SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
We investigated co-varied changes in muscle activity during voluntary sway tasks that required a quick shift of the center of pressure (COP). We hypothesized that multi-muscle synergies (defined as task-specific covariation of elemental variables, muscle modes) stabilize a COP location in the anterior-posterior direction prior to a voluntary COP shift and that during the shift the synergies would weaken. Standing subjects performed two tasks, a cyclic COP shift over a range corresponding to 80% of the maximal amplitude of voluntary COP shift at 1 Hz and a unidirectional quick COP shift over the same nominal amplitude. The cyclic sway task was used to define muscle modes (M-modes, leg and trunk muscle groups with parallel scaling of muscle activation level within a group) and the relations between small changes in the magnitudes of M-modes [in the principal component analysis (PCA), the M-mode magnitudes are equivalent to PC scores] and COP shifts. A novel approach was used involving PCA applied to indices of muscle integrated activity measured both within a trial and across trials. The unidirectional sway task was performed in a self-paced (SP) manner and under a typical simple reaction time (RT) instruction. M-modes were also defined along trials at those tasks; they have been shown to be similar across tasks. Integrated indices of muscle activity in the SP-sway and RT-sway tasks were transformed into the M-modes. Variance in the M-mode space was partitioned into two components, one that did not affect the average value of COP shift (V (UCM)) and the other that did (V (ORT)). An index (DeltaV) corresponding to the normalized difference between V (UCM) and V (ORT) was computed. During steady-state posture, DeltaV was positive corresponding to most M-mode variance lying in a sub-space corresponding to a stable COP location across trials. Positive DeltaV values have been interpreted as reflecting a multi-M-mode synergy stabilizing the COP location. The magnitude of DeltaV was larger in SP trials than in RT trials. During voluntary COP shifts, the DeltaV magnitude dropped to zero or even became negative. We conclude that M-mode synergies stabilize COP location during quiet standing, while these synergies weaken or disappear during fast voluntary COP shifts. Under RT conditions, the COP stabilizing synergies were weaker supposedly to facilitate a quick COP shift without time for preparation. The suggested method of M-mode identification may potentially be applied to analysis of postural synergies in persons with impaired postural control such as elderly persons, persons with atypical development, or in the course of rehabilitation after an injury.
When location-relevant trials with an incompatible spatial stimulus-response mapping are mixed with location-irrelevant trials, responses on the latter trials are faster when stimulus and response locations do not correspond than when they do. Experiments 1 and 2 showed that this reverse "Simon effect" also occurs when the location information is presented verbally or symbolically on both location-relevant and location-irrelevant trials. The reversal was absent, however, in conditions of Experiments 1-3 in which the mode of presentation was different on the location-relevant trials than on the location-irrelevant trials. Experiment 4 demonstrated that differences in physical characteristics between the location-relevant and location-irrelevant stimuli were not sufficient to eliminate the reverse Simon effect. These findings imply that the short-term associations between stimulus location information and responses defined for the location-relevant task are relatively mode specific.
The trial-to-trial variability of the different components of corticospinal volleys evoked by transcranial electrical stimulation of the motor cortex using a constant stimulus intensity was measured from epidural recordings during surgery to correct scoliosis. The recordings were made when there was no operative interference, and blood pressure, temperature, ventilation and anaesthetic regimen were stable. A simple D wave with a single negative peak of 10-30 microV amplitude was recorded in 4 patients. It varied little in amplitude (S.D.s < 8% for 100 consecutive single responses). In 4 patients the stimulus was adjusted to produce a complex D wave with 3 components, the earliest 2 of which arise from subcortical/brain-stem sites. The variability of amplitude of these components was high (S.D.s of 13-50%), but the variability of latency was low (S.D.s of 2-3%). Eighteen I waves were recorded in 6 of the subjects. Their variability from trial to trial was similar to that of the components of the complex D wave. It is argued that there would be greater trial-to-trial variability of the corticospinal volley in the awake state, particularly when the stimulus was magnetic rather than electrical. Explanations for changes in the compound muscle action potential produced by transcranial stimulation, electrical or magnetic, must take into account that a constant stimulus does not evoke an identical descending volley.
