Whole-blood transcriptome analysis reveals distinct gene expression signatures in paediatric patients with sickle cell anaemia before and after exercise.

Sickle cell anaemia (SCA) patients display elevated levels of circulating pro-inflammatory cytokines and endothelial activation markers compared to healthy peers. The impact of exercise on the pro-inflammatory state in SCA remains unclear. This study aimed to characterize the whole-blood transcriptome profile in response to an acute bout of exercise in paediatric SCA patients. Twenty-three SCA participants (13 ± 3 years, 52% girls) and 17 healthy controls (14 ± 3 years, 29% girls) performed eight 2-min bouts of cycle ergometry interspersed with 1-min rest intervals. Whole-blood transcriptome profile (RNA-seq) was performed before and after exercise. At baseline, gene pathways associated with gas transport in erythrocytes were up-regulated in SCA patients compared to controls. Following exercise, gene pathways associated with innate immunity were altered in both groups. Interaction analyses revealed 160 annotated genes (101 up- and 59 down-regulated) that differentially altered by exercise in SCA patients. Moreover, genes that exhibited a blunted response to exercise in SCA patients were enriched in the IL-17 signalling pathway, suggesting an impaired innate immune response to exercise. This data will contribute to the development of evidence-based exercise prescription guidelines for this patient population.

Exercise Training Attenuates the Muscle Mitochondria Genomic Response to Bed Rest.

PURPOSE: Exercise training during the National Aeronautics and Space Administration (NASA) 70-day bed rest study effectively counteracted the decline in aerobic capacity, muscle mass, strength, and endurance. We aimed to characterize the genomic response of the participants' vastus lateralis (VL) on day 64 of bed rest with and without exercise countermeasures. METHODS: Twenty-two healthy young males were randomized into three groups: 1) bed rest only (n = 7), 2) bed rest + aerobic (6 d/wk) and resistance training (3 d/wk) on standard equipment (n = 7), and 3) bed rest + aerobic and resistance training using a flywheel device (n = 8). The VL gene and microRNA microarrays were analyzed using GeneSpring GX 14.9.1. RESULTS: Bed rest significantly altered the expression of 2113 annotated genes in at least one out of the three study groups (fold change (FC) > 1.2; P < 0.05). Interaction analysis revealed that exercise attenuated the bed rest effect of 511 annotated genes (FC 1.2, P < 0.05). In the bed rest only group, a predominant downregulation of genes was observed while in the two exercise groups there was a notable attenuation or reversal of this effect, with no significant differences between the two exercise modalities. Enrichment analysis identified functional categories and gene pathways, many of them related to the mitochondria. Additionally, bed rest significantly altered the expression of 35 microRNAs (FC > 1.2, P < 0.05) with no difference between the three groups. Twelve are known to regulate some of the mitochondrial-related genes that were altered following bed rest. CONCLUSIONS: Mitochondrial gene expression was a significant component of the molecular response to long-term bed rest. While exercise attenuated the FC in the downregulation of many genes, it did not completely counteract all the molecular consequences.

Effects of exercise on whole-blood transcriptome profile in children with overweight/obesity.

BACKGROUND: The current knowledge about the molecular mechanisms underlying the health benefits of exercise is still limited, especially in childhood. We set out to investigate the effects of a 20-week exercise intervention on whole-blood transcriptome profile (RNA-seq) in children with overweight/obesity. METHODS: Twenty-four children (10.21 ± 1.33 years, 46% girls) with overweight/obesity, were randomized to either a 20-week exercise program (intervention group; n = 10), or to a no-exercise control group (n = 14). Whole-blood transcriptome profile was analyzed using RNA-seq by STRT technique with GlobinLock technology. RESULTS: Following the 20-week exercise intervention program, 161 genes were differentially expressed between the exercise and the control groups among boys, and 121 genes among girls (p-value <0.05), while after multiple correction, no significant difference between exercise and control groups persisted in gene expression profiles (FDR >0.05). Genes enriched in GO processes and molecular pathways showed different immune response in boys (antigen processing and presentation, infections, and T cell receptor complex) and in girls (Fc epsilon RI signaling pathway) (FDR <0.05). CONCLUSION: These results suggest that 20-week exercise intervention program alters the molecular pathways involved in immune processes in children with overweight/obesity.

Cardiorespiratory fitness and circadian rhythms in adolescents: a pilot study.

Although cardiorespiratory fitness (CRF), an important marker of youth health, is associated with earlier sleep/wake schedule, its relationship with circadian rhythms is unclear. This study examined the associations between CRF and rhythm variables in adolescents. Eighteen healthy adolescents (10 females and 8 males; Mage = 14.6 ± 2.3 yr) completed two study visits on weekdays bracketing an ambulatory assessment during summer vacation. Visit 1 included in-laboratory CRF assessment (peak V̇o2) using a ramp-type progressive cycle ergometry protocol and gas exchange measurement, which was followed by 7-14 days of actigraphy to assess sleep/wake patterns and 24-h activity rhythms. During Visit 2, chronotype, social jetlag (i.e., the difference in midsleep time between weekdays and weekends), and phase preference were assessed using a questionnaire, and hourly saliva samples were collected to determine the dim light melatonin onset (DLMO) phase. All analyses were adjusted for sex, pubertal status, and physical activity. Greater peak V̇o2 was associated with earlier sleep/wake times and circadian phase measures, including acrophase, UP time, DOWN time, last activity peak (LAP) time, and chronotype (all P < 0.05). Peak V̇o2 was negatively associated with social jetlag (P = 0.02). In addition, the mixed-model analysis revealed a significant interaction effect between peak V̇o2 and actigraphy-estimated hour-by-hour activity patterns (P < 0.001), with the strongest effects observed at around the time of waking (0600-1000). In healthy adolescents, better CRF was associated with an earlier circadian phase and increased activity levels notably during the morning. Future studies are needed to investigate the longitudinal effects of the interactions between CRF and advanced rhythms on health outcomes.NEW & NOTEWORTHY In healthy adolescents, better cardiorespiratory fitness, as assessed by the gold standard measure [laboratory-based assessment of peak oxygen consumption (V̇o2)], was associated with earlier circadian timing of sleep/wake patterns, rest-activity rhythms and chronotype, and less social jetlag. These findings highlight the close interrelationships between fitness and rhythms and raise the possibility that maintaining higher cardiorespiratory fitness levels alongside earlier sleep/wake schedule and activity rhythms may be important behavioral intervention targets to promote health in adolescents.

Gene-exercise interaction on brain health in children with overweight/obesity: the ActiveBrains randomized controlled trial.

We investigated the interaction between a genetic score and an exercise intervention on brain health in children with overweight/obesity. One hundred one children with overweight/obesity (10.0 ± 1.5 yr, 59% girls) were randomized into a 20-wk combined exercise intervention or a control group. Several cognitive and academic outcomes were measured with validated tests. Hippocampal volume was quantified using magnetic resonance imaging. Six brain health-related polymorphisms [rs6265 (BDNF), rs2253206 (CREB1), rs2289656 (NTRK2), rs4680 (COMT), rs429358, and rs7412 (APOE)] were genotyped. Cognitive flexibility and academic skills improved significantly more in the exercise than in the control group only in the children with a "favorable" genetic profile [mean z-score, 0.41-0.67 (95% CI 0.11 to 1.18)], yet not in those with "less favorable" genetic profile. An individual response analysis showed that children responded to exercise in cognitive flexibility only in the "genetically favorable" group [i.e., 62% of them had a meaningful (≥0.2 Cohen d) increase in the exercise group compared with only 25% in the control group]. This finding was consistent in per-protocol and intention-to-treat analyses (P = 0.01 and P = 0.03, respectively). The results were not significant or not consistent for the rest of outcomes studied. Our findings suggest that having a more favorable genetic profile makes children with overweight/obesity more responsive to exercise, particularly for cognitive flexibility.NEW & NOTEWORTHY Interindividual differences have been reported in brain health-related outcomes in response to exercise interventions in adults, which could be partially explained by genetic background differences. However, the role of genetic polymorphisms on brain health-related outcomes in response to exercise interventions remains unexplored in pediatric population. The current study in children with overweight/obesity showed that a genetic score composed of six brain health-related polymorphisms (BDNF, CREB1, NTRK2, COMT, and APOE) regulated the exercise-induced response on several brain health outcomes, yet mainly and more consistently on cognitive flexibility.

