CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms.

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry-independent mechanisms.

Genetic correlation of the plasma lipidome with type 2 diabetes, prediabetes and insulin resistance in Mexican American families.

BACKGROUND: Differential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits. RESULTS: We used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, presence of prediabetes and homeostatic model of assessment - insulin resistance. We found that 44 lipid species were significantly genetically correlated with one or more of the three T2D-related traits. Majority of these lipid species belonged to the diacylglycerol (DAG, 17 species) and triacylglycerol (TAG, 17 species) classes. Six lipid species (all belonging to the triacylglycerol class and containing palmitate at the first position) were significantly genetically correlated with all the T2D-related traits. CONCLUSIONS: Our results imply that: a) not all plasma lipid species are genetically informative for T2D pathogenesis; b) the DAG and TAG lipid classes partially share genetic basis of T2D; and c) 1-palmitate containing TAGs may provide additional insights into the genetic basis of T2D.

Lipidomics in the Study of Hypertension in Metabolic Syndrome.

PURPOSE OF REVIEW: The entire gamut of changes in the lipid profile that precede, predict, and correlate with hypertension in metabolic syndrome is unknown. RECENT FINDINGS: The power, resolution, and accuracy of lipidomic assay technologies have brought us to the threshold of another information explosion. Understanding of hypertension and its pathophysiology especially within the setting of metabolic syndrome has been greatly improved by recent lipidomic studies. Hypertension in metabolic syndrome differs from other forms of hypertension, and recent studies have highlighted this difference in many interesting ways. Mounting evidence points towards a derangement of the sphingolipid pathway that may trigger the precursor clinical conditions of hypertension as well as hypertension itself. In this review, we summarize the available published literature in this field and propose a unifying hypothesis based on the published evidence. Recent studies have created substantial interest and advances in the understanding of hypertension in metabolic syndrome. Studies that directly test these concepts within a lipidomic framework are urgently needed.

Lipidomic risk score independently and cost-effectively predicts risk of future type 2 diabetes: results from diverse cohorts.

BACKGROUND: Detection of type 2 diabetes (T2D) is routinely based on the presence of dysglycemia. Although disturbed lipid metabolism is a hallmark of T2D, the potential of plasma lipidomics as a biomarker of future T2D is unknown. Our objective was to develop and validate a plasma lipidomic risk score (LRS) as a biomarker of future type 2 diabetes and to evaluate its cost-effectiveness for T2D screening. METHODS: Plasma LRS, based on significantly associated lipid species from an array of 319 lipid species, was developed in a cohort of initially T2D-free individuals from the San Antonio Family Heart Study (SAFHS). The LRS derived from SAFHS as well as its recalibrated version were validated in an independent cohort from Australia--the AusDiab cohort. The participants were T2D-free at baseline and followed for 9197 person-years in the SAFHS cohort (n = 771) and 5930 person-years in the AusDiab cohort (n = 644). Statistically and clinically improved T2D prediction was evaluated with established statistical parameters in both cohorts. Modeling studies were conducted to determine whether the use of LRS would be cost-effective for T2D screening. The main outcome measures included accuracy and incremental value of the LRS over routinely used clinical predictors of T2D risk; validation of these results in an independent cohort and cost-effectiveness of including LRS in screening/intervention programs for T2D. RESULTS: The LRS was based on plasma concentration of dihydroceramide 18:0, lysoalkylphosphatidylcholine 22:1 and triacyglycerol 16:0/18:0/18:1. The score predicted future T2D independently of prediabetes with an accuracy of 76%. Even in the subset of initially euglycemic individuals, the LRS improved T2D prediction. In the AusDiab cohort, the LRS continued to predict T2D significantly and independently. When combined with risk-stratification methods currently used in clinical practice, the LRS significantly improved the model fit (p < 0.001), information content (p < 0.001), discrimination (p < 0.001) and reclassification (p < 0.001) in both cohorts. Modeling studies demonstrated that LRS-based risk-stratification combined with metformin supplementation for high-risk individuals was the most cost-effective strategy for T2D prevention. CONCLUSIONS: Considering the novelty, incremental value and cost-effectiveness of LRS it should be used for risk-stratification of future T2D.

Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families.

Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS.

Increased waist circumference is independently associated with hypothyroidism in Mexican Americans: replicative evidence from two large, population-based studies.