We present a new decision-making model that can account for trial-by-trial variability induced by a process ("pre-process") that occurs before an explicit sensory signal specifying a later motor response. A process after explicit sensory signals, referred to herein as the "post-process", has been investigated by a variety of so-called rise-to-threshold models including the LATER model. The LATER model formulates post-process variability but treats the pre-process as fixed within a block of an experiment. We propose an extension of the LATER model, which we call the extended LATER (ELATER) model, to account for trial-by-trial variability of both pre- and post-processes together. We present the mathematical formulation of the ELATER model and analyze its characteristics, including numerical examples and an example of saccade latency data in reward-manipulated conditions with caudate activity. The ELATER model is useful for investigating decision making by taking account of trial-by-trial variability of both pre- and post-processes.
The aim of this study was to evaluate a dynamic stability test and a functional balance test for trial-to-trial reproducibility and stability over time. In the dynamic stability test a subject stood on the force platform and moved his center of pressure through the targets shown on a computer screen. Functional balance was measured by a test in which the subject had to walk as fast as possible across a wooden plank without falling off. Both tests are repeated six times in two testing periods with an interval of two months. The subjects were 29 male firefighters aged 33 - 56 years. According to intraclass correlation coefficients the functional balance test showed good to excellent (0.78 - 0.96) trial-to-trial reproducibility and stability over time, and the results of the dynamic stability test were moderate (0.16 - 0.81). Individual variation in the repeated tests was considerable. However, the limits of agreement in the functional balance test (+/- 2 - 3 s) and in the performance time of the dynamic stability test (+/- 4 - 5 s) would be reasonable for practical use. Furthermore, the test-retest stability improved when the reliability was estimated from the best of at least three repeated trials with the functional balance test and the best of at least five trials with the dynamic stability test.
The present study investigates sequential modulations of the Simon effect. The Simon effect involves faster responses to spatially corresponding than to noncorresponding stimuli, even when stimulus position is irrelevant. Recently, the Simon effect has been shown to decrease or to disappear after noncorresponding predecessor trials. Possible explanations for these sequential modulations include (a) the gating of position-based response activation (conflict monitoring), (b) repetition or alternation effects, and (c) the interaction between feature integration (binding) processes and stimulus-response (S-R) correspondence. Three experiments tested different predictions of these models by comparing Simon effects after neutral trials with those after corresponding and noncorresponding trials, respectively, and by varying the stimulus-onset asynchrony (SOA) between and within experiments. Experiments 1 and 2 revealed large Simon effects after corresponding trials, intermediate Simon effects after neutral trials, and small (or no) Simon effects after noncorresponding trials. Moreover, some systematic effects of S-R repetitions and S-R alternations were observed. Finally, the sequential modulations were maximal at short SOAs and decreased with increasing SOA, but still occurred at an SOA of 6 seconds. The results seem to exclude repetition or alternation effects as the main cause of sequential modulations of the Simon effect, but both conflict monitoring and binding may contribute to these effects.
BACKGROUND: The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was designed to examine whether annual screening tests for these four tumor sites result in reduced disease-related mortality. We assessed the impact of trial participation on both health-related quality of life (HRQL) and trial adherence. METHODS: Participants (N = 432; 217 in the control arm and 215 in screening arm) were accrued from the Georgetown University PLCO site from May through December 1998. Screening-arm participants were interviewed by telephone at baseline (prescreening), shortly after notification of screening results (short-term follow-up), and 9 months after notification of screening results (intermediate-term follow up). Control-arm participants completed a baseline and 1-year follow-up assessment. Logistic regression analyses were conducted. RESULTS: Participants reported high levels of HRQL and satisfaction with their decision to participate. Screening-arm participants with abnormal screening results had a higher level of intrusive thoughts about cancer than those with all normal results (odds ratio [OR] = 2.9, 95% confidence interval [CI] = 1.3 to 6.3) at the short-term follow-up but not at the intermediate-term follow-up (when abnormal test results were known to be false positive; OR = 1.9, 95% CI = 0.89 to 4.2). Trial adherence was statistically significantly better among participants who had received all normal results in the previous year's screening tests (93.7% versus 78.7%; OR = 3.7, CI = 1.1 to 12.0) than in those who received at least one abnormal result. In the control arm, adherence (defined as returning annual questionnaires) was positively associated with education (OR = 3.4, 95% CI = 1.4 to 8.4) and sex, with women being more likely to return questionnaires than men (OR = 2.1, 95% CI = 1.05 to 4.4). CONCLUSIONS: It is feasible to collect HRQL measures as part of a large cancer screening trial. Prior abnormal screening results were related to short-term HRQL but not to intermediate-term HRQL. Trial adherence was poorer among those who had received previous false-positive results. These results suggest several methods for improving adherence in this and other subgroups.
Responding for intravenous injections of morphine was studied using a discrete-trials procedure in squirrel monkeys. For one group, each session consisted of 10 trials at an inter-trial interval of 15 min; for the second group, each session consisted of 100 trials at an inter-trial interval of 1.5 min. When different injection doses of morphine (1-1000 mug/kg per injection), including saline as a control procedure, were substituted at random for blocks of five consecutive sessions, the frequency of morphine self-administration was found to be an inverted U-shaped function of the injection dose. This relationship was observed in each group of monkeys, despite a 10-fold difference in the total amount of the drug which was available for self-administration per session when a given injection dose was substituted for both groups. The results show that the injection dose of morphine acted as a primary determinant of response probability, even under circumstances in which trial spacing imposed a significant delay between consecutive opportunities for drug self-administration,
We used an intrinsic optical imaging technique to examine postnatal developmental changes in the rat barrel response to a single whisker movement. We compared the optical response patterns between control and de-whiskered rats, from which whiskers were removed except for the D1 whisker just after birth. Barrel responses were evoked by D1-whisker movement stimulation, and the intrinsic optical signals were detected from the somatosensory cortex through the dura mater. In the control rats, the area of the barrel response decreased gradually as postnatal development proceeded from 2 to 7 wk, until reaching the adult pattern. On the other hand, in the de-whiskered rats, the barrel response area did not change during development and showed a larger size than in the control rats. We also compared the trial-to-trial variations in the barrel responses between the two groups. In the control rats, trial-to-trial variations in the optical responses were observed under the same conditions of whisker stimulation, and the extent of the variations decreased with postnatal development up to 7 wk. In the de-whiskered rats, trial-to-trial variations were also observed, but the extent was larger and unchanged during development. In both groups, the positions of the response area were the same with respect to the bregma. These results suggest that the decrease in the area and variations in the optical responses are caused by interactions of the corresponding whisker barrel with neighboring barrels and that these interactions are necessary for the developmental stabilization of the intracortical horizontal connections, which are widespread and have high plasticity in early postnatal periods.
This symposium provided a useful forum for the discussion of issues relating to the design and conduct of clinical trials. There is a need for greater awareness of the complexity of modern day trials, in which a host of statistical, logistical, regulatory and ethical issues are involved. Issues discussed ranged from the effect of sample size on the outcome, and subgroup analysis, to defining and maintaining discrete endpoints. Some useful debate centred on the use of meta-analysis and the current limitations of combining information from different data sets. This brought up the subjects of trial registries and raw data repositories for all clinical trials. Progress and relevance of the Cochrane collaboration were reviewed. The economics of clinical trials was another important topic. Regulatory issues such as the role of data and safety monitoring boards (DSMB) and the guidelines in place for effective data monitoring and progress analysis were discussed. Representatives of government organisations and industry gave both European and American perspectives. This report however focuses specifically on the section devoted to the subject of clinical trials in developing countries.
Stimuli attended-to locations in visual space are usually detected with higher speed and accuracy than stimuli at unattended positions. It has been argued that this effect is due to "sensory gating" mechanisms that modulate the flow of perceptual information from attended and unattended positions. In the present experiments, event-related potentials (ERPs) were recorded to stimuli that were preceded either by a valid or by an invalid positional cue (trial-by-trial cuing). When overt responses were required only to infrequent target stimuli on valid trials (Experiment 1) or to all validly cued stimuli (Experiment 2B), but not to invalid trials, systematic enhancements of early sensory-evoked potentials were found. These effects were smaller when both validly and invalidly cued stimuli required a response (Experiment 2A). These findings are interpreted as evidence that sensory gating processes are activated during the trial-by-trial cuing of spatial attention. Furthermore, valid stimuli elicited a greater negativity than invalid stimuli at midline electrodes following the early enhancements of sensory-evoked potentials. This possibly reflects an additional enhanced processing of attended-to locations.
Recent experimental work has provided evidence that trial-to-trial variability of sensory-evoked responses in cortex can be explained as a linear superposition of random ongoing background activity and a stationary response. While studying single trial variability and state-dependent modulation of evoked responses in auditory cortex of ketamine/xylazine-anesthetized rats, we have observed an apparent violation of this model. Local field potential and unit spike trains were recorded and analyzed during different anesthesia depths-deep, medium, and light-which were defined by the pattern of ongoing cortical activity. Estimation of single trial evoked response was achieved by considering whole waveforms, rather than just one or two peak values from each wave. Principal components analysis was used to quantitatively classify waveforms on the basis of their time courses (i.e., shapes). We found that not only average response but also response variability is modulated by depth of anesthesia. Trial-to-trial variability is highest under medium levels of anesthesia, during which ongoing cortical activity exhibits rhythmic population bursting activity. By triggering the occurrence of stimuli from the spontaneously occurring burst events, we show that the observed variability can be accounted for by the background activity. In particular, the ongoing activity was found to modulate both amplitude and shape (including latency) of evoked local field potentials and evoked unit activity in a manner not predicted by linear superposition of background activity and a stereotyped evoked response. This breakdown of the linear model is likely attributable to rapid transitions between different levels of thalamocortical excitability (e.g., spike-wave discharges), although brain "state" is relatively fixed.
OBJECTIVE: To compare the performance of community- vs university-based clinical centers in 3 multicenter randomized clinical trials of intraocular surgery. METHODS: Each Submacular Surgery Trials clinical center was classified as a university-based center, if the contract to perform as a center was signed by a university official, or as a community-based center. The 2 groups of centers were compared on performance, assessed cumulatively by the Submacular Surgery Trials Quality Assurance and Monitoring Subcommittee. OUTCOME MEASURES: Patient accrual, completion of scheduled examinations, completion of masked vision examinations 2 years after enrollment (the designated primary study end point evaluation time), timeliness of submission of retinal photographs required by protocol to the Photograph Reading Center, completion of health- and vision-related quality-of-life interviews, and timeliness of submission of the primary outcome data to the Coordinating Center after completion of the examination. RESULTS: Almost all centers performed at a very high (good) level, although there was a trend for some community-based centers to be at the lower end of most distributions. CONCLUSIONS: Most community- and university-based centers performed well in these multicenter clinical trials. Monitoring performance and periodically providing feedback to clinical center investigators may encourage excellent performance in areas critical to the success of clinical trials, regardless of whether the center is community or university based.
The NSABP-32 trial is a randomized, phase III clinical trial to compare sentinel node (SN) resection to conventional axillary dissection in clinically node-negative breast cancer patients. The primary aims of the trial are to determine if removal of only SNs provides survival and regional control equivalent to those of axillary dissection, while diminishing the magnitude of surgically related side effects. In order to ensure consistency of the outcomes for this trial, a standardized method of SN surgery has been utilized for all cases. A secondary aim of the B32 trial is to evaluate whether patients with "occult" metastases in the SNs have worse survival. Accrual is taking place at 73 institutions in North America, and 217 surgeons are enrolling patients.
PURPOSE: Novel therapeutic agents in the treatment of recurrent gliomas are urgently needed. Pyrazoloacridine (PZA), a rationally synthesized acridine derivative, has shown promising antitumor activity against glioma lines in combination with platinum compounds. This phase I/II trial of the PZA/carboplatin combination in recurrent glioma patients consisted of two phase I studies (studies 1 and 2) and a phase II trial (study 3). The objectives of studies 1 and 2 were to (a) assess the safety and toxicity and to establish the phase II dose of the pyrazoloacridine/carboplatin combination for recurrent glioma patients on P450 inducing anticonvulsants, and (b) to confirm the phase II dose for patients not on P450 inducing anticonvulsants. The primary objectives of study 3 were to determine the efficacy of the pyrazoloacridine/carboplatin combination in patients with recurrent gliomas, to further assess the toxicity of the combination, and to evaluate the impact of enzyme-inducing anticonvulsants on the pyrazoloacridine metabolism. EXPERIMENTAL DESIGN: Both carboplatin and pyrazoloacridine were administered intravenously every 28 days. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. RESULTS: 14 patients were treated in the two phase I studies and 32 patients in the phase II trial. The phase II dose of the combination was PZA 400 mg/m(2) and carboplatin AUC of 5 every 28 days. Neutropenia (4 patients) and dyspnea (1 patient) was the dose limiting toxicity in the phase I studies. In the phase II trial, the most frequent toxicity was myelosuppression with grade 3 and 4 hematologic adverse events being observed in 22 and 19% of the patients, respectively. The antitumor activity of this regimen was limited; the response rate in the phase II trial was 0%, (95% CI:0-11%) while 12 of the 32 patients (38%) had stable disease with a median duration of 2 months. The percentage of phase II patients who were progression free at three months was 22% and at six months was 16%. Median survival from study entry was 5.0 months for phase I patients and 5.8 months for phase II patients. Pharmacokinetic analysis performed in 8 phase I patients demonstrated no significant impact of the enzyme-inducing anticonvulsants on the pharmacokinetics of pyrazoloacridine. CONCLUSIONS: The phase II dose of the pyrazoloacridine/carboplatin combination is pyrazoloacridine 400 mg/m(2) in combination with carboplatin AUC of 5. Antitumor activity in patients with recurrent gliomas was limited. Initial disease stabilization occurred in approximately 38% of the patients, with median duration of 2 months. Enzyme-inducing anticonvulsants did not affect the pyrazoloacridine metabolism.
