Differential Effects of Isoflurane and Propofol on Upper Airway Dilator Muscle Activity and Breathing

Background: Anesthesia impairs upper airway integrity, but recent data suggest that low doses of some anesthetics increase upper airway dilator muscle activity, an apparent paradox. The authors sought to understand which anesthetics increase or decrease upper airway dilator muscle activity and to study the mechanisms mediating the effect. Methods: The authors recorded genioglossus electromyogram, breathing, arterial blood pressure, and expiratory carbon dioxide in 58 spontaneously breathing rats at an estimated ED 50 (median effective dose) of isoflurane or propofol. The authors further evaluated the dose-response relations of isoflurane under different study conditions: (1) normalization of mean arterial pressure, or end-expiratory carbon dioxide; (2) bilateral lesion of the Kölliker-Fuse nucleus; and (3) vagotomy. To evaluate whether the markedly lower inspiratory genioglossus activity during propofol could be recovered by increasing flow rate, a measure of respiratory drive, the authors performed an additional set of experiments during hypoxia or hypercapnia. Results: In vagally intact rats, tonic and phasic genioglossus activity were markedly higher with isoflurane compared with propofol. Both anesthetics abolished the genioglossus negative pressure reflex. Inspiratory flow rate and anesthetic agent predicted independently phasic genioglossus activity. Isoflurane dose-dependently decreased tonic and increased phasic genioglossus activity, and increased flow rate, and its increasin

Working in the Public Interest Law Conference

Entirely student organized, WIPI seeks to bring together eminent practitioners in their respective fields, students, and faculty to discuss practical approaches to lawyering which can best serve the poor. Practical methods of challenging poverty are often not covered in traditional law school courses. This conference seeks to remedy that and provide dynamic, creative ways to combat poverty through the vehicle of the law

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

A cognitive behavioural model of the bidirectional relationship between disordered eating and diabetes self care in people with type 1 diabetes mellitus

AIMS: This qualitative study aimed to develop the first cognitive-behavioural-therapy model outlining the development and maintenance of disordered eating in type 1 diabetes and report on recovery strategies and resilience factors to improve previous theoretical models of type 1 diabetes and disordered eating. METHODS: Twenty-three women (n=9 with type 1 diabetes and disordered eating, n=5 with type 1 diabetes recovering from disordered eating, and n=9 with type 1 diabetes without disordered eating) participated in semi-structured interviews. Data were analysed using grounded theory and individual cognitive-behavioural formulations were developed for each participant to inform the development/maintenance and resilience models. RESULTS: The development/maintenance model summarises commonly experienced vicious cycles of thoughts, feelings and behaviours in type 1 diabetes and disordered eating. The resilience model summarises strategies/knowledge acquired by those with type 1 diabetes in recovery from disordered eating and individuals with type 1 diabetes who did not develop disordered eating. Early adverse life events, past psychiatric history, perfectionist personality traits, difficult experiences around type 1 diabetes diagnosis and its relentless daily management sensitise individuals to eating, weight and shape cues. Alongside physical symptoms/complications, unhelpful interpersonal reactions and inadequate healthcare, vicious cycles of thoughts, feelings and behaviours develop. "Good enough" psychological adaptation to type 1 diabetes, integrating type 1 diabetes into one's identity, self-care and compassion around eating, weight and shape were key protective/post-traumatic resilience factors. CONCLUSIONS: This first cognitive-behavioural-therapy model of type 1 diabetes and disordered eating informed by personal experience will inform an intervention for type 1 diabetes and disordered eating

A cognitive behavioural model of the bidirectional relationship between disordered eating and diabetes self care in people with type 1 diabetes mellitus

AIMS: This qualitative study aimed to develop the first cognitive-behavioural-therapy model outlining the development and maintenance of disordered eating in type 1 diabetes and report on recovery strategies and resilience factors to improve previous theoretical models of type 1 diabetes and disordered eating. METHODS: Twenty-three women (n=9 with type 1 diabetes and disordered eating, n=5 with type 1 diabetes recovering from disordered eating, and n=9 with type 1 diabetes without disordered eating) participated in semi-structured interviews. Data were analysed using grounded theory and individual cognitive-behavioural formulations were developed for each participant to inform the development/maintenance and resilience models. RESULTS: The development/maintenance model summarises commonly experienced vicious cycles of thoughts, feelings and behaviours in type 1 diabetes and disordered eating. The resilience model summarises strategies/knowledge acquired by those with type 1 diabetes in recovery from disordered eating and individuals with type 1 diabetes who did not develop disordered eating. Early adverse life events, past psychiatric history, perfectionist personality traits, difficult experiences around type 1 diabetes diagnosis and its relentless daily management sensitise individuals to eating, weight and shape cues. Alongside physical symptoms/complications, unhelpful interpersonal reactions and inadequate healthcare, vicious cycles of thoughts, feelings and behaviours develop. "Good enough" psychological adaptation to type 1 diabetes, integrating type 1 diabetes into one's identity, self-care and compassion around eating, weight and shape were key protective/post-traumatic resilience factors. CONCLUSIONS: This first cognitive-behavioural-therapy model of type 1 diabetes and disordered eating informed by personal experience will inform an intervention for type 1 diabetes and disordered eating

Developing a novel intervention for type 1 diabetes and disordered eating using a participatory action design process: Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY)

AIMS: To develop a cognitive behavioural therapy-based intervention for people with type 1 diabetes and disordered eating using Experience-Based Co-Design as part of the Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY). METHODS: Fifteen people with type 1 diabetes and experience of disordered eating (33 ± 11 years old, 22 ± 12 years diabetes duration) and 25 healthcare professionals working in type 1 diabetes or eating disorders (44 ± 9 years old; 14 ± 10 years of professional experience) attended six Experience-Based Co-Design workshops from July 2019 to March 2020 to collaboratively develop intervention content. RESULTS: We developed a cognitive behaviour therapy intervention ‘toolkit’ that can be tailored for individual patient needs. Participants designed and revised toolkit materials to ensure acceptability and relevance for people with diabetes and disordered eating by engaging in guided discussion, brainstorming, and rapid testing to review toolkit prototypes in an iterative process. Workshop themes were ‘Insulin titration’; ‘Hypoglycaemia’; ‘Coming to terms with diabetes’; ‘Fear of weight gain’; ‘Toolkit revision’; and ‘Practical elements of STEADY therapy’. The intervention is focussed on improving diabetes self-care and embedded in a multidisciplinary healthcare approach. The intervention will be delivered in 12 sessions by a diabetes specialist nurse trained in cognitive behavioural therapy. CONCLUSIONS: Through an iterative co-design process, people with type 1 diabetes and healthcare professionals collaboratively developed a novel intervention toolkit that can be used with a wide range of disordered eating presentations. The intervention will be tested in the STEADY feasibility randomised controlled trial