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Background: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer’s disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. Objectives: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. Methods: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/ care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. Results: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. Conclusions: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or

Background: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. Method(s): We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. Discussion(s): Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. Trial identifiers: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.Copyright © 2021, The Author(s).

Introduction Emerging evidence indicates that rehabilitation can improve ataxia, mobility and independence in everyday activities in individuals with hereditary cerebellar ataxia. However, with the rarity of the genetic ataxias and known recruitment challenges in rehabilitation trials, most studies have been underpowered, non-randomised or non-controlled. This study will be the first, appropriately powered randomised controlled trial to examine the efficacy of an outpatient and home-based rehabilitation programme on improving motor function for individuals with hereditary cerebellar ataxia. Methods and analysis This randomised, single-blind, parallel group trial will compare a 30-week rehabilitation programme to standard care in individuals with hereditary cerebellar ataxia. Eighty individuals with a hereditary cerebellar ataxia, aged 15 years and above, will be recruited. The rehabilitation programme will include 6 weeks of outpatient land and aquatic physiotherapy followed immediately by a 24-week home exercise programme supported with fortnightly physiotherapy sessions. Participants in the standard care group will be asked to continue their usual physical activity. The primary outcome will be the motor domain of the Functional Independence Measure. Secondary outcomes will measure the motor impairment related to ataxia, balance, quality of life and cost-effectiveness. Outcomes will be administered at baseline, 7 weeks, 18 weeks and 30 weeks by a physiotherapist blinded to group allocation. A repeated measures mixed-effects linear regression model will be used to analyse the effect of the treatment group for each of the dependent continuous variables. The primary efficacy analysis will follow the intention-to-treat principle. Ethics and dissemination The study has been approved by the Monash Health Human Research Ethics Committee (HREC/18/MonH/418) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Re

Background: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. Method(s): We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. Discussion(s): Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. Trial identifiers: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.Copyright © 2021, The Author(s).

Introduction Emerging evidence indicates that rehabilitation can improve ataxia, mobility and independence in everyday activities in individuals with hereditary cerebellar ataxia. However, with the rarity of the genetic ataxias and known recruitment challenges in rehabilitation trials, most studies have been underpowered, non-randomised or non-controlled. This study will be the first, appropriately powered randomised controlled trial to examine the efficacy of an outpatient and home-based rehabilitation programme on improving motor function for individuals with hereditary cerebellar ataxia. Methods and analysis This randomised, single-blind, parallel group trial will compare a 30-week rehabilitation programme to standard care in individuals with hereditary cerebellar ataxia. Eighty individuals with a hereditary cerebellar ataxia, aged 15 years and above, will be recruited. The rehabilitation programme will include 6 weeks of outpatient land and aquatic physiotherapy followed immediately by a 24-week home exercise programme supported with fortnightly physiotherapy sessions. Participants in the standard care group will be asked to continue their usual physical activity. The primary outcome will be the motor domain of the Functional Independence Measure. Secondary outcomes will measure the motor impairment related to ataxia, balance, quality of life and cost-effectiveness. Outcomes will be administered at baseline, 7 weeks, 18 weeks and 30 weeks by a physiotherapist blinded to group allocation. A repeated measures mixed-effects linear regression model will be used to analyse the effect of the treatment group for each of the dependent continuous variables. The primary efficacy analysis will follow the intention-to-treat principle. Ethics and dissemination The study has been approved by the Monash Health Human Research Ethics Committee (HREC/18/MonH/418) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Re

IntroductionType 2 diabetes has been linked to greater cognitive decline, but other glycemic parameters such as prediabetes, diabetes control and treatment, and HOMA-IR and HbA(1c) diabetes-related biomarkers have shown inconsistent results. Furthermore, there is limited research assessing these relationships in short-term studies. Thus, we aimed to examine 2-year associations between baseline diabetes/glycemic status and changes in cognitive function in older participants at high risk of cardiovascular disease. MethodsWe conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. At baseline, participants were categorized by diabetes status (no-diabetes, prediabetes, and <5 or >= 5-year diabetes duration), and also by diabetes control. Furthermore, insulin resistance (HOMA-IR) and glycated hemoglobin (HbA(1c)) levels were measured, and antidiabetic medications were recorded. Linear and logistic regression models, adjusted by potential confounders, were fitted to assess associations between glycemic status and changes in cognitive function. ResultsPrediabetes status was unrelated to cognitive decline. However, compared to participants without diabetes, those with >= 5-year diabetes duration had greater reductions in GCF (beta=-0.11 (95%CI -0.16;-0.06)], as well as in processing speed and executive function measurements. Inverse associations were observed between baseline HOMA-IR and changes in GCF [beta=-0.0094 (95%CI -0.0164;-0.0023)], but also between HbA(1c) levels and changes in GCF [beta=-0.0085 (95%CI -0.0115, -0.0

Background: Diet can help preserve lung function in smokers, as well as aid individuals who avoid smoking. This study aimed to evaluate the effectiveness of a nutritional intervention, using the Social Networks 2.0 tool, to increase adherence to the Mediterranean diet (MD) and improve lung function in smokers without prior respiratory disease. Methods: A randomized controlled parallel design was used. The participants were assigned to either the intervention or control group. Data from representative smokers without respiratory disease (n = 77) aged 18-70 years were analyzed. The participants completed a validated semi-quantitative food-frequency questionnaire, and their adherence to the diet was evaluated by using the questionnaire called the Mediterranean Diet Adherence Score (MEDAS, with 14 items), which considers & GE;9 points to indicate high adherence. The lung function was assessed by spirometry. Associations among variables were determined by logistic regression. Results: A comparison of the variables at the end of the study between the control and intervention groups showed that the intervention significantly increased adherence to the MD based on the MEDAS questionnaire (0.69 (2.1) vs. 2.05 (2.03); p = 0.009). Specifically, the consumption of fruits was increased after two years in both groups; however, a more significant increase was detected in the intervention group (121 (178) vs. 12.7 (167) in the control group; p-value = 0.008). In the unadjusted analysis, the intervention only showed a statistical significant increase in the score of adherence to the MD (beta: 1.36; 95% CI 0.35; 2.3; p = 0.009), and this increase was maintained after adjusting for age and sex (beta: 1.15; 95% CI 0.05; 2.2; p = 0.040) and after adjusting for various sociodemographic, life

Background: Point-of-care ultrasound (POCUS) is emerging as a reliable and valid clinical tool that impacts diagnosis and clinical decision-making as well as timely intervention for optimal patient management. This makes its utility in patients admitted to internal medicine wards attractive. However, there is still an evidence gap in all the medical setting of how its use affects clinical variables such as length of stay, morbidity, and mortality. Methods/design: A prospective randomized controlled trial assessing the effect of a surface POCUS of the heart, lungs, and femoral and popliteal veins performed by an internal medicine physician during the first 24 h of patient admission to the unit with a presumptive cardiopulmonary diagnosis. The University of Melbourne iHeartScan, iLungScan, and two-point venous compression protocols are followed to identify left and right ventricular function, significant valvular heart disease, pericardial and pleural effusion, consolidation, pulmonary edema, pneumothorax, and proximal deep venous thrombosis. Patient management is not commanded by the protocol and is at the discretion of the treating team. A total of 250 patients will be recruited at one tertiary hospital. Participants are randomized to receive POCUS or no POCUS. The primary outcome measured will be hospital length of stay. Secondary outcomes include the change in diagnosis and management, 30-day hospital readmission, and healthcare costs. Discussion(s): This study will evaluate the clinical impact of multi-organ POCUS in internal medicine patients admitted with cardiopulmonary diagnosis on the hospital length of stay. Recruitment of participants commenced in September 2018 and is estimated to be completed by March 2020. Trial registration: Australian and New Zealand Clinical Trial Registry, ACTRN12618001442291. Registered on 28 August 2018.Copyright © 2020 The Author(s).

