Existing microarray genotype-calling algorithms adopt either SNP-by-SNP (SNP-wise) or sample-by-sample (sample-wise) approaches to calling. We have developed a novel genotype-calling algorithm for ...the Illumina platform, optiCall, that uses both SNP-wise and sample-wise calling to more accurately ascertain genotypes at rare, low-frequency and common variants.
Using data from 4537 individuals from the 1958 British Birth Cohort genotyped on the Immunochip, we estimate the proportion of SNPs lost to downstream analysis due to false quality control failures, and rare variants misclassified as monomorphic, is only 1.38% with optiCall, in comparison to 3.87, 7.85 and 4.09% for Illuminus, GenoSNP and GenCall, respectively. We show that optiCall accurately captures rare variants and can correctly account for SNPs where probe intensity clouds are shifted from their expected positions.
optiCall is implemented in C++ for use on UNIX operating systems and is available for download at http://www.sanger.ac.uk/resources/software/opticall/.
Right ventricular (RV) failure after left ventricular assist device (LVAD) placement is a serious complication and is difficult to predict. In the era of destination therapy and the total artificial ...heart, predicting post-LVAD RV failure requiring mechanical support is extremely important.
We reviewed patient characteristics, laboratory values and hemodynamic data from 266 patients who underwent LVAD placement at the University of Pennsylvania from April 1995 to June 2007.
Of 266 LVAD recipients, 99 required RV assist device (BiVAD) placement (37%). We compared 36 parameters between LVAD (n = 167) and BiVAD patients (n = 99) to determine pre-operative risk factors for RV assist device (RVAD) need. By univariate analysis, 23 variables showed statistically significant differences between the two groups (p < or = 0.05). By multivariate logistic regression, cardiac index < or =2.2 liters/min/m(2) (odds ratio OR 5.7), RV stroke work index < or =0.25 mm Hg . liter/m(2) (OR 5.1), severe pre-operative RV dysfunction (OR 5.0), pre-operative creatinine > or =1.9 mg/dl (OR 4.8), previous cardiac surgery (OR 4.5) and systolic blood pressure < or =96 mm Hg (OR 2.9) were the best predictors of RVAD need.
The most significant predictors for RVAD need were cardiac index, RV stroke work index, severe pre-operative RV dysfunction, creatinine, previous cardiac surgery and systolic blood pressure. Using these data, we constructed an algorithm that can predict which LVAD patients will require RVAD with >80% sensitivity and specificity.
Governments and industries increasingly use offsets to compensate for the unavoidable impacts of development on biodiversity. However, high uncertainty about the biodiversity outcomes of offsetting ...strategies has led to significant criticism in the academic and policy literature, while the ad-hoc application of offset rules within a region may lead to offsets favouring some species and communities at the expense of others. Here we explored opportunities to improve offsetting outcomes through strategic regional offset approaches, underpinned by concepts of complementarity and irreplaceability from the conservation planning literature, in comparison to more commonly used like-for-like approach. We assessed different offsetting strategies in the Hunter Valley, NSW, a rapidly developing region in Australia with an active mining industry. We quantified regional-level biodiversity losses arising from minimal to extensive mining expansion, along with species-specific impacts for 569 flora and fauna species, and prioritized areas for protection, restoration or both to offset the anticipated losses. Accounting for how well the offsets would complement existing protected areas, we compared the area needed for offsetting and the expected biodiversity outcomes among the different strategies. Our results highlight the benefits of a more systematic approach to offsetting in terms of an enhanced understanding of regional-scale impacts, more efficient identification of offset sites and improved biodiversity outcomes. Our approach encourages forward thinking about impending threats to, and opportunities for, biodiversity conservation and could serve as a template for strategic regional offset planning based on plausible scenarios of future biodiversity loss.
•We explore strategic offsetting using complementarity and irreplaceability principles.•Strategic offsetting provided higher biodiversity returns than like-for-like approaches.•The like-for-like approaches tended to miss offsetting targets at medium to high levels of mining.•Mining impacts vary notably between species which is not captured by changes in vegetation types.•Species protection was more efficiently improved by strategic, species based offsetting.
Evolved gas analysis (EGA) data from the Sample Analysis at Mars (SAM) instrument suite indicated Fe-rich smectite, carbonate, oxidized organics, Fe/Mg sulfate, and chloride in sedimentary rocks from ...the Glen Torridon (GT) region of Gale crater that displayed phyllosilicate spectral signatures from orbit. SAM evolved H2O data indicated that the primary phyllosilicate in all GT samples was an Fe-rich dioctahedral smectite (e.g., nontronite) with lesser amounts of a phyllosilicate such as mixed layer talc-serpentine or greenalite-minnesotaite. CO(2) data supported the identification of siderite in several samples, and CO(2) and CO data was also consistent with trace oxidized organic compounds such as oxalate salts. SO(2) data indicated trace and/or amorphous Fe sulfates in all samples and one sample may contain Fe sulfides. SO(2) data points to significant Mg sulfates in two samples, and lesser amounts in several other samples. A lack of evolved O(2) indicated the absence of oxychlorine salts and Mn3+/Mn4+ oxides. The lack of, or very minor, evolved NO revealed absent or very trace nitrate/nitrite salts. HCl data suggested chloride salts in GT samples. Constraints from EGA data on mineralogy and chemistry indicated that the environmental history of GT involved alteration with fluids of variable redox potential, chemistry and pH under a range of fluid-to-rock ratio conditions. Several of the fluid episodes could have provided habitable environmental conditions and carbon would have been available to any past microbes though the lack of significant N could have been a limiting factor for microbial habitability in the GT region.
Objective It is generally accepted that patients who require biventricular assist device support have poorer outcomes than those requiring isolated left ventricular assist device support. However, it ...is unknown how the timing of biventricular assist device insertion affects outcomes. We hypothesized that planned biventricular assist device insertion improves survival compared with delayed conversion of left ventricular assist device support to biventricular assist device support. Methods We reviewed and compared outcomes of 266 patients undergoing left ventricular assist device or biventricular assist device placement at the University of Pennsylvania from April 1995 to June 2007. We subdivided patients receiving biventricular assist devices into planned biventricular assist device (P-BiVAD) and delayed biventricular assist device (D-BiVAD) groups based on the timing of right ventricular assist device insertion. We defined the D-BiVAD group as any failure of isolated left ventricular assist device support. Results Of 266 patients who receivd left ventricular assist devices, 99 (37%) required biventricular assist device support. We compared preoperative characteristics, successful bridging to transplantation, survival to hospital discharge, and Kaplan–Meier 1-year survival between the P-BiVAD (n = 71) and D-BiVAD (n = 28) groups. Preoperative comparison showed that patients who ultimately require biventricular support have similar preoperative status. Left ventricular assist device (n = 167) outcomes in all categories exceeded both P-BiVAD and D-BiVAD group outcomes. Furthermore, patients in the P-BiVAD group had superior survival to discharge than patients in the D-BiVAD group (51% vs 29%, P < .05). One-year and long-term Kaplan–Meier survival distribution confirmed this finding. There was also a trend toward improved bridging to transplantation in the P-BiVAD (n = 55) versus D-BiVAD (n = 22) groups (65% vs 45%, P = .10). Conclusion When patients at high risk for failure of isolated left ventricular assist device support are identified, proceeding directly to biventricular assist device implantation is advised because early institution of biventricular support results in dramatic improvement in survival.
The biomolecular mechanism of nickel carcinogenicity is driven by intracellular Ni cation. The role of nickel catalyst in single‐wall carbon nanotube toxicity will therefore depend on its ...bioavailability, which is highly uncertain due to encapsulation by carbon shells. This article measures the material‐specific Ni release into extra‐ and intracellular physiological fluid phases and suggests practical techniques for managing the metals contribution to SWNT toxicity.
The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique ...EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results.
Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation.
Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy.
This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way.
