A reassuring presence: An evaluation of Bradford District Hospice at Home service

Within the United Kingdom, a developing role for primary care services in cancer and palliative care has resulted in an increase in palliative home care teams. The provision of professional care in the home setting seeks to provide necessary services and enhanced choice for patients whose preference is to die at home. A mismatch between patient preference for home death and the actual number of people who died at home was identified within Bradford, the locality of this study. In response to this mismatch, and reflecting the policy environment of wishing to enhance community service provision, the four Primary Care Trusts (PCTs) in the city sought to offer support to patients who wished to remain in their own homes through the final stages of a terminal illness. To offer this support they set up a dedicated hospice at home team. This would provide services and support for patients in achieving a dignified, symptom free and peaceful death, allowing families to maximise time spent together. The aim of the study was to evaluate the Bradford hospice at home service from the perspective of carers, nurses and General Practitioners. Postal questionnaires were sent to carers (n = 289), district nurses (n = 508) and GP's (n = 444) using Bradford's hospice at home service. Resulting quantitative data was analysed using the Statical Package for Social Sciences (SPSS) and qualitative data was analysed using grounded theory techniques. The data from carers, district nurses and GPs provide general support for the Bradford hospice at home service. Carers valued highly the opportunity to 'fulfil a promise' to the individual who wished to be cared for at home. District nurses and GPs cited the positive impact of access to specialist expertise. This was a 'reassuring presence' for primary healthcare teams and offered 'relief of carer anxiety' by providing prompt, accessible and sensitive care. Carers and health professionals welcomed the increased possibility of patients being cared for at home. The study identified the need to focus on improving skill levels of staff and on ensuring continuity of care

Rhythmic dynamics and synchronization via dimensionality reduction : application to human gait

Reliable characterization of locomotor dynamics of human walking is vital to understanding the neuromuscular control of human locomotion and disease diagnosis. However, the inherent oscillation and ubiquity of noise in such non-strictly periodic signals pose great challenges to current methodologies. To this end, we exploit the state-of-the-art technology in pattern recognition and, specifically, dimensionality reduction techniques, and propose to reconstruct and characterize the dynamics accurately on the cycle scale of the signal. This is achieved by deriving a low-dimensional representation of the cycles through global optimization, which effectively preserves the topology of the cycles that are embedded in a high-dimensional Euclidian space. Our approach demonstrates a clear advantage in capturing the intrinsic dynamics and probing the subtle synchronization patterns from uni/bivariate oscillatory signals over traditional methods. Application to human gait data for healthy subjects and diabetics reveals a significant difference in the dynamics of ankle movements and ankle-knee coordination, but not in knee movements. These results indicate that the impaired sensory feedback from the feet due to diabetes does not influence the knee movement in general, and that normal human walking is not critically dependent on the feedback from the peripheral nervous system

Reverse-Engineering a Transcriptional Enhancer: A Case Study in Drosophila

Abstract Enhancers, or cis-regulatory elements, are the principal determinants of spatiotemporal patterning of gene expression. For reasons of clinical and research utility, it is desirable to build customized enhancers that drive novel gene expression patterns, but currently, we largely rely on “found” genomic elements. Synthetic enhancers, assembled from transcription factor binding sites taken from natural signal-regulated enhancers, generally fail to behave like their wild-type counterparts when placed in transgenic animals, suggesting that important aspects of enhancer function are still unexplored. As a step toward the creation of a truly synthetic regulatory element, we have undertaken an extensive structure–function study of an enhancer of the Drosophila decapentaplegic (dpp) gene that drives expression in the developing visceral mesoderm (VM). Although considerable past efforts have been made to dissect the dppVM enhancer, transgenic experiments presented here indicate that its activity cannot be explained by the known regulators alone. dppVM contains multiple, previously uncharacterized, regulatory sites, some of which exhibit functional redundancy. The results presented here suggest that even the best-studied enhancers must be further dissected before they can be fully understood, and before faithful synthetic elements based on them can be created. Implications for developmental genetics, mathematical modeling, and therapeutic applications are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63213/1/ten.tea.2008.0074.pd

Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli

Identification of Stage‐Specific Genes Associated With Lupus Nephritis and Response to Remission Induction in (NZB × NZW)F1 and NZM2410 Mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108024/1/art38679.pd

Using the signal-to-noise ratio of GPS records to detect motion of structures

Although major breakthroughs have been achieved during the last decades in the use of Global Positioning System (GPS) technology on structural health monitoring, the mitigation of the biases and errors impeding its positioning accuracy remains a challenge. This paper tests an alternative approach that can increase the reliability of the GPS system in structural monitoring by using the spectral content of the signal-to-noise ratio (SNR) of GPS signals to detect frequencies of antenna vibrations. This approach suggests the potential of using SNR data analysis as a supplement to low-quality positioning solution or as a near real-time alert of excessive vibration proceeding the position solution calculation. Experiments, involving a GPS antenna subjected to vertical vibrations of 0.4- to 4.5-cm amplitude at a range of frequencies between 0.007 and 1 Hz, examine the dynamic multipath-induced SNR response corresponding to the antenna motion. Synchronised fluctuations in the SNR time series were observed to reflect the antenna motion and their spectral content to include the frequencies of motion. SNR records from the GPS monitoring of the Wilford suspension bridge were used to validate the SNR sensitivity to controlled vibrations of the bridge deck. The natural frequency of 1.64 Hz was extracted from SNR measurements using spectral analysis on a 6-mm amplitude vibration, and the frequency of the semistatic displacement (∼0.02 Hz) was revealed in the SNR records permitting, after appropriate filtering, the estimation of a few millimetre semistatic displacement from the GPS time series without the need for any other sensor

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial

Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). Patients and methods: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. Results: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. Conclusions: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients

Investigating undesired spatial and temporal boundary effects of congestion charging.

Two types of reported problems are related to the existing congestion charging projects that levy traffic only in a certain area within one or a few time periods during the day. One is that travellers depart earlier or later than a charging period to avoid paying full or part of the congestion charging tolls, which creates two undesired demand peaks that are often greater than available capacity. One peak comes just before the start of congestion charging and the other follows the end of it. We term this phenomenon ‘temporal boundary effect’ of congestion charging. The other reported problem is that travellers would rather stay away from a charging zone than pay congestion charging tolls, which causes undesired congestion on those roads or paths on the edge of the charging zone. We call this phenomenon ‘spatial boundary effect’ generated by congestion charging. This research investigates these boundary effects in the context of simultaneous route and departure time choice dynamic user equilibrium (SRD-DUE) network flows with an aim to gain new insights into congestion charging design. Numerical experiments investigating constant and time-varying congestion charging toll profiles are presented in this paper. This investigation shows that congestion charging may not be able to eliminate hypercongestion efficiently if schemes are not well designed, and can unfortunately give rise to undesired boundary effects and that a simply designed congestion charging scheme with small level toll or time-varying toll profiles can reduce the magnitude of boundary effects but may not be able to fully eliminate such undesired effect