A Mechanized Pediatric Elbow Joint Powered by a De-Based Artificial Skeletal Muscle.

To increase the acceptability of exoskeletons, there is growing attention toward finding an alternative soft actuator that can safely perform at close vicinity of the human body. In this study, we investigated the capability of the dielectric elastomer actuators (DEAs), for muscle-like actuation of rehabilitation robots. First, an artificial skeletal muscle was configured using commercially available stacked DEAs arranged in a 3x4 array of three parallel fibers consisting of four DEAs connected in series. The shortening and force generation capabilities of this artificial muscle were then measured. An alternate 3x5 version of this muscle was mounted on the forearm of an upper extremity phantom model to actuate its elbow joint. The actuation capability of this muscle was then tested under various tensile loads, 1 N to 4 N, placed at the center of mass of the forearm+hand of the phantom model. The active range of motion and angular velocity of the phantom model's tip of the hand were measured using a motion capture system. The 3×4 artificial muscle produced 30.47 N of force and 5.3 mm of maximum shortening. The 3x5 artificial muscle was capable of actuating the elbow flexion 19.5º with 16.2 º/s angular velocity in the sagittal plane, under a 1 N tensile load. The active range of motion was substantially reduced as the tensile loads increased, which limits the capability of these muscles in the current upper extremity exoskeleton design.

Survival analysis in total joint replacement: an alternative method of accounting for the presence of competing risk.

Survival analysis is an important tool for assessing the outcome of total joint replacement. The Kaplan-Meier method is used to estimate the incidence of revision of a prosthesis over time, but does not account appropriately for competing events which preclude revision. In the presence of competing death, this method will lead to statistical bias and the curve will lose its interpretability. A valid comparison of survival results between studies using the method is impossible without accounting for different rates of competing events. An alternative and easily applicable approach, the cumulative incidence of competing risk, is proposed. Using three simulated data sets and realistic data from a cohort of 406 consecutive cementless total hip prostheses, followed up for a minimum of ten years, both approaches were compared and the magnitude of potential bias was highlighted. The Kaplan-Meier method overestimated the incidence of revision by almost 4% (60% relative difference) in the simulations and more than 1% (31.3% relative difference) in the realistic data set. The cumulative incidence of competing risk approach allows for appropriate accounting of competing risk and, as such, offers an improved ability to compare survival results across studies.

Treatment of angina pectoris: associations with symptom severity.

OBJECTIVE: To evaluate whether the frequency of anginal attacks in medically treated patients with stable angina is related to the intensity of anti-anginal treatment, the clinical history and coronary anatomy. METHODS: Analysis of baseline data from the A Coronary disease Trial Investigating Outcome with Nifedipine GITS (ACTION) study, an ongoing placebo-controlled trial in 7669 patients with stable angina pectoris who require anti-anginal treatment. RESULTS: Prior to randomisation, 8% of 7669 patients had no anginal attacks, 63% had occasional, 22% had regular, 4% had frequent and 3% had daily attacks. Men (79% of all patients) and patients with a history of MI (51%) had less frequent anginal attacks (P<0.0001). The number of coronary angiograms ever performed (70% had at least one angiogram), the extent of angiographic coronary disease (32% of those who had angiography had more than two-vessel disease), a history of peripheral artery disease (12%), the number of anti-anginal drugs used (64% were prescribed two or more such medications) and a history of revascularisation (a history of coronary bypass surgery was present in 23% and of balloon dilatation in 26%) were each positively associated with anginal attack frequency. CONCLUSIONS: For the majority of patients with chronic stable angina not on a calcium-antagonist, medical treatment with other anti-anginal drugs is sufficient to control symptoms and only a minority of patients are refractory to medical treatment. Invasive treatments for chronic stable angina are only needed in a small proportion where symptoms persist.

Baseline risk as predictor of treatment benefit: three clinical meta-re-analyses.

A relationship between baseline risk and treatment effect is increasingly investigated as a possible explanation of between-study heterogeneity in clinical trial meta-analysis. An approach that is still often applied in the medical literature is to plot the estimated treatment effects against the estimated measures of risk in the control groups (as a measure of baseline risk), and to compute the ordinary weighted least squares regression line. However, it has been pointed out by several authors that this approach can be seriously flawed. The main problem is that the observed treatment effect and baseline risk measures should be viewed as estimates rather than the true values. In recent years several methods have been proposed in the statistical literature to potentially deal with the measurement errors in the estimates. In this article we propose a vague priors Bayesian solution to the problem which can be carried out using the 'Bayesian inference using Gibbs sampling' (BUGS) implementation of Markov chain Monte Carlo numerical integration techniques. Different from other proposed methods, it uses the exact rather than an approximate likelihood, while it can handle many different treatment effect measures and baseline risk measures. The method differs from a recently proposed Bayesian method in that it explicitly models the distribution of the underlying baseline risks. We apply the method to three meta-analyses published in the medical literature and compare the results with the outcomes of the other recently proposed methods. In particular we compare our approach to McIntosh's method, for which we show how it can be carried out using standard statistical software. We conclude that our proposed method offers a very general and flexible solution to the problem, which can be carried out relatively easily with existing Bayesian analysis software. A confidence band for the underlying relationship between true effect measure and baseline risk and a confidence interval for the value of the baseline risk measure for which there is no treatment effect are easily obtained by-products of our approach.

Implications of trial results: the potentially misleading notions of number needed to treat and average duration of life gained.

Consider a physician advising a patient to start antihypertensive treatment. He has the unenviable task of presenting often conflicting trial data in a comprehensible manner. He must justly represent the known risks and benefits such that his patient can make a reasonably Informed choice. Should the physician cite the number needed to treat or the average duration of life gained to clarify his explanations?

Heart failure treatments: issues of safety versus issues of quality of life.

Congestive heart failure is an important cause of morbidity and mortality in western countries. The profound impact that congestive heart failure has on life expectancy and quality of life has been a continuous stimulus for the development of new drugs for the treatment of this condition. Despite favourable effects on (aspects of) quality of life in short term studies, several of these new agents have been shown to reduce survival in mortality trials. However, patients with severe congestive heart failure may experience such incapacitating symptoms that the question should be raised as to whether an improvement in quality of life makes the increased risk of mortality associated with these new agents acceptable. Drugs which improve quality of life at the expense of an increased risk of mortality can be of value in the treatment of patients with severe congestive heart failure. However, this is only the case if the probability of improvement in quality of life and prolongation of life expectancy for those using the drug exceeds the probability of improvement in quality of life and prolongation of life expectancy for those not using the drug. Unfortunately, most clinical trials in which both mortality and quality of life are evaluated fail to provide information on this composite probability. Despite disappointing results of some recent mortality trials on new pharmacological treatments of congestive heart failure, sound and well designed clinical trials on innovative heart failure treatments in which these composite probabilities are also assessed should be carried out.

Relationship between abortions and seroprevalences to selected infectious agents in dairy cows.

The aim of this study was to determine whether the occurrence of abortion is related to the seroprevalence of abortion-causing infectious agents. In a cross-sectional study, cattle from dairy farms in Switzerland that were defined as having an abortion problem were divided into two groups: cows with a history of abortion within the previous 3 months (cases) and cows without a history of abortion (controls). A positive titre to Leptospira spp. was associated with an increased probability of being a case (OR = 1.74, 95% CI = 1.21-2.47). There were interactions between Coxiella burnetti titre and parity, and between Chlamydia psittaci and C. burnetti titre and breed. Multiparous cases after the second lactation with a positive titre to C. burnetti were less likely (OR = 0.42, 95% CI = 0.22-0.82) to be cases. Swiss Browns (Swiss Braunvieh and Brown Swiss) with a positive titre to C. psittaci and Swiss Browns with a positive titre to C. burnetti were more likely (OR = 1.63, 95% CI = 1.13-2.37 and OR = 1.79, 95% CI = 1.15-2.78, respectively) to be cases. Parity alone was not associated with the occurrence of abortion.

The calcium channel antagonist debate: recent developments.

Recent contributions to the calcium channel antagonist (CCA) debate concern the recommendations in the Sixth Report of the U.S.A. Joint National Committee on Prevention. Detection, Evaluation and Treatment of High Blood Pressure and raise questions about evidence-based medicine. Also, several studies have recently been published. A 4695-patient placebo-controlled trial showed that the CCA nitrendipine significantly reduces cardiovascular complications in older people with systolic hypertension. A 470-patient trial showed a significantly higher rate of myocardial infarction in hypertensive non-insulin-dependent diabetics treated with the CCA nisoldipine than in those treated with the ACE inhibitor enalapril. Non-experimental data (on 84 093 person-years in total) comparing antihypertensive agents in hypertensive women showed mostly non-significant covariate-adjusted total and cardiovascular mortality differences that are difficult to interpret because of potential residual confounding. One report suggested a relationship between CCAs and suicide. A case-control study (9513 cases, 6492 controls) showed that CCAs are unlikely to cause cancer. The current recommendation remains to start treatment of hypertension with diuretics and beta-blockers, but recent studies support the use of sustained release CCAs in cases in which blood pressure cannot be controlled with other agents.

Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System.

AIMS: To present the design of ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS), an ongoing multicentre clinical outcome trial with nifedipine GITS (Gastro-Intestinal Therapeutic System) in patients with stable angina pectoris. METHODS: At least 6000 patients with optimally treated stable angina without depressed left ventricular function are randomized in equal proportions to either nifedipine GITS or matching placebo (starting dose 30 mg, maintenance dose 60 mg once daily). Patients are followed for at least four years. The primary end-point, to be analyzed by assigned treatment, includes all-cause mortality, acute myocardial infarction, emergency coronary angiography for refractory angina, overt heart failure, debilitating stroke and peripheral revascularization. For this end-point, the trial has a power of 95% to detect a relative risk reduction of 18% at the 5%, level of significance, and is large enough to exclude an excess mortality caused by nifedipine GITS of 3.1 deaths per 1000 years of treatment or greater. The pre-specified early termination rule is more conservative in the case of a beneficial effect than in the case of an adverse effect of nifedipine GITS. The first patient was randomized on 29 November, 1996. By the end of April 1998, about 5200 patients had been started on study medication. CONCLUSIONS: Results will be available in the autumn of 2003.

Sudden cardiac death in patients with hypertension. An association with diuretics and beta-blockers?

The cornerstones of current antihypertensive treatment are diuretics and beta-blockers and the efficacy of these drugs in preventing cardiovascular disease is undisputed. This article focuses on the effect of these 2 drug classes on the incidence of sudden death. Numerous studies have shown that thiazide diuretics have a strong, dosage-dependent potassium-depleting effect, and it has been postulated that this may explain why the reduction in risk of coronary heart disease, observed in hypertension trials, was less pronounced than expected. In 7 trials that included sudden death as an end-point; a pooled risk-ratio of sudden death of 1.5 (95% confidence interval 1.1 to 2.0) was observed when non-potassium-sparing diuretics were compared with placebo. Two recent case-control studies have also strongly indicated that the use of thiazides increases the risk of sudden death. Evidence from trials using potassium-sparing diuretic combinations suggests that these may be better tolerated than thiazide monotherapy. Although it was suggested in the 2 recent case-control studies that recipients of beta-blockers are also at an increased risk of sudden death, further studies are required to confirm this finding, particularly since these drugs have several well-documented cardioprotective effects.

Action: a 30,000 patient-years double-blind, placebo-controlled trial of nifedipine GITS in stable angina. ACTION Research Group.

