137 research outputs found

    Paddle to the sea

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    This paper explores human and other-than-human agency through the rhythms experienced during a source to sea canoe journey from Kirkstone Pass in the centre of the Lake District to the Solway Firth.  Musing on the narrative of Holling’s (1941) children’s classic ‘Paddle to the Sea’ this study reflects on the dance of agency experienced by Hollins' character 'Paddle' alongside those which emerge during our own paddle to the sea. Acknowledging privileges in terms of agency, finances and time; what experiences would the researchers have in terms of their sense of space, time and nature connection? Findings included observations around the role of task focus on the sense of time, space and nature connection, some attractive aspects of arrhythmia and the examination of some assumed hierarchical dualities

    Characterization of Aptamer-Protein Complexes by X-ray Crystallography and Alternative Approaches

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    Aptamers are oligonucleotide ligands, either RNA or ssDNA, selected for high-affinity binding to molecular targets, such as small organic molecules, proteins or whole microorganisms. While reports of new aptamers are numerous, characterization of their specific interaction is often restricted to the affinity of binding (KD). Over the years, crystal structures of aptamer-protein complexes have only scarcely become available. Here we describe some relevant technical issues about the process of crystallizing aptamer-protein complexes and highlight some biochemical details on the molecular basis of selected aptamer-protein interactions. In addition, alternative experimental and computational approaches are discussed to study aptamer-protein interactions.

    Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun):a multicentre, single-blinded, randomised clinical trial

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    BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods.METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete.FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 Όg daily to 1000 Όg daily (500 Όg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 Όg once daily to 500 Όg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA.INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden.FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.</p

    Genetic mechanisms of critical illness in COVID-19.

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    Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    Motivational Tiered Assessment: A New Grading Approach for Motivating Information Systems Students

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    Academia places significant weight on grades as a metric to assess how much students have learned (Beatty, 2004). As a form of assessment, however, grades alone do not provide room for feedback and further student development. This paper offers a new direction to information systems (IS) programs to improve student motivation and better assess student learning—motivational tiered assessment (MTA)—that we propose overcomes these concerns. A tiered approach to learning allows students to choose how much effort and commitment they want to apply and assesses students’ competence based on the performance outcome they choose to achieve by meeting a specific set of pre-determined specifications and expectations. We first explain how MTA works. We then delineate how the new system differs from the points-based grading system, which academia commonly uses. We conclude by presenting three class examples that illustrate how one can apply MTA across an IS curriculum

    Evaluation of the self-fitting process with a commercially available hearing aid

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    Background: Hearing aids and personal sound amplification products that are designed to be self-fitted by the user at home are becoming increasingly available in the online marketplace. While these devices are often marketed as a low-cost alternative to traditional hearing health-care, little is known about people’s ability to successfully use and manage them. Previous research into the individual components of a simulated self-fitting procedure has been undertaken, but no study has evaluated performance of the procedure as a whole using a commercial product. Purpose: To evaluate the ability of a group of adults with a hearing loss to set up a pair of commercially available self-fitting hearing aids for their own use and to investigate factors associated with a successful outcome. Research Design: An interventional study that used regression analysis to identify potential contributors to the outcome. Study Sample: Forty adults with mild to moderately severe hearing loss participated in the study: 20 current hearing aid users (the “experienced” group) and 20 with no previous amplification experience (the “new” group). Twenty-four participants attended with partners, who were present to offer assistance with the study task as needed. Data Collection and Analysis: Participants followed a set of written, illustrated instructions to perform a multistep self-fitting procedure with a commercially available self-fitting hearing aid, with optional assistance from a lay partner. Standardized measures of cognitive function, health literacy, locus of control, hearing aid self-efficacy, and manual dexterity were collected. Statistical analysis was performed to examine the proportion of participants in each group who successfully performed the self-fitting procedure, factors that predicted successful completion of the task, and the contributions of partners to the outcome. Results: Fifty-five percent of participants were able to successfully perform the self-fitting procedure. Although the same success rate was observed for both experienced and new participants, the majority of the errors relating to the hearing test and the fine-tuning tasks were made by the experienced participants, while all of the errors associated with physically customizing the hearing aids and most of the insertion errors were made by the new participants. Although the majority of partners assisted in the self-fitting task, their contributions did not significantly influence the outcome. Further, no characteristic or combination of characteristics reliably predicted which participants would be successful at the self-fitting task. Conclusions: Although the majority of participants were able to complete the self-fitting task without error, the provision of knowledgeable support by trained personnel, rather than a fellow layperson, would most certainly increase the proportion of users who are able to achieve success. Refinements to the instructions and the physical design of the hearing aid may also serve to improve the success rate. Further evaluation of the range of self-fitting hearing aids that are now on the market should be undertaken.10 page(s