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Background While international guidelines recommend medication reviews as part of the management of multimorbidity, evidence on how to implement reviews in practice in primary care is lacking. The MultimorbiditY Collaborative Medication Review And Decision Making (MyComrade) intervention is an evidence-based, theoretically informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care. Our aim in this pilot study is to evaluate the feasibility of a trial of the intervention with unique modifications accounting for contextual variations in two neighbouring health systems (Republic of Ireland (ROI) and Northern Ireland (NI)). Methods A pilot cluster randomised controlled trial will be conducted, using a mixed-methods process evaluation to investigate the feasibility of a trial of the MyComrade intervention based on pre-defined progression criteria. A total of 16 practices will be recruited (eight in ROI; eight in NI), and four practices in each jurisdiction will be randomly allocated to intervention or control. Twenty people living with multimorbidity and prescribed ≥ 10 repeat medications will be recruited from each practice prior to practice randomisation. In intervention practices, the MyComrade intervention will be delivered by pairs of general practitioners (GPs) in ROI, and a GP and practice-based pharmacist (PBP) in NI. The GPs/GP and PBP will schedule the time to review the medications together using a checklist. Usual care will proceed in practices in the control arm. Data will be collected via electronic health records and postal questionnaires at recruitment and 4 and 8 months after randomisation. Qualitative interviews to assess the feasibility and acceptability of the intervention and explore experiences related to multimorbidity management will be conducted with a purposive sample of GPs, PBPs, practice administration staff and patients in intervention and control practices. The feasibility of conducting a health economic evaluation as part of a future definitive trial will be assessed. Discussion The findings of this pilot study will assess the feasibility of a trial of the MyComrade intervention in two different health systems. Evaluation of the progression criteria will guide the decision to progress to a definitive trial and inform trial design. The findings will also contribute to the growing evidence-base related to intervention development and feasibility studies. Trial registration ISRCTN Registry, ISRCTN80017020. Date of confirmation is 4/11/2019.

When the bortezomib [PS341], adriamycin and dexamethasone (PAD) regimen was first evaluated, the response rate in untreated patients was much superior to that elicited by conventional chemotherapeutic agents. We demonstrated the efficacy of PAD in relapsed or refractory patients by comparing the response rate obtained in 53 patients who received vincristine, adriamycin and dexamethasone (VAD) or equivalent regimen as induction therapy, using a comparative design in which each patient acted as their own control. Whereas 25 patients had a positive response to VAD, 37 patients had a response to PAD ≤ partial remission (PR) (p = 0.023). Using the more stringent response level of very good PR (VGPR) the results favored the PAD regimen very significantly (p = 0.006) (McNemars test). Similar results were seen using paired M-protein levels from individual patient comparisons. As the PAD regimen was subsequently adopted as the re-induction therapy in the British Society for Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) trial, now concluded, we have retrospectively analyzed the findings from both studies. Comparison of response rates and adverse effects of patients having had previous autologous transplantation (Cohort 1) with the corresponding data from Myeloma X showed close correlation. These findings provide evidence that rapid results may be obtained in the evaluation of newly introduced, and potentially highly effective, anti-tumour agents by direct comparison to the response to the immediately preceding standard regimen, particularly in relatively resistant tumours.

Background Post-term pregnancy is associated with an increased risk of maternal complications, respiratory distress and trauma to the neonate. Amniotic membrane sweeping has been recommended as a simple procedure to promote the spontaneous onset of labour. However, despite its widespread use, there is an absence of evidence on (a) its effectiveness and (b) its optimal timing and frequency. The primary aim of the MILO Study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. We will also assess the acceptability and feasibility of the proposed trial interventions to clinicians and women (through focus group interviews). Methods/design Multicentre, pragmatic, parallel-group, pilot randomised controlled trial with an embedded factorial design. Pregnant women with a live, singleton foetus ≥ 38 weeks gestation; cephalic presentation; longitudinal lie; intact membranes; English speaking and ≥ 18 years of age will be randomised in a 2:1 ratio to membrane sweep versus no membrane sweep. Women allocated randomly to a sweep will then be randomised further (factorial component) to early (from 39 weeks) versus late (from 40 weeks) sweep commencement and a single versus weekly sweep. The proposed feasibility study consists of four work packages, i.e. (1) a multicentre, pilot randomised trial; (2) a health economic analysis; (3) a qualitative study; and (4) a study within the host trial (a SWAT). Outcomes to be collected include recruitment and retention rates, compliance with protocol, randomisation and allocation processes, attrition rates and cost-effectiveness. Focus groups will be held with women and clinicians to explore the acceptability and feasibility of the proposed intervention, study procedures and perceived barriers and enablers to recruitment. Discussion The primary aim of the MILO Study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. Results will inform whether and how the design of the definitive trial as originally envisaged should be delivered or adapted. Trial registration ClinicalTrials.gov NCT04307199. Registered on 12 March 2020

Background Cognitive difficulties experienced by people with multiple sclerosis (MS) impact their quality of life and daily functioning, from childcare and work, to social and self-care activities. Despite the high prevalence of cognitive difficulties seen in MS, there is a lack of developed programmes that target cognition, while also supporting patients by helping them to function well in everyday life. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention. It addresses the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the current research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS. The focus is on feasibility outcomes as well as functioning associated with cognitive difficulty and secondary outcomes related to cognition, fatigue and quality of life. Methods One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment as usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The primary outcome measure is the goal attainment scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention and at 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants’ perspectives will also be examined as part of the feasibility study. Discussion Results will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. In the event that results indicate efficacy, study findings will suggest that COB-MS requires consideration as a means of enhancing cognitive and daily functioning in people living with MS. Trial registration ISRCTN: ISRCTN11462710. Registered on 9 September 2019.

Background: While low sodium intake ( Methods: This is a protocol for two phase IIb randomised, two-group, parallel, open-label, controlled, single centre trials. Participants were aged >40 years with stable blood pressure, unchanged anti-hypertensive medications, willing to modify diet and provided written informed consent. Participants were excluded for abnormal sodium handling, heart failure, high dose diuretics, immunosuppression, pregnancy/lactation, postural hypotension, cognitive impairment, high or low body mass index (BMI) or inclusion in another trial. STICK participants had estimated glomerular filtration rate (eGFR) 30-60ml/min/1.73m2 and were excluded for acute kidney Injury, rapidly declining eGFR; known glomerular disease or current use of non-steroidal anti-inflammatory drugs. For COSIP, participants were excluded for known kidney or cardiovascular disease. Participants were randomized to usual care only (healthy eating) or an additional sodium lowering intervention (target Discussion: These Phase II trials will explore uncertainty about low sodium intake and cardiovascular and kidney biomarkers, and help determine the feasibility of low sodium intake. Trial results will also provide preliminary information to guide a future definitive clinical trial, if indicated. Trial registration: STICK: ClinicalTrials.gov NCT02738736 (04/04/2016); COSIP: ClinicalTrials.gov NCT02458248 (15/05/2016)

Tree-based methods are a non-parametric modelling strategy that can be used in combination with generalized linear models or Cox proportional hazards models, mostly at an exploratory stage. Their popularity is mainly due to the simplicity of the technique along with the ease in which the resulting model can be interpreted. Variable selection bias from variables with many possible splits or missing values has been identified as one of the problems associated with tree-based methods. A number of unbiased recursive partitioning algorithms have been proposed that avoid this bias by using p -values in the splitting procedure of the algorithm. The final tree is obtained using direct stopping rules (pre-pruning strategy) or by growing a large tree first and pruning it afterwards (post-pruning). Some of the drawbacks of pre-pruned trees based on p -values in the presence of interaction effects and a large number of explanatory variables are discussed, and a simple alternative post-pruning solution is presented that allows the identification of such interactions. The proposed method includes a novel pruning algorithm that uses a false discovery rate (FDR) controlling procedure for the determination of splits corresponding to significant tests. The new approach is demonstrated with simulated and real-life examples.

In the resting state (closed or open eyes) electroencephalogram (EEG) and the magnetoencephalogram (MEG), rhythmic brain activity is very evident, typically the 10 Hz alpha rhythm. It has a topographic frequency spectral distribution that is, at first sight, quite similar for both modalities--something not surprising since both EEG and MEG are generated by the same basic oscillations in thalamocortical circuitry which produce primary current densities (PCD). However, different aspects (divergence and curl) of this PCD vector field underpin the two types of signals. Does this difference lead to a different distribution of reconstructed sources for EEG and MEG rhythms? This question is important for the transferal of results from one imaging modality to the other but has surprisingly received scant attention till now. We address this issue by comparing eyes open EEG source spectra recorded from 77 subjects from the Cuban Human Brain Mapping project with the MEG of 63 subjects from the Human Connectome Project. Source spectra for each voxel and frequency were obtained via a novel sparse-covariance inverse method: BC-VARETA based on individualized BEM head models with subject-specific regularization parameters (noise to signal ratio). While curtailing source leakage, the sparse BC VARETA estimator produces a large number of zero activations (zero inflation or ZI) which generates severe problems for traditional statistical methods. We circumvent the ZI problems by employing a novel dimensionality reduction technique known as Zero-inflated Factor Analysis (ZIFA). Both minimum energy and Hotelling’s T-2 tests showed that ZIFA scores for MEG and EEG sources were significantly different at all frequency bands. These results exclude a simple identification of the MEG and EEG sources of resting-state EEG rhythms. Further study is required to determine the relative contribution of instrumental, physical or physiological mechanisms to these differences.

Background: The association of lipid lowering therapy and intracerebral hemorrhage risk is controversial. Methods: We performed a cumulative meta-analysis of lipid lowering trials that reported intracerebral hemorrhage. Statin, fibrate, ezetimibe, PCSK9, and CETP trials were included. We explored whether the association of lipid lowering therapy and risk of intracerebral hemorrhage may vary by baseline low-density lipoprotein (LDL) level, mean change in LDL or baseline cardiovascular risk of population. Results: Among 39 trials (287,651 participants), lipid lowering therapy was not associated with a statistically significant increased risk of intracerebral hemorrhage (ICH) in primary and secondary prevention trials combined (odds ratio [OR], 1.12; 95% confidence interval [CI], .98-1.28). Lipid lowering was associated with an increased risk of ICH in secondary prevention trials (OR, 1.18; 95% CI, 1.00-1.38), but not in primary prevention trials (OR, 1.01; 95% CI, .78-1.30), but the test for interaction was not significant (P for interaction = .31). Meta-regression of baseline LDL or difference in LDL reduction between active and control did not explain significant heterogeneity between studies for ICH risk. Of 1000 individuals treated for 1 year for secondary prevention, we estimated 9.17 (95% CI, 5.78-12.66) fewer ischemic strokes and .48 (95% CI, .06-1.02) more ICH, and a net reduction of 8.69 in all stroke per 1000 person-years. Conclusions: The benefits of lipid lowering therapy in prevention of ischemic stroke greatly exceed the risk of ICH. Concern about ICH should not discourage stroke clinicians from prescribing lipid lowering therapy for secondary prevention of ischemic stroke.

Background The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. Methods Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = ‘Walk unaided’, 2 = ‘With walking aid’ and 3 = ‘Bed-bound’. The margin used to establish non-inferiority was a detrimental change of −0.4 in the mean difference between arms. Results One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30–87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was −0.12 to 0.6. Since −0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2–3 AE compared with six (11%) patients in the SF arm (p = 0.093). Conclusion For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. Clinical Trial Registration Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

To assess the impact of sharing personalised clinical information with people with type 2 diabetes prior to their out-patient consultation on patient involvement during the consultation, diabetes self-management self-efficacy and glycaemic control.A pilot three-arm randomised controlled trial. The 'intervention booklet' group received a booklet including personalised clinical information, a 'general information booklet' control group received a booklet with no personalised clinical information and a 'usual care' control group received no written information.136 people took part. The intervention group were significantly more likely to have shown the booklet to a 'significant other', (48% V 23%, p0.05), brought the booklet with them to the clinic (85% V 35%, p0.005) and to refer to the booklet during the consultation (45% V 13%, p0.005). No significant differences in patient involvement during the consultation, diabetes management self-efficacy or glycaemic control were found between the three groups.Although participants found it useful to receive their clinical results, no differences were found in the patient outcomes measured.Further pilot work on the timing of the intervention, who it is targeted at and what outcomes are measured is warranted before proceeding to a full-scale RCT.

Objectives To measure the number of people who have identified a behaviour change goal and completed an action-plan to meet their goal on completion of a diabetes self-management education programme (DSME) and level of success in sustaining their action-plan. The DSME people attended was Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND). Methods Copies of action-plans were collected from participants. Postal questionnaires were sent to participants one week and three months following DESMOND to assess factors associated with setting and sustaining action-plans. Results 92% (253/275) of participants completed an action-plan. Reducing weight was the area most targeted. Physical activity was the most common goal. 68% (187/275) returned a three month questionnaire. 96% indicated they were still working on their action plan, with 87% reporting they were always/usually meeting their action-plan. 22% said they had discussed their goal with a health care professional (HCP) following DESMOND. Conclusions Goal-setting as part of a DSME can lead to behaviour change. Practice implications Goal-setting as part of a DSME enables participants to set and attain behaviour change goals. Informing HCPs of a person's action-plan following a DSME may further support a person undertaking behaviour change.

In evidence-based medicine, randomised trials are regarded as a gold standard in estimating relative treatment effects. Nevertheless, a potential gain in precision is forfeited by ignoring observational evidence. We describe a simple estimator that combines treatment estimates from randomised and observational data and investigate its properties by simulation. We show that a substantial gain in estimation accuracy, compared with the estimator based solely on the randomised trial, is possible when the observational evidence has low bias and standard error. In the contrasting scenario where the observational evidence is inaccurate, the estimator automatically discounts its contribution to the estimated treatment effect. Meta-analysis extensions, combining estimators from multiple observational studies and randomised trials, are also explored.

Sixty patients with early chronic phase CML (ECPCML) received Nilotinib on a phase II study which included a comparison of the Xpert BCR-ABL Monitor™ PCR system with standardized (IS) BCR-ABL1 real-time quantitative PCR (RQ-PCR). 88% patients achieved MMR with 45% achieving MR4.5. At 3 months BCR-ABL1/ABL1 IS >1% and

Translational Statistics proposes to promote the use of Statistics within research and improve the communication of statistical findings in an accurate and accessible manner to diverse audiences. When statistical models become more complex, it becomes harder to evaluate the role of explanatory variables on the response. For example, the interpretation and communication of the effect of predictors in regression models where interactions or smoothing splines are included can be challenging. Informative graphical representations of statistical models play a critical translational role; static nomograms are one such useful tool to visualise statistical models. In this paper, we propose the use of dynamic nomogram as a translational tool which can accommodate models of increased complexity. In theory, all models appearing in the literature could be accompanied by the corresponding dynamic nomogram to translate models in an informative manner. The R package presented will facilitate this communication for a variety of linear and non-linear models.

Background: This is the first study to examine risk factors for diabetic foot ulceration in Irish general practice. Aim: To determine the prevalence of established risk factors for foot ulceration in a community-based cohort, and to explore the potential for estimated glomerular filtration rate (eGFR) to act as a novel risk factor. Design: A prospective observational study. Methods: Patients with diabetes attending 12 (of 17) invited general practices were invited for foot screening. Validated clinical tests were carried out at baseline to assess for vascular and sensory impairment and foot deformity. Ulcer incidence was ascertained by patient self-report and medical record. Patients were re-assessed 18 months later. Results: Of 828 invitees, 563 (68%) attended screening. On examination 23–25% had sensory dysfunction and 18–39% had evidence of vascular impairment. Using the Scottish Intercollegiate Guidelines Network risk stratification system we found the proportion at moderate and high risk of future ulceration to be 25% and 11%, respectively. At follow-up 16/383 patients (4.2%) developed a new foot ulcer (annual incidence rate of 2.6%). We observed an increasing probability of abnormal vascular and sensory test results (pedal pulse palpation, doppler waveform assessment, 10 g monofilament, vibration perception and neuropathy disability score) with declining eGFR levels. We were unable to show an independent association between new ulceration and reduced eGFR [Odds ratio 1.01; P = 0.64]. Conclusions: Our data show the extent of foot complications in a representative sample of diabetes patients in Ireland. Use of eGFR did not improve identification of patients at risk of foot ulceration.

peer-reviewed Background Physical inactivity is a major, potentially modifiable, risk factor for cardiovascular disease, cancer, and other chronic diseases. Effective, simple, and generalisable interventions that will increase physical activity in populations are needed. Aim To evaluate the effectiveness of a smartphone application (app) to increase physical activity in primary care. Design and setting An 8-week, open-label, randomised controlled trial in rural, primary care in the west of Ireland. Method Android smartphone users >16 years of age were recruited. All participants were provided with similar physical activity goals and information on the benefits of exercise. The intervention group was provided with a smartphone app and detailed instructions on how to use it to achieve these goals. The primary outcome was change in physical activity, as measured by a daily step count between baseline and follow-up. Results A total of 139 patients were referred by their primary care health professional or self-referred. In total, 37 (27%) were screened out and 12 (9%) declined to participate, leaving 90 (65%) patients who were randomised. Of these, 78 provided baseline data (intervention = 37; control = 41) and 77 provided outcome data (intervention = 37; control = 40). The mean daily step count at baseline for intervention and control groups was 4365 and 5138 steps per day respectively. After adjusting, there was evidence of a significant treatment effect (P = 0.009); the difference in mean improvement in daily step count from week 1 to week 8 inclusive was 1029 (95% confidence interval 214 to 1843) steps per day, favouring the intervention. Improvements in physical activity in the intervention group were sustained until the end of the trial. Conclusion A simple smartphone app significantly increased physical activity over 8 weeks in a primary care population.

Background: Sedentary lifestyles are now becoming a major concern for governments of developed and developing countries with physical inactivity related to increased all-cause mortality, lower quality of life, and increased risk of obesity, diabetes, hypertension and many other chronic diseases. The powerful onboard computing capacity of smartphones, along with the unique relationship individuals have with their mobile phones, suggests that mobile devices have the potential to influence behavior. However, no previous trials have been conducted using smartphone technology to promote physical activity. This project has the potential to provide robust evidence in this area of innovation. The aim of this study is to evaluate the effectiveness of a smartphone application as an intervention to promote physical activity in primary care.Methods/design: A two-group, parallel randomized controlled trial (RCT) with a main outcome measure of mean difference in daily step count between baseline and follow up over eight weeks. A minimum of 80 active android smartphone users over 16 years of age who are able to undertake moderate physical activity are randomly assigned to the intervention group (n = 40) or to a control group (n = 40) for an eight week period. After randomization, all participants will complete a baseline period of one week during which a baseline mean daily step count will be established. The intervention group will be instructed in the usability features of the smartphone application, will be encouraged to try to achieve 10,000 steps per day as an exercise goal and will be given an exercise promotion leaflet. The control group will be encouraged to try to walk an additional 30 minutes per day along with their normal activity (the equivalent of 10,000 steps) as an exercise goal and will be given an exercise promotion leaflet. The primary outcome is mean difference in daily step count between baseline and follow-up. Secondary outcomes are systolic and diastolic blood pressure, resting heart rate, mental health score using HADS and quality of life score using Euroqol. Randomization and allocation to the intervention and groups will be carried out by an independent researcher, ensuring the allocation sequence is concealed from the study researchers until the interventions are assigned. The primary analysis is based on mean daily step count, comparing the mean difference in daily step count between the baseline and the trial periods in the intervention and control groups at follow up. This study was funded by the EU Northern Periphery Program through the Implementing Transnational Telemedicine Solutions (ITTS) project (reference number 7.13). peer-reviewed