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The manufacturing of pharmaceutical solid dosage forms, such as tablets involves a large number of successive processing operations including crystallisation of the drug substance, granulation, drying, milling, mixing of the formulation, and compaction. Each step is fraught with manufacturing problems. Undesired adhesion of powders to the surface of the compaction tooling, known as sticking, is a frequent and highly disruptive problem that occurs at the very end of the process chain when the tablet is formed. As an alternative to the mechanistic approaches to address sticking, we introduce two different machine learning strategies to predict sticking directly from the chemical formula of the drug substance, represented by molecular descriptors. An empirical database for sticking behaviour was developed and used to train the machine learning (ML) algorithms to predict sticking properties from molecular descriptors. The ML model has successfully classified sticking/non-sticking behaviour of powders with 100% separation. Predictions were made for materials in the handbook of Pharmaceutical Excipients and a subset of molecules included in the ChemBL database, demonstrating the potential use of machine learning approaches to screen for sticking propensity early at drug discovery and development stages. This is the first-time molecular descriptors and machine learning were used to predict and screen for sticking behaviour. The method has potential to transform the development of medicines by providing manufacturability information at drug screening stage and is potentially applicable to other manufacturing problems controlled by the chemistry of the drug substance.

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Ex situ conservation efforts such as those of zoos, botanical gardens, and seed banks will form a vital complement to in situ conservation actions over the coming decades. It is therefore necessary to pay the same attention to the biological diversity represented in ex situ conservation facilities as is often paid to protected-area networks. Building the phylogenetic diversity of ex situ collections will strengthen our capacity to respond to biodiversity loss. Since 2000, the Millennium Seed Bank Partnership has banked seed from 14% of the world's plant species. We assessed the taxonomic, geographic, and phylogenetic diversity of the Millennium Seed Bank collection of legumes (Leguminosae). We compared the collection with all known legume genera, their known geographic range (at country and regional levels), and a genus-level phylogeny of the legume family constructed for this study. Over half the phylogenetic diversity of legumes at the genus level was represented in the Millennium Seed Bank. However, pragmatic prioritization of species of economic importance and endangerment has led to the banking of a less-than-optimal phylogenetic diversity and prioritization of range-restricted species risks an underdispersed collection. The current state of the phylogenetic diversity of legumes in the Millennium Seed Bank could be substantially improved through the strategic banking of relatively few additional taxa. Our method draws on tools that are widely applied to in situ conservation planning, and it can be used to evaluate and improve the phylogenetic diversity of ex situ collections.

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This multicentre study aimed to assess compliance of the reporting environment with best ergonomic practice and to determine the prevalence of musculoskeletal symptoms related to working as a radiologist. All 148 radiology trainees and consultants in 10 hospitals across the region were invited to complete a musculoskeletal symptoms and reporting ergonomics questionnaire. Best ergonomic reporting practice was defined, following literature review, as being able to alter the following: monitor, desk, chair and armrest height, chair back support, ambient light, and temperature. The frequency that these facilities were available and how often they were used was determined. One hundred and twenty-three out of 148 (83%) radiologists responded, and 38% reported radiology-associated occupational injury. Lower back discomfort was the commonest radiology associated musculoskeletal symptom (41%). Only 13% of those with occupational injury sought the advice of occupational health. No reporting environments conformed completely to best ergonomic practice. Where certain facilities were available, less than a third of radiologists made personal ergonomic adjustments prior to starting a reporting session. Radiologists who had good self-assessed knowledge of best ergonomic practice had significantly less back discomfort than those with poor self-assessed knowledge (P < 0.005). We demonstrated high prevalence of musculoskeletal symptoms amongst radiologists. Poor compliance of the reporting environment with best ergonomic practice, in combination with our other findings of a low level of ergonomic awareness, low rates of making ergonomic adjustments and seeking appropriate help, may be implicated. We hope this study raises awareness of this issue and helps prevent long-term occupational injury amongst radiologists from poor ergonomic practice.

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Radiology plays a central part in the acute stroke management pathway, with its role now widened beyond establishing the diagnosis. This article reviews the role of the non-enhanced computed tomography brain scan, particularly focusing on the hyper-acute presentation of stroke from a radiological perspective.

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Stroke is an important condition with high mortality and morbidity. Radiology plays a central part in the acute stroke management pathway, with its role now widened beyond establishing the diagnosis. This article reviews radiological techniques beyond the non-enhanced computed tomography brain scan.

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We report the case of a radiographically occult tibial fracture diagnosed sonographically and confirmed with CT. Ultrasound signs of cortical discontinuity and a three-layered fluid accumulation in the deep infrapatellar bursa were demonstrated.

