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Biomedical subjects

Scott Brown

Publications and source records attributed to Scott Brown.

At least 19 recordsLinked to original sources
PubMed2007

Pacing Evaluation-Atrial SUpport Study in Cardiac Resynchronization Therapy (PEGASUS CRT): design and rationale.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been demonstrated to be an effective heart failure (HF) therapy. All pivotal trials of CRT to date have used atrial-synchronous biventricular pacing wherein there is no or minimal atrial pacing. In clinical practice, however, physicians often program CRT devices to have atrial rate support pacing, either by increasing the lower rate limit or by activating the rate sensor. OBJECTIVE: The purpose of this study is to evaluate the effect of empiric atrial support pacing in patients with HF who have received a CRT defibrillator (CRT-D) device. METHODS: PEGASUS CRT is a multicenter, 3-arm, randomized clinical trial of approximately 1200 patients receiving a CRT-D device. For the first 6 weeks after implant, devices are programmed to DDD with a lower rate limit of 40 beats/min. At 6 weeks, patients are randomized to DDD-40, DDD-70, or DDDR-40. All randomized patients are followed for 1 year, and at each visit, mortality, HF events, quality of life, New York Heart Association class, and atrial and ventricular arrhythmic episodes are evaluated. An exercise substudy will also be conducted, enrolling a minimum of 375 patients. Patients in this substudy will complete 2 cardiopulmonary exercise tests to evaluate the effect pacing mode has on exercise capacity. This randomized controlled trial will address whether empiric atrial support pacing is of clinical benefit to patients with HF who receive a CRT-D device.

Cardiac Pacing, Artificial↗
PubMed2007

Circadian rhythms in the mating behavior of the cockroach, Leucophaea maderae.

Mating behavior of small populations of virgin males and females of the cockroach Leucophaea maderae were continuously monitored via time-lapse video recording in controlled laboratory conditions. The time of onset of copulation was found to be rhythmic in a light cycle of 12 h light alternated with 12 h of darkness, with the peak of mating behavior occurring near the light to dark transition. This rhythm persisted in constant dim red illumination and constant temperature. In constant conditions, the period of the rhythm was slightly less than 24 h, with a peak of copulation during the late subjective day. These data demonstrated that mating behavior is gated by a circadian clock. When males and females were taken from light cycles that were 12 h out of phase, a bimodal rhythm was observed with one peak in the males' late subjective day and a second peak of equal amplitude in the late subjective day of females. The results indicated that circadian systems in both males and females contribute to the circadian rhythm in copulation. Bilateral section of the optic tracts (OTX) of both males and females abolished the rhythm, but the rhythm persisted when OTX females were paired with intact males or when OTX males were paired with intact females. Furthermore, when OTX males or OTX females were paired with intact animals that were 12 h out of phase, a bimodal rhythm was still observed. These results suggested that the circadian pacemaker in the optic lobes of both male and female cockroaches participates in the control of mating, but that a pacemaker outside the optic lobes is also likely involved. Finally, it was shown that the female's olfactory response (measured by electroantennogram) to components of the male sex pheromone exhibited a circadian rhythm, but the data suggested the peripheral olfactory rhythm is not likely to be involved in the rhythm of mating behavior.

Animals↗
PubMed2006

Is dual-chamber programming inferior to single-chamber programming in an implantable cardioverter-defibrillator? Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in ICDs) study.

