300 research outputs found

    Enhanced Detection of Community-Acquired Pneumonia Pathogens With the BioFire® Pneumonia FilmArray® Panel.

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    Background: Although most observational studies identify viral or bacterial pathogens in 50% or less of patients hospitalized with community-acquired pneumonia (CAP), we previously demonstrated that a multi-test bundle (MTB) detected a potential pathogen in 73% of patients. This study compares detection rates for potential pathogens with the MTB versus the Biofire® Pneumonia FilmArray® panel (BPFA) multiplex PCR platform and presents an approach for integrating BPFA results as a foundation for subsequent antibiotic stewardship (AS) activities. Methods: Between January 2017 to March 2018, all patients admitted for CAP were enrolled. Patients were considered evaluable if all elements of the MTB and the BPFA were completed, and they met other a priori inclusion criteria. The primary endpoint was the percentage of potential pathogens detected using the MTB (8 viral and 6 bacterial targets) versus the BPFA (8 viral and 18 bacterial targets). Blood and sputum cultures were performed on all patients. Two or more procalcitonin (PCT) levels assisted clinical assessments as to whether detected bacteria were invading or colonizing. Results: Of 585 enrolled patients, 274 were evaluable. A potential viral pathogen was detected in 40.5% with MTB versus 60.9% of patients with BPFA with an odds ratio (95% CI) of 9.00 (4.12 to 23.30) p\u3c0.01. A potential bacterial pathogen was identified in 66.4% with the MTB vs 75.5% with the BPFA odds ratio (95% CI) of 2.09 (1.24 to 3.59), p 0.003). Low PCT levels helped identify detected bacteria as colonizers. Keywords: Community-acquired pneumonia; diagnostics; filmarray; pneumonia; procalcitonin

    Prediagnostic Plasma Vitamin D Metabolites and Mortality among Patients with Prostate Cancer

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    Laboratory evidence suggests that vitamin D might influence prostate cancer prognosis.We examined the associations between prediagnostic plasma levels of 25(OH)vitamin D [25(OH)D] and 1,25(OH)(2) vitamin D [1,25(OH)(2)D] and mortality among 1822 participants of the Health Professionals Follow-up Study and Physicians' Health Study who were diagnosed with prostate cancer. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total mortality (n = 595) and lethal prostate cancer (death from prostate cancer or development of bone metastases; n = 202). In models adjusted for age at diagnosis, BMI, physical activity, and smoking, we observed a HR of 1.22 (95% CI: 0.97, 1.54) for total mortality, comparing men in the lowest to the highest quartile of 25(OH)D. There was no association between 1,25(OH)(2)D and total mortality. Men with the lowest 25(OH)D quartile were more likely to die of their cancer (HR: 1.59; 95% CI: 1.06, 2.39) compared to those in the highest quartile (P(trend) = 0.006). This association was largely explained by the association between low 25(OH)D levels and advanced cancer stage and higher Gleason score, suggesting that these variables may mediate the influence of 25(OH)D on prognosis. The association also tended to be stronger among patients with samples collected within five years of cancer diagnosis. 1,25(OH)(2)D levels were not associated with lethal prostate cancer.Although potential bias of less advanced disease due to more screening activity among men with high 25(OH)D levels cannot be ruled out, higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis

    Linewidth of single photon transitions in Mn12_{12}-acetate

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    We use time-domain terahertz spectroscopy to measure the position and linewidth of single photon transitions in Mn12_{12}-acetate. This linewidth is compared to the linewidth measured in tunneling experiments. We conclude that local magnetic fields (due to dipole or hyperfine interactions) cannot be responsible for the observed linewidth, and suggest that the linewidth is due to variations in the anisotropy constants for different clusters. We also calculate a lower limit on the dipole field distribution that would be expected due to random orientations of clusters and find that collective effects must narrow this distribution in tunneling measurements.Comment: 5 pages, accepted to Physical Review

    Time to Initial Debridement and wound Excision (TIDE) in severe open tibial fractures and related clinical outcome: A multi-centre study

