An investigation into the use of the Deprivation of Liberty Safeguards with people with intellectual disabilities

Background: This small, qualitative study sought to develop a richer understanding of the way in which the deprivation of liberty safeguards (DOLS) were being used for people with intellectual disabilities. It is important to note that this study was completed prior to the changes resulting from the P v Cheshire West and Chester Council judgement. Method: Six DOLS cases were identified and two people involved in each case were interviewed (care home managers, key workers, social workers, specialist nurses or psychologists), using semi-structured interviews. The data were analysed using grounded theory techniques. Results: The interviewees described DOLS as providing a framework leading to positive outcomes for the people they supported, in some cases avoiding inpatient stays. However, they had a number of concerns including lack of knowledge and training, potential under use of DOLS and disappointment with case law. Conclusion: Overall, these findings are encouraging in regard to the specific individuals for whom DOLS applications were made; however, they also highlight the need for a stronger agenda regarding wider dissemination of information, and training about DOLS, as well as some reform

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Patient perspectives on delays in diagnosis and treatment of cancer: a qualitative analysis of free-text data

Background: Earlier cancer diagnosis is crucial in improving cancer survival. The International Cancer Benchmarking Partnership Module 4 (ICBP4) is a quantitative survey study that explores the reasons for delays in diagnosis and treatment of breast, colorectal, lung, and ovarian cancer. To further understand the associated diagnostic processes, it is also important to explore the patient perspectives expressed in the free-text comments. Aim: To use the free-text data provided by patients completing the ICBP4 survey to augment the understanding of patients’ perspectives of their diagnostic journey. Design and setting: Qualitative analysis of the free-text data collected in Wales between October 2013 and December 2014 as part of the ICBP4 survey. Newly-diagnosed patients with either breast, ovarian, colorectal, or lung cancer were identified from registry data and then invited by their GPs to participate in the survey. Method: A thematic framework was used to analyse the free-text comments provided at the end of the ICBP4 survey. Of the 905 patients who returned a questionnaire, 530 included comments. Results: The free-text data provided information about patients’ perspectives of the diagnostic journey. Analysis identified factors that acted as either barriers or facilitators at different stages of the diagnostic process. Some factors, such as screening, doctor–patient familiarity, and private treatment, acted as both barriers and facilitators depending on the context. Conclusion: Factors identified in this study help to explain how existing models of cancer diagnosis (for example, the Pathways to Treatment Model) work in practice. It is important that clinicians are aware of how these factors may interact with individual clinical cases and either facilitate, or act as a barrier to, subsequent cancer diagnosis. Understanding and implementing this knowledge into clinical practice may result in quicker cancer diagnoses

Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

Few translational studies have examined how age-at-injury affects the glial response to traumatic brain injury (TBI). We hypothesized that rats injured at post-natal day (PND) 17 would exhibit a greater glial response, that would persist into early adulthood, compared to rats injured at PND35. PND17 and PND35 rats (n = 75) received a mild to moderate midline fluid percussion injury or sham surgery. In three cortical regions [peri-injury, primary somatosensory barrel field (S1BF), perirhinal], we investigated the glial response relative to age-at-injury (PND17 or PND35), time post-injury (2 hours, 1 day, 7 days, 25 days, or 43 days), and post-natal age, such that rats injured at PND17 or PND35 were compared at the same post-natal-age (e.g., PND17 + 25D post-injury = PND42; PND35 + 7D post-injury = PND42). We measured Iba1 positive microglia cells (area, perimeter) and quantified their activation status using skeletal analysis (branch length/cell, mean processes/cell, cell abundance). GFAP expression was examined using immunohistochemistry and pixel analysis. Data were analyzed using Bayesian multivariate multi-level models. Independent of age-at-injury, TBI activated microglia (shorter branches, fewer processes) in the S1BF and perirhinal cortex with more microglia in all regions compared to uninjured shams. TBI-induced microglial activation (shorter branches) was sustained in the S1BF into early adulthood (PND60). Overall, PND17 injured rats had more microglial activation in the perirhinal cortex than PND35 injured rats. Activation was not confounded by age-dependent cell size changes, and microglial cell body sizes were similar between PND17 and PND35 rats. There were no differences in astrocyte GFAP expression. Increased microglial activation in PND17 brain-injured rats suggests that TBI upregulates the glial response at discrete stages of development. Age-at-injury and aging with an injury are translationally important because experiencing a TBI at an early age may trigger an exaggerated glial response. </div