Background: To explore the lived experience of chronic pain and dyskinesia in children and adolescents with cerebral palsy. Method(s): A convergent parallel mixed methods design was undertaken. First, a quantitative cross-sectional study of participants able to self-report their quality of life was undertaken. This study characterised pain chronicity, intensity, body locations, and quality of life. Second, semi-structured interviews were undertaken with a subset of children and adolescents experiencing chronic pain. Result(s): Twenty-five children and adolescents took part in the cross-sectional study, 23 of whom experienced chronic pain and 13 of moderate intensity. Pain was often located in multiple bodily regions (6/21), with no trends in quality of life outcomes detected. Eight participated in semi-structured interviews, which identified three key themes including 'lives embedded with dyskinesia', 'real world challenges of chronic pain', and 'still learning strategies to manage their pain and dyskinesia'. Conclusion(s): A high proportion of children and adolescents with cerebral palsy and dyskinesia who were able to self-report experienced chronic pain. The physical and emotional impacts of living with chronic pain and dyskinesia existed along a spectrum, from those with lesser to greater extent of their impacts. Children and adolescents may benefit from targeted chronic pain education and management within bio-psychosocial models.Copyright © 2020 The Author(s).

OBJECTIVE: This tertiary analysis from AVERT examined fatal and non-fatal Serious Adverse Events (SAEs) at 14 days. METHOD(S): AVERT was a prospective, parallel group, assessor blinded, randomized international clinical trial comparing mobility training commenced <24 hours post stroke, termed very early mobilization (VEM) to usual care (UC). Primary outcome was assessed at 3 months. Included: Patients with ischaemic and haemorrhagic stroke within 24 hours of onset. Treatment with thrombolytics allowed. Excluded: Patients with severe premorbid disability and/or comorbidities. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were non-fatal SAEs classified as neurologic, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIHSS) and age. RESULT(S): 2,104 participants were randomized to VEM (n = 1,054) or UC (n = 1,050) with a median age of 72 years (IQR 63-80) and NIHSS 7 (IQR 4-12). By 14 days, 48 had died in VEM, 32 in UC, age and stroke severity adjusted Odds Ratio of 1.76 (95% CI 1.06-2.92, p = 0.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in intracerebral haemorrhage and >80 years subgroups, but there was no significant treatment by subgroup interaction. No difference in non-fatal SAEs found. CONCLUSION(S): While the overall case fatality at 14 days post-stroke was only 3.8%, mortality adjusted for age and stroke severity was increased with high dose, intensive training compared to usual care. Stroke progression was more common in VEM. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that very early mobilization increases mortality at 14 days post stroke. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12606000185561.Copyright © 2020 American Academy of Neurology.

Background: Point-of-care ultrasound (POCUS) is emerging as a reliable and valid clinical tool that impacts diagnosis and clinical decision-making as well as timely intervention for optimal patient management. This makes its utility in patients admitted to internal medicine wards attractive. However, there is still an evidence gap in all the medical setting of how its use affects clinical variables such as length of stay, morbidity, and mortality. Methods/design: A prospective randomized controlled trial assessing the effect of a surface POCUS of the heart, lungs, and femoral and popliteal veins performed by an internal medicine physician during the first 24 h of patient admission to the unit with a presumptive cardiopulmonary diagnosis. The University of Melbourne iHeartScan, iLungScan, and two-point venous compression protocols are followed to identify left and right ventricular function, significant valvular heart disease, pericardial and pleural effusion, consolidation, pulmonary edema, pneumothorax, and proximal deep venous thrombosis. Patient management is not commanded by the protocol and is at the discretion of the treating team. A total of 250 patients will be recruited at one tertiary hospital. Participants are randomized to receive POCUS or no POCUS. The primary outcome measured will be hospital length of stay. Secondary outcomes include the change in diagnosis and management, 30-day hospital readmission, and healthcare costs. Discussion(s): This study will evaluate the clinical impact of multi-organ POCUS in internal medicine patients admitted with cardiopulmonary diagnosis on the hospital length of stay. Recruitment of participants commenced in September 2018 and is estimated to be completed by March 2020. Trial registration: Australian and New Zealand Clinical Trial Registry, ACTRN12618001442291. Registered on 28 August 2018.Copyright © 2020 The Author(s).

Background: To explore the lived experience of chronic pain and dyskinesia in children and adolescents with cerebral palsy. Method(s): A convergent parallel mixed methods design was undertaken. First, a quantitative cross-sectional study of participants able to self-report their quality of life was undertaken. This study characterised pain chronicity, intensity, body locations, and quality of life. Second, semi-structured interviews were undertaken with a subset of children and adolescents experiencing chronic pain. Result(s): Twenty-five children and adolescents took part in the cross-sectional study, 23 of whom experienced chronic pain and 13 of moderate intensity. Pain was often located in multiple bodily regions (6/21), with no trends in quality of life outcomes detected. Eight participated in semi-structured interviews, which identified three key themes including 'lives embedded with dyskinesia', 'real world challenges of chronic pain', and 'still learning strategies to manage their pain and dyskinesia'. Conclusion(s): A high proportion of children and adolescents with cerebral palsy and dyskinesia who were able to self-report experienced chronic pain. The physical and emotional impacts of living with chronic pain and dyskinesia existed along a spectrum, from those with lesser to greater extent of their impacts. Children and adolescents may benefit from targeted chronic pain education and management within bio-psychosocial models.Copyright © 2020 The Author(s).

OBJECTIVE: This tertiary analysis from AVERT examined fatal and non-fatal Serious Adverse Events (SAEs) at 14 days. METHOD(S): AVERT was a prospective, parallel group, assessor blinded, randomized international clinical trial comparing mobility training commenced <24 hours post stroke, termed very early mobilization (VEM) to usual care (UC). Primary outcome was assessed at 3 months. Included: Patients with ischaemic and haemorrhagic stroke within 24 hours of onset. Treatment with thrombolytics allowed. Excluded: Patients with severe premorbid disability and/or comorbidities. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were non-fatal SAEs classified as neurologic, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIHSS) and age. RESULT(S): 2,104 participants were randomized to VEM (n = 1,054) or UC (n = 1,050) with a median age of 72 years (IQR 63-80) and NIHSS 7 (IQR 4-12). By 14 days, 48 had died in VEM, 32 in UC, age and stroke severity adjusted Odds Ratio of 1.76 (95% CI 1.06-2.92, p = 0.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in intracerebral haemorrhage and >80 years subgroups, but there was no significant treatment by subgroup interaction. No difference in non-fatal SAEs found. CONCLUSION(S): While the overall case fatality at 14 days post-stroke was only 3.8%, mortality adjusted for age and stroke severity was increased with high dose, intensive training compared to usual care. Stroke progression was more common in VEM. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that very early mobilization increases mortality at 14 days post stroke. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12606000185561.Copyright © 2020 American Academy of Neurology.

Магістерська дисертація містить: 78 сторінок, 28 рисунків, 22 таблиці, 27 літературних джерел. Актуальність роботи. Сучасне машинобудування функціонує в умовах скорочених життєвих циклів продукції, великої варіативності замовлень та жорстокої конкуренції, тому підвищення ефективності виробництва в цілому та процесів складання зокрема є актуальним на даний момент. Сьогодні, одним з найбільш ефективних інструментів скорочення затрат, пов‘язаних із складальним виробництвом, є використання методів підвищення технологічності виробу на основі аналізу його конструкції. Мета магістерської дисертації – забезпечення технологічності складального виробу шляхом аналізу особливостей його конструкції. Задачі дослідження: 1. Проаналізувати сучасний стан проблеми оцінювання конструкції виробів з точки зору технологічних процесів складання 2. Виконати порівняльний аналіз методів оцінки та підвищення технологічності складальних виробів. Обґрунтувати вибір методу та оцінити необхідність його вдосконалення. 3. Формалізувати методику підвищення технологічності з’єднань деталей складальних виробів. 4. Виконати практичну перевірку отриманих результатів на прикладі складального виробу 5. Розробити старт-ап проект Об’єкт дослідження – технологічні процеси складального виробництва. Предмет дослідження – конструктивні особливості виробів, які впливають на складність технологічних процесів складання. Наукова новизна одержаних результатів: формалізовано методику підвищення технологічності з’єднань деталей з точки зору процесів складання. Практичне значення. Результати роботи можуть бути використані на виробництві, для навчального процесу, а також для створення систем автоматизованого проектування процесів складання. Апробація. Результати роботи доповідались на XV Міжнародній науково-практичній конференції, Achievement of high school - 20193, 15 - 22 листопада 2019 р., м. Софія, Республіка Болгарія. Пропозиції щодо напряму продовження досліджень. Подальші дослідження можуть бути виконані в напрям, The master's thesis contains: 78 pages, 28 drawings, 22 tables, 27 literary sources. Relevance of work. Modern mechanical engineering operates in the conditions of short life cycles of production, large variability of orders and fierce competition, therefore increase of efficiency of production as a whole and processes of assembly in particular is actual at the moment. Today, one of the most effective cost-cutting tools associated with assembly manufacturing is the use of methods to increase the manufacturability of a product by analyzing its design. The purpose of the master's thesis is to increase the manufacturability of the assembly product on the basis of a formalized analysis of its design. Research objectives: 1. To analyze the current state of the problem of evaluating the design of products in terms of technological processes of assembly 2. Perform a comparative analysis of methods of evaluation and increase the manufacturability of assembly products. Justify the choice of method and evaluate the need for its improvement. 3. Formalize the method of increasing the manufacturability of joints of parts of assembly products. 4. Perform practical verification of the results obtained on the example of the assembly product 5. Develop a start-up project Object of research - technological processes of assembly production. The subject of the study - the design features of products that affect the complexity of technological processes of assembly. Scientific novelty of the obtained results: the technique of increasing the manufacturability of the joints of parts in terms of assembly processes has been formalized. Practical meaning. The results of the work can be used in production, for the educational process, as well as to create systems for automated design of assembly processes. Approbation. The results of the work were reported at the XV International Scientific and Practical Conference, Achievement of high school - 20193, November 15 - 22, 2019, Sofia, Bulgaria.

Background: Patients with haematological malignancies often develop thrombocytopenia as a consequence of either their disease or its treatment. Platelet transfusions are commonly given to raise a low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). Recent studies have shown that many patients continue to experience bleeding despite the use of prophylactic platelet transfusions. Tranexamic acid is an anti-fibrinolytic, which reduces the breakdown of clots formed in response to bleeding. Anti-fibrinolytics have been shown to prevent bleeding, decrease blood loss and use of red cell transfusions in elective and emergency surgery, and are used widely in these settings. The aim of this trial is to test whether giving tranexamic acid to patients receiving treatment for haematological malignancies reduces the risk of bleeding or death and the need for platelet transfusions. Method(s): This is a multinational randomised, double-blind, placebo-controlled, parallel, superiority trial. Patients will be randomly assigned to receive tranexamic acid (given intravenously or orally) or a matching placebo in a 1:1 ratio, stratified by site. Patients with haematological malignancies receiving intensive chemotherapy or stem cell transplantation (or both) who are at least 18 years of age and expected to become severely thrombocytopenic for at least 5 days will be eligible for this trial. The primary outcome of the trial is the proportion of patients who died or had bleeding of World Health Organization grade 2 or above during the first 30 days of the trial. We will measure the rates of bleeding daily by using a short, structured assessment of bleeding, and we will record the number of transfusions given to patients. We will assess the risk of arterial and venous thrombosis for 120 days from the start of trial treatment. Discussion(s): This trial will assess the safety and efficacy of using prophylactic tranexamic acid during a per

Introduction Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age. Methods and analyses We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety. Ethics and dissemination This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findin

Background: International research has focused on screening and mass media campaigns to promote earlier patient presentation and detect lung cancer earlier. This trial tested the effect of a behavioural intervention in people at increased risk of lung cancer on help-seeking for respiratory symptoms. Methods: Parallel, individually randomised controlled trial. Eligible participants were long-term smokers with at least 20 pack-years, aged 55 and above. The CHEST intervention entailed a consultation to discuss and implement a self-help manual, followed by self-monitoring reminders to encourage help-seeking for respiratory symptoms. The control group received a brief discussion about lung health. Both groups had baseline spirometry. Telephone randomisation was conducted, 1:1, stratified Medical Research Council (MRC) dyspnoea score and general practice. Participants could not be blinded; data extraction and statistical analyses were performed blinded to group assignment. The primary outcome was respiratory consultation rates. Results: We randomised 551 participants (274 intervention, 277 control) from whom the primary outcome was determined for 542 (269 intervention, 273 control). There was a 40% relative increase in respiratory consultations in the intervention group: (adjusted rates (95% CI) intervention 0.57 (0.47 to 0.70), control 0.41 (0.32 to 0.52), relative rate 1.40 (1.08 to 1.82); p=0.0123). There were no significant differences in time to first respiratory consultation, total consultation rates or measures of psychological harm. The incremental cost-effectiveness ratio was $A1289 per additional respiratory consultation. Conclusions: A behavioural intervention can significantly increase consulting for respiratory symptoms in patients at increased risk of lung cancer. This intervention could have an important role in primary care as part of a broader approach to improve respiratory health in patients at higher risk. © 2019 Author(s) (or their employer(s)).

Background: Patients with haematological malignancies often develop thrombocytopenia as a consequence of either their disease or its treatment. Platelet transfusions are commonly given to raise a low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). Recent studies have shown that many patients continue to experience bleeding despite the use of prophylactic platelet transfusions. Tranexamic acid is an anti-fibrinolytic, which reduces the breakdown of clots formed in response to bleeding. Anti-fibrinolytics have been shown to prevent bleeding, decrease blood loss and use of red cell transfusions in elective and emergency surgery, and are used widely in these settings. The aim of this trial is to test whether giving tranexamic acid to patients receiving treatment for haematological malignancies reduces the risk of bleeding or death and the need for platelet transfusions. Method(s): This is a multinational randomised, double-blind, placebo-controlled, parallel, superiority trial. Patients will be randomly assigned to receive tranexamic acid (given intravenously or orally) or a matching placebo in a 1:1 ratio, stratified by site. Patients with haematological malignancies receiving intensive chemotherapy or stem cell transplantation (or both) who are at least 18 years of age and expected to become severely thrombocytopenic for at least 5 days will be eligible for this trial. The primary outcome of the trial is the proportion of patients who died or had bleeding of World Health Organization grade 2 or above during the first 30 days of the trial. We will measure the rates of bleeding daily by using a short, structured assessment of bleeding, and we will record the number of transfusions given to patients. We will assess the risk of arterial and venous thrombosis for 120 days from the start of trial treatment. Discussion(s): This trial will assess the safety and efficacy of using prophylactic tranexamic acid during a per

Introduction Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age. Methods and analyses We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety. Ethics and dissemination This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findin

Background: International research has focused on screening and mass media campaigns to promote earlier patient presentation and detect lung cancer earlier. This trial tested the effect of a behavioural intervention in people at increased risk of lung cancer on help-seeking for respiratory symptoms. Methods: Parallel, individually randomised controlled trial. Eligible participants were long-term smokers with at least 20 pack-years, aged 55 and above. The CHEST intervention entailed a consultation to discuss and implement a self-help manual, followed by self-monitoring reminders to encourage help-seeking for respiratory symptoms. The control group received a brief discussion about lung health. Both groups had baseline spirometry. Telephone randomisation was conducted, 1:1, stratified Medical Research Council (MRC) dyspnoea score and general practice. Participants could not be blinded; data extraction and statistical analyses were performed blinded to group assignment. The primary outcome was respiratory consultation rates. Results: We randomised 551 participants (274 intervention, 277 control) from whom the primary outcome was determined for 542 (269 intervention, 273 control). There was a 40% relative increase in respiratory consultations in the intervention group: (adjusted rates (95% CI) intervention 0.57 (0.47 to 0.70), control 0.41 (0.32 to 0.52), relative rate 1.40 (1.08 to 1.82); p=0.0123). There were no significant differences in time to first respiratory consultation, total consultation rates or measures of psychological harm. The incremental cost-effectiveness ratio was $A1289 per additional respiratory consultation. Conclusions: A behavioural intervention can significantly increase consulting for respiratory symptoms in patients at increased risk of lung cancer. This intervention could have an important role in primary care as part of a broader approach to improve respiratory health in patients at higher risk. © 2019 Author(s) (or their employer(s)).

Background and Objectives: The T3 cluster randomised trial aimed to improve Triage, Treatment and Transfer (T3) of patients with acute stroke in Emergency Departments (EDs). Method(s): Our prospective, multicentre, parallel group trial with blinded outcome assessment, randomised EDs 1:1 to receive either the T3 intervention or no support. The intervention targeted: (1) Triage: suspected stroke patients to be assigned to patients with suspected acute stroke triaged as Australian Triage Scale 1 or 2; (2) Treatment: screening for tPA eligibility and administration where applicable; management of fever, hyperglycaemia and swallowing; and (3) rapid Transfer to the stroke unit. The implementation strategy comprised: (i) workshops to determine barriers and solutions; (ii) education; (iii) clinical opinion leaders; (iv) reminders. Primary Outcome: 90-day death or dependency (mRS>2). Secondary Outcomes: 90-day: health status (SF-36), functional dependency (Barthel Index); and 11 in-hospital quality-of-care outcomes. Result(s): 26 eligible sites from three states and one territory participated involving 1879 patients (preimplementation n = 574; post-implementation n = 1305 including 751 patients in intervention sites and 554 in control sites). There were no significant differences between groups for primary outcome of 90-day mRS or secondary patient outcomes. There were no significant differences between groups for 11 quality of care outcomes. Conclusion(s): This large trial used an evidence-based implementation strategy previously shown to be highly effective in stroke units but it did not change ED clinician behaviour. ED is a complex, chaotic environment with competing priorities. Alternative ways to support evidence implementation into ED warrant investigation.

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Background: Limited evidence exists to support very early intensive aphasia rehabilitation after stroke. VERSE is a PROBE trial designed to determine whether two types of intensive aphasia therapy, beginning within 14 days of acute stroke, provide greater therapeutic and cost-effectiveness than usual care. Objective(s): To publish the detailed statistical analysis plan for the VERSE trial prior to unblinding. This statistical analysis plan was based on the published and registered VERSE trial protocol and was developed by the blinded steering committee and management team, led by the trial statistician. This plan was developed using outcome measures and trial data collection forms. Result(s): The VERSE statistical analysis plan is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusion(s): Publication of a statistical analysis plan serves to reduce potential trial reporting bias and outlines transparent pre-specified analyses. Australian New Zealand Clinical Trials Registry (ANZCTR) Registration number: ACTRN12613000776707; Universal Trial Number (UTN) is U1111-1145-4130.Copyright © 2018 World Stroke Organization.

Background and Objectives: The T3 cluster randomised trial aimed to improve Triage, Treatment and Transfer (T3) of patients with acute stroke in Emergency Departments (EDs). Method(s): Our prospective, multicentre, parallel group trial with blinded outcome assessment, randomised EDs 1:1 to receive either the T3 intervention or no support. The intervention targeted: (1) Triage: suspected stroke patients to be assigned to patients with suspected acute stroke triaged as Australian Triage Scale 1 or 2; (2) Treatment: screening for tPA eligibility and administration where applicable; management of fever, hyperglycaemia and swallowing; and (3) rapid Transfer to the stroke unit. The implementation strategy comprised: (i) workshops to determine barriers and solutions; (ii) education; (iii) clinical opinion leaders; (iv) reminders. Primary Outcome: 90-day death or dependency (mRS>2). Secondary Outcomes: 90-day: health status (SF-36), functional dependency (Barthel Index); and 11 in-hospital quality-of-care outcomes. Result(s): 26 eligible sites from three states and one territory participated involving 1879 patients (preimplementation n = 574; post-implementation n = 1305 including 751 patients in intervention sites and 554 in control sites). There were no significant differences between groups for primary outcome of 90-day mRS or secondary patient outcomes. There were no significant differences between groups for 11 quality of care outcomes. Conclusion(s): This large trial used an evidence-based implementation strategy previously shown to be highly effective in stroke units but it did not change ED clinician behaviour. ED is a complex, chaotic environment with competing priorities. Alternative ways to support evidence implementation into ED warrant investigation.

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Background: Limited evidence exists to support very early intensive aphasia rehabilitation after stroke. VERSE is a PROBE trial designed to determine whether two types of intensive aphasia therapy, beginning within 14 days of acute stroke, provide greater therapeutic and cost-effectiveness than usual care. Objective(s): To publish the detailed statistical analysis plan for the VERSE trial prior to unblinding. This statistical analysis plan was based on the published and registered VERSE trial protocol and was developed by the blinded steering committee and management team, led by the trial statistician. This plan was developed using outcome measures and trial data collection forms. Result(s): The VERSE statistical analysis plan is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusion(s): Publication of a statistical analysis plan serves to reduce potential trial reporting bias and outlines transparent pre-specified analyses. Australian New Zealand Clinical Trials Registry (ANZCTR) Registration number: ACTRN12613000776707; Universal Trial Number (UTN) is U1111-1145-4130.Copyright © 2018 World Stroke Organization.

Background: An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta and is associated with a risk of fatal rupture. Experimental studies suggest that myo-inositol may exert beneficial effects on AAAs through favourable changes to biological pathways implicated in AAA pathology. The aim of the Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) trial is to assess if myo-inositol will reduce AAA growth. Methods/design: IMAGEN is a multi-centre, prospective, parallel-group, randomised, double-blind, placebo-controlled trial. A total of 164 participants with an AAA measuring ≥ 30 mm will be randomised to either 2 g of myo-inositol or identical placebo twice daily for 12 months. The primary outcome measure will be AAA growth estimated by increase in total infrarenal aortic volume measured on computed tomographic scans. Secondary outcome measures will include AAA diameter assessed by computed tomography and ultrasound, AAA peak wall stress and peak wall rupture index, serum lipids, circulating AAA biomarkers, circulating RNAs and health-related quality of life. All analysis will be based on the intention-to-treat principle at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to dietary allocation. Discussion: Currently, there is no known medical therapy to limit AAA progression. The IMAGEN trial will be the first randomised trial, to our knowledge, to assess the value of myo-inositol in limiting AAA growth., QC 20180502

Background: Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes. Existing clinical trials have been limited by short duration, low doses of Vitamin D, variability in participants' Vitamin D-deficiency status, and the use of surrogate measures of body composition, insulin sensitivity, and insulin secretion. Objective(s): To address existing knowledge gaps, we conducted a double-blind, randomized, placebo-controlled trial to investigate whether Vitamin D supplementation that is provided in a sufficient dose and duration to Vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of goldstandard methods. We hypothesized that Vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo. Design(s): Sixty-five overweight or obese, Vitamin D-deficient (25-hydroxyVitamin D [25(OH)D] concentration <=50 nmol/L) adults were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk. Before and after the intervention, participants received gold-standard assessments of body composition (via dual X-ray absorptiometry), insulin sensitivity (via hyperinsulinemic-euglycemic clamps), and insulin secretion [via intravenous-glucose-tolerance tests (IVGTTs)]. Result(s): Fifty-four participants completed the study [35 men and 19 women; mean +/- SD age: 31.9 +/- 8.5 y; body mass index (in kg/m2): 30.9 +/- 4.4]. 25(OH)D increased with Vitamin D supplementation compared with placebo (57.0 +/- 21.3 compared with 1.9 +/- 15.1 nmol/L, respectively; P = 0.02). Vitamin D and placebo groups did not differ in change in insulin sensitivity (0.02 +/- 2.0 compared with 20.03 +/- 2.8 mg * kg-1 * min-1, respectively; P = 0.9) or firstphase insulin secretion (-21 +/- 212 compared with 24 +/- 184 mU/L, respectively; P = 0.9). Results remained nonsignificant after adjustment for age, sex

Background Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy. Objectives The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF. Methods This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] <=45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months. Results A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 +/- 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 +/- 13% in the CA group compared with 4.4 +/- 13% in the MRC group (p < 0.0001) and normalized (LVEF >=50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093). Conclusions AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, p

Aim: To compare biochemical clearances with extended-hours haemodialysis (HD) and haemodiafiltration (HDF) and Fresenius FX80 (FX) and Nipro Elisio (NE) dialysers. Background(s): Extended-hours HD has long been regarded as the optimal form of dialysis for solute clearance. With emerging benefits of HDF, it would be prudent to compare these two head-to-head. Method(s): This is a randomized cross-over trial comparing 8-hours HD to 4-hours HDF. 12 NHD patients underwent a baseline 8-hour HD session, and then randomized to either 2 weeks of 8-hour HD or 4-hour HDF with crossover to the alternative treatment after a 2-week washout period. Subjects were additionally randomized to the NE or FX dialyser in a parallel design. Blood and dialysate samples were collected at baseline and at the end of both study periods. Result(s): Mean (SD) age and BMI were 55.1 +/-11.5 years and 36.4 +/-10.8 respectively. Blood flow (Qb) for HD was 250ml/min and dialysate flow (Qd) 300ml/min. For HDF, Qb was 300ml/min and Qd 500ml/min with mean convection rate 86.1ml/min (20.7 L/session). Urea and creatinine reduction ratios were higher with HD compared to HDF (difference 14.0%, 95% CI 10.6,17.3, p<0.001 & 9.1% 95% CI 11.0,7.2, p<0.001). Fibroblast growth factor 23 (FGF23) clearance was superior with HDF (difference 20.1%, 95% CI 8.7,31.6, p=0.001). No difference was seen in reduction ratios for phosphate, retinol binding protein, alpha-1-microglobulin, beta-2-microglobulin (B2M) and fetuin with both modalities. Compared to NE, FX dialyser achieved higher beta-2-microglobulin clearance (Period 1: difference 7.8%, 95% CI 1.3, 14.4, P=0.02, Period 2: 7.5%, 95%CI 1.0, 14.1, p=0.02). Conclusion(s): Small solute clearance was superior with extended-hours HD while HDF enhanced FGF23 clearance. B2M clearance was improved with Fresenius FX80 dialyser.

Introduction: Older adults frequently fall after discharge from hospital. Older people may have low self-perceived risk of falls and poor knowledge about falls prevention. The primary aim of the study is to evaluate the effect of providing tailored falls prevention education in addition to usual care on falls rates in older people after discharge from hospital compared to providing a social intervention in addition to usual care. Methods and analyses: The Back to My Best study is a multisite, single blind, parallel-group randomized controlled trial with blinded outcome assessment and intention-to-treat analysis, adhering to CONSORT guidelines. Patients (n=390) (aged 60 years or older; score more than 7/10 on the Abbreviated Mental Test Score; discharged to community settings) from aged care rehabilitation wards in three hospitals will be recruited and randomly assigned to one of two groups. Participants allocated to the control group shall receive usual care plus a social visit. Participants allocated to the experimental group shall receive usual care and a falls prevention programme incorporating a video, workbook and individualised follow-up from an expert health professional to foster capability and motivation to engage in falls prevention strategies. The primary outcome is falls rates in the first 6 months after discharge, analysed using negative binomial regression with adjustment for participants length of observation in the study. Secondary outcomes are injurious falls rates, the proportion of people who become fallers, functional status and health-related quality of life. Healthcare resource use will be captured from four sources for 6 months after discharge. The study is powered to detect a 30% relative reduction in the rate of falls (negative binomial incidence ratio 0.70) for a control rate of 0.80 falls per person over 6 months. Ethics and dissemination: Results will be presented in peer-reviewed journals and at conferences worldwide. This study is appro

Background and Aims: A very early intensive out-of-bed mobilisation (VEM) protocol after stroke compared to usual care was associated with a reduction in odds of a favourable outcome at 3 months. We report prespecified analyses to determine whether VEM post stroke results in better outcomes for patients at 12 months when compared to usual stroke unit care. Method(s): We performed a prospective, parallel group, assessor-blinded, multi-centre, clinical trial with the following inclusion criteria: admission within 24 hours of stroke and physiological parameters within pre-set limits. Treatment with rt-PA was allowed. Patients with severe premorbid disability and/or severe comorbidities were excluded. Patients were randomised to VEM or usual care. The intervention, delivered by a physiotherapy/ nurse team, started within 24 hours and continued for a maximum of 14 days. Analyses were intention-to-treat. Pre-specified adjusted analyses for 12 month outcomes included: (i) health related quality of life (HRQoL); (ii) favourable outcome mRS 0-2; (iii) deaths; and (iv) time to walking 50 metres unassisted. Result(s): From July 2006 to October 2014, 2104 patients were recruited from five countries. Patient demographics: age median (IQR): 72.5 (62.9- 80.3) years; NIHSS median (IQR): 7 (4-12); rt-PA treated 24.1%. Follow up was completed in 2052 patients (97.5%). No between group differences in: (i) HRQoL (adj median regression: >=0.036 (95% CI-0.045- 0.038, p=0.865); (ii) mRS 0-2 (aOR 0.84, 95% CI 0.68-1.03, p=0.089); (iii) deaths (aOR 1.29, 95% CI 0.96-1.72, p=0.088); (iv) or time to walking (aHR 1.02, 95%CI 0.94-1.13, p=0.553) were found. Conclusion(s): Early intensive mobilisation after stroke did not improve 12 month outcomes after stroke.

Background & Aims: The T3 cluster randomised trial aimed to improve Triage, Treatment and Transfer (T3) of patients with acute stroke in emergency departments (EDs). Method(s): Our prospective, multicentre, parallel group, cluster randomised trial with blinded outcome assessment, randomised EDs 1:1 to receive either the T3 intervention or no support (control EDs). Our evidence-based intervention targeted: (1) Triage: patients with suspected stroke assigned to Australian Triage Scale category 1 or 2 (seen within 10 minutes); (2) Treatment: screening for tPA eligibility and administration of tPA where applicable; protocols for management of fever, hyperglycaemia and swallowing; and (3) rapid Transfer from ED to the stroke unit, implemented using (i) workshops to determine barriers and solutions; (ii) education; (iii) use of clinical opinion leaders; (iv) email, telephone and site visit reminders. Primary Outcome: 90-days post-admission death or dependency (mRS>2). Secondary Outcomes: 90-day: health status (SF-36), functional dependency (Barthel Index), quality of life (EQ-5D); and in-hospital quality-of-care outcomes: triage practices; monitoring and management for thrombolysis, fever, hyperglycaemia, swallowing; and transfer practices. Result(s): Of the 26 eligible sites from three states and one territory in Australia, all (100%) agreed to participate with 2253 patients consenting (pre-implementation n=645; post-implementation n=1608). Of these, 1879 will be analysed (pre-implementation n=574; post-implementation n=1305). In the post-implementation cohort, 751 patients were randomised to the intervention group and 554 to the control group. Data currently are being analysed. Conclusion(s): This large trial will provide rigorous evidence for assisted implementation of nurse-initiated ED stroke protocols aiming to improve outcomes for patients with stroke.

Background: Lumbar microdiscectomy is the most commonly performed spinal surgery procedure, with over 300,000 cases performed annually in the United States alone. Traditionally, patients were advised to restrict post-operative activity as this was believed to reduce the risk of disc reherniation and progressive instability. However, this practice would often delay patients return to work. In contemporary practice many surgeons do not restrict patient post-operative activity due to the perception this practice is unnecessary. We describe a randomised controlled trial to assess the impact of activity restrictions on clinical outcome following lumbar discectomy. Methods/Design: The lumbar microdiscectomy and post-operative activity restriction trial is a multi-centre, randomised, controlled single blinded trial. Two hundred ten patients due to undergo single level lumbar microdiscectomy without a history of previous spine surgery, infection or fracture are randomised to be advised either restricted or unrestricted activity for a period of 30 days following lumbar microdiscectomy. Actual adherence with trial allocation will be monitored bioelectronically via a wearable device. Outcome assessment at follow up will occur at 1, 3, 6 and 12 months. The primary outcome will be a composite endpoint comprising changes in Visual Analogue Scale (Leg and Back), Oswestry Disability Index and the absence of intervertebral disc reherniation or secondary intervention. Discussion(s): This randomised controlled trial will directly compare post-operative protocols of activity restrictions and no restrictions following lumbar discectomy with adherence monitored bioelectronically.Copyright © 2017 The Author(s).

Introduction: Higher calcium dialysate is recommended for quotidian nocturnal hemodialysis (NHD) (>=6 nights/week) to maintain bone health. It is unclear what the optimal calcium dialysate concentration should be for alternate night NHD. We aimed to determine the effect of low calcium (LC) versus high calcium (HC) dialysate on cardiovascular and bone parameters in this population. Method(s): A randomized controlled trial where participants were randomized to LC (1.3 mmol/L, n = 24) or HC dialysate (1.6 or 1.75 mmol/L, n = 26). Primary outcome was change in mineral metabolism markers. Secondary outcomes included change in vascular calcification (VC) scores [CT abdominal aorta (AA) and superficial femoral arteries (SFA)), pulse wave velocity (PWV), bone mineral density (BMD) and left ventricular mass index (LVMI) over 12 months. Finding(s): In the LC group, pre-dialysis ionised calcium decreased -0.12 mmol/L (-0.18-0.06, P = 0.0001) and PTH increased 16 pmol/L (3.5-28.5, p = 0.01) from baseline to 12 months with no significant change in the HC group. In both groups, there was no progression of VC in AA or SFA and no change in PWV, LVMI or BMD. At 12 months, calcimimetics were prescribed in a higher percentage in the LC vs. HC groups (45.5% vs. 10.5%) with a lower proportion of the HC group being prescribed calcitriol (31.5% vs. 72%). Discussion(s): Although dialysate calcium prescription influenced biochemical parameters it was not associated with difference in progression of VC between HC and LC groups. An important finding was the potential impact of alternate night NHD in attenuating progression of VC and inducing stabilisation of LVMI and PWV.Copyright © 2016 International Society for Hemodialysis

BACKGROUND: It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults. METHOD(S): In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality. RESULT(S): From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.7 to 3.1; P = 0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, -2.1 to 3.0; P = 0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome. CONCLUSION(S): The age of transfused red cells did not affect 90-day mortality among critically ill adults.Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Background: Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes. Existing clinical trials have been limited by short duration, low doses of Vitamin D, variability in participants' Vitamin D-deficiency status, and the use of surrogate measures of body composition, insulin sensitivity, and insulin secretion. Objective(s): To address existing knowledge gaps, we conducted a double-blind, randomized, placebo-controlled trial to investigate whether Vitamin D supplementation that is provided in a sufficient dose and duration to Vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of goldstandard methods. We hypothesized that Vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo. Design(s): Sixty-five overweight or obese, Vitamin D-deficient (25-hydroxyVitamin D [25(OH)D] concentration <=50 nmol/L) adults were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk. Before and after the intervention, participants received gold-standard assessments of body composition (via dual X-ray absorptiometry), insulin sensitivity (via hyperinsulinemic-euglycemic clamps), and insulin secretion [via intravenous-glucose-tolerance tests (IVGTTs)]. Result(s): Fifty-four participants completed the study [35 men and 19 women; mean +/- SD age: 31.9 +/- 8.5 y; body mass index (in kg/m2): 30.9 +/- 4.4]. 25(OH)D increased with Vitamin D supplementation compared with placebo (57.0 +/- 21.3 compared with 1.9 +/- 15.1 nmol/L, respectively; P = 0.02). Vitamin D and placebo groups did not differ in change in insulin sensitivity (0.02 +/- 2.0 compared with 20.03 +/- 2.8 mg * kg-1 * min-1, respectively; P = 0.9) or firstphase insulin secretion (-21 +/- 212 compared with 24 +/- 184 mU/L, respectively; P = 0.9). Results remained nonsignificant after adjustment for age, sex

Background Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy. Objectives The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF. Methods This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] <=45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months. Results A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 +/- 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 +/- 13% in the CA group compared with 4.4 +/- 13% in the MRC group (p < 0.0001) and normalized (LVEF >=50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093). Conclusions AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, p

Aim: To compare biochemical clearances with extended-hours haemodialysis (HD) and haemodiafiltration (HDF) and Fresenius FX80 (FX) and Nipro Elisio (NE) dialysers. Background(s): Extended-hours HD has long been regarded as the optimal form of dialysis for solute clearance. With emerging benefits of HDF, it would be prudent to compare these two head-to-head. Method(s): This is a randomized cross-over trial comparing 8-hours HD to 4-hours HDF. 12 NHD patients underwent a baseline 8-hour HD session, and then randomized to either 2 weeks of 8-hour HD or 4-hour HDF with crossover to the alternative treatment after a 2-week washout period. Subjects were additionally randomized to the NE or FX dialyser in a parallel design. Blood and dialysate samples were collected at baseline and at the end of both study periods. Result(s): Mean (SD) age and BMI were 55.1 +/-11.5 years and 36.4 +/-10.8 respectively. Blood flow (Qb) for HD was 250ml/min and dialysate flow (Qd) 300ml/min. For HDF, Qb was 300ml/min and Qd 500ml/min with mean convection rate 86.1ml/min (20.7 L/session). Urea and creatinine reduction ratios were higher with HD compared to HDF (difference 14.0%, 95% CI 10.6,17.3, p<0.001 & 9.1% 95% CI 11.0,7.2, p<0.001). Fibroblast growth factor 23 (FGF23) clearance was superior with HDF (difference 20.1%, 95% CI 8.7,31.6, p=0.001). No difference was seen in reduction ratios for phosphate, retinol binding protein, alpha-1-microglobulin, beta-2-microglobulin (B2M) and fetuin with both modalities. Compared to NE, FX dialyser achieved higher beta-2-microglobulin clearance (Period 1: difference 7.8%, 95% CI 1.3, 14.4, P=0.02, Period 2: 7.5%, 95%CI 1.0, 14.1, p=0.02). Conclusion(s): Small solute clearance was superior with extended-hours HD while HDF enhanced FGF23 clearance. B2M clearance was improved with Fresenius FX80 dialyser.

Introduction: Older adults frequently fall after discharge from hospital. Older people may have low self-perceived risk of falls and poor knowledge about falls prevention. The primary aim of the study is to evaluate the effect of providing tailored falls prevention education in addition to usual care on falls rates in older people after discharge from hospital compared to providing a social intervention in addition to usual care. Methods and analyses: The Back to My Best study is a multisite, single blind, parallel-group randomized controlled trial with blinded outcome assessment and intention-to-treat analysis, adhering to CONSORT guidelines. Patients (n=390) (aged 60 years or older; score more than 7/10 on the Abbreviated Mental Test Score; discharged to community settings) from aged care rehabilitation wards in three hospitals will be recruited and randomly assigned to one of two groups. Participants allocated to the control group shall receive usual care plus a social visit. Participants allocated to the experimental group shall receive usual care and a falls prevention programme incorporating a video, workbook and individualised follow-up from an expert health professional to foster capability and motivation to engage in falls prevention strategies. The primary outcome is falls rates in the first 6 months after discharge, analysed using negative binomial regression with adjustment for participants length of observation in the study. Secondary outcomes are injurious falls rates, the proportion of people who become fallers, functional status and health-related quality of life. Healthcare resource use will be captured from four sources for 6 months after discharge. The study is powered to detect a 30% relative reduction in the rate of falls (negative binomial incidence ratio 0.70) for a control rate of 0.80 falls per person over 6 months. Ethics and dissemination: Results will be presented in peer-reviewed journals and at conferences worldwide. This study is appro

Background and Aims: A very early intensive out-of-bed mobilisation (VEM) protocol after stroke compared to usual care was associated with a reduction in odds of a favourable outcome at 3 months. We report prespecified analyses to determine whether VEM post stroke results in better outcomes for patients at 12 months when compared to usual stroke unit care. Method(s): We performed a prospective, parallel group, assessor-blinded, multi-centre, clinical trial with the following inclusion criteria: admission within 24 hours of stroke and physiological parameters within pre-set limits. Treatment with rt-PA was allowed. Patients with severe premorbid disability and/or severe comorbidities were excluded. Patients were randomised to VEM or usual care. The intervention, delivered by a physiotherapy/ nurse team, started within 24 hours and continued for a maximum of 14 days. Analyses were intention-to-treat. Pre-specified adjusted analyses for 12 month outcomes included: (i) health related quality of life (HRQoL); (ii) favourable outcome mRS 0-2; (iii) deaths; and (iv) time to walking 50 metres unassisted. Result(s): From July 2006 to October 2014, 2104 patients were recruited from five countries. Patient demographics: age median (IQR): 72.5 (62.9- 80.3) years; NIHSS median (IQR): 7 (4-12); rt-PA treated 24.1%. Follow up was completed in 2052 patients (97.5%). No between group differences in: (i) HRQoL (adj median regression: >=0.036 (95% CI-0.045- 0.038, p=0.865); (ii) mRS 0-2 (aOR 0.84, 95% CI 0.68-1.03, p=0.089); (iii) deaths (aOR 1.29, 95% CI 0.96-1.72, p=0.088); (iv) or time to walking (aHR 1.02, 95%CI 0.94-1.13, p=0.553) were found. Conclusion(s): Early intensive mobilisation after stroke did not improve 12 month outcomes after stroke.

Background & Aims: The T3 cluster randomised trial aimed to improve Triage, Treatment and Transfer (T3) of patients with acute stroke in emergency departments (EDs). Method(s): Our prospective, multicentre, parallel group, cluster randomised trial with blinded outcome assessment, randomised EDs 1:1 to receive either the T3 intervention or no support (control EDs). Our evidence-based intervention targeted: (1) Triage: patients with suspected stroke assigned to Australian Triage Scale category 1 or 2 (seen within 10 minutes); (2) Treatment: screening for tPA eligibility and administration of tPA where applicable; protocols for management of fever, hyperglycaemia and swallowing; and (3) rapid Transfer from ED to the stroke unit, implemented using (i) workshops to determine barriers and solutions; (ii) education; (iii) use of clinical opinion leaders; (iv) email, telephone and site visit reminders. Primary Outcome: 90-days post-admission death or dependency (mRS>2). Secondary Outcomes: 90-day: health status (SF-36), functional dependency (Barthel Index), quality of life (EQ-5D); and in-hospital quality-of-care outcomes: triage practices; monitoring and management for thrombolysis, fever, hyperglycaemia, swallowing; and transfer practices. Result(s): Of the 26 eligible sites from three states and one territory in Australia, all (100%) agreed to participate with 2253 patients consenting (pre-implementation n=645; post-implementation n=1608). Of these, 1879 will be analysed (pre-implementation n=574; post-implementation n=1305). In the post-implementation cohort, 751 patients were randomised to the intervention group and 554 to the control group. Data currently are being analysed. Conclusion(s): This large trial will provide rigorous evidence for assisted implementation of nurse-initiated ED stroke protocols aiming to improve outcomes for patients with stroke.

Background: Lumbar microdiscectomy is the most commonly performed spinal surgery procedure, with over 300,000 cases performed annually in the United States alone. Traditionally, patients were advised to restrict post-operative activity as this was believed to reduce the risk of disc reherniation and progressive instability. However, this practice would often delay patients return to work. In contemporary practice many surgeons do not restrict patient post-operative activity due to the perception this practice is unnecessary. We describe a randomised controlled trial to assess the impact of activity restrictions on clinical outcome following lumbar discectomy. Methods/Design: The lumbar microdiscectomy and post-operative activity restriction trial is a multi-centre, randomised, controlled single blinded trial. Two hundred ten patients due to undergo single level lumbar microdiscectomy without a history of previous spine surgery, infection or fracture are randomised to be advised either restricted or unrestricted activity for a period of 30 days following lumbar microdiscectomy. Actual adherence with trial allocation will be monitored bioelectronically via a wearable device. Outcome assessment at follow up will occur at 1, 3, 6 and 12 months. The primary outcome will be a composite endpoint comprising changes in Visual Analogue Scale (Leg and Back), Oswestry Disability Index and the absence of intervertebral disc reherniation or secondary intervention. Discussion(s): This randomised controlled trial will directly compare post-operative protocols of activity restrictions and no restrictions following lumbar discectomy with adherence monitored bioelectronically.Copyright © 2017 The Author(s).

BACKGROUND: It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults. METHOD(S): In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality. RESULT(S): From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.7 to 3.1; P = 0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, -2.1 to 3.0; P = 0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome. CONCLUSION(S): The age of transfused red cells did not affect 90-day mortality among critically ill adults.Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Introduction: Higher calcium dialysate is recommended for quotidian nocturnal hemodialysis (NHD) (>=6 nights/week) to maintain bone health. It is unclear what the optimal calcium dialysate concentration should be for alternate night NHD. We aimed to determine the effect of low calcium (LC) versus high calcium (HC) dialysate on cardiovascular and bone parameters in this population. Method(s): A randomized controlled trial where participants were randomized to LC (1.3 mmol/L, n = 24) or HC dialysate (1.6 or 1.75 mmol/L, n = 26). Primary outcome was change in mineral metabolism markers. Secondary outcomes included change in vascular calcification (VC) scores [CT abdominal aorta (AA) and superficial femoral arteries (SFA)), pulse wave velocity (PWV), bone mineral density (BMD) and left ventricular mass index (LVMI) over 12 months. Finding(s): In the LC group, pre-dialysis ionised calcium decreased -0.12 mmol/L (-0.18-0.06, P = 0.0001) and PTH increased 16 pmol/L (3.5-28.5, p = 0.01) from baseline to 12 months with no significant change in the HC group. In both groups, there was no progression of VC in AA or SFA and no change in PWV, LVMI or BMD. At 12 months, calcimimetics were prescribed in a higher percentage in the LC vs. HC groups (45.5% vs. 10.5%) with a lower proportion of the HC group being prescribed calcitriol (31.5% vs. 72%). Discussion(s): Although dialysate calcium prescription influenced biochemical parameters it was not associated with difference in progression of VC between HC and LC groups. An important finding was the potential impact of alternate night NHD in attenuating progression of VC and inducing stabilisation of LVMI and PWV.Copyright © 2016 International Society for Hemodialysis

Aim: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12-monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion. Method(s): Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia. Result(s): Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01). Interpretation(s): There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis.Copyright © 2015 Mac Keith Press

Background: There are well-documented treatment gaps in secondary prevention of coronary heart disease and no clear guidelines to assist early physical activity after acute coronary syndromes (ACS). Smartphone technology may provide an innovative platform to close these gaps. This paper describes the study design of a randomized controlled trial assessing whether a smartphone-based secondary prevention program can facilitate early physical activity and improve cardiovascular health in patients with ACS. Method(s): We have developed a multi-faceted, patient-centred smartphone-based secondary prevention program emphasizing early physical activity with a graduated walking program initiated on discharge from ACS admission. The program incorporates; physical activity tracking through the smartphone's accelerometer with interactive feedback and goal setting; a dynamic dashboard to review and optimize cardiovascular risk factors; educational messages delivered twice weekly; a photographic food diary; pharmacotherapy review; and support through a short message service. The primary endpoint of the trial is change in exercise capacity, as measured by the change in six-minute walk test distance at 8-weeks when compared to baseline. Secondary endpoints include improvements in cardiovascular risk factor status, psychological well-being and quality of life, medication adherence, uptake of cardiac rehabilitation and re-hospitalizations. Discussion(s): This randomized controlled trial will use a smartphone-phone based secondary prevention program to emphasize early physical activity post-ACS. It will provide evidence regarding the feasibility and utility of this innovative platform in closing the treatment gaps in secondary prevention. Trial registration: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on April 4, 2016. The registration number is ACTRN12616000426482.Copyright © 2016 The Author(s).

Aim: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12-monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion. Method(s): Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia. Result(s): Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01). Interpretation(s): There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis.Copyright © 2015 Mac Keith Press

Background: There are well-documented treatment gaps in secondary prevention of coronary heart disease and no clear guidelines to assist early physical activity after acute coronary syndromes (ACS). Smartphone technology may provide an innovative platform to close these gaps. This paper describes the study design of a randomized controlled trial assessing whether a smartphone-based secondary prevention program can facilitate early physical activity and improve cardiovascular health in patients with ACS. Method(s): We have developed a multi-faceted, patient-centred smartphone-based secondary prevention program emphasizing early physical activity with a graduated walking program initiated on discharge from ACS admission. The program incorporates; physical activity tracking through the smartphone's accelerometer with interactive feedback and goal setting; a dynamic dashboard to review and optimize cardiovascular risk factors; educational messages delivered twice weekly; a photographic food diary; pharmacotherapy review; and support through a short message service. The primary endpoint of the trial is change in exercise capacity, as measured by the change in six-minute walk test distance at 8-weeks when compared to baseline. Secondary endpoints include improvements in cardiovascular risk factor status, psychological well-being and quality of life, medication adherence, uptake of cardiac rehabilitation and re-hospitalizations. Discussion(s): This randomized controlled trial will use a smartphone-phone based secondary prevention program to emphasize early physical activity post-ACS. It will provide evidence regarding the feasibility and utility of this innovative platform in closing the treatment gaps in secondary prevention. Trial registration: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on April 4, 2016. The registration number is ACTRN12616000426482.Copyright © 2016 The Author(s).

To test the efficacy and safety of leuprolide acetate (Lupron Depot®) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot® (11.25 mg leuprolide acetate), high dose Lupron Depot® (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.