BACKGROUND: The INTRINSIC RV (Inhibition of Unnecessary RV Pacing with AVSH in ICDs) study tested the hypothesis that dual-chamber rate-responsive (DDDR) with atrioventricular search hysteresis (AVSH) 60-130 programming is not inferior to single-chamber (VVI)-40 programming in an implantable cardioverter defibrillator with respect to all-cause mortality and heart failure hospitalizations using an equivalence margin of 5%. METHODS AND RESULTS: At 108 centers, 1530 patients with an implantable cardioverter defibrillator indication received a VITALITY AVT (Guidant Corporation, St. Paul, Minn) implantable cardioverter defibrillator programmed consistently to DDDR AVSH 60-130 for the first week. Of those, 988 patients with <20% right ventricular pacing at 1 week were randomized to DDDR AVSH 60-130 or to VVI-40 programming. Among those randomized, 502 were assigned to DDDR AVSH and 486 to VVI. Groups were similar with regard to coronary disease (68%), gender (21% female), and New York Heart Association functional class >I (79%). A total of 32 patients (6.4%) in the DDDR AVSH arm and 46 patients (9.5%) in the VVI arm died or were hospitalized for heart failure during a mean follow-up of 10.4 months (relative risk=0.67, P=0.072 in favor of DDDR AVSH). DDDR AVSH was not inferior to VVI programming (P<0.001). All-cause mortality was not significantly different between the DDDR AVSH arm (3.6%) and the VVI arm (5.1%; P=0.23). The mean percent right ventricular pacing in the DDDR AVSH arm was 10% (median 4%) versus 3% (median 0%) in the VVI arm. CONCLUSIONS: In the INTRINSIC RV trial, among those randomized, DDDR AVSH was associated with similar outcomes as with VVI backup pacing.

Adult↗
PubMed2006

Nanoparticles for bioimaging.

The emergence of synthesis strategies for the fabrication of nanosized contrast agents is anticipated to lead to advancements in understanding biological processes at the molecular level in addition to progress in the development of diagnostic tools and innovative therapies. Imaging agents such as fluorescent dye-doped silica nanoparticles, quantum dots and gold nanoparticles have overcome many of the limitations of conventional contrast agents (organic dyes) such as poor photostability, low quantum yield, insufficient in vitro and in vivo stability, etc. Such particulates are now being developed for absorbance and emission in the near infrared region, which is expected to allow for real time and deep tissue imaging via optical routes. Other efforts to facilitate deep tissue imaging with pre-existing technologies have lead to the development of multimodal nanoparticles which are both optical and MRI active. The main focus of this article is to provide an overview of properties and design of contrast agents such as dye-doped silica nanoparticles, quantum dots and gold nanoparticles for non-invasive bioimaging.

Contrast Media↗
PubMed2006

Effects of a rate smoothing algorithm for prevention of ventricular arrhythmias: results of the Ventricular Arrhythmia Suppression Trial (VAST).

BACKGROUND: Rate smoothing, which is available in some pacemakers and implantable cardioverter defibrillators (ICDs), has been used to prevent Torsades de Pointes in patients with long QT syndrome. Its efficacy in general ventricular arrhythmia prevention has not been determined. OBJECTIVES: The purpose of the Ventricular Arrhythmia Suppression Trial (VAST) was to prospectively investigate whether rate smoothing could significantly reduce the incidence of ventricular tachyarrhythmias in a large, broad population of patients with ICDs. METHODS: Five hundred sixty-nine patients were enrolled at 57 participating centers and implanted with a commercially available Guidant ICD. A single-blinded crossover design was used in which each patient was randomized at implant to one of two treatment sequences: either rate smoothing on (RS On) followed by rate smoothing off (RS Off), or RS Off followed by RS On. This mode sequence was randomly determined and assigned in a 1:1 fashion using randomized permuted blocks by site. Each mode was followed for 6 months. Programming of rate smoothing was prescribed as 12% Down and 12% Up for the duration of the RS On period. RESULTS: Of enrolled patients, 281 were randomized to RS Off followed by RS On, and 288 to RS On followed by RS Off. With RS On, 75 (23%) patients experienced a reduction in arrhythmias, 76 (23%) saw an increase in arrhythmias, and the remaining 176 (54%) had no difference. No significant difference (P = .58) in frequency of arrhythmias with RS On vs RS Off was found. CONCLUSION: Rate smoothing does not result in a reduction in ventricular arrhythmias in a heterogeneous population of patients receiving ICDs.

Adult↗
PubMed2006

Reduction of right ventricular pacing in patients with dual-chamber ICDs.

