Multicentre trial of weekly risedronate on bone density in adults with cystic fibrosis

Background: The aim of this study was to assess the efficacy, tolerability and safety of risedronate in adults with CF. Methods: Patients with a lumbar spine (LS), total hip (TH) or femoral neck (FN) bone mineral density (BMD) Z-score of -1 or less were randomised to receive risedronate 35mg weekly or placebo, and calcium (1g)+vitamin D (800IU). Results: At baseline, BMD Z-scores in the risedronate (n = 17) and placebo (n = 19) groups were similar. By 24. months, 7/17 risedronate patients vs 0/19 placebo patients stopped the study medication due to bone pain. After 24. months treatment, the mean difference (95% CI) in change in LS, TH and FN BMD between the risedronate vs placebo groups was 4.3% (0.4, 8.2) p = 0.03; 4.0% (-0.5, 8.6) p = 0.08; and 2.4% (-3.5, 8.2) p =0.41. Conclusions: After two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo. © 2011 European Cystic Fibrosis Society.

On the Complexity of Universal Leader Election

Electing a leader is a fundamental task in distributed computing. In its implicit version, only the leader must know who is the elected leader. This paper focuses on studying the message and time complexity of randomized implicit leader election in synchronous distributed networks. Surprisingly, the most "obvious" complexity bounds have not been proven for randomized algorithms. The "obvious" lower bounds of O(m) messages (m is the number of edges in the network) and O(D) time (D is the network diameter) are non-trivial to show for randomized (Monte Carlo) algorithms. (Recent results that show that even O(n) (n is the number of nodes in the network) is not a lower bound on the messages in complete networks, make the above bounds somewhat less obvious). To the best of our knowledge, these basic lower bounds have not been established even for deterministic algorithms (except for the limited case of comparison algorithms, where it was also required that some nodes may not wake up spontaneously, and that D and n were not known).

We establish these fundamental lower bounds in this paper for the general case, even for randomized Monte Carlo algorithms. Our lower bounds are universal in the sense that they hold for all universal algorithms (such algorithms should work for all graphs), apply to every D, m, and n, and hold even if D, m, and n are known, all the nodes wake up simultaneously, and the algorithms can make anyuse of node's identities. To show that these bounds are tight, we present an O(m) messages algorithm. An O(D) time algorithm is known. A slight adaptation of our lower bound technique gives rise to an O(m) message lower bound for randomized broadcast algorithms.

An interesting fundamental problem is whether both upper bounds (messages and time) can be reached simultaneously in the randomized setting for all graphs. (The answer is known to be negative in the deterministic setting). We answer this problem partially by presenting a randomized algorithm that matches both complexities in some cases. This already separates (for some cases) randomized algorithms from deterministic ones. As first steps towards the general case, we present several universal leader election algorithms with bounds that trade-off messages versus time. We view our results as a step towards understanding the complexity of universal leader election in distributed networks.

Evaluation of an algorithm to guide patients with type 1 diabetes treated with continuous subcutaneous insulin infusion on how to respond to real-time continuous glucose levels:A randomized controlled trial

OBJECTIVE - To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). RESEARCH DESIGN AND METHODS - Sixty CSII-treated type 1 diabetic participants (aged 13-70 years, including adult and adolescent subgroups, with A1C =9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4-10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (=3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16-32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. RESULTS - In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7-8.2to 7.6% [7.2-8.0]; P <0.03) in group A but not in group B (7.8% [7.5-8.1] to 7.7 [7.3-8.0]; NS) with no difference between groups. More subjects in group A achieved A1C =7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. CONCLUSIONS - Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C =7%. Upon RT-CGM cessation, A1C returned to baseline. © 2010 by the American Diabetes Association.

First steps: study protocol for a randomized controlled trial of the effectiveness of the Group Family Nurse Partnership (gFNP) program compared to routine care in improving outcomes for high-risk mothers and their children and preventing abuse

Background: Evidence from the USA suggests that the home-based Family Nurse Partnership program (FNP), extending from early pregnancy until infants are 24 months, can reduce the risk of child abuse and neglect throughout childhood. FNP is now widely available in the UK. A new variant, Group Family Nurse Partnership (gFNP) offers similar content but in a group context and for a shorter time, until infants are 12 months old. Each group comprises 8 to 12 women with similar expected delivery dates and their partners. Its implementation has been established but there is no evidence of its effectiveness.

Methods/Design: The study comprises a multi-site randomized controlled trial designed to identify the benefits of gFNP compared to standard care. Participants (not eligible for FNP) must be either aged <20 years at their last menstrual period (LMP) with one or more previous live births, or aged 20 to 24 at LMP with low educational qualifications and no previous live births. 'Low educational qualifications' is defined as not having both Maths and English Language GCSE at grade C or higher or, if they have both, no more than four in total at grade C or higher. Exclusions are: under 20 years and previously received home-based FNP and, in either age group, severe psychotic mental illness or not able to communicate in English. Consenting women are randomly allocated (minimized by site and maternal age group) when between 10 and 16 weeks pregnant to either to the 44 session gFNP program or to standard care after the collection of baseline information. Researchers are blind to group assignment. The primary outcomes at 12 months are child abuse potential based on the revised Adult-Adolescent Parenting Inventory and parent/infant interaction coded using the CARE Index based on a video-taped interaction. Secondary outcomes are maternal depression, parenting stress, health related quality of life, social support, and use of services.

Discussion: This is the first study of the effectiveness of gFNP in the UK. Results should inform decision-making about its delivery alongside universal services, potentially enabling a wider range of families to benefit from the FNP curriculum and approach to supporting parenting.

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial

Background: Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.

Methods/Design: Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1: 1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.

Sublinear Bounds for Randomized Leader Election

This paper concerns randomized leader election in synchronous distributed networks. A distributed leader election algorithm is presented for complete n-node networks that runs in O(1) rounds and (with high probability) takes only O(n-vlog3/2n) messages to elect a unique leader (with high probability). This algorithm is then extended to solve leader election on any connected non-bipartiten-node graph G in O(t(G)) time and O(t(G)n-vlog3/2n) messages, where t(G) is the mixing time of a random walk on G. The above result implies highly efficient (sublinear running time and messages) leader election algorithms for networks with small mixing times, such as expanders and hypercubes. In contrast, previous leader election algorithms had at least linear message complexity even in complete graphs. Moreover, super-linear message lower bounds are known for time-efficientdeterministic leader election algorithms. Finally, an almost-tight lower bound is presented for randomized leader election, showing that O(n-v) messages are needed for any O(1) time leader election algorithm which succeeds with high probability. It is also shown that O(n 1/3) messages are needed by any leader election algorithm that succeeds with high probability, regardless of the number of the rounds. We view our results as a step towards understanding the randomized complexity of leader election in distributed networks.

A cluster randomised controlled trial of “Bookstart+”: a book gifting programme

Purpose – The purpose of this paper is to evaluate the effectiveness of a free book gifting programme, called “Bookstart+”, in improving family reading outcomes.

Design/methodology/approach – Bookstart+ consists of a pack of books and reading materials provided to families at their two-year-old child's statutory health visit. The pack is accompanied by a short priming demonstration, delivered by the health visitor, on shared reading. The evaluation took the form of a randomised controlled trial (RCT) with 460 families from the client lists of 115 health visitors.

Findings – The study found evidence of: a positive significant effect on parents’ attitudes to reading and books (Cohen's d=+0.192, p=0.034); no significant effect on parental attitudes to their child reading (d=+0.085, p=0.279); and a negative effect, approaching significance, on public library usage (d=-0.160, p=0.055).

Research limitations/implications – The attrition rate was high, with only 43.9 per cent of the target families completing all of the research. However, this level of attrition did not lead to any significant differences between the control and intervention groups on their pre-test measures.

Practical implications – The study provides recommendations for free book gifting service provision in relation to pack contents and delivery.

Originality/value – This paper contributes to the limited international RCT evidence on free book gifting programmes.

A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.

Methods: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.

Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).

Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

The Beta Agonist Lung Injury Trial Prevention:A Randomized Controlled Trial

Rationale: Experimental studies suggest that pretreatment with b-agonists might prevent acute lung injury (ALI).

Objectives: To determine if in adult patients undergoing elective esophagectomy, perioperative treatment with inhaled b-agonists effects the development of early ALI.

Methods:We conducted a randomized placebo-controlled trial in 12 UK centers (2008-2011). Adult patients undergoing elective esophagectomy were allocated to prerandomized, sequentially numbered treatment packs containing inhaled salmeterol (100 mg twice daily) or a matching placebo. Patients, clinicians, and researchers were masked to treatment allocation. The primary outcome was development of ALI within 72 hours of surgery. Secondary outcomes were ALI within 28 days, organ failure, adverse events, survival, and health-related quality of life. An exploratory substudy measured biomarkers of alveolar-capillary inflammation and injury.

Measurements and Main Results: A total of 179 patients were randomized to salmeterol and 183 to placebo. Baseline characteristics were similar. Treatment with salmeterol did not prevent early lung injury (32 [19.2%] of 168 vs. 27 [16.0%] of 170; odds ratio [OR], 1.25; 95% confidence interval [CI], 0.71-2.22). There was no difference in organ failure, survival, or health-related quality of life.Adverse events were less frequent in the salmeterol group (55 vs. 70; OR, 0.63; 95% CI, 0.39-0.99), predominantly because of a lower number of pneumonia (7 vs. 17; OR, 0.39; 95% CI, 0.16-0.96). Salmeterol reduced some biomarkers of alveolar inflammation and epithelial injury.

Conclusion: Perioperative treatment with inhaled salmeterol was well tolerated but did not prevent ALI.

Clinical trial registered with International Standard Randomized Controlled Trial Register (ISRCTN47481946) and European Union database of randomized Controlled Trials (EudraCT 2007-004096-19).Copyright © 2014 by the American Thoracic Society.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Effectiveness of a programme of exercise on physical function in survivors of critical illness following discharge from the ICU: study protocol for a randomised controlled trial (REVIVE)

Background: Following discharge home from the ICU, patients often suffer from reduced physical function, exercise capacity, health-related quality of life and social functioning. There is usually no support to address these longer term problems, and there has been limited research carried out into interventions which could improve patient outcomes. The aim of this study is to investigate the effectiveness and cost-effectiveness of a 6-week programme of exercise on physical function in patients discharged from hospital following critical illness compared to standard care.

Methods/Design: The study design is a multicentre prospective phase II, allocation-concealed, assessor-blinded, randomised controlled clinical trial. Participants randomised to the intervention group will complete three exercise sessions per week (two sessions of supervised exercise and one unsupervised session) for 6 weeks. Supervised sessions will take place in a hospital gymnasium or, if this is not possible, in the participants home and the unsupervised session will take place at home. Blinded outcome assessment will be conducted at baseline after hospital discharge, following the exercise intervention, and at 6 months following baseline assessment (or equivalent time points for the standard care group). The primary outcome measure is physical function as measured by the physical functioning subscale of the Short-Form-36 health survey following the exercise programme. Secondary outcomes are health-related quality of life, exercise capacity, anxiety and depression, self efficacy to exercise and healthcare resource use. In addition, semi-structured interviews will be conducted to explore participants’ perceptions of the exercise programme, and the feasibility (safety, practicality and acceptability) of providing the exercise programme will be assessed. A within-trial cost-utility analysis to assess the cost-effectiveness of the intervention compared to standard care will also be conducted.

Discussion: If the exercise programme is found to be effective, this study will improve outcomes that are meaningful to patients and their families. It will inform the design of a future multicentre phase III clinical trial of exercise following recovery from critical illness. It will provide useful information which will help the development of services for patients after critical illness.

Quantum annealing of an ising spin-glass by Green's function Monte Carlo

We present an implementation of quantum annealing (QA) via lattice Green's function Monte Carlo (GFMC), focusing on its application to the Ising spin glass in transverse field. In particular, we study whether or not such a method is more effective than the path-integral Monte Carlo- (PIMC) based QA, as well as classical simulated annealing (CA), previously tested on the same optimization problem. We identify the issue of importance sampling, i.e., the necessity of possessing reasonably good (variational) trial wave functions, as the key point of the algorithm. We performed GFMC-QA runs using such a Boltzmann-type trial wave function, finding results for the residual energies that are qualitatively similar to those of CA (but at a much larger computational cost), and definitely worse than PIMC-QA. We conclude that, at present, without a serious effort in constructing reliable importance sampling variational wave functions for a quantum glass, GFMC-QA is not a true competitor of PIMC-QA.

The effect of multiple micronutrient supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: a randomized, placebo-controlled trial:A randomized, placebo-controlled trial

Objectives: This study sought to investigate the effect of a multiple micronutrient supplement on left ventricular ejection fraction (LVEF) in patients with heart failure. Background: Observational studies suggest that patients with heart failure have reduced intake and lower concentrations of a number of micronutrients. However, there have been very few intervention studies investigating the effect of micronutrient supplementation in patients with heart failure. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study involving 74 patients with chronic stable heart failure that compared multiple micronutrient supplementation taken once daily versus placebo for 12 months. The primary endpoint was LVEF assessed by cardiovascular magnetic resonance imaging or 3-dimensional echocardiography. Secondary endpoints were Minnesota Living With Heart Failure Questionnaire score, 6-min walk test distance, blood concentrations of N-terminal prohormone of brain natriuretic peptide, C-reactive protein, tumor necrosis factor alpha, interleukin-6, interleukin-10, and urinary levels of 8-iso-prostaglandin F2 alpha. Results: Blood concentrations of a number of micronutrients increased significantly in the micronutrient supplement group, indicating excellent compliance with the intervention. There was no significant difference in mean LVEF at 12 months between treatment groups after adjusting for baseline (mean difference: 1.6%, 95% confidence interval: -2.6 to 5.8, p = 0.441). There was also no significant difference in any of the secondary endpoints at 12 months between treatment groups. Conclusions: This study provides no evidence to support the routine treatment of patients with chronic stable heart failure with a multiple micronutrient supplement. (Micronutrient Supplementation in Patients With Heart Failure [MINT-HF]; NCT01005303).

Feasibility trial of a film-based educational intervention for increasing boy's and girl's intentions to avoid teenage pregnancy: study protocol

The World Health Organisation, amongst others, recognises that adolescent men have a vital yet neglected role in reducing teenage pregnancies and that there is a pressing need for educational interventions designed especially for them. This study seeks to fill this gap by determining the feasibility of conducting an effectiveness trial of the If I Were Jack intervention in post-primary schools. This 4-week intervention aims to increase teenagers' intentions to avoid unintended pregnancy and addresses gender inequalities in sex education by explicitly focusing on young men. A cluster randomised feasibility trial with embedded process evaluation will determine: recruitment, participation and retention rates; quality of implementation; acceptability and feasibility of the intervention and trial procedures; and costs. (C) 2014 The Authors. Published by Elsevier Ltd.

Serum amyloid A-related inflammation is lowered by increased fruit and vegetable intake, while high-sensitive C-reactive protein, IL-6 and E-selectin remain unresponsive

The present study assessed whether increased fruit and vegetable (F&V) intake reduced the concentrations of the inflammatory marker serum amyloid A (SAA) in serum, HDL2 and HDL3 and whether the latter reduction influenced any of the functional properties of these HDL subfractions. The present study utilised samples from two previous studies: (1) the FAVRIT (Fruit and Vegetable Randomised Intervention Trial) study - hypertensive subjects (systolic blood pressure (BP) range 140-190 mmHg; diastolic BP range 90-110 mmHg) were randomised to receive a 1-, 3- or 6-portion F&V/d intervention for 8 weeks, and (2) the ADIT (Ageing and Dietary Intervention Trial) study - older subjects (65-85 years) were randomised to receive a 2- or 5-portion F&V/d intervention for 16 weeks. HDL2 and HDL3 were isolated by rapid ultracentrifugation. Measurements included the following: serum high-sensitive C-reactive protein (hsCRP) by an immunoturbidimetric assay; serum IL-6 and E-selectin and serum-, HDL2- and HDL3-SAA by ELISA procedures; serum-, HDL2- and HDL3-cholesterol ester transfer protein (CETP) activity by a fluorometric assay. Although the concentrations of hsCRP, IL-6 and E-selectin were unaffected by increasing F&V intake in both studies (P>0·05 for all comparisons), those of SAA in HDL3 decreased in the FAVRIT cohort (P= 0·049) and those in HDL2 and HDL3 decreased in the ADIT cohort (P= 0·035 and 0·032), which was accompanied by a decrease in the activity of CETP in HDL3 in the FAVRIT cohort (P= 0·010) and in HDL2 in the ADIT cohort (P= 0·030). These results indicate that SAA responds to increased F&V intake, while other inflammatory markers remain unresponsive, and this leads to changes in HDL2 and HDL3, which may influence their antiatherogenic potential. Overall, the present study provides tangible evidence of the effectiveness of increased F&V intake, which may be of use to health policy makers and the general public.