BACKGROUND: Mexican Americans are at an increased risk of both thyroid dysfunction and metabolic syndrome (MS). Thus it is conceivable that some components of the MS may be associated with the risk of thyroid dysfunction in these individuals. Our objective was to investigate and replicate the potential association of MS traits with thyroid dysfunction in Mexican Americans. METHODS: We conducted association testing for 18 MS traits in two large studies on Mexican Americans - the San Antonio Family Heart Study (SAFHS) and the National Health and Nutrition Examination Survey (NHANES) 2007-10. A total of 907 participants from 42 families in SAFHS and 1633 unrelated participants from NHANES 2007-10 were included in this study. The outcome measures were prevalence of clinical and subclinical hypothyroidism and thyroid function index (TFI) - a measure of thyroid function. For the SAFHS, we used polygenic regression analyses with multiple covariates to test associations in setting of family studies. For the NHANES 2007-10, we corrected for the survey design variables as needed for association analyses in survey data. In both datasets, we corrected for age, sex and their linear and quadratic interactions. RESULTS: TFI was an accurate indicator of clinical thyroid status (area under the receiver-operating-characteristic curve to detect clinical hypothyroidism, 0.98) in both SAFHS and NHANES 2007-10. Of the 18 MS traits, waist circumference (WC) showed the most consistent association with TFI in both studies independently of age, sex and body mass index (BMI). In the SAFHS and NHANES 2007-10 datasets, each standard deviation increase in WC was associated with 0.13 (p < 0.001) and 0.11 (p < 0.001) unit increase in the TFI, respectively. In a series of polygenic and linear regression models, central obesity (defined as WC ≥ 102 cm in men and ≥88 cm in women) was associated with clinical and subclinical hypothyroidism independent of age, sex, BMI and type 2 diabetes in both datasets. Estimated prevalence of hypothyroidism was consistently high in those with central obesity, especially below 45y of age. CONCLUSIONS: WC independently associates with increased risk of thyroid dysfunction. Use of WC to identify Mexican American subjects at high risk of thyroid dysfunction should be investigated in future studies.

Roles of zinc in the pathophysiology of acute diarrhea.

Zinc has caught wide scientific attention for the conceptual promise it has to offer for prevention, control and treatment of acute diarrhea. This review focuses on the mechanisms by which zinc might contribute to the pathogenesis of acute diarrhea and the degree of success achieved in diarrhea control and treatment by zinc supplementation. Animal and in vitro studies have continued to fascinate the scientific fraternity and form a solid basis for the potential use of zinc supplementation against diarrhea. However, emerging evidence in terms of controlled studies in humans beckons a more complete understanding of the mechanistic basis for zinc supplementation. Current evidence indicates that studies specifically addressing the variability in response to zinc supplementation need to be undertaken to better comprehend these mechanisms.

Evaluation of chemiluminescence, toluidine blue and histopathology for detection of high risk oral precancerous lesions: A cross-sectional study.

BACKGROUND: Early detection holds the key to an effective control of cancers in general and of oral cancers in particular. However, screening procedures for oral cancer are not straightforward due to procedural requirements as well as feasibility issues, especially in resource-limited countries. METHODS: We conducted a cross-sectional study to compare the performance of chemiluminescence, toluidine blue and histopathology for detection of high-risk precancerous oral lesions. We evaluated 99 lesions from 55 patients who underwent chemiluminescence and toluidine blue tests along with biopsy and histopathological examination. We studied inter-as well as intra-rater agreement in the histopathological evaluation and then using latent class modeling, we estimated the operating characteristics of these tests in the absence of a reference standard test. RESULTS: There was a weak inter-rater agreement (kappa < 0.15) as well as a weak intra-rater reproducibility (Pearson's r = 0.28, intra-class correlation rho = 0.03) in the histopathological evaluation of potentially high-risk precancerous lesions. When compared to histopathology, chemiluminescence and toluidine blue retention had a sensitivity of 1.00 and 0.59, respectively and a specificity of 0.01 and 0.79, respectively. However, latent class analysis indicated a low sensitivity (0.37) and high specificity (0.90) of histopathological evaluation. Toluidine blue had a near perfect high sensitivity and specificity for detection of high-risk lesions. CONCLUSION: In our study, there was variability in the histopathological evaluation of oral precancerous lesions. Our results indicate that toluidine blue retention test may be better suited than chemiluminescence to detect high-risk oral precancerous lesions in a high-prevalence and low-resource setting like India.

Influence of variations in CCL3L1 and CCR5 on tuberculosis in a northwestern Colombian population.

We investigated the association of polymorphisms in CCR5, the major human immunodeficiency virus (HIV)-1 coreceptor, and copy number of its potent ligand CCL3L1 with tuberculosis in 298 individuals from Colombia. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. Furthermore, CCR5-HHD was associated with higher CCR5 gene and surface expression. These results substantiate the strong link between the pro-inflammatory effects of CCR5 and its ligands with active tuberculosis and suggest that chemokine-chemokine receptor genetic determinants may influence tuberculosis in addition to HIV/AIDS.

Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study.

Type 2 diabetes (T2D) is a complex metabolic derangement that has a strong genetic basis. There is substantial population-specificity in the association of genetic variants with T2D. The Indian urban Sindhi population is at a high risk of T2D. The genetic basis of T2D in this population is unknown. We interrogated 28 pooled whole blood genomes of 1402 participants from the Diabetes In Sindhi Families In Nagpur (DISFIN) study using Illumina's Global Screening Array. From a total of 608,550 biallelic variants, 140 were significantly associated with T2D after adjusting for comorbidities, batch effects, pooling error, kinship status and pooling variation in a random effects multivariable logistic regression framework. Of the 102 well-characterized genes that these variants mapped onto, 70 genes have been previously reported to be associated with T2D to varying degrees with known functional relevance. Excluding open reading frames, intergenic non-coding elements and pseudogenes, our study identified 22 novel candidate genes in the Sindhi population studied. Our study thus points to the potential, interesting candidate genes associated with T2D in an ethnically endogamous population. These candidate genes need to be fully investigated in future studies.

What zinc supplementation does and does not achieve in diarrhea prevention: a systematic review and meta-analysis.

BACKGROUND: Prevention of diarrhea has presented indomitable challenges. A preventive strategy that has received significant interest is zinc supplementation. Existing literature including quantitative meta-analyses and systematic reviews tend to show that zinc supplementation is beneficial however evidence to the contrary is augmenting. We therefore conducted an updated and comprehensive meta-analytical synthesis of the existing literature on the effect of zinc supplementation in prevention of diarrhea. METHODS: EMBASE®, MEDLINE ® and CINAHL® databases were searched for published reviews and meta-analyses on the use of zinc supplementation for the prevention childhood diarrhea. Additional RCTs published following the meta-analyses were also sought. Effect of zinc supplementation on the following five outcomes was studied: incidence of diarrhea, prevalence of diarrhea, incidence of persistent diarrhea, incidence of dysentery and incidence of mortality. The published RCTs were combined using random-effects meta-analyses, subgroup meta-analyses, meta-regression, cumulative meta-analyses and restricted meta-analyses to quantify and characterize the role of zinc supplementation with the afore stated outcomes. RESULTS: We found that zinc supplementation has a modest beneficial association (9% reduction) with incidence of diarrhea, a stronger beneficial association (19% reduction) with prevalence of diarrhea and occurrence of multiple diarrheal episodes (28% reduction) but there was significant unexplained heterogeneity across the studies for these associations. Age, continent of study origin, zinc salt and risk of bias contributed significantly to between studies heterogeneity. Zinc supplementation did not show statistically significant benefit in reducing the incidence of persistent diarrhea, dysentery or mortality. In most instances, the 95% prediction intervals for summary relative risk estimates straddled unity. CONCLUSIONS: Demonstrable benefit of preventive zinc supplementation was observed against two of the five diarrhea-related outcomes but the prediction intervals straddled unity. Thus the evidence for a preventive benefit of zinc against diarrhea is inconclusive. Continued efforts are needed to better understand the sources of heterogeneity. The outcomes of zinc supplementation may be improved by identifying subgroups that need zinc supplementation.

Independent association of meteorological characteristics with initial spread of Covid-19 in India.

Whether weather plays a part in the transmissibility of the novel Coronavirus Disease-19 (COVID-19) is still not established. We tested the hypothesis that meteorological factors (air temperature, relative humidity, air pressure, wind speed and rainfall) are independently associated with transmissibility of COVID-19 quantified using the basic reproduction rate (R0). We used publicly available datasets on daily COVID-19 case counts (total n = 108,308), three-hourly meteorological data and community mobility data over a three-month period. Estimated R0 varied between 1.15 and 1.28. Mean daily air temperature (inversely), wind speed (positively) and countrywide lockdown (inversely) were significantly associated with time dependent R0, but the contribution of countrywide lockdown to variability in R0 was over three times stronger as compared to that of temperature and wind speed combined. Thus, abating temperatures and easing lockdown may concur with increased transmissibility of COVID-19 in India.

Genetic association of anthropometric traits with type 2 diabetes in ethnically endogamous Sindhi families.

