Towards generic modelling of hospital wards: Reuse and redevelopment of simple models

This is the final version. Available on open access from Taylor & Francis via the DOI in this recordGeneric simulation models are designed to enable model reuse. We argue that there are two weaknesses within the generic simulation modelling literature. Firstly, that generic models sacrifice the relative simplicity of a bespoke simulation model for flexibility. Secondly, that generic models are published in conceptual form only. If researchers cannot access computer implementation of models, then there is little incentive or benefit to recode one over coding a simpler bespoke simulation model. We introduce an incremental approach to generic modelling in discrete-event simulation. We develop an archetype setting-specific generic model of a hospital ward. The archetype model is first developed and applied in a rehabilitation ward setting. Then a second team applies the model in a specialised intensive care setting. We report the successes, obstacles and redevelopment needed for reuse of the generic model along with how the results of these studies were used to inform healthcare delivery.National Institute for Health Research (NIHR

Special phase transformation and crystal growth pathways observed in nanoparticles†

Phase transformation and crystal growth in nanoparticles may happen via mechanisms distinct from those in bulk materials. We combine experimental studies of as-synthesized and hydrothermally coarsened titania (TiO(2)) and zinc sulfide (ZnS) with thermodynamic analysis, kinetic modeling and molecular dynamics (MD) simulations. The samples were characterized by transmission electron microscopy, X-ray diffraction, synchrotron X-ray absorption and scattering, and UV-vis spectroscopy. At low temperatures, phase transformation in titania nanoparticles occurs predominantly via interface nucleation at particle–particle contacts. Coarsening and crystal growth of titania nanoparticles can be described using the Smoluchowski equation. Oriented attachment-based crystal growth was common in both hydrothermal solutions and under dry conditions. MD simulations predict large structural perturbations within very fine particles, and are consistent with experimental results showing that ligand binding and change in aggregation state can cause phase transformation without particle coarsening. Such phenomena affect surface reactivity, thus may have important roles in geochemical cycling

Quantum Measurement Theory in Gravitational-Wave Detectors

The fast progress in improving the sensitivity of the gravitational-wave (GW) detectors, we all have witnessed in the recent years, has propelled the scientific community to the point, when quantum behaviour of such immense measurement devices as kilometer-long interferometers starts to matter. The time, when their sensitivity will be mainly limited by the quantum noise of light is round the corner, and finding the ways to reduce it will become a necessity. Therefore, the primary goal we pursued in this review was to familiarize a broad spectrum of readers with the theory of quantum measurements in the very form it finds application in the area of gravitational-wave detection. We focus on how quantum noise arises in gravitational-wave interferometers and what limitations it imposes on the achievable sensitivity. We start from the very basic concepts and gradually advance to the general linear quantum measurement theory and its application to the calculation of quantum noise in the contemporary and planned interferometric detectors of gravitational radiation of the first and second generation. Special attention is paid to the concept of Standard Quantum Limit and the methods of its surmounting.Comment: 147 pages, 46 figures, 1 table. Published in Living Reviews in Relativit

PPS, a Large Multidomain Protein, Functions with Sex-Lethal to Regulate Alternative Splicing in Drosophila

Alternative splicing controls the expression of many genes, including the Drosophila sex determination gene Sex-lethal (Sxl). Sxl expression is controlled via a negative regulatory mechanism where inclusion of the translation-terminating male exon is blocked in females. Previous studies have shown that the mechanism leading to exon skipping is autoregulatory and requires the SXL protein to antagonize exon inclusion by interacting with core spliceosomal proteins, including the U1 snRNP protein Sans-fille (SNF). In studies begun by screening for proteins that interact with SNF, we identified PPS, a previously uncharacterized protein, as a novel component of the machinery required for Sxl male exon skipping. PPS encodes a large protein with four signature motifs, PHD, BRK, TFS2M, and SPOC, typically found in proteins involved in transcription. We demonstrate that PPS has a direct role in Sxl male exon skipping by showing first that loss of function mutations have phenotypes indicative of Sxl misregulation and second that the PPS protein forms a complex with SXL and the unspliced Sxl RNA. In addition, we mapped the recruitment of PPS, SXL, and SNF along the Sxl gene using chromatin immunoprecipitation (ChIP), which revealed that, like many other splicing factors, these proteins bind their RNA targets while in close proximity to the DNA. Interestingly, while SNF and SXL are specifically recruited to their predicted binding sites, PPS has a distinct pattern of accumulation along the Sxl gene, associating with a region that includes, but is not limited to, the SxlPm promoter. Together, these data indicate that PPS is different from other splicing factors involved in male-exon skipping and suggest, for the first time, a functional link between transcription and SXL–mediated alternative splicing. Loss of zygotic PPS function, however, is lethal to both sexes, indicating that its role may be of broad significance

