Inadvertent Lead Placement In The Left Ventricle: A Case Report And Brief Review

Inadvertent lead placement in the left ventricle (LV) is an uncommon and often under-diagnosed complication of cardiac device implantation. Thromboembolic (TE) events are common and usually secondary to fibrosis or thrombus formation on or around the lead. Anticoagulation can prevent TE events. Percutaneous and surgical LV lead extractions have been performed successfully, but the risks of percutaneous lead removal are not well-defined. In this report, we describe a case of inadvertent LV lead placement and briefly review the contemporary literature

A Genome-Wide association Study of Obstructive Heart Defects among Participants in the National Birth Defects Prevention Study

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (

A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia

Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validity of 2SLS relies on a representative sample randomly selected from a study cohort or a population for genome-wide association study (GWAS), which is not always true in practice. For example, the extreme phenotype sequencing (EPS) design is widely used to investigate genetic determinants of an outcome in GWAS as it bears many advantages such as efficiency, low sequencing or genotyping cost, and large power in detecting the involvement of rare genetic variants in disease etiology. In this paper, we develop a novel, versatile, and efficient approach, namely MR analysis under Extreme or random Phenotype Sampling (MREPS), for one-sample MR analysis based on samples drawn through either the random sampling design or the nonrandom EPS design. In simulations, MREPS provides unbiased estimates for causal effects, correct type I errors for causal effect testing. Furthermore, it is robust under different study designs and has high power. These results demonstrate the superiority of MREPS over the widely used standard 2SLS approach. We applied MREPS to assess and highlight the causal effect of total fetal hemoglobin on anemia risk in patients with sickle cell anemia using two independent cohort studies. A user-friendly Shiny app web interface was implemented for professionals to easily explore the MREPS

A bootstrap approach for assessing the uncertainty of outcome probabilities when using a scoring system

Background: Scoring systems are a very attractive family of clinical predictive models, because the patient score can be calculated without using any data processing system. Their weakness lies in the difficulty of associating a reliable prognostic probability with each score. In this study a bootstrap approach for estimating confidence intervals of outcome probabilities is described and applied to design and optimize the performance of a scoring system for morbidity in intensive care units after heart surgery. Methods: The bias-corrected and accelerated bootstrap method was used to estimate the 95% confidence intervals of outcome probabilities associated with a scoring system. These confidence intervals were calculated for each score and each step of the scoring-system design by means of one thousand bootstrapped samples. 1090 consecutive adult patients who underwent coronary artery bypass graft were assigned at random to two groups of equal size, so as to define random training and testing sets with equal percentage morbidities. A collection of 78 preoperative, intraoperative and postoperative variables were considered as likely morbidity predictors. Results: Several competing scoring systems were compared on the basis of discrimination, generalization and uncertainty associated with the prognostic probabilities. The results showed that confidence intervals corresponding to different scores often overlapped, making it convenient to unite and thus reduce the score classes. After uniting two adjacent classes, a model with six score groups not only gave a satisfactory trade-off between discrimination and generalization, but also enabled patients to be allocated to classes, most of which were characterized by well separated confidence intervals of prognostic probabilities. Conclusions: Scoring systems are often designed solely on the basis of discrimination and generalization characteristics, to the detriment of prediction of a trustworthy outcome probability. The present example demonstrates that using a bootstrap method for the estimation of outcome-probability confidence intervals provides useful additional information about score-class statistics, guiding physicians towards the most convenient model for predicting morbidity outcomes in their clinical context

FLAMINGOS-2: The Facility Near-Infrared Wide-field Imager & Multi-Object Spectrograph for Gemini

We report on the design and status of the FLAMINGOS-2 instrument - a fully-cryogenic facility near-infrared imager and multi-object spectrograph for the Gemini 8-meter telescopes. FLAMINGOS-2 has a refractive all-spherical optical system providing 0.18-arcsecond pixels and a 6.2-arcminute circular field-of-view on a 2048x2048-pixel HAWAII-2 0.9-2.4 mm detector array. A slit/decker wheel mechanism allows the selection of up to 9 multi-object laser-machined plates or 3 long slits for spectroscopy over a 6x2-arcminute field of view, and selectable grisms provide resolutions from $\sim$ 1300 to $\sim$3000 over the entire spectrograph bandpass. FLAMINGOS-2 is also compatible with the Gemini Multi-Conjugate Adaptive Optics system, providing multi-object spectroscopic capabilities over a 3x1-arcminute field with high spatial resolution (0.09-arcsec/pixel). We review the designs of optical, mechanical, electronics, software, and On-Instrument WaveFront Sensor subsystems. We also present the current status of the project, currently in final testing in mid-2006.Comment: Submitted to SPIE Astronomical Telescopes & Instrumentation; 12 pages, incl. color figure

Soluble urokinase plasminogen activator receptor is associated with kidney disease and its progression in sickle cell anemia

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A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery = 3978; Nreplication = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT = 440; Nreplication_TDT = 275) and case–control analyses separately in infants (Ndiscovery_CCI = 1635; Nreplication_CCI = 990) and mothers (case status defined by infant; Ndiscovery_CCM = 1703; Nreplication_CCM = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery = 4.08 × 10−9; preplication = 2.44 × 10−4). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery = 1.61 × 10−7; preplication = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10−6) with OHD in only the discovery sample. In the case–control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds (× discovery < 1 × 10−5 and preplication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery = 1.42 × 10−6; preplication = 0.04). Additional SNPs with pdiscovery < 1 × 10−5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings

Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 – 0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 – 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis