Hypoalbuminemia increases complications in elderly patients operated for hip fracture.

BACKGROUND: Hip fracture is a major cause of morbidity and mortality in elderly people. A drop in serum albumin after hip surgery has been reported, but few data are available on the effect on complications. The aim of this study was to assess the role of two distinct orthopedic surgical procedures (fixation or prosthesis) and pre-surgery albumin serum level on the development of clinical complications. METHODS: Of 176 subjects aged 65 and older with hip fracture hospitalized either in orthopedics or geriatrics ward in a 15-month period, the data of 152 patients were analyzed. Interventions were fixation or prosthesis. Measurements included gender, age, surgical procedure, medical complications, admission albumin level (g/L), and post-surgical albumin level (g/L). RESULTS: All patients (n = 152), regardless of the surgical procedure, underwent a loss of albumin from (mean ± standard deviation) 32.6 ± 4.3 to 25.0 ± 3.8 g/L. Complications were associated with albumin level both at pre-surgery (no complications mean ± SD 33.9 ± 3.5 g/L; n = 80; complications mean ± SD 31.2 ± 4.7 g/L; n = 72; p < 0.001) and post-surgery (no complications mean ± SD 26.2 ± 3.5 g/L; n = 80; complications mean ± SD 23.7 ± 3.6 g/L; n = 72; p < 0.001). When considering a multivariable model, an increased risk in the incidence of complications was found in subjects with preoperative albumin below 30 g/L (reference albumin greater than or equal to 30 g/L; OR 3.74; CI 95% 1.43-9.80) and in subjects undergoing prosthesis procedure (reference: fixation; OR 1.97; CI 95% 1.00-3.88). CONCLUSIONS: We observed that fixation and prosthesis were associated with a decrease in albumin level. Given a low pre-surgery level of albumin, the risk of complications was higher than in patient with pre-surgery normal level of albumin. This pilot study suggests further prospective research, considering whether albumin administration could be effective in preventing a fall in the albumin level after surgery, thus reducing the postoperative complication rate.

Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS.

BACKGROUND: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections. OBJECTIVE: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNß1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570). METHODS: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model. RESULTS: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen's d: RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNß1a (p < 0.001) or placebo (p < 0.001). CONCLUSION: Ocrelizumab effectively reduced thalamic volume loss compared with IFNß1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

Factor H interferes with the adhesion of sickle red cells to vascular endothelium: a novel disease-modulating molecule.

Sickle cell disease is an autosomal recessive genetic red cell disorder with a worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of clinical complications of sickle cell disease. In this study we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from patients with sickle cell disease. There was also deposition of C3b on sickle red cell membranes, which is promoted locally by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar "stop-and-go" motion of sickle cell red blood cells on tumor factor-α-activated vascular endothelial surfaces. Using the C3b/iC3b binding plasma protein factor Has an inhibitor of C3b cell-cell interactions, we found that factor H and its domains 19-20 prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells. We documented that factor H acts by preventing the adhesion of sickle red cells to P-selectin and/or the Mac-1 receptor (CD11b/CD18), supporting the activation of the alternative pathway of complement as an additional mechanism in the pathogenesis of acute sickle cell related vaso-occlusive crises. Our data provide a rationale for further investigation of the potential contribution of factor H and other modulators of the alternative complement pathway with potential implications for the treatment of sickle cell disease.

Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.

AIM: Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. METHODS: This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. RESULTS: We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00). CONCLUSION: Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.

Hemoglobin Concentration Affects Electroencephalogram During Cardiopulmonary Bypass: An Indication for Neuro-Protective Values.

