Atrial Onset Research Articles

Can health-related quality of life (HRQoL) predict conditional survival (CS) in metastatic renal cell carcinoma? Results from a large phase 3 trial.

691 Background: In the absence of mature overall survival (OS) endpoints, interim clinical trial data can be used to predict long-term survival in patients (pts) with advanced malignancies and inform trial continuation, treatment preference, and reimbursement decisions. Research shows that HRQoL assessments can be associated with OS, offering potential utility for validated HRQoL scales. We describe a predictive model used to determine the extent to which HRQoL data could predict CS (survival conditional on progression at either 6 or 12 months). Methods: Using pt-level data from a large phase III trial of nivolumab vs everolimus, a simulation approach with a survival random forest algorithm identified factors statistically important in predicting CS from a large number of covariates measured at baseline. Stepwise Cox proportional hazard survival models were fitted using covariates identified as important. Baseline scores and change over time were tested to determine the influence on the predictive power of the HRQoL data. Results: For both nivolumab and everolimus, baseline FKSI values were significant predictors of CS; median survival times roughly doubled for pts with baseline FKSI scores ≥30 vs pts with scores < 30 (nivolumab, 31.3-16.6; everolimus, 26.6-11). Baseline FKSI scores were the most important predictor vs the other baseline covariates from the survival random forest simulation, and a statistically significant covariate when fitting a stepwise Cox proportional hazard survival model. Change in scores over time influenced CS for pts with high baseline scores, and pts who demonstrated improvement in scores vs baseline had significantly higher CS vs pts with low baseline and no improvement in scores vs baseline. However, when examining change in HRQoL score over time, the statistical importance of the covariate begins to diminish due to high correlations with factors such as adverse events and weight change. Conclusions: We found that HRQoL data, specifically the FKSI, could be useful in predicting CS, especially at the onset of a trial. The importance of the FKSI score in predicting CS could be a powerful complement to existing clinical prognostic factors.

Attentional capture during attentional awakening.

We investigated whether attentional set is available at the beginning of a trial or whether it develops gradually within a trial. Thus, we manipulated the time from the onset of a trial to a target and observers' search strategy. We also observed the effect of the presence or absence of distractors as an index of the temporal development of attentional set. Participants identified a target letter embedded in a stream of rapidly presented nontargets while ignoring peripheral distractors. Baseline accuracy when no peripheral distractor was presented increased as the target appeared later in the stream, suggesting attentional awakening. Identification accuracy was impaired by the presence of peripheral distractors (i.e., attentional capture) early in the stream only when observers adopted the feature search mode. The magnitude of attentional capture increased over the course of the first 1,000 ms of a trial under the singleton detection and feature search modes. These results suggest that singleton detection mode requires time for a bottom-up signal to be effective in capturing attention, whereas the feature search mode does not require such a warm-up period to be effective and is available from the beginning of viewing the stream.

Mediation in Entrepreneurship

In Romania, the mediation has become a mandatory prior procedure, together with the direct conciliation in disputes of a commercial nature, following the amendments to the Code of Civil Procedure by Law. 202/2010. Mediation occurs both in the extra-procedural, ie before the onset of a trial before the court, and also in the trial stage, ie once someone had claimed summons, calls or appeals. The need for cooperation with the entrepreneurial environment in order to increase his competitiveness and his assertion at European and global level effort leads to increasing the EU Member States efforts in order to offer theirs citizens some clear and convincing answers regarding the business environment and their own business. The need for mediation occurs in a conflict with the business partner, in contract implementation problems (large delays in payments, non-delivery or delay in delivery of goods/services requested, etc.), where the firm is threatened with insolvency, foreclosure or other proceedings likely to put own business in difficulty. If no one wants to go to court or, even if already reached, mediation may be the most advantageous way to end as soon as possible the conflict which is likely to damage the business. In this context we will show, in what follows, the advantages and the benefits of mediation in the context of voluntary dispute resolution within the business environment.

Interval timing with a beat frequency model connecting phase resetting and network response

Time perception is essential for normal physiological and behavioral responses, e.g., recalling stored data and planning future actions, and is deregulated in a series of neuropathologies, e.g., Parkinson’s disease. It is commonly accepted that processing temporal information involves a neural mechanism mimicking a stopwatch such as in the Scalar Expectancy Theory [1]. Organisms have multiple neural timing mechanisms that can span more than 10 orders of magnitude form circadian (24 hours) to interval (minutes) to millisecond timing [2]. Our focus is on modeling neural networks responsible for interval timing. In designing any computational model of interval timing, we must acknowledge an experimentally observed fact: the plot of mean response time versus the standard deviation of the distribution for different timing intervals is linear (scalar property). The established paradigm assumes an internal clock model in which pulses that are emitted regularly by a pacemaker are temporarily stored in an accumulator. At the time of reward or feedback, the number of pulses stored in the accumulator is transferred to the reference memory for future use. During “peak-interval procedure” (in which the participants are asked to reproduce the criterion interval) it is assumed that the internal clock is reset and pulses stored into accumulator until the current count match the memorized value stored during the training. The model we used assumes that timing is an emergent activity originated in the thalamo-cortico-striatal loops [2,3]. In this striatal beat-frequency (SBF) model, timing is based on the coincidental activation of medium spiny neurons in the basal ganglia by cortical neural oscillators [2,3]. The cortical oscillators are assumed to be synchronized at the onset of a trial, and to oscillate at a fixed frequency throughout the criterion interval. In our computational model, the oscillator block is composed of independent spiking neurons with intrinsic frequencies fi which, due to varying factors (biological noise, background neural activity from other cortical areas, etc.), are randomly distributed according to a certain density probability function. The synchronization of cortical oscillations at trial onset and the experience-dependent changes in cortico-striatal transmission are thought to be modulated by the dopaminergic neurons in the substatia nigra pars compacta and ventral tegmental area. A memory block stores the criterion time value c memorized during the training process. However, both storage and retrieval of criterion time to and from memory units is affected by biological context (brain state) and is modeled by randomly distributing criterion time according to a certain density probability function [3]. All timing models must connect the objective time with the subjective time. The subjective time is strongly influenced by brain’s state through neuromodulators. For example, dopamine advances the response whereas achetylcholine can induce a delay of the response in a fixed interval experiment. The mechanism involved could be through a direct change in firing frequency due to neurotransmitter action and it was modeled as a separate clock block. The decision block is an essential component of any timing mechanism that relates internal perception of time intervals with external action. A straightforward mechanism of implementing decision-making uses a set of synaptic weights derived from the memorized criterion time [3]. The weights computed from the memorized criterion constitute the reference vector of weighs. The decision block estimates the projection of the current weights on the vector of weight reference weight. The model correctly reproduced measured behavioral data.

A practical approach to the evaluation of antihypertensive agents in infants and children: study design and outcome measures

Background: The causes of hypertension, especially in infants and young children, are largely secondary to systemic diseases, and primary hypertension is uncommon in this population. Objective: The aim of this article was to discuss some of the problems involved in designing appropriate antihypertensive trials for children and to suggest the essential features of a well-designed trial in the pediatric population. Methods: A review of pediatric studies was conducted to define the features of childhood hypertension. Results: This review showed that numerous therapeutic approaches have been used, making many of the identified studies difficult to interpret. Conclusions: The design of studies of antihypertensive medications in children requires a novel approach. The method of measuring blood pressure is pivotal; 24-hour ambulatory blood pressure monitoring is the optimal method. Because children with secondary hypertension may be symptomatic, a washout period before the onset of a trial's drug phase will permit the investigator to use the patient as his or her own control. Whether children should be exposed to a second period of hypertension and symptoms in a randomized washout period at the end of several weeks of therapy is controversial. Study end points include blood pressure measurements (systolic and diastolic) versus appropriate percentiles, an attenuation of the dip in nocturnal blood pressure, and the concept of blood pressure load (the percentage of time with elevated blood pressure values). Safe and effective guidelines can be designed for therapeutic trials of pediatric hypertension. The result will be enhancement of the therapeutic choices available for children with hypertension.

