Patient decision making about organ quality in liver transplantation

It is challenging to discuss the use of high‐risk organs with patients, in part because of the lack of information about how patients view this topic. This study was designed to determine how patients think about organ quality and to test formats for risk communication. Semistructured interviews of 10 patients on the waiting list revealed limited understanding about the spectrum of organ quality and a reluctance to consider anything but the best organs. A computerized quantitative survey was then conducted with an interactive graph to elicit the risk of graft failure that patients would accept. Fifty‐eight percent of the 95 wait‐listed patients who completed the survey would accept only organs with a risk of graft failure of 25% or less at 3 years, whereas 18% would accept only organs with the lowest risk possible (19% at 3 years). Risk tolerance was increased when the organ quality was presented relative to average organs rather than the best organs and when feedback was provided about the implications for organ availability. More than three‐quarters of the patients reported that they wanted an equal or dominant role in organ acceptance decisions. Men tended to prefer lower risk organs (mean acceptable risk = 29%) in comparison with women (mean acceptable risk = 35%, P = 0.04), but risk tolerance was not associated with other demographic or clinical characteristics (eg, the severity of liver disease). In summary, patients want to be involved in decisions about organ quality. Patients' risk tolerance varies widely, and their acceptance of high‐risk organs can be facilitated if we present the risks of graft failure with respect to average organs and provide feedback about the implications for organ availability. Liver Transpl, 2011. © 2011 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88081/1/22437_ftp.pd

Designing for difference: lessons from a cross-disciplinary implementation of Universal Design for Learning

Funded by the Teaching Innovation Project (2016/17) 'Towards Equitable Engagement: the Impact of UDL on Student Perceptions of Learning'Universal Design for Learning (UDL) is a pedagogical framework that seeks to provide students with flexible ways of learning, flexiblestudyresources,andflexiblewaysoftestinglearning. Just as Universal Design (UD) provides for difference of physical ability amongst users, UDL provides for difference of learning styles amongst students. Like UD, UDL assumes that learner difference, not commonality, is the norm. 1 De Montfort University (DMU) is a public teaching and research university located in the city of Leicester in the East Midlands of England. In 2016, DMU adopted UDL as part of a university- wide program to offset the consequences of changes to central government support for students with disabilities. Alongside a significant investment in lecture capture and replay technology, DMU’s adoption of the principles of UDL has challenged faculty members teaching at all levels and in all disciplines to re- appraise the accessibility and inclusivity of their teaching. This paper discusses research-in-progress from a cross-discipline survey of the implementation of the principles of UDL at DMU.* The project examines the perceptions and feelings of freshman students from a range of different backgrounds and in a range of subjects about the impact of UDL on their experience of higher education. When complete, the project will evaluate how the implementation of the principles and ideas of UDL are interpreted and applied by students, alongside their recom- mendations for the academic practice of staff

Use of protracted CPAP as a supportive treatment for COVID-19 pneumonitis and associated outcomes: a national cohort study

Background: Continuous positive airway pressure (CPAP) has been increasingly deployed to manage patients with COVID-19 and hypoxemic respiratory failure, often for protracted periods. However, concerns about protracted CPAP have been raised. This study aims to examine the use of CPAP for patients with COVID-19 and the outcomes after protracted use. Methods: This is a national cohort study of all adults admitted to Scottish critical care units with COVID-19 from 01/03/20 to 25/12/21 that received CPAP. Protracted CPAP was defined as ≥ 5 continuous days of CPAP. Outcomes included CPAP failure rate (institution of invasive mechanical ventilation (IMV) or death), mortality, and outcomes following institution of IMV. Multivariable logistic regression was performed to assess the impact of protracted CPAP on mortality after IMV. Results: 1961 patients with COVID-19 received CPAP for COVID pneumonitis with 733 patients (37.4%) receiving protracted CPAP. CPAP failure occurred in 891 (45.4%): 544 patients (27.7%) received IMV and 347 patients (17.7%) died in critical care without IMV. Hospital mortality rate was 41.3% for the population. For patients that subsequently commenced IMV, hospital mortality was 58.7% for the standard duration CPAP group and 73.9% for the protracted duration CPAP group (p=0.003), however, there was no statistical difference in hospital mortality after adjustment for confounders (OR 1.4, (95% CI 0.84, 2.33, p=0.195). Conclusions: Protracted CPAP was used frequently for managing patients with COVID-19. Whilst it was not associated with worse outcomes for those patients who subsequently required IMV, this may be due to residual confounding and differences in processes of care

Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. RESULTS: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. CONCLUSION: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.This work was supported by Cancer Research UK (C1094/A11728 to CMLW and NGB for the RAPPER study, C26900/A8740 to GCB, C5047A17528 to RE), the Royal College of Radiologists (GCB), Prostate Cancer UK (P2012148 to RE), The ELLIPSE Consortium on behalf of the GAME-ON Network, The National Institute for Health Research (GCB), Addenbrooke’s Charitable Trust (GCB), NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, The National Institute for Health Research Cambridge Biomedical Research Centre (NGB), UK Medical Research Council (LD), the Experimental Cancer Medicine Centre (CMLW), the Royal Marsden NHS Foundation Trust (DPD), the United States National Institutes of Health (1R01CA134444 to BSR), the American Cancer Society (RSGT-05-200-01-CCE to BSR), the United States Department of Defense (PC074201 to BSR), Mount Sinai Tisch Cancer Institute Developmental Fund Award (BSR), the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030 to AV), Fondo Europeo de Desarrollo Regional (FEDER 2007-2013 to AV), Xunta de Galicia and the European Social Fund (POS-A/2013/034 to LF), and the Alberta Cancer Board Research Initiative Program (103.0393.71760001404 to MP). Laboratory infrastructure for the RAPPER study was funded by Cancer Research UK [C8197/A10123]. DD acknowledges support from the National Institute for Health Research RM/ICR Biomedical Research Centre and all the researchers at the Royal Marsden Hospital and the Institute of Cancer Research. The RAPPER cohort comprises patients and data recruited into the RT01 and CHHiP UK radiotherapy trials. The RT01 trial was supported by the UK Medical Research Council. The CHHiP trial (CRUK/06/016) was supported by the Department of Health and Cancer Research UK (C8262/A7253); trial recruitment was facilitated within centers by the National Institute for Health Research Cancer Research Network.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group

The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3-O-phosphate

Solid tumours vary in sensitivity to the vascular disrupting agent combretastatin A-4 3-O-phosphate (CA4P), but underlying factors are poorly understood. The signaling sphingolipid, sphingosine-1-phosphate (S1P), promotes vascular barrier integrity by promoting assembly of VE-cadherin/β-catenin complexes. We tested the hypothesis that tumour pre-treatment with S1P would render tumours less susceptible to CA4P. S1P (1μM) pretreatment attenuated an increase in endothelial cell (HUVEC) monolayer permeability induced by 10μM CA4P. Intravenously administered S1P (8mg/kg/hr for 20 minutes then 2mg/kg/hr for 40 minutes), reduced CA4Pinduced (30mg/kg) blood fow shut-down in fbrosarcoma tumours in SCID mice (n≥7 per group), as measured by tumour retention of an intravenously administered fuorescent lectin. A trend towards in vivo protection was also found using laser Doppler fowmetry. Immunohistochemical staining of tumours ex vivo revealed disrupted patterns of VE-cadherin in vasculature of mice treated with CA4P, which were decreased by pretreatment with S1P. S1P treatment also stabilized N-cadherin junctions between endothelial cells and smooth muscle cells in culture, and stabilized tubulin flaments in HUVEC monolayers. We conclude that the rapid shutdown of tumour microvasculature by CA4P is due in part to disruption of adherens junctions and that S1P has a protective effect on both adherens junctions and the endothelial cell cytoskeleton

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD