Nedocromil sodium is a pyranoquinoline dicarboxylic acid derivative, formulated in a metered-dose inhaler. Because nedocromil sodium has in vitro and in vivo anti-inflammatory properties, it was evaluated in a group of steroid-dependent patients with asthma to observe how well it might be tolerated and for evidence of any beneficial effects. In a double-blind, group-comparative study, 127 patients received nedocromil sodium and 61 received placebo, administered as two puffs of 2 mg, four times per day, for 12 weeks. Ten patients developed adverse reactions, seven receiving active drug and three patients receiving placebo. Two patients of each group withdrew because of worsening asthma. Despite selecting patients whose asthma was stable, when they were receiving established therapeutic regimens that included steroids and bronchodilators, it was found that diary-card symptom scores, morning and evening peak expiratory flow rate values, and inhaled beta-agonist usage all demonstrated slight but significant benefit with addition of nedocromil sodium. It is concluded that the inhaled, anti-inflammatory agent, nedocromil sodium, may be added to asthma-treatment regimens with the reasonable expectation of further modest symptomatic benefit.
To update the 2005 Cancer Care Ontario practice guidelines for the diagnosis and treatment of adult patients with a suspected or confirmed diagnosis of extradural malignant spinal cord compression (MESCC).
A review and analysis of data published from January 2004 to May 2011. The systematic literature review included published randomized control trials (RCTs), systematic reviews, meta-analyses, and prospective/retrospective studies.
An RCT of radiation therapy (RT) with or without decompressive surgery showed improvements in pain, ambulatory ability, urinary continence, duration of continence, functional status, and overall survival. Two RCTs of RT (30 Gy in eight fractions vs. 16 Gy in two fractions; 16 Gy in two fractions vs. 8 Gy in one fraction) in patients with a poor prognosis showed no difference in ambulation, duration of ambulation, bladder function, pain response, in-field failure, and overall survival. Retrospective multicenter studies reported that protracted RT schedules in nonsurgical patients with a good prognosis improved local control but had no effect on functional or survival outcomes.
If not medically contraindicated, steroids are recommended for any patient with neurologic deficits suspected or confirmed to have MESCC. Surgery should be considered for patients with a good prognosis who are medically and surgically operable. RT should be given to nonsurgical patients. For those with a poor prognosis, a single fraction of 8 Gy should be given; for those with a good prognosis, 30 Gy in 10 fractions could be considered. Patients should be followed up clinically and/or radiographically to determine whether a local relapse develops. Salvage therapies should be introduced before significant neurologic deficits occur.
There is scarce information in literature about the decisions made by ethics committees concerning the clinical studies they have reviewed. A retrospective, detailed review of 666 applications, their amendments and the ethics committees' statements was undertaken. All protrocols of clinical studies on medicinal products submitted to and reviewed by the ethics committees of two university hospitals during the years 1992, 1994, 1996 and 1998 were investigated. Most of the studies were international (50%), multicenter (71%), phase III trials (41%) on a new clinical entity, (38%). Validity of the clinical drug study applications was acceptable in more than half of the cases (364; 55%), while 91 (14%) were approved with advisory comments, 153 (23%) had to be amended, 35 (5%) were left pending and 23 (3%) were rejected. Most of the questions pertained to informed consent and the study protcol. In accordance with precious results, our findings support the opinion that the submitted documents need to be improved, especially with regard to informed consent and study protocols, in order to gain better Good Clinical Practice (GCP) compliance. Well-defined, documented operating procedures of the ethics committees would have facilitated the practical issues in the review process.
This project studies the effect of group-based Acceptance and Commitment Therapy (ACT) following Attention Bias Modification (ABM) on residual symptoms in recurrent depression. ACT is a cognitive-behavioral intervention combining acceptance and mindfulness processes with commitment and behavior-change processes. ACT enjoys modest empirical support in treating depression and has also shown promising results in secondary prevention of depression. The experimental cognitive bias modification (ABM) procedure has been shown to reduce surrogate markers of depression vulnerability in patients in remission from depression. The aim of the current project is to investigate if the effect of group-based ACT on reducing residual depressive symptoms can be enhanced by preceding it with ABM. Also, assessment of the relationship between conceptually relevant therapeutic processes and outcome will be investigated.
An invitation to participate in this project was extended to 120 individuals within a larger sample who had just completed a separate randomized, multisite, clinical trial (referred to hereafter as Phase 1) in which they received either ABM (n = 60) or a control condition without bias modification (n = 60). This larger Phase-1 sample consisted of 220 persons with a history of at least two episodes of major depression who were currently in remission or not fulfilling the criteria of major depression. After its inclusion, Phase-1 participants from the Sørlandet site (n = 120) were also recruited for this study in which they received an 8-week group-based ACT intervention. Measures will be taken immediately after Phase 1, 1 month, 2 months, 6 months, and 1 year after the conclusion of Phase 1.
This study sequentially combines acceptable, nondrug interventions from neuropsychology and cognitive-behavioral psychology in treating residual symptoms in depression. The results will provide information about the effectiveness of treatment and on mechanisms and processes of change that may be valuable in understanding and further developing ABM and ACT, combined and alone.
ClinicalTrials.gov, Identifier: NCT02648165 . Registered on 6 January 2016.
BACKGROUND: Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer. METHODS: Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40-46 Gy in 20-25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5). FINDINGS: After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1.05 (95% CI 0.75-1.48; p=0.77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1.04; 95% CI 0.84-1.29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6.1%. INTERPRETATION: Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity.
Comment In: Lancet. 2009 Jan 10;373(9658):97-919070890
Admission hyperglycemia has been associated with worse outcomes in ischemic stroke. We hypothesized that hyperglycemia (glucose >8.0 mmol/l) in the hyperacute phase would be independently associated with increased mortality, symptomatic intracerebral hemorrhage (SICH), and poor functional status at 90 days in stroke patients treated with intravenous tissue plasminogen activator (IV-tPA).
Using data from the prospective, multicenter Canadian Alteplase for Stroke Effectiveness Study (CASES), the association between admission glucose >8.0 mmol/l and mortality, SICH, and poor functional status at 90 days (modified Rankin Scale >1) was examined. Similar analyses examining glucose as a continuous measure were conducted.
Of 1,098 patients, 296 (27%) had admission hyperglycemia, including 18% of those without diabetes and 70% of those with diabetes. After multivariable logistic regression, admission hyperglycemia was found to be independently associated with increased risk of death (adjusted risk ratio 1.5 [95% CI 1.2-1.9]), SICH (1.69 [0.95-3.00]), and a decreased probability of a favorable outcome at 90 days (0.7 [0.5-0.9]). An incremental risk of death and SICH and unfavorable 90-day outcomes was observed with increasing admission glucose. This observation held true for patients with and without diabetes.
In this cohort of IV-tPA-treated stroke patients, admission hyperglycemia was independently associated with increased risk of death, SICH, and poor functional status at 90 days. Treatment trials continue to be urgently needed to determine whether this is a modifiable risk factor for poor outcome.
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Research in traumatic brain injury (TBI) is challenging for several reasons; in particular, the heterogeneity between patients regarding causes, pathophysiology, treatment, and outcome. Advances in basic science have failed to translate into successful clinical treatments, and the evidence underpinning guideline recommendations is weak. Because clinical research has been hampered by non-standardised data collection, restricted multidisciplinary collaboration, and the lack of sensitivity of classification and efficacy analyses, multidisciplinary collaborations are now being fostered. Approaches to deal with heterogeneity have been developed by the IMPACT study group. These approaches can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid haemorrhage. Rather than trying to limit heterogeneity, we might also be able to exploit it by analysing differences in treatment and outcome between countries and centres in comparative effectiveness research. This approach has great potential to advance care in patients with TBI.
This retrospective analysis of electrocardiographic (ECG) data investigated the cardiovascular effects of paroxetine 10-50 mg/day in pediatric patients (7-18 years of age). Data were collected from three 8- to 10-week, randomized, placebo-controlled, double-blind trials of paroxetine in pediatric patients with major depressive disorder or obsessive-compulsive disorder.
Electrocardiograms (ECGs) were retrospectively retrieved from 63 study sites in the United States and Canada. Only patients with at least one screening and one on-treatment ECG were included. ECGs were analyzed for heart rate, QT interval corrected using Bazett's formula (QTcB) and Fridericia's formula (QTcF), at screening and while being treated. PR, R-R, and QRS intervals and the maximum change in QTcB and QTcF from screening to endpoint were determined. Clinically significant thresholds were defined a priori.
A total of 1,451 ECGs from 449 patients receiving placebo (n = 207), paroxetine (n = 200), or imipramine (n = 42) were analyzed. Treatment with paroxetine did not significantly increase QTcB or QTcF or any ECG parameters compared with placebo. Treatment with imipramine significantly increased heart rate and QTcB, R-R, and QRS intervals compared with either paroxetine or placebo.
Data from this retrospective study indicate that paroxetine (10-50 mg/day) is unlikely to be associated with significant ECG changes in medically healthy pediatric patients.