Parent initiated prednisolone for acute asthma in children of school age : randomised controlled crossover trial

Objective To evaluate the efficacy of a short course of parent initiated oral prednisolone for acute asthma in children of school age.

Design Double blind, randomised, placebo controlled, crossover trial in which episodes of asthma, rather than participants, were randomised to treatment.

Setting The Barwon region of Victoria, Australia.

Participants Children aged 5-12 years with a history of recurrent episodes of acute asthma.

Intervention A short course of parent initiated treatment with prednisolone (1 mg/kg a day) or placebo.

Main outcome measures The primary outcome measure was the mean daytime symptom score over seven days. Secondary outcome measures were mean night time symptom score over seven days, use of health resources, and school absenteeism.

Results 230 children were enrolled in the study. Over a three year period, 131 (57%) of the participants contributed a total of 308 episodes of asthma that required parent initiated treatment: 155 episodes were treated with parent initiated prednisolone and 153 with placebo. The mean daytime symptom score was 15% lower in episodes treated with prednisolone than in those treated with placebo (geometric mean ratio 0.85, 95% CI 0.74 to 0.98; P=0.023). Treatment with prednisolone was also associated with a 16% reduction in the night time symptom score (geometric mean ratio 0.84, 95% CI 0.70 to 1.00; P=0.050), a reduced risk of health resource use (odds ratio 0.54, 95% CI 0.34 to 0.86; P=0.010), and reduced school absenteeism (mean difference −0.4 days, 95% CI −0.8 to 0.0 days; P=0.045).

Conclusion A short course of oral prednisolone initiated by parents when their child experiences an episode of acute asthma may reduce asthma symptoms, health resource use, and school absenteeism. However, the modest benefits of this strategy must be balanced against potential side effects of repeated short courses of an oral corticosteroid.

DSM-5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data

Background:
To describe the frequency of mixed specifier as proposed in DSM-5 in bipolar I patients with manic episodes, and to evaluate the effect of mixed specifier on symptom severity and treatment outcome.

Methods:
This post-hoc analysis used proxies for DSM-5 mixed features specifier by using MADRS or PANSS items.

Results:
Of the 960 patients analysed, 34%, 18% and 4.3% of patients, respectively, had ≥3 depressive features with mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS) symptoms. In patients with ≥3 depressive features and independent of treatment: MADRS remission (score ≤12) rate decreased with increasing severity (61–43%) and YMRS remission (score ≤12) was similar for mild and moderate patients (36–37%), but higher for severe (54%). In asenapine-treated patients, the MADRS remission rate was stable regardless of baseline depressive symptom severity (range 64–67%), whereas remission decreased with increasing severity with olanzapine (63–38%) and placebo (49–25%). Reduction in YMRS was significantly greater for asenapine compared with placebo at day 2 across the 3 severity cut-offs and continued to decrease throughout the treatment period. The difference between olanzapine and placebo was statistically significant in mild and moderate patients.

Limitations:
Results are from post-hoc analyses.

Conclusions:
These analyses support the validity of proposed DSM-5 criteria. They confirm that depressive features are frequent in bipolar patients with manic episodes. With increasing baseline severity of depressive features, treatment outcome was poorer with olanzapine and placebo, but remained stable with asenapine.

The TFOS international workshop on contact lens discomfort : report of the subcommittee on clinical trial design and outcomes

The goal of this report is to review previously published clinical trials addressing contact lens discomfort (CLD) to identify appropriate trial design and outcome parameters to guide future clinical research that will characterize and investigate possible causes of CLD. A further goal is to identify possible confounding features of clinical trial design and performance in order to reduce bias in conduct of future trials or analysis of data from those trials.

Effects of vitamin D supplementation on neuroplasticity in older adults: a double-blinded, placebo-controlled randomised trial

Summary - Vitamin D can improve muscle function and reduce falls, but whether it can strengthen neural connections within the brain and nervous system is not known. This 10-week randomised controlled trial indicates that treatment with 2,000 IU/day vitamin D3 does not significantly alter neuroplasticity relative to placebo in older adults.
Introduction - The purpose of this study was to examine the effects of vitamin D supplementation on neuroplasticity, serum brain-derived neurotrophic factor (BDNF) and muscle strength and function in older adults.
Methods - This was a 10-week double-blinded, placebo-controlled randomised trial in which 26 older adults with 25-hydroxyvitamin D [25OHD] concentrations 25–60 nmol/L were randomised to 2,000 IU/day vitamin D3 or matched placebo. Single- and paired-pulse transcranial magnetic stimulation applied over the motor cortex was used to assess changes in motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI), as measures of corticospinal excitability and inhibition respectively, by recording electromyography (EMG) responses to stimulation from the wrist extensors. Changes in muscle strength, stair climbing power, gait (timed-up-and-go), dynamic balance (four square step test), serum 25(OH)D and BDNF concentrations were also measured.
Results - After 10 weeks, mean 25(OH)D levels increased from 46 to 81 nmol/L in the vitamin D group with no change in the placebo group. The vitamin D group experienced a significant 8–11 % increase in muscle strength and a reduction in cortical excitability (MEP amplitude) and SICI relative to baseline (all P < 0.05), but these changes were not significantly different from placebo. There was no effect of vitamin D on muscle power, function or BDNF.
Conclusions - Daily supplementation with 2,000 IU vitamin D3 for 10 weeks had no significant effect on neuroplasticity compared to placebo, but the finding that vitamin D treatment alone was associated with a decrease in corticospinal excitability and intracortical inhibition warrants further investigation as this suggests that it may improve the efficacy of neural transmission within the corticospinal pathway.

The Dutch Obesity Intervention in Teenagers (DOiT) cluster controlled implementation trial: intervention effects and mediators and moderators of adiposity and energy balance-related behaviours

 Background: The Dutch Obesity Intervention in Teenagers (DOiT) programme is an evidence-based obesity prevention programme tailored to adolescents attending the first two years of prevocational education in the Netherlands. The initial programme showed promising results during an effectiveness trial. The programme was adapted and prepared for nationwide dissemination. To gain more insight into the process of translating evidence-based approaches into ‘real world’ (i.e., ‘natural’) conditions, our research aims were to evaluate the impact of the DOiT-implementation programme on adolescents’ adiposity and energy balance-related behaviours during natural dissemination and to explore the mediating and moderating factors underlying the DOiT intervention effects.
Methods: We conducted a cluster-controlled implementation trial with 20 voluntary intervention schools (n=1002 adolescents) and 9 comparable control schools (n = 484 adolescents). We measured adolescents’ body height and weight, skinfold thicknesses, and waist circumference. We assessed adolescents’ dietary and physical activity behaviours by means of self-report. Data were collected at baseline and at 20-months follow-up. We used multivariable multilevel linear or logistic regression analyses to evaluate the intervention effects and to test the hypothesised behavioural mediating factors. We checked for potential effect modification by gender, ethnicity and education level.
Results: We found no significant intervention effects on any of the adiposity measures or behavioural outcomes. Furthermore, we found no mediating effects by any of the hypothesised behavioural mediators. Stratified analyses for gender showed that the intervention was effective in reducing sugar-containing beverage consumption in girls (B = -188.2 ml/day; 95% CI = -344.0; -32.3). In boys, we found a significant positive intervention effect on breakfast frequency (B = 0.29 days/week; 95% CI = 0.01; 0.58). Stratified analyses for education level showed an adverse intervention effect (B = 0.09; 95% CI = 0.02; 0.16) on BMI z-scores for adolescents attending the vocational education track.
Conclusions: Although not successful in changing adolescents’ adiposity, the DOiT-implementation programme had some beneficial effects on specific obesity-related behaviours in subgroups. This study underlines the difficulty of translating intervention effectiveness in controlled settings to real world contexts. Adaptations to the implementation strategy are needed in order to promote implementation as intended by the teachers.

Validity of 12-month falls recall in community-dwelling older women participating in a clinical trial

Objectives. To compare 12-month falls recall with falls reported prospectively on daily falls calendars in a clinical trial of women aged ≥70 years. Methods. 2,096 community-dwelling women at high risk of falls and/or fracture completed a daily falls calendar and standardised interviews when falls were recorded, for 12 months. Data were compared to a 12-month falls recall question that categorised falls status as “no falls,” “a few times,” “several,” and “regular” falls. Results. 898 (43%) participants reported a fall on daily falls calendars of whom 692 (77%) recalled fall(s) at 12 months. Participants who did not recall a fall were older (median 79.3 years versus 77.8 years, ). Smaller proportions of fallers who sustained an injury or accessed health care failed to recall a fall (all ). Among participants who recalled “no fall,” 85% reported zero falls on daily calendars. Few women selected falls categories of “several times” or “regular” (4.1% and 0.4%, resp.) and the sensitivity of these categories was low (30% to 33%). Simply categorising participants into fallers or nonfallers had 77% sensitivity and 94% specificity. Conclusion. For studies where intensive ascertainment of falls is not feasible, 12-month falls recall questions with fewer responses may be an acceptable alternative.

Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians: a model process

BACKGROUND: The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients. METHODS: The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug. RESULTS: Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug. CONCLUSIONS: Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE).

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD.

Guided imagery to improve functional outcomes post-anterior cruciate ligament repair: randomized-controlled pilot trial

Imagery can improve functional outcomes post-anterior cruciate ligament repair (ACLR). Research is needed to investigate potential mechanisms for this effect. The aim of this study was to (a) evaluate the effectiveness of an imagery intervention to improve functional outcomes post-ACLR, and (b) explore potential mechanisms. A randomized-controlled pilot trial was conducted. Participants were randomized to guided imagery and standard rehabilitation or standard rehabilitation alone (control). The primary outcome was knee strength 6-month post-operatively. Secondary outcomes were knee laxity at 6-months, and change in psychological (self-efficacy) and neurohormonal (adrenaline, noradrenaline, dopamine) variables. Participants (n=21; 62% male) were 34.86 (SD 8.84) years. Following the intervention, no statistical differences between groups for knee strength extension at 180°/s (t=-0.43, P=0.67), or at 60°/s (t=-0.72, P=0.48) were found. A statistically significant effect was found for knee laxity, F=4.67, P<0.05, mean difference of -3.02 (95% CI -4.44 to -1.60), favoring the intervention. No differences were found for self-efficacy; however, an overall effect was found for noradrenaline, F(1, 19) 19.65, P<0.001, η(2) =0.52, and dopamine, F(1, 19) 6.23, P=0.02, η(2) =0.29, favoring the intervention. This imagery intervention improved knee laxity and healing-related neurobiological factors.

Clinical trial adaptation by matching evidence in complementary patient sub-groups of auxiliary blinding questionnaire responses

Clinical trial adaptation refers to any adjustment of the trial protocol after the onset of the trial. Such adjustment may take on various forms, including the change in the dose of administered medicines, the frequency of administering an intervention, the number of trial participants, or the duration of the trial, to name just some possibilities. The main goal is to make the process of introducing new medical interventions to patients more efficient, either by reducing the cost or the time associated with evaluating their safety and efficacy. The principal challenge, which is an outstanding research problem, is to be found in the question of how adaptation should be performed so as to minimize the chance of distorting the outcome of the trial. In this paper we propose a novel method for achieving this. Unlike most of the previously published work, our approach focuses on trial adaptation by sample size adjustment i.e. by reducing the number of trial participants in a statistically informed manner. We adopt a stratification framework recently proposed for the analysis of trial outcomes in the presence of imperfect blinding and based on the administration of a generic auxiliary questionnaire that allows the participants to express their belief concerning the assigned intervention (treatment or control). We show that this data, together with the primary measured variables, can be used to make the probabilistically optimal choice of the particular sub-group a participant should be removed from if trial size reduction is desired. Extensive experiments on a series of simulated trials are used to illustrate the effectiveness of our method.

Sodium bicarbonate infusion in patients undergoing orthotopic liver transplantation: a single center randomized controlled pilot trial

BACKGROUND: Liver transplantation-associated acute kidney injury (AKI) carries significant morbidity and mortality. We hypothesized that sodium bicarbonate would reduce the incidence and/or severity of liver transplantation-associated AKI. METHODS: In this double-blinded pilot RCT, adult patients undergoing orthotopic liver transplantation were randomized to an infusion of either 8.4% sodium bicarbonate (0.5 mEq/kg/h for the first hour; 0.15 mEq/kg/h until completion of surgery); (n = 30) or 0.9% sodium chloride (n = 30). Primary outcome: AKI within the first 48 h post-operatively.RESULTS: There were no significant differences between the two treatment groups with regard to baseline characteristics, model for end-stage liver disease and acute physiology and chronic health evaluation (APACHE) II scores, and pre-transplantation renal function. Intra-operative factors were similar for duration of surgery, blood product requirements, crystalloid and colloid volumes infused and requirements for vasoactive therapy. Eleven patients (37%) in the bicarbonate group and 10 patients (33%) in the sodium chloride group developed a post-operative AKI (p = 0.79). Bicarbonate infusion attenuated the degree of immediate post-operative metabolic acidosis; however, this effect dissipated by 48 h. There were no significant differences in ventilation hours, ICU or hospital length of stay, or mortality. CONCLUSIONS: The intra-operative infusion of sodium bicarbonate did not decrease the incidence of AKI in patients following orthotopic liver transplantation.

Laboratory and non-laboratory-based risk prevention models for secondary prevention of cardiovascular disease : the LIPID study

Aims : The aims of this study were to examine whether risk prediction models for recurrent cardiovascular disease (CVD) events have prognostic value, and to particularly examine the performance of those models based on non-laboratory data. We also aimed to construct a risk chart based on the risk factors that showed the strongest relationship with CVD.

Methods and results : Cox proportional hazards models were used to calculate a risk score for each recurrent event in a CVD patient who was enrolled in a very large randomized controlled clinical trial. Patients were then classified into groups according to quintiles of their risk score. These risk models were validated by calibration and discrimination analyses based on data from patients recruited in New Zealand for the same study. Non-laboratory-based risk factors, such as age, sex, body mass index, smoking status, angina grade, history of myocardial infarction, revascularization, stroke, diabetes or hypertension and treatment with pravastatin, were found to be significantly associated with the risk of developing a recurrent CVD event. Patients who were classified into the medium and high-risk groups had two-fold and four-fold the risk of developing a CVD event compared with those in the low-risk group, respectively. The risk prediction models also fitted New Zealand data well after recalibration.

Conclusion : A simpler non-laboratory-based risk prediction model performed equally as well as the more comprehensive laboratory-based risk prediction models. The risk chart based on the further simplified Score Model may provide a useful tool for clinical cardiologists to assess an individual patient's risk for recurrent CVD events.