Effects of physical exercise, LEGO, and Minecraft activities on anxiety in underserved children with autism: Study design and methodological strategies.

Anxiety is a common comorbidity for individuals with ASD, and there is some preliminary data about the efficacy of physical exercise to alleviate anxiety. However, we are not aware of any studies that have compared the effects of a physical exercise program on anxiety in underserved children with ASD using a randomized controlled research design. This paper describes a method to evaluate and compare the efficacy of an 8-week physical exercise intervention with a sedentary play intervention to alleviate anxiety in young children with autism spectrum disorders (ASD) from underserved backgrounds. We assessed anxiety and its physical symptoms using the parent-rated Child Behavior Checklist DSM-5 anxiety (CBCL DSM-5) subscale, the child-rated Screen for Childhood Anxiety Related Emotional Disorder (SCARED), the parent-rated Child's Sleep Habits Questionnaire (CSHQ), and salivary cortisol. We also utilized the Physical Activity Questionnaire for Older Children (PAQ-C) to assess physical activity level and identify compounds. Unique components of this study include: •Implementation of novel physical exercise and sedentary play interventions that have been designed for children with ASD.•Recruitment of predominantly underserved and non-English speaking families.

Functional Data Analysis for Predicting Pediatric Failure to Complete Ten Brief Exercise Bouts.

Physiological response to physical exercise through analysis of cardiopulmonary measurements has been shown to be predictive of a variety of diseases. Nonetheless, the clinical use of exercise testing remains limited because interpretation of test results requires experience and specialized training. Additionally, until this work no methods have identified which dynamic gas exchange or heart rate responses influence an individual's decision to start or stop physical activity. This research examines the use of advanced machine learning methods to predict completion of a test consisting of multiple exercise bouts by a group of healthy children and adolescents. All participants could complete the ten bouts at low or moderate-intensity work rates, however, when the bout work rates were high-intensity, 50% refused to begin the subsequent exercise bout before all ten bouts had been completed (task failure). We explored machine learning strategies to model the relationship between the physiological time series, the participant's anthropometric variables, and the binary outcome variable indicating whether the participant completed the test. The best performing model, a generalized spectral additive model with functional and scalar covariates, achieved 93.6% classification accuracy and an F1 score of 93.5%. Additionally, functional analysis of variance testing showed that participants in the 'failed' and 'success' groups have significantly different functional means in three signals: heart rate, oxygen uptake rate, and carbon dioxide uptake rate. Overall, these results show the capability of functional data analysis with generalized spectral additive models to identify key differences in the exercise-induced responses of participants in multiple bout exercise testing.

Heart rate and gas exchange dynamic responses to multiple brief exercise bouts (MBEB) in early- and late-pubertal boys and girls.

