Introduction Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722–9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. Methods We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants’ blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. Results Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9–1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). Conclusion In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

This paper describes the development process of the ‘SKIP IT’ text messaging intervention to promote smoking cessation during pregnancy. Smoking during pregnancy is a major risk to mother and infant health. Pregnant women who smoke are more likely to experience complications during pregnancy, and babies born to women who smoke are likely to experience ongoing health needs. Previous interventions for reducing smoking in pregnant women have shown limited effectiveness. The objective was to develop an effective intervention to promote smoking cessation during pregnancy by examining the complex set of needs for facilitating positive behaviour change. This included engaging with clinicians and the target group of pregnant smokers to ensure the intervention is feasible and acceptable. Due to the linear nature of this development methods and results are presented together. Step 1: Literature review methods A series of literature reviews were carried to explore existing psychological theory relating to smoking cessation during pregnancy. The result was six ‘elements’ that, if achieved, are likely to increase the likelihood of a successful quit attempt: Step 2: Qualitative interviews Qualitative interviews were conducted with key stakeholder groups. The setting for this qualitative work was one large maternity unit in Scotland. Evidence supporting each of the ‘elements’ developed from the literature review was present. Step 3: Intervention development Evidence from the literature reviews and qualitative interviews was collated and a prototype intervention was developed based on storytelling and images. The final intervention consisted of frequent text messages sent to participants from a fictional character, ‘Megan’, who was designed as a coping model. Images corresponding to the current size of the fetus were sent weekly. Step 4: Alpha testing The intervention underwent alpha testing where the intervention was taken to a wider stakeholder group for feedback. The writing group refined the intervention to reflect changes to current smoking cessation technology, including e-cigarettes and extended the intervention to be delivered up to 6 weeks post-birth. Step 5: Focus groups and user feedback Qualitative user testing was carried out the two health boards. The views of the target group were used to develop an intervention that was demonstrated to be feasible in practice and both acceptable and engaging for participants. Step 6: Refining texts and coding Text messages were refined based on the user feedback. The final text messages were coded for the presence of Behavioural Change Techniques (BCTs) by two coders. We have developed a narrative and image-based intervention delivering by text message with the aim of supporting smoking cessation in pregnant women. Importantly, the intervention is rooted in an in-depth understanding of the target group, and their needs. Trials registration ClinicalTrials.gov Protocol ID: RMS2119.

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.

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.

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.

Background: Angiotensin-converting enzyme inhibitors and leucine are promising potential treatments for sarcopenia. Neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. Objectives: To determine the efficacy of leucine and perindopril in improving physical function in older people with sarcopenia, to evaluate the effect of leucine and perindopril on muscle mass and to evaluate the predictive biomarkers of sarcopenia. Design: A placebo-controlled, parallel group, double-blind, randomised 2 × 2 factorial trial. Setting: Primary care and geriatric medicine secondary care departments in 14 UK centres. Participants: Adults aged ≥ 70 years with low muscle strength and mass, without contraindications to angiotensin-converting enzyme inhibitors and without known diagnosis-specific skeletal myopathy. Interventions: Eligible participants were randomised 1 : 1 to receive 4 mg of oral perindopril or a matching placebo and, separately, were randomised 1 : 1 to receive 2.5 g of oral leucine powder or a matching placebo powder taken thrice daily with meals. Randomisation was performed using an interactive web-based randomisation system run independently of the research team to preserve allocation concealment. Main outcome measures: The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over the 12-month follow-up period. Other outcome measures included appendicular muscle mass, EQ-5D (EuroQol-5 Dimensions) quality-of-life score, grip strength, quadriceps strength, 6-minute walk distance, activities of daily living, hip bone mineral density and insulin resistance. All adverse events and falls were recorded. Protein-, DNA (deoxyribonucleic acid)- and RNA (ribonucleic acid)-based biomarkers were collected at baseline and at 3 and 12 months. Results: We screened 320 people and randomised 145 participants. Participants had a mean age of 79 (standard deviation 6) years, 78 (54%) were women and the mean SPPB was 7.0 (standard deviation 2.4). The median adherence was lower for perindopril than for placebo (76% vs. 96%; p < 0.001). Perindopril did not improve the primary outcome (adjusted treatment effect –0.1 points, 95% confidence interval –1.2 to 1.0 points). Quality of life was worse in the perindopril group (treatment effect –12 points, 95% confidence interval –21 to –3 points) and more adverse events occurred in the perindopril group (n = 218 vs. n = 165). Falls rates between the groups were similar and other secondary outcomes showed no significant treatment effect. For leucine compared with placebo, 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% confidence interval –1.0 to 1.1 points). No significant treatment effect was found for any secondary outcome. There were similar numbers of adverse events and falls in both groups. Limitations: The trial did not reach its original recruitment target; this trial alone cannot confidently exclude clinically important effects of either perindopril or leucine. Future work: Further exploration of biomarkers predicting response to sarcopenia interventions is warranted. Conclusions: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis confirmed the lack of efficacy of both treatments in improving physical performance. Study registration: This trial is registered as ISRCTN90094835 and EudraCT 2014-003455-61. The systematic review is registered as PROSPERO CRD42014013398. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.

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.Crown Copyright (c) 2022 Published by Elsevier B.V. CC_BY_NC_ND_4.0

Abstract 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.

Abstract Background Sarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre‐screening, performance of a questionnaire on physical function conducted as part of the pre‐screening telephone call, and performance of bioimpedance measurement to identify low muscle mass. Methods Hospital‐based recruitment took place through inpatient and outpatient geriatric medicine services. Local research nurses reviewed medical notes and approached potentially eligible patients. Primary care recruitment reviewed primary care lists from collaborating practices, sending mailshots to patients aged 70 and over who were not taking angiotensin‐converting enzyme inhibitors. Telephone pre‐screening was conducted either by research nurses at each site or centrally by Tayside Clinical Trials Unit. The 10‐point SARC‐F questionnaire was used for pre‐screening. De‐identified recruitment information was held on a central electronic tracking system and analysed using SPSS. Bioimpedance was measured using the Akern BIA 101 system, with the Sergi equation used to estimate lean mass. Results Fourteen UK sites recruited to the trial. The 1202 sets of notes in hospital‐based care were reviewed at these sites; 7 participants (0.6% of total notes screened) were randomized. From primary care, 13 808 invitations were sent; 138 (1.0% of total invited) were randomized. 633/2987 primary care respondents were pre‐screened centrally; the mean number of calls per respondent was 2.3. For 10 sites where central and local pre‐screening could be compared, the conversion rate from pre‐screening to randomization was 18/588 (3.1%) for centralized calls, compared with 73/1814 (4.0%) for local pre‐screening calls (P = 0.29). A weak relationship was seen between higher (worse) SARC‐F score at screening and lower likelihood of progression to randomization (r = −0.08, P = 0.03). Muscle mass estimates generated using the Sergi equation were systematically biased, and a recalibrated equation for bioimpedance‐estimated muscle mass was derived. Conclusions Primary care recruitment led to higher response rates and overall numbers randomized than hospital‐based recruitment. Centralized pre‐screening saved local research nurses' time but did not improve conversion to randomization. SARC‐F did not help to target screening activity in this sarcopenia trial, and a recalibration of the equation for estimating muscle mass from bioimpedance measures may improve accuracy of the screening process.

Background: Highly-effective direct acting antiviral drugs (DAAs) provide the opportunity to eliminate Hepatitis C (HCV) infection. This study examined whether a community pharmacy pathway increased treatment uptake, treatment completion and cure rates for people receiving opioid substitution therapy (OST), compared to conventional care.Methods: This cluster randomised trial was performed in 55 community pharmacies with patients receiving OST. Pharmacists either referred patients with evidence of HCV antibodies to conventional care (27 pharmacies) or assessed them in the pharmacy (28 pharmacies). All pharmacies were trained to offer dried blood spot testing (DBST). In the pharmacy arm, infection with HCV genotype 1 or 3 was confirmed, assessment bloods were taken, and DAAs were prescribed by a pharmacist. In the comparison arm, the patient received care outside the pharmacy. Once prescribed, medication in both arms was delivered as daily modified directly observed therapy alongside OST. The primary outcome was number of patients achieving sustained virologic response 12 weeks (SVR12) after treatment completion compared to total number of people receiving OST treatment at participating pharmacies.Findings: More OST users in the pharmacy arm versus the conventional care arm agreed to DBST (245 vs 145, OR 2∙292, 0∙968-5∙427, p=0∙059); more patients diagnosed with HCV, initiated (112 vs 61, OR 1∙889, 1∙276-2∙789, p=0∙0015) and completed treatment (108 vs 58, OR 1∙928, 1∙321-2∙813, p=0∙0007); more patients achieved the primary endpoint SVR12 in the pharmacy arm compared to the conventional arm (98 vs 43, OR 2∙375, 1∙555-3∙628, p< 0∙0001).Interpretation: Utilising pharmacists to deliver an HCV pathway, made testing and treatment more accessible for patients, whilst ensuring improved reach and maintaining high treatment success rates. Use of this pathway could form a key part on an integrated approach to HCV elimination.Trial Registration: Trial registration: NCT02706223.Funding Statement: Partnership between the Scottish Government, Gilead Sciences Inc. and Bristol Myers-Squib.Declaration of Interests: Dr Radley: Honorariums from Gilead and Abbvie; Research Grants from Gilead and Roche. Prof Donnan: Research grants from Novo Nordisk, GSK, Shire pharmaceuticals, Gilead and Bristol Myers Squibb. Member of the New Drugs Committee of the Scottish Medicines Consortium. Dr Barclay: Speakers fees from Abbvie, Gilead, and advisory board fees from Abbvie, BMS, Gilead, MSD. Professor Dillon: Research Grants, and Honorariums from Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck Roche Sharp & Dohme and Roche. All other authors declare no competing interests.Ethics Approval Statement: Ethics approval granted by East of Scotland Research Ethics Committee 2 (15/ES/0086), sponsor, research & development and Caldecott approvals by University of Dundee, NHS Tayside, NHS Grampian and NHS Greater Glasgow and Clyde.

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.

Background: In 2016, 26% of UK men were estimated to be obese. Systematic reviews suggest that few men engage in formal weight loss interventions that support weight reduction and improve health. Objective: To co-produce, with patient and public involvement, an acceptable and feasible randomised controlled trial design to test a men-only weight management intervention. Design: This was a two-phase feasibility study. Phase 1 was the development of intervention components, study procedures and materials including a discrete choice experiment with survey questions. Phase 2 was an individually randomised three-arm feasibility trial over 12 months. Qualitative interviews were conducted at 3 and 12 months. Setting: The setting was two sites in Scotland that had disadvantaged urban and rural areas and differed in employment levels and ethnic groups. Participants: In phase 1, 1045 men with obesity were recruited by Ipsos MORI (London, UK; www.ipsos.com/ipsos-mori/en-uk) to represent the UK population. In phase 2, 105 men with obesity were recruited in the community or through general practice obesity registers. Qualitative interviews were conducted with 50 men at 3 months and with 33 men at 12 months. Interventions: The trial arms were narrative short message service (SMS) for 12 months (SMS only), financial endowment incentive informed by loss aversion and linked to achievement of weight loss targets plus narrative SMS for 12 months (SMS + I), and waiting list control group for 12 months followed by 3 months of an alternative SMS style developed based on feedback from men who had received the narrative SMS (control). Main outcome measures: The main outcome measures were acceptability and feasibility of recruitment, retention, engagement, intervention components and trial procedures. Outcomes were assessed by examining procedural, quantitative and qualitative data at 3, 6 and 12 months. Results: The most acceptable incentive strategy, based on the discrete choice experiment results, was to verify weight loss of 5% at 3 months, verify weight loss of 10% at 6 months and maintain weight loss of 10% at 12 months. Overall, 105 men with obesity from across the socioeconomic spectrum were successfully recruited to target, 59% of whom lived in more disadvantaged areas. Retention at 12 months was acceptable (74%) and was higher among individuals from disadvantaged areas. Narrative SMS were acceptable to many men, with a minority reporting negative reactions. Incentives were acceptable but were not the primary motivation for behaviour change. Twelve men in the incentive arm (33%) secured at least some money and three (8%) secured the full amount. Both intervention arms lost some weight, with greater weight loss in the arm that received SMS and incentives. The alternative SMS based on men’s feedback received no strong negative reactions. Limitations: Fewer participants from the SMS + I arm (64%) completed the study at 12 months than did those in the SMS-only (79%) and control (83%) arms. The reasons for this difference were complex. Conclusions: The men-only weight management intervention consisting of narrative SMS and financial incentives was acceptable and feasible, meeting the progression criteria for a full trial. Tailoring of SMS may improve acceptability and retention. Future work: Minor refinements to the intervention components based on the study findings will be made prior to testing in a multisite definitive randomised controlled trial. Trial registration: ClinicalTrials.gov NCT03040518. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 11. See the NIHR Journals Library website for further project information.

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 pound per correct diagnosis, and a saving to the NHS of 3,216 pound 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. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The myriad of neuropsychiatric manifestations reported in myotonic dystrophy type 1 may have its origin in alterations of complex brain network interactions at the structural level. In this study, we tested the hypothesis that altered white matter microstructural integrity and network organisation were present in a cohort of individuals with DM1 compared to unaffected controls, which was expected to be associated with CNS related disease manifestations of DM1. We performed a cross-sectional neuropsychological assessment and brain MRI in 25 myotonic dystrophy type 1 (DM1) patients and 26 age, sex and educational level matched unaffected controls. Patients were recruited from the Dutch cohort of the OPTIMISTIC study, a concluded trial which had included ambulant, genetically confirmed DM1 patients who were severely fatigued. We applied graph theoretical analysis on structural networks derived from diffusion tensor imaging (DTI) data and deterministic tractography to determine global and local network properties and performed group-wise comparisons. Furthermore, we analysed the following variables from structural MRI imaging: semi-quantitative white matter hyperintensity load andwhite matter tract integrity using tract-based spatial statistics (TBSS). Structural white matter networks in DM1 were characterised by reduced global efficiency, local efficiency and strength, while the network density was compatible to controls. Other findings included increased white matter hyperintensity load, and diffuse alterations of white matter microstructure in projection, association and commissural fibres. DTI and network measures were associated (partial correlations coefficients ranging from 0.46 to 0.55) with attention (d2 Test), motor skill (Purdue Pegboard test) and visual-constructional ability and memory (copy subtest of the Rey-Osterrieth Complex Figure Test). DTI and network measures were not associated with clinical measures of fatigue (checklist individual strength, fatigue subscale) or apathy (apathy evaluation scale - clinician version). In conclusion, our study supports the view of brain involvement in DM1 as a complex network disorder, characterised by white matter network alterations that may have relevant neuropsychological correlations. This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013; grant agreement n° 305,697) and the Marigold Foundation.

Background: 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 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, which would maximise early diagnosis of liver related diseases. Our aim was to determine whether this new pathway of care, Intelligent Liver Function testing (iLFT) increased diagnosis of liver disease and was cost-effective.

Background: Vitamin D is known to be involved in the immune response to hepatitis C virus infection and preliminary data suggests that supplementation may improve response to treatment with interferon and ribavirin. Methods: The ViaDUCT study was a pilot, multi-centre, randomised, double-blind, placebo-controlled, parallel group clinical trial. Participants with hepatitis C who were planned for treatment were recruited and were randomised to 100,000 units oral vitamin D3 supplementation or placebo each month whilst undergoing treatment with interferon and ribavirin-based regimens. The primary outcome was sustained virologic responseat 12 weeks. Secondary outcomes were to identify the proportion of patients who dropped out and to assess for any increase in treatment-related toxicity. Study analyses were performed by modified intention to treat of the primary outcome which was compared between the two arms using logistic regression. Results: 72 participants were randomised; 35 to vitamin D and 37 to placebo. The mean age of participants was 42.5 and 41.7 years respectively. The majority of trial participants were male 25 (71%) in the vitamin D arm and 24 (65%) in the placebo arm. Following treatment, 60 (83%) attended for assessment of sustained virologic response at 12 weeks. Sustained virologic response was achieved in 82.9% (95%CI 67.3-91.9%) in the vitamin D arm and 73.0% (95%CI 57.0-84.6%) in the placebo arm. The odds of sustained virologic response at 12 weeks in the intervention arm was not significantly greater than in the placebo arm (adjusted odds ratio 1.74; 95%CI 0.43-6.97, p= 0.44). Adverse events were in keeping with the expected side effect profile of interferon and ribavirin based regimens. Conclusion: Vitamin D supplementation did not significantly improve sustained virologic response when added to interferon and ribavirin-based treatment. The apparent effect size observed would require a largertrial to establish any true effect of this adjunctive therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02053519, URL: https://clinicaltrials.gov/ct2/show/ NCT02053519, East of Scotland Research Ethics committee: 13/ES/0116