Functional Assessment of Stroke-Induced Regulation of miR-20a-3p and Its Role as a Neuroprotectant.

MicroRNAs have gained popularity as a potential treatment for many diseases, including stroke. This study identifies and characterizes a specific member of the miR-17-92 cluster, miR-20a-3p, as a possible stroke therapeutic. A comprehensive microRNA screening showed that miR-20a-3p was significantly upregulated in astrocytes of adult female rats, which typically have better stroke outcomes, while it was profoundly downregulated in astrocytes of middle-aged females and adult and middle-aged males, groups that typically have more severe stroke outcomes. Assays using primary human astrocytes and neurons show that miR-20a-3p treatment alters mitochondrial dynamics in both cell types. To assess whether stroke outcomes could be improved by elevating astrocytic miR-20a-3p, we created a tetracycline (Tet)-induced recombinant adeno-associated virus (rAAV) construct where miR-20a-3p was located downstream a glial fibrillary acidic protein promoter. Treatment with doxycycline induced miR-20-3p expression in astrocytes, reducing mortality and modestly improving sensory motor behavior. A second Tet-induced rAAV construct was created in which miR-20a-3p was located downstream of a neuron-specific enolase (NSE) promoter. These experiments demonstrate that neuronal expression of miR-20a-3p is vastly more neuroprotective than astrocytic expression, with animals receiving the miR-20a-3p vector showing reduced infarction and sensory motor improvement. Intravenous injections, which are a therapeutically tractable treatment route, with miR-20a-3p mimic 4 h after middle cerebral artery occlusion (MCAo) significantly improved stroke outcomes including infarct volume and sensory motor performance. Improvement was not observed when miR-20a-3p was given immediately or 24 h after MCAo, identifying a unique delayed therapeutic window. Overall, this study identifies a novel neuroprotective microRNA and characterizes several key pathways by which it can improve stroke outcomes.

The relationship between energy expenditure and physical functions in patients hospitalised for stroke.

We assessed the relationship between energy expenditure (EE) and Functional Independence Measure motor items (FIM-M) score, Berg Balance Scale (BBS) score, and comfortable walking speed (CWS) in patients hospitalised for stroke. The total EE per day (TEE), EE during rehabilitation (REE), and EE during activities other than rehabilitation (OEE) were measured using a single-axis acceleration sensor in 36 patients hospitalised for the first stroke episode. In addition, the relationships between each type of EE and FIM-M, BBS, and CWS were investigated. In these patients (mean age 66.2 ± 10.6 years), the median values of TEE, REE, and OEE were 41.8 kcal, 18.5 kcal, and 16.6 kcal, respectively. Correlations were observed between each EE type and all physical function indices. Following the stratification of patients into two groups (high and low) based on the level of physical function, a significant correlation between EE type and physical function was observed only in the low BBS group. EE was correlated with overall physical function indices, but the trend differed depending on physical ability. When patients were stratified based on ability, there were several groups with no significant correlation. Therefore, several patients were unable to achieve an appropriate EE for their level of physical function.

Benefit-Risk Tradeoffs in Assessment of New Drugs and Devices.

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit-risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit-risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit-Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit-risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit-risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions.

Oxygen Cost During Walking in Individuals With Stroke: Hemiparesis Versus Cerebellar Ataxia.