BACKGROUND: Unnecessary right ventricular (RV) pacing in patients with implantable cardioverter defibrillators (ICD) may adversely affect heart failure morbidity and total mortality. Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) is a prospective, multicenter, randomized trial evaluating outcomes in ICD recipients programmed to single-chamber pacing (VVI) versus dual-chamber (DDDR) pacing with AV search hysteresis (AVSH). METHODS: Patients underwent ICD implant (for standard indications). The ICD was programmed to DDDR with AVSH regardless of any need for pacing. Rate-adaptive pacing was set at 60-130 ppm with dynamic AV delay from 200 to 90 ms. AVSH was programmed to search every 32 intervals and extend the AV delay by 50%. One week post-implant patients with ICDs were interrogated to assess the percentage of RV pacing with the expectation that most would have <20% RV pacing and would be randomized into INTRINSIC RV. Early analysis showed that targets for randomization were not met. AVSH parameters were modified under a protocol amendment to increase AV delay extension to 100%. We report findings related to this programming change based upon analyses of (nonrandomized) data pre- and post-amendment. RESULTS: Twenty-one percent of patients (n = 314) were enrolled pre-amendment and 79% (n = 1,216) were enrolled post-amendment. The mean percentage of RV pacing at the 1-week visit was 41.4 +/- 29.6% pre-amendment and 14.7 +/- 22.6% post-amendment (P < 0.0001). The proportion of patients eligible for randomization (RV pacing <20% at the 1-week visit) was 31.2% pre-amendment and 76.8% post-amendment (P < 0.0001). CONCLUSION: AVSH can dramatically reduce the percentage of RV pacing among ICD recipients.

Aged↗
PubMed2006

A critical test of the failure-to-engage theory of task switching.

When people switch between two tasks, their performance on each is worse than when they perform that task in isolation. One theory of this "switch cost" is the failure-to-engage (FTE) theory, which posits that observed responses are a simple mixture of prepared and unprepared response strategies. The probability that participants use prepared processes can be manipulated experimentally (e.g., by changing preparation time). The FTE theory is a binary mixture model and therefore makes a strong prediction about the existence of fixed points in response time distributions. We found evidence contradicting this prediction, using data from 20 participants in a standard task-switching paradigm. In this article, we examine reasons for the failure of the FTE theory, and we demonstrate that a generalized version of FTE theory accommodates our data.

Adolescent↗
PubMed2005

A ballistic model of choice response time.

Almost all models of response time (RT) use a stochastic accumulation process. To account for the benchmark RT phenomena, researchers have found it necessary to include between-trial variability in the starting point and/or the rate of accumulation, both in linear (R. Ratcliff & J. N. Rouder, 1998) and nonlinear (M. Usher & J. L. McClelland, 2001) models. The authors show that a ballistic (deterministic within-trial) model using a simplified version of M. Usher and J. L. McClelland's (2001) nonlinear accumulation process with between-trial variability in accumulation rate and starting point is capable of accounting for the benchmark behavioral phenomena. The authors successfully fit their model to R. Ratcliff and J. N. Rouder's (1998) data, which exhibit many of the benchmark phenomena.

Choice Behavior↗
PubMed2005

Practice increases the efficiency of evidence accumulation in perceptual choice.

Most models of choice response time base decisions on evidence accumulated over time. A fundamental distinction among these models concerns whether each piece of evidence is equally weighted (lossless accumulation) or unequally weighted (leaky accumulation). The authors tested a hypothesis derived from A. Heathcote and S. Brown's (2002) self-exciting expert competitor (SEEXC) model of skill acquisition: that evidence accumulation becomes less leaky with practice. The hypothesis was supported by observation that the effects of prime stimuli increased with practice. The authors used metacontrast masked primes, which could not be consciously discriminated by most participants, to avoid methodological problems associated with conscious strategy changes. The form of the law of practice in the data is also shown to be consistent with the SEEXC model.

Analysis of Variance↗
PubMed2005

The dynamics of experimentally induced criterion shifts.

Investigations of decision making have typically assumed stationarity, even though commonly observed "context effects" are dynamic by definition. Mirror effects are an important class of context effects that can be explained by changes in participants' decision criteria. When easy and difficult conditions are blocked alternately and a mirror effect is observed, participants must repeatedly change their decision criteria. The authors investigated the time course of these criterion changes and observed the buildup of mirror effects on a trial-by-trial basis. The data are consistent with slow, systematic changes in decision criteria that lag behind stimulus changes. The length of this lag is considerable: analysis of a simple dynamic signal-detection model suggests participants take an average of around 14 trials to adjust to new decision environments. This trial-level measurement of experimentally induced changes has implications for traditional blockwise analyses of data and for models of decision making.

