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Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.
Inalienable Possessions tests anthropology's traditional assumptions about kinship, economics, power, and gender in an exciting challenge to accepted theories of reciprocity and marriage exchange. Focusing on Oceania societies from Polynesia to Papua New Guinea and including Australian Aborigine groups, Annette Weiner investigates the category of possessions that must not be given or, if they are circulated, must return finally to the giver. Reciprocity, she says, is only the superficial aspect of exchange, which overlays much more politically powerful strategies of 'keeping-while-giving'. The idea of keeping-while-giving places women at the heart of the political process, however much that process may vary in different societies, for women possess a wealth of their own that gives them power. Power is intimately involved in cultural reproduction, and Weiner describes the location of power in each society, showing how the degree of control over the production and distribution of cloth wealth coincides with women's rank and the development of hierarchy in the community. Other inalienable possessions, whether material objects, landed property, ancestral myths, or sacred knowledge, bestow social identity and rank as well. Calling attention to their presence in Western history, Weiner points out that her formulations are not limited to Oceania. The paradox of keeping-while-giving is a concept certain to influence future developments in ethnography and the theoretical study of gender and exchange.
BACKGROUND: Most older adults prefer to age in place, and supporting older adults to remain in their own homes and communities is also favored by policy makers. Technology can play a role in staying independent, active and healthy. However, the use of technology varies considerably among older adults. Previous research indicates that current models of technology acceptance are missing essential predictors specific to community-dwelling older adults. Furthermore, in situ research within the specific context of aging in place is scarce, while this type of research is needed to better understand how and why community-dwelling older adults are using technology. OBJECTIVE: To explore which factors influence the level of use of various types of technology by older adults who are aging in place and to describe these factors in a comprehensive model. METHODS: A qualitative explorative field study was set up, involving home visits to 53 community-dwelling older adults, aged 68-95, living in the Netherlands. Purposive sampling was used to include participants with different health statuses, living arrangements, and levels of technology experience. During each home visit: (1) background information on the participants' chronic conditions, major life events, frailty, cognitive functioning, subjective health, ownership and use of technology was gathered, and (2) a semistructured interview was conducted regarding reasons for the level of use of technology. The study was designed to include various types of technology that could support activities of daily living, personal health or safety, mobility, communication, physical activity, personal development, and leisure activities. Thematic analysis was employed to analyze interview transcripts. RESULTS: The level of technology use in the context of aging in place is influenced by six major themes: challenges in the domain of independent living; behavioral options; personal thoughts on technology use; influence of the social network; influence of organizations, and the role of the physical environment. CONCLUSION: Older adults' perceptions and use of technology are embedded in their personal, social, and physical context. Awareness of these psychological and contextual factors is needed in order to facilitate aging in place through the use of technology. A conceptual model covering these factors is presented.
Job satisfaction is often described as an affective response to one's job, but is usually measured largely as a cognitive evaluation of job features. This paper explores several hypothesized relationships between real time affect while working and standard measures of job satisfaction. Experience sampling methodology was used to obtain up to 50 reports of immediate mood and emotions from 121 employed persons over a two week period. As expected, real time affect is related to overall satisfaction but is not identical to satisfaction. Moment to moment affect is more strongly related to a faces measure of satisfaction than to more verbal measures of satisfaction. Positive and negative emotions both make unique contributions to predicting overall satisfaction, and affect accounts for variance in overall satisfaction above and beyond facet satisfactions. Frequency of net positive emotion is a stronger predictor of overall satisfaction than is intensity of positive emotion. It is concluded that affect while working is a missing piece of overall job attitude, as well as a phenomenon worthy of investigation in its own right. Implications for further research and for improving the conceptualization and measurement of job satisfaction are discussed. Copyright © 2000 John Wiley & Sons, Ltd.
OBJECTIVE: Heavy alcohol use is widespread among college students, particularly in those social situations where the risk of rape rises. Few studies have provided information on rapes of college women that occur when they are intoxicated. The purpose of the present study was to present prevalence data for rape under the condition of intoxication when the victim is unable to consent and to identify college and individual-level risk factors associated with that condition. METHOD: The study utilizes data from 119 schools participating in three Harvard School of Public Health College Alcohol Study surveys. The analytic sample of randomly selected students includes 8,567 women in the 1997 survey, 8,425 in the 1999 survey, and 6,988 in the 2001 survey. RESULTS: Roughly one in 20 (4.7%) women reported being raped. Nearly three quarters (72%) of the victims experienced rape while intoxicated. Women who were under 21, were white, resided in sorority houses, used illicit drugs, drank heavily in high school and attended colleges with high rates of heavy episodic drinking were at higher risk of rape while intoxicated. CONCLUSIONS: The high proportion of rapes found to occur when women were intoxicated indicates the need for alcohol prevention programs on campuses that address sexual assault, both to educate men about what constitutes rape and to advise women of risky situations. The findings that some campus environments are associated with higher levels of both drinking and rape will help target rape prevention programs at colleges.
The “looking-while-listening” methodology uses real-time measures of the time course of young children’s gaze patterns in response to speech. This procedure is low in task demands and does not require automated eyetracking technology, similar to “preferential-looking” procedures. However, the looking-whilelistening methodology differs critically from preferential-looking procedures in the methods used for data reduction and analysis, yielding high-resolution measures of speech processing from moment to moment, rather than relying on summary measures of looking preference. Because children’s gaze patterns are time-locked to speech and coded frame-by-frame, each 5-min experiment response latencies can be coded with millisecond precision on multiple trials over multiple items, based on data from thousands of frames in each experiment. The meticulous procedures required in the collection, reduction, and multiple levels of analysis of such detailed data are demanding, but well worth the effort, revealing a dynamic and nuanced picture of young children’s developing skill in finding meaning in spoken language.
Given that the ability to attend to a task without distraction underlies performance in a wide variety of contexts, training one's ability to stay on task should result in a similarly broad enhancement of performance. In a randomized controlled investigation, we examined whether a 2-week mindfulness-training course would decrease mind wandering and improve cognitive performance. Mindfulness training improved both GRE reading-comprehension scores and working memory capacity while simultaneously reducing the occurrence of distracting thoughts during completion of the GRE and the measure of working memory. Improvements in performance following mindfulness training were mediated by reduced mind wandering among participants who were prone to distraction at pretesting. Our results suggest that cultivating mindfulness is an effective and efficient technique for improving cognitive function, with wide-reaching consequences.
Agriculture is a resource-intensive enterprise. The manner in which food production systems utilize resources has a large influence on environmental quality. To evaluate prospects for conserving natural resources while meeting increased demand for cereals, we interpret recent trends and future trajectories in crop yields, land and nitrogen fertilizer use, carbon sequestration, and greenhouse gas emissions to identify key issues and challenges. Based on this assessment, we conclude that avoiding expansion of cultivation into natural ecosystems, increased nitrogen use efficiency, and improved soil quality are pivotal components of a sustainable agriculture that meets human needs and protects natural resources. To achieve this outcome will depend on raising the yield potential and closing existing yield gaps of the major cereal crops to avoid yield stagnation in some of the world's most productive systems. Recent trends suggest, however, that increasing crop yield potential is a formidable scientific challenge that has proven to be an elusive goal.
We examine the tradeoff between privacy and usability of statistical databases. We model a statistical database by an n-bit string d1,..,dn, with a query being a subset q ⊆ [n] to be answered by Σiεq di. Our main result is a polynomial reconstruction algorithm of data from noisy (perturbed) subset sums. Applying this reconstruction algorithm to statistical databases we show that in order to achieve privacy one has to add perturbation of magnitude (Ω√n). That is, smaller perturbation always results in a strong violation of privacy. We show that this result is tight by exemplifying access algorithms for statistical databases that preserve privacy while adding perturbation of magnitude Õ(√n).For time-T bounded adversaries we demonstrate a privacypreserving access algorithm whose perturbation magnitude is ≈ √T.
The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.
EAE is a mouse T cell-mediated autoimmune disease of the CNS used to model the human condition MS. The contributions of B cells to EAE initiation and progression are unclear. In this study, we have shown that EAE disease initiation and progression are differentially influenced by the depletion of B cells from mice with otherwise intact immune systems. CD20 antibody-mediated B cell depletion before EAE induction substantially exacerbated disease symptoms and increased encephalitogenic T cell influx into the CNS. Increased symptom severity resulted from the depletion of a rare IL-10-producing CD1dhiCD5+ regulatory B cell subset (B10 cells), since the adoptive transfer of splenic B10 cells before EAE induction normalized EAE in B cell-depleted mice. While transfer of regulatory B10 cells was maximally effective during early EAE initiation, they had no obvious role during disease progression. Rather, B cell depletion during EAE disease progression dramatically suppressed symptoms. Specifically, B cells were required for the generation of CD4+ T cells specific for CNS autoantigen and the entry of encephalitogenic T cells into the CNS during disease progression. These results demonstrate reciprocal regulatory roles for B cells during EAE immunopathogenesis. The therapeutic effect of B cell depletion for the treatment of autoimmunity may therefore depend on the relative contributions and the timing of these opposing B cell activities during the course of disease initiation and pathogenesis.
<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> This paper addresses the connectedness issue in multiagent coordination, i.e., the problem of ensuring that a group of mobile agents stays connected while achieving some performance objective. In particular, we study the rendezvous and the formation control problems over dynamic interaction graphs, and by adding appropriate weights to the edges in the graphs, we guarantee that the graphs stay connected. </para>
Severe droughts have been associated with regional-scale forest mortality worldwide. Climate change is expected to exacerbate regional mortality events; however, prediction remains difficult because the physiological mechanisms underlying drought survival and mortality are poorly understood. We developed a hydraulically based theory considering carbon balance and insect resistance that allowed development and examination of hypotheses regarding survival and mortality. Multiple mechanisms may cause mortality during drought. A common mechanism for plants with isohydric regulation of water status results from avoidance of drought-induced hydraulic failure via stomatal closure, resulting in carbon starvation and a cascade of downstream effects such as reduced resistance to biotic agents. Mortality by hydraulic failure per se may occur for isohydric seedlings or trees near their maximum height. Although anisohydric plants are relatively drought-tolerant, they are predisposed to hydraulic failure because they operate with narrower hydraulic safety margins during drought. Elevated temperatures should exacerbate carbon starvation and hydraulic failure. Biotic agents may amplify and be amplified by drought-induced plant stress. Wet multidecadal climate oscillations may increase plant susceptibility to drought-induced mortality by stimulating shifts in hydraulic architecture, effectively predisposing plants to water stress. Climate warming and increased frequency of extreme events will probably cause increased regional mortality episodes. Isohydric and anisohydric water potential regulation may partition species between survival and mortality, and, as such, incorporating this hydraulic framework may be effective for modeling plant survival and mortality under future climate conditions.
The effects of mental workload on visual search and decision making were studied in real traffic conditions with 12 participants who drove an instrumented car. Mental workload was manipulated by having participants perform several mental tasks while driving. A simultaneous visual-detection and discrimination test was used as performance criteria. Mental tasks produced spatial gaze concentration and visual-detection impairment, although no tunnel vision occurred. According to ocular behavior analysis, this impairment was due to late detection and poor identification more than to response selection. Verbal acquisition tasks were innocuous compared with production tasks, and complex conversations, whether by phone or with a passenger, are dangerous for road safety.
The discovery of audiovisual mirror neurons in monkeys gave rise to the hypothesis that premotor areas are inherently involved not only when observing actions but also when listening to action-related sound. However, the whole-brain functional formation underlying such "action-listening" is not fully understood. In addition, previous studies in humans have focused mostly on relatively simple and overexperienced everyday actions, such as hand clapping or door knocking. Here we used functional magnetic resonance imaging to ask whether the human action-recognition system responds to sounds found in a more complex sequence of newly acquired actions. To address this, we chose a piece of music as a model set of acoustically presentable actions and trained non-musicians to play it by ear. We then monitored brain activity in subjects while they listened to the newly acquired piece. Although subjects listened to the music without performing any movements, activation was found bilaterally in the frontoparietal motor-related network (including Broca's area, the premotor region, the intraparietal sulcus, and the inferior parietal region), consistent with neural circuits that have been associated with action observations, and may constitute the human mirror neuron system. Presentation of the practiced notes in a different order activated the network to a much lesser degree, whereas listening to an equally familiar but motorically unknown music did not activate this network. These findings support the hypothesis of a "hearing-doing" system that is highly dependent on the individual's motor repertoire, gets established rapidly, and consists of Broca's area as its hub.
Normal human subjects and patients with lesions of the olivocerebellar system threw balls of clay at a visual target while wearing wedge prism spectacles. Normal subjects initially threw in the direction of prism-bent gaze, but with repeated throws adapted to hit the target. Patients with generalized cerebellar atrophy, inferior olive hypertrophy, or focal infarcts in the distribution of the posterior inferior cerebellar artery, in the ipsilateral inferior peduncle, in the contralateral basal pons or in the ipsilateral middle cerebellar peduncle had impaired or absent prism adaptation. Patients with infarcts in the distribution of the posterior inferior cerebellar artery usually had impaired or absent adaptation but little or no ataxia. By contrast, patients with damage in the distribution of the superior cerebellar artery or in cerebellar thalamus usually had ataxia but preserved adaptation. These results implicate climbing fibres from the contralateral inferior olive via the ipsilateral inferior cerebellar peduncle, mossy fibres from the contralateral pontocerebellar nuclei via the ipsilateral middle cerebellar peduncle, and posterior inferior cerebellar artery territory cortex as being critical for this adaptation. The dentatothalamic projection and the superior cerebellar artery territory cortex are not necessary for this adaptation.
Feldman M. P., Francis J. and Bercovitz, J. (2005) Creating a cluster while building a firm: entrepreneurs and the formation of industrial clusters, Regional Studies39, 129-141. The objective of the paper is to provide a theoretical model of cluster development that is informed by an appreciative interpretation of case studies. It argues that entrepreneurs are a critical element in the formation of clusters. Entrepreneurs are important actors in the development of clusters as complex adaptive systems, where the external resources associated with clusters are developed over time. Entrepreneurs who adapt to both constructive crises and new opportunities create the factors and conditions that facilitate their business interests and, in turn, contribute to the development of external resources. The paper examines the initial factors that influence the decision to become an entrepreneur and examine how external factors influence the formation and location of high-technology clusters. Feldman M. P., Francis J. et Bercovitz, J. (2005) L'établissment d'un regroupement au fur et à mesure de la création d'entreprise: les entrepreneurs et l'établissement des regroupements industriels, Regional Studies39, 129-141. Cet article cherche à construire un modèle théorique du développement des regroupements guidé par une interprétation sensible des études de cas. On considère que les entrepreneurs constituent un facteur clé dans l'établissement des regroupements. Les entrepreneurs sont des agents importants dans le développement des regroupements en tant que systèmes complexes adaptables, o[ugrave] les ressources externes liées aux regroupements se développent sur le temps. Les entrepreneurs qui s'adaptent et aux crises avantageuses, et aux nouvelles possibilités, créent les facteurs et les conditions qui favorisent leurs affaires et, à leur tour, contribuent au développement des ressources externes. On examine les premiers facteurs qui influencent la décision individuelle de devenir entrepreneur, et on étudie comment les facteurs externes influencent l'établissement et la localisation des regroupements qui sont à la pointe de la technologie. Feldman M. P., Francis J. und Bercovitz, J. (2005) Schaffung eines Clusters in Verbindung mit dem Aufbau einer Firma: Unternehmer und Clusterbildung der Industrie, Regional Studies39, 129-141. Dieser Aufsatz beabsichtigt, ein theoretisches Modell einer Clusterentwicklung vorzustellen, das auf einer bewertenden Interpretation von Fallstudien beruht. Es wird die These aufgestellt, daß Unternehmer bei Clusterbildung ein kritisches Element darstellen. Unternehmer sind wichtige Spieler bei der Entwicklung von Clustern als komplexen Mittlersystemen, in denen die externen, mit Clustern in Verbindung stehenden Resourcen erst im Laufe der Zeit entwickelt werden. Unternehmer, die sich sowohl konstruktiven Krisen als auch neu auftauchenden Gelegenheiten anzupassen verstehen, schaffen Faktoren und Voraussetzungen, die ihren Geschäftsinteressen entgegenkommen, und selbst wiederum zur Entwicklung externer Resourcen beitragen. Die Autoren untersuchen die anfänglichen Faktoren, welche die Entscheidung, Unternehmer zu werden, beeinflussen, und inwiefern externe Faktoren Bildung und Standort hochtechnologischer Cluster bestimmen. Feldman M. P., Francis J. y Bercovitz, J. (2005) Crear un cluster mientras se construye una empresa: emprendedores (entrepreneurs) y la formación de clusters industriales, Regional Studies39, 129-141. El objetivo de este artículo es ofrecer un modelo teórico de desarrollo de clusters basado en una interpretación apreciativa de estudios de casos. Sostenemos que los emprendedores son uno de los elementos críticos en el desarrollo de clusters como sistemas de adaptación complejos, donde los recursos externos que se asocian con los clusters se desarrollan a lo largo del tiempo. Los emprendedores, los cuales se adaptan tanto a crisis constructivas como a nuevas oportunidades, crean los factores y las condiciones que facilitan los intereses de sus negocios y, como resultado, contribuyen al desarrollo de los recursos externos. Examinamos los factores que influyen inicialmente en su decisión de convertirse en emprendedores y examinamos de qué forma los factores externos influyen la formación y localización de clusters de alta tecnología.
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OBJECTIVES: This study evaluated the effectiveness (changes in health behaviors, health status, and health service utilization) of a self-management program for chronic disease designed for use with a heterogeneous group of chronic disease patients. It also explored the differential effectiveness of the intervention for subjects with specific diseases and comorbidities. METHODS: The study was a six-month randomized, controlled trial at community-based sites comparing treatment subjects with wait-list control subjects. Participants were 952 patients 40 years of age or older with a physician-confirmed diagnosis of heart disease, lung disease, stroke, or arthritis. Health behaviors, health status, and health service utilization, as determined by mailed, self-administered questionnaires, were measured. RESULTS: Treatment subjects, when compared with control subjects, demonstrated improvements at 6 months in weekly minutes of exercise, frequency of cognitive symptom management, communication with physicians, self-reported health, health distress, fatigue, disability, and social/role activities limitations. They also had fewer hospitalizations and days in the hospital. No differences were found in pain/physical discomfort, shortness of breath, or psychological well-being. CONCLUSIONS: An intervention designed specifically to meet the needs of a heterogeneous group of chronic disease patients, including those with comorbid conditions, was feasible and beneficial beyond usual care in terms of improved health behaviors and health status. It also resulted in fewer hospitalizations and days of hospitalization.
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