Natural patterns of physical activity in youth are characterized by brief periods of exercise of varying intensity interspersed with rest. To better understand systemic physiologic response mechanisms in children and adolescents, we examined five responses [heart rate (HR), respiratory rate (RR), oxygen uptake (V̇O2 ), carbon dioxide production (V̇CO2 ), and minute ventilation (V̇E), measured breath-by-breath] to multiple brief exercise bouts (MBEB). Two groups of healthy participants (early pubertal: 17 female, 20 male; late-pubertal: 23 female, 21 male) performed five consecutive 2-min bouts of constant work rate cycle-ergometer exercise interspersed with 1-min of rest during separate sessions of low- or high-intensity (~40% or 80% peak work, respectively). For each 2-min on-transient and 1-min off-transient we calculated the average value of each cardiopulmonary exercise testing (CPET) variable (Y̅). There were significant MBEB changes in 67 of 80 on- and off-transients. Y̅ increased bout-to-bout for all CPET variables, and the magnitude of increase was greater in the high-intensity exercise. We measured the metabolic cost of MBEB, scaled to work performed, for the entire 15 min and found significantly higher V̇O2 , V̇CO2 , and V̇E costs in the early-pubertal participants for both low- and high-intensity MBEB. To reduce breath-by-breath variability in estimation of CPET variable kinetics, we time-interpolated (second-by-second), superimposed, and averaged responses. Reasonable estimates of τ (<20% coefficient of variation) were found only for on-transients of HR and V̇O2 . There was a remarkable reduction in τHR following the first exercise bout in all groups. Natural patterns of physical activity shape cardiorespiratory responses in healthy children and adolescents. Protocols that measure the effect of a previous bout on the kinetics of subsequent bouts may aid in the clinical utility of CPET.

Corrigendum: Transcriptional and epigenetic response to sedentary behavior and physical activity in children and adolescents: A systematic review.

[This corrects the article DOI: 10.3389/fped.2022.917152.].

Transcriptional and Epigenetic Response to Sedentary Behavior and Physical Activity in Children and Adolescents: A Systematic Review.

Background: The links of sedentary behavior and physical activity with health outcomes in children and adolescents is well known. However, the molecular mechanisms involved are poorly understood. We aimed to synthesize the current knowledge of the association of sedentary behavior and physical activity (acute and chronic effects) with gene expression and epigenetic modifications in children and adolescents. Methods: PubMed, Web of Science, and Scopus databases were systematically searched until April 2022. A total of 15 articles were eligible for this review. The risk of bias assessment was performed using the Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews and/or a modified version of the Downs and Black checklist. Results: Thirteen studies used candidate gene approach, while only 2 studies performed high-throughput analyses. The candidate genes significantly linked to sedentary behavior or physical activity were: FOXP3, HSD11B2, IL-10, TNF-α, ADRB2, VEGF, HSP70, SOX, and GPX. Non-coding Ribonucleic acids (RNAs) regulated by sedentary behavior or physical activity were: miRNA-222, miRNA-146a, miRNA-16, miRNA-126, miR-320a, and long non-coding RNA MALAT1. These molecules are involved in inflammation, immune function, angiogenic process, and cardiovascular disease. Transcriptomics analyses detected thousands of genes that were altered following an acute bout of physical activity and are linked to gene pathways related to immune function, apoptosis, and metabolic diseases. Conclusion: The evidence found to date is rather limited. Multidisciplinary studies are essential to characterize the molecular mechanisms in response to sedentary behavior and physical activity in the pediatric population. Larger cohorts and randomized controlled trials, in combination with multi-omics analyses, may provide the necessary data to bring the field forward. Systematic Review Registration: [www.ClinicalTrials.gov], identifier [CRD42021235431].

Diffuse optical spectroscopic method for tissue and body composition assessment.

SIGNIFICANCE: Growing levels of obesity and metabolic syndrome have driven demand for more advanced forms of body composition assessment. While various techniques exist to measure body composition, devices are typically expensive and not portable, involve radiation [in the case of dual-energy x-ray absorptiometry (DXA)], and are limited to analysis of adiposity while metabolic information from blood supply and oxygenation are not considered. AIM: We evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used to predict site-specific adiposity and percent fat (whole body) while simultaneously providing information about local tissue hemoglobin levels and oxygenation. APPROACH: DOSI measures of tissue composition in gastrocnemius, quadriceps, abdomen, and biceps, DXA whole-body composition, and ultrasound-derived skin and adipose tissue thickness (SATT) in the quadriceps were obtained from 99 individuals aged 7 to 34 years old. RESULTS: Various DOSI-derived parameters were correlated with SATT and an optical method is proposed for estimating SATT using a newly defined parameter, the optical fat fraction (OFF), which considers all parameters that correlate with SATT. Broadband absorption and scattering spectra from study participants with the thinnest (SATT ≈ 0.25 ± 0.02 cm) and thickest SATT (SATT ≈ 1.55 ± 0.14 cm), representing best estimates for pure in vivo lean and fatty tissue, respectively, are reported. Finally, a trained prediction model is developed which allows DOSI assessment of OFF to predict DXA body-fat percentage, demonstrating that DOSI can be used to quantify body composition. CONCLUSIONS: This study shows that DOSI can be used to assess the adiposity of specific tissues or the entire human body, and the OFF parameter is defined for corroboration and further evaluation in future research.

Safety and effectiveness of resistance training in patients with late onset Pompe disease - a pilot study.

Pompe disease is a progressive myopathy resulting from deficiency in lysosomal enzyme acid α-glucosidase (GAA), which leads to glycogen accumulation in lysosomes primarily in skeletal and cardiac muscle. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA works well in alleviating the cardiomyopathy; however, many patients continue to have progressive muscle weakness. The purpose of this study was to evaluate the effectiveness of a respiratory training combined with 24-week supervised resistance training program on muscle strength (measured by Biodex)), and respiratory function including maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP) in subjects with late onset Pompe disease receiving ERT. Ten subjects participated in a 24-week resistance exercise program, three times per week, in addition to respiratory muscle exercise training six days per week. Overall, at the end of the resistance training program, as measured by Biodex dynamometry, the leg extensor strength improved by 10.5 ±â€¯3.2Nm. (

Pediatric Cardiopulmonary Exercise Testing: Interoperability Through Domain Analysis Modeling and a National Survey.

PURPOSE: The electronic health record, data science advances, and dynamic environmental and infectious threats to child health highlight the need for harmonized and interoperable approaches to pediatric cardiopulmonary exercise testing (CPET). Accordingly, we developed a terminology harmonization in exercise medicine and exercise science domain analysis model (THEMES DAM) to structure CPET data elements. METHODS: THEMES DAM identified 114 data elements, including participant information, calibration, equipment, protocols, laboratory personnel, encouragement strategies, and analysis procedures. We used the THEMES DAM, vetted by the international data standards organization HL7, to construct a current-state survey of pediatric CPET centers in the United States. Forty-eight of 101 centers responded to a questionnaire covering seven major topic areas (38 items). RESULTS: Centers predominantly performed between 100 and 500 tests annually. Cardiac disease represented 55% of referrals. Almost all centers calibrated gas concentrations and flow daily, but 42% never calibrated their treadmill or cycle ergometers. All centers measured V̇O2peakbut calculated differently. Centers used a variety of protocols (e.g., for treadmill: 61%, Bruce; 43%, modified Bruce; 59%, other); 44% calculated CPET slopes from submaximal portions of CPET (e.g., V̇O2-HR). All centers verbally encouraged participants, but only 40% used a standardized approach. The interpretation of CPET was done by physicians (60%), exercise physiologists (25%), exercise technicians (10%), nurses (1%), or others (4%). Ninety-one percent would agree to collaborate in multicenter research, 89% to establish dynamic reference values, and 83% to better interpret CPET. CONCLUSIONS: The survey data and the implementation of THEMES DAM could accelerate interoperability across multiple centers. This would facilitate a nimble approach to create pediatric reference values responsive to the constantly changing health environment and stimulate novel approaches to CPET research and clinical application.

Kids With Altitude: Acute Mountain Sickness and Changes in Body Mass and Total Body Water in Children Travelling to 3800 m.