Background. Understanding the factors that limit mobility in stroke patients is fundamental for proposing appropriate rehabilitation strategies. A high oxygen cost during walking (Cw) has a strong impact on the community ambulation of hemiparetic patients. The Cw in poststroke cerebellar ataxia is poorly evaluated, unlike hemiparetic gait. Objective. To compare the oxygen cost/self-selected walking speed (S) relationship in stroke individuals with cerebellar ataxia or hemiparetic gait. Methods. Thirty-three subjects were included (14 cerebellar stroke, 19 hemispheric stroke), with stroke confirmed by brain imaging and able to walk without human assistance. We measured Cw using the Metamax3B. The relationship between Cw and self-selected walking speed was modelled by logistic regression and then compared between the cerebellar and hemispheric groups. Results. No significant difference was found between the 2 groups for all characteristics of the population, except motor impairments, spasticity, and ataxia (P < .01). We identified 2 separate Cw/S relationships with different logistic regression equations for the 2 groups. Faster than 0.4 m s-1, Cw was 30.6% to 39.9% higher in patients with cerebellar stroke in comparison with hemispheric stroke individuals. The Cw was correlated with ataxia (r = 0.88; P < .001) in the cerebellar group, whereas there was a correlation with motor impairments (r = -0.61; P < .01), spasticity (r = 0.59; P < .01), and ataxia (r = 0.81; P < .01) in hemispheric stroke individuals. Conclusion. The Cw in poststroke cerebellar ataxia is significantly higher compared with hemiparetic patients at an equivalent walking speed. The impact on community walking needs to be explored in stroke survivors with cerebellar stroke.

Reproducibility of Different Methodologies to Calculate Oxygen Consumption and Oxygen Cost During Walking in Chronic Stroke Survivors.

OBJECTIVE: The most common methods to calculate energy costs are based on measured oxygen uptake during walking a standardized distance or time. Unfortunately, it is unclear which method is most reliable to determine energy cost of walking in stroke survivors. The objective of this study was to evaluate the 3 most commonly used methods for calculating oxygen consumption and -cost by assessing test-retest reliability and measurement error in community dwelling chronic stroke survivors during a 6 Minute Walk Test. METHODS: In this secondary analysis of a longitudinal study, reproducibility of the outcome of walking distance, walking speed, oxygen consumption and oxygen cost from 3 methods (Kendall's tau, assumed steady-state and total walking time oxygen consumption) were determined using Intraclass Correlation Coefficient, Standard Error of Measurement and Smallest Detectable Change. RESULTS: 20 from the 31 participants successfully performed the 6 minute walk test-retest within a timeframe of 1 month. Within the 2 tests the reproducibility of walking distance and walking speed was high. The 3 methods to determine reproducibility for oxygen cost and oxygen consumption were considered good (Kendall's tau), good (assumed steady-state) and excellent (total walking time). CONCLUSIONS: The method using oxygen consumption and -cost over the total walking time resulted in the highest reproducibility considering the Intraclass Correlation Coefficient, its 95% Confidence Interval, and smaller absolute differences.

Energy consumption and cost during walking with different modalities of assistance after stroke: a systematic review and meta-analysis.

Purpose: To estimate pooled rates of gross and net energy consumption (ml/kg/min and J/kg/min) and energy cost (ml/kg/m and J/kg/m) during level surface walking with different assistance modalities post-stroke.Materials and Methods: Four databases were searched using keywords related to stroke, walking, and energy requirements. Three independent reviewers screened 3296 records and included 42 studies in quantitative analysis.Results: Pooled rates without significant important heterogeneity were identified for: gross energy consumption during unassisted overground walking at comfortable walking speed (10.55 ml/kg/min; 95% CI [9.93-11.16]), gross energy consumption during treadmill walking with rigid exoskeleton assistance (7.08 ml/kg/min; 95% CI [6.52-7.65]), gross energy cost during unassisted overground walking in patients with chronic stroke (0.24 ml/kg/m; 95% CI [0.28-0.48]), gross energy cost during unassisted treadmill walking in patients with subacute stroke (0.45 ml/kg/m; 95% CI 0.45-0.45]), and net energy cost during overground walking with assistive devices and orthoses in patients with chronic stroke (4.12 J/kg/m, 95% CI [3.55-4.69]).Conclusions: Walking, unassisted and with the use of assistive devices and lower limb orthoses, induces low- to moderate-intensity exercise as recommended by exercise guidelines for stroke survivors. Future studies should explore whether bodyweight-supported or robot-assisted walking can also reach moderate-intensity.Implications for RehabilitationTo induce sufficient cardiorespiratory stress during gait rehabilitation (i.e., moderate-intensity), therapists should train ambulatory patients with stroke without any assistance or if needed with the help of assistive devices or lower limb orthoses.For severely impaired patients who cannot walk independently, therapists could use bodyweight support systems, exoskeletons, or end-effectors to induce low-intensity aerobic exercise.

