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As you read this, trillions of microbes are growing on your face, between your teeth, and deep within your gut. To them your body is like a rainforest: rich in [...]

In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00–111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level α to 0.042 for a 2 × 3 × 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E. [ABSTRACT FROM AUTHOR]

Memorializing history in the landscape reflects deep-seated cultural needs. This process not only pays homage to the actions, events, or persons deemed significant at a particular point in time, but it also offers a chance for the creators of the historic marker to write their version of history and to use an interpretive format that highlights their understanding and values. The significance of selecting historical interpretations for commemoration plays a key role in shaping social memory.

Colloform textures have been described from many of the world's sulphide ore deposits and involve formation of distinct microcrystalline layers. These textures provide information related to sequential stages of ore formation, yet their mechanism of growth is poorly understood. This study has analysed a series of colloform samples from the Galmoy Zn + Pb mine, Ireland. Results indicate that the growth sequence is not always intuitive and layers that appear stratigraphic upon cursory observation may not be. The crystal preferred orientation (CPO) of discrete colloform layers abruptly switches between different orientation axes. Examination of the same layers using in situ laser sulphur isotope analysis reveals equally striking changes in [delta][sup.34]S signature between end-member bacteriogenic (-25[per thousand]) and hydrothermal (+10[per thousand]) sources. Although these results, combined with petrographic observation, allow the determination of a probable growth history, there is no correlation between shifting CPO and [delta][sup.34]S signature. Trace element analysis reveals changes in trace element sequestration between colloform layers. Cadmium- and chlorine-rich layers correspond to a hydrothermal sulphur source, whereas iron-rich layers correspond to a bacteriogenic sulphur source. In the absence of alternative mechanisms we suggest that the most likely factors influencing CPO changes are temperature and degree of supersaturation during two-fluid mixing.

Primary colloform textures preserved in ore deposits can be a useful tool in understanding changing conditions of ore formation due to the sequential development of the colloform layers. However, the growth controls that influence formation of these textures are poorly understood. To try to address this problem, samples from two ore deposits, Greens Creek in Alaska and Ezuri in Japan, have been systematically analyzed for grain size and shape, crystal preferred orientation (CPO), sulfur isotope composition, and trace element content. Grain size and shape varies between layers of equant, ~20 [micro]m crystals to acicular and elongate crystals up to several millimeters in length. Electron backscatter diffraction (EBSD) reveals that both samples have an initial random orientation of crystals with CPO in subsequent layers developed either about , , or crystallographic axes. Despite similarity in texture, the sulfur isotope results from Greens Creek colloforms have a very negative, open-system bacteriogenic [delta][sup.34]S between -40 and -32[per thousand], whereas the Ezuri colloform has a positive [delta][sup.34]S 0f ~+5[per thousand], typical of hydrothermal sulfur in Kuroko ores. Trace element results indicate variability in As, Sb, and Cu distribution. Whereas trace element variability at Greens Creek appears to be related to changes in [delta][sup.34]S, with a heavier signature correlating with sequestration of Sb in outer layers, overall the detailed analyses reveal that in both Greens Creek and Ezuri, there is no systematic correlation between sulfur source or trace element sequestration and CPO. This suggests that the abrupt changes in CPO recorded appear most likely to be influenced by changes in degree of supersaturation. Keywords: Pyrite, colloform, supersaturation, trace elements, S isotopes, EBSD

Rumors of a giant cross hidden deep in the Colorado Rocky Mountains finally proved true in 1873 with William Henry Jackson's photograph of Mount of the Holy Cross. Henry Wadsworth [...]

Orientation contrast imaging and quantitative electron back-scatter diffraction analysis of a zircon collected from an Indian Ocean gabbro reveal intragrain crystallographic misorientations (up to 14[degrees]) and low-angle orientation boundaries concentrated in the zircon tips. These features represent the formation and migration of dislocations and provide the first evidence of crystal-plastic deformation of zircon under crustal conditions. Panchromatic and wavelength cathodoluminescence (CL), combined with quantitative rare earth element (REE) ion microprobe analyses, demonstrate modification of zircon REE chemistry within the areas of crystal plasticity. These data indicate that the enhanced diffusion of REEs into the zircon is spatially linked to the presence of dislocations that behave as high-diffusivity pathways, increasing bulk diffusion rates and effective diffusion distances in the zircon by several orders of magnitude. In addition, discrete ~2 [micro]m zones of reduced panchromatic CL correspond exactly to the position of low-angle orientation boundaries and demonstrate a defect dependence on CL signal at high dislocation densities. The presence of deformation-related crystal-plastic microstructures in zircon, and their role in modifying elemental diffusion, questions the commonly made assumption of chemical robustness and has fundamental implications for the interpretation of zircon trace-element and isotopic data. Keywords: microstructure, diffusion, deformation, geochemistry, EBSD.

Objectives. We investigated the relationship between breastfeeding, asthma and atopy, and child body mass index (BMI). Methods. From a prospective birth cohort (n=2860) in Perth, Western Australia, 2195 children were followed up to age 6 years. Asthma was defined as doctor-diagnosed asthma and wheeze in the last year, and atopy was determined by skin prick test of 1596 children. Breastfeeding, BMI, asthma, and atopy were regressed allowing for confounders and the propensity score for overweight. Results. Using fractional polynomials, we found no association between breastfeeding and overweight. Less exclusive breastfeeding was associated with increased asthma and atopy, and BMI increased with asthma. Conclusions. Less exclusive breastfeeding leads to increases in child asthma and atopy and a higher BMI is a risk factor for asthma.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration‐time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax), to be included within the tighter acceptance range of 90.00–111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one‐size‐fits‐all" criterion is particularly questionable when the within‐subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within‐subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00–125.00% acceptance range for highly variable drugs. The 80.00–125.00% acceptance range is narrowed, only if the within‐subject variability is lower than 30%, down to the current NTI acceptance range of 90.00–111.11% when the within‐subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within‐subject variability is 20–30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within‐subject variability are frequently exposed to bioavailability differences larger than 10%. [ABSTRACT FROM AUTHOR]

An estimate of total factor productivity (TFP) change in the New England ground fish fishery from 1964 to 1993 is given, using a procedure similar to Squires method. SquireEs method extends standard TFP measurement by including the effect of fluctuations in stock abundance.