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1.
Comparative effectiveness research aims, in part, to provide evidence most relevant to clinical decision making. One decision relevant to hypertensive patients is which therapeutic drug class is the most safe and effective. In addition, once a drug class has been chosen it would be useful to know whether there are differences in effectiveness between drugs within class. Randomized trials are unlikely to provide sufficient evidence for answering these questions. We therefore propose a modeling approach that can be used to address the questions using administrative databases. We propose a Bayesian hierarchical model, where drugs are nested within their corresponding class. We account for the type of missing data that are common in these databases using a pattern mixture model. The methodology is illustrated using data from a comparative effectiveness study of antihypertensive medications. 相似文献
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Evolutionary radiations, times of profound diversification of species against a broader background of more muted evolutionary
change, have long been considered one of the fundamental patterns in the fossil record. Further, given the important role
geological, environmental, and climatic processes play in causing speciation, analyzing the biogeographic context of radiations
can yield important insight into their evolutionary mechanisms. In this study we examine biogeographic patterns and quantify
rates of speciation in a diverse group of Devonian trilobites, the calmoniids, that has been hailed as a classic paleontological
example of an evolutionary radiation. In particular, a phylogenetic biogeographic analysis—modified Brooks Parsimony Analysis—was
used to examine the processes and geographic setting of speciation within the group. Results indicate that the Malvinokaffric
Realm was a geographically complex area, and this geographic complexity created various opportunities for speciation via geodispersal
and vicariance that created the fuel that fed the speciation in these taxa. Part of the geographic complexity was created
not only by the inherent geologic backdrop of the region, but the overlying changes of sea level rise and fall. Rates of speciation
were highest when sea level was lowest. Low sea level encouraged isolation of faunas in different tectonic basins. By contrast,
sea level rise facilitated range expansion and geodispersal to other distinct tectonic basins, and speciation rates concomitantly
fell; however, the taxa with the expanded ranges were later fodder for diversification when sea level fell again. Here we
present a view of evolutionary radiations driven fundamentally by external abiotic factors—geology and climate—that cause
range expansion and opportunities for geographic isolation with resultant rapid speciation. 相似文献
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To date, most studies comparing prospective and retrospective timing have failed to use long durations and tasks with a certain degree of ecological validity. The present study assessed the effect of the timing paradigm on playing video games in a “naturalistic environment” (gaming centers). In addition, as it involved gamers, it provided an opportunity to examine the effect of gaming profile on time estimation. A total of 116 participants were asked to estimate prospectively or retrospectively a video game session lasting 12, 35 or 58 minutes. The results indicate that time is perceived as longer in the prospective paradigm than in the retrospective one, although the variability of estimates is the same. Moreover, the 12-minute session was perceived as longer, proportionally, than the 35- and 58-minute sessions. The study also revealed that the number of hours participants spent playing video games per week was a significant predictor of time estimates. To account for the main findings, the differences between prospective and retrospective timing are discussed in quantitative terms using a proposed theoretical framework, which states that both paradigms use the same cognitive processes, but in different proportions. Finally, the hypothesis that gamers play more because they underestimate time is also discussed. 相似文献
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Application of Quality by Design to the Process Development of Botanical Drug Products: A Case Study
This paper was designed to assess the value of quality by design (QbD) to improve the manufacturing process understanding of botanical drug products. Ethanol precipitation, a widely used unit operation in the manufacture of botanical drug products was employed to illustrate the use of QbD, taking the process of danshen (the dry root of Salvia miltiorrhiza Bunge) as an example. The recovery of four active pharmaceutical ingredients (APIs) and the removal of saccharides were used to represent the performance of ethanol precipitation. Potentially critical variables, including density of concentrate, ethanol consumption, and settling temperature were identified through risk assessment methods. Design of experiments (DOE) was used to evaluate the effects of the potentially critical factors on the performance of ethanol precipitation. It was observed that higher density of concentrate leads to higher removal of saccharides, but results in lower recovery of APIs. With the rise of ethanol consumption, the recovery of different APIs behaves in different ways. A potential design space of ethanol precipitation operation was established through DOE studies. The results in this work facilitate the enhanced understanding of the relationships between multiple factors (material attributes and process parameters) and the performance of ethanol precipitation. This case study demonstrated that QbD is a powerful tool to develop manufacturing process of botanical drug products. 相似文献
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Scott Newman Karen D. Howarth Chris D. Greenman Graham R. Bignell Simon Tavaré Paul A. W. Edwards 《PloS one》2013,8(6)
Many tumors have highly rearranged genomes, but a major unknown is the relative importance and timing of genome rearrangements compared to sequence-level mutation. Chromosome instability might arise early, be a late event contributing little to cancer development, or happen as a single catastrophic event. Another unknown is which of the point mutations and rearrangements are selected. To address these questions we show, using the breast cancer cell line HCC1187 as a model, that we can reconstruct the likely history of a breast cancer genome. We assembled probably the most complete map to date of a cancer genome, by combining molecular cytogenetic analysis with sequence data. In particular, we assigned most sequence-level mutations to individual chromosomes by sequencing of flow sorted chromosomes. The parent of origin of each chromosome was assigned from SNP arrays. We were then able to classify most of the mutations as earlier or later according to whether they occurred before or after a landmark event in the evolution of the genome, endoreduplication (duplication of its entire genome). Genome rearrangements and sequence-level mutations were fairly evenly divided earlier and later, suggesting that genetic instability was relatively constant throughout the life of this tumor, and chromosome instability was not a late event. Mutations that caused chromosome instability would be in the earlier set. Strikingly, the great majority of inactivating mutations and in-frame gene fusions happened earlier. The non-random timing of some of the mutations may be evidence that they were selected. 相似文献
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Background
Acetylcholinesterase inhibitors (AChEIs) are widely used to delay cognitive decline in Alzheimer''s disease. Observational studies in routine clinical practice have shown cognitive improvement in some groups of patients receiving these agents but longitudinal trajectories before and after AChEI initiation have not previously been considered.Objectives
To compare trajectories of cognitive function before and after AChEI initiation and investigate predictors of these differences.Method
A retrospective longitudinal study was constructed using data from 2460 patients who received AChEIs and who had routine data on cognitive function (Mini-Mental State Examination; MMSE) before and after AChEI initiation. Longitudinal MMSE change was modelled using three-piece linear mixed models with the following segments: 0–12 months prior to AChEI initiation, 0–6 months and 6–36 months after initiation.Results
MMSE decline was reversed (in that the slope was improved by an average 4.2 units per year, 95% CI 3.5–4.8) during the 6-month period following AChEI initiation compared with the slope in the one year period before AChEI initiation. The slope in the period from 6–36 months following AChEI initiation returned to the pre-initiation downward trajectory. The differences in slopes in the 1 year period prior to AChEI initiation and in the 6 months after initiation were smaller among those with higher MMSE scores at the time of AChEI initiation, among those who received a vascular dementia diagnosis at any point, and among those receiving antipsychotic agents.Conclusion
In this naturalistic observational study, changes in cognitive trajectories around AChEI initiation were similar to those reported in randomised controlled trials. The magnitude of the difference in slopes between the 1 year period prior to AChEI initiation and the 6 month period after AChEI initiation was related to level of cognitive function at treatment initiation, vascular comorbidity and antipsychotic use. 相似文献12.
Enrico Premi Franco Cauda Roberto Gasparotti Matteo Diano Silvana Archetti Alessandro Padovani Barbara Borroni 《PloS one》2014,9(9)
Background
Monogenic dementias represent a great opportunity to trace disease progression from preclinical to symptomatic stages. Frontotemporal Dementia related to Granulin (GRN) mutations presents a specific framework of brain damage, involving fronto-temporal regions and long inter-hemispheric white matter bundles. Multimodal resting-state functional MRI (rs-fMRI) is a promising tool to carefully describe disease signature from the earliest disease phase.Objective
To define local connectivity alterations in GRN related pathology moving from the presymptomatic (asymptomatic GRN mutation carriers) to the clinical phase of the disease (GRN- related Frontotemporal Dementia).Methods
Thirty-one GRN Thr272fs mutation carriers (14 patients with Frontotemporal Dementia and 17 asymptomatic carriers) and 38 healthy controls were recruited. Local connectivity measures (Regional Homogeneity (ReHo), Fractional Amplitude of Low Frequency Fluctuation (fALFF) and Degree Centrality (DC)) were computed, considering age and gender as nuisance variables as well as the influence of voxel-level gray matter atrophy.Results
Asymptomatic GRN carriers had selective reduced ReHo in the left parietal region and increased ReHo in frontal regions compared to healthy controls. Considering Frontotemporal Dementia patients, all measures (ReHo, fALFF and DC) were reduced in inferior parietal, frontal lobes and posterior cingulate cortex. Considering GRN mutation carriers, an inverse correlation with age in the posterior cingulate cortex, inferior parietal lobule and orbitofrontal cortex was found.Conclusions
GRN pathology is characterized by functional brain network alterations even decades before the clinical onset; they involve the parietal region primarily and then spread to the anterior regions of the brain, supporting the concept of molecular nexopathies. 相似文献13.
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Laurence Flori Sébastien Fritz Florence Jaffrézic Mekki Boussaha Ivo Gut Simon Heath Jean-Louis Foulley Mathieu Gautier 《PloS one》2009,4(8)
Dairy cattle breeds have been subjected over the last fifty years to intense artificial selection towards improvement of milk production traits. In this study, we performed a whole genome scan for differentiation using 42,486 SNPs in the three major French dairy cattle breeds (Holstein, Normande and Montbéliarde) to identify the main physiological pathways and regions which were affected by this selection. After analyzing the population structure, we estimated FST within and across the three breeds for each SNP under a pure drift model. We further considered two different strategies to evaluate the effect of selection at the genome level. First, smoothing FST values over each chromosome with a local variable bandwidth kernel estimator allowed identifying 13 highly significant regions subjected to strong and/or recent positive selection. Some of them contained genes within which causal variants with strong effect on milk production traits (GHR) or coloration (MC1R) have already been reported. To go further in the interpretation of the observed signatures of selection we subsequently concentrated on the annotation of differentiated genes defined according to the FST value of SNPs localized close or within them. To that end we performed a comprehensive network analysis which suggested a central role of somatotropic and gonadotropic axes in the response to selection. Altogether, these observations shed light on the antagonism, at the genome level, between milk production and reproduction traits in highly producing dairy cows. 相似文献
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In this paper we present statistical analysis of English texts from Wikipedia. We try to address the issue of language complexity empirically by comparing the simple English Wikipedia (Simple) to comparable samples of the main English Wikipedia (Main). Simple is supposed to use a more simplified language with a limited vocabulary, and editors are explicitly requested to follow this guideline, yet in practice the vocabulary richness of both samples are at the same level. Detailed analysis of longer units (n-grams of words and part of speech tags) shows that the language of Simple is less complex than that of Main primarily due to the use of shorter sentences, as opposed to drastically simplified syntax or vocabulary. Comparing the two language varieties by the Gunning readability index supports this conclusion. We also report on the topical dependence of language complexity, that is, that the language is more advanced in conceptual articles compared to person-based (biographical) and object-based articles. Finally, we investigate the relation between conflict and language complexity by analyzing the content of the talk pages associated to controversial and peacefully developing articles, concluding that controversy has the effect of reducing language complexity. 相似文献
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Female preference for male song in acoustic insects is primarily influenced by call energy or power, but nonenergy features such as the relative timing of male calls may also be critical in preference. Preferences for leading calls, which may be a type of precedence effect, are an example of the latter factor. In various species, females preferentially orient toward the leading of two or more spatially separated calls presented in controlled playback experiments, however the importance of this effect on mate choice in actual choruses and natural populations is generally unknown. We studied the determinants of mate choice in reenacted choruses of the tettigoniid Ephippiger ephippiger, a species in which females prefer leading calls in two-choice experiments, and neighboring males adjust their relative call timing in a way that reduces the incidence of following calls. We found that mate choice, as indicated by the pattern of female settlement, largely reflects call rate and call constancy. But, we also found suggestions that female choice is influenced by the acoustic neighborhood in which a male sings, males in neighborhoods with more overall singing being preferred, and by a males incidence of leading calls relative to his neighbors. Although statistically inconclusive owing to few relevant samples, we note that the level of preference for leading calls observed in E. ephippiger choruses is comparable to that found in controlled playback experiments. 相似文献
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Guido Caldarelli Alessandro Chessa Fabio Pammolli Gabriele Pompa Michelangelo Puliga Massimo Riccaboni Gianni Riotta 《PloS one》2014,9(5)
In this paper we present an analysis of the behavior of Italian Twitter users during national political elections. We monitor the volumes of the tweets related to the leaders of the various political parties and we compare them to the elections results. Furthermore, we study the topics that are associated with the co-occurrence of two politicians in the same tweet. We cannot conclude, from a simple statistical analysis of tweet volume and their time evolution, that it is possible to precisely predict the election outcome (or at least not in our case of study that was characterized by a “too-close-to-call” scenario). On the other hand, we found that the volume of tweets and their change in time provide a very good proxy of the final results. We present this analysis both at a national level and at smaller levels, ranging from the regions composing the country to macro-areas (North, Center, South). 相似文献
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Calf (Bos taurus) depredation by the federally endangered Florida panther (Puma concolor coryi) on ranches in southwest Florida is an important issue because ranches represent mixed landscapes that provide habitat critical to panther recovery. The objectives of this study were to (1) quantify calf depredation by panthers on two ranches in southwest Florida, and (2) develop a habitat suitability model to evaluate the quality of panther hunting habitat on ranchlands, assess whether the model could predict predation risk to calves, and discuss its potential to be incorporated into an incentive-based compensation program. We ear-tagged 409 calves with VHF transmitters on two ranches during 2011–2013 to document calf mortality. We developed a model to evaluate the quality of panther hunting habitat on private lands in southwest Florida using environmental variables obtained from the Florida Natural Areas Inventory (FNAI) Cooperative Landcover Database and nocturnal GPS locations of panthers provided by the Florida Fish and Wildlife Conservation Commission (FWC). We then tested whether the model could predict the location of calf depredation sites. Tagged calf loss to panthers varied between the two ranches (0.5%/yr to 5.3%/yr) and may have been influenced by the amount of panther hunting habitat on each ranch as the ranch that experienced higher depredation rates contained a significantly higher probability of panther presence. Depredation sites of tagged calves had a significantly greater probability of panther presence than depredation sites of untagged calves that were found by ranchers in open pastures. This suggests that there may be more calves killed in high risk environments than are being found and reported by ranchers and that panthers can hunt effectively in open environments. It also suggests that the model may provide a means for evaluating the quality of panther hunting habitat and the corresponding risk of depredation to livestock across the landscape. We suggest that our approach could be applied to prioritize and categorize private lands for participation in a Payment for Ecosystem Services program that compensates landowners for livestock loss and incentivizes conserving high quality habitat for large carnivores where livestock depredation is a concern. 相似文献
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The present study examined the neural mechanisms of attention modulation on timing using ERP and sLORETA measurements in a dual-task paradigm. We parametrically varied the attention to the durations of a 1000-Hz pure tone and further localized the cortical regions that were sensitive to the attention modulation on timing. Results demonstrated that the attention modulation might happen at early stage, approximately 200 ms after stimulus presentation. The P2 component at frontal area served as an early neural correlate of attention effects on timing. More importantly, the contingent negative variation (CNV) appeared at fronto-central area was sensitive to the attention effect. In addition, the supplementary motor area (SMA) was assumed to be one of the key regions for selectively attending to and estimating time. These findings provide temporal and spatial correlates of attention-modulated time processing and potentially help to investigate the neural mechanisms of patients with time perception deficits. 相似文献