Prevalence of non-aureus Staphylococcus species causing intramammary infections in Canadian dairy herds

Non-aureus staphylococci (NAS), the microorganisms most frequently isolated from bovine milk worldwide, are a heterogeneous group of numerous species. To establish their importance as a group, the distribution of individual species needs to be determined. In the present study, NAS intramammary infection (IMI) was defined as a milk sample containing ≥1,000 cfu/mL in pure or mixed culture that was obtained from a cohort of cows assembled by the Canadian Bovine Mastitis Research Network. Overall, 6,213 (6.3%) of 98,233 quarter-milk samples from 5,149 cows and 20,305 udder quarters were associated with an NAS IMI. Of the 6,213 phenotypically identified NAS isolates, 5,509 (89%) were stored by the Canadian Bovine Mastitis Research Network Mastitis Pathogen Collection and characterized using partial sequencing of the rpoB housekeeping gene, confirming 5,434 isolates as NAS. Prevalence of each NAS species IMI was estimated using Bayesian models, with presence of a specific NAS species as the outcome. Overall quarter-level NAS IMI prevalence was 26%. The most prevalent species causing IMI were Staphylococcus chromogenes (13%), Staphylococcus simulans (4%), Staphylococcus haemolyticus (3%), Staphylococcus xylosus (2%), and Staphylococcus epidermidis (1%). The prevalence of NAS IMI as a group was highest in first-parity heifers and was evenly distributed throughout cows in parities ≥2. The IMI prevalence of some species such as S. chromogenes, S. simulans, and S. epidermidis differed among parities. Overall prevalence of NAS IMI was 35% at calving, decreased over the next 10 d, and then gradually increased until the end of lactation. The prevalence of S. chromogenes, Staphylococcus gallinarum, Staphylococcus cohnii, and Staphylococcus capitis was highest at calving, whereas the prevalence of S. chromogenes, S. haemolyticus, S. xylosus, and S. cohnii increased during lactation. Although the overall prevalence of NAS IMI was similar across barn types, the prevalence of S. simulans, S. xylosus, S. cohnii, Staphylococcus saprophyticus, S. capitis, and Staphylococcus arlettae IMI was higher in tie-stall barns; the prevalence of S. epidermidis IMI was lowest; and the prevalence of S. chromogenes and Staphylococcus sciuri IMI was highest in bedded-pack barns. Staphylococcus simulans, S. epidermidis, S. xylosus, and S. cohnii IMI were more prevalent in herds with intermediate to high bulk milk somatic cell count (BMSCC) and S. haemolyticus IMI was more prevalent in herds with high BMSCC, whereas other common NAS species IMI were equally prevalent in all 3 BMSCC categories. Distribution of NAS species IMI differed among the 4 regions of Canada. In conclusion, distribution differed considerably among NAS species IMI; therefore, accurate identification (species level) is essential for studying NAS epidemiology

An Improved Implementation and Abstract Interface for Hybrid

Hybrid is a formal theory implemented in Isabelle/HOL that provides an interface for representing and reasoning about object languages using higher-order abstract syntax (HOAS). This interface is built around an HOAS variable-binding operator that is constructed definitionally from a de Bruijn index representation. In this paper we make a variety of improvements to Hybrid, culminating in an abstract interface that on one hand makes Hybrid a more mathematically satisfactory theory, and on the other hand has important practical benefits. We start with a modification of Hybrid's type of terms that better hides its implementation in terms of de Bruijn indices, by excluding at the type level terms with dangling indices. We present an improved set of definitions, and a series of new lemmas that provide a complete characterization of Hybrid's primitives in terms of properties stated at the HOAS level. Benefits of this new package include a new proof of adequacy and improvements to reasoning about object logics. Such proofs are carried out at the higher level with no involvement of the lower level de Bruijn syntax.Comment: In Proceedings LFMTP 2011, arXiv:1110.668

The Development of Peptide-Based Tools for the Analysis of Angiogenesis

SummaryLimitations to the application of molecularly targeted cancer therapies are the inability to accurately match patient with effective treatment and the absence of a prompt readout of posttreatment response. Noninvasive agents that rapidly report vascular endothelial growth factor (VEGF) levels using positron emission tomography (PET) have the potential to enhance anti-angiogenesis therapies. Using phage display, two distinct classes of peptides were identified that bind to VEGF with nanomolar affinity and high selectivity. Co-crystal structures of these different peptide classes demonstrate that both bind to the receptor-binding region of VEGF. 18F-radiolabelling of these peptides facilitated the acquisition of PET images of tumor VEGF levels in a HM7 xenograph model. The images obtained from one 59-residue probe, 18F-Z-3B, 2 hr postinjection are comparable to those obtained with anti-VEGF antibody B20 72 hr postinjection. Furthermore, VEGF levels in growing SKOV3 tumors were followed using 18F-Z-3B as a PET probe with VEGF levels increasing with tumor size

A Nonperturbative Eliasson's Reducibility Theorem

This paper is concerned with discrete, one-dimensional Schr\"odinger operators with real analytic potentials and one Diophantine frequency. Using localization and duality we show that almost every point in the spectrum admits a quasi-periodic Bloch wave if the potential is smaller than a certain constant which does not depend on the precise Diophantine conditions. The associated first-order system, a quasi-periodic skew-product, is shown to be reducible for almost all values of the energy. This is a partial nonperturbative generalization of a reducibility theorem by Eliasson. We also extend nonperturbatively the genericity of Cantor spectrum for these Schr\"odinger operators. Finally we prove that in our setting, Cantor spectrum implies the existence of a $G_\delta$-set of energies whose Schr\"odinger cocycle is not reducible to constant coefficients

Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89 Zr 4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice

Abstract A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of 89 Zr; subsequently, it was used as a bi-functional chelator for preparation of 89 Zr-labeled antibodies. Quantitative chelation of 89 Zr 4+ with the octadentate ligand forming 89 ZrL complex was achieved under mild conditions within 15 minutes. The 89 Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic 89 Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of 89 Zr 4+ from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with 89 Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of 89 Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control 89 Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of 89 Zr-labeled monoclonal antibodies for immunoPET studies

Appropriate referral and selection of patients with chronic pain for spinal cord stimulation: European consensus recommendations and e-health tool

Background: Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic, neuropathic-like and ischaemic pain. However, the heterogeneity of patients in daily clinical practice makes it often challenging to determine which patients are eligible for this treatment, resulting in undesirable practice variations. This study aimed to establish patient-specific recommendations for referral and selection of SCS in chronic pain. Methods: A multidisciplinary European panel used the RAND/UCLA Appropriateness Method (RUAM) to assess the appropriateness of (referral for) SCS for 386 clinical scenarios in four pain areas: chronic low back pain and/or leg pain, complex regional pain syndrome, neuropathic pain syndromes and ischaemic pain syndromes. In addition, the panel identified a set of psychosocial factors that are relevant to the decision for SCS treatment. Results: Appropriateness of SCS was strongly determined by the neuropathic or neuropathic-like pain component, location and spread of pain, anatomic abnormalities and previous response to therapies targeting pain processing (e.g. nerve block). Psychosocial factors considered relevant for SCS selection were as follows: lack of engagement, dysfunctional coping, unrealistic expectations, inadequate daily activity level, problematic social support, secondary gain, psychological distress and unwillingness to reduce high-dose opioids. An educational e-health tool was developed that combines clinical and psychosocial factors into an advice on referral/selection for SCS. Conclusions: The RUAM was useful to establish a consensus on patient-specific criteria for referral/selection for SCS in chronic pain. The e-health tool may help physicians learn to apply an integrated approach of clinical and psychosocial factors. Significance: Determining the eligibility of SCS in patients with chronic pain requires careful consideration of a variety of clinical and psychosocial factors. Using a systematic approach to combine evidence from clinical studies and expert opinion, a multidisciplinary European expert panel developed detailed recommendations to support appropriate referral and selection for SCS in chronic pain. These recommendations are available as an educational e-health tool (https://www.scstool.org/)

Erosion by an Alpine glacier

Assessing the impact of glaciation on Earth’s surface requires understanding glacial erosion processes. Developing erosion theories is challenging because of the complex nature of the erosion processes and the difficulty of examining the ice/bedrock interface of contemporary glaciers. We demonstrate that the glacial erosion rate is proportional to the ice-sliding velocity squared, by quantifying spatial variations in ice-sliding velocity and the erosion rate of a fast-flowing Alpine glacier. The nonlinear behavior implies a high erosion sensitivity to small variations in topographic slope and precipitation. A nonlinear rate law suggests that abrasion may dominate over other erosion processes in fast-flowing glaciers. It may also explain the wide range of observed glacial erosion rates and, in part, the impact of glaciation on mountainous landscapes during the past few million years

A Solvable Regime of Disorder and Interactions in Ballistic Nanostructures, Part I: Consequences for Coulomb Blockade

We provide a framework for analyzing the problem of interacting electrons in a ballistic quantum dot with chaotic boundary conditions within an energy $E_T$ (the Thouless energy) of the Fermi energy. Within this window we show that the interactions can be characterized by Landau Fermi liquid parameters. When $g$, the dimensionless conductance of the dot, is large, we find that the disordered interacting problem can be solved in a saddle-point approximation which becomes exact as $g\to\infty$ (as in a large-N theory). The infinite $g$ theory shows a transition to a strong-coupling phase characterized by the same order parameter as in the Pomeranchuk transition in clean systems (a spontaneous interaction-induced Fermi surface distortion), but smeared and pinned by disorder. At finite $g$, the two phases and critical point evolve into three regimes in the $u_m-1/g$ plane -- weak- and strong-coupling regimes separated by crossover lines from a quantum-critical regime controlled by the quantum critical point. In the strong-coupling and quantum-critical regions, the quasiparticle acquires a width of the same order as the level spacing $\Delta$ within a few $\Delta$'s of the Fermi energy due to coupling to collective excitations. In the strong coupling regime if $m$ is odd, the dot will (if isolated) cross over from the orthogonal to unitary ensemble for an exponentially small external flux, or will (if strongly coupled to leads) break time-reversal symmetry spontaneously.Comment: 33 pages, 14 figures. Very minor changes. We have clarified that we are treating charge-channel instabilities in spinful systems, leaving spin-channel instabilities for future work. No substantive results are change

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1

The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. Zr-89-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.1). Three aspects of ADC biology were measured and compared: efficacy was measured in tumor growth inhibition studies; target expression was measured by immunohistochemistry and flow cytometry; and tumor antibody uptake was measured with In-111-mAbs and gamma counting or with Zr-89-immunoPET. Within each model, the mAb with the highest tumor uptake showed the greatest potency as an ADC. Sensitivity between models varied, with the LuCaP77 model showing weak efficacy despite high target expression and high antibody uptake. Ex vivo analysis confirmed the in vivo results, showing a correlation between expression, uptake and ADC efficacy. We conclude that Zr-89-immunoPET data can demonstrate which ADC candidates achieve the penetration, binding, and internalization necessary for efficacy in tumors sensitive to the toxic payload