Return to Employment After Stroke in Young Adults: How Important Is the Speed and Energy Cost of Walking?

Background and Purpose- A quarter of individuals who experience a stroke are under the age of 65 years (defined as young adults), and up to 44% will be unable to return to work poststroke, predominantly because of walking difficulties. No research study has comprehensively analyzed walking performance in young adult's poststroke. The primary aim of this study is to investigate how a stroke in young adults affects walking performance (eg, walking speed and metabolic cost) compared with healthy age-matched controls. The secondary aim is to determine the predictive ability of walking performance parameters for return to employment poststroke. Methods- Forty-six individuals (18-40 years: n=6, 41-54 years: n=21, 55-65 years: n=19) who have had a stroke and 15 healthy age-matched able-bodied controls were recruited from 6 hospital sites in Wales, United Kingdom. Type, location, cause of stroke, and demographic factors (eg, employment status) were recorded. Temporal and spatial walking parameters were measured using 3-dimensional gait analysis. Metabolic energy expenditure and metabolic cost of walking were captured during 3 minutes of walking at self-selected speed from measurements of oxygen consumption. Results- Stroke participants walked slower (P<0.004) and less efficiently (P<0.002) than the controls. Only 23% of stroke participants returned to employment poststroke. Walking speed was the strongest predictor (sensitivity, 0.90; specificity, 0.82) for return to work (P=0.004) with a threshold of 0.93 m/s identified: individuals able to walk faster than 0.93 m/s were significantly more likely to return to work poststroke than those who walked slower than this threshold. Conclusions- This study is the first to capture walking performance parameters of young adults who have had a stroke and identifies slower and less efficient walking. Walking speed emerged as the strongest predictor for return to employment. It is recommended that walking speed be used as a simple but sensitive clinical indicator of functional performance to guide rehabilitation and inform readiness for return to work poststroke.

Homeostasis model assessment of insulin resistance and outcome of ischemic stroke in non-diabetic patients - a prospective observational study.

BACKGROUND: Insulin resistance (IR) in relation to diabetes is a risk factor for ischemic stroke (IS), whereas less is known about non-diabetic IR and outcome after IS. METHODS: In non-diabetic IS (n = 441) and controls (n = 560) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), IR was investigated in relation to IS severity and functional outcome. IR was evaluated acutely and after 3 months using the Homeostasis model assessment of IR (HOMA-IR). Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS). Functional outcome was evaluated using the modified Rankin Scale (mRS) after 3 months, 2 and 7 years. Associations were evaluated by logistic regression. RESULTS: Higher acute and 3-month HOMA-IR was observed in IS compared to the controls (both p < 0.001) and in severe compared to mild IS (both p < 0.05). High acute HOMA-IR was associated with poor outcome (mRS 3-6) after 3 months and 7 years [crude Odds ratios (ORs), 95% confidence intervals (CIs) 1.50, 1.07-2.11 and 1.59, 1.11-2.30, respectively], but not after 2 years. These associations lost significance after adjustment for all covariates including initial stroke severity. In the largest IS subtype (cryptogenic stroke), acute HOMA-IR was associated with poor outcome after 2 years also after adjustment for age and stroke severity (OR 2.86, 95% CI 1.01-8.12). CONCLUSIONS: In non-diabetic IS patients, HOMA-IR was elevated and related to stroke severity, but after adjustment for IS severity, the associations between HOMR-IR and poor outcome lost significance. This could suggest that elevated IR mostly is a part of the acute IS morbidity. However, in the subgroup of cryptogenic stroke, the associations with poor outcome withstood correction for stroke severity.

Test-retest reliability of the Mini Nutritional Assessment and its relationship with quality of life in patients with stroke.

