Comparative Effectiveness of Step-up Therapies in Children with Asthma Prescribed Inhaled Corticosteroids : A Historical Cohort Study

This work was supported by the Respiratory Effectiveness Group. Acknowledgments We thank the Respiratory Effectiveness Group for funding this work, Annie Burden for assistance with statistics, and Simon Van Rysewyk and Lisa Law for assistance with medical writing.Peer reviewedPostprin

Orbital magnetoelectric coupling in band insulators

Magnetoelectric responses are a fundamental characteristic of materials that break time-reversal and inversion symmetries (notably multiferroics) and, remarkably, of "topological insulators" in which those symmetries are unbroken. Previous work has shown how to compute spin and lattice contributions to the magnetoelectric tensor. Here we solve the problem of orbital contributions by computing the frozen-lattice electronic polarization induced by a magnetic field. One part of this response (the "Chern-Simons term") can appear even in time-reversal-symmetric materials and has been previously shown to be quantized in topological insulators. In general materials there are additional orbital contributions to all parts of the magnetoelectric tensor; these vanish in topological insulators by symmetry and also vanish in several simplified models without time-reversal and inversion those magnetoelectric couplings were studied before. We give two derivations of the response formula, one based on a uniform magnetic field and one based on extrapolation of a long-wavelength magnetic field, and discuss some of the consequences of this formula.Comment: 13 page

Strains for studying Spore killer elements in four Neurospora species

This note gives a comprehensive list of stocks useful for working with Spore killer elements, including reference strains for use as testers, genetically marked derivatives, and strains sensitive and resistant to killing by Sk-1K, Sk-2K, and . Geographical site of origin is indicted for the various killer alleles. Many of the strains are newly deposited in FGSC. Some are listed also under other categories. Updated versions of the list will appear in future FGSC Stock Lists (Part IV, Special Purpose Stocks)

Skeletal loading in animals

A number of in vivo skeletal loading models have been developed to test specific hypotheses addressing the key mechanical and biochemical signals involved in bone’s adaptive response to loading. Exercise protocols, osteotomy procedures, loading of surgically implanted pins, and force application through the soft tissues are common approaches to alter the mechanical environment of a bone. Although each animal overload model has a number of assets and limitations, models employing extrinsic forces allow greater control of the mechanical environment. Sham controls, for both surgical intervention (when performed) and loading, are required to unequivocally demonstrate that responses to loading are mechanically adaptive. Collectively, extrinsic loading models have fostered a greater understanding of the mechanical signals important for stimulating bone cells, and highlighted the roles of key signaling molecules in the adaptive response

A maximum-likelihood method for improving faint source flux and color estimates

Flux estimates for faint sources or transients are systematically biased high because there are far more truly faint sources than bright. Corrections which account for this effect are presented as a function of signal-to-noise ratio and the (true) slope of the faint-source number-flux relation. The corrections depend on the source being originally identified in the image in which it is being photometered. If a source has been identified in other data, the corrections are different; a prescription for calculating the corrections is presented. Implications of these corrections for analyses of surveys are discussed; the most important is that sources identified at signal-to-noise ratios of four or less are practically useless.Comment: 9 pp., accepted for publication in PAS

Cooling Tests of an Airplane Equipped with an NACA Cowling and a Wing-duct Cooling System

Cooling tests were made of a Northrop A-17A attack airplane successively equipped with a conventional.NACA cowling and with a wing-duct cooling system. The method of cooling the engine by admitting air from the propeller slipstream into wing ducts, passing it first through the accessory compartment and then over the engine from rear to front, appeared to offer possibilities for improved engine cooling, increased cooling of the accessories, and better fairing of the power-plant installation. The results showed that ground cooling for the wing duct system without cowl flap was better than for the NACA cowling with flap; ground cooling was appreciably improved by installing a cowl flap. Satisfactory temperatures were maintained in both climb and high-speed flight, but, with the use of conventional baffles, a greater quantity of cooling air appeared to be required for the wing duct system

CART Raman Lidar Aerosol and Water Vapor Measurements in the Vicinity of Clouds

Aerosol and water vapor profiles acquired by the Raman lidar instrument located at the Climate Research Facility (CRF) at Southern Great Plains (SGP) provide data necessary to investigate the atmospheric variability in the vicinity of clouds near the top of the planetary boundary layer (PBL). Recent CARL upgrades and modifications to the routine processing algorithms afforded the necessarily high temporal and vertical data resolutions for these investigations. CARL measurements are used to investigate the behavior of aerosol backscattering and extinction and their correlation with water vapor and relative humidity

Applying UK real world primary care data to predict asthma attacks in 3776 well-characterised children : a retrospective cohort study

FUNDING This analysis was funded by Respiratory Effectiveness Group DATA AVAILABILITY STATEMENT Data are available from Clinical Practice Research Datalink (https://www.cprd.com/home/) and Optimum Patient Care (http://optimumpatientcare.org/about-us/).Peer reviewedPublisher PD

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. Case example:Naproxen

Background Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases. Methods In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middle-out approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a “worst/best case” dissolution scenario and average bioequivalence was assessed according to Cmax, AUC and Tmax. Results VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 min would lie comfortably within the bioequivalence limits for Cmax and AUC. Based on the establishment of VBE, a dissolution “safe space” was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated. Conclusion Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. Case example:Naproxen

Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases. Methods: In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middle-out approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a “worst/best case” dissolution scenario and average bioequivalence was assessed according to Cmax, AUC and tmax. Results: VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 minutes would lie comfortably within the bioequivalence limits for Cmax and AUC. Based on the establishment of VBE, a dissolution “safe space” was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated. Conclusion: Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk