Computationally Efficient Nonparametric Importance Sampling

The variance reduction established by importance sampling strongly depends on the choice of the importance sampling distribution. A good choice is often hard to achieve especially for high-dimensional integration problems. Nonparametric estimation of the optimal importance sampling distribution (known as nonparametric importance sampling) is a reasonable alternative to parametric approaches.In this article nonparametric variants of both the self-normalized and the unnormalized importance sampling estimator are proposed and investigated. A common critique on nonparametric importance sampling is the increased computational burden compared to parametric methods. We solve this problem to a large degree by utilizing the linear blend frequency polygon estimator instead of a kernel estimator. Mean square error convergence properties are investigated leading to recommendations for the efficient application of nonparametric importance sampling. Particularly, we show that nonparametric importance sampling asymptotically attains optimal importance sampling variance. The efficiency of nonparametric importance sampling algorithms heavily relies on the computational efficiency of the employed nonparametric estimator. The linear blend frequency polygon outperforms kernel estimators in terms of certain criteria such as efficient sampling and evaluation. Furthermore, it is compatible with the inversion method for sample generation. This allows to combine our algorithms with other variance reduction techniques such as stratified sampling. Empirical evidence for the usefulness of the suggested algorithms is obtained by means of three benchmark integration problems. As an application we estimate the distribution of the queue length of a spam filter queueing system based on real data.Comment: 29 pages, 7 figure

The Role of Attorney Fee Shifting in Public Interest Litigation

BACKGROUND: Brain tissue segmentation of white matter (WM), grey matter (GM), and cerebrospinal fluid (CSF) are important in neuroradiological applications. Quantitative Mri (qMRI) allows segmentation based on physical tissue properties, and the dependencies on MR scanner settings are removed. Brain tissue groups into clusters in the three dimensional space formed by the qMRI parameters R1, R2 and PD, and partial volume voxels are intermediate in this space. The qMRI parameters, however, depend on the main magnetic field strength. Therefore, longitudinal studies can be seriously limited by system upgrades. The aim of this work was to apply one recently described brain tissue segmentation method, based on qMRI, at both 1.5 T and 3.0 T field strengths, and to investigate similarities and differences. METHODS: In vivo qMRI measurements were performed on 10 healthy subjects using both 1.5 T and 3.0 T MR scanners. The brain tissue segmentation method was applied for both 1.5 T and 3.0 T and volumes of WM, GM, CSF and brain parenchymal fraction (BPF) were calculated on both field strengths. Repeatability was calculated for each scanner and a General Linear Model was used to examine the effect of field strength. Voxel-wise t-tests were also performed to evaluate regional differences. RESULTS: Statistically significant differences were found between 1.5 T and 3.0 T for WM, GM, CSF and BPF (p<0.001). Analyses of main effects showed that WM was underestimated, while GM and CSF were overestimated on 1.5 T compared to 3.0 T. The mean differences between 1.5 T and 3.0 T were -66 mL WM, 40 mL GM, 29 mL CSF and -1.99% BPF. Voxel-wise t-tests revealed regional differences of WM and GM in deep brain structures, cerebellum and brain stem. CONCLUSIONS: Most of the brain was identically classified at the two field strengths, although some regional differences were observed

Contribution of Stretch to the Change of Activation Properties of Muscle Fibers in the Diaphragm at the Transition from Fetal to Neonatal Life

The transition from fetal to postnatal life involves clearance of liquid from the lung and airways, and rapid formation of a functional residual capacity. Despite the importance of the diaphragm in this process, the impact of birth on the mechanical and functional activity of its muscle fibers is not known. This study determined the contractile characteristics of individual “skinned” diaphragm fibers from 70 days (0.47) gestation to after birth in sheep. Based on differential sensitivity to the divalent ions calcium (Ca2+) and strontium (Sr2+), all fibers in the fetal diaphragm were classified as “fast,” whereas fibers from the adult sheep diaphragm exhibited a “hybrid” phenotype where both “fast” and “slow” characteristics were present within each single fiber. Transition to the hybrid phenotype occurred at birth, was evident after only 40 min of spontaneous breathing, and could be induced by simple mechanical stretch of diaphragm fibers from near-term fetuses (∼147 days gestation). Both physical stretch of isolated fibers, and mechanical ventilation of the fetal diaphragm in situ, significantly increased sensitivity to Ca2+ and Sr2+, maximum force generating capacity, and decreased passive tension in near-term and preterm fetuses; however, only fibers from near-term fetuses showed a complete transition to a “hybrid” activation profile. These findings suggest that stretch associated with the transition from a liquid to air-filled lung at birth induces physical changes of proteins determining the activation and elastic properties of the diaphragm. These changes may allow the diaphragm to meet the increased mechanical demands of breathing immediately after birth

Bcl-x Pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia

The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature central nervous system (CNS) and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-x(L) (the long form) is anti-apoptotic, while Bcl-x(S) (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-x(L) while increasing Bcl-x(S). Specific knockdown of Bcl-x(S) attenuated apoptosis. In order to further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing. We found that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-x(L) 5′ splice site, altering the Bcl-x(L)/Bcl-x(S) ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre-mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-x(S) shRNA into the hippocampus of rats prior to neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury, and may potentially provide novel targets for intervention

Addressing alcohol and tobacco harms in remote Indigenous communities and rapid responses to mental health crises in regional centres

Alcohol Management Plans (AMPs) were initially designed as part of a wide range of innovative and significant Queensland Government reforms. As well as supply control, these promised to reduce alcohol and substance misuse and violence through demand reduction by addressing key social determinants: economic development; education and training, land and sustainable natural resource management, housing, and health 3, 4. The limited available evidence in the peer-reviewed published literature points to some favourable impacts of restrictions 5, 6, including a reduction in indicators of serious injury in some communities to historically low levels 7. These favourable findings were reflected in an internal Queensland Government review 4. However, the evidence that these initial positive effects were experienced in all communities, or that they have been sustained, particularly after the most recent round of restrictions in 2008, has become equivocal 8. This paper was the first in a unique evaluation research program designed to examine the health and social effects of Queensland�s AMPs 1, 9. It investigates issues surrounding implementation of the designed AMP intervention components, specifically their perceived impacts on alcohol supply and consumption, violence, injury and community health and well-being. Perceptions and experiences are reported of the community leaders, service providers and relevant organisations with a mandate or responsibility for alcohol-related matters in the affected AMP communities and nearby towns.The research reported in this paper is a project of the Australian Primary Health Care Research Institute, which is supported by a grant from the Australian Government Department of Health and Ageing under the Primary Health Care Research, Evaluation and Development Strategy

E7(7) formulation of N=2 backgrounds

In this paper we reformulate N=2 supergravity backgrounds arising in type II string theory in terms of quantities transforming under the U-duality group E7(7). In particular we combine the Ramond--Ramond scalar degrees of freedom together with the O(6,6) pure spinors which govern the Neveu-Schwarz sector by considering an extended version of generalised geometry. We give E7(7)-invariant expressions for the Kahler and hyperkahler potentials describing the moduli space of vector and hypermultiplets, demonstrating that both correspond to standard E7(7) coset spaces. We also find E7(7) expressions for the Killing prepotentials defining the scalar potential, and discuss the equations governing N=1 vacua in this formalism.Comment: 40 pages, final version to appear in JHE

Information exchange networks for chronic illness care in primary care practices: an observational study

Contains fulltext : 88018.pdf (publisher's version ) (Open Access)BACKGROUND: Information exchange networks for chronic illness care may influence the uptake of innovations in patient care. Valid and feasible methods are needed to document and analyse information exchange networks in healthcare settings. This observational study aimed to examine the usefulness of methods to study information exchange networks in primary care practices, related to chronic heart failure, diabetes and chronic obstructive pulmonary disease. METHODS: The study was linked to a quality improvement project in the Netherlands. All health professionals in the practices were asked to complete a short questionnaire that documented their information exchange relations. Feasibility was determined in terms of response rates and reliability in terms of reciprocity of reports of receiving and providing information. For each practice, a number of network characteristics were derived for each of the chronic conditions. RESULTS: Ten of the 21 practices in the quality improvement project agreed to participate in this network study. The response rates were high in all but one of the participating practices. For the analysis, we used data from 67 health professionals from eight practices. The agreement between receiving and providing information was, on average, 65.6%. The values for density, centralization, hierarchy, and overlap of the information exchange networks showed substantial variation between the practices as well as between the chronic conditions. The most central individual in the information exchange network could be a nurse or a physician. CONCLUSIONS: Further research is needed to refine the measure of information networks and to test the impact of network characteristics on the uptake of innovations

Providing web-based feedback and social norms information to reduce student alcohol intake: a multisite investigation

BACKGROUND: Unhealthy alcohol use among university students is cause for concern, yet the level of help seeking behavior for alcohol use is low within the student population. Electronic brief interventions delivered via the Internet present an alternative to traditional treatments and could enable the delivery of interventions on a population basis. Further evidence is needed of the effectiveness of Internet-delivered interventions and of their generalizability across educational institutions.OBJECTIVE: Our objective was to evaluate the effectiveness across 4 UK universities of a Web-based intervention for student alcohol use.METHODS: In total, 1112 participants took part. Participants were stratified by educational institution, gender, age group, year of study, and self-reported weekly consumption of alcohol and randomly assigned to either the control arm or to the immediate or delayed intervention arms. Intervention participants gained access to the intervention between weeks 1 to 7 or weeks 8 to 15, respectively. The intervention provided electronic personalized feedback and social norms information on drinking behavior accessed by logging on to a website. Participants registered interest by completing a brief screening questionnaire and were then asked to complete 4 further assessments across the 24 weeks of the study. Assessments included a retrospective weekly drinking diary, the Alcohol Use Disorders Identification Test (AUDIT), and a readiness-to-change algorithm. The outcome variable was the number of units of alcohol consumed in the last week. The effect of treatment arm and time on units consumed last week and average units consumed per drinking occasion were investigated using repeated measures multivariate analysis of covariance (MANCOVA). In addition, the data were modeled using a longitudinal regression with time points clustered within students.RESULTS: MANCOVA revealed a main effect of time on units of alcohol consumed over the last week. A longitudinal regression model showed an effect of assessment across time predicting that participants who completed at least 2 assessments reduced their drinking. The model predicted an additional effect of being assigned to an intervention arm, an effect that increased across time. Regression analysis predicted that being male or being assigned to an intervention arm increased the odds of not completing all assessments. The number of units of alcohol consumed over the last week at registration, age, university educational institution, and readiness to change were not predictive of completion.CONCLUSIONS: Delivering an electronic personalized feedback intervention to students via the Internet can be effective in reducing weekly alcohol consumption. The effect does not appear to differ by educational institution. Our model suggested that monitoring alone is likely to reduce weekly consumption over 24 weeks but that consumption could be further reduced by providing access to a Web-based intervention. Further research is needed to understand the apparent therapeutic effect of monitoring and how this can be utilized to enhance the effectiveness of brief Web-based intervention

Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

Study Protocol - Alcohol Management Plans (AMPs) in remote indigenous communities in Queensland: their impacts on injury, violence, health and social indicators and their cost-effectiveness

BACKGROUND: In 2002/03 the Queensland Government responded to high rates of alcohol-related harm in discrete Indigenous communities by implementing alcohol management plans (AMPs), designed to include supply and harm reduction and treatment measures. Tighter alcohol supply and carriage restrictions followed in 2008 following indications of reductions in violence and injury. Despite the plans being in place for over a decade, no comprehensive independent review has assessed to what level the designed aims were achieved and what effect the plans have had on Indigenous community residents and service providers. This study will describe the long-term impacts on important health, economic and social outcomes of Queensland’s AMPs. METHODS/DESIGN: The project has two main studies, 1) outcome evaluation using de-identified epidemiological data on injury, violence and other health and social indicators for across Queensland, including de-identified databases compiled from relevant routinely-available administrative data sets, and 2) a process evaluation to map the nature, timing and content of intervention components targeting alcohol. Process evaluation will also be used to assess the fidelity with which the designed intervention components have been implemented, their uptake and community responses to them and their perceived impacts on alcohol supply and consumption, injury, violence and community health. Interviews and focus groups with Indigenous residents and service providers will be used. The study will be conducted in all 24 of Queensland’s Indigenous communities affected by alcohol management plans. DISCUSSION: This evaluation will report on the impacts of the original aims for AMPs, what impact they have had on Indigenous residents and service providers. A central outcome will be the establishment of relevant databases describing the parameters of the changes seen. This will permit comprehensive and rigorous surveillance systems to be put in place and provided to communities empowering them with the best credible evidence to judge future policy and program requirements for themselves. The project will inform impending alcohol policy and program adjustments in Queensland and other Australian jurisdictions.The study was funded by the National Health and Medical Research Council of Australia (NHMRC, Project Grant #APP1042532), with additional support from the Australian Primary Health Care Research Institute-funded Centre for Research Excellence for the Prevention of Chronic Conditions in Rural and Remote High Risk Populations at James Cook University & University Adelaide. Dr Caryn West is a National Health and Medical Research Council of Australia Early Career Research Post – Doctoral Fellow (NHMRC ECR, #APP1070931).Associate Professor Clough holds a NHMRC Career Development Award (#APP1046773)