Same/Different Concept Learning by Capuchin Monkeys in Matching-to-Sample Tasks

The ability to understand similarities and analogies is a fundamental aspect of human advanced cognition. Although subject of considerable research in comparative cognition, the extent to which nonhuman species are capable of analogical reasoning is still debated. This study examined the conditions under which tufted capuchin monkeys (Cebus apella) acquire a same/different concept in a matching-to-sample task on the basis of relational similarity among multi-item stimuli. We evaluated (i) the ability of five capuchin monkeys to learn the same/different concept on the basis of the number of items composing the stimuli and (ii) the ability to match novel stimuli after training with both several small stimulus sets and a large stimulus set. We found the first evidence of same/different relational matching-to-sample abilities in a New World monkey and demonstrated that the ability to match novel stimuli is within the capacity of this species. Therefore, analogical reasoning can emerge in monkeys under specific training conditions

CCR3 and Choroidal Neovascularization

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly in industrialized countries. The “wet” AMD, characterized by the development of choroidal neovacularization (CNV), could result in rapid and severe loss of central vision. The critical role of vascular endothelial growth factor A (VEGF-A) in CNV development has been established and VEGF-A neutralization has become the standard care for wet AMD. Recently, CCR3 was reported to play an important role in CNV development and that CCR3 targeting was reported to be superior to VEGF-A targeting in CNV suppression. We investigated the role of CCR3 in CNV development using the Matrigel induced CNV and found that in both rats and mice, CNV was well-developed in the control eyes as well as in eyes treated with CCR3 antagonist SB328437 or CCR3 neutralizing antibodies. No statistically significant difference in CNV areas was found between the control and SB328437 or CCR3-ab treated eyes. Immunostaining showed no specific expression of CCR3 in or near CNV. In contrast, both VEGF-A neutralizing antibodies and rapamycin significantly suppressed CNV. These results indicate that CCR3 plays no significant role in CNV development and question the therapeutic approach of CCR3 targeting to suppress CNV. On the other hand, our data support the therapeutic strategies of VEGF-A and mTOR (mammalian target of rapamycin) targeting for CNV

Symbiotic relationship between brain structure and dynamics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Modulation of EEG spectral edge frequency during patterned pneumatic oral stimulation in preterm infants

Background—Stimulation of the nervous system plays a central role in brain development and neurodevelopmental outcome. Thalamocortical and corticocortical development is diminished in premature infants and correlated to electroencephalography (EEG) progression. The purpose of this study was to determine the effects of orocutaneous stimulation on the modulation of spectral edge frequency, fc=90% (SEF-90) derived from EEG recordings in preterm infants. Methods—Twenty two preterm infants were randomized to experimental and control conditions. Pulsed orocutaneous stimulation was presented during gavage feedings begun at around 32 weeks postmenstrual age (PMA). The SEF-90 was derived from 2-channel EEG recordings. Results—Compared to the control condition, the pulsed orocutaneous stimulation produced a significant reorganization of SEF-90 in the left (p = 0.005) and right (p \u3c 0.0001) hemispheres. Notably, the left and right hemisphere showed a reversal in the polarity of frequency shift, demonstrating hemispheric asymmetry in the frequency domain. Pulsed orocutaneous stimulation also produced a significant pattern of short term cortical adaptation and a long term neural adaptation manifest as a 0.5 Hz elevation in SEF-90 after repeated stimulation sessions. Conclusion—This is the first study to demonstrate the modulating effects of a servo-controlled oral somatosensory input on the spectral features of EEG activity in preterm infants

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodeling. Recently microglial cells have been shown to be responsible for a portion of synaptic remodeling, but the remaining mechanisms remain mysterious. Here we report a new role for astrocytes in actively engulfing CNS synapses. This process helps to mediate synapse elimination, requires the Megf10 and Mertk phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections and retain excess functional synapses. Lastly, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify Megf10 and Mertk as critical players in the synapse remodeling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes

Contrasting Epidemic Histories Reveal Pathogen-Mediated Balancing Selection on Class II MHC Diversity in a Wild Songbird

The extent to which pathogens maintain the extraordinary polymorphism at vertebrate Major Histocompatibility Complex (MHC) genes via balancing selection has intrigued evolutionary biologists for over half a century, but direct tests remain challenging. Here we examine whether a well-characterized epidemic of Mycoplasmal conjunctivitis resulted in balancing selection on class II MHC in a wild songbird host, the house finch (Carpodacus mexicanus). First, we confirmed the potential for pathogen-mediated balancing selection by experimentally demonstrating that house finches with intermediate to high multi-locus MHC diversity are more resistant to challenge with Mycoplasma gallisepticum. Second, we documented sequence and diversity-based signatures of pathogen-mediated balancing selection at class II MHC in exposed host populations that were absent in unexposed, control populations across an equivalent time period. Multi-locus MHC diversity significantly increased in exposed host populations following the epidemic despite initial compromised diversity levels from a recent introduction bottleneck in the exposed host range. We did not observe equivalent changes in allelic diversity or heterozygosity across eight neutral microsatellite loci, suggesting that the observations reflect selection rather than neutral demographic processes. Our results indicate that a virulent pathogen can exert sufficient balancing selection on class II MHC to rescue compromised levels of genetic variation for host resistance in a recently bottlenecked population. These results provide evidence for Haldane's long-standing hypothesis that pathogens directly contribute to the maintenance of the tremendous levels of genetic variation detected in natural populations of vertebrates