Hemodilution during cardiopulmonary bypass (CPB) is widely used to decrease transfusion and improve microcirculation but has drawbacks, such as diminished hemoglobin levels. Among others, reduced brain oxygenation accounts for neurological adverse outcomes after CPB. The aim of the present study was to ascertain if and how continuous electroencephalogram (EEG) during CPB is affected by hematocrit level and what should be the minimum value to avoid significant frequency band shifts on the EEG. A comparative study design was used with 16 subjects undergoing elective mitral valve repair/replacement. EEG was continuously recorded during the surgical procedure (from anesthesia induction to 20 min after CPB end). Data were marked at relevant time points (T0: before CPB start; T1: after 30 min from CPB beginning; T2: at CPB end), and the following 2 min EEG analyzed with a fast Fourier transform to obtain relative power for delta, theta, alpha, and beta bands. A general linear model for repeated measure was used to study interactions of time (T0, T1, and T2, EEG frequency band, and topographical distribution. The relative powers for each electrode were calculated and represented using topographic maps. Power spectrum differences between time points (T2-T1; T2-T0; T1-T0) were calculated for each electrode, and differences >10%, considered indicative of neuronal sufferance, were included in further analysis. Cutoff hemoglobin values that maximize the proportion of correctly classified EEG band shifts were obtained by previous definition were obtained. At T2, diffuse EEG slowing in delta and theta bands was detected; a minor slowing over anterior regions was evident at T1 for the theta band. Decrements in EEG power greater than 10% were detected only for the delta band at T2. Hemoglobin concentration levels at which no slowing increase was evident were 9.4 mg/dL (Ht: 28.2%) at T1 and 9.2 mg/dL (Ht: 27.6%) at T2. EEG burst-suppression pattern related to a lesser degree of slowing at T2. In conclusion, we propose hemoglobin cutoff levels that prevent EEG slowing indicative of neuronal sufferance. In addition, burst-suppression EEG patterns offer higher central nervous system protection as measured on EEG.

Subcutaneous ocrelizumab in multiple sclerosis: Results of the Phase 1b OCARINA I study.

OBJECTIVE: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825). METHODS: Patients with relapsing or primary progressive multiple sclerosis (aged 18-65 years; Expanded Disability Status Scale score 0.0-6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 mg. Following dose escalation, new patients in Group A were randomized (1:1) to receive a single 600 mg intravenous ocrelizumab dose or the candidate subcutaneous dose, which was predicted to result in similar exposure as the 600 mg intravenous dose while being safe and well tolerated. The area under the concentration-time curve for both formulations was used to select the subcutaneous ocrelizumab dose. Patients in all cohorts could enter a dose-continuation phase. RESULTS: Eighty-eight and 47 patients were enrolled into Group A and B, respectively; most patients were female (72.7%/63.0%), and mean age at baseline was 45.7 and 39.7 years, respectively. Subcutaneous ocrelizumab was well tolerated across all doses tested. The 920 mg subcutaneous ocrelizumab dose was selected for the OCARINA II study based on pharmacokinetic and safety data. INTERPRETATION: Subcutaneous ocrelizumab may provide patients with multiple sclerosis with an additional treatment option.

Mild asthma and chronic bronchitis seem to influence functional exercise capacity: a multi-case control study.

BACKGROUND: In the Genes Environment Interaction in Respiratory Diseases population-based multi-case control study, we investigated whether asthma, chronic bronchitis (CB) and rhinitis were associated with a reduced 6-minute walk distance (6MWD), and whether the 6MWD determinants were similar for subjects with/without respiratory diseases. METHODS: Cases of asthma (n = 360), CB (n = 120), rhinitis (n = 203) and controls (no respiratory diseases: n = 302) were recruited. The variation in the 6MWD across the groups was analyzed by ANCOVA, adjusting for gender, age, height, weight and comorbidity. The 6MWD determinants were studied by linear regression, and heterogeneity across the cases and controls was investigated. RESULTS: The 6MWD differed across cases and controls (p = 0.01). It was shorter for cases of asthma (-17.1, 95% CI -28.3 to -5.8 m) and CB (-20.7, 95% CI: -36.6 to -4.8 m) than for controls (604 ± 68 m on average), but not for cases of rhinitis. The negative association between age and the 6MWD was significant for cases of CB, but not for the other groups (p = 0.001). CONCLUSIONS: Even at the level of severity found in the general population, asthma and CB could influence the 6MWD, which seems to reflect the functional exercise level for daily physical activities. The negative association between ageing and the 6MWD was particularly strong in subjects with CB. Our report adds to the mounting evidence that CB is not a trivial condition, especially in the ageing adult population, and it supports the importance of monitoring functional capacity and of physical reconditioning in mild asthma.

A minimum of 10-year follow-up of the Burch-Schneider cage and bulk allografts for the revision of pelvic discontinuity.

Eighteen consecutive hips with pelvic discontinuity and associated periprosthetic bone deficiency were treated with bulk allografts and Burch-Schneider antiprotrusio cage. Clinical and radiographic follow-up was performed at an average of 13.5 (range, 10.5-16.6) years. Three cages required re-revision because of infection (1) and aseptic loosening (2). Average Harris hip score improved from 31.9 to 77.0 points (P < .001). A severe resorption of the bone graft occurred in 2 hips. The stability of the cage was detected in 13 cases. The cumulative survival rate at 16.6 years with acetabular revision for any reason, radiographic loosening, or unhealing of the discontinuity as the end point was 72.2%. The use of Burch-Schneider cage and bulk allografts is an effective technique for the treatment of pelvic discontinuity.

Effects of Respiratory Disorders on Smoking Cessation and Re-Initiation in an Italian Cohort Study.

The present study aims to prospectively assess the influence of respiratory disorders on smoking cessation and re-initiation. Three population-based Italian cohorts answered a questionnaire on respiratory health and smoking habits during 1998-2001 and after a mean follow-up (SD) of 9.1 (0.8) years. Out of 1874 current smokers and 1166 ex-smokers at baseline, 965 (51.5%) and 735 (63.0%) reported their smoking status at follow-up. From current smokers, 312 had stopped smoking at follow-up, while 86 ex-smokers had resumed smoking. People reporting asthma at baseline were more likely to stop smoking than the other subjects (48.6% vs. 31.7%), while people reporting allergic rhinitis or chronic cough/phlegm had a higher probability to resume smoking (16.7% vs. 10.5% and 20.7% vs. 10.4%, respectively). In the multivariable logistic model, smoking relapse strongly decreased with increasing abstinence duration in people without chronic cough/phlegm (OR for ≥7.5 years vs. <7.5 years = 0.23, 95% CI 0.20-0.27), while no effect was detected in people with chronic cough/phlegm (p for interaction = 0.039). Smoking cessation was enhanced in asthmatic subjects, while people with allergic rhinitis or chronic cough/phlegm were at higher risk to resume smoking. Chronic cough/phlegm blunted the decrease in smoking resumption associated with longer abstinence duration.

Complement activation in the plasma and placentas of women with different subsets of antiphospholipid syndrome.

PROBLEM: As antiphospholipid antibody-positive women with adverse pregnancy outcomes have higher plasma complement activation product levels, and the placentas of women with antiphospholipid syndrome (APS) exhibit C4d complement component deposition, complement activation involvement has been hypothesized in APS pregnancy complications. METHOD OF STUDY: Plasma levels of C5a and C5b-9 complement components of 43 APS non-pregnant patients and 17 pregnant APS women were measured using enzyme-linked immunosorbent assay. The results were compared with those of 16 healthy non-pregnant women and eight healthy pregnant women, respectively. Placenta samples of five APS patients at high risk of pregnancy complications and of five healthy controls were subjected to immunoblotting analysis with specific antibodies to C5b-9 and CD46, CD55, CD59 complement regulators. RESULTS: The mean plasma C5a and C5b-9 levels were significantly higher in the non-pregnant APS patients with previous thrombosis ± pregnancy morbidity (P = .0001 and P = .0034, respectively) and in the pregnant APS women with adverse outcomes (P = .0093 for both). Similarly, C5b-9 amounts were significantly higher in the adverse pregnancy outcome placenta (P = .0115) than in those associated to a favorable outcome. The mean CD46, CD55 and CD59 amounts were, instead, lower, although not always significantly, in the placentas of all the high-risk APS women with respect to the control placentas. CONCLUSION: Data analysis demonstrated that there was significant complement activation in the more severe subset of APS patients and in only the adverse pregnancy outcome APS women. Further studies will clarify whether the lower CD46, CD55, and CD59 expressions in the APS placentas are limited to only high-risk APS patients.

Spritz: a server for the prediction of intrinsically disordered regions in protein sequences using kernel machines.

Intrinsically disordered proteins have long stretches of their polypeptide chain, which do not adopt a single native structure composed of stable secondary and tertiary structure in the absence of binding partners. The prediction of intrinsically disordered regions in proteins from sequence is increasingly becoming of interest, as the presence of many such regions in the complete genome sequences are discovered and important functional roles are associated with them. We have developed a machine learning approach based on two support vector machines (SVM) to discriminate disordered regions from sequence. The SVM are trained and benchmarked on two sets, representing long and short disordered regions. A preliminary version of Spritz was shown to perform consistently well at the recent biannual CASP-6 experiment [Critical Assessment of Techniques for Protein Structure Prediction (CASP), 2004]. The fully developed Spritz method is freely available as a web server at http://distill.ucd.ie/spritz/ and http://protein.cribi.unipd.it/spritz/.

Impact of pelvic floor muscle training on sexual function of women with urinary incontinence and a comparison of electrical stimulation versus standard treatment (IPSU trial): a randomised controlled trial.

AIMS: To evaluate the clinical and cost-effectiveness of electric stimulation plus standard pelvic floor muscle training compared to standard pelvic floor muscle training alone in women with urinary incontinence and sexual dysfunction. METHODS: Single centre two arm parallel group randomised controlled trial conducted in a Teaching hospital in England. Participants were women presenting with urinary incontinence and sexual dysfunction. The interventions compared were electric stimulation versus standard pelvic floor muscle training. OUTCOME MEASURES: included Prolapse and Incontinence Sexual function Questionnaire (PISQ) physical function dimension at post-treatment (primary); other dimensions of PISQ, SF-36; EQ-5D, EPAQ, resource use, adverse events and cost-effectiveness (secondary outcomes). RESULTS: 114 women were randomised (Intervention n=57; Control group n=57). 64/114 (56%). PARTICIPANTS: had valid primary outcome data at follow-up (Intervention 30; Control 34). The mean PISQ-PF dimension scores at follow-up were 33.1 (SD 5.5) and 32.3 (SD 5.2) for the Intervention and Control groups respectively; with the Control group having a higher (better) score. After adjusting for baseline score, BMI, menopausal status, time from randomisation and baseline oxford scale score the mean difference was -1.0 (95% CI: -4.0 to 1.9; P=0.474). There was no differences between the groups in any of the secondary outcomes at follow-up. Within this study, the use of electrical stimulation was cost-effective with very small incremental costs and quality adjusted life years (QALYs). CONCLUSIONS: In women presenting with urinary incontinence in conjunction with sexual dysfunction, physiotherapy is beneficial to improve overall sexual function. However no specific form of physiotherapy is beneficial over another. Trial registration ISRCTN09586238.

Open-label, cluster randomised controlled trial and economic evaluation of a brief letter from a GP on unscheduled medical contacts associated with the start of the school year: the PLEASANT trial.

BACKGROUND: Asthma is seasonal with peaks in exacerbation rates in school-age children associated with the return to school following the summer vacation. A drop in prescription collection in August is associated with an increase in the number of unscheduled contacts after the school return. OBJECTIVE: To assess whether a public health intervention delivered in general practice reduced unscheduled medical contacts in children with asthma. DESIGN: Cluster randomised trial with trial-based economic evaluation. Randomisation was at general practice level, stratified by size of practice. The intervention group received a letter from their general practitioner (GP) in late July outlining the importance of (re)taking asthma medication before the return to school. The control group was usual care. SETTING: General practices in England and Wales. PARTICIPANTS: 12 179 school-age children in 142 general practices (70 randomised to intervention). MAIN OUTCOME: Proportion of children aged 5-16 years who had an unscheduled contact in September. Secondary endpoints included collection of prescriptions in August and medical contacts over 12 months (September-August). Economic endpoints were quality-adjusted life-years gained and health service costs. RESULTS: There was no evidence of effect (OR 1.09; 95% CI 0.96 to 1.25 against treatment) on unscheduled contacts in September. The intervention increased the proportion of children collecting a prescription in August by 4% (OR 1.43; 95% CI 1.24 to 1.64). The intervention also reduced the total number of medical contacts between September-August by 5% (incidence ratio 0.95; 95% CI 0.91 to 0.99).The mean reduction in medical contacts informed the health economics analyses. The intervention was estimated to save £36.07 per patient, with a high probability (96.3%) of being cost-saving. CONCLUSIONS: The intervention succeeded in increasing children collecting prescriptions. It did not reduce unscheduled care in September (the primary outcome), but in the year following the intervention, it reduced the total number of medical contacts. TRIAL REGISTRATION NUMBER: ISRCTN03000938; Results.

Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM): study protocol for a randomised controlled trial.

BACKGROUND: The number of people with diabetes is growing rapidly. Diabetes can cause nerve damage leading to severe pain in the feet, legs and hands, which is known as diabetic peripheral neuropathic pain (DPNP). In the UK, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment for DPNP. If this is not effective, adding one of the other drugs in combination with the first is recommended. NICE points out that these recommendations are not based on robust evidence. The OPTION-DM randomised controlled trial has been designed to address this evidence deficit, with the aims of determining the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP. METHODS/DESIGN: A multicentre, double-blind, centre-stratified, multi-period crossover study with equal allocation to sequences (1:1:1:1:1:1) of treatment pathways. Three hundred and ninety-two participants will be recruited from secondary care DPNP centres in the UK. There are three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline and duloxetine supplemented with pregabalin. All participants will receive all three pathways and randomisation will determine the order in which they are received. The primary outcome is the difference between 7-day average 24-h pain scores on an 11-point NRS scale measured during the final follow-up week of the treatment pathway. Secondary outcomes for efficacy, cost-effectiveness, safety, patient-perceived tolerability and subgroup analysis will be measured at week 6 and week 16 of each pathway. DISCUSSION: The study includes direct comparisons of the mainstay treatment for DPNP. This novel study is designed to examine treatment pathways and capture clinically relevant outcomes which will make the results generalisable to current clinical practice. The study will also provide information on health economic outcomes and will include a subgroup study to provide information on whether patient phenotypes predict response to treatment. TRIAL REGISTRATION: ISRCTN17545443 . Registered on 12 September 2016.

Antidepressant-Induced Acute Liver Injury: A Case-Control Study in an Italian Inpatient Population.

INTRODUCTION: Pre-marketing clinical trials show that antidepressant-induced liver injury seems to be a rare adverse event. Because of short follow-up trial duration, the incidence of liver injury due to antidepressant use could be underestimated. OBJECTIVES: We aimed to quantify the risk of acute liver injury associated with antidepressant use through a case-control analysis among an inpatient population. METHODS: A multicenter study was carried out in nine Italian hospitals from October 2010 to January 2014, within the DILI-IT (Drug-Induced Liver Injury in Italy) study project. After exclusion of all patients with a clear competing cause of liver injury, cases were defined as adults admitted to the hospital with a diagnosis of acute liver injury, while controls had any other acute clinical condition not related to the liver. Antidepressant exposure was evaluated within 90 days prior to the date of the first sign/symptom of liver injury. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated as a measure of risk estimates for liver injury. RESULTS: We included 17 cases exposed to antidepressants matched to 99 controls. According to the features of liver injury, all cases showed symptomatic liver function test abnormalities at hospital admission, with the main signs/symptoms represented by fatigue, nausea, asthenia, or dark urine. Citalopram was the antidepressant mostly involved in the increase of liver enzymes, mainly alanine aminotransferase. Compared with non-use, current use of antidepressants was associated with a significantly increased risk of liver injury (adjusted OR, ORADJ, 1.84; 95% CI 1.02-3.32). Specifically, an increased, but not significant, risk of developing liver injury was observed for citalopram, a selective serotonin-reuptake inhibitor (ORADJ 1.82; 95% CI 0.60-5.53). CONCLUSION: The use of antidepressants is not as safe in terms of liver injury as expected; instead, the risk of antidepressant-induced liver injury is likely underestimated. The lack of significance does not reflect the absence of risk, but rather suggests the need to evaluate it in a wider setting of antidepressant users.

The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge. OBJECTIVE: To assess the feasibility of recruiting patients, collecting data and delivering EPR to patients with AECOPD to evaluate EPR compared with usual care. DESIGN: Parallel-group, pilot 2 × 2 factorial randomised trial with nested qualitative research and an economic analysis. SETTING: Two acute hospital NHS trusts. Recruitment was carried out from September 2015 to April 2016 and follow-up was completed in July 2016. PARTICIPANTS: Eligible patients were those aged ≥ 35 years who were admitted with AECOPD, who were non-acidotic and who maintained their blood oxygen saturation level (SpO2) within a prescribed range. Exclusions included the presence of comorbidities that affected the ability to undertake the interventions. INTERVENTIONS: (1) Hospital EPR: muscle training delivered at the patient's hospital bed using a cycle ergometer and (2) home EPR: a pulmonary rehabilitation programme delivered in the patient's home. Both interventions were delivered by trained physiotherapists. Participants were allocated on a 1 : 1 : 1 : 1 ratio to (1) hospital EPR (n = 14), (2) home EPR (n = 15), (3) hospital EPR and home EPR (n = 14) and (4) control (n = 15). Outcome assessors were blind to treatment allocation; it was not possible to blind patients. MAIN OUTCOME MEASURES: Feasibility of recruiting 76 participants in 7 months at two centres; intervention delivery; views on intervention/research acceptability; clinical outcomes including the 6-minute walk distance (6WMD); and costs. Semistructured interviews with participants (n = 27) and research health professionals (n = 11), optimisation assessments and an economic analysis were also undertaken. RESULTS: Over 7 months 449 patients were screened, of whom most were not eligible for the trial or felt too ill/declined entry. In total, 58 participants (76%) of the target 76 participants were recruited to the trial. The primary clinical outcome (6MWD) was difficult to collect (hospital EPR, n = 5; home EPR, n = 6; hospital EPR and home EPR, n = 5; control, n = 5). Hospital EPR was difficult to deliver over 5 days because of patient discharge/staff availability, with 34.1% of the scheduled sessions delivered compared with 78.3% of the home EPR sessions. Serious adverse events were experienced by 26 participants (45%), none of which was related to the interventions. Interviewed participants generally found both interventions to be acceptable. Home EPR had a higher rate of acceptability, mainly because patients felt too unwell when in hospital to undergo hospital EPR. Physiotherapists generally found the interventions to be acceptable and valued them but found delivery difficult because of staffing issues. The health economic analysis results suggest that there would be value in conducting a larger trial to assess the cost-effectiveness of the hospital EPR and hospital EPR plus home EPR trial arms and collect more information to inform the hospital cost and quality-adjusted life-year parameters, which were shown to be key drivers of the model. CONCLUSIONS: A full-scale randomised controlled trial using this protocol would not be feasible. Recruitment and delivery of the hospital EPR intervention was difficult. The data obtained can be used to design a full-scale trial of home EPR. Because of the small sample and large confidence intervals, this study should not be used to inform clinical practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18634494. 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. 22, No. 11. See the NIHR Journals Library website for further project information.

Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme.

BACKGROUND: Substantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope. OBJECTIVES: To review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UK's National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. DATA SOURCES AND STUDY SELECTION: HTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed. DATA EXTRACTION: Information was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers. MAIN OUTCOME MEASURES: Target sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data). RESULTS: This review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43-2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79-97%). CONCLUSIONS: There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.

Bridging the age gap in breast cancer: evaluation of decision support interventions for older women with operable breast cancer: protocol for a cluster randomised controlled trial.

INTRODUCTION: While breast cancer outcomes are improving steadily in younger women due to advances in screening and improved therapies, there has been little change in outcomes among the older age group. It is inevitable that comorbidities/frailty rates are higher, which may increase the risks of some breast cancer treatments such as surgery and chemotherapy, many older women are healthy and may benefit from their use. Adjusting treatment regimens appropriately for age/comorbidity/frailty is variable and largely non-evidence based, specifically with regard to rates of surgery for operable oestrogen receptor-positive disease and rates of chemotherapy for high-risk disease. METHODS AND ANALYSIS: This multicentre, parallel group, pragmatic cluster randomised controlled trial (RCT) (2015-18) reported here is nested within a larger ongoing 'Age Gap Cohort Study' (2012-18RP-PG-1209-10071), aims to evaluate the effectiveness of a complex intervention of decision support interventions to assist in the treatment decision making for early breast cancer in older women. The interventions include two patient decision aids (primary endocrine therapy vs surgery/antioestrogen therapy and chemotherapy vs no chemotherapy) and a clinical treatment outcomes algorithm for clinicians. ETHICS AND DISSEMINATION: National and local ethics committee approval was obtained for all UK participating sites. Results from the trial will be submitted for publication in international peer-reviewed scientific journals. IRAS REFERENCE: 115550. TRIAL REGISTRATION NUMBER: European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2015-004220-61;Pre-results. Sponsor's Protocol Code Number Sheffield Teaching Hospitals STH17086. ISRCTN 32447*.

PLEASANT: Preventing and Lessening Exacerbations of Asthma in School-age children Associated with a New Term - a cluster randomised controlled trial and economic evaluation.

BACKGROUND: Asthma episodes and deaths are known to be seasonal. A number of reports have shown peaks in asthma episodes in school-aged children associated with the return to school following the summer vacation. A fall in prescription collection in the month of August has been observed, and was associated with an increase in the number of unscheduled contacts after the return to school in September. OBJECTIVE: The primary objective of the study was to assess whether or not a NHS-delivered public health intervention reduces the September peak in unscheduled medical contacts. DESIGN: Cluster randomised trial, with the unit of randomisation being 142 NHS general practices, and trial-based economic evaluation. SETTING: Primary care. INTERVENTION: A letter sent (n = 70 practices) in July from their general practitioner (GP) to parents/carers of school-aged children with asthma to remind them of the importance of taking their medication, and to ensure that they have sufficient medication prior to the start of the new school year in September. The control group received usual care. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of children aged 5-16 years who had an unscheduled medical contact in September 2013. Supporting end points included the proportion of children who collected prescriptions in August 2013 and unscheduled contacts through the following 12 months. Economic end points were quality-adjusted life-years (QALYs) gained and costs from an NHS and Personal Social Services perspective. RESULTS: There is no evidence of effect in terms of unscheduled contacts in September. Among children aged 5-16 years, the odds ratio (OR) was 1.09 [95% confidence interval (CI) 0.96 to 1.25] against the intervention. The intervention did increase the proportion of children collecting a prescription in August (OR 1.43, 95% CI 1.24 to 1.64) as well as scheduled contacts in the same month (OR 1.13, 95% CI 0.84 to 1.52). For the wider time intervals (September-December 2013 and September-August 2014), there is weak evidence of the intervention reducing unscheduled contacts. The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children collecting prescriptions in August as well as having scheduled contacts in the same month. These unscheduled contacts in September could be a result of the intervention, as GPs may have wanted to see patients before issuing a prescription. The economic analysis estimated a high probability that the intervention was cost-saving, for baseline-adjusted costs, across both base-case and sensitivity analyses. There was no increase in QALYs. LIMITATION: The use of routine data led to uncertainty in the coding of medical contacts. The uncertainty was mitigated by advice from a GP adjudication panel. CONCLUSIONS: The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children both collecting prescriptions and having scheduled contacts in August. After September there is weak evidence in favour of the intervention. The intervention had a favourable impact on costs but did not demonstrate any impact on QALYs. The results of the trial indicate that further work is required on assessing and understanding adherence, both in terms of using routine data to make quantitative assessments, and through additional qualitative interviews with key stakeholders such as practice nurses, GPs and a wider group of children with asthma. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03000938. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 93. See the HTA programme website for further project information.