Development of a spatially and timely resolved CFD model of a steam sterilizer to predict the load temperature and the theoretical inactivation of bacteria based on sterilization parameters

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Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKR

Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen

Toxic effects of phenothiazines on the eye

Publications about the retinotoxic action of phenothiazine derivatives led the author to undertake an ophthalmological investigation in two psychiatric hospitals in The Netherlands. The pharmacological actions of phenothiazine preparations are listed and a survey of the phenothiazine derivatives which are at present in use is given. Some retinotoxic substances are discussed and a survey is given of the literature on the ocular complications of phenothiazine therapy. The eyes of 561 patients were examined. of whom 541 are included in this study. 343 of these patients(63.4 %) were found to have retinopathy. The correlation between the retinopathy and the total dose of phenothiazine preparations taken. and between the retinopathy and the duration of treatment. was highly significant. The correlation between the retinopathy and the average daily dose taken was significant. The retinopathy was associated with a reduced standing potential of the eye. as determined by electro-oculography. It was possibly responsible for diminished visual acuity in some cases, and for an abnormally large proportion of protans in the group of patients with colour defects. It was not possible to ascribe a more severe retinotoxic action to one or more specific phenothiazine derivatives than to others. In the author's opinion regular examination of the eyes of patients who are being treated with phenothiazine preparations in high dosage and for for a long period of time is indicated

Quantifying climate change impacts on low flows of small high mountain watersheds: A nonstationary approach

Study region: The Utah Wasatch Mountains along the eastern Great Basin and the western Rocky Mountains. Study focus: Changes in seasonal precipitation patterns and summer evaporation rates due to increases in temperatures will have severe impacts on low flows of the mountainous watersheds affecting downstream water availability and thus impacting ecosystems and drinking water supplies under future climate change. Reliable prediction of climate change impacts on future low flows needs to consider both the extremity of climatic variables and the physical characteristics of the watersheds. This study analyzes low flows of small mountainous watersheds addressing nonstationarity of climatic parameters and estimates the impact of climate change on low flow, combining nonstationarity and outcome of a physically distributed hydrologic model. MACA statistically downscaled climate data have been used as inputs to the DHSVM model to estimate future low flows for both near term (2036–2044) and distant future (2091–2099) under RCP4.5 and 8.5 scenarios.New Hydrological Insights for the Region: Nonstationary models with time (5 watersheds) or temperature (2 watersheds) as the covariate in the location-scale provided the best performance. This study demonstrated that RCP4.5 has more severe impact on the low flow frequency and volume in the near future than RCP8.5. In contrast, the effect of RCP8.5 is more dominant on the low flow regimes in the distant future than RCP4.5

Captured streams and springs in combined sewers: A review of the evidence, consequences and opportunities

Captured streams and springs may be flowing in combined sewers, increasing clean baseflow in pipes and wastewater treatment works (WwTWs), reducing pipe capacity and increasing treatment costs. The UK water industry is aware of this in principle, but there has been no explicit discussion of this in the published literature, nor have there been any known attempts to manage it. Instead, the current focus is on the similar intrusion of groundwater infiltration through pipe cracks and joints. We have conducted a thorough review of literature and international case studies to investigate stream and spring capture, finding several examples with convincing evidence that this occurs. We identify three modes of entry: capture by conversion, capture by interception, and direct spring capture. Methods to identify and quantify capture are limited, but the experience in Zurich suggests that it contributed 7–16% of the baseflow reaching WwTWs. There are negative impacts for the water industry in capital and operational expenditure, as well as environmental and social impacts of loss of urban streams. For a typical WwTW (Esholt, Bradford) with 16% of baseflow from captured streams and springs, we conservatively estimate annual costs of £2 million to £7 million. A detailed case study from Zurich is considered that has successfully separated captured baseflow into daylighted streams through the urban area, with multiple economic, environmental and social benefits. We conclude that there is a strong case for the UK water industry to consider captured streams and springs, quantify them, and assess the merits of managing them

The RESTORE Study Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema

Objective: To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). Design: A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. Participants: We included 345 patients aged >= 18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. Methods: Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). Main Outcome Measures: Mean average change in BCVA from baseline to month 1 through 12 and safety. Results: Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P = 15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 mu m) and ranibizumab + laser (-128.3 mu m) versus laser (-61.3 mu m; both P <0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P <0.05 for composite score and vision-related subscales) versus laser. Patients received similar to 7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. Conclusions: Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011; 118: 615-625 (C) 2011 by the American Academy of Ophthalmolog

Electronic Energy Transport in c-Si Irradiated with X-ray Beam Under Grazing Incidence Angles

The rapid development of a new generation of X-ray radiation sources providing ultrashort (from atto- to femtoseconds) pulses creates unique possibilities for generating high energy density states of matter. Instruments, like free-electron lasers (FELs) produce pulses of very high intensity and allow to extend the optical studies of radiation induced phase transitions of solids. The excitation of solid materials with x-ray femtosecond pulses offers a number of advantages over irradiation with femtosecond optical lasers. First of all the energy deposition process is not influenced by optical nonlinearities i.e. multiphoton absorption and free carrier absorption. Moreover the absorption depth can be varied over many orders of magnitude. E.g. for silicon it changes from a few nanometres up to hundreds of microns. Therefore, ultrashort X-ray pulses allow the preparation of well-defined excitation conditions in variable sample volumes and thus to study the energy transport processes. Single shot irradiations of the Si flat mirror were performed at SACLA FEL facilities in the range of 5.5 – 12 keV photon energies, at normal and grazing incidence angles. Observed radiation induced structural modification of materials is related to melting of silicon and its resolidification and a have threshold nature. The experimental damage thresholds are the highest in case of the irradiations below the critical angles. In these cases the energy density of the radiation absorbed at the sample’s surface can reach above a melting threshold (approx. 1eV/atom) without any structural modification. This may be explained by the transport of the energy out of the excitation volume (limited to the absorption skin depth) by hot electrons on the time scales shorter than the one typical for the electron-phonon coupling (~2 ps for Si). Modelling of the energy transport by ballistic electrons has been performed by means of the PENELOPE simulation code