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Background: The addition of trastuzumab (H) to pre-operative chemotherapy in HER2+ breast cancer (H+BC) increases the rate of pathological complete response (pCR). TCH is a widely used adjuvant regimen in early stage H+BC. Lapatinib (L) is a small molecule HER2 antagonist that produces responses following H failure, and has been reported to augment H activity in combination in vitro. We compared neo-adjuvant docetaxel, carboplatin (TC) + H v TCL v TCHL in pts with H+BC. Methods: Pts with stages Ic–III H+BC were randomized to receive neo-adjuvant TCH, TCL or TCHL (ICORG/CTRIAL-IE 10-05, NCT01485926 www.clinicaltrials.gov). Pts subsequently underwent surgery and received H post-operatively for 1 year from the first dose of H. The primary endpoint of the trial was pCR. Secondary objectives were overall survival (OS) and relapse-free survival (RFS) and molecular and pharmacological markers of response. This study was supported by GSK, Novartis, The Cancer Clinical Research Trust and The Caroline Foundation. Results: When the NCIC CTG MA.31 trial reported inferior outcomes for L compared to H, we discontinued the TCL arm. This abstract reports data on the 76 pts recruited to the TCH and TCHL arms only, who included stage II (69.7%; n=53) or stage III disease (21.1%; n=16, with stage unknown for 9.2% (n=7). The final analysis set numbered 75 pts. Clinicopathological characteristics were well balanced between arms. The pCR rate of the two arms TCHL and TCH were virtually identical at 51.6% and 52.8% respectively (Fisher’s test p-value: 1.000). TCHL pts had significantly superior 5 year relapse-free survival (relative risk (RR) 0.171, 95% CI 0.041 – 0.713; log-rank test p-value = 0.009). OS was comparable between the TCH and TCHL groups (RR 0.205, 95% CI 0.025 – 1.675); log-rank test p-value = 0.2). Median RFS and OS were not reached. The most frequent serious adverse event was diarrhoea which occurred in 21.3% (n=16/75) pts (Grade 3 diarrhoea 13/16). One pt (TCH arm) who did not have protocol-mandated prophylactic G-CSF had a Grade 5 toxicity. One TCHL pt had a self-limiting diverticular perforation. There was a significantly higher frequency of severe diarrhoea in pts who received the TCHL regimen (Grade 3+, 32.4% vs 10.5%, p=0.038). The use of prophylactic loperamide reduced the frequency of diarrhoea in both the TCHL arm (86.2% vs 44.4%, p=0.004) and in the TCH arm (58.8% vs 24%, p=0.009). A post lock audit with minimum 9-year follow-up showed relapse rates of 15% TCHL vs 33% TCH. Conclusions: The study did not meet its primary pCR endpoint possibly due to a high TCH pCR rate, and small numbers. TCHL produced a statistically significant improvement in RFS compared to TCH. TCHL produced a higher rate of gastro-intestinal toxicity, but the use of loperamide significantly reduced the frequency of diarrhoea. These data suggest that anti-HER2 TKIs merit further investigation in the neo-adjuvant treatment of early stage H+BC. Table 1. pCR rates, 5 year RFS and OS results for ICORG/CTRIAL-IE 10-05 (NCT01485926) study pts. * significant, p Citation Format: John Crown, Denis M. Collins, Alex J. Eustace, Maccon Keane, Linda Coate, John Kennedy, Seamus O’Reilly, Catherine Kelly, Miriam O’Connor, Michael J. Martin, Conleth Murphy, Karen Duffy, Janice Walshe, Thamir Mahgoub, Giuseppe Gullo, Brian Moulton, Alberto Alvarez-Iglesias, Imelda Parker, Bryan Hennessy. Five year follow up of a randomized phase II comparison of neo-adjuvant docetaxel, carboplatin, trastuzumab with or without lapatinib in HER-2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-09.

The efficacy and safety of primary re-irradiation for MSCC are not known. Our aim was to establish the efficacy and safety of biologically effective dose-based re-irradiation.Patients presenting with MSCC at a previously irradiated spine segment, and not proceeding with surgical decompression, were eligible. A 3 Gray per fraction experimental schedule (minimum 18 Gy/6 fractions, maximum 30 Gy/10 fractions) was used, delivering a maximum cumulative spinal dose of 100 GyTwenty-two patients were enroled, of whom eleven were evaluable for the primary outcome. Nine of eleven (81.8%) had stable or improved Tomita scores at 5 weeks. One of eight (12.5%) evaluable for late toxicity developed RIM.Re-irradiation is an efficacious treatment for MSCC. There is a risk of RIM with a cumulative dose of 120 GyCancer Trials Ireland (ICORG 07-11); NCT00974168.

Oral anti-cancer medications (OAMs) are being used increasingly within cancer care. OAMs offer the potential to improve patient convenience and increase hospital capacity. The clinical assessment for each cycle of OAMs requires specialist patient review often performed in the acute hospital. Consequently, any improvement in patient expediency or increased hospital capacity is not realised. This study aimed to develop and pilot the specialist assessment of patients receiving OAMs by an Advanced Nurse Practitioner (ANP) in a community setting. The primary aim of this pilot study was to assess the feasibility of a community-based ANP-led integrated oncology care model for adults receiving OAMs in Ireland who met the pre-specified eligibility criteria. The objectives were to determine the feasibility of a definitive trial of this intervention by measuring patient safety, acceptability to patients and staff and cost of the new model of care. This single-centre pilot study provided patient care (n = 37) to those receiving OAM therapies within a community setting for a 4-month period. Consent rate was high with no attrition other than for clinical reasons. There were 151 contacts with the sample during that time. Results demonstrated that the ANP-led intervention and new model for OAM care was safe, highly acceptable to patients and staff and that related healthcare costs could be captured. Based on the success of this pilot study the authors conclude that an ANP-led integrated oncology care model for adults receiving OAMs within a community setting is feasible, and a definitive trial is warranted. Trial Registration Trial registration: ISRCTN, ISRCTN10401455. Registered 30 November 2020, https://doi.org/10.1186/ISRCTN10401455

BACKGROUND: While low sodium intake (40 years with stable blood pressure (BP), without heart failure or postural hypotension were randomised to intensive dietary counselling (target sodium intake

ImportancePsychosocial stress is considered a modifiable risk factor for stroke. Given the prevalence of chronic and acute exposure to stress, it represents a potentially attractive target for population-health interventions.ObjectivesTo determine the association of psychosocial stress with the risk of acute stroke and explore factors that might modify the association of stress with risk of acute stroke in a large international population.Design, Setting, and ParticipantsINTERSTROKE is an international retrospective case-control study of risk factors for first acute stroke in 32 countries in Asia, North and South America, Europe, Australia, the Middle East, and Africa. A total of 13 462 patients with stroke and 13 488 matched controls were recruited between January 11, 2007, and August 8, 2015. The present analyses were performed from June 1 to 30, 2021, and included 13 350 cases and 13 462 controls with available data on psychosocial stress.ExposuresPsychosocial stress and occurrence of stressful life events within the preceding year were measured using a standardized questionnaire of self-reported stress at home and work.Main Outcomes and MeasuresThe association of stress with acute stroke and its subtypes was examined using multivariable conditional logistic regression and factors that might modify the association, particularly self-reported locus of control.ResultsAmong 26 812 participants included in the analysis, the mean (SD) age of cases was 62.2 (13.6) years; that of controls, 61.3 (13.3) years; 7960 cases (59.6%) and 8017 controls (59.6%) were men. Several periods of stress and permanent stress were reported for 2745 cases (20.5%) and 1933 controls (14.4%), with marked regional variation in prevalence, with the lowest in China (201 of 3981 [5.0%] among controls and 364 of 3980 [9.1%] among cases) and highest in South East Asia (233 of 855 [26.1%] among controls and 241 of 782 [30.8%] among cases). Increased stress at home (odds ratio [OR], 1.95 [95% CI, 1.77-2.15]) and at work (OR, 2.70 [95% CI, 2.25-3.23]) and recent stressful life events (OR, 1.31 [95% CI, 1.19-1.43]) were associated with an increased risk of acute stroke on multivariable analyses (vs no self-reported stress). Higher locus of control at home was associated with a reduced odds of all stroke (OR, 0.73 [95% CI, 0.68-0.79]), and higher locus of control both at work and at home were associated with a lower odds of acute stroke and significantly diminished the association with stress at work (OR, 2.20 [95% CI, 1.88-2.58]; P = .008 for interaction) and home (OR, 1.69 [95% CI, 1.44-1.98]; P < .001 for interaction) for acute stroke.Conclusions and RelevancePsychosocial stress is a common risk factor for acute stroke. The findings of this case-control study suggest that higher locus of control is associated with lower risk of stroke and may be an important effect modifier of the risk associated with psychosocial stress.

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.

BackgroundNon-pharmaceutical interventions (NPI) play a key role in managing epidemics, yet it is challenging to evaluate their impacts on disease spread and outcomes.MethodsTo estimate the effect of a mask-wearing intervention to mitigate the spread of SARS-CoV-2 on the island of Ireland, we focused on the potential for interindividual infectious contact over time as the outcome. This is difficult to measure directly; in a companion paper we estimated it using a multi-strain epidemiological model. We used data on mask-wearing and mobility in both Northern Ireland (NI) and the Republic of Ireland (ROI) to predict independently the estimated infectious contact over time. We made counterfactual predictions of infectious contact rates and hospitalisations under a hypothetical intervention where 90% of the population were wearing masks during early 2020, when in reality few people were wearing masks in public; this was mandated in both jurisdictions on 10th August 2020.ResultsThere were 1601 hospitalisations with COVID-19 in NI between 12th March and 10th August 2020, and 1521 in ROI between 3rd April and 10th August 2020. Under the counterfactual mask-wearing scenario, we estimated 512 (95% CI 400, 730) hospitalisations in NI, and 344 (95% CI 266, 526) in ROI, during the same periods.ConclusionsWe have estimated a large effect of population mask-wearing on COVID-19 hospitalisations. This could be partly due to other factors that were also changing over time.

Mathematical modelling plays a key role in understanding and predicting the epidemiological dynamics of infectious diseases. We construct a flexible discrete-time model that incorporates multiple viral strains with different transmissibilities to estimate the changing infectious contact that generates new infections. Using a Bayesian approach, we fit the model to longitudinal data on hospitalisation with COVID-19 from the Republic of Ireland and Northern Ireland during the first year of the pandemic. We describe the estimated change in infectious contact in the context of governmentmandated non-pharmaceutical interventions in the two jurisdictions on the island of Ireland. We take advantage of the fitted model to conduct counterfactual analyses exploring the impact of lockdown timing and introducing a novel, more transmissible variant. We found substantial differences in infectious contact between the two jurisdictions during periods of varied restriction easing and December holidays. Our counterfactual analyses reveal that implementing lockdowns earlier would have decreased subsequent hospitalisation substantially in most, but not all cases, and that an introduction of a more transmissible variant - without necessarily being more severe - can cause a large impact on the health care burden.

Reliable remote cognitive testing could provide a safer assessment of cognitive impairment in multiple sclerosis (MS) during the COVID-19 pandemic and thereafter. Here we aimed to investigate the reliability and feasibility of administering Brief International Cognitive Assessment for MS (BICAMS) and the Trail-Making Test (TMT) to people with MS online. Between-group differences on BICAMS and the TMT were examined in a sample of 68 participants. Group 1 (N = 34) was tested in-person pre-pandemic. Group 2 was tested remotely. Within-group differences for in-person and virtual administrations were examined for Group 1. No significant differences between virtual and in-person administrations of the CVLT-II and SDMT were detected. BVMT-R scores were significantly higher for virtual administrations (M = 20.59, SD = 6.65) compared to in-person administrations (M = 16.35, SD = 6.05), possibly indicating inter-rater differences. Strong positive correlations were found for in-person and virtual scores within Group 1 on the CVLT-II (r = .84), SDMT (r = .85), TMT-A (r = .88), TMT-B (r = .76) and BVMT-R (r = .72). No significant differences between in-person and remote administrations of CVLT-II and SDMT in people living with MS were detected. Recommendations for future studies employing the TMT and BVMT-R online are provided. This study-within-a-trial was conducted within a trial funded by the Health Research Board (Ireland) under a Definitive Interventions and Feasibility Award [grant number DIFA-FA-2018-027]. peer-reviewed

295 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) remains controversial, specifically whether multimodal therapy or perioperative chemotherapy is superior. Neo-AEGIS was designed as the first randomized clinical trial (RCT) to directly compare the multimodal CROSS regimen (carboplatin/paclitaxel, 41.4Gy radiation therapy) with a modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) regimen (pre-2018) and more latterly the FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin) regimen. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5% for peri-operative chemotherapy. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 34.2 (0.43-111.8) months, there were 186 deaths, 91 CROSS and 95 MAGIC/FLOT arm, with 3-year estimated survival probability of 57% (95% CI 49,64) and 55% (95% CI 47,62), respectively [(HR 1.03 (95%CI. 0.77-1.38))]. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy in the primary outcome of overall survival, notwithstanding greater proxy markers of local tumor response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in clinical decision making in modern practice. Clinical trial information: NCT01726452 . [Table: see text]

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: This protocol describes a double-blind, randomised non-inferiority study-within-a-trial (SWAT), comparing the effects of a patient-designed-and-informed participant information sheet with a standard, researcher-designed participant information sheet on recruitment, retention, decision certainty, participant information sheet understanding and likeability. The SWAT is part of a larger trial that aims to evaluate the feasibility and preliminary efficacy of a cognitive occupation-based programme for people with MS (COB-MS) on cognitive and daily functioning for people with multiple sclerosis. Methods: During the study, 120 people with multiple sclerosis will be randomly allocated to one of the two groups, where they will either receive a standard participant information sheet or a patient-designed participant information sheet. Recruitment and retention will be analysed, as well as decision certainty, likability and understanding. Discussion: Results will provide recommendations for recruitment, consent and retention for future trials, as well as shed some light on the factors influencing the understanding and likeability of a trial’s participant information sheet. Recommendations will also be made regarding patient and public involvement in developing and/or aiding the development of participant information sheets. Registration: SWAT: Northern Ireland Hub for Trials Methodology Research SWAT Repository Store (SWAT105). COB-MS trial: ISRCTN11462710.

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.

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.

Globally numerous regions have been identified with elevated arsenic within groundwater which can result in potential adverse health risks. In Ireland, a previous national-scale research assessment of groundwater identified isolated clusters of elevated arsenic and indicated that lithology was a major controlling factor on arsenic in groundwater. Complementary comparisons of national-scale and regional-scale groundwater assessments of arsenic are lacking in Europe when compared to other global regions. The aims of this study were to demonstrate the value of a regional-scale groundwater hydrochemistry dataset with an existing national-scale approach, describe anomalies that can become the focus of attention for public health and economic reasons, and to provide a wider context for arsenic in groundwater within Ireland and Europe. Regional-scale data using 470 locations comprising 1,493 analyses using several hydrochemical parameters (arsenic, pH, conductivity, iron, manganese, sodium, potassium, calcium, magnesium, and total hardness) in south west Ireland were integrated with geological, hydrogeological, and land use datasets. Statistical analysis was performed using a combination of methods including score tests of geological groups using an empirical cumulative distribution function plot in addition to spatial analysis. Results revealed that hydrochemical parameters exhibited different spatial clusters, which was generally associated with lithology. Arsenic was elevated in sandstone derived bedrock. Weak correlation of arsenic with other hydrochemical parameters were observed and redox-sensitive elements like manganese and iron showed a greater diversity in spatial occurrence. This study has shown that the variation of hydrochemical parameters are controlled by regional geology. Finally, the paper focuses on anomalies identified by concentrations of individual ions or statistical associations in the context of, for example, historical mineral exploration and mining in the area and also discusses whether groundwater chemistry sampling on this scale can assist in future mineral exploration, as well as guiding the future development of high quality public and private water supplies. Funding based on research grant-aided by the Department of Communications, Energy and Natural Resources under the National Geoscience Programme 2007-2013. The views expressed in this study are the author's own and do not necessarily reflect the views and opinions of the Minister for Communications, Energy and Natural Resources. The authors acknowledge support of the HEA under PRTLI4 for licensing OSI Digital Imagery through the Ryan Institute. This work includes Ordnance Survey Ireland data reproduced under OSi License number NUIG220212. Unauthorized reproduction infringes Ordnance Survey Ireland and Government of Ireland copyright. © Ordnance Survey Ireland, 2012. The authors would like to thank the members of local government for data collection (particularly David Lenihan) and David Ball and Taly Hunter Williams for providing invaluable discussions on the manuscript. The authors would also like to thank David Ball for preparation of Figure 2 for this paper. peer-reviewed

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.

Chronic diseases tend to depend on a large number of risk factors, both environmental and genetic. Average attributable fractions were introduced by Eide and Gefeller as a way of partitioning overall disease burden into contributions from individual risk factors; this may be useful in deciding which risk factors to target in disease interventions. Here, we introduce new estimation methods for average attributable fractions that are appropriate for both case–control designs and prospective studies. Confidence intervals, derived using Monte Carlo simulation, are also described. Finally, we introduce a novel approximation for the sample average attributable fraction that will ensure a computationally tractable approach when the number of risk factors is large. An R package, averisk, implementing the methods described in this manuscript can be downloaded from the CRAN repository. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by grant from European Research Council. peer-reviewed

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.

The mean residual life function provides a clear and simple summary of the effect of a treatment or a risk factor in units of time, avoiding hazard ratios or probability scales, which require careful interpretation. Estimation of the mean residual life is complicated by the upper tail of the survival distribution not being observed as, for example, patients may still be alive at the end of the follow-up period. Various approaches have been developed to estimate the mean residual life in the presence of such right censoring. In this work, a novel semi-parametric method that combines existing non-parametric methods and an extreme value tail model is presented, where the limited sample information in the tail (prior to study termination) is used to estimate the upper tail behaviour. This approach will be demonstrated with simulated and real-life examples. Copyright © 2015 John Wiley & Sons, Ltd.

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