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Abstract Background Chronic kidney disease (CKD) prevalence is steadily increasing, in part due to increased multimorbidity in our aging global population. When progression to kidney failure cannot be avoided, people need unbiased information to inform decisions about whether to start dialysis, if or when indicated, or continue with holistic person-centred care without dialysis (conservative kidney management). Comparisons suggest that while there may be some survival benefit from dialysis over conservative kidney management, in people aged 80 years and over, or with multiple health problems or frailty, this may be at the expense of quality of life, hospitalisations, symptom burden and preferred place of death. Prepare for Kidney Care aims to compare preparation for a renal dialysis pathway with preparation for a conservative kidney management pathway, in relation to quantity and quality of life in multimorbid, frail, older people with advanced CKD. Methods This is a two-arm, superiority, parallel group, non-blinded, individual-level, multi-centre, pragmatic trial, set in United Kingdom National Health Service (NHS) kidney units. Patients with advanced CKD (estimated glomerular filtration rate

Abstract Background Outreach clinics were part of efforts to maximise uptake in COVID-19 vaccination. Methods We used controlled interrupted time series, matching on age, sex, deprivation and vaccination eligibility date, to determine the effect of outreach clinics on time to first COVID-19 vaccine, using a population-based electronic health record database of 914,478 people, from December 2020 to December 2021; people living within 1 mile of each outreach clinics were exposed. Results 50% of 288,473 exposed citizens were white British, and 71% were aged 0–49 years. There was no evidence for an overall statistically significant increase in cumulative percentage vaccinated due to the outreach clinic at 6 weeks, with an overall pooled effect estimate of -0.07% (95% CI: -1.15%, 1.02%). The pooled estimate for increased cumulative vaccine uptake varied slightly depending on how the analysis was stratified; by ethnic group it was − 0.12% (95% CI: -0.90%, 0.66%); by age group it was − 0.06% (95% CI: -0.41%, 0.28%); and by deprivation it was 0.03% (95% CI: -0.74%, 0.79%). Conclusions Living within a mile of an outreach clinic was not associated with higher vaccine uptake. Evaluation of future outreach clinics should consider the relative importance of travel amongst other barriers to accessing vaccines.

Abstract Background An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants. Objective To describe which methodological adjustments were made to the study protocol because of these developments. Methods We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan. Discussion This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.

Abstract Background Approximately, 8% of community-based adults aged ≥ 50 years in England are frail. Frailty has been found to be associated with poorer outcomes after joint replacement. Targeting frailty preoperatively via exercise and protein supplementation has the potential to improve outcomes for people undergoing joint replacement. Prior to proceeding with a randomised controlled trial (RCT), a feasibility study is necessary to address key uncertainties and explore how to optimise trial design and delivery. Methods The Joint PRehabilitation with Exercise and Protein (Joint PREP) study is a feasibility study for a multicentre, two-arm, parallel group, pragmatic, RCT to evaluate the clinical and cost-effectiveness of prehabilitation for frail patients undergoing total hip or knee replacement. Sixty people who are ≥ 65 years of age, frail according to the self-reported Groningen Frailty Indicator, and scheduled to undergo total hip or knee replacement at 2–3 hospitals in England and Wales will be recruited and randomly allocated on a 1:1 ratio to the intervention or usual care group. The usual care group will receive the standard care at their hospital. The intervention group will be given a daily protein supplement and will be asked to follow a home-based, tailored daily exercise programme for 12 weeks before their operation, in addition to usual care. Participants will be supported through six follow-up calls from a physiotherapist during the 12-week intervention period. Study questionnaires will be administered at baseline and 12 weeks after randomisation. Embedded qualitative research with patients will explore their experiences of participating, reasons for nonparticipation, and/or reasons for withdrawal or treatment discontinuation. Primary feasibility outcomes will be eligibility and recruitment rates, adherence to the intervention, and acceptability of the trial and the intervention. Discussion This study will generate important data regarding the feasibility of a RCT to evaluate a prehabilitation intervention for frail patients undergoing total hip and knee replacement. A future phase-3 RCT will determine if preoperative exercise and protein supplementation improve the recovery of frail patients after primary joint replacement. Trial registration ISRCTN11121506, registered 29 September 2022.

Abstract Background Hip fractures are devastating injuries causing disability, dependence, and institutionalisation, yet hospital care is highly variable. This study aimed to determine hospital organisational factors associated with recovery of mobility and change in patient residence after hip fracture. Methods A cohort of patients aged 60 + years in England and Wales, who sustained a hip fracture from 2016 to 2019 was examined. Patient-level Hospital Episodes Statistics, National Hip Fracture Database, and mortality records were linked to 101 factors derived from 18 hospital-level organisational metrics. After adjustment for patient case-mix, multilevel models were used to identify organisational factors associated with patient residence at discharge, and mobility and residence at 120 days after hip fracture. Results Across 172 hospitals, 165,350 patients survived to discharge, of whom 163,230 (99%) had post-hospital discharge destination recorded. 18,323 (11%) died within 120 days. Among 147,027 survivors, 58,344 (40%) across 143 hospitals had their residence recorded, and 56,959 (39%) across 140 hospitals had their mobility recorded, at 120 days. Nineteen organisational factors independently predicted residence on hospital discharge e.g., return to original residence was 31% (95% confidence interval, CI:17–43%) more likely if the anaesthetic lead for hip fracture had time allocated in their job plan, and 8–13% more likely if hip fracture service clinical governance meetings were attended by an orthopaedic surgeon, physiotherapist or anaesthetist. Seven organisational factors independently predicted residence at 120 days. Patients returning to their pre-fracture residence was 26% (95%CI:4–42%) more likely if hospitals had a dedicated hip fracture ward, and 20% (95%CI:8–30%) more likely if treatment plans were proactively discussed with patients and families on admission. Seventeen organisational factors predicted mobility at 120 days. More patients re-attained their pre-fracture mobility in hospitals where (i) care involved an orthogeriatrician (15% [95%CI:1-28%] improvement), (ii) general anaesthesia was usually accompanied by a nerve block (7% [95%CI:1-12%], and (iii) bedside haemoglobin testing was routine in theatre recovery (13% [95%CI:6-20%]). Conclusions Multiple, potentially modifiable, organisational factors are associated with patient outcomes up to 120 days after a hip fracture, these factors if causal should be targeted by service improvement initiatives to reduce variability, improve hospital hip fracture care, and maximise patient independence.

Abstract Background Providing informal care for a person with Parkinson’s disease (PD) can be a demanding process affecting several dimensions of a caregiver’s life and potentially causing caregiver burden. Despite the emerging literature on caregiver burden in people with PD, little is known about the inter-relationship between quantitative and qualitative findings. Filling this knowledge gap will provide a more holistic approach to develop and design innovations aiming at reducing or even preventing caregiver burden. This study aimed to characterize the determinants of caregiver burden among informal caregivers of persons with PD, in order to facilitate the development of tailored interventions that reduce caregiver burden. Methods We conducted a cross-sectional study in The Netherlands using a sequential mixed methods approach, entailing a quantitative study of 504 persons with PD and their informal caregivers as well as a qualitative study in a representative subsample of 17 informal caregivers. The quantitative study included a standardized questionnaire of caregiver burden (Zarit Burden Inventory) and patient-related (Beck Depression Inventory, State-Trait Anxiety Inventory, Acceptance of Illness Scale, MDS-Unified Parkinson’s Disease Rating Scale part II on motor functions in daily life, Self-assessment Parkinson’s Disease Disability Score), caregiver-related (Brief Coping Orientation to Problems Experience Inventory, Caregiver Activation Measurement, Multidimensional Scale of Perceived Social Support) and interpersonal determinants (sociodemographic variables including among others gender, age, education, marital status and working status). The qualitative study consisted of semi-structured interviews. Multivariable regression and thematic analysis were used to analyse quantitative and qualitative data, respectively. Results A total of 337 caregivers were women (66.9%), and the majority of people with PD were men (N = 321, 63.7%). The mean age of persons with PD was 69.9 (standard deviation [SD] 8.1) years, and the mean disease duration was 7.2 (SD 5.2) years. A total of 366 (72.6%) persons with PD had no active employment. The mean age of informal caregivers was 67.5 (SD 9.2) years. Most informal caregivers were female (66.9%), had no active employment (65.9%) and were the spouse of the person with PD (90.7%). The mean Zarit Burden Inventory score was 15.9 (SD 11.7). The quantitative study showed that a lack of active employment of the person affected by PD was associated with a higher caregiver burden. The qualitative study revealed cognitive decline and psychological or emotional deficits of the person with PD as additional patient-related determinants of higher caregiver burden. The following caregiver-related and interpersonal determinants were associated with higher caregiver burden: low social support (quantitative study), concerns about the future (qualitative study), the caregiving-induced requirement of restrictions in everyday life (qualitative study), changes in the relationship with the person with PD (qualitative study) and a problem-focused or avoidant coping style (both studies). Integration of both data strands revealed that qualitative findings expanded quantitative findings by (1) distinguishing between the impact of the relationship with the person with PD and the relationship with others on perceived social support, (2) revealing the impact of non-motor symptoms next to motor symptoms and (3) revealing the following additional factors impacting caregiver burden: concern about the future, perceived restrictions and limitations in performing daily activities due to the disease, and negative feelings and emotional well-being. Qualitative findings were discordant with the quantitative finding demonstrating that problem-focused was associated with a higher caregiver burden. Factor analyses showed three sub-dimensions of the Zarit Burden Inventory: (i) role intensity and resource strain, (2) social restriction and anger and (3) self-criticism. Quantitative analysis showed that avoidant coping was a determinant for all three subscales, whereas problem-solved coping and perceived social support were significant predictors on two subscales, role intensity and resource strain and self-criticism. Conclusions The burden experienced by informal caregivers of persons with PD is determined by a complex interplay of patient-related, caregiver-related and interpersonal characteristics. Our study highlights the utility of a mixed-methods approach to unravel the multidimensional burden experienced by informal caregivers of persons with chronic disease. We also offer starting points for the development of a tailored supportive approach for caregivers.

Abstract Background People living with Parkinson’s disease experience progressive motor and non-motor symptoms, which negatively impact on health-related quality of life and can lead to an increased risk of hospitalisation. It is increasingly recognised that the current care models are not suitable for the needs of people with parkinsonism whose care needs evolve and change as the disease progresses. This trial aims to evaluate whether a complex and innovative model of integrated care will increase an individual’s ability to achieve their personal goals, have a positive impact on health and symptom burden and be more cost-effective when compared with usual care. Methods This is a single-centre, randomised controlled trial where people with parkinsonism and their informal caregivers are randomised into one of two groups: either PRIME Parkinson multi-component model of care or usual care. Adults ≥18 years with a diagnosis of parkinsonism, able to provide informed consent or the availability of a close friend or relative to act as a personal consultee if capacity to do so is absent and living in the trial geographical area are eligible. Up to three caregivers per patient can also take part, must be ≥18 years, provide informal, unpaid care and able to give informed consent. The primary outcome measure is goal attainment, as measured using the Bangor Goal Setting Interview. The duration of enrolment is 24 months. The total recruitment target is n=214, and the main analyses will be intention to treat. Discussion This trial tests whether a novel model of care improves health and disease-related metrics including goal attainment and decreases hospitalisations whilst being more cost-effective than the current usual care. Subject to successful implementation of this intervention within one centre, the PRIME Parkinson model of care could then be evaluated within a cluster-randomised trial at multiple centres.

Abstract Background The UK’s living-donor kidney transplant (LDKT) activity falls behind that of many other countries internationally, with less than 20% of those eligible receiving a LDKT each year. Certain individuals with kidney disease in the UK appear to be particularly disadvantaged in accessing a LDKT; the most socioeconomically deprived people with kidney disease are 60% less likely to receive a LDKT than the least deprived. Improving equity in living-donor kidney transplantation has been highlighted as an international research priority. Methods This feasibility trial was designed to determine the feasibility of delivery and acceptability of a multicomponent intervention designed to improve access to living-donor kidney transplantation. The intervention comprises three main components: (i) a meeting between a home educator and the transplant candidate for a dedicated discussion about living-donor kidney transplantation, living kidney donation and potential donors; (ii) a standardized letter from a healthcare professional to a candidate’s potential donors and (iii) a home-based education and family engagement session including two home educators, the transplant candidate and their family. The primary objectives are to establish the feasibility (i) of delivering the developed intervention in existing care pathways and (ii) of undertaking a randomised controlled trial of the intervention. A mixed-methods parallel process evaluation will investigate the acceptability, implementation and mechanisms of impact of the intervention. The trial is based at two UK hospitals: a transplanting hospital and a non-transplanting referral hospital. Individuals are eligible if they are ≥ 18 years old, are active on the kidney transplant waiting list or have been referred for transplant listing and do not have a potential living-donor undergoing surgical assessment. Randomisation will be undertaken with concealed allocation. Participants will be randomly allocated 1:1 to (i) the intervention or (ii) usual care, stratified by site to ensure a balance in terms of local differences. Minimisation will be used to ensure balance in sex, age group and socioeconomic strata, with probability weighting of 0.8 in order to reduce predictability. The primary outcomes are recruitment (% of those eligible and invited who consent to randomisation) and retention (% of participants completing follow-up). Discussion Findings will inform the design of a future fully powered, randomised controlled trial to formally evaluate the effectiveness of the intervention at improving equitable access to living-donor kidney transplantation. Trial registration ISRCTN Registry ISRCTN10989132 Applied 30/10/20.

Abstract Background There is large individual variation in both clinical presentation and progression between Parkinson’s disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting. Methods Replicating across three large Parkinson’s cohorts (Oxford Discovery cohort (n = 842)/Tracking UK Parkinson’s study (n = 1807) and Parkinson’s Progression Markers Initiative (n = 472)) with clinical observational measures collected longitudinally over 5–10 years, we developed a Bayesian multiple phenotypes mixed model incorporating genetic relationships between individuals able to explain many diverse clinical measurements as a smaller number of continuous underlying factors (“phenotypic axes”). Results When applied to disease severity at diagnosis, the most influential of three phenotypic axes “Axis 1” was characterised by severe non-tremor motor phenotype, anxiety and depression at diagnosis, accompanied by faster progression in cognitive function measures. Axis 1 was associated with increased genetic risk of Alzheimer’s disease and reduced CSF Aβ1-42 levels. As observed previously for Alzheimer’s disease genetic risk, and in contrast to Parkinson’s disease genetic risk, the loci influencing Axis 1 were associated with microglia-expressed genes implicating neuroinflammation. When applied to measures of disease progression for each individual, integration of Alzheimer’s disease genetic loci haplotypes improved the accuracy of progression modelling, while integrating Parkinson’s disease genetics did not. Conclusions We identify universal axes of Parkinson’s disease phenotypic variation which reveal that Parkinson’s patients with high concomitant genetic risk for Alzheimer’s disease are more likely to present with severe motor and non-motor features at baseline and progress more rapidly to early dementia.

Abstract Background Bladder symptoms are common in Parkinson’s disease (PD), affecting half of all individuals. These have significant impact on quality of life as well as implications for morbidity, contributing to falls and hospital admission. The treatment of bladder symptoms can be complicated by the tendency to side-effects in people with PD including cognitive impairment and gait instability with anti-muscarinics. The development of new, better treatments is therefore warranted. Tibial nerve stimulation is a form of neuromodulation demonstrated to improve overactive bladder symptoms in non-neurogenic cohorts. Previously requiring hospital attendance, we aim to explore the use of this intervention using a simple device that can be used by patients at home. Methods STRIPE is a phase II randomised control trial of tibial nerve stimulation delivered by the Geko™ device, a small, self-adhesive neuromuscular stimulation device currently used for thromboembolism prophylaxis post-surgery. Active tibial nerve stimulation will be compared to sham stimulation, with participants blinded to treatment allocation and undertaking outcome assessment whilst still blinded. Participants will be asked to self-administer stimulation at home twice per week, for 30 min per session, over the course of 3 months. Primary outcome measure will be the International Consultation on Incontinence Overactive Bladder Questionnaire (OAB) at week 12. Secondary outcomes will include pre- and post-intervention bladder diary (frequency, urgency episodes, nocturia), patient perception of global change, bowel function and bladder-related quality of life. Participants will be recruited from the Proactive Integrated Management and Empowerment (PRIME) cross-sectional trial in which participants have been screened for bladder symptoms and invited to take part, as well as clinician referral from around the region. Discussion This trial will involve a randomised control trial of a novel and easy to use method of delivering tibial nerve stimulation for PD in the patient’s own home. This may potentially have huge benefit, avoiding the problems with side effects that can be seen with anti-muscarinics and providing a new potential modality of treatment. Trial registration ISRCTN11484954. Registered on 22 June 2021.

Abstract Background More than a third of the 65,000 people living with kidney failure in the UK attend a dialysis unit 2–5 times a week to have their blood cleaned for 3–5 h. In haemodialysis (HD), toxins are removed by diffusion, which can be enhanced using a high-flux dialyser. This can be augmented with convection, as occurs in haemodiafiltration (HDF), and improved outcomes have been reported in people who are able to achieve high volumes of convection. This study compares the clinical- and cost-effectiveness of high-volume HDF compared with high-flux HD in the treatment of kidney failure. Methods This is a UK-based, multi-centre, non-blinded randomised controlled trial. Adult patients already receiving HD or HDF will be randomised 1:1 to high-volume HDF (aiming for 21+ L of substitution fluid adjusted for body surface area) or high-flux HD. Exclusion criteria include lack of capacity to consent, life expectancy less than 3 months, on HD/HDF for less than 4 weeks, planned living kidney donor transplant or home dialysis scheduled within 3 months, prior intolerance of HDF and not suitable for high-volume HDF for other clinical reasons. The primary outcome is a composite of non-cancer mortality or hospital admission with a cardiovascular event or infection during follow-up (minimum 32 months, maximum 91 months) determined from routine data. Secondary outcomes include all-cause mortality, cardiovascular- and infection-related morbidity and mortality, health-related quality of life, cost-effectiveness and environmental impact. Baseline data will be collected by research personnel on-site. Follow-up data will be collected by linkage to routine healthcare databases — Hospital Episode Statistics, Civil Registration, Public Health England and the UK Renal Registry (UKRR) in England, and equivalent databases in Scotland and Wales, as necessary — and centrally administered patient-completed questionnaires. In addition, research personnel on-site will monitor for adverse events and collect data on adherence to the protocol (monthly during recruitment and quarterly during follow-up). Discussion This study will provide evidence of the effectiveness and cost-effectiveness of HD as compared to HDF for adults with kidney failure in-centre HD or HDF. It will inform management for this patient group in the UK and internationally. Trial registration ISRCTN10997319 . Registered on 10 October 2017

Abstract Background Patients with brain tumours often present with non-specific symptoms. Correctly identifying who to prioritise for urgent brain imaging is challenging. Brain tumours are amongst the commonest cancers diagnosed as an emergency presentation. A verbal fluency task (VFT) is a rapid triage test affected by disorders of executive function, language and processing speed. We tested whether a VFT could support identification of patients with a brain tumour. Methods This proof-of-concept study examined whether a VFT can help differentiate patients with a brain tumour from those with similar symptoms (i.e. headache) without a brain tumour. Two patient populations were recruited, (a) patients with known brain tumour, and (b) patients with headache referred for Direct-Access Computed-Tomography (DACT) from primary care with a suspicion of a brain tumour. Semantic and phonemic verbal fluency data were collected prospectively. Results 180 brain tumour patients and 90 DACT patients were recruited. Semantic verbal fluency score was significantly worse for patients with a brain tumour than those without (P < 0.001), whether comparing patients with headache, or patients without headache. Phonemic fluency showed a similar but weaker difference. Raw and incidence-weighted positive and negative predictive values were calculated. Conclusion We have demonstrated the potential role of adding semantic VFT score performance into clinical decision making to support triage of patients for urgent brain imaging. A relatively small improvement in the true positive rate in patients referred for DACT has the potential to increase the timeliness and efficiency of diagnosis and improve patient outcomes.

Abstract Background Culminating evidence shows that current care does not optimally meet the needs of persons with parkinsonism, their carers and healthcare professionals. Recently, a new model of care was developed to address the limitations of usual care: Proactive and Integrated Management and Empowerment in Parkinson’s Disease (PRIME Parkinson). From 2021 onwards, PRIME Parkinson care will replace usual care in a well-defined region in The Netherlands. The utility of PRIME Parkinson care will be evaluated on a single primary endpoint (parkinsonism-related complications), which reflects the health of people with parkinsonism. Furthermore, several secondary endpoints will be measured for four dimensions: health, patient and carer experience, healthcare professional experience, and cost of healthcare. The reference will be usual care, which will be continued in other regions in The Netherlands. Methods This is a prospective observational study which will run from January 1, 2020 until December 31, 2023. Before the new model of care will replace the usual care in the PRIME Parkinson care region all baseline assessments will take place. Outcomes will be informed by two data sources. We will use healthcare claims-based data to evaluate the primary endpoint, and costs of healthcare, in all persons with parkinsonism receiving PRIME Parkinson care (estimated number: 2,000) and all persons with parkinsonism receiving usual care in the other parts of The Netherlands (estimated number: 48,000). We will also evaluate secondary endpoints by performing annual questionnaire-based assessments. These assessments will be administered to a subsample across both regions (estimated numbers: 1,200 persons with parkinsonism, 600 carers and 250 healthcare professionals). Discussion This prospective cohort study will evaluate the utility of a novel integrated model of care for persons with parkinsonism in The Netherlands. We anticipate that the results of this study will also provide insight for the delivery of care to persons with parkinsonism in other regions and may inform the design of a similar model for other chronic health conditions.

Abstract Background Hospital admissions for Ambulatory Care Sensitive Conditions (ACSCs) are potentially avoidable. Dementia is one of the leading chronic conditions in terms of variability in ACSC admissions by general practice, as well as accounting for around a third of UK emergency admissions. Methods Using Bayesian multilevel linear regression models, we examined the ecological association of organizational characteristics of general practices (ACSC n=7076, non-ACSC n=7046 units) and Clinical Commissioning Groups (CCG n=212 units) in relation to ACSC and non-ACSC admissions for people with dementia in England. Results The rate of hospital admissions are variable between GP practices, with deprivation and being admitted from home as risk factors for admission for ACSC and non-ACSC admissions. The budget allocated by the CCG to mental health shows diverging effects for ACSC versus non-ACSC admissions, so it is likely there is some geographic variation. Conclusions A variety of factors that could explain avoidable admissions for PWD at the practice level were examined; most were equally predictive for avoidable and non-avoidable admissions. However, a high amount of variation found at the practice level, in conjunction with the diverging effects of the CCG mental health budget, implies that guidance may be applied inconsistently, or local services may have differences in referral criteria. This indicates there is potential scope for improvement.

Abstract Background The risk of acute kidney injury (AKI) attributable to renin angiotensin aldosterone (RAAS) inhibitors and diuretics remains unclear. Methods We conducted a prospective cohort study using the Clinical Practice Research Datalink (2008–2015) linked to Hospital Episode Statistics – Admitted Patient Care and Office for National Statistics mortality data. Patients were included if they had one or more chronic diagnoses requiring medication. Exposed patients had a first ever prescription for RAAS inhibitors/diuretics during the study period. AKI risk associated with exposure was determined by multivariable Cox regression, propensity score-adjusted Cox regression and a prior event rate ratio (PERR) analysis. Results One hundred forty thousand nine hundred fifty-two individuals were included. Increased AKI risk in the exposed group was demonstrated in both the multivariable and propensity score-adjusted cox regressions (HR 1.23 (95% CI 1.04–1.45) and HR 1.24 (1.05–1.47) respectively). The PERR analysis provided a similar overall hazard ratio with a wider confidence interval (HR 1.29 (0.94–1.63)). The increased AKI risk in the exposed group was present only in those receiving two or more antihypertensives. Absolute AKI risk was small. Conclusions RAAS inhibitors/diuretics result in an increased risk of AKI. The absolute increase in AKI risk is small, however, and needs to be considered in the context of any potential benefits.

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Abstract Background Increasing physical activity in older adults remains a key public health priority in countries with a high burden of non-communicable disease, yet current interventions have failed to substantially increase population uptake with UK data suggesting that only half of 65–74 year olds report meeting recommended levels. The aim of this study was to conduct a systematic and inductive qualitative synthesis of the large body of qualitative research describing what influences physical activity at this age, and older adults’ experiences of physical activity. Methods A qualitative meta-ethnography was chosen as the study design as this inductive approach can provide novel insights and generate new theory about physical activity and ageing. Papers were identified by searching electronic databases and key citations. Peer-reviewed primary qualitative studies and systematic reviews were included if they met the following inclusion criteria: community-dwelling participants aged 60 years or older or in the retirement transition period; reporting on leisure-time physical activity; utilising a rigorous qualitative methodology. A line of argument approach was employed to generate a theory about how older adults think and feel about physical activity. Results Thirty-nine papers met the inclusion criteria and were synthesised. The emergent theory suggested transition to older age can challenge people’s sense of self and their role in life. Physical activity can help in regaining feelings of purpose, of being needed in collective group activity, and by creating habitual routine and structure to the day. In overcoming real and perceived barriers, and by taking up or sustaining physical activities, older adults can further build self-esteem all of which contributes to a fulfilling older age. Conclusion Current failures to increase population levels of physical activity in older adults may be explained by an approach overly focused on the health benefits of activity. Insights from this study suggest we need to reframe our approach to consider the wider set of goals and aspirations which are of greater personal importance to older adults, and future interventions should focus on how physical activity can contribute to life satisfaction, sense of purpose, and sense of role fulfilment in older age. Trial registration Registered prospectively on PROSPERO on 29th March 2013: CRD42013003796.

Abstract Background More people are living longer lives leading to a growth in the population of older adults, many of whom have comorbidities and low levels of physical function. Physical activity in later life can prevent or delay age-related disability. Identifying a cost-effective means of increasing physical activity in older adults therefore remains an important public health priority. Physical Activity Facilitation (PAF) is an intervention shown to increase physical activity in adults with depression. The PAF model was modified for a population of older adults at risk of disability. This study aimed to assess the feasibility of undertaking a definitive RCT of the PAF intervention in the target population. Methods A pilot randomised controlled trial (RCT) was delivered through primary care. Patients at risk of disability and who were not meeting recommended levels of physical activity were recruited through postal invitation and direct approach in the practice waiting room. Those meeting eligibility criteria were enrolled and randomised at a 2:1 ratio to the PAF intervention and control. Behaviour change techniques were used by facilitators with participants over the telephone and face-to-face for 6 months. Outcome measures including physical function, physical activity, depression, social support, and quality of life were collected at baseline and at 6 months. Results A high proportion of patients responded to the initial invitation (68%), yet many were ineligible due to high levels of self-reported physical activity and baseline physical function. Fifty-one participants were recruited to the trial, with an average age of 74 years (range 65–89), and there were high rates of adherence and retention to the study (94% follow-up at 6 months). The majority of outcome data collected from participants was complete; however, the validated scale used to measure self-reported physical activity was associated with high levels of missing data. Conclusions The findings of this pilot RCT suggest that it is feasible to deliver a definitive RCT of the PAF intervention in this population. Further work is required to improve the efficiency of recruitment and to minimise missing data from self-reported physical activity measures. Trial registration Current controlled trials ISRCTN80470273. Registered 25 October 2013.

Abstract Background Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. Methods The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. Results There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10− 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10− 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10− 6 and P = 3 × 10− 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10− 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. Conclusion In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts.

Abstract Background There is growing consensus on the importance of identifying age-related inequities in the receipt of public health and healthcare interventions, but concerns regarding conceptual and methodological rigour in this area of research. Establishing age inequity in receipt requires evidence of a difference that is not an artefact of poor measurement of need or receipt; is not warranted on the grounds of patient preference or clinical safety; and is judged to be unfair. Method A systematic, thematic literature review was undertaken with the objective of characterising recent research approaches. Studies were eligible if the population was in a country within the Organisation for Economic Co-operation and Development and analyses included an explicit focus on age-related patterns of healthcare receipt including those 60 years or older. A structured extraction template was applied. Extracted material was synthesised in thematic memos. A set of categorical codes were then defined and applied to produce summary counts across key dimensions. This process was iterative to allow reconciliation of discrepancies and ensure reliability. Results Forty nine studies met the eligibility criteria. A wide variety of concepts, terms and methodologies were used across these studies. Thirty five studies employed multivariable techniques to produce adjusted receipt-need ratios, though few clearly articulated their rationale, indicating the need for great conceptual clarity. Eighteen studies made reference to patient preference as a relevant consideration, but just one incorporated any kind of adjustment for this factor. Twenty five studies discussed effectiveness among older adults, with fourteen raising the possibility of differential effectiveness, and one differential cost-effectiveness, by age. Just three studies made explicit reference to the ethical nature of healthcare resource allocation by age. While many authors presented suitably cautious conclusions, some appeared to over-stretch their findings concluding that observed differences were ‘inequitable’. Limitations include possible biases in the retrieved material due to inconsistent database indexing and a focus on OECD country populations and studies with English titles. Conclusions Caution is needed among clinicians and other evidence-users in accepting claims of healthcare ‘ageism’ in some published papers. Principles for improved research practice are proposed.

Systolic blood pressure (SBP) differs between the brachial artery and aorta. Prospective data suggest that central pressure predicts future cardiovascular events, but it is unclear if it is superior to brachial pressure. Methods and Results: A systematic review and individual participant data meta-analysis from 15 studies was undertaken. Study-specific associations of central and brachial pressure with cardiovascular outcomes, with and without mutual adjustment, were determined using Cox proportional hazard models, and random effect models to estimate pooled estimates. Of 22,433 participants, 908 had a myocardial infarction (MI) and 641 a stroke. The pooled age, sex, height and heart rate adjusted hazard ratio (HR) [95% CI] per SD increase in brachial SBP was 1.17 [1.03, 1.32] for MI and 1.28 [1.13, 1.46] for stroke and 1.16 [1.02, 1.33] and 1.33 [1.15, 1.53] for central SBP, respectively. Mutual adjustment attenuated the HRs for MI: brachial SBP (1.16 [0.90, 1.48]), central SBP (1.09 [0.87, 1.38]) and stroke: brachial SBP (1.18 [0.97, 1.42]), central SBP (1.19 [0.99, 1.44]). However, associations between central SBP and stroke, after adjustment for brachial SBP, were higher in those aged