Manouchehr Ardjomand-Hessabi

CLOTBUST-Hands Free Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke

Background and Purpose— The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. Methods— All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. Results— Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5–29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%–64%) complete and 2 of 20 (10%; 95% confidence interval, 1%–32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%–82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%–49) patients had a modified Rankin scale of 0 to 1. Conclusions— Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.

Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder

Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2–8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

The University of Texas Houston Stroke Registry (UTHSR): implementation of enhanced data quality assurance procedures improves data quality

BackgroundLimited information has been published regarding standard quality assurance (QA) procedures for stroke registries. We share our experience regarding the establishment of enhanced QA procedures for the University of Texas Houston Stroke Registry (UTHSR) and evaluate whether these QA procedures have improved data quality in UTHSR.MethodsAll 5093 patient records that were abstracted and entered in UTHSR, between January 1, 2008 and December 31, 2011, were considered in this study. We conducted reliability and validity studies. For reliability and validity of data captured by abstractors, a random subset of 30 records was used for re-abstraction of select key variables by two abstractors. These 30 records were re-abstracted by a team of experts that included a vascular neurologist clinician as the “gold standard”. We assessed inter-rater reliability (IRR) between the two abstractors as well as validity of each abstractor with the “gold standard”. Depending on the scale of variables, IRR was assessed with Kappa or intra-class correlations (ICC) using a 2-way, random effects ANOVA. For assessment of validity of data in UTHSR we re-abstracted another set of 85 patient records for which all discrepant entries were adjudicated by a vascular neurology fellow clinician and added to the set of our “gold standard”. We assessed level of agreement between the registry data and the “gold standard” as well as sensitivity and specificity. We used logistic regression to compare error rates for different years to assess whether a significant improvement in data quality has been achieved during 2008–2011.ResultsThe error rate dropped significantly, from 4.8% in 2008 to 2.2% in 2011 (P < 0.001). The two abstractors had an excellent IRR (Kappa or ICC ≥ 0.75) on almost all key variables checked. Agreement between data in UTHSR and the “gold standard” was excellent for almost all categorical and continuous variables.ConclusionsEstablishment of a rigorous data quality assurance for our UTHSR has helped to improve the validity of data. We observed an excellent IRR between the two abstractors. We recommend training of chart abstractors and systematic assessment of IRR between abstractors and validity of the abstracted data in stroke registries.

Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting by early childhood. Lead is a toxic metal shown to cause neurodevelopmental disorders in children. Several studies have investigated the possible association between exposure to lead and ASD, but their findings are conflicting. Using data from 100 ASD cases (2–8 years of age) and their age- and sex-matched typically developing controls, we investigated the association between blood lead concentrations (BLC) and ASD in Jamaican children. We administered a questionnaire to assess demographic and socioeconomic information as well as exposure to potential lead sources. We used General Linear Models (GLM) to assess the association of BLC with ASD status as well as with sources of exposure to lead. In univariable GLM, we found a significant difference between geometric mean blood lead concentrations of ASD cases and controls (2.25 μg/dL cases vs. 2.73 μg/dL controls, p < 0.05). However, after controlling for potential confounders, there were no significant differences between adjusted geometric mean blood lead concentrations of ASD cases and controls (2.55 μg/dL vs. 2.72 μg/dL, p = 0.64). Our results do not support an association between BLC and ASD in Jamaican children. We have identified significant confounders when assessing an association between ASD and BLC.

Coordination and management of multisite complementary and alternative medicine (CAM) therapies: Experience from a multisite reflexology intervention trial