BACKGROUND & OBJECTIVE: Malnutrition is one of commonly issues in patients with stroke. The Mini Nutritional Assessment (MNA) is a widely used measure for assessing nutritional status in patients with stroke. A nutritional measure with acceptable test-retest reliability allows clinicians to consistently assess patients' nutritional status. Knowledge of the relationship between nutritional status and quality of life (QOL) could guide clinicians to improve QOL in patients with stroke more effectively. This study aimed to examine test-retest reliability of the MNA and its relationship with QOL in patients with stroke. METHODS: Fifty-nine patients participated in the test-retest reliability study and the correlation between the MNA and WHO Quality of Life-BREF (WHOQOL-BREF) study. A repeated-assessments design (1 week apart) was used to examine the test-retest reliability of the MNA. RESULTS: The intraclass correlation coefficient for the MNA was 0.91. The minimal detectable change and percentage of minimal detectable change for the MNA were 2.1 and 8.2%, respectively. The MNA was positively associated with the QOL (r = 0.32; p = 0.013). The result of linear regression analysis shows that after controlling for age, sex and activities of daily living functions, only the MNA was significantly associated with the WHOQOL-BREF (r2 = 0.104; p = 0.008). CONCLUSIONS: The MNA has satisfactory test-retest reliability that is useful for repeatedly assessing the nutritional status of patients with stroke. The MDC of the MNA has acceptable random measurement error which is useful for determining whether the change score of a patient is outside the range of random measurement error. Future studies that recruit stroke patients in the acute stage is needed to further examine the relationship between the nutritional status and QOL.

MRI Assessment of Oxygen Metabolism and Hemodynamic Status in Symptomatic Intracranial Atherosclerotic Stenosis: A Pilot Study.

BACKGROUND AND PURPOSE: Hemodynamic and metabolic impairment in intracranial atherosclerotic stenosis (ICAS) may promote stroke vulnerability particularly in borderzone areas. Perfusion and oxygen mapping magnetic resonance imaging (MRI) may provide useful information in this setting. METHODS: In this pilot study, patients with symptomatic atherosclerotic anterior circulation stenosis ≥60%, without other sources of ischemic stroke, were included. High-resolution vessel wall MRI quantified the stenosis degree, and hemodynamic and metabolic impairment was assessed at baseline using dynamic susceptibility contrast perfusion and multiparametric quantitative blood-oxygen-level-dependent (mqBOLD) oxygenation MRI. All parameters were assessed within both hemispheres and in borderzone areas. RESULTS: Forty-three subjects with intracranial artery narrowing were screened from November 2014 to January 2016. Eleven patients met the study criteria (mean ± standard deviation age = 64.4 ± 10.6 years, the mean degree of stenosis was 76.9 ± 23.4%). No interhemispheric differences were observed across oxygen (cerebral metabolic rate of oxygen and tissular saturation of oxygen) or perfusion (mean transit time, time to maximum, Tmax , normalized cerebral blood volume [nCBV], and normalized cerebral blood flow) parameters. A positive correlation was observed between the stenosis degree and ipsilateral nCBV (R = .77, P = .008). In addition, a significant increase in CBV was observed in anterior cortical borderzones ipsilateral to stenosis (nCBV = 7.20 ± 1.81 vs. 5.45 ± 1.40 mL/100 g, P = .02). CONCLUSION: Symptomatic ICAS had no global impact on perfusion and oxygen mapping MRI at resting state. A significant increase in nCBV was found within anterior borderzone areas.

Compendium of Physical Activities Strongly Underestimates the Oxygen Cost During Activities of Daily Living in Stroke Patients.