Timely participant recruitment remains a significant challenge for most clinical trials. We evaluated the effects on participant recruitment of communication between the central trial coordinators and the clinical sites in the setting of a large international multi-centre clinical trial. The effects of communication were determined in a single-blind randomised controlled trial involving 167 clinical sites in 19 countries. Clinical sites were randomised to either additional or usual communication strategies - the additional communication group received a communication package based on additional, individually-tailored feedback about recruitment, in addition to the usual correspondence from the central trial coordinators that was provided to the control group. The two study outcomes were the median time to half randomisation target and the median total number of participants randomised per clinical site. Eighty-five clinical centres were randomised to receive additional communication and 82 to receive usual communication. At the conclusion of recruitment, there was no significant difference in the median number of participants randomised per centre between the additional and usual groups (37.5 vs. 37.0, p=0.68). The median time to half randomisation target was lower in the additional communication group compared to the usual group, however this difference did not achieve conventional levels of statistical significance (4.4 months vs. 5.8 months, p=0.08). The findings suggest that the additional communication strategy may be of some incremental benefit in helping sites achieve recruitment targets sooner.
OBJECTIVE: To improve the survival of women with stage IV epithelial ovarian cancer the Southwest Oncology Group conducted a phase II trial examining two novel treatment strategies: (a) modification of the chemotherapy regimen (carboplatin/paclitaxel) based on evidence of response during treatment and (b) "maintenance therapy," with the monthly administration of single agent paclitaxel (maximum 2 years). METHODS: Individuals with histologically documented stage IV ovarian, fallopian tube, or peritoneal cancers initially received a maximum of 3 courses of single agent carboplatin (AUC 6), with the decision to administer a subsequent course based on specific response criteria (i.e., declines in serum CA-125 or shrinkage of measurable mass lesions). This was followed by single agent paclitaxel (150 mg/m(2)), delivered every 2 weeks for a maximum of 6 courses, again based on evidence of continued response to the treatment program. Finally, in the absence of disease progression or unacceptable toxicity, patients received single agent paclitaxel (175 mg/m2) for a maximum of 24 monthly courses. The primary study end point was 2-year overall survival, which was to be compared to the survival of a previously published historical control population [stage IV ovarian cancer patients treated with a "standard" cisplatin/paclitaxel regimen (GOG 111; McGuire WP, N Eng E J Med 1996; 334:1)]. This analysis was employed to determine if this novel strategy was worthy of further clinical investigation in a controlled clinical trial. RESULTS: There were 53 patients entered this multicenter study, of whom 50 were evaluable for toxicity and 51 for survival. There were 2 treatment-related deaths. Grades 2 and 3 neutrotoxicity were observed in 18 and 4% of patients, respectively. There were no major treatment-related protocol violations. The overall 2-year survival was 48% (95% CI, 34-62%), compared to 60% for the historical control group. CONCLUSIONS: While this trial demonstrated the feasibility of delivering a treatment regimen requiring frequent alternations in therapy based on predetermined changes in objective parameters of response, further exploration of this specific management approach does not appear warranted in stage IV ovarian cancer, based on the survival outcome compared to a reasonably similar historical control population. As this trial demonstrates, the prospective determination of clinical end points in a phase II study (e.g., 2-year survival) that will lead to continued evaluation of a particular investigative strategy in a large-scale randomized trial can be an effective method to reduce the bias and uncertainty often associated with this complex decision process.