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BACKGROUND: The Alberta Hip and Knee Replacement Project developed a new evidence-based clinical pathway (NCP) for total hip (THR) and knee (TKR) replacement. The aim was to facilitate the delivery of services in a timely and cost-effective manner while achieving the highest quality of care for the patient across the full continuum of care from patient referral to an orthopedic surgeon through surgery, recovery, and rehabilitation. The purpose of this article is to provide an overview of the study design, rationale, and execution of this project as a model for health technology assessment based on comparative effectiveness of alternative clinical pathways. METHODS: A pragmatic randomized controlled trial study design was used to evaluate the NCP compared with the standard of care (SOC) for these procedures. The pragmatic study design was selected as a rigorous approach to produce high quality evidence suitable for informing decisions between relevant interventions in real clinical practice. The NCP was evaluated in three of the nine regional health authorities (RHAs) in Alberta with dedicated central intake clinics offering multidisciplinary care teams, constituting 80 percent of THR and TKR surgeries performed annually in Alberta. Patients were identified in the offices of twenty orthopedic surgeons who routinely performed THR or TKR surgeries. Evaluation outcome measures were based on the six dimensions of the Alberta Quality Matrix for Health (AQMH): acceptability, accessibility, appropriateness, effectiveness, efficiency and safety. Data were collected prospectively through patient self-completed questionnaires at baseline and 3 and 12 months after surgery, ambulatory and inpatient chart reviews, and electronic administrative data. RESULTS: The trial design was successful in establishing similar groups for rigorous evaluation. Of the 4,985 patients invited to participate, 69 percent of patients consented. A total of 3,434 patients were randomized: 1,712 to SOC and 1,722 to the NCP. The baseline characteristics of patients in the two study arms, including demographics, comorbidity as measured by CDS and exposure to pain medications, and health-related quality of life, as measured by Western Ontario and McMaster Universities Osteoarthritis Index and Short Form-36, were similar. CONCLUSIONS: The Alberta Hip and Knee Replacement Project demonstrates the feasibility and advantages of applying a pragmatic randomized controlled trial to ascertain comparative effectiveness. This is a model for health technology assessment that incorporates how clinical pathways can be effectively evaluated.

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The spatiotemporal dynamics of chemical plumes in natural environments imposes complex time-varying responses on chemical detectors, challenging the use of conventional chemical analysis instrumentation, which often relies upon precisely controlled sampling of analytes. Insects take a different approach to this problem, typically exposing their diversity of chemical receptors to the full extent of the space-time dynamics inherent to these environments. Here we adopt a similar approach, by exposing differentially tuned chemosensor arrays to analytes dispersed in naturally turbulent chemical plumes from a point source. We propose a novel sensor preprocessing metric for complex time-varying chemosensor responses, termed sensor variation, which after normalization generates a stable array response fingerprint representative of the analyte generating the response, and is invariant over a range of distances from the source and source volumes. When applied to chemosensor array response time series, the resultant fingerprints are demonstrated to reliably support chemical classification of a group of pure analytes advected from a point source. By comparing classification performance to the same analytes at equivalent concentrations in controlled sampling conditions, we show that chemical source classification can be achieved in turbulent chemical plumes with similar accuracy to controlled experimental conditions.

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The contribution of time to the encoding of information by the nervous system is still controversial. The olfactory system is one of the standard preparations where this issue is empirically investigated. For instance, output neurons of the antennal lobe or the olfactory bulb display odor stimulus induced temporal modulations of their firing rate at a scale of hundreds of milliseconds. The role of these temporal patterns in the encoding of odor stimuli, however, is not yet known. Here, we use optical imaging of the projection neurons of the moth antennal lobe to address this question. First, we present a biophysically derived model that provides an accurate description of the calcium response of projection neurons. On the basis of this model, we subsequently show that the calcium response of the projection neurons displays a stimulus specific temporal structure. Finally, we demonstrate that an encoding scheme that includes this temporal information boosts classification performance by 60% as compared to a purely spatial encoding. Although the putative role of combinatorial spatio-temporal encoding strategies has been the subject of debate, our results for the first time establish quantitatively that such an encoding strategy is used by the insect brain.

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Natural odors are often complex mixtures of different compounds. These mixtures can be perceived to have qualities that are different from their components. Moreover, components can be difficult to distinguish within a blend, even if those components are identifiable when presented individually. Thus, odor components can interact along the olfactory pathway in a nonlinear fashion such that the mixture is not perceived simply as the sum of its components. Here we investigated odor-evoked changes in Ca2+ concentration to binary blends of plant-related substances in individually identified glomeruli in the moth Spodoptera littoralis. We used a wide range of blend ratios and a range of concentrations below the level at which glomerular responses become saturated. We found no statistically significant cases where the mixture response was greater than both component responses at the same total concentration (synergistic interactions) and no statistically significant cases where the mixture response was less than either component presented individually (suppressive interactions). Therefore, we conclude that, for the plant mixtures studied, information of their components is preserved in the neural representations encoded at the first stage of olfactory processing in this moth species.