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    © 2018 Elsevier Ltd Background: Recent national (NICE) guidelines in England recommend that initial debridement and wound excision of open tibial fractures take place within 12 h of the time of injury, a change from the previous target of 24 h. This study aims to assess the effect of timing of the initial debridement and wound excision on major infective complications, the impact of the new guidance, and the feasibility of adhering to the 12 h target within the infrastructure currently existing in four major trauma centres in England. Methods: A retrospective review was performed of Gustilo-Anderson grade 3B open tibial fractures presenting acutely to four Major Trauma Centres (MTCs) in England with co-located plastic surgery services over a ten-month period. The incidence of deep infective complications was compared between patients who underwent initial surgery according to the new NICE guidance and those who did not. Patients warranting emergency surgery for severely contaminated injury, concomitant life-threatening injury and neurovascular compromise were excluded. Multi-variable logistic regression analysis was performed to assess the effect of timing of surgical debridement on development of deep infective complications. Results: 112 patients with 116 fractures were included. Six fractures (5.2%) developed deep infective complications. 38% (n = 44) underwent primary debridement within 12 h and 90% within 24 h. There was no significant difference in the incidence of major infective complications if debrided in less than or greater than 12 h (4.5% vs 5.6%, p = 1.00). Logistic regression found no significant relationship between timing of wound excision and development of deep infection. There was no significant decrease in mean time to debridement following introduction of new national guidance (13.6 vs 16.1 h) in these four MTCs. Conclusion: Overall, the rate of deep infection in high energy open tibial fractures managed within the four major trauma centes is low. Achieving surgical debridement within 12 h is challenging within the current infrastructure, and it is unclear whether adhering to this target will significantly affect the incidence of severe infective complications. Debridement within 24 h appears achievable. If a 12-h target is to be met, it is vital to ensure dedicated orthoplastic capacity is adequately resourced

    The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove

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    Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China

    Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage

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    The E3 ubiquitin ligase Rad18 mediates tolerance of replication fork-stalling bulky DNA lesions, but whether Rad18 mediates tolerance of bulky DNA lesions acquired outside S-phase is unclear. Using synchronized cultures of primary human cells, we defined cell cycle stage-specific contributions of Rad18 to genome maintenance in response to ultraviolet C (UVC) and H2O2-induced DNA damage. UVC and H2O2 treatments both induced Rad18-mediated proliferating cell nuclear antigen mono-ubiquitination during G0, G1 and S-phase. Rad18 was important for repressing H2O2-induced (but not ultraviolet-induced) double strand break (DSB) accumulation and ATM S1981 phosphorylation only during G1, indicating a specific role for Rad18 in processing of oxidative DNA lesions outside S-phase. However, H2O2-induced DSB formation in Rad18-depleted G1 cells was not associated with increased genotoxin sensitivity, indicating that back-up DSB repair mechanisms compensate for Rad18 deficiency. Indeed, in DNA LigIV-deficient cells Rad18-depletion conferred H2O2-sensitivity, demonstrating functional redundancy between Rad18 and non-homologous end joining for tolerance of oxidative DNA damage acquired during G1. In contrast with G1-synchronized cultures, S-phase cells were H2O2-sensitive following Rad18-depletion. We conclude that although Rad18 pathway activation by oxidative lesions is not restricted to S-phase, Rad18-mediated trans-lesion synthesis by Polη is dispensable for damage-tolerance in G1 (because of back-up non-homologous end joining-mediated DSB repair), yet Rad18 is necessary for damage tolerance during S-phase

    Modelling direct and indirect water requirements of construction

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    Water consumed directly by the construction industry is known to be of little importance. However, water consumed in the manufacture of goods and services required by construction may be significant in the context of a building\u27s life cycle water requirements and the national water budget. This paper evaluates the significance of water embodied in the construction of individual buildings. To do this, an input-output-based hybrid embodied water analysis was undertaken on 17 Australian non-residential case studies. It was found that there is a considerable amount of water embodied in construction. The highest value was 20.1 kilolitres (kL)/m2 gross floor area (GFA), representing many times the enclosed volume of the building, and many years worth of operational water. The water required by the main construction process is minimal. However, the water embodied in building materials is considerable. These findings suggest that the selection of elements and materials has a great impact on a building\u27s embodied water. This research allows the construction industry to evaluate design and construction in broad environmental terms to select options that might be cost neutral or possibly cost positive while retaining their environmental integrity. The research suggests policies focused on operational water consumption alone are inadequate. <br /

    Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

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    Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl- CoA isomerase (PECI) on chromosome 6. Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclearencoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis
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