Local political leadership and the modernisation of local government

Political leadership has been a key element of central government’s attempts to ‘modernise’ local government over the past decade, within a discourse that emphasised ‘strong’ and ‘visible’ leadership and the role of leaders and leadership in driving change within local authorities. In the context of such an approach, and also taking account of academic discourse, this article draws upon interviews with nearly thirty individuals in leadership positions in local authorities in England, Scotland and Wales to assess their experiences of leadership and their views of some aspects of the role and work of councils. It suggests that whilst there is broad convergence between the aspirations of government and the narratives that emerge from these leaders on some aspects of local political leadership, there are also differences, perhaps most notably over the relationship between changes to decision making structures and the loci of political power

The in vivo neuroprotective role of the normal cellular prion protein /

The role of prion protein (PrPC) as a crucial factor in the pathogenesis of the Transmissible Spongiform Encephalopathies (TSE's) is well known. However, the physiologic role of this highly conserved protein in vivo is thus far, largely unknown. In vitro evidence shows that PrPC may have a neuroprotective role, inhibiting Bax-mediated apoptosis, by preventing the conformational change of Bax, which is one of the early steps leading to Bax activation and subsequently, apoptosis. In vivo evidence indicates that in some transgenic mouse models overexpressing a mutant prion protein that result in neuronal death, the simultaneous expression of PrP protects against this neuronal death. The pathogenesis of the neuronal death in these in vivo models is unknown. Our objective was to determine if PrPC could protect against Bax-mediated cell death in vivo. We used two experimental paradigms to investigate this neuroprotective role of PrPC in vivo.The first paradigm involved an external insult (ethanol injection) to 7 day old mice, which induces massive Bax-mediated neuronal death. We then quantified the number of active caspase 3 positive cells, as a downstream marker of Bax activation, induced in mice on various genetic backgrounds, PrP overexpressors (PrpOexp), PrP wild-type (PrP+/+ ) and PrP knockout (PrP0/0). We also examined Bax activation by immunoprecipitation of subcellular fractions, as well as total Bax activation and cytochrome c release directly in ex-vivo mouse brains. In addition, we examined the insertion of active Bax into the mitochondrial membrane, also using subcellular fractionation.The second paradigm involves an internal insult (physiological Bax-mediated neuronal death during embryonic development). This insult results in massive Bax-mediated cell death in embryonic mice that do not express the natural antagonist of Bax i.e. BClxL. We have therefore created 3 lines of transgenic mice expressing Syrian Hamster PrP (SHaPrP) under the control of the Bclx promoter, to cross with Bclx+/- mice to see if the SHaPrP can assume the role of Bclx in Bclx knockout mice and rescue the neuronal cell death.In the first paradigm, greater numbers of neurons undergoing apoptosis following ethanol insult were seen in PrP0/0 than in PrP +/+ mice, although the differences were not statistically significant. The ex-vivo examination of mouse brains did not provide definitive results.In the second paradigm, 3 lines of transgenic mice have been created and are in various stages of breeding to obtain the required genotypes to test our hypothesis. The level of expression of SHaPrP in these mice is below the level of detection via western blot or immunoprecipitation.The trend shown in our results suggests that in vivo, PrPC may provide some protection for neurons from Bax-mediated cell death as a result of an external insult. Research is ongoing to see if PrPC can protect neurons in vivo against developmental Bax-mediated cell death. The work presented here highlights the variability and technical difficulty inherent with in vivo studies, particularly when the available knowledge of the biochemical pathways involved is incomplete

Predicting outcome in childhood diffuse midline gliomas using magnetic resonance imaging based texture analysis