OBJECTIVE: The aim of the study was to measure the metabolic equivalent task when performing physical activities of daily living in poststroke individuals. DESIGN: Poststroke individuals who were able to walk without human assistance were recruited and asked to perform the following activities of daily living: washing dishes (activity code: 05041 in Ainsworth's compendium), walking at a slow pace of less than 2 mph (activity code: 17151), climbing stairs (activity code: 17133), and walking down stairs (activity code: 17070). The metabolic equivalent task was measured along these activities using a portable breath gas exchange analyzer. The measured values were then compared with Ainsworth's compendium. RESULTS: Thirty-five participants were included (mean [SD] age = 64.3 [14.3] yrs). The mean (SD) resting metabolic rate was 3.08 (0.79) ml O2 kg(-1) min(-1). The metabolic equivalent task values were significantly higher than the compendium values: metabolic equivalent task washing dishes = 2.57 (0.96) versus 1.80 for compendium; metabolic equivalent task walking = 4.16 (0.93) versus 2.00 for compendium; metabolic equivalent task climbing stairs = 5.90 (1.43) versus 4.00 for compendium; metabolic equivalent task walking down stairs = 3.29 (0.48) versus 3.50 for compendium. CONCLUSIONS: The metabolic equivalent tasks during activities were higher than Ainsworth's compendium. Stroke individuals are thus exposed to high oxygen requirements when performing activities of daily living, which could have a strong impact on their ability to perform these activities in real life.

MiR-34a and stroke: Assessment of non-modifiable biological risk factors in cerebral ischemia.

Aging of the nervous system, and the occurrence of age-related brain diseases such as stroke, are associated with changes to a variety of cellular processes controlled by many distinct genes. MicroRNAs (miRNAs), short non-coding functional RNAs that can induce translational repression or site-specific cleavage of numerous target mRNAs, have recently emerged as important regulators of cellular senescence, aging, and the response to neurological insult. Here, we focused on the assessment of the role of miR-34a in stroke. We noted increases in miR-34a expression in the blood of stroke patients as well as in blood and brain of mice subjected to experimental stroke. Our methodical genetic manipulation of miR-34a expression substantially impacted stroke-associated preclinical outcomes and we have in vitro evidence that these changes may be driven at least in part by disruptions to blood brain barrier integrity and mitochondrial oxidative phosphorylation in endothelial cells. Finally, aging, independent of brain injury, appears to be associated with shifts in circulating miRNA profiles. Taken together, these data support a role for miRNAs, and specifically miR-34a, in brain aging and the physiological response to age-related neurological insult, and lay the groundwork for future investigation of this novel therapeutic target.

[A comparative assessment of indicators of platelet aggregation and interleukins in patients with different outcomes of ischemic stroke]. / Sravnitel'naia otsenka pokazatelei agregatsii trombotsitov i interleikinov u bol'nykh s razlichnym iskhodom ishemicheskogo insul'ta.

AIM: To compare indicators of platelet aggregation (PA) and the level of interleukins IL-1ß, IL-4, IL-6, IL-18 in patients with ischemic stroke (IS). MATERIAL AND METHODS: A prospective clinical cohort study involved 108 IS patients classified into group 1 (survivors) and group 2 (fatal outcomes). The studies were conducted in the most acute and acute phases of IS. The level of interleukins was measured by enzyme immunoassay method. PA was evaluated by the nephelometric method. RESULTS AND CONCLUSION: PA, IL-1ß and IL-6 indicators in the most acute phase of IS were significantly higher in the 2nd group compared to the 1st group. In the 1st group, there was a reduction in the levels of IL-1ß and IL-6, and an increase in the level of IL-4 in the acute phase compared to the most acute period of IS, whereas patients of the 2nd group showed further increase in IL-1ß and IL-6, and reduction of IL-4 levels. In surviving acute IS patients, the reduction in PA and the level of pro-inflammatory interleukins IL-1b, IL-6 and IL-18, and the increase in the level of anti-inflammatory interleukin IL-4 were accompanied with improvements in the clinical condition, whereas the negative dynamics of the aforementioned indicators was recorded in deceased patients.

Montreal Cognitive Assessment score correlates with regional cerebral blood flow in post-stroke patients.

