A decision aid to support family carers of people living with dementia towards the end of life: Co-production process, outcome and reflections

open access articleBackground Family carers of people living with dementia often need support with making decisions about care. Many find end-of-life care decisions particularly difficult. The aim of this article is to present an evidence- and theoretical-based process for developing a decision aid to support family carers of people with dementia towards the end-of-life. Methods Following a systematic process, we developed a decision aid using coproduction methods and matrices to synthesize data from a systematic review and qualitative interviews with people living with dementia and family carers. Data were presented to coproduction workshops of people living with dementia, family carers, practitioners and professionals. Development was guided by the Ottawa Decision Support Framework and a modified Interprofessional Shared Decision-Making model. Results The decision aid covers four decision areas: (1) changes in care; (2) eating and drinking difficulties; (3) everyday well-being; and (4) healthcare, tests and medication. We present an interactive decision aid, using a variety of approaches including written text, Frequently Asked Questions, top tips and illustrative quotes from people living with dementia and family carers. Conclusion This is the first decision aid that focusses on multiple decisions towards the end-of-life in dementia care. The process offers a template for others to develop decision aids or similar interventions, and how to include people living with dementia in coproduction. Patient or Public Contribution Family carers provided feedback on data collection, data analysis and the decision aid, and one is a coauthor. People living with dementia and family carers were integral to the coproduction workshops

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PURPOSE: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. EXPERIMENTAL DESIGN: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. RESULTS: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. CONCLUSIONS: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).This study was supported by Merck & Co., Inc. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research), the National Institute for Health Research (NIHR) Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), the NIHR Clinical Research Facility (to the Royal Marsden NHS Foundation Trust) and the Cancer Research UK and EPSRC Cancer Imaging Centre. T.A. Yap is the recipient of the 2011 Rebecca and Nathan Milikowsky – PCF Young Investigator Award and is supported by the NIHR. M.O. Leach is an NIHR Senior Investigator.This is the accepted manuscript. The final version is available from AACR at http://clincancerres.aacrjournals.org/content/early/2014/09/19/1078-0432.CCR-14-0868

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Changed activation, oxygenation, and pain response of chronically painful muscles to repetitive work after training interventions: a randomized controlled trial

The aim of this randomized controlled trial was to assess changes in myalgic trapezius activation, muscle oxygenation, and pain intensity during repetitive and stressful work tasks in response to 10 weeks of training. In total, 39 women with a clinical diagnosis of trapezius myalgia were randomly assigned to: (1) general fitness training performed as leg-bicycling (GFT); (2) specific strength training of the neck/shoulder muscles (SST) or (3) reference intervention without physical exercise. Electromyographic activity (EMG), tissue oxygenation (near infrared spectroscopy), and pain intensity were measured in trapezius during pegboard and stress tasks before and after the intervention period. During the pegboard task, GFT improved trapezius oxygenation from a relative decrease of −0.83 ± 1.48 μM to an increase of 0.05 ± 1.32 μM, and decreased pain development by 43%, but did not affect resting levels of pain. SST lowered the relative EMG amplitude by 36%, and decreased pain during resting and working conditions by 52 and 38%, respectively, without affecting trapezius oxygenation. In conclusion, GFT performed as leg-bicycling decreased pain development during repetitive work tasks, possibly due to improved oxygenation of the painful muscles. SST lowered the overall level of pain both during rest and work, possibly due to a lowered relative exposure as evidenced by a lowered relative EMG. The results demonstrate differential adaptive mechanisms of contrasting physical exercise interventions on chronic muscle pain at rest and during repetitive work tasks

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021

BACKGROUND: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. METHODS: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. RESULTS: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. CONCLUSIONS: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. CLINICAL TRIALS REGISTRATION: NCT04811664

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Management of immunotherapy related adverse effects

Background: Over the last 5years ever since Ipilimumab received FDA approval for the treatment of metastatic melanoma, immunotherapy as a treatment modality is making its presence felt in oncology clinics across the globe. While initially approved for the treatment of metastatic melanoma alone, the immunotherapy repertoire is ever expanding with its’ utility being assessed for in the metastatic and adjuvant setting. The adverse effect profile from immunotherapy drugs differs from that of conventional chemotherapy that oncological services have trained in managing over the last few decades. This raises the need for educating health care professionals as the scenarios that patients present with at acute admissions or in clinic secondary to immune related adverse effects (iRAEs) can often be misleading.Aims: This review aims to synopsise the common and less common iRAEs and highlight their varied presentations, in addition to stressing the need to institute timely immunosuppression, which forms the cornerstone in the management of iRAEs.Recommendations: iRAEs have been recognised more frequently and in greater severity in dose dense and combination treatment regimens. While dermatological, gastrointestinal, hepatic toxicities in addition to endocrinopathies are the most commonly encountered iRAEs though other organ systems can be involved. The appropriate grading of an iRAEs’ severity, delaying or discontinuing immunotherapy based treatment, supportive care, commencement of immunosuppression (with corticosteroids and/or steroid sparing agents) and a multidisciplinary approach are key constituents in the treatment pathway of iRAEs.Conclusion: Early recognition of iRAEs and timely commencement of appropriate immunosuppression is imperative in order to reduce the risk of significant morbidity and potential mortality. The management of iRAEs warrants a multidisciplinary approach which would be aided by the development of local guidelines and educational activities directed at providing health care professionals with the information and tools required to recognise and appropriately treat iRAE

A web-based dementia education program and its application to an Australian web-based dementia care competency and training network : integrative systematic review

Background: Dementia education that meets quality and safety standards is paramount to ensure a highly skilled dementia care workforce. Web-based education provides a flexible and cost-effective medium. To be successful, Web-based education must contain features that promote learning and support knowledge translation into practice. The Dementia Care Competency and Training Network (DCC&TN) has developed an innovative Web-based program that promotes improvement of the attitudes, knowledge, skills, behavior, and practice of clinicians, regardless of their work setting, in order to improve the quality of life for people living with dementia. Objective: This review aims to (1) determine the key features that are associated with an effective and functional Web-based education program—an effective and functional Web-based program is defined as one that measures results, is accessible, is user friendly, and translates into clinical practice—and (2) determine how these features correlate with the DCC&TN. Methods: Six electronic databases—Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), AusHealth, Nursing@Ovid, and Google Scholar—were searched for articles published between 2009 and 2018 using the following keywords: Education, Distance, Continuing, Learning, Online, Web-Based, Internet, Dementia, Program Evaluation, Validation Studies, Outcome and Process Assessment Healthcare, Nursing, Assisted Instruction, and Facilitated. The Critical Appraisal Skills Programme (CASP) and Kirkpatrick’s model for the evaluation of training were used to ensure quality and rigor of the analysis. Results: A total of 46 studies met the inclusion criteria. In total, 14 key features were associated with an effective Web-based learning environment, which enabled the environment to be as follows: self-directed, individualized, interactive, multimodal, flexible, accessible, consistent, cost-effective, measurable with respect to participant satisfaction, equitable, facilitated, nurturing of critical thinking and reflection, supportive of creating a learning community, and translated into practice. These features were further categorized into five subgroups: applicability, attractiveness, functionality, learner interaction, and implementation into practice. Literature frequently cites Kirkpatrick’s four-level model of evaluation and application in the review of education and training; however, few studies appeared to integrate all four levels of Kirkpatrick’s model. Features were then correlated against the DCC&TN, with an encouraging connection found between these features and their inclusion within the content and structure of the DCC&TN. Conclusions: A total of 14 key features were identified that support an effective and functional Web-based learning environment. Few studies incorporated Kirkpatrick’s salient elements of the model—reaction, learning, behavior, and results—in their evaluation and clinical application. It could, therefore, be considered prudent to include Kirkpatrick’s levels of training evaluation within studies of dementia training. There were few studies that evaluated Web-based dementia education programs, with even fewer reporting evidence that Web-based training could increase staff confidence, knowledge, skills, and attitudes toward people with dementia and be sustainable over time. The DCC&TN appeared to contain the majority of key features and is one of the few programs inclusive of hospital, community, and residential care settings. The 14 key features can potentially enhance and complement future development of online training programs for health sciences education and beyond. The DCC&TN model could potentially be used as a template for future developers and evaluators of Web-based dementia training