Performance of Genotype Imputation for Rare Variants Identified in Exons and Flanking Regions of Genes

Genotype imputation has the potential to assess human genetic variation at a lower cost than assaying the variants using laboratory techniques. The performance of imputation for rare variants has not been comprehensively studied. We utilized 8865 human samples with high depth resequencing data for the exons and flanking regions of 202 genes and Genome-Wide Association Study (GWAS) data to characterize the performance of genotype imputation for rare variants. We evaluated reference sets ranging from 100 to 3713 subjects for imputing into samples typed for the Affymetrix (500K and 6.0) and Illumina 550K GWAS panels. The proportion of variants that could be well imputed (true r2>0.7) with a reference panel of 3713 individuals was: 31% (Illumina 550K) or 25% (Affymetrix 500K) with MAF (Minor Allele Frequency) less than or equal 0.001, 48% or 35% with 0.001<MAF< = 0.005, 54% or 38% with 0.005<MAF< = 0.01, 78% or 57% with 0.01<MAF< = 0.05, and 97% or 86% with MAF>0.05. The performance for common SNPs (MAF>0.05) within exons and flanking regions is comparable to imputation of more uniformly distributed SNPs. The performance for rare SNPs (0.01<MAF< = 0.05) was much more dependent on the GWAS panel and the number of reference samples. These results suggest routine use of genotype imputation for extending the assessment of common variants identified in humans via targeted exon resequencing into additional samples with GWAS data, but imputation of very rare variants (MAF< = 0.005) will require reference panels with thousands of subjects

Ureteral Stent Retrieval Using the Crochet Hook Technique in Females

INTRODUCTION: We developed a method for ureteral stent removal in female patients that requires no cystoscopy or fluoroscopic guidance using a crochet hook. In addition, we also investigated the success rate, complications and pain associated with this procedure. METHODS: A total of 40 female patients (56 stents) underwent the removal of ureteral stents. All procedures were carried out with the patients either under anesthesia, conscious sedation, or analgesic suppositories as deemed appropriate for each procedure including Shock Wave Lithotripsy (SWL), Ureteroscopy (URS), Percutaneous Nephrolithotomy (PCNL), and ureteral stent removal. At the time of these procedures, fluoroscopy and/or cystoscopy were prepared, but they were not used unless we failed to successfully remove the ureteral stent using the crochet hook. In addition, matched controls (comprising 50 stents) which were removed by standard ureteral stent removal using cystoscopy were used for comparison purposes. RESULTS: A total of 47 of the 56 stents (83.9%) were successfully removed. In addition, 47 of 52 (90.4%) were successfully removed except for two migrated stents and two heavily encrusted stents which could not be removed using cystoscopy. Ureteral stent removal using the crochet hook technique was unsuccessful in nine patients, including two encrustations and two migrations. Concerning pain, ureteral stent removal using the crochet hook technique showed a lower visual analogue pain scale (VAPS) score than for the standard technique using cystoscopy. CONCLUSIONS: Ureteral stent removal using a crochet hook is considered to be easy, safe, and cost effective. This technique is also easy to learn and is therefore considered to be suitable for use on an outpatient basis

Search for a Technicolor omega_T Particle in Events with a Photon and a b-quark Jet at CDF

If the Technicolor omega_T particle exists, a likely decay mode is omega_T -> gamma pi_T, followed by pi_T -> bb-bar, yielding the signature gamma bb-bar. We have searched 85 pb^-1 of data collected by the CDF experiment at the Fermilab Tevatron for events with a photon and two jets, where one of the jets must contain a secondary vertex implying the presence of a b quark. We find no excess of events above standard model expectations. We express the result of an exclusion region in the M_omega_T - M_pi_T mass plane.Comment: 14 pages, 2 figures. Available from the CDF server (PS with figs): http://www-cdf.fnal.gov/physics/pub98/cdf4674_omega_t_prl_4.ps FERMILAB-PUB-98/321-

Validity of the Postoperative Morbidity Survey after abdominal aortic aneurysm repair—a prospective observational study