To assess the overall balance between efficacy and safety of the long-action calcium antagonist nifedipine gastrointestinal therapeutic system (GITS) in patients with stable symptomatic coronary artery disease (CAD), a large multicentre placebo-controlled double-blind trial called ACTION has been mounted (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS). Patients are eligible if they have proven CAD on antianginal treatment in stable clinical condition for at least 3 months without heart failure. The left ventricular ejection fraction must be above 40%. Patients not already on lipid-lowering therapy will be evaluated and such treatment will be started based on current guidelines before randomisation. After washout of an already given calcium antagonist, more than 6000 patients in total will be randomised in equal proportions to either nifedipine GITS 60 mg once daily or placebo. The mean clinical follow-up will be 5 years, with no restrictions on concomitant medication (with the exception of digitalis, calcium antagonists and class III antiarrhythmics). The primary end-point will be survival free of major cardiovascular events (i.e. survival free of acute myocardial infarction, emergency coronary angiography, overt heart failure, stroke and peripheral revascularisation). The study has 95% power to detect a significant (p < 0.05) 18% improvement of this end-point and is of sufficient size to exclude an excess mortality of 3.1 per 1000 patient-years. In this first stable angina trial of this size and scope, 185 centres in Canada, Europe, Israel, Australia and New Zealand will participate. Recruitment will start in November 1996 and is planned to be completed in 2 years.

Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial.

PRIMARY OBJECTIVE: To determine the effects of pimobendan 2.5 and 5 mg daily on exercise capacity in patients with chronic heart failure. DESIGN: A randomised, double blind, placebo controlled trial of the addition of pimobendan to conventional treatment with a minimum follow up of 24 weeks. SETTING: Outpatient cardiology clinics in six European countries. PATIENTS: 317 patients with stable symptomatic heart failure, objectively impaired exercise capacity, and an ejection fraction of 45% or lower who were treated with at least an angiotensin converting enzyme inhibitor and a diuretic and who tolerated a test dose of pimobendan. RESULTS: Compared with placebo, both pimobendan 2.5 and 5 mg daily improved exercise duration (bicycle ergometry) by 6% (P = 0.03 and 0.05) after 24 weeks of treatment. At that time 63% of patients allocated to pimobendan and 59% of those allocated to placebo were alive and able to exercise to at least the same level as at entry (P = 0.5). No significant effects on oxygen consumption (assessed in a subgroup of patients) and on quality of life (assessed by questionnaire) were observed. Pimobendan was well tolerated. Proarrhythmic effects (24-hour electrocardiography) were not observed. In both pimobendan groups combined the hazard of death was 1.8 (95% confidence interval 0.9 to 3.5) times higher than in the placebo group. CONCLUSIONS: Pimobendan improves exercise capacity in patients with chronic heart failure who are also on conventional treatment. The balance between benefit and risk of treatment with this compound remains to be established however.

Meta-analysis of morbidity and mortality in five exercise capacity trials evaluating ramipril in chronic congestive cardiac failure.

In 5 separate exercise capacity trials in similar patients with chronic congestive heart failure performed in Europe, the United States, and South Africa, 627 patients were randomized to ramipril and 428 to placebo. The dose of ramipril ranged from 1.25 to 20 mg/day. Follow-up was at 12 or 24 weeks. None of the trials were designed to assess efficacy with regard to clinical outcome. To assess in the combined experience whether there was an effect of ramipril on mortality, hospitalization, functional classification (New York Heart Association class), and exercise capacity, we pooled data from each trial and performed a mata-analysis. Of the patients randomized to ramipril and placebo, respectively, and based on intention to treat, 14 (2.2%) and 18 (3.8%) patients died (odds ratio 0.60, 95% confidence interval 0.28 to 1.29), and 59 (9.4%) and 67 (14.3%) patients died or were hospitalized (odds ratio 0.68, 95% confidence interval 0.46 to 1.00). The New York Heart Association class improved in 29% and 25% respectively, whereas 8% and 15% deteriorated (p=0.04, based on intention to treat; death and hospitalization considered as deterioration). In ranked comparisons based on intention to treat and with imputation of exercise time as 0 for patients who were unable to exercise because of death or who were hospitalized, exercise capacity was significantly improved by rampril. We concluded that rampiril is likely to have an effect on mortality, morbidity, and functional capacity in patients with chronic congestive heart failure similar to that of other angiotensin-converting enzyme inhibitors.

Mega-trials: is meta-analysis an alternative?

Large scale placebo-controlled trials with clinical end-points are not possible when other compounds with proven efficacy are already available. Hence, the question arises whether the available experience from placebo-controlled phase III trials can be analysed jointly to assess whether an effect on clinical end-points exists. This question was answered for the new ACE inhibitor ramipril, with which five exercise capacity trials were done in similar patients with heart failure. Meta-analysis showed that ramipril reduced the occurrence of the combined event death or hospitalisation by 32% (P = 0.05), based on the customary 'intention-to-treat' comparison for large scale trials. From this analysis, the lesson has been learnt that a drug development programme must be carefully planned to allow for this type of meta-analysis.

Diuretics, beta-blockers, and the risk for sudden cardiac death in hypertensive patients.

OBJECTIVE: To determine whether the use of non-potassium-sparing diuretics and beta-blockers is associated with an excess risk for sudden cardiac death in hypertensive patients. DESIGN: Case-control study. SETTING: Rotterdam, the Netherlands. PATIENTS: 257 case-patients who had died suddenly while receiving drug therapy for hypertension and 257 living controls also receiving drug therapy for hypertension. MEASUREMENTS: Detailed information on medication use and clinical characteristics of all case-patients and controls was collected from the files of general practitioners. Additional information on medication use was obtained from computerized pharmacy records. RESULTS: Patients receiving non-potassium-sparing diuretics had an increased risk for sudden cardiac death (relative risk, 1.8 [95% CI, 1.0 to 3.1]) compared with a reference group treated primarily with potassium-sparing diuretics. The corresponding relative risk for beta-blocker use was 1.7 (CI, 1.1 to 2.6). The use of non-potassium-sparing diuretics without beta-blockers was associated with a higher risk for sudden death (relative risk, 2.2 [CI, 1.1 to 4.6]) than was concomitant use of non-potassium-sparing diuretics and beta-blockers (relative risk, 1.4 [CI, 0.6 to 3.0]). The risk for sudden cardiac death among recipients of non-potassium-sparing diuretics was more pronounced in those who had been receiving the diuretic for less than 1 year and in those aged 75 years or younger. CONCLUSIONS: The use of non-potassium-sparing diuretics and beta-blockers is associated with an increased risk for sudden cardiac death. This association may offset part of the mortality benefit of these drugs in the treatment of hypertension.

Does drug treatment improve survival? Reconciling the trials in mild-to-moderate hypertension.

OBJECTIVE: To evaluate whether drug treatment for mild-to-moderate hypertension in middle-aged patients improves survival and to study how the conflicting results of individual trials may be explained. STUDY SELECTION: A meta-analysis was performed, including seven randomized trials in mild-to-moderate hypertensive (diastolic blood pressure 90-114 mmHg) middle-aged patients. DATA EXTRACTION: A comparison was made between all-cause mortality and fatal coronary heart disease and stroke in the intervention and control group of the individual trials, using a method of meta-analysis based on weighted linear regression. RESULTS: In trials with a high all-cause mortality rate (> 6 per 1000 patient-years) in the control group, antihypertensive drug treatment increased life expectancy. When all-cause mortality in the control group was low, treatment showed no effect or even an opposite effect. Findings on mortality from coronary heart disease were similar, whereas drug treatment decreased stroke mortality irrespective of the incidence of stroke in the control group. CONCLUSIONS: Drug treatment for mild-to-moderate hypertension in middle-aged patients may reduce all-cause mortality and the risk of fatal coronary events when treatment is initiated in those beyond a certain baseline mortality risk. Drug treatment in hypertensive patients at a lower mortality risk has no influence on or may even increase mortality.