Abstract: Patients with inflammatory rheumatic conditions such as rheumatoid arthritis, polymyalgia rheumatica and ankylosing spondylitis are at increased risk of common comorbidities such as cardiovascular disease, osteoporosis and anxiety and depression which lead to increased morbidity and mortality. These associated morbidities are often un-recognized and under-treated. While patients with other long-term conditions such as diabetes are invited for routine reviews in primary care, which may include identification and management of co-morbidities, at present this does not occur for patients with inflammatory conditions, and thus, opportunities to diagnose and optimally manage these comorbidities are missed. Objective: To evaluate the feasibility and acceptability of a nurse-led integrated care review (the INtegrating and improving Care for patients with infLammatory rheUmatological DisordErs in the community (INCLUDE) review) for people with inflammatory rheumatological conditions in primary care. Design: A pilot cluster randomized controlled trial will be undertaken to test the feasibility and acceptability of a nurse-led integrated primary care review for identification, assessment and initial management of common comorbidities including cardiovascular disease, osteoporosis and anxiety and depression. A process evaluation will be undertaken using a mixed methods approach including participant self-reported questionnaires, a medical record review, an INCLUDE EMIS template, intervention fidelity checking using audio-recordings of the INCLUDE review consultation and qualitative interviews with patient participants, study nurses and study general practitioners (GPs) Discussion: Success of the pilot study will be measured against the engagement, recruitment and study retention rates of both general practices and participants. Acceptability of the INCLUDE review to patients and practitioners and treatment fidelity will be explored using a parallel process evaluation. Trial Registration: ISRCTN12765345.

Abstract: The lipolytic effects of catecholamines are mediated through members of the β2-adrenergic receptor (BAR-2) family. Previous studies have suggested that genetic variants in the BAR-2 gene may be associated with obesity in some populations. To our knowledge, no studies have directly examined the effects of this polymorphism on circulating nonesterified fatty acid (NEFA) levels. To explore this issue further, a cohort of 604 Caucasian individuals (aged 40–65 yr) was genotyped for a common polymorphism in the BAR-2 gene (Gly16Arg), and the relationships between genotype, body mass index (BMI), NEFA, and lipid levels were examined. Women bearing the Arg16 allele had higher BMI values (P & lt; 0.01) than Gly16Gly women. Women carriers of the Arg16Arg genotype had lower fasting plasma NEFAs (P & lt; 0.01) and greater suppression of NEFAs (P & lt; 0.01) after an oral glucose load than women bearing the Gly16 allele. In multivariate analysis after adjustment for age, sex, and smoking status, the interaction between the BAR-2 genotype and BMI in determining fasting NEFA concentrations was statistically significant (P & lt; 0.05). The availability of objective measures of total energy expenditure in this population permitted the further examination of interactions, particularly that between genotype and physical activity. In the population as a whole, after adjustment for confounding by age, smoking, and BMI, the effect of the Arg16Arg genotype on the suppression of NEFA levels was modified by physical activity level (P for interaction & lt;0.05). These data suggest the existence in this population of a gene-physical activity interaction on NEFA levels.

Abstract: Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes. Objectives The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use. Design This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices. Setting This trial was set in five NHS ambulance services in England and Wales. Participants Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged 〈  16 years, if the cardiac arrest had been caused by anaphylaxis or life-threatening asthma, or if adrenaline had already been given. Interventions Participants were randomised to either adrenaline (1 mg) or placebo in a 1 : 1 allocation ratio by the opening of allocation-concealed treatment packs. Main outcome measures The primary outcome was survival to 30 days. The secondary outcomes were survival to hospital admission, survival to hospital discharge, survival at 3, 6 and 12 months, neurological outcomes and health-related quality of life through to 6 months. The economic evaluation assessed the incremental cost per quality-adjusted life-year gained from the perspective of the NHS and Personal Social Services. Participants, clinical teams and those assessing patient outcomes were masked to the treatment allocation. Results From December 2014 to October 2017, 8014 participants were assigned to the adrenaline ( n  = 4015) or to the placebo ( n  = 3999) arm. At 30 days, 130 out of 4012 participants (3.2%) in the adrenaline arm and 94 out of 3995 (2.4%) in the placebo arm were alive (adjusted odds ratio for survival 1.47, 95% confidence interval 1.09 to 1.97). For secondary outcomes, survival to hospital admission was higher for those receiving adrenaline than for those receiving placebo (23.6% vs. 8.0%; adjusted odds ratio 3.83, 95% confidence interval 3.30 to 4.43). The rate of favourable neurological outcome at hospital discharge was not significantly different between the arms (2.2% vs. 1.9%; adjusted odds ratio 1.19, 95% confidence interval 0.85 to 1.68). The pattern of improved survival but no significant improvement in neurological outcomes continued through to 6 months. By 12 months, survival in the adrenaline arm was 2.7%, compared with 2.0% in the placebo arm (adjusted odds ratio 1.38, 95% confidence interval 1.00 to 1.92). An adjusted subgroup analysis did not identify significant interactions. The incremental cost-effectiveness ratio for adrenaline was estimated at £1,693,003 per quality-adjusted life-year gained over the first 6 months after the cardiac arrest event and £81,070 per quality-adjusted life-year gained over the lifetime of survivors. Additional economic analyses estimated incremental cost-effectiveness ratios for adrenaline at £982,880 per percentage point increase in overall survival and £377,232 per percentage point increase in neurological outcomes over the first 6 months after the cardiac arrest. Limitations The estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome. Conclusions Adrenaline improved long-term survival, but there was no evidence that it significantly improved neurological outcomes. The incremental cost-effectiveness ratio per quality-adjusted life-year exceeds the threshold of £20,000–30,000 per quality-adjusted life-year usually supported by the NHS. Future work Further research is required to better understand patients’ preferences in relation to survival and neurological outcomes after out-of-hospital cardiac arrest and to aid interpretation of the trial findings from a patient and public perspective. Trial registration Current Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 25. See the NIHR Journals Library website for further project information.

Abstract: Usual primary care for patients with musculoskeletal pain varies widely and treatment outcomes are suboptimal. Stratified care involves targeting treatments according to patient subgroups, in the hope of maximising treatment benefit and reducing potential harm or unnecessary interventions. This programme developed a new prognostic stratified primary care approach, where treatments are matched to a patient’s risk of future persistent pain and disability based on a prognostic tool, and compared this with usual care. Objectives In four linked work packages, we refined and validated a prognostic tool [the Keele STarT MSK (Subgrouping for Targeted Treatment for Musculoskeletal pain) Tool] to identify risk of poor outcome and defined cut-off scores to distinguish patient risk subgroups (work package 1); defined and agreed new matched treatment options for each risk subgroup and developed a support package for delivery of stratified care (work package 2); tested the feasibility of delivering the stratified approach through a pilot randomised controlled trial and externally validated the prognostic tool (work package 3); and tested the effectiveness of the approach by comparing the clinical effectiveness and cost-effectiveness of stratified primary care with that of usual care through a cluster randomised controlled trial with embedded health economic and qualitative studies (work package 4). Setting General practices and linked musculoskeletal services in the West Midlands of England, UK. Participants Adults registered with participating practices consulting with back, neck, shoulder, knee or multisite musculoskeletal pain, and clinicians involved in managing these patients. Design The programme included the following work packages: work package 1 – a prospective cohort study in 12 practices; work package 2 – an evidence synthesis, consensus group workshops and qualitative studies; work package 3 – a cluster feasibility and pilot trial in eight practices; and work package 4 – a main cluster randomised controlled trial in 24 practices, with health economic analyses and process evaluation. Interventions Stratified care comprised training general practitioners to use the tool and match patients to treatment options depending on their risk subgroup. Usual care comprised usual non-stratified primary care without formal stratification tools. Main outcome measures Cohort primary end points included function (Short Form questionnaire-36 items physical component score) and pain intensity (numerical rating scale). The trial primary end point for patient outcomes was pain intensity (monthly for 6 months) (0–10 numerical rating scale). An audit of primary care electronic medical records evaluated the impact of stratified care on clinical decision-making regarding patient management. Results Work package 1 – the cohort study ( n = 1890 patients) refined and validated a new 10-item tool with which to stratify patients with the five most common musculoskeletal pain presentations. The tool subgroups patients into three strata with different characteristics and prognoses. Work package 2: 17 treatment options were recommended – four for patients at low risk, 10 for patients at medium risk and 15 for patients at high risk. Work package 3: the feasibility and pilot trial included 524 patients, and the learning led to amendments to several tool items and a reduced set of treatments (14 in total). Work package 4: in the main trial, 1211 patients consented to data collection (534 in stratified care, 677 in usual care). Stratified primary care did not lead to statistically significant differences in the primary patient outcome of pain intensity [stratified care mean 4.4 (standard deviation 2.3) vs. usual care mean 4.6 (standard deviation 2.4); adjusted mean difference –0.16, 95% confidence interval –0.65 to 0.34; p = 0.535]. Where differences were observed, these were largely isolated to patients at high risk of poor outcome (the smallest subgroup), in favour of stratified care. Positive differences were, however, observed in general practitioner clinical decision-making, with increased provision of written self-management information and referrals to physiotherapy, plus reductions in prescription medication. The economic evaluation demonstrated that costs of care were similar across trial arms (£6.85, 95% confidence interval –£107.82 to £121.54 more for stratified care), with incremental quality-adjusted life-years of 0.0041 (95% confidence interval –0.0013 to 0.0094), representing a net quality-adjusted life-year gain. Stratified care was associated with an incremental cost-effectiveness ratio of £1670 per additional quality-adjusted life-year gained. At a willingness-to-pay threshold (λ) of £20,000 per quality-adjusted life-year, the incremental net monetary benefit was £132 and the probability of stratified care being cost-effective was approximately 73%. The very small differences suggest caution in the interpretation of this result. The qualitative findings revealed that general practitioners felt stratified care had a positive role in informing clinical decision-making, helped them to give greater attention to psychosocial issues and take a more functional approach, and facilitated negotiations with patients about treatment options such as imaging. Limitations The randomised controlled trial was not powered to detect differences between stratified and usual care for patients in each risk subgroup (low, medium and high) nor with each different musculoskeletal pain presentation. The stratified care electronic medical record template ‘fired’ only once per patient. Conclusions The Keele STarT MSK Tool is a valid instrument with which to discriminate between, and predict outcomes of, primary care patients with musculoskeletal pain. Although the randomised trial showed no significant benefit in patient-reported outcomes compared with usual care, some aspects of clinical decision-making improved and the approach was cost-effective. Future work The Keele STarT MSK Tool has been shared with over 1000 tool license requestees, leading to other work. Trial data sets have also led to other work, developing personalised prognostic models for back and neck pain patients (the European Union-funded Back-UP project). The challenge remains how to improve outcomes for primary care patients with musculoskeletal pain. Trial registration This trial is registered as ISRCTN15366334. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research ; Vol. 11, No. 4. See the NIHR Journals Library website for further project information.

Abstract: Previous epidemiological studies have suggested an association between low levels of physical activity, fitness and the metabolic cardiovascular syndrome. However, many studies have used subjective non-quantitative questionnaire-based methods for assessing physical activity which do not distinguish between the different dimensions of this complex exposure, and in which measurement error in the exposure has not been estimated. These deficiencies in the measurement of this exposure complicate the interpretation of the results of epidemiological studies, and consequently make it difficult to design appropriate interventions and to estimate the expected benefit which would result from intervention. In particular, it is unclear whether public health advice should be to increase total energy expenditure, or to attempt to raise fitness by recommending periods of vigorous activity. To separate the effects of fitness and total energy expenditure in the aetiology of the metabolic cardiovascular syndrome, we measured the physical activity level (PAL), defined as total energy expenditure: BMR, and fitness (maximum O 2 consumption ( V o 2 max per kg), measured in a sub-maximal test) in a cross-sectional population-based study of 162 adults aged 30–40 years. Heart-rate monitoring with individual calibration was used to measure total energy expenditure using the HRFlex method (Ceesay et al. 1989) which has been validated previously against doubly-labelled water and whole-body calorimetry. The relationship between a single measure of PAL, V o 2 max per kg and the usual or habitual level for each exposure was measured in a sub-study of twenty-two subjects who undertook four repeated measures over the course of 1 year. This study design allows the reliability coefficient to be computed, which is used to adjust the observed associations for measurement error in the exposure. Twelve men (16.4%) and sixteen women (18.0%) were defined as having one or more features of the metabolic cardiovascular syndrome. The univariate odds ratio for each increasing quartile for PAL was 0.64 (95 % CI 0.43–0.94) and was 0.49 (95 % CI 0.32–0.74) for V o 2 max per kg, suggesting that the association with the metabolic cardiovascular syndrome was stronger for fitness than for PAL. However, after adjustment for obesity and sex, and correction for exposure measurement error, the odds ratio per quartile for PAL was 0.32 (95 % CI 0.13–0.83) and 0.44 (95 % CI 0.24–0.78) for V o 2 max per kg. Thus, although univariate analysis would suggest that fitness has a stronger association with the metabolic cardiovascular syndrome than PAL, this conclusion is reversed once confounding and the differences in measurement error are considered. We conclude from the present study that the metabolic cardiovascular syndrome is strongly associated with reduced habitual energy expenditure. The method employed to assess the exposure in the present study demonstrates the utility of assessing a known dimension of physical activity using a physiologically-based and objective measure with repeated estimation to adjust for measurement error. Such quantitative epidemiological data provide the basis for planning and evaluating the expected benefit of population-level interventions.

Abstract: To compare the clinical effectiveness of adding a single ultrasound guided intra-articular hip injection of corticosteroid and local anaesthetic to advice and education in adults with hip osteoarthritis. Design Pragmatic, three arm, parallel group, single blind, randomised controlled trial. Setting Two community musculoskeletal services in England. Participants 199 adults aged ≥40 years with hip osteoarthritis and at least moderate pain: 67 were randomly assigned to receive advice and education (best current treatment (BCT)), 66 to BCT plus ultrasound guided injection of triamcinolone and lidocaine, and 66 to BCT plus ultrasound guided injection of lidocaine. Interventions BCT alone, BCT plus ultrasound guided intra-articular hip injection of 40 mg triamcinolone acetonide and 4 mL 1% lidocaine hydrochloride, or BCT plus ultrasound guided intra-articular hip injection of 5 mL 1% lidocaine. Participants in the ultrasound guided arms were masked to the injection they received. Main outcome measures The primary outcome was self-reported current intensity of hip pain (0-10 Numerical Rating Scale) over six months. Outcomes were self-reported at two weeks and at two, four, and six months. Results Mean age of the study sample was 62.8 years (standard deviation 10.0) and 113 (57%) were women. Average weighted follow-up rate across time points was 93%. Greater mean improvement in hip pain intensity over six months was reported with BCT plus ultrasound-triamcinolone-lidocaine compared with BCT: mean difference −1.43 (95% confidence interval −2.15 to −0.72), P 〈 0.001; standardised mean difference −0.55 (−0.82 to −0.27). No difference in hip pain intensity over six months was reported between BCT plus ultrasound-triamcinolone-lidocaine compared with BCT plus ultrasound-lidocaine (−0.52 (−1.21 to 0.18)). The presence of ultrasound confirmed synovitis or effusion was associated with a significant interaction effect favouring BCT plus ultrasound-triamcinolone-lidocaine (−1.70 (−3.10 to −0.30)). One participant in the BCT plus ultrasound-triamcinolone-lidocaine group with a bioprosthetic aortic valve died from subacute bacterial endocarditis four months after the intervention, deemed possibly related to the trial treatment. Conclusions Ultrasound guided intra-articular hip injection of triamcinolone is a treatment option to add to BCT for people with hip osteoarthritis. Trial registration EudraCT 2014-003412-37; ISRCTN50550256 .

Abstract: The fasting concentration of non-esterified fatty acids (NEFA) and the degree to which it declines during an oral glucose tolerance test are closely associated with insulin resistance and glucose intolerance. However, relatively few studies have described possible environmental determinants of NEFA concentrations. Physical activity is likely to be related to NEFA levels, but habitual activity level is difficult to quantify in epidemiological studies. In particular, it is unclear whether NEFA is more closely related to cardio-respiratory fitness or to habitual energy expenditure. In order to quantify these relationships, we analysed data from the Ely prospective population-based study in which 931 subjects underwent a glucose tolerance test with measurements of cardio-respiratory fitness and 4 d energy expenditure by heart-rate monitoring, a technique previously validated against whole-body calorimetry and doubly-labelled water. In order to estimate the latent variables of usual fitness and energy expenditure, a subset of 190 subjects underwent repeat testing on three further occasions over 1 year. In analyses adjusting only for age and sex, energy expenditure and cardio-respiratory fitness were both negatively correlated with the total area under the NEFA curve following the oral glucose load (standardised β coefficients -0·030 and -0·039 respectively; both P 〈 0·001) However, further adjustment for degree of obesity and bivariate measurement error suggested that the effect of energy expenditure was significantly greater than that for fitness (-0·047 and -0·005 respectively). These results suggest that the area under the NEFA curve in the oral glucose tolerance test, a measure of insulin sensitivity, is strongly associated with the habitual level of physical activity.

Abstract: Increasing the precision of measurements of total energy expenditure in population-based epidemiological studies is important for accurately quantifying the relationship between this exposure and disease. Current questionnaire-based methods cannot accurately quantify total energy expenditure, although they may provide an estimate of the frequency of vigorous activities. Heart rate monitoring with individual calibration has been advocated as a method for assessing energy expenditure in field studies and has been compared with the ‘gold standard’ techniques of doubly-labelled water and indirect calorimetry. However the method has previously only been used on small and selected populations. This study was, therefore, established to test the feasibility of using heart rate monitoring in a population-based study of adults. A total of 167 individuals aged 30–40 years were randomly selected and underwent 4 d heart-rate monitoring. Only three individuals could not complete the protocol. The mean physical activity level (PAL) measured over 4 d was 1.89 (sd 0.40) in men and 1.76 (sd 0.31) in women. There was no difference between mean PAL on weekend days compared with weekdays (mean paired difference 0.0008, 95% CI −0.06 to + 0.06). The estimate of mean PAL was not correlated with BMI, percentage body fat or the waist:hip ratio. It was, however, correlated with cardio-respiratory fitness as measured by VO 2max per kg (Spearman rank correlation coefficient 0.50 in men and 0.42 in women). The pattern of energy expenditure was assessed by calculating the percentage of daytime hours in which PAL was greater than five times basal energy expenditure. This measure was strongly correlated with the mean PAL in both men (Spearman correlation coefficient 0.77) and women (0.71). We conclude that heart-rate monitoring is a feasible method for assessing the pattern and total level of energy expenditure in medium-sized epidemiological studies. It may also prove useful as the reference technique for calibrating questionnaires to estimate energy expenditure in larger scale studies.