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ObjectivesTo identify the factors that determine treatment choices following pre-dialysis education.DesignRetrospective cohort study using data linkage with univariate and multivariate analyses using linked data.SettingSecondary care National Health Service Wales healthcare system.ParticipantsAll people in Wales over 18 years diagnosed with established kidney disease, who received pre-dialysis education between 1 January 2016 and 12 December 2018.Main outcome measuresPatient choice of dialysis modality and any kidney replacement therapy started.ResultsMean age was 67 years; n=1207 (60%) were male, n=878 (53%) had ≥3 comorbidities, n=805 (66%) had mobility problems, n=700 (57%) had pain symptoms, n=641 (52%) had anxiety or were depressed, n=1052 (61.6%) lived less than 30 min from their treatment centre, n=619 (50%) were on a spectrum of frail to extremely vulnerable. n=424 (25%) chose home dialysis, n=552 (32%) chose hospital-based dialysis, n=109 (6%) chose transplantation, n=231 (14%) chose maximum conservative management and n=391 (23%) were ‘undecided’. Main reasons for not choosing home dialysis were lack of motivation/low confidence in capacity to self-administer treatment, lack of home support and unsuitable housing. Patients who choose home dialysis were younger, had lower comorbidities, lower frailty and higher quality of life scores. Multivariate analysis found that age and frailty were predictors of choice, but we did not find any other demographic associations. Of patients who initially chose home dialysis, only n=150 (54%) started on home dialysis.ConclusionThere is room for improvement in current pre-dialysis treatment pathways. Many patients remain undecided about dialysis choice, and others who may have chosen home dialysis are still likely to start on unit haemodialysis.

ObjectivesTo explore how people with chronic kidney disease who are pre-dialysis, family members and healthcare professionals together navigate common shared decision-making processes and to assess how this impacts future treatment choice.DesignCoproductive qualitative study, underpinned by the Making Good Decisions in Collaboration shared decision-model. Semistructured interviews with a purposive sample from February 2019 - January 2020. Interview data were analysed using framework analysis. Coproduction of logic models/roadmaps and recommendations.SettingFive Welsh kidney services.Participants95 participants (37 patients, 19 family members and 39 professionals); 44 people supported coproduction (18 patients, 8 family members and 18 professionals).FindingsShared decision-making was too generic and clinically focused and had little impact on people getting onto home dialysis. Preferences of where, when and how to implement shared decision-making varied widely. Apathy experienced by patients, caused by lack of symptoms, denial, social circumstances and health systems issues made future treatment discussions difficult. Families had unmet and unrecognised needs, which significantly influenced patient decisions. Protocols containing treatment hierarchies and standards were understood by professionals but not translated for patients and families. Variation in dialysis treatment was discussed to match individual lifestyles. Patients and professionals were, however, defaulting to the perceived simplest option. It was easy for patients to opt for hospital-based treatments by listing important but easily modifiable factors.ConclusionsShared decision-making processes need to be individually tailored with more attention on patients who could choose a home therapy but select a different option. There are critical points in the decision-making process where changes could benefit patients. Patients need to be better educated and their preconceived ideas and misconceptions gently challenged. Healthcare professionals need to update their knowledge in order to provide the best advice and guidance. There needs to be more awareness of the costs and benefits of the various treatment options when making decisions.

Human blood Vγ9/Vδ2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vγ9/Vδ2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vγ9/Vδ2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vγ9/Vδ2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-α dependent proliferation of Vγ9/Vδ2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting γδ T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis--characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity--show a selective activation of local Vγ9/Vδ2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The γδ T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of γδ T cells and TNF-α and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive γδ T cells in early infection and suggest novel diagnostic and therapeutic approaches.

Context Too many people living with chronic kidney disease are opting for and starting on hospital‐based dialysis compared to a home‐based kidney replacement therapy. Dialysis services are becoming financially unsustainable. Objective This study aimed to assess the efficacy of coproductive research in chronic kidney disease service improvement to achieve greater sustainability. Design A 2‐year coproductive service improvement study was conducted with multiple stakeholders with the specific intention of maximizing engagement with the national health kidney services, patients and public. Setting and Participants A national health kidney service (3 health boards, 18 dialysis units), patients and families (n = 50), multidisciplinary teams including doctors, nurses, psychologists, social workers, and so forth (n = 68), kidney charities, independent dialysis service providers and wider social services were part of this study. Findings Coproductive research identified underutilized resources (e.g., patients on home dialysis and social services) and their potential, highlighted unmet social care needs for patients and families and informed service redesign. Education packages were reimagined to support the home dialysis agenda including opportunities for wider service input. The impacts of one size fits all approaches to dialysis on specialist workforce skills were made clearer and also professional, patient and public perceptions of key sustainability policies. Discussion and Conclusions Patient and key stakeholders mapped out new ways to link services to create more sustainable models of kidney health and social care. Maintaining principles of knowledge coproduction could help achieve financial sustainability and move towards more prudent adult chronic kidney disease services. Patient or Public Contribution Involved in developing research questions, study design, management and conduct, interpretation of evidence and dissemination.

IntroductionKidney disease is common, affecting up to 1 in 10 of the adult population, and the numbers are expected to rise over the next decade. There are three main treatments that are available to patients with kidney disease: transplantation, dialysis and supportive care without dialysis. Dialysis can occur in a dialysis unit or in a person’s home, but unit-based dialysis remains the most common initial treatment for patients in Wales. This is a cause for concern as most studies suggest that it is associated with the lowest quality of life and the highest mortality, and is a more expensive treatment option.This study aims to identify the factors that lead to patients choosing unit-based haemodialysis rather than home-based dialysis with a view to informing future changes in patient education and service commissioning in Wales. A secondary aim is to determine if the co-production of research leads to more sustainable services.Methods and analysisThis mixed-method study taking place between October 2018 and September 2020 will use a sequential explanatory design whereby the descriptive quantitative cross-sectional analysis of linked health and administrative data sets inform qualitative data collection from patients, carers and health and care professionals. Qualitative findings will be used to interpret or explain quantitative descriptive results. Additional strands to the study include a review of materials and education provided to patients and an economic review of treatment modalities.Ethics and disseminationThe study will be conducted in accordance with the principles expressed in the Declaration of Helsinki. It has full approval from Health and Care Research Wales Research Ethics Committee #5. As a co-productive study involving patients, clinicians, third sector partners and academics, findings from this study will be shared on a continual basis. Study results will be published in peer-reviewed journals and presented at national and international conferences.

ObjectivesA rapid growth in the reported rates of acute kidney injury (AKI) has led to calls for greater attention and greater resources for improving care. However, the reported incidence of AKI also varies more than tenfold between previous studies. Some of this variation is likely to stem from methodological heterogeneity. This study explores the extent of cross-population variation in AKI incidence after minimising heterogeneity.DesignPopulation-based cohort study analysing data from electronic health records from three regions in the UK through shared analysis code and harmonised methodology.SettingThree populations from Scotland, Wales and England covering three time periods: Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012.ParticipantsAll residents in each region, aged 15 years or older.Main outcome measuresPopulation incidence of AKI and AKI phenotype (severity, recovery, recurrence). Determined using shared biochemistry-based AKI episode code and standardised by age and sex.ResultsRespectively, crude AKI rates (per 10 000/year) were 131, 138, 139, 151 and 124 (p=0.095), and after standardisation for age and sex: 147, 151, 146, 146 and 142 (p=0.257) for Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012. The pattern of variation in crude rates was robust to any modifications of the AKI definition. Across all populations and time periods, AKI rates increased substantially with age from ~20 to ~550 per 10 000/year among those aged <40 and ≥70 years.ConclusionWhen harmonised methods are used and age and sex differences are accounted for, a similar high burden of AKI is consistently observed across different populations and time periods (~150 per 10 000/year). There are particularly high rates of AKI among older people. Policy-makers should be careful not draw simplistic assumptions about variation in AKI rates based on comparisons that are not rigorous in methodological terms.

Glucose control is a significant predictor of mortality in diabetic peritoneal dialysis (PD) patients. During PD, the local toxic effects of intra-peritoneal glucose are well recognized, but despite large amounts of glucose being absorbed, the systemic effects of this in non-diabetic patients are not clear. We sought to clarify whether dialysate glucose has an effect upon systemic glucose metabolism. We analysed the Global Fluid Study cohort, a prospective, observational cohort study initiated in 2002. A subset of 10 centres from 3 countries with high data quality were selected (368 incident and 272 prevalent non-diabetic patients), with multilevel, multivariable analysis of the reciprocal of random glucose levels, and a stratified-by-centre Cox survival analysis. The median follow up was 5.6 and 6.4 years respectively in incident and prevalent patients. On multivariate analysis, serum glucose increased with age (β = -0.007, 95%CI -0.010, -0.004) and decreased with higher serum sodium (β = 0.002, 95%CI 0.0005, 0.003) in incident patients and increased with dialysate glucose (β = -0.0002, 95%CI -0.0004, -0.00006) in prevalent patients. Levels suggested undiagnosed diabetes in 5.4% of prevalent patients. Glucose levels predicted death in unadjusted analyses of both incident and prevalent groups but in an adjusted survival analysis they did not (for random glucose 6-10 compared with <6, Incident group HR 0.92, 95%CI 0.58, 1.46, Prevalent group HR 1.42, 95%CI 0.86, 2.34). In prevalent non-diabetic patients, random glucose levels at a diabetic level are under-recognised and increase with dialysate glucose load. Random glucose levels predict mortality in unadjusted analyses, but this association has not been proven in adjusted analyses.

Human blood Vγ9/Vδ2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vγ9/Vδ2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vγ9/Vδ2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vγ9/Vδ2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-α dependent proliferation of Vγ9/Vδ2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting γδ T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis - characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity - show a selective activation of local Vγ9/Vδ2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The γδ T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of γδ T cells and TNF-α and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive γδ T cells in early infection and suggest novel diagnostic and therapeutic approaches.

IntroductionMultimorbidity is widely recognised as the presence of two or more concurrent long-term conditions, yet remains a poorly understood global issue despite increasing in prevalence.We have created the Wales Multimorbidity e-Cohort (WMC) to provide an accessible research ready data asset to further the understanding of multimorbidity. Our objectives are to create a platform to support research which would help to understand prevalence, trajectories and determinants in multimorbidity, characterise clusters that lead to highest burden on individuals and healthcare services, and evaluate and provide new multimorbidity phenotypes and algorithms to the National Health Service and research communities to support prevention, healthcare planning and the management of individuals with multimorbidity.Methods and analysisThe WMC has been created and derived from multisourced demographic, administrative and electronic health record data relating to the Welsh population in the Secure Anonymised Information Linkage (SAIL) Databank. The WMC consists of 2.9 million people alive and living in Wales on the 1 January 2000 with follow-up until 31 December 2019, Welsh residency break or death. Published comorbidity indices and phenotype code lists will be used to measure and conceptualise multimorbidity.Study outcomes will include: (1) a description of multimorbidity using published data phenotype algorithms/ontologies, (2) investigation of the associations between baseline demographic factors and multimorbidity, (3) identification of temporal trajectories of clusters of conditions and multimorbidity and (4) investigation of multimorbidity clusters with poor outcomes such as mortality and high healthcare service utilisation.Ethics and disseminationThe SAIL Databank independent Information Governance Review Panel has approved this study (SAIL Project: 0911). Study findings will be presented to policy groups, public meetings, national and international conferences, and published in peer-reviewed journals.

Study of interactions among fishes and benthic invertebrates off southern California's Santa Catalina Island showed the great extent to which taxa are defined by trophic relations. The dominant fishes there are acanthopterygian teleosts, with the serranine serranid Paralabrax clathratus morphologically nearest the evolutionary mainstream. Because mainstream species have morphologies similar to their progenitors, marine communities have a long history of adaptations to threats from generalized predators like P. clathratus. Species examined at Santa Catalina indicate this experience has produced four basic defenses: smallness, which presents difficulties for predators with large and simply constructed feeding mechanisms; dissemblance, as through camouflage, which makes detection by visual hunters difficult; inedibility, which is attained by incorporating materials that an unspecialized digestive system cannot accommodate; and nocturnality, which results in avoiding diurnal predators altogether. Examination of trophic relations among the major fishes in Santa Catalina communities shows each with specialized ways to counter these defenses. Prey smallness has been met by reducing size of mouth relative to size of prey, either by evolving as smaller fishes or through structural changes in head and jaws. Prey dissemblance has been accommodated through enhanced visual acuity and varied means to remain an unrecognized threat while waiting for prey to move. Inedibility has been countered by developing specialized features of the alimentary tract, including dentition, while adjustments to nocturnality have included enhanced sensory capabilities that detect prey in low light. These adaptations to prey defenses define varied lines of divergence from the teleost mainstream as represented atbreak Santa Catalina.[PUBLICATION ABSTRACT]