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Simon DS Fraser, Steve George Academic Unit of Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, Hampshire, UKAbstract: Several health outcomes (including mortality) and health-related behaviors are known to be worse in Scotland than in comparable areas of Europe and the United Kingdom. Within Scotland, Greater Glasgow (in West Central Scotland) experiences disproportionately poorer outcomes independent of measurable variation in socioeconomic status and other important determinants. Many reasons for this have been proposed, particularly related to deprivation, inequalities, and variation in health behaviors. The use of models (such as the application of Bradford Hill’s viewpoints on causality to the different hypotheses) has provided useful insights on potentially causal mechanisms, with health behaviors and inequalities likely to represent the strongest individual candidates. This review describes the evolution of our understanding of Glasgow’s excess mortality, summarizes some of the key work in this area, and provides some suggestions for future areas of exploration. In the context of demographic change, the experience in Glasgow is an important example of the complexity that frequently lies behind observed variations in health outcomes within and between populations. A comprehensive explanation of Glasgow’s excess mortality may continue to remain elusive, but is likely to lie in a complex and difficult-to-measure interplay of health determinants acting at different levels in society throughout the life course. Lessons learned from the detailed examination of different potentially causative determinants in Scotland may provide useful methodological insights that may be applied in other settings. Ongoing efforts to unravel the causal mechanisms are needed to inform public health efforts to reduce health inequalities and improve outcomes in Scotland.Keywords: Glasgow effect, mortality, inequalities, determinants

Background: Menopause represents a pivotal physiological transition characterized by hormonal fluctuations and an augmented susceptibility to chronic diseases. The relationship between menopause and heightened disease risk may be attributed in part to alterations in low-grade chronic inflammation and adiposity., Methods: Three databases were searched for studies assessing differences in inflammation and body adiposity between pre- and postmenopausal women. Meta-analysis examined the association between menopausal status and key inflammatory biomarkers, including leptin, adiponectin, interleukin-6, tumour necrosis factor-α and c-reactive protein, and indices of body adiposity (fat mass, waist circumference, waist-to-hip-ratio and body mass index). The National Institute of Health Quality Assessment Tool for Observational and Cross-sectional studies was used to evaluate quality of studies, and GRADE-assessed evidence certainty., Results: Levels of adiponectin and leptin were higher in postmenopausal women than in premenopausal women [(1.30 μg/ml, 95 % CI; 0.56 to 2.03 μg/ml, p = 0.001), (0.88 ng/ml; 95 % CI: 0.22 to 1.52; p = 0.008)]. A trend towards significance was observed for tumour necrosis factor-α (0.59 pg/ml, 95 % CI; -0.07 to 1.26 pg/ml, p = 0.080), with no significant differences in interleukin-6 and c-reactive protein [(0.83 pg/ml, 95 % CI; -0.24 to 1.91 pg/ml, p = 0.128), (0.06 mg/ml, 95 % CI; -0.17 to 0.29, p = 0.606)]. Postmenopausal women had greater waist circumference, waist-to-hip-ratio and body mass index than premenopausal women [(0.74 cm; 95 % CI: 1.02 to 0.47; p ≤0.001), (0.78; 95 % CI: 1.47 to -0.09; p = 0.027), (0.31 kg/m 2 ; 95 % CI: 0.50 to 0.12; p = 0.001)]., Conclusions: Postmenopausal women had higher adipokine levels and greater adiposity. However, given the low certainty of the available evidence, future prospective cohort studies assessing inflammatory changes over the menopausal transition are warranted to inform future clinical decisions. Protocol registered on the Open Science Framework (OSF-ID: 10.17605/OSF.IO/DY8T6)., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis., Methods: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP., Results: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers., Conclusion: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood., Trial Registration: EudraCT 2019-000580-24 (17 May 2019)., (© 2024. The Author(s).)

Background: Women develop addiction and drug-related health consequences after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed clinically for multiple drugs, including opioids. Preclinical studies indicate that this is a biologically based phenomenon; however, these studies have focused exclusively on cocaine, and none have considered health effects., Methods: In this study, we used a rat (Sprague Dawley) model to determine sex differences in the time course for the development of an opioid addiction-like phenotype, as defined by the development of physical dependence (withdrawal-induced weight loss) and an increase in motivation for fentanyl (under a progressive-ratio schedule). Effects were determined following either 10 days (optimized, experiment 1) or 3 days (threshold, experiment 2) of extended-access fentanyl self-administration (24 hours/day, fixed ratio 1, 2- to 5-minute trials/hour) or following short-access fentanyl self-administration (subthreshold, experiment 3; fixed ratio 1, up to 40 infusions/day). Opioid-related adverse health effects were also determined (experiment 4)., Results: Motivation for fentanyl was similarly increased in males and females following 10 days of extended-access self-administration (experiment 1), was transiently increased in females, but not males, following 3 days of extended-access self-administration (experiment 2) and was not increased in either sex following short-access self-administration (experiment 3). Females developed fentanyl-associated adverse health effects more readily than males (experiment 4), with particularly robust differences during extended-access self-administration and withdrawal., Conclusions: As with findings in humans, female rats developed opioid addiction-like features and adverse health consequences more readily than male rats. These data provide support for a biologically based telescoping effect in females for opioids, particularly for opioid-related adverse health consequences., (© 2024 The Authors.)

Background: Treatment burden represents the work patients undertake because of their health care, and the impact of that effort on the patient. Most research has focused on older adults (aged >65 years) with multiple long-term conditions (multimorbidity) (MLTC-M), but there are now more younger adults (aged 18-65 years) living with MLTC-M and they may experience treatment burden differently. Understanding experiences of treatment burden, and identifying those most at risk of high treatment burden, are important for designing primary care services to meet their needs., Aim: To understand the treatment burden associated with MLTC-M, for people aged 18-65 years, and how primary care services affect this burden., Design & Setting: Mixed-methods study in up to 33 primary care practices in two UK regions., Method: The following two approaches will be used: (i) in-depth qualitative interviews with adults living with MLTC-M (approximately 40 participants) to understand their experiences of treatment burden and the impact of primary care, with a think-aloud aspect to explore face validity of a novel short treatment burden questionnaire (STBQ) for routine clinical use in the initial 15 interviews; (ii) cross-sectional patient survey (approximately 1000 participants), with linked routine medical record data to examine the factors associated with treatment burden for people living with MLTC-M, and to test the validity of STBQ., Conclusion: This study will generate in-depth understanding of the treatment burden experienced by people aged 18-65 years living with MLTC-M, and how primary care services affect this burden. This will inform further development and testing of interventions to reduce treatment burden, and potentially influence MLTC-M trajectories and improve health outcomes., (Copyright © 2023, The Authors.)

Background: Most people living with multiple long-term condition multimorbidity (MLTC-M) are under 65 (defined as 'early onset'). Earlier and greater accrual of long-term conditions (LTCs) may be influenced by the timing and nature of exposure to key risk factors, wider determinants or other LTCs at different life stages. We have established a research collaboration titled 'MELD-B' to understand how wider determinants, sentinel conditions (the first LTC in the lifecourse) and LTC accrual sequence affect risk of early-onset, burdensome MLTC-M, and to inform prevention interventions., Aim: Our aim is to identify critical periods in the lifecourse for prevention of early-onset, burdensome MLTC-M, identified through the analysis of birth cohorts and electronic health records, including artificial intelligence (AI)-enhanced analyses., Design: We will develop deeper understanding of 'burdensomeness' and 'complexity' through a qualitative evidence synthesis and a consensus study. Using safe data environments for analyses across large, representative routine healthcare datasets and birth cohorts, we will apply AI methods to identify early-onset, burdensome MLTC-M clusters and sentinel conditions, develop semi-supervised learning to match individuals across datasets, identify determinants of burdensome clusters, and model trajectories of LTC and burden accrual. We will characterise early-life (under 18 years) risk factors for early-onset, burdensome MLTC-M and sentinel conditions. Finally, using AI and causal inference modelling, we will model potential 'preventable moments', defined as time periods in the life course where there is an opportunity for intervention on risk factors and early determinants to prevent the development of MLTC-M. Patient and public involvement is integrated throughout., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RKO is a member of the National Institute for Health and Care Excellence (NICE) Technology Appraisal Committee, member of the NICE Decision Support Unit (DSU), and associate member of the NICE Technical Support Unit (TSU). She has served as a paid consultant to the pharmaceutical industry, providing unrelated methodological advice. She reports teaching fees from the Association of British Pharmaceutical Industry (ABPI) and the University of Bristol., (© The Author(s) 2023.)

Background: Foetal and early childhood development contributes to the risk of adult non-communicable diseases such as hypertension and cardiovascular disease. We aimed to investigate whether kidney size at birth is associated with markers of kidney function at 7-11 years., Methods: Foetal kidney dimensions were measured using ultrasound scans at 34 weeks gestation and used to derive kidney volume (cm 3 ) in 1802 participants in the Born in Bradford (BiB) birth cohort. Blood and urine samples were taken from those who participated in the BiB follow-up at 7-11 years (n = 630) and analysed for serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP). Estimated glomerular filtration rate (eGFR) was calculated using Schwartz creatinine only and combined with cystatin C, and cystatin C only Zappitelli and Filler equations. Linear regression was used to examine the association between foetal kidney volume and eGFR, ACR, PCR and blood pressure, unadjusted and adjusted for confounders., Results: Kidney volume was positively associated in adjusted models with eGFR calculated using Schwartz combined (0.64 ml/min diff per unit increase in volume, 95% CI 0.25 to 1.02), Zappitelli (0.79, 95% CI 0.38 to 1.20) and Filler (2.84, 95% CI 1.40 to 4.28). There was an association with the presence of albuminuria but not with its level, or with other urinary markers or with blood pressure., Conclusion: Foetal kidney volume was associated with small increases in eGFR in mid-childhood. Longitudinal follow-up to investigate the relationship between kidney volume and markers of kidney function as children go through puberty is required., (© 2023. The Author(s).)

Background: Treatment burden is a patient-centred concept describing the effort required of people to look after their health and the impact this has on their functioning and wellbeing. High treatment burden is more likely for people with multiple long-term conditions (LTCs). Validated treatment burden measures exist, but have not been widely used in practice or as research outcomes., Aim: To establish whether changes in organisation and delivery of health systems and services improve aspects contributing to treatment burden for people with multiple LTCs., Design and Setting: Systematic review of randomised controlled trials (RCTs) investigating the impact of system-level interventions on at least one outcome relevant to previously defined treatment burden domains among adults with ≥2 LTCs., Method: The Embase, Ovid MEDLINE, and Web of Science electronic databases were searched for terms related to multimorbidity, system-level change, and treatment burden published between January 2010 and July 2021. Treatment burden domains were derived from validated measures and qualitative literature. Synthesis without meta-analysis (SWiM) methodology was used to synthesise results and study quality was assessed using the Cochrane risk-of-bias (version 2) tool., Results: The searches identified 1881 articles, 18 of which met the review inclusion criteria. Outcomes were grouped into seven domains. There was some evidence for the effect of system-level interventions on some domains, but the studies exhibited substantial heterogeneity, limiting the synthesis of results. Some concern over bias gave low confidence in study results., Conclusion: System-level interventions may affect some treatment burden domains. However, adoption of a standardised outcome set, incorporating validated treatment burden measures, and the development of standard definitions for care processes in future research would aid study comparability., (© The Authors.)

Background: Treatment burden is the effort required of patients to look after their health and the impact this has on their functioning and wellbeing. Little is known about change in treatment burden over time for people with multimorbidity., Aim: To quantify change in treatment burden, determine factors associated with this change, and evaluate a revised single-item measure for high treatment burden in older adults with multimorbidity., Design and Setting: A 2.5-year follow-up of a cross-sectional postal survey via six general practices in Dorset, England., Method: GP practices identified participants of the baseline survey. Data on treatment burden (measured using the Multimorbidity Treatment Burden Questionnaire; MTBQ), sociodemographics, clinical variables, health literacy, and financial resource were collected. Change in treatment burden was described, and associations assessed using regression models. Diagnostic test performance metrics evaluated the revised single-item measure relative to the MTBQ., Results: In total, 300 participants were recruited (77.3% response rate). Overall, there was a mean increase of 2.6 (standard deviation 11.2) points in treatment burden global score. Ninety-eight (32.7%) and 53 (17.7%) participants experienced an increase and decrease, respectively, in treatment burden category. An increase in treatment burden was associated with having >5 long-term conditions (adjusted β 8.26, 95% confidence interval [CI] = 4.20 to 12.32) and living >10 minutes (versus ≤10 minutes) from the GP (adjusted β 3.88, 95% CI = 1.32 to 6.43), particularly for participants with limited health literacy (mean difference: adjusted β 9.59, 95% CI = 2.17 to 17.00). The single-item measure performed moderately (sensitivity 55.7%; specificity 92.4%., Conclusion: Treatment burden changes over time. Improving access to primary care, particularly for those living further away from services, and enhancing health literacy may mitigate increases in burden., (© The Authors.)

Objectives: The prevalence of multiple long-term condition (LTC) multimorbidity is increasing with younger onset among socioeconomically deprived populations. Research on life course trajectories towards multimorbidity is limited and early-onset multimorbidity poorly characterised. Understanding sentinel conditions (the first LTC occurring in the life course), the sequence of LTC accrual and the permanency of the reporting of LTCs may help identify time points for prevention efforts. We used a longitudinal birth cohort to estimate the prevalence of a common three-condition early-onset multimorbidity (multiple long-term condition multimorbidity (MLTC-M)) group at midlife, describe the frequency of sentinel conditions, the sequence of LTC accrual and explore the permanency of one of these conditions: psychological distress., Setting: 1970 British Cohort Study (BCS70)., Participants: 17 196 cohort members born in 1970., Outcome Measures: Prevalence of the most common three-condition multimorbidity group at age 46. The nature and timing of sentinel conditions, the sequencing patterns of subsequent LTC accrual and the permanency of the reporting of psychological distress., Results: At age 46 high blood pressure, psychological distress and back pain were the most common three-condition MLTC-M group, (4.3%, n=370). A subgroup of 164 (44.3%) people provided complete information on LTC across all time points. Psychological distress measured by the Malaise Index was the most common sentinel condition, occurring in 25.0% (n=41), followed by back pain (22%, n=36). At age 26, 45.1% (75/164) reported their sentinel condition. The most common sequence of LTC accrual was the co-reporting of psychological distress and back pain followed by high blood pressure. Almost one-third (30.5%, n=50) reported a variation of psychological distress across the adult life course., Conclusion: In these exploratory analyses, psychological distress and back pain were the most common sentinel conditions, and along with high blood pressure these three conditions represented the most common three-condition MLTC-M group. These analyses suggest that birth cohorts, like the BCS70, may usefully inform life course-multimorbidity research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: We investigated the feasibility of recruiting patients unemployed for more than 3 months with chronic pain using a range of methods in primary care in order to conduct a pilot trial of Individual Placement and Support (IPS) to improve quality of life outcomes for people with chronic pain., Methods: This research was informed by people with chronic pain. We assessed the feasibility of identification and recruitment of unemployed patients; the training and support needs of employment support workers to integrate with pain services; acceptability of randomisation, retention through follow-up and appropriate outcome measures for a definitive trial. Participants randomised to IPS received integrated support from an employment support worker and a pain occupational therapist to prepare for, and take up, a work placement. Those randomised to Treatment as Usual (TAU) received a bespoke workbook, delivered at an appointment with a research nurse not trained in vocational rehabilitation., Results: Using a range of approaches, recruitment through primary care was difficult and resource-intensive (1028 approached to recruit 37 eligible participants). Supplementing recruitment through pain services, another 13 people were recruited (total n = 50). Randomisation to both arms was acceptable: 22 were allocated to IPS and 28 to TAU. Recruited participants were generally not 'work ready', particularly if recruited through pain services., Conclusion: A definitive randomised controlled trial is not currently feasible for recruiting through primary care in the UK. Although a trial recruiting through pain services might be possible, participants could be unrepresentative in levels of disability and associated health complexities. Retention of participants over 12 months proved challenging, and methods for reducing attrition are required. The intervention has been manualised.

Background: Disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate and azathioprine, are commonly used to treat rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Blood-test safety monitoring is mainly undertaken in primary care. Normal blood results are common., Aim: To determine the frequency and associations of persistently normal blood tests in patients with RA prescribed methotrexate, and patients with IBD prescribed azathioprine., Design and Setting: Two-year retrospective study of a cohort taken from an electronic pseudonymised primary care/laboratory database covering >1.4 million patients across Hampshire, UK., Method: Patients with RA and IBD, and associated methotrexate and azathioprine prescriptions, respectively, were identified. Tests and test thresholds recommended by the National Institute for Health and Care Excellence were applied. Persistent normality was defined as no abnormalities of any tests nor alanine aminotransferase (ALT), white blood count (WBC), neutrophils, and estimated glomerular filtration rate (eGFR) individually. Logistic regression was used to identify associations with test normality., Results: Of 702 265 adults, 7102 had RA and 8597 had IBD. In total, 3001 (42.3%) patients with RA were prescribed methotrexate and 1162 (13.5%) patients with IBD were prescribed azathioprine; persistently normal tests occurred in 1585 (52.8%) and 657 (56.5%) of the populations, respectively. In patients with RA on methotrexate, 585 (19.5%) had eGFR, 219 (7.3%) ALT, 217 (7.2%) WBC, and 202 (6.7%) neutrophil abnormalities. In patients with IBD on azathioprine, 138 (11.9%) had WBC, 88 (7.6%) eGFR, 72 (6.2%) ALT, and 65 (5.6%) neutrophil abnormalities. Those least likely to have persistent test normality were older and/or had comorbidities., Conclusion: Persistent test normality is common when monitoring these DMARDs, with few hepatic or haematological abnormalities. More stratified monitoring approaches should be explored., (© The Authors.)

Mutations in RNA-binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb, and neurological symptoms. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription, and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. We show a developmental role for Hnrnpul1 in zebrafish, resulting in reduced body and fin growth and missing bones. Defects in craniofacial tendon growth and adult-onset caudal scoliosis are also seen. We demonstrate a role for Hnrnpul1 in alternative splicing and transcriptional regulation using RNA-sequencing, particularly of genes involved in translation, ubiquitination, and DNA damage. Given its cross-species conservation and role in splicing, it would not be surprising if it had a role in human development. Whole-exome sequencing detected a homozygous frameshift variant in HNRNPUL1 in 2 siblings with congenital limb malformations, which is a candidate gene for their limb malformations. Zebrafish Hnrnpul1 mutants suggest an important developmental role of hnRNPUL1 and provide motivation for exploring the potential conservation of ancient regulatory circuits involving hnRNPUL1 in human development., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)

Background: Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burden of CKD worldwide and the low cost of aspirin., Methods: ATTACK is a pragmatic multicentre, prospective, randomised, open-label, blinded endpoint adjudication superiority trial of aspirin 75 mg daily vs. standard care for the primary prevention of CVD in 25,210 people aged 18 years and over with CKD recruited from UK Primary Care. Participants aged 18 years and over with CKD (GFR category G1-G4) will be identified in Primary Care and followed up using routinely collected data and annual questionnaires for an average of 5 years. The primary outcome is the time to first major vascular event (composite of non-fatal MI, non-fatal stroke and cardiovascular death [excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage]). Deaths from other causes (including fatal bleeding) will be treated as competing events. The study will continue until 1827 major vascular events have occurred. The principal safety outcome is major intracranial and extracranial bleeding; this is hypothesised to be increased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding., Discussion: This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access., Trial Registration: ISRCTN: ISRCTN40920200 . EudraCT: 2018-000644-26 ., Clinicaltrials: gov: NCT03796156., (© 2022. The Author(s).)

Background: Decline in kidney function can result in adverse health outcomes. The Oxford Renal Cohort Study has detailed baseline assessments from 884 participants ≥60 years of age., Aim: To determine the proportion of participants with a decline in estimated glomerular filtration rate (eGFR), identify determinants of decline, and determine proportions with chronic kidney disease (CKD) remission., Design and Setting: Observational cohort study in UK primary care., Method: Data were used from baseline and annual follow-up assessments to monitor change in kidney function. Rapid eGFR decline was defined as eGFR decrease >5 ml/min/1.73 m 2 /year, improvement as eGFR increase >5 ml/min/1.73 m 2 /year, and remission in those with CKD at baseline and eGFR >60 ml/min/1.73 m 2 during follow-up. Cox proportional hazard models were used to identify factors associated with eGFR decline., Results: There was a net decline in eGFR in the 884 participants over 5 years of follow-up. In 686 participants with >2 eGFR tests with a median follow-up of 2.1 years, 164 (24%) evidenced rapid GFR decline, 185 (27%) experienced eGFR improvement, and 82 of 394 (21%) meeting CKD stage 1-4 at baseline experienced remission. In the multivariable analysis, smoking status, higher systolic blood pressure, and being known to have CKD at cohort entry were associated with rapid GFR decline. Those with CKD stage 3 at baseline were less likely to exhibit GFR decline compared with normal kidney function., Conclusion: This study established that 24% of people evidenced rapid GFR decline whereas 21% evidenced remission of CKD. People at risk of rapid GFR decline may benefit from closer monitoring and appropriate treatment to minimise risks of adverse outcomes, although only a small proportion meet the National Institute for Health and Care Excellence criteria for referral to secondary care., (© The Authors.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pain and inflammation. NSAID complications include acute kidney injury (AKI), causing burden to patients and health services through increased morbidity, mortality, and hospital admissions., Aim: To measure the extent of NSAID prescribing in an adult population, the degree to which patients with potential higher risk of AKI were exposed to NSAIDs, and to quantify their risk of AKI., Design & Setting: Retrospective 2-year closed-cohort study., Method: A retrospective cohort of adults was identified from a pseudonymised electronic primary care database in Hampshire, UK. The cohort had clinical information, prescribing data, and complete GP- and hospital-ordered biochemistry data. NSAID exposure (minimum one prescription in a 2-month period) was categorised as never, intermittent, and continuous, and first AKI using the national AKI e-alert algorithm. Descriptive statistics and logistic regression were used to explore NSAID prescribing patterns and AKI risk., Results: The baseline population was 702 265. NSAID prescription fell from 19 364 (2.8%) to 16 251 (2.4%) over 2 years. NSAID prescribing was positively associated with older age, female sex, greater socioeconomic deprivation, and certain comorbidities (diabetes, hypertension, osteoarthritis, and rheumatoid arthritis) and negatively with cardiovascular disease (CVD) and heart failure. Among those prescribed NSAIDs, AKI was associated with older age, greater deprivation, chronic kidney disease (CKD), CVD, heart failure, diabetes, and hypertension., Conclusion: Despite generally good prescribing practice, NSAID prescribing was identified in some people at higher risk of AKI (for example, patients with CKD and older) for whom medication review and NSAID deprescribing should be considered., (Copyright © 2022, The Authors.)

Objective: To investigate the relative impact of generic entry and National Institute for Health and Care Excellence clinical guidelines on prescribing using statins as an exemplar., Design: Retrospective analysis of statin prescribing in primary care and cost simulation model., Setting: Royal College of General Practitioners Research and Surveillance Centre (RCGP R&SC) database and Prescription Cost Analysis (PCA) database., Participants: New patients prescribed statins for the first time between July 2003 and September 2018., Main Outcome Measures: Shares of new patients prescribed one of the five statins available in the British National Formulary, and cost of prescribing statins to new and existing patients in primary care in England., Results: General trends of statin' prescriptions were largely driven by a decrease in acquisition costs triggered by patent expiration, preceding NICE guidelines which themselves did not seem to affect prescription trends. Significant heterogeneity is observed in the prescription of the most cost-effective statin acrossGPs. A cost simulation shows that, between 2004 and 2018, the NHS could have saved £2.8bn (around 40% of the £6.3bn spent on statins during this time) if all GP practices had prescribed only the most cost-effective treatment., Conclusions: There is potential for large savings for the NHS if new and, whenever possible, ongoing patients are promptly switched to the first medicine that becomes available as generic within a therapeutic class as long as it has similar efficacy to still-patented medicines.

Background: Growing demand from an increasingly ageing population with multimorbidity has resulted in complex health and social care needs requiring more integrated services. Integrating primary care with social services could utilise resources more efficiently, and improve experiences for patients, their families, and carers. There is limited evidence on progress including key barriers to and drivers of integration to inform large-scale national change., Aim: To elicit stakeholder views on drivers and barriers of integrated primary care and social services, and highlight opportunities for successful implementation., Design and Setting: A qualitative interview study., Method: Semi-structured interviews with maximum variation sampling to capture stakeholder views across services and professions., Results: Thirty-seven interviews were conducted across England with people including GPs, nurses, social care staff, commissioners, local government officials, voluntary and private sector workers, patients, and carers. Drivers of integration included groups of like-minded individuals supported by good leadership, expanded interface roles to bridge gaps between systems, and co-location of services. Barriers included structural and interdisciplinary tension between professions, organisational self-interest, and challenges in record sharing., Conclusion: Drivers and barriers to integration identified in other contexts are also present in primary care and social services. Benefits of integration are unlikely to be realised if these are not addressed in the design and execution of new initiatives. Efforts should go beyond local- and professional-level change to include wider systems- and policy-level initiatives. This will support a more systems-wide approach to integrated care reform, which is necessary to meet the complex and growing needs of an ageing multimorbid population., (© The Authors.)

Background: Treatment burden is the effort required of patients to look after their health, and the impact this has on their wellbeing. Quantitative data on treatment burden for patients with multimorbidity are sparse, and no single-item treatment burden measure exists., Aim: To determine the extent of, and associations with, high treatment burden among older adults with multimorbidity, and to explore the performance of a novel single-item treatment burden measure., Design and Setting: Cross-sectional postal survey via general practices in Dorset, UK., Method: Patients ≥55 years, living at home, with three or more long-term conditions (LTCs) were identified by practices. Treatment burden was measured using the Multimorbidity Treatment Burden Questionnaire. Data collected were sociodemographics, LTCs, medications, and characteristics including health literacy and financial resource. Associations with high treatment burden were investigated via logistic regression. Performance of a novel single-item measure of treatment burden was also evaluated., Results: A total of 835 responses were received (response rate 42%) across eight practices. Patients' mean age was 75 years, 55% were female ( n = 453), and 99% were white ( n = 822). Notably, 39% of patients self-reported fewer than three LTCs ( n = 325). Almost one-fifth (18%) of responders reported high treatment burden ( n = 150); making lifestyle changes and arranging appointments were particular sources of difficulty. After adjustment, limited health literacy and financial difficulty displayed strong associations with high treatment burden; more LTCs and more prescribed regular medications were also independently associated. The single-item measure discriminated moderately between high and non-high burden with a sensitivity of 89%, but a specificity of 58%., Conclusion: High treatment burden was relatively common, underlining the importance of minimising avoidable burden. More vulnerable patients, with less capacity to manage, are at greater risk of being overburdened. Further development of a single-item treatment burden measure is required., (© The Authors.)

Background: In sarcoidosis, blood monocytes, circulating precursors of granuloma macrophages, display enhanced inflammatory cytokine production, reduced expression of the regulatory (inhibitory) receptor CD200R, and altered subsets defined by CD14 and CD16. Regulatory receptors serve to dampen monocyte and macrophage inflammatory responses. We investigated the relationship between monocyte subsets and regulatory receptor expression in sarcoidosis., Methods: Multiparameter flow cytometry was used to perform detailed analyses of cell surface regulatory molecules on freshly isolated blood immune cells from patients with chronic pulmonary sarcoidosis and age-matched healthy controls., Results: 25 patients with chronic pulmonary sarcoidosis (median duration of disease 22 months) who were not taking oral corticosteroids or other immunomodulators were recruited. Nonclassical monocytes were expanded in sarcoidosis and exhibited significantly lower expression of regulatory receptors CD200R, signal regulatory protein-α and CD47 than classical or intermediate monocytes. In sarcoidosis, all three monocyte subsets had significantly reduced CD200R and CD47 expression compared with healthy controls. A dichotomous distribution of CD200R was seen on classical and intermediate monocytes in the sarcoidosis population, with 14 out of 25 (56%) sarcoidosis patients having a CD200R low phenotype and 11 out of 25 (44%) having a CD200R high phenotype. These distinct sarcoidosis monocyte phenotypes remained consistent over time., Conclusions: Nonclassical monocytes, which are expanded in sarcoidosis, express very low levels of regulatory receptors. Two distinct and persistent phenotypes of CD200R expression in classical and intermediate monocytes could be evaluated as sarcoidosis biomarkers., Competing Interests: Conflict of interest: S.D. Fraser reports grants from SarcoidosisUK/British Lung Foundation, during the conduct of the study. Conflict of interest: M.G. Crooks reports grants from SarcoidosisUK/British Lung Foundation, during the conduct of the study. Conflict of interest: P.M. Kaye reports grants from SarcoidosisUK/British Lung Foundation, during the conduct of the study. Conflict of interest: S.P. Hart reports grants from SarcoidosisUK/British Lung Foundation, during the conduct of the study., (Copyright ©ERS 2021.)

Objective: Chronic kidney disease (CKD) is often a multimorbid condition and progression to more severe disease is commonly associated with increased management requirements, including lifestyle change, more medication and greater clinician involvement. This study explored patients' and kidney care team's perspectives of the nature and extent of this workload (treatment burden) and factors that support capacity (the ability to manage health) for older individuals with CKD., Design: Qualitative semistructured interview and focus group study., Setting and Participants: Adults (aged 60+) with predialysis CKD stages G3-5 (identified in two general practitioner surgeries and two renal clinics) and a multiprofessional secondary kidney care team in the UK., Results: 29 individuals and 10 kidney team members were recruited. Treatment burden themes were: (1) understanding CKD, its treatment and consequences, (2) adhering to treatments and management and (3) interacting with others (eg, clinicians) in the management of CKD. Capacity themes were: (1) personal attributes (eg, optimism, pragmatism), (2) support network (family/friends, service providers), (3) financial capacity, environment (eg, geographical distance to unit) and life responsibilities (eg, caring for others). Patients reported poor provision of CKD information and lack of choice in treatment, whereas kidney care team members discussed health literacy issues. Patients reported having to withdraw from social activities and loss of employment due to CKD, which further impacted their capacity., Conclusion: Improved understanding of and measures to reduce the treatment burden (eg, clear information, simplified medication, joined up care, free parking) associated with CKD in individuals as well as assessment of their capacity and interventions to improve capacity (social care, psychological support) will likely improve patient experience and their engagement with kidney care services., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic cough is a distressing symptom for many people with pulmonary sarcoidosis. Continuous treatment with a macrolide antibiotic may improve cough. We aimed to assess the potential efficacy of azithromycin in patients with sarcoidosis and self-reported cough., Methods: We conducted a noncontrolled, open-label clinical trial of azithromycin 250 mg once daily for 3 months in patients with pulmonary sarcoidosis who reported a chronic cough. The primary outcome was number of coughs in 24 h. Secondary outcomes were cough visual analogue scales and quality of life measured using the Leicester Cough Questionnaire and King's Sarcoidosis Questionnaire. Safety outcomes included QTc interval on ECG. Measurements were made at baseline and after 1 and 3 months of treatment., Results: All 21 patients were white, median age 57 years, 9 males, 12 females, median 3 years since diagnosis. Five were taking oral corticosteroids and none were taking other immunosuppressants. Twenty patients completed the trial. The median (range) number of coughs in 24 h was 228 (43-1950) at baseline, 122 (20-704) at 1 month, and 81 (16-414) at 3 months (p=0.002, Friedman's test). The median reduction in cough count at 3 months was 49.6%. There were improvements in all patient-reported outcomes. Azithromycin was well tolerated., Conclusion: In a noncontrolled open-label trial in people with sarcoidosis who reported a chronic cough, 3 months of treatment with azithromycin led to improvements in a range of cough metrics. Azithromycin should be tested as a treatment for sarcoidosis cough in a randomised placebo-controlled trial., Competing Interests: Conflict of interest: S.D. Fraser reports grants from SarcoidosisUK during the conduct of the study. Conflict of interest: S. Thackray-Nocera has nothing to disclose. Conflict of interest: M. Shepherd has nothing to disclose. Conflict of interest: R. Flockton has nothing to disclose. Conflict of interest: C. Wright has nothing to disclose. Conflict of interest: W. Sheedy has nothing to disclose. Conflict of interest: K. Brindle has nothing to disclose. Conflict of interest: A.H. Morice has nothing to disclose. Conflict of interest: P.M. Kaye reports grants from SarcoidosisUK during the conduct of the study. Conflict of interest: M.G. Crooks reports grants from SarcoidosisUK during the conduct of the study. Conflict of interest: S.P. Hart reports grants from SarcoidosisUK during the conduct of the study., (Copyright ©ERS 2020.)

Objectives: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care., Design: Cross-sectional analysis at 5-year follow-up in a prospective cohort study., Setting: Thirty-two general practitioner surgeries in England., Participants: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5 years and had complete follow-up data for HRQoL and functional status (FS)., Primary and Secondary Outcome Measures: HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ≤70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result., Results: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p<0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p<0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p<0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p<0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p<0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend <0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend <0.001)), and for obese (body mass index (BMI) ≥30 kg/m 2 ) versus BMI <25 kg/m 2 : (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend <0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend <0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p<0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (≥30 mg/mmol vs <3 mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p<0.001), 2.18 (95% CI 0.80 to 5.96, p for trend <0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend <0.001) and 4.23 (95% CI 2.48 to 7.20), respectively)., Conclusions: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment., Trial Registration Number: National Institute for Health Research Clinical Research Portfolio Study Number 6632., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Purpose: There is currently no true macrophage cell line and in vitro experiments requiring these cells currently require mitogenic stimulation of a macrophage precursor cell line (THP-1) or ex vivo maturation of circulating primary monocytes. In this study, we characterise a human macrophage cell line, derived from THP-1 cells, and compare its phenotype to the THP-1 cells., Methods: THP-1 cells with and without mitogenic stimulation were compared to the newly derived macrophage-like cell line (Daisy) using microscopy, flow cytometry, phagocytosis assays, antigen binding assays and gene microarrays., Results: We show that the cell line grows predominantly in an adherent monolayer. A panel of antibodies were chosen to investigate the cell surface phenotype of these cells using flow cytometry. Daisy cells expressed more CD11c, CD80, CD163, CD169 and CD206, but less CD14 and CD11b compared with mitogen-stimulated THP-1 cells. Unlike stimulated THP-1 cells which were barely able to bind immune complexes, Daisy cells showed large amounts of immune complex binding. Finally, although not statistically significant, the phagocytic ability of Daisy cells was greater than mitogen-stimulated THP-1 cells, suggesting that the cell line is more similar to mature macrophages., Conclusions: The observed phenotype suggests that Daisy cells are a good model of human macrophages with a phenotype similar to human alveolar macrophages.

Aim: To examine international time trends in the incidence of renal replacement therapy (RRT) for end-stage renal disease (ESRD) by primary renal disease (PRD)., Methods: Renal registries reporting on patients starting RRT per million population for ESRD by PRD from 2005 to 2014, were identified by internet search and literature review. The average annual percentage change (AAPC) with a 95% confidence interval (CI) of the time trends was computed using Joinpoint regression., Results: There was a significant decrease in the incidence of RRT for ESRD due to diabetes mellitus (DM) in Europe (AAPC = -0.9; 95%CI -1.3; -0.5) and to hypertension/renal vascular disease (HT/RVD) in Australia (AAPC = -1.8; 95%CI -3.3; -0.3), Canada (AAPC = -2.9; 95%CI -4.4; -1.5) and Europe (AAPC = -1.1; 95%CI -2.1; -0.0). A decrease or stabilization was observed for glomerulonephritis in all regions and for autosomal dominant polycystic kidney disease (ADPKD) in all regions except for Malaysia and the Republic of Korea. An increase of 5.2-16.3% was observed for DM, HT/RVD and ADPKD in Malaysia and the Republic of Korea., Conclusion: Large international differences exist in the trends in incidence of RRT by primary renal disease. Mapping of these international trends is the first step in defining the causes and successful preventative measures of CKD., (© 2018 Asian Pacific Society of Nephrology.)

IPF biomarker improved by ICS/LABA http://ow.ly/CHub30gzHry., Competing Interests: Conflicts of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Large observational databases linking kidney function and other routine patient health data are increasingly being used to study acute kidney injury (AKI). Routine health care data show an apparent rise in the incidence of population AKI and an increase in acute dialysis. Studies also report an excess in mortality and adverse renal outcomes after AKI, although with variation depending on AKI severity, baseline, definition of renal recovery, and the time point during follow-up. However, differences in data capture, AKI awareness, monitoring, recognition, and clinical practice make comparisons between health care settings and periods difficult. In this review, we describe the growing role of large databases in determining the incidence and prognosis of AKI and evaluating initiatives to improve the quality of care in AKI. Using examples, we illustrate this use of routinely collected health data and discuss the strengths, limitations, and implications for researchers and clinicians., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

In sarcoidosis, the proinflammatory cytokines interferon gamma, tumour necrosis factor and interleukin-6 are released by monocyte-derived macrophages and lymphocytes in the lungs and other affected tissues. Regulatory receptors expressed on monocytes and macrophages act to suppress cytokine production, and reduced expression of regulatory receptors may thus promote tissue inflammation. The aim of this study was to characterise the role of regulatory receptors on blood monocytes in patients with sarcoidosis. Cytokine release in response to stimulation of whole blood was measured in healthy controls and Caucasian non-smoking patients with sarcoidosis who were not taking disease modifying therapy. Expression of the regulatory molecules IL-10R, SIRP-α/β, CD47, CD200R, and CD200L was measured by flow cytometry, and functional activity was assessed using blocking antibodies. Stimulated whole blood and monocytes from patients with sarcoidosis produced more TNF and IL-6 compared with healthy controls. 52.9% of sarcoidosis patients had monocytes characterised by low expression of CD200R, compared with 11.7% of controls (p < 0.0001). Patients with low monocyte CD200R expression produced higher levels of proinflammatory cytokines. In functional studies, blocking the CD200 axis increased production of TNF and IL-6. Reduced expression of CD200R on monocytes may be a mechanism contributing to monocyte and macrophage hyper-activation in sarcoidosis.

Purpose of Review: With ageing populations, the prevalence of multimorbidity is increasing. This review discusses recent developments in the understanding of multimorbidity in the context of chronic kidney disease (CKD). It explores the associated treatment burden and the implications for key outcomes and patient care., Recent Findings: Comorbidity and polypharmacy are common in CKD, even at early stages, and are associated with significant treatment burden. Both 'concordant' and 'discordant' comorbidities have a negative impact on mortality, cardiovascular disease, hospitalisation and length of stay. In addition, quality of life is influenced by many factors beyond CKD, including comorbidities and certain medications. Several factors may reduce treatment burden for people with CKD, though research on this is at an early stage. Although patient activation is desirable to support self-management amongst people with multimorbidity, there are significant challenges that impact patient capacity amongst elderly populations with complex needs., Summary: Comorbidities are common in CKD and have important implications for patients, clinicians and health services.

Chronic kidney disease (CKD) is an important and common noncommunicable condition globally. In national and international guidelines, CKD is defined and staged according to measures of kidney function that allow for a degree of risk stratification using commonly available markers. It is often asymptomatic in its early stages, and early detection is important to reduce future risk. The risk of cardiovascular outcomes is greater than the risk of progression to end-stage kidney disease for most people with CKD. CKD also predisposes to acute kidney injury - a major cause of morbidity and mortality worldwide. Although only a small proportion of people with CKD progress to end-stage kidney disease, renal replacement therapy (dialysis or transplantation) represents major costs for health care systems and burden for patients. Efforts in primary care to reduce the risks of cardiovascular disease, acute kidney injury, and progression are therefore required. Monitoring renal function is an important task, and primary care clinicians are well placed to oversee this aspect of care along with the management of modifiable risk factors, particularly blood pressure and proteinuria. Good primary care judgment is also essential in making decisions about referral for specialist nephrology opinion. As CKD commonly occurs alongside other conditions, consideration of comorbidities and patient wishes is important, and primary care clinicians have a key role in coordinating care while adopting a holistic, patient-centered approach and providing continuity. This review aims to summarize the vital role that primary care plays in predialysis CKD care and to outline the main considerations in its identification, monitoring, and clinical management in this context., Competing Interests: The authors report no conflicts of interest in this work.

Background: Early recognition of acute kidney injury (AKI) is important. It frequently develops first in the community. KDIGO-based AKI e-alert criteria may help clinicians recognize AKI in hospitals, but their suitability for application in the community is unknown., Methods: In a large renal cohort (n = 50 835) in one UK health authority, we applied the NHS England AKI 'e-alert' criteria to identify and follow three AKI groups: hospital-acquired AKI (HA-AKI), community-acquired AKI admitted to hospital within 7 days (CAA-AKI) and community-acquired AKI not admitted within 7 days (CANA-AKI). We assessed how AKI criteria operated in each group, based on prior blood tests (number and time lag). We compared 30-day, 1- and 5-year mortality, 90-day renal recovery and chronic renal replacement therapy (RRT)., Results: In total, 4550 patients met AKI e-alert criteria, 61.1% (2779/4550) with HA-AKI, 22.9% (1042/4550) with CAA-AKI and 16.0% (729/4550) with CANA-AKI. The median number of days since last blood test differed between groups (1, 52 and 69 days, respectively). Thirty-day mortality was similar for HA-AKI and CAA-AKI, but significantly lower for CANA-AKI (24.2, 20.2 and 2.6%, respectively). Five-year mortality was high in all groups, but followed a similar pattern (67.1, 64.7 and 46.2%). Differences in 5-year mortality among those not admitted could be explained by adjusting for comorbidities and restricting to 30-day survivors (hazard ratio 0.91, 95% confidence interval 0.80-1.04, versus hospital AKI). Those with CANA-AKI (versus CAA-AKI) had greater non-recovery at 90 days (11.8 versus 3.5%, P < 0.001) and chronic RRT at 5 years (3.7 versus 1.2%, P < 0.001)., Conclusions: KDIGO-based AKI criteria operate differently in hospitals and in the community. Some patients may not require immediate admission but are at substantial risk of a poor long-term outcome., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Multimorbidity is a growing concern for healthcare systems, with many countries experiencing demographic transition to older population profiles. Chronic kidney disease (CKD) is common but often considered in isolation. The extent and prognostic significance of its comorbidities is not well understood. This study aimed to assess the extent and prognostic significance of 11 comorbidities in people with CKD stage 3., Methods: A prospective cohort of 1741 people with CKD stage 3 was recruited from primary care between August 2008 and March 2010. Participants underwent medical history, clinical assessment, blood and urine sampling. Comorbidity was defined by self-reported doctor-diagnosed condition, disease-specific medication or blood results (hemoglobin), and treatment burden as number of ongoing medications. Logistic regression was used to identify associations with greater treatment burden (taking >5 medications) and greater multimorbidity (3 or more comorbidities). Kaplan Meier plots and multivariate Cox proportional hazards models were used to investigate associations between multimorbidity and all-cause mortality., Results: One thousand seven hundred forty-one people were recruited, mean age 72.9 +/-9 years. Mean baseline eGFR was 52 ml/min/1.73 m(2). Only 78/1741 (4 %) had no comorbidities, 453/1741 (26 %) had one, 508/1741 (29 %) had two and 702/1741 (40 %) had >2. Hypertension was common (88 %), 30 % had 'painful condition', 24 % anemia, 23 %, ischaemic heart disease, 17 % diabetes and 12 % thyroid disorders. Median medication use was 5 medications (interquartile range 3-8) and increased with degree of comorbidity. Greater treatment burden and multimorbidity were independently associated with age, smoking, increasing body mass index and decreasing eGFR. Treatment burden was also independently associated with lower education status. After median 3.6 years follow-up, 175/1741 (10 %) died. Greater multimorbidity was independently associated with mortality (hazard ratio 2.81 (95 % confidence intervals 1.72-4.58), p < 0.001) for 3 or more comorbidities vs 0 or 1)., Conclusions: Isolated CKD was rare and multimorbidity the norm in this cohort of people with moderate CKD. Increasing multimorbidity was associated with greater medication burden and poorer survival. CKD management should include consideration of comorbidities.

Background: Chronic kidney disease (CKD) diagnosis relies on glomerular filtration rate (eGFR) estimation, traditionally using the creatinine-based Modification of Diet in Renal Disease (MDRD) equation. The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation performs better in estimating eGFR and predicting mortality and CKD progression risk. Cystatin C is an alternative glomerular filtration marker less influenced by muscle mass. CKD risk stratification is improved by combining creatinine eGFR with cystatin C and urinary albumin to creatinine ratio (uACR). We aimed to identify the impact of introducing CKDEPI and cystatin C on the estimated prevalence and risk stratification of CKD in England and to describe prevalence and associations of cystatin C., Methods and Findings: Cross sectional study of 5799 people in the nationally representative 2009 and 2010 Health Surveys for England., Primary Outcome Measures: prevalence of MDRD, CKDEPI and cystatin C-defined eGFR<60 ml/min/1.73 m(2); prevalence of CKD biomarker combinations (creatinine, cystatin C, uACR). Using CKDEPI instead of MDRD reduced the prevalence of eGFR<60 ml/min/1.73 m(2) from 6.0% (95% CI 5.4-6.6%) to 5.2% (4.7-5.8%) equivalent to around 340,000 fewer individuals in England. Those reclassified as not having CKD evidenced a lower risk profile. Prevalence of cystatin C eGFR<60 ml/min/1.73 m(2) was 7.7% and independently associated with age, lack of qualifications, being an ex-smoker, BMI, hypertension, and albuminuria. Measuring cystatin C in the 3.9% people with CKDEPI-defined eGFR<60 ml/min/1.73 m(2) without albuminuria (CKD Category G3a A1) reclassified about a third into a lower risk group with one of three biomarkers and two thirds into a group with two of three. Measuring cystatin C in the 6.7% people with CKDEPI eGFR >60 ml/min/1.73 m(2) with albuminuria (CKD Category G1-2) reclassified almost a tenth into a higher risk group., Limitations: Cross sectional study, single eGFR measure, no measured ('true') GFR., Conclusions: Introducing the CKDEPI equation and targeted cystatin C measurement reduces estimated CKD prevalence and improves risk stratification.

Background: Chronic kidney disease (CKD) is predominantly managed in primary care in the UK, but there is evidence of under-identification leading to lack of inclusion on practice chronic disease registers, which are necessary to ensure disease monitoring. Guidelines for CKD patients recommend urinary albumin to creatinine ratio (uACR) testing to identify albuminuria to stratify risk and guide management. This study aimed to describe the pattern and associations of timely CKD registration and uACR testing., Methods: A retrospective cohort of individuals with incident CKD 3-5 (two estimated glomerular filtration rates (eGFR) <60 ml/min/1.73 m(2) ≥ three months apart) between 2007 and 2013 was identified from a linked database containing primary and secondary care data. Descriptive statistics and Cox proportional hazards models were used to identify associations with patient characteristics of timely CKD registration and uACR testing (within a year of first low eGFR)., Results: 12,988 people with CKD 3-5 were identified from 88 practices and followed for median 3.3 years. During this time period, 3235 (24.9%) were CKD-registered and 4638/12,988 (35.7%) had uACR testing (median time to CKD registration 307 days and to uACR test 379 days). 1829 (14.1%) were CKD-registered and 2229 (17.2%) had uACR testing within one year. Amongst people whose CKD was registered within a year, 676/1829 (37.0%) had uACR testing within a year (vs. 1553/11,159 (13.9%) of those not registered (p < 0.001)). Timely uACR testing varied by year, with a sharp rise in proportion in 2009 (when uACR policy changed). Timely CKD registration was independently associated with lower eGFR, being female, earlier year of joining the cohort, having diabetes, hypertension, or cardiovascular disease but not with age. Timely uACR testing was associated with timely CKD registration, younger age, having diabetes, higher baseline eGFR and later year of joining the cohort., Conclusions: Better systems are needed to support timely CKD identification, registration and uACR testing in primary care in order to facilitate risk stratification and appropriate clinical management.

Background: Renal replacement therapy rates are inversely related to socioeconomic status (SES) in developed countries. The relationship between chronic kidney disease (CKD) and SES is less clear. This study examined the relationships between SES and CKD and albuminuria in England., Methods: Data from the Health Survey for England 2009 and 2010 were combined. The prevalence of CKD 3-5 and albuminuria was calculated, and logistic regression used to determine their association with five individual-level measures and one area-level measure of SES., Results: The prevalence of CKD 3-5 was 5.2% and albuminuria 8.0%. Age-sex-adjusted CKD 3-5 was associated with lack of qualifications [odds ratio (OR) 2.27 (95% confidence interval 1.40-3.69)], low income [OR 1.50 (1.02-2.21)] and renting tenure [OR 1.36 (1.01-1.84)]. Only tenure remained significant in fully adjusted models suggesting that co-variables were on the causal pathway. Albuminuria remained associated with several SES measures on full adjustment: low income [OR 1.55 (1.14-2.11)], no vehicle [OR 1.38 (1.05-1.81)], renting [OR 1.31 [1.03-1.67)] and most deprived area-level quintile [OR 1.55 (1.07-2.25)]., Conclusions: CKD 3-5 and albuminuria were associated with low SES using several measures. For albuminuria this was not explained by known measured causal factors., (© The Author 2013. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Novel markers may help to improve risk prediction in CKD. One potential candidate is tissue advanced glycation end product accumulation, a marker of cumulative metabolic stress, which can be assessed by a simple noninvasive measurement of skin autofluorescence. Skin autofluorescence correlates with higher risk of cardiovascular events and mortality in people with diabetes or people requiring RRT, but its role in earlier CKD has not been studied., Design, Setting, Participants, & Measurements: A prospective cohort of 1741 people with CKD stage 3 was recruited from primary care between August 2008 and March 2010. Participants underwent medical history, clinical assessment, blood and urine sampling for biochemistry, and measurement of skin autofluorescence. Kaplan-Meier plots and multivariate Cox proportional hazards models were used to investigate associations between skin autofluorescence (categorical in quartiles) and all-cause mortality., Results: In total, 1707 participants had skin autofluorescence measured; 170 (10%) participants died after a median of 3.6 years of follow-up. The most common cause of death was cardiovascular disease (41%). Higher skin autofluorescence was associated significantly with poorer survival (all-cause mortality, P<0.001) on Kaplan-Meier analysis. Univariate and age/sex-adjusted Cox proportional hazards models showed that the highest quartile of skin autofluorescence was associated with all-cause mortality (hazard ratio, 2.64; 95% confidence interval, 1.71 to 4.08; P<0.001 and hazard ratio, 1.84; 95% confidence interval, 1.18 to 2.86; P=0.003, respectively, compared with the lowest quartile). This association was not maintained after additional adjustment to include cardiovascular disease, diabetes, smoking, body mass index, eGFR, albuminuria, and hemoglobin., Conclusions: Skin autofluorescence was not independently associated with all-cause mortality in this study. Additional research is needed to clarify whether it has a role in risk prediction in CKD., (Copyright © 2014 by the American Society of Nephrology.)

Background and Objective: Proteinuria assessment is key in investigating chronic kidney disease (CKD) but uncertainty exists regarding optimal methods. Albuminuria, reflecting glomerular damage, is usually measured, but non-albumin proteinuria (NAP), reflecting tubular damage, may be important. This study investigated the prevalence and associations of albuminuria and NAP, and the optimum number of urine specimens required., Methods: 1,741 patients with CKD stage 3, recruited from primary care, underwent medical history, clinical assessment, blood sampling, and submitted three early morning urine samples for albumin to creatinine ratio (uACR) and protein to creatinine ratios (uPCR). Albuminuria was defined as uACR ≥ 3 mg/mmol in at least two of three samples. Isolated NAP was defined as uPCR ≥ 17 mg/mmol in two of three samples and uACR <3 mg/mmol in all three. Prevalence and associations of albuminuria and NAP, degree of agreement between single uACR and average of three uACRs, and urine albumin to protein ratio (uAPR  =  uACR/uPCR) were identified., Results: Albuminuria prevalence was 16% and NAP 6%. Using a <1 mg/mmol threshold for uACR reduced NAP prevalence to 3.6%. Independent associations of albuminuria were: males (OR 3.06 (95% CI, 2.23-4.19)), diabetes (OR 2.14 (1.53-3.00)), lower estimated glomerular filtration rate ((OR 2.06 (1.48-2.85) 30-44 vs 45-59), and high sensitivity CRP ((OR 1.70 (1.25-2.32)). NAP was independently associated with females (OR 6.79 (3.48-13.26)), age (OR 1.62 (1.02-2.56) 80 s vs 70-79) and high sensitivity CRP ((OR 1.74 (1.14-2.66)). Of those with uPCR ≥ 17 mg/mmol, 62% had uAPR<0.4. Sensitivity of single uACR was 95%, specificity 98%, PPV 90%. Bland Altman plot one vs average of three uACRs showed: mean difference 0.0064 mg/mmol (SD 4.69, limits of agreement -9.19 to +9.20, absolute mean difference 0.837)., Conclusions: In CKD stage 3, albuminuria has associations distinct from those of isolated NAP (except for inflammatory markers). Single uACR categorised albuminuria but average of three performed better for quantification.

Background: Poorly controlled hypertension is independently associated with mortality, cardiovascular risk and disease progression in chronic kidney disease (CKD). In the UK, CKD stage 3 is principally managed in primary care, including blood pressure (BP) management. Controlling BP is key to improving outcomes in CKD. This study aimed to investigate associations of BP control in people with CKD stage 3., Methods: 1,741 patients with CKD 3 recruited from 32 general practices for the Renal Risk in Derby Study underwent medical history, clinical assessment and biochemistry testing. BP control was assessed by three standards: National Institute for Health and Clinical Excellence (NICE), National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Descriptive statistics were used to compare characteristics of people achieving and not achieving BP control. Univariate and multivariate logistic regression was used to identify factors associated with BP control., Results: The prevalence of hypertension was 88%. Among people with hypertension, 829/1426 (58.1%) achieved NICE BP targets, 512/1426 (35.9%) KDOQI targets and 859/1426 (60.2%) KDIGO targets. Smaller proportions of people with diabetes and/or albuminuria achieved hypertension targets. 615/1426 (43.1%) were only taking one antihypertensive agent. On multivariable analysis, BP control (NICE and KDIGO) was negatively associated with age (NICE odds ratio (OR) 0.27; 95% confidence interval (95% CI) 0.17-0.43) 70-79 compared to <60), diabetes (OR 0.32; 95% CI 0.25-0.43)), and albuminuria (OR 0.56; 95% CI 0.42-0.74)). For the KDOQI target, there was also association with males (OR 0.76; 95% CI 0.60-0.96)) but not diabetes (target not diabetes specific). Older people were less likely to achieve systolic targets (NICE target OR 0.17 (95% CI 0.09,0.32) p < 0.001) and more likely to achieve diastolic targets (OR 2.35 (95% CI 1.11,4.96) p < 0.001) for people >80 compared to < 60)., Conclusions: Suboptimal BP control was common in CKD patients with hypertension in this study, particularly those at highest risk of adverse outcomes due to diabetes and or albuminuria. This study suggests there is scope for improving BP control in people with CKD by using more antihypertensive agents in combination while considering issues of adherence and potential side effects.

Background: Health literacy (HL) is important in chronic disease. This review aimed to evaluate the literature evidence on prevalence and associations of limited HL in chronic kidney disease (CKD)., Methods: Seven databases were searched using terms for CKD and HL. Studies were included that ascertained the prevalence of limited HL using a validated tool in adults with CKD of any stage. The primary outcome was an objectively measured prevalence of limited HL in a population with CKD. The secondary outcome was associations of limited HL. Two reviewers assessed study inclusion and quality. Prevalence values were combined using a random-effect model to give overall prevalence., Results: Eighty-two studies were identified from searching, of which six met the inclusion criteria. The total number of people in all studies was 1405. Five studies were in dialysis or transplant populations, and all were from the USA. There was a significant heterogeneity in the prevalence of limited HL [9-32% (median 25%, inter-quartile range 16%)]. The pooled prevalence of limited HL in all studies was 22.7% (95% confidence interval 20.6-24.8%), but study heterogeneity limited the generalizability of this combined prevalence. The review identified associations between limited HL and socio-economic factors (lower education attainment, lower income), and certain process and outcome measures (lower likelihood of referral for transplant, higher mortality)., Conclusions: Limited HL is common among people with CKD and independently associated with socio-economic factors and health outcomes. It may represent an important determinant of inequality in CKD.

This article presents a novel application of small and wide angle X-ray scattering (SWAXS) in the assessment of aspirin and lactose content in a binary pharmaceutical powder formulation. It is shown that the content correlates with the intensity of the SAXS signal and the intensity of polymorph fingerprints in the WAXS spectra that are collected from the same samples. Because the polymorph WAXS fingerprints and the SAXS signal are two independent characteristics of the same sample, simultaneous SWAXS analysis provides the basis for a dual independent assessment of the same contents., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background/aims: For most people with chronic kidney disease (CKD), cardiovascular disease (CVD) risk exceeds risk of progression to end-stage renal disease. This study aimed to investigate the distribution of cardiovascular risk in CKD stage 3 by socio-economic status (SES; measured by area deprivation and educational attainment) and CKD diagnosis awareness., Methods: 1,741 patients with CKD 3 recruited from primary-care practices for the Renal Risk in Derby Study were assessed for cardiovascular risk factors. Ten-year cardiovascular risk, estimated using Framingham and QRISK2 risk prediction algorithms in eligible subgroups, was dichotomised at ≥ 20% (a threshold for clinical action in the UK), and compared by SES and awareness of CKD diagnosis using logistic regression., Results: Patients with lower SES had greater adjusted odd ratios (OR) of smoking, diabetes and previous CVD, but not of central obesity, hypertension, elevated total/high-density-lipoprotein cholesterol ratio or albuminuria. Using Framingham scoring (n = 672), the adjusted OR of having ≥ 20% 10-year risk were 2.87 [95% confidence interval (CI) 1.41-5.84] in the lowest deprivation quintile compared to the highest, 2.52 (95% CI: 1.52-4.00) in those without qualifications compared to those with qualifications, and 1.54 (95% CI: 1.09-2.17) in those unaware of their CKD diagnosis compared to those aware of it. QRISK2 scoring (n = 1,071) showed a similar association with education status [OR: 2.45 (95% CI: 1.63-3.67)] and lack of CKD awareness [OR: 1.46 (95% CI: 1.05-2.03)], but not with deprivation [OR: 1.12 (95% CI: 0.55-2.27)]., Conclusion: An elevated CVD risk is associated with a lower education status and lack of awareness of CKD diagnosis in people with CKD 3., (Copyright © 2013 S. Karger AG, Basel.)

Background: Active transport policies are being developed across Europe designed to have health and environmental benefits. There is little evidence of impact on physical activity of active transport strategies which modify the built environment. Cycling represents one virtually carbon-neutral form of transport that can help to address declining levels of exercise., Methods: A systematic literature review of experimental or observational studies that objectively evaluated the effect of the built environment on cycling., Results: A total of 21 studies met the inclusion criteria, all of which were observational studies. Eleven studies identified objectively measured environmental factors with a significant positive association with cycling. The environmental factors identified as being positively associated with cycling included presence of dedicated cycle routes or paths, separation of cycling from other traffic, high population density, short trip distance, proximity of a cycle path or green space and for children projects promoting 'safe routes to school'. Negative environmental factors were perceived and objective traffic danger, long trip distance, steep inclines and distance from cycle paths. Of the seven studies which focused primarily on the impact of cycle routes, four demonstrated a statistically significant positive association., Conclusion: Although the study identified environmental factors with positive and negative associations with cycling behaviour, many other types of environmental policies and interventions have yet to be rigorously evaluated. Policies promoting cycle lane construction appear promising but the socio-demographic distribution of their effects on physical activity is unclear. The wider impact of active transport policies on health and inequalities across Europe must be explored.

The vasculature tailors to the needs of different tissues and organs. Molecular, structural, and functional specializations are observed in different vascular beds, but few genetic models give insight into how these differences arise. We identify a unique cerebrovascular mutation in the zebrafish affecting the integrity of blood vessels supplying the brain. The zebrafish bubblehead (bbh) mutant exhibits hydrocephalus and severe cranial hemorrhage during early embryogenesis, whereas blood vessels in other regions of the embryo appear intact. Here we show that hemorrhages are associated with poor cerebral endothelial-mesenchymal contacts and an immature vascular pattern in the head. Positional cloning of bbh reveals a hypomorphic mutation in betaPix, a binding partner for the p21-activated kinase (Pak) and a guanine nucleotide exchange factor for Rac and Cdc42. betaPix is broadly expressed during embryonic development and is enriched in the brain and in large blood vessels. By knockdown of specific betaPix splice variants, we show that they play unique roles in embryonic vascular stabilization or hydrocephalus. Finally, we show that Pak2a signaling is downstream of betaPix. These data identify an essential in vivo role for betaPix and Pak2a during embryonic development and illuminate a previously unrecognized pathway specifically involved in cerebrovascular stabilization.

Major vessels of the vertebrate circulatory system display evolutionarily conserved and reproducible anatomy, but the cues guiding this stereotypic patterning remain obscure. In the nervous system, axonal pathways are shaped by repulsive cues provided by ligands of the semaphorin family that are sensed by migrating neuronal growth cones through plexin receptors. We show that proper blood vessel pathfinding requires the endothelial receptor PlexinD1 and semaphorin signals, and we identify mutations in plexinD1 in the zebrafish vascular patterning mutant out of bounds. These results reveal the fundamental conservation of repulsive patterning mechanisms between axonal migration in the central nervous system and vascular endothelium during angiogenesis.

Exon enhancers are accessory pre-mRNA splicing signals that stimulate exon splicing. One class of proteins, the serine-arginine-rich (SR) proteins, have been demonstrated to bind enhancers and activate splicing. Here we report that A/C-rich exon enhancers (ACE elements) are recognized by the human YB-1 protein, a non-SR protein. Sequence-specific binding of YB-1 was observed both to an ACE derived from an in vivo iterative selection protocol and to ACE elements in an alternative exon (v4) from the human CD44 gene. The ACE element that was the predominant YB-1 binding site in CD44 exon v4 was required for maximal in vivo splicing and in vitro spliceosome assembly. Expression of wild-type YB-1 increased inclusion of exon v4, whereas a truncated form of YB-1 did not. Stimulation of exon v4 inclusion by wild-type YB-1 required the ACE necessary for YB-1 binding in vitro, suggesting that YB-1 stimulated exon inclusion in vivo by binding to an exonic ACE element. These observations identify a protein in addition to SR proteins that participates in the recognition of exon enhancers.

Expression of messenger RNA (mRNA) in both embryonic and adult cells may be profoundly influenced by untranslated sequences in the 3'-end. Elements in the 3'-untranslated regions (UTRs) of messengers are known to influence messenger stability, polyadenylation, and translation. We have examined the effects of the 3'-UTR of Xenopus laevis c-mycI (either alone or in combination with the 5'-first exon) on the expression of a chloramphenicol acetyltransferase (CAT) reporter in Xenopus embryos. The Xenopus c-mycI 3'-UTR enhanced messenger translation independent of the 5'-UTR. RNase H analysis indicated that the Xenopus c-mycI 3'-UTR can promote the cytoplasmic polyadenylation of CAT mRNA in embryos. The result suggests that the post-fertilization enhancement of translation caused by the c-mycI 3'-UTR may be a consequence of cytoplasmic polyadenylation. A uridine (U)-rich sequence in the Xenopus c-mycI 3'-UTR that may be responsible for polyadenylation is similar to an element that destabilizes mammalian c-myc transcripts. We discuss the possibility that U-rich sequences may play a dual role by destabilizing growth-related transcripts in adult cells and stimulating their polyadenylation during development, and we propose that a switch in the role of such sequences in adult cells could lead to stabilization of these messengers, increased translation, and abnormal growth control.

We have investigated the effects of 3' noncoding elements in enhancing translation of messengers having translation-inhibiting 5' untranslated regions (UTRs). The translation of transcripts bearing the 5' UTRs of either human c-myc or a synthetic hairpin structure upstream of a chloramphenicol acetyltransferase (CAT) reporter sequence is greatly attenuated in early embryos of Xenopus laevis. Translation of transcripts bearing the human c-myc-5' UTR was markedly stimulated by the presence of 3' poly(A). Transcripts bearing the 5' hairpin element were insensitive to the presence of poly(A), but they were extremely sensitive to the composition of the 3' UTR. A GC-rich distal sequence repressed translation, whereas a proximal GGAAU sequence promoted translation of these transcripts. Our results support the concept that long-range interactions between the 5' and 3' ends of transcripts are important in regulating translation in Xenopus embryos.