Showing papers by "Glenfield Hospital published in 2014"

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Exercise based rehabilitation for heart failure

Abstract: Background People with heart failure experience marked reductions in their exercise capacity, which has detrimental effects on their activities of daily living, health-related quality of life and ultimately their hospital admission rate and mortality. Study characteristics We searched the scientific literature for randomised controlled trials (experiments in which two or more interventions, possibly including a control intervention or no intervention, are compared by being randomly allocated to participants) looking at the effectiveness of exercise-based treatments compared with no exercise on heart failure in adults over 18 years of age. The inclusion criteria of this updated review were extended to consider not only HF due to reduced ejection fraction (HFREF or 'systolic HF') (ejection fraction is a measure of how well your heart is pumping), but also HF due to preserved ejection fraction (HFPEF or 'diastolic HF'). The search is current to January 2013. Key results We found 33 RCTs that included 4740 participants. The findings of this update are consistent with the previous (2010) version of this Cochrane review and show important benefits of exercise-based rehabilitation that include a reduction in the risk of hospital admissions due to HF and improvements in health-related quality of life compared with not undertaking exercise. There was a high level of variation across studies in health-related quality of life outcome. While the majority of evidence was for exercise-based rehabilitation in people with HFREF, this update did identify a broader evidence base that included higher risk (New York Heart Association class IV) and older people, people with HFPEF and more programmes conducted in a home-based setting. We found no evidence to suggest that exercise training programmes cause harm in terms of an increase in the risk of death in either the short or longer term. A small body of economic evidence was identified indicating exercise-based rehabilitation to be cost-effective. Further evidence is needed to understand the effect of exercise training in people with HFPEF better and the costs and effects of exclusively home-based exercise rehabilitation programmes.

Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer.

Abstract: Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small-cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a new lymph node map. Some changes in this map have an important impact on mediastinal staging. Moreover, more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of computed tomography (CT)-enlarged or positron emission tomography (PET)-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography [endobronchial ultrasonography (EBUS)/esophageal ultrasonography (EUS)] with fine-needle aspiration (FNA) is the first choice (when available), since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred to mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumours ≤ 3 cm located in the outer third of the lung. In central tumours or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and FNA or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumours >3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high standardized uptake value. For restaging, invasive techniques providing histological information are advisable. Both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging. An integrated strategy using endoscopic staging techniques to prove mediastinal nodal disease and mediastinoscopy to assess nodal response after induction therapy needs further study.

An official European Respiratory Society statement on physical activity in COPD

Abstract: This European Respiratory Society (ERS) statement provides a comprehensive overview on physical activity in patients with chronic obstructive pulmonary disease (COPD). A multidisciplinary Task Force of experts representing the ERS Scientific Group 01.02 ''Rehabilitation and Chronic Care'' determined the overall scope of this statement through consensus. Focused literature reviews were conducted in key topic areas and the final content of this Statement was agreed upon by all members. The current knowledge regarding physical activity in COPD is presented, including the definition of physical activity, the consequences of physical inactivity on lung function decline and COPD incidence, physical activity assessment, prevalence of physical inactivity in COPD, clinical correlates of physical activity, effects of physical inactivity on hospitalisations and mortality, and treatment strategies to improve physical activity in patients with COPD. This Task Force identified multiple major areas of research that need to be addressed further in the coming years. These include, but are not limited to, the disease-modifying potential of increased physical activity, and to further understand how improvements in exercise capacity, dyspnoea and self-efficacy following interventions may translate into increased physical activity. The Task Force recommends that this ERS statement should be reviewed periodically (e.g. every 5-8 years).

An early rehabilitation intervention to enhance recovery during hospital admission for an exacerbation of chronic respiratory disease: randomised controlled trial

Abstract: Objective To investigate whether an early rehabilitation intervention initiated during acute admission for exacerbations of chronic respiratory disease reduces the risk of readmission over 12 months and ameliorates the negative effects of the episode on physical performance and health status. Design Prospective, randomised controlled trial. Setting An acute cardiorespiratory unit in a teaching hospital and an acute medical unit in an affiliated teaching district general hospital, United Kingdom. Participants 389 patients aged between 45 and 93 who within 48 hours of admission to hospital with an exacerbation of chronic respiratory disease were randomised to an early rehabilitation intervention (n=196) or to usual care (n=193). Main outcome measures The primary outcome was readmission rate at 12 months. Secondary outcomes included number of hospital days, mortality, physical performance, and health status. The primary analysis was by intention to treat, with prespecified per protocol analysis as a secondary outcome. Interventions Participants in the early rehabilitation group received a six week intervention, started within 48 hours of admission. The intervention comprised prescribed, progressive aerobic, resistance, and neuromuscular electrical stimulation training. Patients also received a self management and education package. Results Of the 389 participants, 320 (82%) had a primary diagnosis of chronic obstructive pulmonary disease. 233 (60%) were readmitted at least once in the following year (62% in the intervention group and 58% in the control group). No significant difference between groups was found (hazard ratio 1.1, 95% confidence interval 0.86 to 1.43, P=0.4). An increase in mortality was seen in the intervention group at one year (odds ratio 1.74, 95% confidence interval 1.05 to 2.88, P=0.03). Significant recovery in physical performance and health status was seen after discharge in both groups, with no significant difference between groups at one year. Conclusion Early rehabilitation during hospital admission for chronic respiratory disease did not reduce the risk of subsequent readmission or enhance recovery of physical function following the event over 12 months. Mortality at 12 months was higher in the intervention group. The results suggest that beyond current standard physiotherapy practice, progressive exercise rehabilitation should not be started during the early stages of the acute illness. Trial registration Current Controlled Trials ISRCTN05557928.

Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

Abstract: Blood pressure (BP) is a heritable risk factor for cardiovascular disease To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis We replicated findings in an independent set of 68,368 individuals of European ancestry Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2 Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules In summary, we identified previously unknown loci associated with BP Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification

Prevalence of Eating Disorders amongst Dancers: A Systemic Review and Meta-Analysis

Abstract: Eating disorders in dancers are thought to be common, but the exact rates remain to be clarified. The aim of this study is to systematically compile and analyse the rates of eating disorde rs in dancers. A literature search, appraisal and meta-analysis were conducted. Thi rty-three relevant studies were published between 1966 and 2013 with sufficient data for extraction. Primary data were extracted as raw numbers or confidence intervals. Risk ratios and 95% confidence intervals were calculated for controlled studies. The overall prevalence of eating disorders was 12.0% (16.4% for ballet dancers), 2.0% (4% for bal let dancers) for anorexia, 4.4% (2% for ballet dancers) for bulimia and 9.5% (14.9% for ballet dancers) for eating disorders not otherwise specified (EDNOS). The dancer group had higher mean scores on the EAT-26 and the Eating Disorder Inventory subscales. Dancers, in general, had a higher risk of suffering from eating disorders in general, anorexia nervosa and EDNOS, but no higher risk of suffering from bulimia nervosa. The study concluded that as dancers had a three times higher risk of suffering from eating disorders, particularly anorexia nervosa and EDNOS, specifically designed services for this population should be considered

Telomere length in circulating leukocytes is associated with lung function and disease

Abstract: Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated age ...

Preoperative mediastinal lymph node staging for non-small cell lung cancer: 2014 update of the 2007 ESTS guidelines.

Abstract: Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. Over the last years more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of CT-enlarged or PET-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography (EBUS/EUS) with fine needle aspiration is the first choice (when available) since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred over mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumors ≤3 cm located in the outer third of the lung. In central tumors or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and fine needle aspiration or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumors larger than 3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high SUV uptake.

Survival of patients with small cell lung cancer undergoing lung resection in England, 1998–2009

Abstract: Introduction Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC), except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected SCLC is limited but this is widely offered. Methods Data on 359 873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC or non-SCLC (NSCLC)) and whether they underwent a surgical resection. We explored their survival using Kaplan–Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socioeconomic status. Results The survival of 465 patients with resected SCLC was lower than patients with resected NSCLC (5-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 ‘elective’ SCLC cases where the diagnosis was most likely known before resection than for the subgroup of 267 ‘incidental’ cases where the SCLC diagnosis was likely to have been made after resection. Conclusions These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. Patients with SCLC treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected patients with SCLC.

Towards a safety net for management of 22q11.2 deletion syndrome: guidelines for our times.

Abstract: The commonest autosomal deletion, 22q11.2 deletion syndrome (22q11DS) is a multisystem disorder varying greatly in severity and age of identification between affected individuals. Holistic care is best served by a multidisciplinary team, with an anticipatory approach. Priorities tend to change with age, from feeding difficulties, infections and surgery of congenital abnormalities particularly of the heart and velopharynx in infancy and early childhood to longer-term communication, learning, behavioural and mental health difficulties best served by evaluation at intervals to consider and initiate management. Regular monitoring of growth, endocrine status, haematological and immune function to enable early intervention helps in maintaining health. Conclusion: Guidelines to best practice management of 22q11DS based on a literature review and consensus have been developed by a national group of professionals with consideration of the limitations of available medical and educational resources.

Subclinical diastolic dysfunction in young adults with Type 2 diabetes mellitus: a multiparametric contrast-enhanced cardiovascular magnetic resonance pilot study assessing potential mechanisms

Abstract: Aims To assess the cardiac, vascular, anthropometric, and biochemical determinants of subclinical diastolic dysfunction in younger adults with Type 2 diabetes mellitus (T2DM) using multiparametric contrast-enhanced cardiovascular magnetic resonance (CMR) imaging. Methods and results Twenty adults <40 years with T2DM [mean age 31.8(6.6) years, T2DM duration 4.7(4.0) years] and 20 age and sex-matched controls [10 obese non-diabetic controls and 10 lean controls (LC)] were studied. Cardiac volumes and function, circumferential strain and peak early diastolic strain rate (PEDSR), myocardial perfusion reserve, aortic stiffness (distensibility, pulse-wave velocity), focal fibrosis on late gadolinium enhancement, and pre- and post-contrast T1 mapping for contrast agent partition coefficient (subset, n = 26) were determined by CMR. In the T2DM cohort, mean aortic distensibility correlated with PEDSR ( r = 0.564, P = 0.023) and diabetes duration correlated inversely with PEDSR ( r = −0.534, P = 0.015) on univariate analysis. There was a close association between PEDSR and peak systolic strain ( r = −0.580, P = 0.007). Conclusion In young adults with T2DM, diabetes duration and aortic distensibility were associated with diastolic dysfunction. Interventional studies are required to assess whether cardiac dysfunction can be reversed in this phenotype of patients.

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

Abstract: Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Treatment outcome of patients with comorbid type 1 diabetes and eating disorders.

Abstract: Background Co-morbidity between Type 1 Diabetes Mellitus (T1DM) and eating disorders (ED) has been previously described; however the effect of this illness on the outcomes for conventional ED treatments has not been previously investigated. This study aims to compare clinical, psychopathological and personality features between two samples of ED individuals: those with comorbid T1DM and those without (No-DM); and to identify differences in treatment outcomes between the groups.

The European initiative for quality management in lung cancer care

Abstract: Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.

'Consumed by breathing' - a critical interpretive meta-synthesis of the qualitative literature.

Abstract: ObjectiveTo derive an improved understanding of how patients respond to, appraise, and understand the experience of an acute exacerbation of chronic obstructive pulmonary disease via a critical interpretive meta-synthesis.MethodsSearch terms – Exacerbate* OR hospital* AND ‘Chronic obstructive’ OR emphysema OR bronchitis AND interview* OR qualitative. Inclusion criteria – Primary research published in English of patients’ experiences of an acute exacerbation of chronic obstructive pulmonary disease. Data extraction and synthesis – eight papers were identified. Data were extracted by three researchers and constructs elicited via reciprocal translational analysis.FindingsThemes reflected two domains of understanding an acute exacerbation: (1) Acute effect – encompassing intense emotions, somatic awareness and patients need for rescue. (2) Sustained regulation – reflecting life as interrupted, ongoing beliefs and behaviour and help-seeking.DiscussionAcute exacerbations of chronic obstructive pulmonary disease...

Genome-Wide Association Study Identifies Variants in Casein Kinase II (CSNK2A2) to be Associated With Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort

Abstract: Background— Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. Methods and Results— Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals ( P –6 ) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β=−0.38; P =4.5×10 −8 ). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals ( P –5 ) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies ( P Conclusions— By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.

Mobile ECMO team for inter-hospital transportation of patients with ARDS: a retrospective case series.

Abstract: Introduction: Transport of patients undergoing extracorporeal membrane oxygenation is currently available in 5 referral centers in our country. Methods: Retrospective case series of patients managed by our mobile extracorporeal membrane oxygenation team and transferred to San Gerardo University Hospital from December 2004 to December 2012. Results: 42 patients were transported. The mean age was 42.11 (standard deviation ±18.11) years, with a range between 2 years and 70. 14 patients were females (33%) and 28 males (67%). The average transport distance was 121.69 km (±183.08) with a range between 9 km and 1044 Km. The mission’s mean time was equal to 508 minutes (±185) with range of 120-960 minutes. 29 patients (69%) were transported with extracorporeal membrane oxygenation support, while 13 patients (31%) were transported with conventional ventilation. In 28 patients (97%) a veno-venous bypass was utilized, while in one case (3%) a Veno-Arterial cannulation was performed. 32 patients survived (76%) and have been discharged alive from hospital. No major clinical or technical issues were observed during the transport. Conclusions: According to our data, we conclude that a dedicated mobile team allowed safe ground transportation of patients with severe acute lung injury to our tertiary care institution.

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Abstract: Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9 , were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema. These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.

Influence of CO2 on neurovascular coupling: interaction with dynamic cerebral autoregulation and cerebrovascular reactivity

Abstract: PaCO2 affects cerebral blood flow (CBF) and its regulatory mechanisms, but the interaction between neurovascular coupling (NVC), cerebral autoregulation (CA), and cerebrovascular reactivity to CO2 (CVR), in response to hypercapnia, is not known. Recordings of cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end‐tidal CO2 (EtCO2) were performed in 18 subjects during normocapnia and 5% CO2 inhalation while performing a passive motor paradigm. Together with BP and EtCO2, a gate signal to represent the effect of stimulation was used as input to a multivariate autoregressive‐moving average model to calculate their separate effects on CBFv. Hypercapnia led to a depression of dynamic CA at rest and during stimulation in both hemispheres (P <0.02) as well as impairment of the NVC response, particularly in the ipsilateral hemisphere (P <0.01). Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The CBFv step responses to each individual input (BP, EtCO2, stimulation) allowed identification of the influences of hypercapnia and neuromotor stimulation on CA, CVR, and NVC, which have not been previously described, and also confirmed the depressing effects of hypercapnia on CA and NVC. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation. Dynamic multivariate modeling can identify the complex interplay between different CBF regulatory mechanisms and should be recommended for studies involving similar interactions, such as the effects of exercise or posture on cerebral hemodynamics.