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We study how individual components of a complex behavior, so-called behavioral units, should be sequentially arranged when the overall goal is energy efficiency. We apply an optimization scheme to an existing probabilistic model of C. elegans chemical gradient navigation and find a family of solutions that share common properties. This family is used to analyze general principles of behavioral unit organization, which give rise to search strategies that match qualitatively with those observed in the animal. Specifically, the reorientation behavior emerging in energy efficient virtual worm searchers mimics the pirouette strategy observed in C. elegans, and the virtual worms dwell at the peak of the gradient. Our model predicts that pirouettes are in part associated with the inability to evaluate the gradient during a turn and that the animal does not act upon gradient information while reversing. Together, our results indicate that energy efficiency is an important factor in determining C. elegans gradient navigation. Our framework for the analysis of complex behaviors may, in the future, be used as part of an integrated approach to studying the neural basis of these behaviors.

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Programmable logic designs are presented that achieve exact integration of leaky integrate-and-fire soma and dynamical synapse neuronal models and incorporate spike-time dependent plasticity and axonal delays. Highly accurate numerical performance has been achieved by modifying simpler forward-Euler-based circuitry requiring minimal circuit allocation, which, as we show, behaves equivalently to exact integration. These designs have been implemented and simulated at the behavioral and physical device levels, demonstrating close agreement with both numerical and analytical results. By exploiting finely grained parallelism and single clock cycle numerical iteration, these designs achieve simulation speeds at least five orders of magnitude faster than the nervous system, termed here hyper-real-time operation, when deployed on commercially available field-programmable gate array (FPGA) devices. Taken together, our designs form a programmable logic construction kit of commonly used neuronal model elements that supports the building of large and complex architectures of spiking neuron networks for real-time neuromorphic implementation, neurophysiological interfacing, or efficient parameter space investigations.

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Two recent experimental studies /20,21/ revealed that odorant-evoked activity-dependent competition is significant in the organisation and maintenance of the olfactory system. In this paper, we investigate the generation of a chemotopic sensory map in the olfactory bulb through three models driven by high-density optical chemosensor arrays which have similar properties to olfactory receptor neurons. By exposing the sensor arrays to various odours, these models were subjected to Hebbian learning to achieve self-organisation, potentially explaining the activity-dependent competition demonstrated by these recent studies. Our final model also predicts a role for periglomerular cells in the formation of the chemotopic sensory map in the olfactory bulb.

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Biological olfactory neurons are deployed as a population, most responding to a large variety of chemical compounds, that is, they possess unspecific receptive fields. The question of whether this unspecificity results from some physical constraint placed upon chemical transduction, or on the other hand, is beneficial to system performance is unclear. In this paper we employ the notion of Fisher information to address this question by quantifying how both the distribution and the tunings of the receptive fields within olfactory receptor populations affect the optimal estimation performance of the system. Our results show that overlapping sensory neuron tunings that respond to common chemical compounds have better estimation performance than perfectly specific tunings. Our results suggest two phenomena that might represent general principles of organization within biological sensory systems responding to multiple stimuli: maximization of the diversity of tunings and homogeneity in the distribution of these different receptive fields across the stimulus space (independent of the statistics of the input stimuli). Our model predicts that a local randomized mechanism controlling receptor specificities generates optimal multidimensional stimulus estimation, for which there is some experimental evidence from the biology.

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In this paper automatic sensor identification of sensor classes within a high-density randomized array, without a priori knowledge of sensor locations, is demonstrated. Two different fluorescence-based sensor types, with hundreds of replicates each, were randomly distributed into an optical imaging fiber array platform. The sensor element types were vapor-sensitive microspheres with the environmentally-sensitive fluorescent dye Nile Red adsorbed on their surface. Nile Red undergoes spectral changes when exposed to different microenvironmental polarity conditions, e.g. microsphere surface polarity or odor exposure. These reproducible sensor spectral changes, or sensor-response profiles, enable sensors within a randomized array to be grouped into categories by optical decoding methods. Two computational decoding methods (supervised and unsupervised) are introduced; equal classification rates were achieved for both. By comparing sensor responses from a randomized array with those obtained from known (control) arrays, 587 sensors were correctly classified with 99.32% accuracy. Although both methods were equally effective, the unsupervised method, which uses sensor response changes to odor exposure, is a better decoding model for the vapor-sensitive arrays studied, because it relies only on the odor-response profiles. Another decoding technique employed the emission spectra of the sensors and is more applicable to other types of multiplexed fluorescence-based arrays and assays. The sensor-decoding techniques are compared to demonstrate that sensors within high-density optical chemosensor arrays can be positionally-registered, or decoded, with no additional overhead in time or expense other than collecting the sensor-response profiles.