Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself

Tissue resolved, gene structure refined equine transcriptome.

BackgroundTranscriptome interpretation relies on a good-quality reference transcriptome for accurate quantification of gene expression as well as functional analysis of genetic variants. The current annotation of the horse genome lacks the specificity and sensitivity necessary to assess gene expression especially at the isoform level, and suffers from insufficient annotation of untranslated regions (UTR) usage. We built an annotation pipeline for horse and used it to integrate 1.9 billion reads from multiple RNA-seq data sets into a new refined transcriptome.ResultsThis equine transcriptome integrates eight different tissues from 59 individuals and improves gene structure and isoform resolution, while providing considerable tissue-specific information. We utilized four levels of transcript filtration in our pipeline, aimed at producing several transcriptome versions that are suitable for different downstream analyses. Our most refined transcriptome includes 36,876 genes and 76,125 isoforms, with 6474 candidate transcriptional loci novel to the equine transcriptome.ConclusionsWe have employed a variety of descriptive statistics and figures that demonstrate the quality and content of the transcriptome. The equine transcriptomes that are provided by this pipeline show the best tissue-specific resolution of any equine transcriptome to date and are flexible for several downstream analyses. We encourage the integration of further equine transcriptomes with our annotation pipeline to continue and improve the equine transcriptome

Protocol for an HTA report: Does therapeutic writing help people with long-term conditions? Systematic review, realist synthesis and economic modelling

This article is made available through the Brunel Open Access Publishing Fund. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/Introduction: Long-term medical conditions (LTCs) cause reduced health-related quality of life and considerable health service expenditure. Writing therapy has potential to improve physical and mental health in people with LTCs, but its effectiveness is not established. This project aims to establish the clinical and cost-effectiveness of therapeutic writing in LTCs by systematic review and economic evaluation, and to evaluate context and mechanisms by which it might work, through realist synthesis. Methods: Included are any comparative study of therapeutic writing compared with no writing, waiting list, attention control or placebo writing in patients with any diagnosed LTCs that report at least one of the following: relevant clinical outcomes; quality of life; health service use; psychological, behavioural or social functioning; adherence or adverse events. Searches will be conducted in the main medical databases including MEDLINE, EMBASE, PsycINFO, The Cochrane Library and Science Citation Index. For the realist review, further purposive and iterative searches through snowballing techniques will be undertaken. Inclusions, data extraction and quality assessment will be in duplicate with disagreements resolved through discussion. Quality assessment will include using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Data synthesis will be narrative and tabular with meta-analysis where appropriate. De novo economic modelling will be attempted in one clinical area if sufficient evidence is available and performed according to the National Institute for Health and Care Excellence (NICE) reference case.National Institute for Health Research Health Technology Assessment (NIHR HTA) Programm

Case ascertainment of heat illness in the British Army: evidence of under-reporting from analysis of Medical and Command notifications, 2009-2013.

Heat illness in the Armed Forces is considered preventable. The UK military relies upon dual Command and Medical reporting for case ascertainment, investigation of serious incidents and improvement of preventive practices and policy. This process could be vulnerable to under-reporting.To establish whether heat illness in the British Army has been under-reported, by reviewing concordance of reporting to the Army Incident Notification Cell (AINC) and the Army Health Unit (AHU) and to characterise the burden of heat illness reported by these means.Analysis of anonymised reporting databases held by the AHU and AINC, for the period 2009-2013.565 unique cases of heat illness were identified. Annual concordance of reporting ranged from 9.6% to 16.5%. The overall rate was 13.3%. July was the month with the greatest number of heat illness reports (24.4% of total reporting) and the highest concordance rate (30%). Reports of heat illness from the UK (n=343) exceeded overseas notifications (n=221) and showed better concordance (17.1% vs 12.8%). The annual rate of reported heat illness varied widely, being greater in full-time than reservist personnel (87 vs 23 per100 000) and highest in full-time untrained personnel (223 per100 000).The risk of heat illness was global, year-round and showed dynamic local variation. Failure to dual-report casualties impaired case ascertainment of heat illness across Command and Medical chains. Current preventive guidance, as applied in training and on operations, should be critically evaluated to ensure that risk of heat illness is reduced as low as possible. Clear procedures for casualty notification and surveillance are required in support of this and should incorporate communication within and between the two reporting chains

The Meaning of Empathy in the Context of Clinical Nursing Practice Among Senior Baccalaureate Nursing Students:

Thesis advisor: Chris LeeEmpathy is a vital element in the formation of meaningful and trusting relationships between nurses and patients. Studies indicate that empathetic providers promote both increased patient satisfaction and better health outcomes for patients. Given the significance of empathy, what stood out is the gap in knowledge regarding the meaning of empathy from the perspective of senior baccalaureate nursing students just prior to entering the health care context as registered nurses. The purpose of this study was to understand the meaning of empathy, in the context of clinical nursing practice from the perspective of senior baccalaureate nursing students. A hermeneutic phenomenological approach was used in the research analysis. The key research questions were: What is the meaning of empathy in the context of clinical nursing practice among senior baccalaureate students? How does clinical nursing practice shape and nurture empathy for senior baccalaureate nursing students? The researcher anticipates this study to be the first, which delineates the meaning of empathy in the context of clinical nursing practice among senior baccalaureate nursing students. Three essential themes surfaced during analysis, discovering every patient is a human person, empathy helps patients feel visible, heard and understood, and empathy breaks through bias towards patients. The results also suggest that clinical nursing practice among undergraduate nursing students shapes and nurtures empathy.Thesis (PhD) — Boston College, 2022.Submitted to: Boston College. Connell School of Nursing.Discipline: Nursing

Evaluating the Impact of Dry January 2016

The North West Coast (NWC) Academic Health Science Network (AHSN) has identified harms caused by alcohol as a specific area of work in the region. In particular, the AHSN is keen to support innovative initiatives where they can have a direct effect on the reduction of alcohol-related attendances and admissions in Emergency Departments (EDs) and Urgent Care Centres (UCCs). The Public Health Institute at Liverpool John Moores University was invited to conduct an evaluation to help gauge the success of the campaign using mixed methodologies. The evaluation was composed of: a comparison and analysis of Dry January participation data (shared by HITCH on behalf of Alcohol Concern); Trauma and Injury Intelligence Group (TIIG) data and North West Ambulance Service (NWAS) data; and, semi-structured interviews with key stakeholders within companies who participated in the Dry January campaign

Intravenous lipid emulsion and dexmedetomidine for treatment of feline permethrin intoxication: A report from 4 cases

Four cases of feline permethrin intoxication are described. The cause of intoxication is the application of canine permethrin spot-on product (Advantix®, Bayer) by the owners. Principal clinical guidelines recommends the use of anticonvulsant drugs to treat seizures or neurological symptoms after initial stabilization and dermal decontamination. The use of lipid emulsion had an increasing interest in the last decade for treatment of toxicosis caused by lipophylic drugs as reported in human and in veterinary medical practices. All cats presented in this study, were treated with intravenous lipid emulsion (ILE) at variable dosages, and dexmedetomidine was also administered by intravenous way. No adverse reaction such as thrombophlebitis, overload circulation or others was noticed during and after administration of ILE. Dexmedetomidine was proved to be helpful in tranquillizing the cats. All cats were discharged in good condition faster than other cases treated without their use

PCB-Related Alteration of Thyroid Hormones and Thyroid Hormone Receptor Gene Expression in Free-Ranging Harbor Seals (Phoca vitulina)

Persistent organic pollutants are environmental contaminants that, because of their lipophilic properties and long half-lives, bioaccumulate within aquatic food webs and often reach high concentrations in marine mammals, such as harbor seals (Phoca vitulina). Exposure to these contaminants has been associated with developmental abnormalities, immunotoxicity, and reproductive impairment in marine mammals and other high-trophic-level wildlife, mediated via a disruption of endocrine processes. The highly conserved thyroid hormones (THs) represent one vulnerable endocrine end point that is critical for metabolism, growth, and development in vertebrates. We characterized the relationship between contaminants and specific TH receptor (TR ) gene expression in skin/blubber biopsy samples, as well as serum THs, from free-ranging harbor seal pups (n = 39) in British Columbia, Canada, and Washington State, USA. We observed a contaminant-related increase in blubber TR-α gene expression [total polychlorinated biphenyls (∑PCBs); r = 0.679; p < 0.001] and a concomitant decrease in circulating total thyroxine concentrations (∑PCBs; r = −0.711; p < 0.001). Consistent with results observed in carefully controlled laboratory and captive feeding studies, our findings suggest that the TH system in harbor seals is highly sensitive to disruption by environmental contaminants. Such a disruption not only may lead to adverse effects on growth and development but also could have important ramifications for lipid metabolism and energetics in marine mammals

The development of a new measure of quality of life in the management of gastro-oesophageal reflux disease: the Reflux Questionnaire.

INTRODUCTION This paper reports on the development of a new measure of health-related quality of life for use among patients with gastro-oesophageal reflux disease (GORD), funded as part of the REFLUX trial. This is a large UK multi centre trial that aims to compare the clinical and cost effectiveness of minimal access surgery with best medical treatment for patients with GORD within the NHS. Method Potential items were identified via a series of interviews and focus groups carried out with patients who were receiving/had received medical or surgical treatment for GORD. The final measure consisted of 31 items covering 7 categories (Heartburn; Acid reflux; Wind; Eating and swallowing; Bowel movements; Sleep; Work, physical and social activities). The measure produced two outputs: a quality of life score (RQLS) and five Reflux symptom scores. Reliability (internal consistency), criterion validity with the SF-36 and, sensitivity to change in terms of relationship with reported change in prescribed medication were assessed amongst a sample of 794 patients recruited into the trial. RESULTS The measure was shown to be internally consistent, to show criterion validity with the SF-36 and sensitive to changes in patients use of prescribed medication at baseline and 3 month follow-up. DISCUSSION The Reflux questionnaire is a new self-administered questionnaire for use amongst patients with GORD. Initial findings suggest that the new measure is valid, reliable, acceptable to respondents and simple to administer in both a clinical and research context