BACKGROUND: Ethnically endogamous populations can shed light on the genetics of type 2 diabetes. Such studies are lacking in India. We conducted this study to determine the genetic and environmental contributions of anthropometric traits to type 2 diabetes risk in the Sindhi families in central India. METHODS: We conducted a family study in Indian Sindhi families with at least one case of type 2 diabetes. Variance components methods were used to quantify the genetic association of 18 anthropometric traits with eight type 2 diabetes related traits. Univariate and bivariate polygenic models were used to determine the heritability, genetic and environmental correlation of anthropometric traits with type 2 diabetes related traits. RESULTS: We included 1,152 individuals from 112 phenotyped families. The ascertainment-bias corrected prevalence of type 2 diabetes was 35%. Waist circumference, hip circumference and the biceps, triceps, subscapular and medial calf skinfold thicknesses were polygenically and significantly associated with type 2 diabetes. The range of heritability of the anthropometric traits and type 2 diabetes related traits was 0.27-0.73 and 0.00-0.39, respectively. Heritability of type 2 diabetes as a discrete trait was 0.35. Heritability curves demonstrated a substantial local influence of type 2 diabetes related traits. Bivariate trait analyses showed that biceps and abdominal skinfold thickness and all waist-containing indexes were strongly genetically correlated with type 2 diabetes. CONCLUSIONS: In this first study of Sindhi families, we found evidence for genetic and environmental concordance of anthropometric traits with type 2 diabetes. Future studies need to probe into the genetics of type 2 diabetes in this population.

Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease.

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 × 10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation.

Bayesian estimates of the prevalence of ß-thalassemia trait in voluntary blood donors of central India: a survey.

Early detection of ß-thalassemia (ß-thal) trait is important. Voluntary blood donors represent an important group who are accessible and cooperative for this purpose. However, the usefulness of this population in ß-thal trait detection programs has not been studied in India. We conducted a hematological survey of 5,045 blood donors who visited the Bhopal Memorial Hospital & Research Centre, Bhopal in central India. Using robust Bayesian methods, we estimated the prevalence of ß-thal trait. The overall prevalence of ß-thal trait in the study population was 9.59% [95% confidence interval (95% CI) 8.78-10.4%]. The prevalence of ß-thal trait varied across the states of origin and within the state of Madhya Pradesh. We observed a cline effect for ß-thal trait prevalence in relation to the latitude (p = 0.024). We conclude that blood donors offer an attractive adjunct to ß-thal trait detection in national programs. Our study also offers insights into the ß-thal trait gene flow and migration in India.

Degree of hyperglycemia independently associates with hospital mortality and length of stay in critically ill, nondiabetic patients: Results from the ANZICS CORE binational registry.

PURPOSE: Hyperglycemia (HG) in critically ill patients influences clinical outcomes and hospitalization costs. We aimed to describe association of HG with hospital mortality and length of stay in large scale, real-world scenario. MATERIALS: From The Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) we included 739,152 intensive care unit (ICU) patients admitted during 2007-2016. Hyperglycemia was quatified using midpoint blood glucose level (MBGL). Association with outcomes (hospital mortality and length of stay (LOS)) was tested using multivariable, mixed effects, 2-level hierarchical regression. RESULTS: Degree of HG (defined using MBGL as a continuous variable) was significantly associated with hospital mortality and longer hospital stay in a dose-dependent fashion. The fourth, third and second MBGL (compared to the first) quartiles were associated with hospital mortality (odds ratio 1.34, 1.05 and 0.97, respectively) and longer hospital stay (1.56, 1.38 and 0.93 days, respectively). These associations were stronger associations in trauma (especially head injury), neurological disease and coma patients. Significant variation across ICUs was observed for all associations. CONCLUSIONS: In this largest study of nondiabetic ICU patients, HG was associated with both study outcomes. This association was differential across ICUs and diagnostic categories.

Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial.

BACKGROUND: Diarrhea causes an estimated 2.5 million child deaths in developing countries each year, 35% of which are due to acute diarrhea. Zinc and copper stores in the body are known to be depleted during acute diarrhea. Our objectives were to evaluate the efficacy of zinc and copper supplementation when given with standard treatment to children with acute watery or bloody diarrhea. METHODS: We conducted a double-blind randomized controlled clinical trial in the Department of Pediatrics at Indira Gandhi Government Medical College Nagpur, India. Eight hundred and eight children aged 6 months to 59 months with acute diarrhea were individually randomized to placebo (Pl), zinc (Zn) only, and zinc and copper (Zn+Cu) together with standard treatment for acute diarrhea. RESULTS: The mean duration of diarrhea from enrollment and the mean stool weight during hospital stay were 63.7 hours and 940 grams, respectively, and there were no significant differences in the adjusted means across treatment groups. Similarly, the adjusted means of the amount of oral rehydration solution or intravenous fluids used, the proportion of participants with diarrhea more than 7 days from onset, and the severity of diarrhea indicated by more than three episodes of some dehydration or any episode of severe dehydration after enrollment, did not differ across the three groups. CONCLUSION: The expected beneficial effects of zinc supplementation for acute diarrhea were not observed. Therapeutic Zn or Zn and Cu supplementation may not have a universal beneficial impact on the duration of acute diarrhea in children.