Determination of Dosage Compensation of the Mammalian X Chromosome by RNA-seq is Dependent on Analytical Approach

Background An enduring question surrounding sex chromosome evolution is whether effective hemizygosity in the heterogametic sex leads inevitably to dosage compensation of sex-linked genes, and whether this compensation has been observed in a variety of organisms. Incongruence in the conclusions reached in some recent reports has been attributed to different high-throughput approaches to transcriptome analysis. However, recent reports each utilizing RNA-seq to gauge X-linked gene expression relative to autosomal gene expression also arrived at diametrically opposed conclusions regarding X chromosome dosage compensation in mammals. Results Here we analyze RNA-seq data from X-monosomic female human and mouse tissues, which are uncomplicated by genes that escape X-inactivation, as well as published RNA-seq data to describe relative X expression (RXE). We find that the determination of RXE is highly dependent upon a variety of computational, statistical and biological assumptions underlying RNA-seq analysis. Parameters implemented in short-read mapping programs, choice of reference genome annotation, expression data distribution, tissue source for RNA and RNA-seq library construction method have profound effects on comparing expression levels across chromosomes. Conclusions Our analysis shows that the high number of paralogous gene families on the mammalian X chromosome relative to autosomes contributes to the ambiguity in RXE calculations, RNA-seq analysis that takes into account that single- and multi-copy genes are compensated differently supports the conclusion that, in many somatic tissues, the mammalian X is up-regulated compared to the autosomes

Advancing national climate change risk assessment to deliver national adaptation plans

A wide range of climate vulnerability and risk assessments have been implemented using different approaches at different scales, some with a broad multi-sectoral scope and others focused on single risks or sectors. This paper describes the novel approach to vulnerability and risk assessment which was designed and put into practice in the United Kingdom's Second Climate Change Risk Assessment (CCRA2) so as to build upon its earlier assessment (CCRA1). First, we summarize and critique the CCRA1 approach, and second describe the steps taken in the CCRA2 approach in detail, providing examples of how each was applied in practice. Novel elements of the approach include assessment of both present day and future vulnerability, a focus on the urgency of adaptation action, and a structure focused around systems of receptors rather than conventional sectors. Both stakeholders and reviewers generally regarded the approach as successful in providing advice on current risks and future opportunities to the UK from climate change, and the fulfilment of statutory duty. The need for a well-supported and open suite of impact indicators going forward is highlighted