BACKGROUND Multisite randomized clinical trials allow for increased research collaboration among investigators and expedite data collection efforts. As a result, government funding agencies typically look favorably upon this approach. As the field of complementary and alternative medicine (CAM) continues to evolve, so do increased calls for the use of more rigorous study design and trial methodologies, which can present challenges for investigators. PURPOSE To describe the processes involved in the coordination and management of a multisite randomized clinical trial of a CAM intervention. METHODS Key aspects related to the coordination and management of a multisite CAM randomized clinical trial are presented, including organizational and site selection considerations, recruitment concerns and issues related to data collection and randomization to treatment groups. Management and monitoring of data, as well as quality assurance procedures are described. Finally, a real world perspective is shared from a recently conducted multisite randomized clinical trial of reflexology for women diagnosed with advanced breast cancer. RESULTS The use of multiple sites in the conduct of CAM-based randomized clinical trials can provide an efficient, collaborative and robust approach to study coordination and data collection that maximizes efficiency and ensures the quality of results. CONCLUSIONS Multisite randomized clinical trial designs can offer the field of CAM research a more standardized and efficient approach to examine the effectiveness of novel therapies and treatments. Special attention must be given to intervention fidelity, consistent data collection and ensuring data quality. Assessment and reporting of quantitative indicators of data quality should be required.

Factors associated with blood lead concentrations of children in Jamaica

Lead is a heavy metal known to be detrimental to neurologic, physiologic, and behavioral health of children. Previous studies from Jamaica reported that mean lead levels in soil are four times that of lead levels in some other parts of the world. Other studies detected lead levels in fruits and root vegetables, which were grown in areas with lead contaminated soil. In this study, we investigate environmental factors associated with blood lead concentrations in Jamaican children. The participants in this study comprised 125 typically developing (TD) children (ages 2–8 years) who served as controls in an age- and sex-matched case-control study that enrolled children from 2009–2012 in Jamaica. We administered a questionnaire to assess demographic and socioeconomic information as well as potential exposures to lead through food. Using General Linear Models (GLMs), we identified factors associated with blood lead concentrations in Jamaican children. The geometric mean blood lead concentration (GMBLC) in the sample of children in this study was 2.80 μg dL−1. In univariable GLM analyses, GMBLC was higher for children whose parents did not have education beyond high school compared to those whose parents had attained this level (3.00 μg dL−1 vs. 2.31 μg dL−1; P = 0.05), children living near a high traffic road compared to those who did not (3.43 μg dL−1 vs. 2.52 μg dL−1; P < 0.01), and children who reported eating ackee compared to those who did not eat this fruit (2.89 μg dL−1 vs. 1.65 μg dL−1; P < 0.05). In multivariable analysis, living near a high traffic road was identified as an independent risk factor for higher adjusted GMBLC (3.05 μg dL−1 vs. 2.19 μg dL−1; P = 0.01). While our findings indicate that GMBLC in Jamaican children has dropped by at least 62% during the past two decades, children living in Jamaica still have GMBLC that is twice that of children in more developed countries. In addition, we have identified significant risk factors for higher blood lead concentrations in Jamaican children. We believe increasing awareness among parents regarding these risk factors could potentially lead to a lower level of lead exposure in Jamaican children.

Regular Exercise Is Associated With Better Functional Outcomes In Ankylosing Spondylitis