Lack of association of the APOE epsilon 4 allele with the risk of obstructive sleep apnea: meta-analysis and meta-regression.

STUDY OBJECTIVES: Reports on the association of polymorphisms in the gene encoding apolipoprotein E (APOE)--a vital macromolecule in cholesterol metabolism--with obstructive sleep apnea (OSA) have provided conflicting results. Our objective was to meta-analytically synthesize the existing evidence for the association of the APOE epsilon4 allele with the risk of OSA. DESIGN: Random effects meta-analysis and meta-regression. SETTING: Genetic epidemiological studies reporting the association of APOE epsilon4 allele with OSA susceptibility. PATIENTS OR PARTICIPANTS: Synthesis of APOE epsilon4 allele data from 6,508 subjects including 1,901 cases of OSA and 4,607 controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Eight studies were included in the random effects meta-analysis; the summary effect size measured as odds ratio (OR) for association of the APOE epsilon4 allele with the risk of OSA was found to be 1.13 (95% confidence interval 0.86-1.47). There was a statistically significant heterogeneity (I2 = 72%, P = 0.001) across study results that was not explained by the mean age, proportion of males, or the proportion possessing the APOE epsilon4 allele or when grouped based on the geographic location of the study. CONCLUSIONS: The hypothesis that the APOE epsilon4 allele may be causally associated with OSA cannot be supported on the basis of published literature.

Factors influencing the benefit of adjunctive devices during percutaneous coronary intervention in ST-segment elevation myocardial infarction: meta-analysis and meta-regression.

BACKGROUND: Routine use of adjunctive devices to percutaneous coronary intervention (PCI) for the treatment of patients of ST-segment elevation myocardial infarction (STEMI) is questionable. Also, the clinical characteristics of STEMI patients that can modulate the treatment benefits of adjunctive devices are not fully understood. OBJECTIVE: To synthesize the existing literature to summarize the therapeutic benefit of the adjunctive devices and to identify the patient characteristics which relate to this therapeutic benefit. METHODS: We conducted (i) meta-analyses of the randomized controlled trials (RCT) comparing the performance of the adjunctive devices with PCI for three reperfusion-related outcomes: myocardial blush grade (MBG) < 3, failed ST-segment resolution (STR), and Thrombolysis In Myocardial Infarction (TIMI) flow grade < 3; (ii) stepwise meta-regressions of the effect of trial characteristics on between-trial heterogeneity; and (iii) analyses to examine whether the reperfusion-related end-points explained the between-trial difference in cardiac death and major adverse cardiac events (MACE). RESULTS: Our meta-analyses represent data from 23 RCT and 5,728 subjects. The overall therapeutic benefit attributable ranged from 32 to 35% for the reperfusion-related outcomes, and thrombectomy devices were more beneficial than the distal protection devices.Meta-regression identified gender, receipt of glycoprotein (GP) IIb/IIIa inhibitor, and baseline TIMI flow grade as significant predictors of improved reperfusion across trials. The available clinical trials were individually underpowered and not designed to detect the influence of adjunctive devices on death or MACE. CONCLUSIONS: Routine use of adjunctive devices cannot be recommended. Thrombus burden, treatment with GPIIb/IIIa inhibitors, and gender may modify the reperfusion benefit of adjunctive devices.

Arbitrary units are a composite and useful measure of muscle sympathetic nerve activity.

In humans, the muscle sympathetic nerve activity (MSNA) signal is challenging to detect, record and analyze. Several methods exist that attempt to capture the latent construct of MSNA. We directly compared the performance of five MSNA parameters: burst frequency, burst incidence, median burst amplitude, arbitrary units (AU) and fractal dimension (FD). The MSNA signal was recorded in 33 subjects for approximately 30 min before, during and after the application of a graded cold pressor test stimulus at 18 degrees C, 10 degrees C and 2 degrees C in random order with an adequate wash-out period. Using coefficient of variation, Shannon's entropy and principal component analysis, we observed that these five parameters defined two physical and conceptual domains of MSNA-frequency and amplitude. Since AU combines information from both these domains, we observed that it explained maximum inter-subject and inter-experimental segment variation. FD did not explain the inter-subject variability and was identified as a unique parameter in the factor analysis. Epidemiological studies that attempt to quantify MSNA may consistently use AU as the parameter for quantification of MSNA.