Evaluation of the discriminative stimulus effects of venlafaxine, a potential antidepressant, in rhesus monkeys

AbstractThe discriminative stimulus effects of the novel antidepressant venlafaxine were examined in rhesus monkeys. Separate groups of monkeys discriminated either 0.56 or 1.0 mg/kg (i.g.) d‐amphetamine (N = 3) or 10 mg/kg (i.g.) pentobarbital (N = 4) from saline, in a discrete‐trials shock avoidance/escape paradigm. In d‐amphetamine‐trained monkeys, 10–17 mg/kg venlafaxine occasioned only saline‐appropriate responding and had minimal effect on response latency in alll monkeys. The highest dose of venlafaxine tested (30 mg/kg) occasioned at least 95% d‐amphetamine‐lever responding in two of three monkeys. Following this dose, the average latency to respond after the onset of a trial increased substantially in both monkeys; in one monkey avoidance responding was disrupted and shocks were occasionally received. In the third monkey, 30 mg/kg venlafaxine occasioned only saline‐lever responding and had no effect on response latency. In pentobarbital‐trained monkeys, venlafaxine (3.0–30 mg/kg) occasioned primarily saline‐lever responding and these doses had minimal effects on response latency. In general, venlafaxine was more potent in d‐amphetamine‐trained monkeys than in pentobarbital‐trained monkeys in its effects on response latency. Drug discrimination procedures in animals have been shown to differentiate compunds in a manner that is consistent with their subjective effects. Thus, result from the present experiment suggest that venlafaxine may produce subjective effects similar to d‐amphetamine in some individuals, but only at high doses.

Vocalizations as measures of pain in monkeys

Because vocalizations have been utilized as measures of pain reactivity and are reduced in frequency by systemic morphine in rodents, vocalization patterns of monkeys were analyzed in detail to determine whether specific relationships to pain could be established. Vocalizations were recorded as monkeys performed on tasks that presented the opportunity either to acquire food reinforcement or escape electrical stimulation (ES) of one leg. Three of 5 monkeys vocalized during sessions on the escape task, and 2 of 3 monkeys vocalized while performing for food reinforcement. The amplitudes and durations of vocalizations did not vary significantly over bins of time within the intertriai intervals of 1 min, and these aspects of the monkeys' calls were not affected by the intensity of the electrocutaneous stimulation or by morphine. Although the frequency of vocalizations was greatest within a reactive period of 6–12 sec following onset of a trial, vocalization frequency was not uniquely related to the occurrence of painful stimulation. Rates of vocal calls in the reactive period were higher following presentation only of a tone (that had been paired with shock in previous sessions) than following electrocutaneous stimulation, and vocalization frequency was not directly related to the intensity of painful stimulation. Furthermore, the vocalization patterns were similar for monkeys performing aversive or appetitive responses. Finally, systemic morphine reduced the frequency of vocalizations overall, without evidence for a selective effect on vocal calls elicited by painful stimulation. This result suggests a direct effect of morphine on the neural circuitry subserving vocalizations. Spectrographs of vocalizations revealed that 2 monkeys emitted a ‘broken scream’ call that occurred most often as the first vocalization following strong electrocutaneous stimulation, and 0.25 mg/kg of morphine reduced the frequency with which strong shock elicited these vocalizations. Although broken screams appeared to represent vocalizations in response to aversion, they also occurred following presentation of a tone that had been paired with shock, and therefore they do not reliably indicate the presence of pain.

Scaling of events spaced in time

Pigeons were trained to peck on a key, which could be lit by red or green light, and produce feeder-light stimuli intermittently. On some trials, food followed the fourth feeder flash providing the key color was red, while on other trials food followed the sixteenth flash providing the color was green. The change in color from red to green was produced by a peck to a second, changeover key. Pigeons typically responded in the presence of red until four or more flashes occured and then, if food had not been delivered, changed the main-key color and responded on the green key. Following training, the variable-interval schedule arranging-feeder light events was changed to longer and shorter values to alter the amount of time (and number of responses) between events. Data from these test days indicate that the change from red to green was influenced by the number of events, but also by the time elapsed and/or responses emitted since the onset of a trial. The results suggest multiple sources of related information and stimulus control when events and behavior occur over time.

Electrophysiological correlates of state-dependent learning

Fourteen male Sprague-Dawley rats were implanted with recording electrodes in both the mesencephalic reticular formation (MRF) and the anterior polysensory cortex. After recovery, they were trained in a state-dependent learning paradigm utilizing a two-way shuttle avoidance procedure. We found that the animals trained under 15 mg/kg sodium pentobarbital learned the task faster than the saline-trained animals. Both recording sites showed a frequency difference between avoidance trials and error trials. Only the MRF showed a significant change in frequency at the onset of a trial. After criterion was reached, the animals were given overtraining trials. It was found that transfer to the opposite drug state was related positively to the amount of overtraining given. The MRF frequency in the test situation showed a difference between trials in which there was a response and those in which there was not. These results are discussed in relation to John’s hypothesized circuits mediating the retrieval of memory.

Behavioral system and apparatus for tone-detection and choice reaction times in the cat.

An efficacious operant-conditioning procedure for psychophysical experiments with cats is described. The system features (a) restraint of the cat and the use of the liquid reinforcement delivery cup to control orientation with respect to the stimuli, (b) a minimum of apparatus between the cat and a free-field sound source, (c) two response pedals so that separate "Yes" and "No" responses are defined, (d) a discrete trial procedure with reaction time (RT) defined as the time from the onset of a trial until the occurrence of a response, and (e) an effective liquid reinforcer and simple delivery system. Operation of the system was demonstrated with the method of constant stimuli. Detectability was directly related, and median RT for correct "Yes" responses inversely related, to tone sound pressure.

Heart rate regulation as skill learning: strength-endurance versus cardiac reaction time.

ABSTRACTFleishman's (1966) model of complex motor skill learning is applied to viscera) self‐regulation. Five different underlying abilities are illustrated: strength, endurance, steadiness, control precision, and reaction time. In the experiment, 16 subjects were pre and post tested with instructions alone for degree of cardiac Strength and Endurance control (SE) (maximally increase or decrease heart rate and sustain it for a minute) and degree of cardiac Reaction Time control (RT) (produce a small, 3 sec burst of increased or decreased heart rate as quickly as possible to the onset of a trial). All subjects received heart rate biofeedback during training, but half practiced SE while the other practiced RT. It was predicted that cardiac learning would be specific to the skill practiced during biofeedback, with little transfer to the other task. The data indicated that SE training led to improved SE control (30%) accompanied by a slight decrement in RT control (‐5%). Conversely, RT training led to markedly improved RT control (120%)H accompanied by a small decrement in SE control(18%). The value of conceptualizing complex visceral skills as reflecting learned patterns of underlying neurophysiological abilities is illustrated.

Auditory feedback and conditioning of the single motor unit.

ABSTRACTThe effects of direct auditory feedback of the electromyogram (EMG) on learning to control a single motor unit (SMU) were investigated. Seventeen human subjects were injected with bipolar fine‐wire electrodes into the tibialis anterior muscle. A trial light indicated the onset of a trial. If the subject activated an SMU, a correct light appeared. A non‐SMU response was followed by an incorrect light. All subjects received an initial training series with auditory EMG feedback followed by a retest at 2 weeks without EMG feedback. Speed of initial learning was substantially improved by direct EMG feedback. The nature and amount of learning, including the ability to use proprioceptive cues in controlling an SMU, were not affected, nor was retention of learning.

Two discrimination test apparatuses for primates

This paper describes two test apparatuses developed to facilitate discrimination learning studies with primates. The semiautomated apparatus provides for presentation of stereometric stimulus materials through the illumination of lamps which make a one-way mirror transparent at the onset of a trial. The totally automated test system was developed to facilitate the collection of Transfer Index (TI) measurements, measurements intended to provide for equitable assessments of the learning-set capabilities of diverse primate genera. The TI test procedures and the system’s operations provide for criterional mastery (67% or 84% responses correct) of two-ehoice visual discrimination problems, consisting of projected patterns, then reversal of cues for the 10 test trials that are of particular significance in calculation of the TI scores.

Conditioning of a single motor unit.

Abstract : Seventeen human Ss were injected with bipolar fine wire electrodes into the tibialis anterior muscle. A start light indicated the onset of a trial. If Ss activated a single motor unit, a correct light appeared. With no additional feedback, Ss learned to isolate and control a single motor unit within 500 trials and demonstrated significant improvement during a relearning series. (Author)