Exploring the choices and outcomes of older patients with advanced kidney disease.

A lack of data on patient choices and outcomes at the time of pre-dialysis planning limits meaningful shared decision making, particularly in older frailer patients. In this large retrospective cohort study of patients aged over 70 seen by the pre-dialysis clinic (2004-2016) of a large single centre in the United Kingdom (1,216 patients), age, sex, comorbidity, poverty and frailty were used to predict choice of renal replacement therapy (RRT) over maximum conservative management (MCM). The impact of patient choice of RRT versus MCM was used to predict survival from the time of choice using multivariable Cox proportional hazards regression. Older age, female sex, greater poverty and greater frailty were associated with choosing MCM, whilst comorbidity had no significant impact on choice. At 5 years of follow up, 49% of all patients had died without receiving RRT. Over 70% of the patients choosing MCM died with better kidney function than the median level at which those starting RRT initiated treatment. Frailty and age were better predictors of survival than comorbidity and in patients with at least moderate frailty, RRT offered no survival benefit over MCM. In conclusion, analysing outcomes from the time of choice may improve shared decision making. Frailty should be routinely assessed and collected and further work may help predict which patients are unlikely to survive or progress to end stage renal disease and may not need to be burdened with making a pre-dialysis choice.

A descriptive model of shared decision making derived from routine implementation in clinical practice ('Implement-SDM'): Qualitative study.

OBJECTIVE: Research is needed to understand how Shared Decision-Making (SDM) is enacted in routine clinical settings. We aimed to 1) describe the process of SDM between clinicians and patients; 2) examine how well the SDM process compares to a prescriptive model of SDM, and 3) propose a descriptive model based on observed SDM in routine practice. METHODS: Patients with chronic kidney disease and early stage breast cancer were recruited consecutively via Cardiff and Vale University Health Board (UK) teams. Consultations were audio-recorded, transcribed and thematically analysed. RESULTS: Seventy-six consultations were observed: 26 pre-dialysis consultations and two consultations each for 25 breast cancer patients. Key stages of the 'Three Talk Model' were observed. However, we also observed more elements and greater complexity: a distinct preparation phase; tailored and evolving integrative option conversation; patients and clinicians developing 'informed preferences'; distributed and multi-stage decisions; and a more open-ended planning discussion. Use of decision aids was limited. CONCLUSION: A more complex picture was observed compared with previous portrayals in current theoretical models. PRACTICE IIMPLICATIONS: The model can provide a basis for future training and initiatives to promote SDM, and tackle the gap between what is advocated in policy, but rarely achieved in practice.

Ability of observer and self-report measures to capture shared decision-making in clinical practice in the UK: a mixed-methods study.

OBJECTIVES: To examine how observer and self-report measures of shared decision-making (SDM) evaluate the decision-making activities that patients and clinicians undertake in routine consultations. DESIGN: Multi-method study using observational and self-reported measures of SDM and qualitative analysis. SETTING: Breast care and predialysis teams who had already implemented SDM. PARTICIPANTS: Breast care consultants, clinical nurse specialists and patients who were making decisions about treatment for early-stage breast cancer. Predialysis clinical nurse specialists and patients who needed to make dialysis treatment decisions. METHODS: Consultations were audio recorded, transcribed and thematically analysed. SDM was measured using Observer OPTION-5 and a dyadic SureScore self-reported measure. RESULTS: Twenty-two breast and 21 renal consultations were analysed. SureScore indicated that clinicians and patients felt SDM was occurring, but scores showed ceiling effects for most participants, making differentiation difficult. There was mismatch between SureScore and OPTION-5 score data, the latter showing that each consultation lacked at least some elements of SDM. Highest scoring items using OPTION-5 were 'incorporating patient preferences into decisions' for the breast team (mean 18.5, range 12.5-20, SD 2.39) and 'eliciting patient preferences to options' for the renal team (mean 16.15, range 10-20, SD 3.48). Thematic analysis identified that the SDM encounter is difficult to measure because decision-making is often distributed across encounters and time, with multiple people, it is contextually adapted and can involve multiple decisions. CONCLUSIONS: Self-reported measures can broadly indicate satisfaction with SDM, but do not tell us about the quality of the interaction and are unlikely to capture the multi-staged nature of the SDM process. Observational measures provide an indication of the extent to which elements of SDM are present in the observed consultation, but cannot explain why some elements might not be present or scored lower. Findings are important when considering measuring SDM in practice.

Training: improving antenatal detection and outcomes of congenital heart disease.

OBJECTIVES: This study describes the design, delivery and efficacy of a regional fetal cardiac ultrasound training programme. This programme aimed to improve the antenatal detection of congenital heart disease (CHD) and its effect on fetal and postnatal outcomes. DESIGN SETTING AND PARTICIPANTS: This was a prospective study that compared antenatal CHD detection rates by professionals from 13 hospitals in Wales before and after engaging in our 'skills development programme'. Existing fetal cardiac practice and perinatal outcomes were continuously audited and progressive targets were set. The work was undertaken by the Welsh Fetal Cardiovascular Network, Antenatal Screening Wales (ASW), a superintendent sonographer and a fetal cardiologist. INTERVENTIONS: A core professional network was established, engaging all stakeholders (including patients, health boards, specialist commissioners, ASW, ultrasonographers, radiologists, obstetricians, midwives and paediatricians). A cardiac educational lead (midwife, superintendent sonographer, radiologist, obstetrician, or a fetal medicine specialist) was established in each hospital. A new cardiac anomaly screening protocol ('outflow tract view') was created and training on the new protocol was systematically delivered at each centre. Data were prospectively collected and outcomes were continuously audited: locally by the lead fetal cardiologist; regionally by the Congenital Anomaly Register and Information Service in Wales; and nationally by the National Institute for Cardiac Outcomes and Research (NICOR) in the UK. MAIN OUTCOME MEASURES: Patient satisfaction; improvements in individual sonographer skills, confidence and competency; true positive referral rate; local hospital detection rate; national detection rate of CHD; clinical outcomes of selected cardiac abnormalities; reduction of geographical health inequality; cost efficacy. RESULTS: High levels of patient satisfaction were demonstrated and the professional skill mix in each centre was improved. The confidence and competency of sonographers was enhanced. Each centre demonstrated a reduction in the false-positive referral rate and a significant increase in cardiac anomaly detection rate. According to the latest NICOR data, since implementing the new training programme Wales has sustained its status as UK lead for CHD detection. Health outcomes of children with CHD have improved, especially in cases of transposition of the great arteries (for which no perinatal mortality has been reported since 2008). Standardised care led to reduction of geographical health inequalities with substantial cost saving to the National Health Service due to reduced false-positive referral rates. Our successful model has been adopted by other fetal anomaly screening programmes in the UK. CONCLUSIONS: Antenatal cardiac ultrasound mass training programmes can be delivered effectively with minimal impact on finite healthcare resources. Sustainably high CHD detection rates can only be achieved by empowering the regional screening workforce through continuous investment in lifelong learning activities. These should be underpinned by high quality service standards, effective care pathways, and robust clinical governance and audit practices.

Frailty and comorbidity are independent predictors of outcome in patients referred for pre-dialysis education.

BACKGROUND: The incidence of chronic kidney disease (CKD) is rising and is likely to continue to do so for the foreseeable future, with the fastest growth seen among adults ≥75 years of age. Elderly patients with advanced CKD are likely to have a higher burden of comorbidity and frailty, both of which may influence their disease outcome. For these patients, treatment decisions can be complex, with the current lack of robust prognostic tools hindering the shared decision-making process. The current study aims to assess the impact of comorbidity and frailty on the outcomes of patients referred for pre-dialysis education. METHODS: We performed a single-centre study of patients (n = 283) referred for pre-dialysis education between 2010 and 2012. The Charlson Comorbidity Index (CCI) and Clinical Frailty Scale (CFS) were used to assess comorbid disease burden and frailty, respectively. Follow-up data were collected until February 2015. RESULTS: The CCI and CFS scores at the time of referral to the pre-dialysis service were independent predictors of mortality. Within the study follow-up period, 76% of patients with a high CFS score at the time of pre-dialysis education had died, with 63% of these patients not commencing dialysis before death. CONCLUSION: A relatively simple frailty scale and comorbidity score could be used to predict survival and better inform the shared decision-making process for patients with advanced kidney disease.

Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex.

The prevalence and mechanistic significance of self-association among substrate adaptors for the Cul-Rbx family of ubiquitin ligases remain unclear. We now report that it is as a homodimer that the substrate adaptor Keap1 interacts with Cul3. The resulting complex facilitates ubiquitylation of the Nrf2 transcription factor but only when this substrate possesses within its Neh2 domain a second cryptic Keap1-binding site, the DLG motif, in addition to its previously described ETGE site. Both motifs recognize overlapping surfaces on Keap1, and the seven lysine residues of Nrf2 that act as ubiquitin acceptors lie between them. Based on these data, we propose a "fixed-ends" model for Nrf2 ubiquitylation in which each binding site becomes tethered to a separate subunit of the Keap1 homodimer. This two-site interaction between Keap1 and Nrf2 constrains the mobility of the target lysine residues in the Neh2 domain, increasing their average concentration in the vicinity of the Rbx-bound ubiquitin-conjugating enzyme, and thus the rate at which the transcription factor is ubiquitylated. We show that self-association is a general feature of Cul3 substrate adaptors and propose that the fixed-ends mechanism is commonly utilized to recruit, orientate, and ubiquitylate substrates upon this family of ubiquitin ligases.

Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron.

The Nrf2 transcription factor is more rapidly turned over in cells grown under homeostatic conditions than in those experiencing oxidative stress. The variable turnover of Nrf2 is accomplished through the use of at least two degrons and its redox-sensitive interaction with the Kelch-repeat protein Keap1. In homeostatic COS1 cells, the Neh2 degron confers on Nrf2 a half-life of less than 10 min. Analyses of deletion mutants of a Gal4(HA)mNeh2 fusion protein and full-length mNrf2 indicate that full redox-sensitive Neh2 destabilizing activity depends upon two separate sequences within this N-terminal domain. The DIDLID element (amino acids 17-32) is indispensable for Neh2 activity and appears necessary to recruit a ubiquitin ligase to the fusion protein. A second motif within Neh2, the ETGE tetrapeptide (amino acids 79-82), allows the redox-sensitive recruitment of Nrf2 to Keap1. This interaction, which occurs only in homeostatic cells, enhances the capacity of the Neh2 degron to direct degradation by functioning downstream of ubiquitination mediated by the DIDLID element. By contrast with the situation under homeostatic conditions, the Neh2 degron is neither necessary nor sufficient to account for the characteristic half-life of Nrf2 in oxidatively stressed cells. Instead, the previously uncharacterized, redox-insensitive Neh6 degron (amino acids 329-379) is essential to ensure that the transcription factor is still appropriately turned over in stressed cells, albeit with an increased half-life of 40 min. A model can now be proposed to explain how the turnover of this protein adapts in response to alterations in cellular redox state.