BACKGROUND: Currently, there is no standardised tool used to capture morbidity following abdominal aortic aneurysm (AAA) repair. The aim of this prospective observational study was to validate the Postoperative Morbidity Survey (POMS) according to its two guiding principles: to only capture morbidity substantial enough to delay discharge from hospital and to be a rapid, simple screening tool. METHODS: A total of 64 adult patients undergoing elective infrarenal AAA repair participated in the study. Following surgery, the POMS was recorded daily, by trained research staff with the clinical teams blinded, until hospital discharge or death. We modelled the data using Cox regression, accounting for the competing risk of death, with POMS as a binary time-dependent (repeated measures) internal covariate. For each day for each patient, ‘discharged’ (yes/no) was the event, with the elapsed number of days post-surgery as the time variable. We derived the hazard ratio for any POMS morbidity (score 1–9) vs. no morbidity (zero), adjusted for type of repair (endovascular versus open), age and aneurysm size. RESULTS: The hazard ratio for alive discharge with any POMS-recorded morbidity versus no morbidity was 0.130 (95 % confidence interval 0.070 to 0.243). The median time-to-discharge was 13 days after recording any POMS morbidity vs. 2 days after scoring zero for POMS morbidity. Compliance with POMS completion was 99.5 %. CONCLUSIONS: The POMS is a valid tool for capturing short-term postoperative morbidity following elective infrarenal AAA repair that is substantial enough to delay discharge from hospital. Daily POMS measurement is recommended to fully capture morbidity and allow robust analysis. The survey could be a valuable outcome measure for use in quality improvement programmes and future research

HIV-1 Populations in Semen Arise through Multiple Mechanisms

HIV-1 is present in anatomical compartments and bodily fluids. Most transmissions occur through sexual acts, making virus in semen the proximal source in male donors. We find three distinct relationships in comparing viral RNA populations between blood and semen in men with chronic HIV-1 infection, and we propose that the viral populations in semen arise by multiple mechanisms including: direct import of virus, oligoclonal amplification within the seminal tract, or compartmentalization. In addition, we find significant enrichment of six out of nineteen cytokines and chemokines in semen of both HIV-infected and uninfected men, and another seven further enriched in infected individuals. The enrichment of cytokines involved in innate immunity in the seminal tract, complemented with chemokines in infected men, creates an environment conducive to T cell activation and viral replication. These studies define different relationships between virus in blood and semen that can significantly alter the composition of the viral population at the source that is most proximal to the transmitted virus

Experience of road and other trauma by the opiate dependent patient: a survey report

Background: Trauma plays an important role in the experience of many patients with substance use disorder, but is relatively under-studied particularly in Australia. The present survey examined the lifetime prevalence of various forms of trauma including driving careers in the context of relevant medical conditions. Methods: A survey was undertaken in a family medicine practice with a special interest in addiction medicine in Brisbane, Australia. Results: Of 350 patients surveyed, 220 were substance dependent, and 130 were general medical patients. Addicted patients were younger (mean ± S.D. 33.72 ± 8.14 vs. 44.24 ± 16.91 years, P < 0.0001) and had shorter driving histories (15.96 ± 8.50 vs. 25.54 ± 15.03 years, P < 0.0001). They had less driving related medical problems (vision, spectacle use, diabetes) but more fractures, surgical operations, dental trauma and assaults. Addicted patients also had significantly worse driving histories on most parameters measured including percent with driving suspensions (O.R. = 7.70, C.I. 4.38-13.63), duration of suspensions (1.71 ± 3.60 vs. 0.11 ± 0.31 years, P < 0.0001), number of motor vehicle collisions (2.00 ± 3.30 vs. 1.10 ± 1.32, P = 0.01), numbers of cars repaired (1.73 ± 3.59 vs. 1.08 ± 1.60, P = 0.042), rear end collisions (O.R. = 1.90, CI 1.13-3.25), running away after car crashes (O.R. = 26.37, CI 4.31-1077.48), other people hospitalized (O.R. = 2.00, C.I. 0.93-4.37, P = 0.037) and people killed (17 vs. 0 P = 0.0005). Upon multivariate analysis group membership was shown to be a significant determinant of both cars repaired and cars hit when controlled for length of driving history. Hence use of all types of drugs (O.R. = 10.07, C.I. 8.80-14.72) was more common in addicted patients as were general (O.R. = 3.64, C.I. 2.99-4.80) and road (O.R.= 2.73, C.I. 2.36-3.15) trauma. Conclusion: This study shows that despite shorter driving histories, addicted patients have worse driving careers and general trauma experience than the comparison group which is not explained by associated medical conditions. Trauma is relevant to addiction management at both the patient and policy levels. Substance dependence policies which focus largely on prevention of virus transmission likely have too narrow a public health focus, and tend to engender an unrealistically simplistic and trivialized view of the addiction syndrome. Reduction of drug driving and drug related trauma likely require policies which reduce drug use per se, and are not limited to harm reduction measures alone

MicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial Cells

BACKGROUND: MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated. METHODOLOGY/PRINCIPAL FINDINGS: We first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization. CONCLUSIONS/SIGNIFICANCE: Our results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB