Maintaining musculoskeletal health using a behavioural therapy approach: a population-based randomised controlled trial (the MAmMOTH Study).

OBJECTIVE: Cognitive-behavioural therapy (CBT) has been shown to be effective in the management of chronic widespread pain (CWP); we now test whether it can prevent onset among adults at high risk. METHODS: A population-based randomised controlled prevention trial, with recruitment through UK general practices. A mailed screening questionnaire identified adults at high risk of CWP. Participants received either usual care (UC) or a short course of telephone CBT (tCBT). The primary outcome was CWP onset at 12 months assessed by mailed questionnaire. There were seven secondary outcomes including quality of life (EuroQol Questionnaire-five dimensions-five levels/EQ-5D-5L) used as part of a health economic assessment. RESULTS: 996 participants were randomised and included in the intention-to-treat analysis of which 825 provided primary outcome data. The median age of participants was 59 years; 59% were women. At 12 months there was no difference in the onset of CWP (tCBT: 18.0% vs UC: 17.5%; OR 1.05; 95% CI 0.75 to 1.48). Participants who received tCBT were more likely to report better quality of life (EQ-5D-5L utility score mean difference 0.024 (95% CI 0.009 to 0.040)); and had 0.023 (95% CI 0.007 to 0.039) more quality-adjusted life-years at an additional cost of £42.30 (95% CI -£451.19 to £597.90), yielding an incremental cost-effectiveness ratio of £1828. Most secondary outcomes showed significant benefit for the intervention. CONCLUSIONS: A short course of tCBT did not prevent onset of CWP in adults at high risk, but improved quality of life and was cost-effective. A low-cost, short-duration intervention benefits persons at risk of CWP. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02668003).

Defining and measuring multimorbidity: a systematic review of systematic reviews.

Background: Multimorbidity, the coexistence of multiple health conditions, is a growing public health challenge. Research and intervention development are hampered by the lack of consensus regarding defining and measuring multimorbidity. The aim of this systematic review was to pool the findings of systematic reviews examining definitions and measures of multimorbidity. Methods: Medline, Embase, PubMed and Cochrane were searched from database inception to February 2017. Two authors independently screened titles, abstracts and full texts and extracted data from the included papers. Disagreements were resolved with a third author. Reviews were quality assessed. Results: Of six reviews, two focussed on definitions and four on measures. Multimorbidity was commonly defined as the presence of multiple diseases or conditions, often with a cut-off of two or more. One review developed a holistic definition including biopsychosocial and somatic factors as well as disease. Reviews recommended using measures validated for the outcome of interest. Disease counts are an alternative if no validated measure exists. Conclusions: To enable comparison between studies and settings, researchers and practitioners should be explicit about their choice of definition and measure. Using a cut-off of two or more conditions as part of the definition is widely adopted. Measure selection should be based on tools validated for the outcome being considered. Where there is no validated measure, or where multiple outcomes or populations are being considered, disease counts are appropriate.

Development of Risk Prediction Equations for Incident Chronic Kidney Disease.

Importance: Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions. Objective: To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR). Design, Setting, and Participants: Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540). Exposures: Demographic and clinical factors. Main Outcomes and Measures: Incident eGFR of less than 60 mL/min/1.73 m2. Results: Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25. Conclusions and Relevance: Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

Geographical mobility of UK trainee doctors, from family home to first job: a national cohort study.

BACKGROUND: The UK faces geographical variation in the recruitment of doctors. Understanding where medical graduates choose to go for training is important because doctors are more likely to consider practicing in areas where they completed postgraduate training. The wider literature also suggests that there is a relationship between origin and background, and where doctors wish to train/work. Thus, the purpose of this paper is to investigate the geographical mobility of UK medical graduates from different socio-economic groups in terms of where they wish to spend their first years of postgraduate training. METHODS: This was an observational study of Foundation Programme (FP) doctors who graduated from 33 UK medical schools between 2012 and 2014. Data was accessed via the UK medical education database (UKMED: https://www.ukmed.ac.uk/ ). Chi-square tests were used to examine the relationships between doctor's sociodemographic characteristics and the dependent variable, average driving time from parental home to foundation school/region. Generalised Linear Mixed Models (GLMM) were used to estimate the effects of those factors in combination against the outcome measure. RESULTS: The majority of doctors prefer to train at foundation schools that are reasonably close to the family home. Those who attended state-funded schools, from non-white ethnic groups and/or from lower socio-economic groups were significantly more likely to choose foundation schools nearer their parental home. Doctors from disadvantaged backgrounds (as determined by entitlement to free school meals, OR = 1.29, p = 0.003 and no parental degree, OR = 1.34, p < 0.001) were associated with higher odds of selecting a foundation schools that were closer to parental home. CONCLUSION: The data suggests that recruiting medical students from lower socioeconomic groups and those who originate from under-recruiting areas may be at least part of the solution to filling training posts in these areas. This has obvious implications for the widening access agenda, and equitable distribution of health services.

Post-discharge kidney function is associated with subsequent ten-year renal progression risk among survivors of acute kidney injury.

The extent to which renal progression after acute kidney injury (AKI) arises from an initial step drop in kidney function (incomplete recovery), or from a long-term trajectory of subsequent decline, is unclear. This makes it challenging to plan or time post-discharge follow-up. This study of 14651 hospital survivors in 2003 (1966 with AKI, 12685 no AKI) separates incomplete recovery from subsequent renal decline by using the post-discharge estimated glomerular filtration rate (eGFR) rather than the pre-admission as a new reference point for determining subsequent renal outcomes. Outcomes were sustained 30% renal decline and de novo CKD stage 4, followed from 2003-2013. Death was a competing risk. Overall, death was more common than subsequent renal decline (37.5% vs 11.3%) and CKD stage 4 (4.5%). Overall, 25.7% of AKI patients had non-recovery. Subsequent renal decline was greater after AKI (vs no AKI) (14.8% vs 10.8%). Renal decline after AKI (vs no AKI) was greatest among those with higher post-discharge eGFRs with multivariable hazard ratios of 2.29 (1.88-2.78); 1.50 (1.13-2.00); 0.94 (0.68-1.32) and 0.95 (0.64-1.41) at eGFRs of 60 or more; 45-59; 30-44 and under 30, respectively. The excess risk after AKI persisted over ten years of study, irrespective of AKI severity, or post-episode proteinuria. Thus, even if post-discharge kidney function returns to normal, hospital admission with AKI is associated with increased renal progression that persists for up to ten years. Follow-up plans should avoid false reassurance when eGFR after AKI returns to normal.

Intermediate and Long-term Outcomes of Survivors of Acute Kidney Injury Episodes: A Large Population-Based Cohort Study.

BACKGROUND: The long-term prognosis after acute kidney injury (AKI) is variable. It is unclear how the prognosis of AKI and its relationship to prognostic factors (baseline kidney function, AKI severity, prior AKI episodes, and recovery of kidney function) change as follow-up progresses. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: The Grampian Laboratory Outcomes Morbidity and Mortality Study II (GLOMMS-II) is a large regional population cohort with complete serial biochemistry and outcome data capture through data linkage. From GLOMMS-II, we followed up 17,630 patients hospitalized in 2003 through to 2013. PREDICTORS: AKI identified using KDIGO (Kidney Disease: Improving Global Outcomes) serum creatinine criteria, characterized by baseline kidney function (estimated glomerular filtration rate [eGFR] ≥ 60, 45-59, 30-44, and <30mL/min/1.73m2), AKI severity (KDIGO stage), 90-day recovery of kidney function, and prior AKI episodes. OUTCOMES: Intermediate- (30-364 days) and long-term (1-10 years) mortality and long-term renal replacement therapy. MEASUREMENTS: Poisson regression in time discrete intervals. Multivariable Cox regression for those at risk in the intermediate and long term, adjusted for age, sex, baseline comorbid conditions, and acute admission circumstances. RESULTS: Of 17,630 patients followed up for a median of 9.0 years, 9,251 died. Estimated incidences of hospital AKI were 8.4% and 17.6% for baseline eGFRs≥60 and <60mL/min/1.73m2, respectively. Intermediate-term (30-364 days) adjusted mortality HRs for AKI versus no AKI were 2.48 (95% CI, 2.15-2.88), 2.50 (95% CI, 2.04-3.06), 1.90 (95% CI, 1.51-2.39), and 1.63 (95% CI, 1.20-2.22) for eGFRs≥60, 45 to 59, 30 to 44, and <30mL/min/1.73m2, respectively. Among 1-year survivors, long-term HRs were attenuated: 1.44 (95% CI, 1.31-1.58), 1.25 (95% CI, 1.09-1.43), 1.21 (95% CI, 1.03-1.42), and 1.08 (95% CI, 0.85-1.36), respectively. The excess long-term hazards in AKI were lower for lower baseline eGFRs (P for interaction = 0.01). LIMITATIONS: Nonprotocolized observational data. No adjustment for albuminuria. CONCLUSIONS: The prognostic importance of a discrete AKI episode lessens over time. Baseline kidney function is of greater long-term importance.

Acute kidney injury as an independent risk factor for unplanned 90-day hospital readmissions.

BACKGROUND: Reducing readmissions is an international priority in healthcare. Acute kidney injury (AKI) is common, serious and also a global concern. This analysis evaluates AKI as a candidate risk factor for unplanned readmissions and determines the reasons for readmissions. METHODS: GLOMMS-II is a large population cohort from one health authority in Scotland, combining hospital episode data and complete serial biochemistry results through data-linkage. 16453 people (2623 with AKI and 13830 without AKI) from GLOMMS-II who survived an index hospital admission in 2003 were used to identify the causes of and predict readmissions. The main outcome was "unplanned readmission or death" within 90 days of discharge. In a secondary analysis, the outcome was limited to readmissions with acute pulmonary oedema. 26 candidate predictors during the index admission included AKI (defined and staged 1-3 using an automated e-alert algorithm), prior AKI episodes, baseline kidney function, index admission circumstances and comorbidities. Prediction models were developed and assessed using multivariable logistic regression (stepwise variable selection), C statistics, bootstrap validation and decision curve analysis. RESULTS: Three thousand sixty-five (18.6%) patients had the main outcome (2702 readmitted, 363 died without readmission). The outcome was strongly predicted by AKI. Multivariable odds ratios for AKI stage 3; 2 and 1 (vs no AKI) were 2.80 (2.22-3.53); 2.23 (1.85-2.68) and 1.50 (1.33-1.70). Acute pulmonary oedema was the reason for readmission in 26.6% with AKI and eGFR < 60; and 4.0% with no AKI and eGFR ≥ 60. The best stepwise model from all candidate predictors had a C statistic of 0.698 for the main outcome. In a secondary analysis, a model for readmission with acute pulmonary oedema had a C statistic of 0.853. In decision curve analysis, AKI improved clinical utility when added to any model, although the incremental benefit was small when predicting the main outcome. CONCLUSIONS: AKI is a strong, consistent and independent risk factor for unplanned readmissions - particularly readmissions with acute pulmonary oedema. Pre-emptive planning at discharge should be considered to minimise avoidable readmissions in this high risk group.

KDIGO-based acute kidney injury criteria operate differently in hospitals and the community-findings from a large population cohort.

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 Maintaining Musculoskeletal Health (MAmMOTH) Study: Protocol for a randomised trial of cognitive behavioural therapy versus usual care for the prevention of chronic widespread pain.

BACKGROUND: Cognitive behavioural therapy (CBT) has been shown to improve outcomes for patients with fibromyalgia, and its cardinal feature chronic widespread pain (CWP). Prediction models have now been developed which identify groups who are at high-risk of developing CWP. It would be beneficial to be able to prevent the development of CWP in these people because of the high cost of symptoms and because once established they are difficult to manage. We will test the hypothesis that among patients who are identified as at high-risk, a short course of telephone-delivered CBT (tCBT) reduces the onset of CWP. We will further determine the cost-effectiveness of such a preventative intervention. METHODS: The study will be a two-arm randomised trial testing a course of tCBT against usual care for prevention of CWP. Eligible participants will be identified from a screening questionnaire sent to patients registered at general practices within three Scottish health boards. Those returning questionnaires indicating they have visited their doctor for regional pain in the last 6 months, and who have two of, sleep problems, maladaptive behaviour response to illness, or high number of somatic symptoms, will be invited to participate. After giving consent, participants will be randomly allocated to either tCBT or usual care. We aim to recruit 473 participants to each treatment arm. Participants in the tCBT group will have an initial assessment with a CBT therapist by telephone, then 6 weekly sessions, and booster sessions 3 and 6 months after treatment start. Those in the usual care group will receive no additional intervention. Follow-up questionnaires measuring the same items as the screening survey questionnaire will be sent 3, 12 and 24 months after start of treatment. The main outcome will be CWP at the 12 month questionnaire. DISCUSSION: This will be the first trial of an intervention aimed at preventing fibromyalgia or CWP. The results of the study will help to inform future treatments for the prevention of chronic pain, and aetiological models of its development. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02668003URL: Please check that the following URLs are working. If not, please provide alternatives: NCT02668003Alternative is: https://www.clinicaltrials.gov/ct2/show/NCT02668003> . Date registered: 28-Jan-2016.

Looking to the future: predicting renal replacement outcomes in a large community cohort with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is common and important due to poor outcomes. An ability to stratify CKD care based on outcome risk should improve care for all. Our objective was to develop and validate 5-year outcome prediction tools in a large population-based CKD cohort. Model performance was compared with the recently reported 'kidney failure risk equation' (KFRE) models. METHODS: Those with CKD in the Grampian Laboratory Outcomes Mortality and Morbidity Study-I (3396) and -II (18 687) cohorts were used to develop and validate a renal replacement therapy (RRT) prediction tool. The discrimination, calibration and overall performance were assessed. The net reclassification index compared performance of the developed model and the 3- and 4-variable KFRE model to predict RRT in the validation cohort. RESULTS: The developed model (with measures of age, sex, excretory renal function and proteinuria) performed well with a C-statistic of 0.938 (0.918-0.957) and Hosmer-Lemeshow (HL) χ(2) statistic 4.6. In the validation cohort (18 687), the developed model falsely identified fewer as high risk (414 versus 3278 individuals) compared with the KFRE 3-variable model (measures of age, sex and excretory renal function), but had more false negatives (58 versus 21 individuals). The KFRE 4-variable model could only be applied to 2274 individuals because of a lack of baseline urinary albumin creatinine ratio data, thus limiting its use in routine clinical practice. CONCLUSIONS: CKD outcome prediction tools have been developed by ourselves and others. These tools could be used to stratify care, but identify both false positives and -negatives. Further refinement should optimize the balance between identifying those at increased risk with clinical utility for stratifying care.

Acute kidney injury-how does automated detection perform?

BACKGROUND: Early detection of acute kidney injury (AKI) is important for safe clinical practice. NHS England is implementing a nationwide automated AKI detection system based on changes in blood creatinine. Little has been reported on the similarities and differences of AKI patients detected by this algorithm and other definitions of AKI in the literature. METHODS: We assessed the NHS England AKI algorithm and other definitions using routine biochemistry in our own health authority in Scotland in 2003 (adult population 438 332). Linked hospital episode codes (ICD-10) were used to identify patients where AKI was a major clinical diagnosis. We compared how well the algorithm detected this subset of AKI patients in comparison to other definitions of AKI. We also evaluated the potential 'alert burden' from using the NHS England algorithm in comparison to other AKI definitions. RESULTS: Of 127 851 patients with at least one blood test in 2003, the NHS England AKI algorithm identified 5565 patients. The combined NHS England algorithm criteria detected 91.2% (87.6-94.0) of patients who had an ICD-10 AKI code and this was better than any individual AKI definition. Some of those not captured could be identified by algorithm modifications to identify AKI in retrospect after recovery, but this would not be practical in real-time. Any modifications also increased the number of alerted patients (2-fold in the most sensitive model). CONCLUSIONS: The NHS England AKI algorithm performs well as a diagnostic adjunct in clinical practice. In those without baseline data, AKI may only be seen in biochemistry in retrospect, therefore proactive clinical care remains essential. An alternative algorithm could increase the diagnostic sensitivity, but this would also produce a much greater burden of patient alerts.

Charlson index scores from administrative data and case-note review compared favourably in a renal disease cohort.

BACKGROUND: The Charlson index is a widely used measure of comorbidity. The objective was to compare Charlson index scores calculated using administrative data to those calculated using case-note review (CNR) in relation to all-cause mortality and initiation of renal replacement therapy (RRT) in the Grampian Laboratory Outcomes Mortality and Morbidity Study (GLOMMS-1) chronic kidney disease cohort. METHODS: Modified Charlson index scores were calculated using both data sources in the GLOMMS-1 cohort. Agreement between scores was assessed using the weighted Kappa. The association with outcomes was assessed using Poisson regression, and the performance of each was compared using net reclassification improvement. RESULTS: Of 3382 individuals, median age 78.5 years, 56% female, there was moderate agreement between scores derived from the two data sources (weighted kappa 0.41). Both scores were associated with mortality independent of a number of confounding factors. Administrative data Charlson scores were more strongly associated with death than CNR scores using net reclassification improvement. Neither score was associated with commencing RRT. CONCLUSION: Despite only moderate agreement, modified Charlson index scores from both data sources were associated with mortality. Neither was associated with commencing RRT. Administrative data compared favourably and may be superior to CNR when used in the Charlson index to predict mortality.

Definitions of progression in chronic kidney disease--predictors and relationship to renal replacement therapy in a population cohort with a 6 year follow-up.

BACKGROUND: Chronic kidney disease (CKD) is common, important and associated with increased healthcare needs due to CKD progression. Definitions of renal disease progression are multiple, and not always comparable. A measure of 'progression' directly comparable with renal replacement therapy (RRT) initiation would identify 'progressors' in research and for healthcare planning. METHODS: The Grampian Laboratory Outcomes Morbidity and Mortality Study (GLOMMS-I) is a community cohort with CKD from 2003, followed up to June 2009 for (i) RRT initiation and (ii) 'progression': sustained reduction in estimated glomerular filtration rate (eGFR) by 15 mL/min/1.73 m2 (equivalent to CKD stage change), or to <10 mL/min/1.73 m2, whichever occurs first. Predictors were baseline demographics and comorbidity. The use of the Kidney Disease: Improving Global Outcomes-2012 progression definition was also explored. RESULTS: Two thousand two hundred and eighty-nine and 1044 had Stage 3 and 4 CKD, 44% were males. Overall, RRT initiation and progression rates were 0.97 and 3.50 per 100 patient-years (py). Females had significantly lower progression and RRT initiation rates. The progression rate was not dependent on CKD stage [incidence rate ratio (IRR) for Stage 4 (versus Stage 3) 0.9 (95% CI 0.8-1.2)], whereas the RRT initiation rate was [IRR 5.6 (95% CI 3.8-8.2)]. Increased proteinuria was associated with both greater RRT initiation and progression rates. CONCLUSIONS: Progression and RRT initiation rate ratios allow comparison of predictors of these outcomes. Higher rates of both in males suggest that greater RRT initiation rate is biological rather than due to preferential treatment. Similar progression but very different RRT initiation rates in Stage 3 and 4 CKD suggests that CKD stage effect on RRT initiation is a function of endpoint proximity rather than faster renal function deterioration.

Chronic kidney disease, a useful trigger for proactive primary care? Mortality results from a large U.K. cohort.

BACKGROUND: Much of the emphasis for primary care management of chronic kidney disease (CKD) has focused on cardiovascular risk; however, many patients die of other causes. Aim. In order to guide future primary care management of CKD, we report the causes of death from a large U.K. CKD cohort linked to health care administrative data. DESIGN, SETTING AND METHODS: The Grampian Laboratory Outcomes Mortality and Morbidity Study (GLOMMS-1) is a community cohort of people with established CKD, identified in 2003 and followed up for 6 years. Causes of death were available from death certificates. The relative likelihood of different causes of death was compared to the general population. RESULTS: When standardized for age and sex, mortality was 4.7 (95% confidence interval 4.5-4.9) times higher in GLOMMS-1 than the general population. Non-cardiovascular diseases accounted for 1076 (50.9%) of deaths, 3.7 times more common than in the age- and sex-matched general population. For those with stages 3 and 4 CKD, without cardiovascular disease at baseline, a non-cardiovascular cause accounted for almost two-thirds of deaths. In those 75 years and older, dementia and falls were among the main non-cardiovascular causes of death. CONCLUSIONS: Mortality in those with CKD is high, with non-cardiovascular diseases accounting for more than half of all deaths. While there is evidence that intervention may benefit those at risk of cardiovascular death, most of the non-cardiovascular causes of death identified were not readily amenable to prevention. A mechanism to identify which patients may benefit from intervention to prevent cardiovascular disease or renal disease progression is needed.

STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol.

INTRODUCTION: Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. METHODS AND ANALYSIS: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as "standard of care" in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately. ETHICS AND DISSEMINATION: The protocol was reviewed by South Central-Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. TRIAL REGISTRATION NUMBER: ISRCTN10665760.

Translating chronic kidney disease epidemiology into patient care--the individual/public health risk paradox.

BACKGROUND: Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6-year follow-up (≈ 13,000 patient-years). METHODS: A cohort had previously been identified with CKD-sustained reduced eGFR over at least 3 months and case note review. Six-year (13,339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex-specific mortality rates were compared to the general population. RESULTS: Of 3414 individuals (most Stage 3b-5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15-25 and 75-85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15-45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient-years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15-45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning. CONCLUSIONS: The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome.

Systematic voiding programme in adults with urinary incontinence following acute stroke: the ICONS-II RCT.

BACKGROUND: Urinary incontinence affects around half of stroke survivors in the acute phase, and it often presents as a new problem after stroke or, if pre-existing, worsens significantly, adding to the disability and helplessness caused by neurological deficits. New management programmes after stroke are needed to address urinary incontinence early and effectively. OBJECTIVE: The Identifying Continence OptioNs after Stroke (ICONS)-II trial aimed to evaluate the clinical effectiveness and cost-effectiveness of a systematic voiding programme for urinary incontinence after stroke in hospital. DESIGN: This was a pragmatic, multicentre, individual-patient-randomised (1 : 1), parallel-group trial with an internal pilot. SETTING: Eighteen NHS stroke services with stroke units took part. PARTICIPANTS: Participants were adult men and women with acute stroke and urinary incontinence, including those with cognitive impairment. INTERVENTION: Participants were randomised to the intervention, a systematic voiding programme, or to usual care. The systematic voiding programme comprised assessment, behavioural interventions (bladder training or prompted voiding) and review. The assessment included evaluation of the need for and possible removal of an indwelling urinary catheter. The intervention began within 24 hours of recruitment and continued until discharge from the stroke unit. MAIN OUTCOME MEASURES: The primary outcome measure was severity of urinary incontinence (measured using the International Consultation on Incontinence Questionnaire) at 3 months post randomisation. Secondary outcome measures were taken at 3 and 6 months after randomisation and on discharge from the stroke unit. They included severity of urinary incontinence (at discharge and at 6 months), urinary symptoms, number of urinary tract infections, number of days indwelling urinary catheter was in situ, functional independence, quality of life, falls, mortality rate and costs. The trial statistician remained blinded until clinical effectiveness analysis was complete. RESULTS: The planned sample size was 1024 participants, with 512 allocated to each of the intervention and the usual-care groups. The internal pilot did not meet the target for recruitment and was extended to March 2020, with changes made to address low recruitment. The trial was paused in March 2020 because of COVID-19, and was later stopped, at which point 157 participants had been randomised (intervention, n = 79; usual care, n = 78). There were major issues with attrition, with 45% of the primary outcome data missing: 56% of the intervention group data and 35% of the usual-care group data. In terms of the primary outcome, patients allocated to the intervention group had a lower score for severity of urinary incontinence (higher scores indicate greater severity in urinary incontinence) than those allocated to the usual-care group, with means (standard deviations) of 8.1 (7.4) and 9.1 (7.8), respectively. LIMITATIONS: The trial was unable to recruit sufficient participants and had very high attrition, which resulted in seriously underpowered results. CONCLUSIONS: The internal pilot did not meet its target for recruitment and, despite recruitment subsequently being more promising, it was concluded that the trial was not feasible owing to the combined problems of poor recruitment, poor retention and COVID-19. The intervention group had a slightly lower score for severity of urinary incontinence at 3 months post randomisation, but this result should be interpreted with caution. FUTURE WORK: Further studies to assess the effectiveness of an intervention starting in or continuing into the community are required. TRIAL REGISTRATION: This trial is registered as ISRCTN14005026. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 31. See the NIHR Journals Library website for further project information.

Urinary incontinence affects around half of stroke survivors. It causes embarrassment and distress, affecting patients' ability to take part in rehabilitation. It also has a major impact on families and may determine whether or not patients are able to return home. Finding the underlying cause and addressing it can prevent, cure or reduce problems. Doing this in a systematic way for everyone with incontinence problems as early as possible after the stroke, while they are still in hospital, may work best. We also wanted to avoid using catheters in the bladder to drain the urine away, as these are often unnecessary and can cause urinary tract infections. This study aimed to test whether or not continence problems and the use of urinary catheters could be reduced if everyone with incontinence was fully assessed and given the right management and support early after hospital admission. We also wanted to find out if the benefits outweighed the costs. We planned to involve 1024 men and women with incontinence from 18 stroke units in the study, with 512 people receiving the intervention and 512 receiving usual care. However, the trial was paused because of COVID-19, at which time only 157 participants had been recruited. When we were thinking about restarting the study and looked at its progress, we found that not enough people had agreed to take part and, of those who had agreed, many had not returned their outcome questionnaires. This indicated that the trial was not feasible and should not restart. We could not make any firm conclusions about whether or not the intervention worked, as not enough people were involved. We found that stays in hospital after stroke are shorter than they were in the past. This suggests that future studies investigating ways of treating incontinence should consider interventions with management and support for incontinence that continue after patients leave the hospital.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Comparison of patient survival in non-diabetic transplant-listed patients initially treated with haemodialysis or peritoneal dialysis.

BACKGROUND: It is still not known whether patients survive longer on one modality of dialysis compared to the other. We have tried to answer this question using data from the Scottish Renal Registry. METHODS: To avoid the confounding effects of co-morbidity, we limited our survival analysis to those patients listed for a renal transplant and excluded patients with a primary renal diagnosis (PRD) of diabetic nephropathy. We studied patients starting dialysis between 01 January 1982 and 31 December 2006. RESULTS: Three thousand one hundred and ninety-seven patients fulfilled our criteria. A Kaplan-Meier plot showed no difference in survival between initial dialysis modality (log-rank P = 0.996). In the Cox regression model, initial dialysis modality was not a significant predictor of survival; hazard ratio = 0.97 (95% CI 0.80 to 1.18) after adjusting for age, sex and PRD. Age at the start of dialysis, hazard ratio = 1.05 (95% CI 1.04 to 1.06) and a PRD group of 'multi-system disease' or 'unknown' were found to significantly influence survival. When survival was also censored for change in modality, there was no difference in survival over the whole study period with the hazard of death for patients on haemodialysis compared to those on peritoneal dialysis being 1.04 (95% CI 0.78 to 1.38; P = 0.803). Age at the start of dialysis remained a significant predictor of death. CONCLUSIONS: This study shows that there was no survival advantage between initial dialysis modalities in non-diabetic patients who are deemed healthy enough for listing for a renal transplant.

Side-by-side comparison of an open-chamber (TM 300) and a closed-chamber (Vapometer™) transepidermal water loss meter.

BACKGROUND: The measurement of transepidermal water loss (TEWL) is used to monitor changes in the stratum corneum's permeability to water vapor. This measurement is widely used in the cosmetics industry and in dermatology research. However, only limited work has been undertaken to assess the comparability of results from different TEWL meters over an extended range of measurements. METHODS: This study compared the results of TEWL measurements between two commonly used open-chamber and closed-chamber TEWL devices. Five hundred and forty measurements were taken in 17 participants on the dorsum and palm of both hands on two different days and the order of the devices was randomized. RESULTS: The results showed that the open TEWL meter's capacity for measuring high values of TEWL was restricted, and that the closed-chamber TEWL meter was less sensitive to differences in the lower range of measurements. CONCLUSION: Both devices have their strengths for different applications, but their results cannot be directly compared. We were unable to find a statistical model that would allow us to transform the measurements made on one device for a comparison with the results generated by the other device.