INTRODUCTION: We explored the incidence of acute mountain sickness (AMS) and extravascular lung water (ELW) in children in relation to changes in body composition and peripheral blood oxygenation (SpO2) during 1 week of acclimatization to 3800 m. METHODS: In a prospective cohort study, 10 children (7 female, ages 7-14 y) and 10 sex-matched adults (ages 23-44 y) traveled via automobile from sea level to 3000 m for 2 nights, followed by 4 nights at 3800 m. Each morning, body mass and body water (bioelectrical impedance), SpO2 (pulse oximetry), AMS (Lake Louise Questionnaire), and ELW (transthoracic echocardiography) were measured. RESULTS: No differences were found between children and adults in SpO2 or ELW. At 3800 m 7 of 10 children were AMS+ vs 4 of 10 adults. Among those AMS+ at 3800 m, the severity was greater in children compared to adults (5±1 vs 3 ± 0; P=0.005). Loss of body mass occurred more quickly in children (day 5 vs day 7) and to a greater extent (-7±3% vs -2±2%; P<0.001); these changes were mediated via a larger relative loss in total body water in children than in adults (-6±5% vs -2±2%; P=0.027). CONCLUSIONS: Children demonstrated a higher incidence of AMS than adults, with greater severity among those AMS+. The loss of body water and body mass at high altitude was also greater in children, albeit unrelated to AMS severity. In addition to awareness of AMS, strategies to maintain body weight and hydration in children traveling to high altitudes should be considered.

Self-Reported Physical Activity and Asthma Risk in Children.

BACKGROUND: Increased physical activity (PA) may protect against asthma but PA can trigger asthma symptoms. OBJECTIVE: To investigate relationships between moderate-to-vigorous PA (MVPA) assessed during routine care visits and incident asthma. METHODS: For this retrospective cohort, 542,486 children between 2 and 17 years from 2010 to 2017 were included who had an MVPA assessment (exercise vital sign) during routine care visits. The association of MVPA and asthma was analyzed using Cox proportional hazards regression models as a function of age, with MVPA and body mass index (BMI) being time-varying factors, adjusted for race and ethnicity, socioeconomic status, and air pollution. RESULTS: The mean MVPA was 5.4 (standard deviation: 4.4) hours/week. Crude asthma incidence density rate (IDR) was highest in children with <1 hour/week of MVPA (IDR: 9.07, 95% confidence interval [CI]: 8.79, 9.36) and lowest in children engaging in 4 to 7 hours/week of MVPA (IDR: 6.55, 95% CI: 6.33, 6.77). In adjusted models, an increase in MVPA was associated with lower asthma risk in children reporting 0 hour/week of MVPA (hazard ratio: 0.981, 95% CI: 0.973, 0.990). In children with ≥8 hours/week of MVPA, an increase in MVPA was associated with higher asthma risk (1.005, 95% CI: 1.002, 1.009). There was no significant BMI by MVPA interaction. CONCLUSION: Increasing MVPA in children with low activity levels is associated with lower asthma risk; children reporting high levels of activity may experience greater asthma risk as their activity levels increase further. Understanding the role of PA in the development of asthma and assessing MVPA during routine care visits in children may help to develop targeted interventions and guide asthma management.

Safety of maximal cardiopulmonary exercise testing in individuals with sickle cell disease: a systematic review.

OBJECTIVE: We evaluated the safety of maximal cardiopulmonary exercise testing (CPET) in individuals with sickle cell disease (SCD). Maximal CPET using gas exchange analysis is the gold standard for measuring cardiopulmonary fitness in the laboratory, yet its safety in the SCD population is unclear. DESIGN: Systematic review. DATA SOURCES: Systematic search of Medline (PubMed), EMBASE, Cochrane, ClinicalTrials.gov and professional society websites for all published studies and abstracts through December 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Two reviewers independently extracted data of interest from studies that assessed safety outcomes of maximal CPET in children and adults with SCD. A modified version of the Newcastle-Ottawa Scale was used to assess for risk of bias in studies included. RESULTS: In total, 24 studies met inclusion/exclusion criteria. Adverse events were reported separately or as part of study results in 36 (3.8%) of 939 participants with SCD undergoing maximal CPET in studies included. Most adverse events were related to transient ischaemic changes on ECG monitoring or oxygen desaturation during testing, which did not result in arrhythmias or other complications. Only 4 (0.43%) of 939 participants experienced pain events due to maximal CPET. CONCLUSION: Maximal CPET appears to be a safe testing modality in children and adults with SCD and can be used to better understand the physiological basis of reduced exercise capacity and guide exercise prescription in this population. Some studies did not focus on reporting adverse events related to exercise testing or failed to mention safety monitoring, which contributed to risk of bias.