An improved measurement of the decay $B^0_S$ → $μ^+μ^-$ and searches for the decays $B^0$ → $μ^+μ^+$ and $B^0_S$ → $μ^+μ^-γ$ are performed at the LHCb experiment using data collected in proton-proton ...collisions at $\sqrt{s}$ = 7, 8 and 13 TeV. corresponding to integrated luminosities of 1, 2 and 6 fb-1, respectively. The $B^0_S$ → $μ^+μ^-$ branching fraction and effective lifetime are measured to be $\mathscr{B}$($B^0_S$ → $μ^+μ^-$) = (3.09$^{(+0.46+0.15)}_{(-0.43-0.11)}$) x 10-9 and $τ(B^0_s →μ^+μ^-)$ = (2.07 ± 0.29 ± 0.03) ps, respectively, where the uncertainties include both statistical and systematic contributions. No significant signal for $B^0$ → $μ^+μ^-$ and $B^0_S$ → $μ^+μ^-γ$ decays is found and the upper limits $\mathscr{B}$($B^0$ → $μ^+μ^-$) < 2.6 x 10-10 and $B^0_S$ → $μ^+μ^-γ$ < 2.0 x 10-9 at 95% confidence level are determined, where the latter is limited to the range $m_{μμ}$ > 4.9 GeV/c2. Additionally, the ratio between the $B^0$ → $μ^+μ^-$ and $B^0_S$ → $μ^+μ^-$ branching fractions is measured to be $\mathscr{R}_{μ+μ-}$ < 0.095 at 95% confidence level. The results are in agreement with the Standard Model predictions.
The production fractions of B¯s0 and Λb0 hadrons, normalized to the sum of B− and B¯0 fractions, are measured in 13 TeV pp collisions using data collected by the LHCb experiment, corresponding to an ...integrated luminosity of 1.67 fb−1. These ratios, averaged over the b hadron transverse momenta from 4 to 25 GeV and pseudorapidity from 2 to 5, are 0.122±0.006 for B¯s0, and 0.259±0.018 for Λb0, where the uncertainties arise from both statistical and systematic sources. The Λb0 ratio depends strongly on transverse momentum, while the B¯s0 ratio shows a mild dependence. Neither ratio shows variations with pseudorapidity. The measurements are made using semileptonic decays to minimize theoretical uncertainties. In addition, the ratio of D+ to D0 mesons produced in the sum of B¯0 and B− semileptonic decays is determined as 0.359±0.006±0.009, where the uncertainties are statistical and systematic.
While recent studies suggest that interleukin (IL)-1β production is modulated by macroautophagy or sensors of endoplasmic reticulum (ER) stress upon pro-inflammatory insult, autophagy and IL-1β ...production during viral infection has not been fully investigated. This was addressed using respiratory syncytial virus (RSV), which is associated with lung immunopathology, IL-1, and IL-17a secretion in severely infected patients. Mice deficient in the autophagy-associated protein Map1-LC3b (LC3b(-/-)) developed increased IL-17a-dependent lung pathology upon infection. RSV-infected LC3b(-/-) dendritic cells (DCs) fail to upregulate autophagosome formation, secrete IL-1β and IL-6, and elicit IL-17a production from CD4+ T cells. Bone marrow chimeras revealed that both structural and hematopoietic LC3b deficiency contribute to the development of IL-17a-dependent lung pathology in vivo. Further investigation revealed airway epithelium as the primary source of IL-1β during infection, whereas inhibition of the ER-stress sensor inositol-requiring protein-1 in primary airway epithelial cells reduced IL-1β production identifying a primary ER stress pathway. Finally, blockade of IL-1 receptor signaling in RSV-infected LC3b(-/-) mice abolished IL-17a-dependent lung pathology. These findings provide novel mechanistic insight into the contribution of autophagy- and ER stress-dependent cytokine production that initiate and maintain aberrant Th17 responses, while identifying IL-1 as a potential therapeutic target in the treatment of severe respiratory viral infections.
PDF