BACKGROUND: Diffuse midline gliomas (DMG) are aggressive brain tumours, previously known as diffuse intrinsic pontine gliomas (DIPG), with 10% overall survival (OS) at 18 months. Predicting OS will help refine treatment strategy in this patient group. MRI based texture analysis (MRTA) is novel image analysis technique that provides objective information about spatial arrangement of MRI signal intensity (heterogeneity) and has potential to be imaging biomarker. OBJECTIVES: To investigate MRTA in predicting OS in childhood DMG. METHODS: Retrospective study of patients diagnosed with DMG, based on radiological features, treated at our institution 2007-2017. MRIs were acquired at diagnosis and 6 weeks after radiotherapy (54Gy in 30 fractions). MRTA was performed using commercial available TexRAD research software on T2W sequence and Apparent Diffusion Coefficient (ADC) maps encapsulating tumour in the largest single axial plane. MRTA comprised filtration-histogram technique using statistical and histogram metrics for quantification of texture. Kaplan-Meier survival analysis determined association of MRI texture parameters with OS. RESULTS: 32 children 2-14 years (median 7 years) were included. MRTA was undertaken on T2W (n=32) and ADC (n=22). T2W-MRTA parameters were better at prognosticating than ADC-MRTA. Children with homogenous tumour texture, at medium scale on diagnostic T2W MRI, had worse prognosis (Mean of Positive Pixels (MPP): p=0.005, mean: p=0.009, SD: p=0.011, kurtosis: p=0.037, entropy: p=0.042). Best predictor MPP was able to stratify patients into poor and good prognostic groups with median survival of 7.5 months versus 17.5 months, respectively. CONCLUSIONS: DMG with more homogeneous texture on diagnostic MRI is associated with worse prognosis. Texture parameter MPP is the most predictive marker of OS in childhood DMG

Atlas construction and spatial normalisation to facilitate radiation-induced late effects research in childhood cancer

Reducing radiation-induced side effects is one of the most important challenges in paediatric cancer treatment. Recently, there has been growing interest in using spatial normalisation to enable voxel-based analysis of radiation-induced toxicities in a variety of patient groups. The need to consider three-dimensional distribution of doses, rather than dose-volume histograms, is desirable but not yet explored in paediatric populations. In this paper, we investigate the feasibility of atlas construction and spatial normalisation in paediatric radiotherapy. We used planning computed tomography (CT) scans from twenty paediatric patients historically treated with craniospinal irradiation to generate a template CT that is suitable for spatial normalisation. This childhood cancer population representative template was constructed using groupwise image registration. An independent set of 53 subjects from a variety of childhood malignancies was then used to assess the quality of the propagation of new subjects to this common reference space using deformable image registration (i.e., spatial normalisation). The method was evaluated in terms of overall image similarity metrics, contour similarity and preservation of dose-volume properties. After spatial normalisation, we report a dice similarity coefficient of 0.95±0.05, 0.85±0.04, 0.96±0.01, 0.91±0.03, 0.83±0.06 and 0.65±0.16 for brain and spinal canal, ocular globes, lungs, liver, kidneys and bladder. We then demonstrated the potential advantages of an atlas-based approach to study the risk of second malignant neoplasms after radiotherapy. Our findings indicate satisfactory mapping between a heterogeneous group of patients and the template CT. The poorest performance was for organs in the abdominal and pelvic region, likely due to respiratory and physiological motion and to the highly deformable nature of abdominal organs. More specialised algorithms should be explored in the future to improve mapping in these regions. This study is the first step toward voxel-based analysis in radiation-induced toxicities following paediatric radiotherapy

Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma

Background and Purpose: State-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma. Materials and Methods: The risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT. Results: The risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01–1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively. Conclusions: PBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection

Thermophysical properties of lysozyme (protein) solutions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76692/1/AIAA-392-587.pd

Parents' responses to prognostic disclosure at diagnosis of a child with a high‐risk brain tumor: Analysis of clinician‐parent interactions and implications for clinical practice

Background: Previous studies have found that parents of children with cancer desire more prognostic information than is often given even when prognosis is poor. We explored in audio‐recorded consultations the kinds of information they seek. / Methods: Ethnographic study including observation and audio recording of consultations at diagnosis. Consultations were transcribed and analyzed using an interactionist perspective including tools drawn from conversation and discourse analysis. / Results: Enrolled 21 parents and 12 clinicians in 13 cases of children diagnosed with a high‐risk brain tumor (HRBT) over 20 months at a tertiary pediatric oncology center. Clinicians presented prognostic information in all cases. Through their questions, parents revealed what further information they desired. Clinicians made clear that no one could be absolutely certain what the future held for an individual child. Explicit communication about prognosis did not satisfy parents’ desire for information about their own child. Parents tried to personalize prognostic information and to apply it to their own situation. Parents moved beyond prognostic information presented and drew conclusions, which could change over time. Parents who were present in the same consultations could form different views of their child's prognosis. / Conclusion: Population level prognostic information left parents uncertain about their child's future. The need parents revealed was not for more such information but rather how to use the information given and how to apply it to their child in the face of such uncertainty. Further research is needed on how best to help parents deal with uncertainty and make prognostic information actionable