Clinical evaluation of a novel subcutaneous lactate monitor.

Lactate levels are commonly used as an indirect measure to assess metabolic stress in clinical conditions like sepsis. Dynamic lactate measurements are recommended to assess and guide treatment in patients with shock and other critical care conditions. A minimally invasive, continuous lactate monitor has potential to improve clinical decisions and patient care. The purpose of the study was to evaluate continuous lactate measurements of a novel enzymatic Continuous Lactate Monitor (CLM) developed in our laboratory. Lactate levels were monitored during incremental cycling exercise challenges as a tool for hyperlactatemia. Six healthy individuals 18-45 y/o (4 males, 2 females) participated in the study. CLM devices were inserted subcutaneously in the postero-lateral trunk below the renal angle, one hour before the exercise challenge. Each exercise challenge consisted of a 3 to 12-min warm up period, followed by up to 7, 4-min incremental workload bouts separated by rest intervals. Continuous lactate measurements obtained from CLM were compared with commercial lactate analyzer (Abbott iSTAT) measurements of venous blood (plasma) drawn from the antecubital vein. Blood was drawn at up to 25 time points spanning the duration of before exercise, during exercise, and up to 120 min post exercise. Area under the curve (AUC), and delay time were calculated to compare the CLM readings with plasma lactate concentration. Average plasma lactate concentration increased from 1.02 to 16.21 mM. Ratio of AUC derived from CLM to plasma lactate was 1.025 (0.990-1.058). Average dynamic delay time of CLM to venous plasma lactate was 5.22 min (2.87-10.35). Insertion sites examined 48 h after CLM removal did not show signs of side effects and none required medical attention upon examination. The newly developed CLM has shown to be a promising tool to continuously measure lactate concentration in a minimally invasive fashion. Results indicate the CLM can provide needed trends in lactate over time. Such a device may be used in the future to improve treatment in clinical conditions such as sepsis.

Genetic Factors, Brain Atrophy, and Response to Rehabilitation Therapy After Stroke.

OBJECTIVE: Patients show substantial differences in response to rehabilitation therapy after stroke. We hypothesized that specific genetic profiles might explain some of this variance and, secondarily, that genetic factors are related to cerebral atrophy post-stroke. METHODS: The phase 3 ICARE study examined response to motor rehabilitation therapies. In 216 ICARE enrollees, DNA was analyzed for presence of the BDNF val66met and the ApoE ε4 polymorphism. The relationship of polymorphism status to 12-month change in motor status (Wolf Motor Function Test, WMFT) was examined. Neuroimaging data were also evaluated (n=127). RESULTS: Subjects were 61±13 years old (mean±SD) and enrolled 43±22 days post-stroke; 19.7% were BDNF val66met carriers and 29.8% ApoE ε4 carriers. Carrier status for each polymorphism was not associated with WMFT, either at baseline or over 12 months of follow-up. Neuroimaging, acquired 5±11 days post-stroke, showed that BDNF val66met polymorphism carriers had a 1.34-greater degree of cerebral atrophy compared to non-carriers (P=.01). Post hoc analysis found that age of stroke onset was 4.6 years younger in subjects with the ApoE ε4 polymorphism (P=.02). CONCLUSION: Neither the val66met BDNF nor ApoE ε4 polymorphism explained inter-subject differences in response to rehabilitation therapy. The BDNF val66met polymorphism was associated with cerebral atrophy at baseline, echoing findings in healthy subjects, and suggesting an endophenotype. The ApoE ε4 polymorphism was associated with younger age at stroke onset, echoing findings in Alzheimer's disease and suggesting a common biology. Genetic associations provide insights useful to understanding the biology of outcomes after stroke.