OBJECTIVE: Valid and reliable measures are needed to assess post-stroke cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been considered a superior screening test to the Mini-Mental State Examination (MMSE) for patients with post-stroke cognitive impairment, particularly in executive function, which may be related to reduction in regional cerebral blood flow (rCBF). In this study, we determined whether MoCA and MMSE scores correlate with rCBF assessed with SPECT in the subacute phase after ischemic stroke. PATIENTS AND METHODS: We retrospectively enrolled 28 patients who were admitted to the Red Cross Otsu Hospital with acute cerebral infarction, which was confirmed by magnetic resonance imaging (MRI), if they underwent cognitive assessment (MoCA/MMSE) and 123I-IMP SPECT imaging within 3 weeks post-stroke during a study period of 5 months. Correlation analyses between rCBF and MoCA or MMSE scores were performed by statistical parametric mapping (SPM) and volume-of-interest (VOI) analyses. RESULTS: Total MoCA score correlated with the rCBF in the prefrontal cortex, cingulate cortex, caudate nucleus and thalamus by SPM analysis (uncorrected p < 0.001; cluster-level corrected p < 0.05). Among the subtest scores of MoCA, visuoexecutive function, attention, language and delayed recall scores were positively correlated with rCBF in the prefrontal cortex by VOI analysis (p < 0.05). However, total MMSE score did not correlate significantly with any of the rCBF measures. CONCLUSIONS: Post-stroke cognitive performance assessed with MoCA positively correlated with rCBF in brain regions mainly comprising the prefrontal-subcortical circuits. The findings of this hypothesis-generating study support the notion that MoCA is useful for assessing post-stroke cognitive status.

The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study.

BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort. METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping. RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores. CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

Homeostasis model assessment of insulin resistance in relation to the poor functional outcomes in nondiabetic patients with ischemic stroke.

Whether insulin resistance (IR) predicts worse functional outcome in ischemic stroke is still a matter of debate. The aim of the present study is to determine the association between IR and risk of poor outcome in 173 Chinese nondiabetic patients with acute ischemic stroke. This is a prospective, population-based cohort study. Insulin sensitivity, expressed by the homeostasis model assessment (HOMA) of insulin sensitivity (HOMA index = (fasting insulin × fasting glucose)/22.5). IR was defined by HOMA-IR index in the top quartile (Q4). Functional impairment was evaluated at discharge using the modified Rankin scale (mRS). The median (interquartile range) HOMA-IR was 2.14 (1.17-2.83), and Q4 was at least 2.83. There was a significantly positive correlation between HOMA-IR and National Institutes of Health Stroke Scale (r = 0.408; P<0.001). In multivariate analyses, patients in IR group were associated with a higher risk of poor functional outcome (odds ratio (OR) = 3.23; 95% confidence interval (CI) = 1.75-5.08; P=0.001). In multivariate models comparing the third and fourth quartiles against the first quartile of the HOMA-IR, levels of HOMA-IR were associated with poor outcome, and the adjusted risk of poor outcome increased by 207% (OR = 3.05 (95% CI 1.70-4.89), P=0.006) and 429% (5.29 (3.05-9.80), P<0.001). In a receiver operating characteristic curve (ROC) analysis of poor outcome, the area under the curve (AUC) increased from 0.80 to 0.84 (95% CI: 0.79-0.88) by adding HOMA-IR to clinical examination variables (P=0.02). High HOMA-IR index is associated with a poor functional outcome in nondiabetic patients with acute ischemic stroke.

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.

BACKGROUND: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics. METHODS: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death. RESULTS: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk. CONCLUSIONS: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.

The Energy Cost of Steady State Physical Activity in Acute Stroke.

