Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Randomized clinical trial: Direct-acting antivirals as treatment for hepatitis C in people who inject drugs: Delivered in needle and syringe programs via directly observed therapy versus fortnightly collection.

Hepatitis C virus (HCV) treatment in people who inject drugs (PWID) is delivered within settings frequented by PWID, such as needle and syringe programs (NSP). The optimal direct-acting antiviral (DAA) dispensing regimen among NSP clients is unknown. This study compared cures (Sustained virologic response 12 weeks post-treatment, [SVR12 ]) across three dispensing schedules to establish non-inferiority of fortnightly dispensing versus directly observed therapy. The ADVANCE HCV study was a randomized, unblinded trial, recruiting PWID attending NSP in Tayside, Scotland, between January 2018 and November 2019. HCV-positive participants were randomized to receive DAAs via directly observed therapy, fortnightly provision or fortnightly provision with psychological intervention. A modified intention to treat analysis was used to identify differences in cures between the three treatment regimes. The study was registered with clinicaltrials.gov; NCT03236506. A total of 110 participants completed the study. 33 participants received directly observed therapy, with 90.91% SVR12 ; 37 received fortnightly provision, with 86.49% SVR12 and 40 received fortnightly provision and psychological intervention at treatment initiation, with 92.50% SVR12 . Analysis showed no significant difference in SVR12 (p = 0.67). This study did not demonstrate a statistically significant difference in cure rate between groups. This provides evidence of the non-inferiority of fortnightly dispensing of direct-acting antivirals (DAAs) compared to directly observed therapy among PWID. It suggests that tight control of adherence through directly observed therapy dispensing of DAAs among this population offers no therapeutic advantage. Therefore, less restrictive dispensing patterns can be used, tailored to patient convenience.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Promoting smoking cessation during pregnancy: A feasibility and pilot trial of a digital storytelling intervention delivered via text-messaging.

OBJECTIVE: Smoking during pregnancy causes risks to mother and infant health. We investigated the feasibility and likely success of SKIP-IT, a narrative and picture-based smoking cessation intervention delivered via text messages. METHODS: A feasibility and pilot trial. We aimed to recruit 70 pregnant women who smoked, randomised to usual care alone, or usual care and the SKIP-IT intervention, between 12 weeks of pregnancy and 6 weeks post due-date. Outcomes assessed were recruitment, retention, acceptability of, and engagement with the intervention, smoking behaviour, intentions, perceived risk, and self-efficacy. RESULTS: Of 312 women initially approached by smoking cessation services only 54 (17%) agreed to be contacted by the research team. Twenty were then either ineligible or uncontactable and 28 (82%) participated. Most women reported texts to be entertaining and helpful. The proportion of women not smoking at follow-up was lower in the intervention group, but numbers were too small to draw conclusions about effectiveness. CONCLUSION: The intervention was acceptable, but difficulty in making initial and follow-up contacts meant our methods were unfeasible for a larger trial. PRACTICE IMPLICATIONS: Digital Storytelling interventions could help women quit smoking, but further research is required to identify alternative methods for studies with pregnant women who smoke.

Clinical effectiveness of pharmacist-led versus conventionally delivered antiviral treatment for hepatitis C virus in patients receiving opioid substitution therapy: a pragmatic, cluster-randomised trial.

BACKGROUND: Highly effective direct-acting antiviral drugs provide the opportunity to eliminate hepatitis C virus (HCV) infection, but established pathways can be ineffective. We aimed to examine whether a community pharmacy care pathway increased treatment uptake, treatment completion, and cure rates for people receiving opioid substitution therapy, compared with conventional care. METHODS: This cluster-randomised trial was done in Scottish community pharmacies. Before participants were recruited, pharmacies were randomly assigned (1:1) to refer patients with evidence of HCV antibodies to conventional care or offered them care in the pharmacy (pharmacist-led care). Pharmacies were stratified by location. All pharmacies were trained to offer dried blood spot testing. All eligible participants had received opioid substitution therapy for approximately 3 months, and those eligible to receive treatment in the pharmacist-led care pathway were HCV PCR positive, were infected with HCV genotype 1 or 3, and were willing to have a pharmacist supervise their antiviral drug administration. Neither pharmacists nor patients were masked to treatment allocation. In both groups, assessment blood samples were taken, infection with HCV was confirmed, and daily oral ledipasvir-sofosbuvir (90 mg ledipasivir plus 400 mg sofosbuvir) for 8 weeks for genotype 1 or daily oral sofosbuvir (400 mg) plus oral daclatasvir (60 mg) for 12 weeks for genotype 3 was prescribed by a nurse (conventional care group) or pharmacist (pharmacist-led care group). In the conventional care group, the patient received care at a treatment centre. Once prescribed, medication in both groups was delivered as daily modified directly observed therapy alongside opioid substitution therapy in the participants' pharmacy where treatment was observed on 6 days per week. The primary outcome was the number of patients with sustained virological response 12 weeks after completion of treatment (SVR12) as a proportion of the number of people receiving opioid substitution therapy at participating pharmacies. Participants were monitored at each visit for nausea and fatigue; other adverse events were recorded as free text. Secondary outcomes compared key points on treatment pathway between the two groups. These key points were the proportion of patients having dry blood spot testing, the proportion of patients initiating HCV treatment, the proportion of patients completing the 8 or 12 week HCV course of treatment, and the proportion of patients with sustained virological response at 12 months. This study is registered with ClinicalTrials.gov, NCT02706223. FINDINGS: 56 pharmacies were randomly assigned (28 to each group; one pharmacy withdrew from the conventional care group). The 55 participating pharmacies included 2718 patients receiving opioid substitution therapy (1365 in the pharmacist-led care group and 1353 in the conventional care group). More patients met the primary endpoint of SVR12 in the pharmacist-led care group (98 [7%] of 1365) than in the conventional care group (43 [3%] of 1353; odds ratio 2·375, 95% CI 1·555-3·628, p<0·0001). More users of opioid substitution therapy in the pharmacist-led care group versus the conventional care group agreed to dry blood spot testing (245 [18%] of 1365 vs 145 [11%] of 1353, 2·292, 0·968-5·427, p=0·059); initiated treatment (112 [8%] of 1365 vs 61 [4%] of 1353, 1·889, 1·276-2·789, p=0·0015) and completed treatment (108 [8%] of 1365 vs 58 [4%] of 1353, 1·928, 1·321-2·813, p=0·0007). The data for sustained virological response at 12 months are not reported in this study: patients remain in follow-up for this outcome. No serious adverse events were recorded. INTERPRETATION: Using pharmacists to deliver an HCV care pathway made testing and treatment more accessible for patients, improved engagement, and maintained high treatment success rates. The use of this pathway could be a key part of an integrated and effective approach to HCV elimination at a community level. FUNDING: Partnership between the Scottish Government, Gilead Sciences, and Bristol-Myers Squib.

Game of Stones: feasibility randomised controlled trial of how to engage men with obesity in text message and incentive interventions for weight loss.

OBJECTIVES: To examine the acceptability and feasibility of narrative text messages with or without financial incentives to support weight loss for men. DESIGN: Individually randomised three-arm feasibility trial with 12 months' follow-up. SETTING: Two sites in Scotland with high levels of disadvantage according to Scottish Index for Multiple Deprivation (SIMD). PARTICIPANTS: Men with obesity (n=105) recruited through community outreach and general practitioner registers. INTERVENTIONS: Participants randomised to: (A) narrative text messages plus financial incentive for 12 months (short message service (SMS)+I), (B) narrative text messages for 12 months (SMS only), or (C) waiting list control. OUTCOMES: Acceptability and feasibility of recruitment, retention, intervention components and trial procedures assessed by analysing quantitative and qualitative data at 3, 6 and 12 months. RESULTS: 105 men were recruited, 60% from more disadvantaged areas (SIMD quintiles 1 or 2). Retention at 12 months was 74%. Fewer SMS+I participants (64%) completed 12-month assessments compared with SMS only (79%) and control (83%). Narrative texts were acceptable to many men, but some reported negative reactions. No evidence emerged that level of disadvantage was related to acceptability of narrative texts. Eleven SMS+I participants (31%) successfully met or partially met weight loss targets. The cost of the incentive per participant was £81.94 (95% CI £34.59 to £129.30). Incentives were acceptable, but improving health was reported as the key motivator for weight loss. All groups lost weight (SMS+I: -2.51 kg (SD=4.94); SMS only: -1.29 kg (SD=5.03); control: -0.86 kg (SD=5.64) at 12 months). CONCLUSIONS: This three-arm weight management feasibility trial recruited and retained men from across the socioeconomic spectrum, with the majority from areas of disadvantage, was broadly acceptable to most participants and feasible to deliver. TRIAL REGISTRATION NUMBER: NCT03040518.

Intelligent liver function testing (iLFT): A trial of automated diagnosis and staging of liver disease in primary care.

BACKGROUND & AIMS: Liver function tests (LFTs) are frequently requested blood tests which may indicate liver disease. LFTs are commonly abnormal, the causes of which can be complex and are frequently under investigated. This can lead to missed opportunities to diagnose and treat liver disease at an early stage. We developed an automated investigation algorithm, intelligent liver function testing (iLFT), with the aim of increasing the early diagnosis of liver disease in a cost-effective manner. METHODS: We developed an automated system that further investigated abnormal LFTs on initial testing samples to generate a probable diagnosis and management plan. We integrated this automated investigation algorithm into the laboratory management system, based on minimal diagnostic criteria, liver fibrosis estimation, and reflex testing for causes of liver disease. This algorithm then generated a diagnosis and/or management plan. A stepped-wedged trial design was utilised to compare LFT outcomes in general practices in the 6 months before and after introduction of the iLFT system. Diagnostic outcomes were collated and compared. RESULTS: Of eligible patients with abnormal LFTs, 490 were recruited to the control group and 64 were recruited to the intervention group. The primary diagnostic outcome was based on the general practitioner diagnosis, which agreed with the iLFT diagnosis in 67% of cases. In the iLFT group, the diagnosis of liver disease was increased by 43%. Additionally, there were significant increases in the rates of GP visits after diagnosis and the number of referrals to secondary care in the iLFT group. iLFT was cost-effective with a low initial incremental cost-effectiveness ratio of £284 per correct diagnosis, and a saving to the NHS of £3,216 per patient lifetime. CONCLUSIONS: iLFT increases liver disease diagnoses, improves quality of care, and is highly cost-effective. This can be achieved with minor changes to working practices and exploitation of functionality existing within modern laboratory diagnostics systems. LAY SUMMARY: There is a growing epidemic of advanced liver disease, this could be offset by early detection and management. Checking liver blood tests (LFTs) should be an opportunity to diagnose liver problems, but abnormal results are often incompletely investigated. In this study we were able to substantially increase the diagnostic yield of the abnormal LFTs using the automated intelligent LFT system. With the addition of referral recommendations and management plans, this strategy provides optimum investigation and management of LFTs and is cost saving to the NHS.

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial.

BACKGROUND: Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1. METHODS: We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklist-individual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central web-based system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep-wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10-14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0-100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with baseline scores as a covariate. Safety data were presented as descriptives. This trial is registered with ClinicalTrials.gov, number NCT02118779. FINDINGS: Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1-Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI -0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (-2·02, -4·02 to -0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. INTERPRETATION: Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1. FUNDING: The European Union Seventh Framework Programme.

Process evaluation of the Data-driven Quality Improvement in Primary Care (DQIP) trial: quantitative examination of variation between practices in recruitment, implementation and effectiveness.

OBJECTIVES: The cluster randomised trial of the Data-driven Quality Improvement in Primary Care (DQIP) intervention showed that education, informatics and financial incentives for general medical practices to review patients with ongoing high-risk prescribing of non-steroidal anti-inflammatory drugs and antiplatelets reduced the primary end point of high-risk prescribing by 37%, where both ongoing and new high-risk prescribing were significantly reduced. This quantitative process evaluation examined practice factors associated with (1) participation in the DQIP trial, (2) review activity (extent and nature of documented reviews) and (3) practice level effectiveness (relative reductions in the primary end point). SETTING/PARTICIPANTS: Invited practices recruited (n=33) and not recruited (n=32) to the DQIP trial in Scotland, UK. OUTCOME MEASURES: (1) Characteristics of recruited versus non-recruited practices. Associations of (2) practice characteristics and 'adoption' (self-reported implementation work done by practices) with documented review activity and (3) of practice characteristics, DQIP adoption and review activity with effectiveness. RESULTS: (1) Recruited practices had lower performance in the quality and outcomes framework than those declining participation. (2) Not being an approved general practitioner training practice and higher self-reported adoption were significantly associated with higher review activity. (3) Effectiveness ranged from a relative increase in high-risk prescribing of 24.1% to a relative reduction of 77.2%. High-risk prescribing and DQIP adoption (but not documented review activity) were significantly associated with greater effectiveness in the final multivariate model, explaining 64.0% of variation in effectiveness. CONCLUSIONS: Intervention implementation and effectiveness of the DQIP intervention varied substantially between practices. Although the DQIP intervention primarily targeted review of ongoing high-risk prescribing, the finding that self-reported DQIP adoption was a stronger predictor of effectiveness than documented review activity supports that reducing initiation and/or re-initiation of high-risk prescribing is key to its effectiveness. TRIAL REGISTRATION NUMBER: NCT01425502; Post-results.

Leucine and ACE inhibitors as therapies for sarcopenia (LACE trial): study protocol for a randomised controlled trial.

BACKGROUND: Sarcopenia (the age-related loss of muscle mass and function) is a major contributor to loss of mobility, falls, loss of independence, morbidity and mortality in older people. Although resistance training is effective in preventing and reversing sarcopenia, many older people are sedentary and either cannot or do not want to exercise. This trial examines the efficacy of supplementation with the amino acid leucine and/or angiotensin converting enzyme inhibition to potentially improve muscle mass and function in people with sarcopenia. Promising preliminary data exist from small studies for both interventions, but neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. METHODS: Leucine and ACE inhibitors in sarcopenia (LACE) is a multicentre, masked, placebo-controlled, 2 × 2 factorial randomised trial evaluating the efficacy of leucine and perindopril (angiotensin converting enzyme inhibitor (ACEi)) in patients with sarcopenia. The trial will recruit 440 patients from primary and secondary care services across the UK. Male and female patients aged 70 years and over with sarcopenia as defined by the European Working Group on Sarcopenia (based on low total skeletal muscle mass on bioimpedance analysis and either low gait speed or low handgrip strength) will be eligible for participation. Participants will be excluded if they have a contraindication to, or are already taking, an ACEi, angiotensin receptor blocker or leucine. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at all points between baseline and 12 months. Secondary outcomes include appendicular muscle mass measured using dual-energy X-ray absorptiometry, muscle strength, activities of daily living, quality of life, activity using pedometer step counts and falls. Participants, clinical teams, outcomes assessors and trial analysts are masked to treatment allocation. A panel of biomarkers including microRNAs, neurohormones, genetic polymorphisms and markers of inflammation relevant to muscle pathophysiology will be measured to explore predictors of response and further elucidate mechanisms underlying sarcopenia. Participants will receive a total of 12 months of either perindopril or placebo and either leucine or placebo. DISCUSSION: The results will provide the first robust test of the overall clinical and cost-effectiveness of these novel therapies for older patients with sarcopenia. TRIAL REGISTRATION: ISRCTN, ISRCTN90094835 . Registered on 18 February 2015.

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD. METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD. FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

Safer Prescribing--A Trial of Education, Informatics, and Financial Incentives.

BACKGROUND: High-risk prescribing and preventable drug-related complications are common in primary care. We evaluated whether the rates of high-risk prescribing by primary care clinicians and the related clinical outcomes would be reduced by a complex intervention. METHODS: In this cluster-randomized, stepped-wedge trial conducted in Tayside, Scotland, we randomly assigned participating primary care practices to various start dates for a 48-week intervention comprising professional education, informatics to facilitate review, and financial incentives for practices to review patients' charts to assess appropriateness. The primary outcome was patient-level exposure to any of nine measures of high-risk prescribing of nonsteroidal antiinflammatory drugs (NSAIDs) or selected antiplatelet agents (e.g., NSAID prescription in a patient with chronic kidney disease or coprescription of an NSAID and an oral anticoagulant without gastroprotection). Prespecified secondary outcomes included the incidence of related hospital admissions. Analyses were performed according to the intention-to-treat principle, with the use of mixed-effect models to account for clustering in the data. RESULTS: A total of 34 practices underwent randomization, 33 of which completed the study. Data were analyzed for 33,334 patients at risk at one or more points in the preintervention period and for 33,060 at risk at one or more points in the intervention period. Targeted high-risk prescribing was significantly reduced, from a rate of 3.7% (1102 of 29,537 patients at risk) immediately before the intervention to 2.2% (674 of 30,187) at the end of the intervention (adjusted odds ratio, 0.63; 95% confidence interval [CI], 0.57 to 0.68; P<0.001). The rate of hospital admissions for gastrointestinal ulcer or bleeding was significantly reduced from the preintervention period to the intervention period (from 55.7 to 37.0 admissions per 10,000 person-years; rate ratio, 0.66; 95% CI, 0.51 to 0.86; P=0.002), as was the rate of admissions for heart failure (from 707.7 to 513.5 admissions per 10,000 person-years; rate ratio, 0.73; 95% CI, 0.56 to 0.95; P=0.02), but admissions for acute kidney injury were not (101.9 and 86.0 admissions per 10,000 person-years, respectively; rate ratio, 0.84; 95% CI, 0.68 to 1.09; P=0.19). CONCLUSIONS: A complex intervention combining professional education, informatics, and financial incentives reduced the rate of high-risk prescribing of antiplatelet medications and NSAIDs and may have improved clinical outcomes. (Funded by the Scottish Government Chief Scientist Office; ClinicalTrials.gov number, NCT01425502.).

Quantifying the real life risk profile of inhaled corticosteroids in COPD by record linkage analysis.

BACKGROUND: Inhaled corticosteroids (ICS), especially when prescribed in combination with long-acting ß2 agonists have been shown to improve COPD outcomes. Although there is consistent evidence linking ICS with adverse effects such as pneumonia, the complete risk profile is unclear with conflicting evidence on any association between ICS and the incidence or worsening of existing diabetes, cataracts and fractures. We investigated this using record linkage in a Dundee COPD population. METHODS: A record linkage study linking COPD and diabetes datasets with prescription, hospitalisation and mortality data via a unique Community Health Index (CHI) number. A Cox regression model was used to determine the association between ICS use and new diabetes or worsening of existing diabetes and hospitalisations for pneumonia, fractures or cataracts after adjusting for potential confounders. A time dependent analysis of exposure comparing time on versus off ICS was used to take into account patients changing their exposure status during follow-up and to prevent immortal time bias. RESULTS: 4305 subjects (3243 exposed to ICS, total of 17,229 person-years of exposure and 1062 non exposed, with a follow-up of 4,508 patient-years) were eligible for the study. There were 239 cases of new diabetes (DM) and 265 cases of worsening DM, 550 admissions for pneumonia, 288 hospitalisations for fracture and 505 cataract related admissions. The hazard ratio for the association between cumulative ICS and outcomes were 0.70 (0.43-1.12), 0.57 (0.24-1.37), 1.38 (1.09-1.74), 1.08 (0.73-1.59) and 1.42 (1.07-1.88) after multivariate analysis respectively. CONCLUSION: The use of ICS in our cohort was not associated with new onset of diabetes, worsening of existing diabetes or fracture hospitalisation. There was however an association with increased cataracts and pneumonia hospitalisations.

Effectiveness of newspaper advertising for patient recruitment into a clinical trial.

AIMS: To measure the impact of newspaper advertising across Scotland on patient interest, and subsequent recruitment into the Standard Care vs. Celecoxib Outcome Trial (SCOT), a clinical trial investigating the cardiovascular safety of non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis. METHODS: Newspaper advertisements about the SCOT trial were placed sequentially in regional and national Scottish newspapers. The number of phone calls as a result of exposure to the advertisements and ongoing study recruitment rates were recorded before, during and after the advertising campaign. To enroll in SCOT individuals had to be registered with a participating GP practice. RESULTS: The total cost for the advertising campaign was £46 250 and 320 phone calls were received as a result of individuals responding to the newspaper advertisements. One hundred and seventy-two individuals were identified as possibly suitable to be included in the study. However only 36 were registered at participating GP practices, 17 completed a screening visit and 15 finally were randomized into the study. The average cost per respondent individual was £144 and the average cost per randomized patient was £3083. Analysis of recruitment rate trends showed that there was no impact of the newspaper advertising campaign on increasing recruitment into SCOT. CONCLUSIONS: Advertisements placed in local and national newspapers were not an effective recruitment strategy for the SCOT trial. The advertisements attracted relatively small numbers of respondents, many of whom did not meet study inclusion criteria or were not registered at a participating GP practice.