SUPPLEMENTSex Bias In Autoimmune Diseases : Increased Risk Of 47,XXX In Systemic Lupus Erythematosus (SLE) and Sjogrens Syndrome (SS) Supports The Gene Dose HypothesisBackground/Purpose: Human FoxP3+ Th-cells are heterogeneous in function and include not only suppressive cells (TRegs) but also nonsuppressive cells that abundantly secrete proinflammatory cytokines. We have previously shown that FoxP3+ Th-cells were increased in GPA-patients during remission as compared to healthy controls (HCs). In this group of patients, however, we observed a defective suppressor function of TRegs, and an increase in the percentage of Th-17 cells. These observations make it tempting to investigate whether increased FoxP3+ Th-cells in GPA-patients are attributed to an increase in the cytokine-secreting non-suppressive FoxP3+Th-cells. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 46 GPA-patients in remission and from 22 age- and sex-matched HCs. Expression of CD4, CD45RO, and FoxP3 were determined by flow cytometric analysis. The expression levels of FoxP3 and CD45RO were used for distinction between activated suppressor TRegs (FoxP3HighCD45RO+; ASTReg), resting suppressor TRegs (FoxP3LowCD45RO-; RSTReg), and cytokine-secreting non-suppressor TRegs (FoxP3LowCD45RO+; NONTReg) cells. Intracellular expression of IFNg, IL-17, and IL-21 were determined in the various FoxP3+ Th-cell subsets after in vitro activation of PBMCs by PMA and Ca-Ionophore. Results: A significant increase in the frequency of NONTReg cells was observed in GPA-patients as compared with HCs, whereas no differences were detected in RSTReg- and ASTReg cells between GPA-patients and HCs. The distribution of RSTReg- and NONTReg cells did not differ between ANCA-negative and ANCA-positive patients, whereas lower percentages of ASTReg cells were observed in ANCA-positive patients as compared to ANCA-negative patients and HCs. Importantly, a significant increase in the percentage of IL-17+ and IL-21+ cells was seen within the NONTRegcells from ANCA-positive patients (n= 9) when compared to ANCA-negative (n= 10) and HCs (n= 12), whereas no differences were found between ANCA-negative and HCs. Conclusion: Increased FoxP3 expression in Th-cells from GPA-patients is related to an increase in a subset of non-suppressive Th-cells. Increased production of IL-17 and IL-21 cytokines, in NONTReg cells from ANCApositive patients points towards FoxP3+ effector cells and decrease in suppressive TReg cells in relation to ANCA production.Complex Functional Effects Within The HLA Contribute To Sjogrens Syndrome Pathogenesis and May Influence Both Transcriptional Regulation and Peptide Binding

Opiate Use In Patients With Ankylosing Spondylitis

SUPPLEMENTSex Bias In Autoimmune Diseases : Increased Risk Of 47,XXX In Systemic Lupus Erythematosus (SLE) and Sjogrens Syndrome (SS) Supports The Gene Dose HypothesisBackground/Purpose: Human FoxP3+ Th-cells are heterogeneous in function and include not only suppressive cells (TRegs) but also nonsuppressive cells that abundantly secrete proinflammatory cytokines. We have previously shown that FoxP3+ Th-cells were increased in GPA-patients during remission as compared to healthy controls (HCs). In this group of patients, however, we observed a defective suppressor function of TRegs, and an increase in the percentage of Th-17 cells. These observations make it tempting to investigate whether increased FoxP3+ Th-cells in GPA-patients are attributed to an increase in the cytokine-secreting non-suppressive FoxP3+Th-cells. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 46 GPA-patients in remission and from 22 age- and sex-matched HCs. Expression of CD4, CD45RO, and FoxP3 were determined by flow cytometric analysis. The expression levels of FoxP3 and CD45RO were used for distinction between activated suppressor TRegs (FoxP3HighCD45RO+; ASTReg), resting suppressor TRegs (FoxP3LowCD45RO-; RSTReg), and cytokine-secreting non-suppressor TRegs (FoxP3LowCD45RO+; NONTReg) cells. Intracellular expression of IFNg, IL-17, and IL-21 were determined in the various FoxP3+ Th-cell subsets after in vitro activation of PBMCs by PMA and Ca-Ionophore. Results: A significant increase in the frequency of NONTReg cells was observed in GPA-patients as compared with HCs, whereas no differences were detected in RSTReg- and ASTReg cells between GPA-patients and HCs. The distribution of RSTReg- and NONTReg cells did not differ between ANCA-negative and ANCA-positive patients, whereas lower percentages of ASTReg cells were observed in ANCA-positive patients as compared to ANCA-negative patients and HCs. Importantly, a significant increase in the percentage of IL-17+ and IL-21+ cells was seen within the NONTRegcells from ANCA-positive patients (n= 9) when compared to ANCA-negative (n= 10) and HCs (n= 12), whereas no differences were found between ANCA-negative and HCs. Conclusion: Increased FoxP3 expression in Th-cells from GPA-patients is related to an increase in a subset of non-suppressive Th-cells. Increased production of IL-17 and IL-21 cytokines, in NONTReg cells from ANCApositive patients points towards FoxP3+ effector cells and decrease in suppressive TReg cells in relation to ANCA production.Complex Functional Effects Within The HLA Contribute To Sjogrens Syndrome Pathogenesis and May Influence Both Transcriptional Regulation and Peptide Binding