular effects of prolonged exercise training.

Counterregulatory response to insulin-induced hypoglycemia in trained and nontrained humans.

The aim of the present series of experiments was to investigate the hormonal counterregulatory response to insulin-induced hypoglycemia in trained and nontrained healthy individuals. Five endurance athletes and six controls were administered intravenous insulin infusion at a rate of 0.15 U/kg/h until plasma glucose reached 50 mg/dL. The mean duration of the infusion in the trained and nontrained subjects corresponded to 18.6 and 26.3 minutes (P less than .01), suggesting that the former were characterized by an increased insulin sensitivity. Plasma glucose levels were similar in the two groups at the end of the insulin infusion, as well as during the postinfusion recovery period. Forty-five minutes after the end of the infusion, plasma glucose levels were not significantly different from the preinfusion levels in the two groups. During this period of glycemia recovery, the increases in plasma glucagon, epinephrine, norepinephrine, and growth hormone were at least 50% lower in the trained than in the nontrained subjects. The increase in heart rate and oxygen uptake during the same period of time was significantly higher in the trained subjects. To determine whether this reduced hormonal response to hypoglycemia was due to reduced insulin levels or to an increased sensitivity to counterregulatory hormones, we investigated the effect of epinephrine on plasma glucose in two other groups of trained and nontrained subjects. In response to a constant epinephrine infusion of 0.01 or 0.1 micrograms/kg fat-free mass (FFM)/min, plasma glucose levels increased similarly in the two groups. In conclusion, these results indicate that trained subjects are characterized by a normal recovery from hypoglycemia despite a reduced response of counterregulatory factors.(ABSTRACT TRUNCATED AT 250 WORDS)