OBJECTIVE: Cardiorespiratory fitness levels are very low after stroke, indicating that the majority of stroke survivors are unable to independently perform daily activities. Physical fitness training improves exercise capacity poststroke; however, the optimal timing and intensity of training is unclear. Understanding the energy cost of steady-state activity is necessary to guide training prescription early poststroke. We aimed to determine if acute stroke survivors can reach steady state (oxygen-uptake variability ≤2.0 mL O2/kg/min) during physical activity and if the energy cost of steady state activity differs from healthy controls. MATERIAL AND METHODS: We recruited 23 stroke survivors less than 2 weeks poststroke. Thirteen were able to walk independently and performed a 6-minute walk (median age 78 years, interquartile range [IQR] 70-85), and 7 who were unable to walk independently performed 6 minutes of continuous sit-to-stands (median age 78 years, IQR 74-79) and we recruited 10 healthy controls (median age 73 years, IQR 70-77) who performed both 6 minutes of walking and sit-to-stands. Our primary outcome was energy cost (oxygen-uptake) during steady state activity (i.e., walking and continuous) sit-to-stands, measured by a mobile metabolic cart. RESULTS: All stroke survivors were able to reach steady state. Energy costs of walking was higher in stroke than in controls (mean difference .10 mL O2/kg/m, P = .02); the difference in energy costs during sit-to-stands was not significant (mean difference .11 mL O2/kg/sts, P = .45). CONCLUSIONS: Acute stroke survivors can reach a steady state during activity, indicating they are able to perform cardiorespiratory exercise. Acute stroke survivors require more energy per meter walked than controls.

Can energy expenditure be accurately assessed using accelerometry-based wearable motion detectors for physical activity monitoring in post-stroke patients in the subacute phase?

Background In the subacute stroke phase, the monitoring of ambulatory activity and activities of daily life with wearable sensors may have relevant clinical applications. Do current commercially available wearable activity trackers allow us to objectively assess the energy expenditure of these activities? The objective of the present study was to compare the energy expenditure evaluated by indirect calorimetry during the course of a scenario consisting of everyday activities while estimating the energy expenditure using several commercialised wearable sensors in post-stroke patients (less than six months since stroke). Method Twenty-four patients (age 68.2 ± 13.9; post-stroke delay 34 ± 25 days) voluntarily participated in this study. Each patient underwent a scenario of various everyday tasks (transfer, walking, etc.). During the implementation, patients wore 14 wearable sensors (Armband, Actigraph GT3X, Actical, pedometer) to obtain an estimate of the energy expenditure. The actual energy expenditure was concurrently determined by indirect calorimetry. Results Except for the Armband worn on the non-plegic side, the results of our study show a significant difference between the energy expenditure values estimated by the various sensors and the actual energy expenditure when the scenario is considered as a whole. Conclusion The present results suggest that, for a series of everyday tasks, the wearable sensors underestimate the actual energy expenditure values in post-stroke patients in the subacute phase and are therefore not accurate. Several factors are likely to confound the results: types of activity, prediction equations, the position of the sensor and the hemiplegia side.

Personalized Analysis by Validation of Monte Carlo for Application of Pathways in Cardioembolic Stroke.

BACKGROUND Cardioembolic stroke (CES), which causes 20% cause of all ischemic strokes, is associated with high mortality. Previous studies suggest that pathways play a critical role in the identification and pathogenesis of diseases. We aimed to develop an integrated approach that is able to construct individual networks of pathway cross-talk to quantify differences between patients with CES and controls. MATERIAL AND METHODS One biological data set E-GEOD-58294 was used, including 23 normal controls and 59 CES samples. We used individualized pathway aberrance score (iPAS) to assess pathway statistics of 589 Ingenuity Pathways Analysis (IPA) pathways. Random Forest (RF) classification was implemented to calculate the AUC of every network. These procedures were tested by Monte Carlo Cross-Validation for 50 bootstraps. RESULTS A total of 28 networks with AUC >0.9 were found between CES and controls. Among them, 3 networks with AUC=1.0 had the best performance for classification in 50 bootstraps. The 3 pathway networks were able to significantly identify CES versus controls, which showed as biomarkers in the regulation and development of CES. CONCLUSIONS This novel approach could identify 3 networks able to accurately classify CES and normal samples in individuals. This integrated application needs to be validated in other diseases.