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

The templated zeolite-analogue GaPO-34 (CHA structure type) crystallises from a gel precursor Ga2O3:2H3PO4:1HF:1.7SDA:70H2O (where SDA = structure directing agent), treated hydrothermally for 24 hours at 170 °C using either pyridine or 1-methylimizadole as SDA and one of either poorly crystalline ε-Ga2O3 or γ-Ga2O3 as gallium precursor. If the same gels are stirred for periods shorter than 2 hours but treated under identical hydrothermal conditions, then a second phase crystallises, free of GaPO-34. If β-Ga2O3 is used as a reagent only the second phase is found to crystallise, irrespective of gel aging time. The competing phase, which we denote GaPO-34A, has been structurally characterised using synchrotron powder X-ray diffraction for the pyridine material, GaPO-34A(pyr), and using single-crystal X-ray diffraction for the 1-methylimiazole material, GaPO-34A(mim). The structure of GaPO-34A(pyr), P1 @#x0305;, a = 10.22682(6) Å, b = 12.09585(7) Å, c = 13.86713(8) Å, α = 104.6531(4) °, β = 100.8111(6) °, γ = 102.5228(6) °, contains 7 unique gallium sites and 6 phosphorus sites, with empirical formula [Ga7P6O24(OH)2F3(H2O)2].2(C5NH6). GaPO-34A(mim) is isostructural but is modelled as a half volume unit cell, P1 @#x0305;, a = 5.0991(2) Å, b = 12.0631(6) Å, c = 13.8405(9) Å, α = 104.626(5) °, β = 100.346(5) °, γ = 101.936(4) °, with a gallium and a bridging fluoride partially occupied and two partially occupied SDA sites. Solid-state 31P and 71Ga NMR spectroscopy confirms the structural complexity of GaPO-34A with signals resulting from overlapping lineshapes from multiple Ga and P sites, while 1H and 13C solid-state NMR spectra confirm the presence of the protonated SDA and provide evidence for disorder in the SDA. The protonated SDA is located in 14-ring one-dimensional channels with hydrogen bonding deduced from the SDA nitrogens to framework oxygen distances. Upon thermal treatment to investigate SDA removal, structure collapse occurs, which may be due the large number of bridging hydroxides and fluorides in the as-made material, and the unequal amounts of gallium and phosphorus present

Traumatic Brain Injury Characteristics Predictive of Subsequent Sleep-Wake Disturbances in Pediatric Patients

Simple Summary Traumatic brain injury is a leading cause of death and disabilities in children and adolescents. Poor sleep after brain injury can slow recovery and worsen outcomes. We investigated clinical sleep problems following pediatric brain injury. We examined characteristics of the injury and details about the patients that may be risk factors for developing sleep problems. The number of patients that developed problems with their sleep after a brain injury was similar between genders. The probability of insomnia increased with increasing patient age. The probability of &lsquo;difficulty sleeping&rsquo; was highest in 7&ndash;9 year-old brain-injured patients. Older patients had a shorter time between brain injury and sleep problems compared to younger patients. Patients with severe brain injury had the shortest time between brain injury and development of sleep problems, whereas patients with mild or moderate brain injury had comparable times between brain injury and the onset of poor sleep. Multiple characteristics of brain injury and patient details were identified as risk factors for developing sleep problems following a brain injury in children. Untreated sleep problems after a brain injury can worsen symptoms, lengthen hospital stays, and delay return to school. Identifying risk factors could improve the diagnosis, management, and treatment of sleep problems in survivors of pediatric brain injury. Abstract The objective of this study was to determine the prevalence of sleep-wake disturbances (SWD) following pediatric traumatic brain injury (TBI), and to examine characteristics of TBI and patient demographics that might be predictive of subsequent SWD development. This single-institution retrospective study included patients diagnosed with a TBI during 2008&ndash;2019 who also had a subsequent diagnosis of an SWD. Data were collected using ICD-9/10 codes for 207 patients and included the following: age at initial TBI, gender, TBI severity, number of TBIs diagnosed prior to SWD diagnosis, type of SWD, and time from initial TBI to SWD diagnosis. Multinomial logit and negative-binomial models were fit to investigate whether the multiple types of SWD and the time to onset of SWD following TBI could be predicted by patient variables. Distributions of SWD diagnosed after TBI were similar between genders. The probability of insomnia increased with increasing patient age. The probability of &lsquo;difficulty sleeping&rsquo; was highest in 7&ndash;9 year-old TBI patients. Older TBI patients had shorter time to SWD onset than younger patients. Patients with severe TBI had the shortest time to SWD onset, whereas patients with mild or moderate TBI had comparable times to SWD onset. Multiple TBI characteristics and patient demographics were predictive of a subsequent SWD diagnosis in the pediatric population. This is an important step toward increasing education among providers, parents, and patients about the risk of developing SWD following TBI. &nbsp;</p