Attention↗
PubMed2005

Influence of denatured and intermediate states of folding on protein aggregation.

We simulate the aggregation thermodynamics and kinetics of proteins L and G, each of which self-assembles to the same alpha/beta [corrected] topology through distinct folding mechanisms. We find that the aggregation kinetics of both proteins at an experimentally relevant concentration exhibit both fast and slow aggregation pathways, although a greater proportion of protein G aggregation events are slow relative to those of found for protein L. These kinetic differences are correlated with the amount and distribution of intrachain contacts formed in the denatured state ensemble (DSE), or an intermediate state ensemble (ISE) if it exists, as well as the folding timescales of the two proteins. Protein G aggregates more slowly than protein L due to its rapidly formed folding intermediate, which exhibits native intrachain contacts spread across the protein, suggesting that certain early folding intermediates may be selected for by evolution due to their protective role against unwanted aggregation. Protein L shows only localized native structure in the DSE with timescales of folding that are commensurate with the aggregation timescale, leaving it vulnerable to domain swapping or nonnative interactions with other chains that increase the aggregation rate. Folding experiments that characterize the structural signatures of the DSE, ISE, or the transition state ensemble (TSE) under nonaggregating conditions should be able to predict regions where interchain contacts will be made in the aggregate, and to predict slower aggregation rates for proteins with contacts that are dispersed across the fold. Since proteins L and G can both form amyloid fibrils, this work also provides mechanistic and structural insight into the formation of prefibrillar species.

Bacterial Proteins↗
PubMed2004

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure.

RATIONALE: Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability. OBJECTIVE: This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure. METHODS: Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an "inappropriate" phase when conditioning stimuli were absent and reward presentation would be delayed. RESULTS: Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase. CONCLUSIONS: Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.

Animals↗
PubMed2004

Intermediates and the folding of proteins L and G.

We use a minimalist protein model, in combination with a sequence design strategy, to determine differences in primary structure for proteins L and G, which are responsible for the two proteins folding through distinctly different folding mechanisms. We find that the folding of proteins L and G are consistent with a nucleation-condensation mechanism, each of which is described as helix-assisted beta-1 and beta-2 hairpin formation, respectively. We determine that the model for protein G exhibits an early intermediate that precedes the rate-limiting barrier of folding, and which draws together misaligned secondary structure elements that are stabilized by hydrophobic core contacts involving the third beta-strand, and presages the later transition state in which the correct strand alignment of these same secondary structure elements is restored. Finally, the validity of the targeted intermediate ensemble for protein G was analyzed by fitting the kinetic data to a two-step first-order reversible reaction, proving that protein G folding involves an on-pathway early intermediate, and should be populated and therefore observable by experiment.

Bacterial Proteins↗
PubMed2004

QMPE: estimating Lognormal, Wald, and Weibull RT distributions with a parameter-dependent lower bound.

We describe and test quantile maximum probability estimator (QMPE), an open-source ANSI Fortran 90 program for response time distribution estimation. QMPE enables users to estimate parameters for the ex-Gaussian and Gumbel (1958) distributions, along with three "shifted" distributions (i.e., distributions with a parameter-dependent lower bound): the Lognormal, Wald, and Weibul distributions. Estimation can be performed using either the standard continuous maximum likelihood (CML) method or quantile maximum probability (QMP; Heathcote & Brown, in press). We review the properties of each distribution and the theoretical evidence showing that CML estimates fail for some cases with shifted distributions, whereas QMP estimates do not. In cases in which CML does not fail, a Monte Carlo investigation showed that QMP estimates were usually as good, and in some cases better, than CML estimates. However, the Monte Carlo study also uncovered problems that can occur with both CML and QMP estimates, particularly when samples are small and skew is low, highlighting the difficulties of estimating distributions with parameter-dependent lower bounds.

Algorithms↗
PubMed2004

Fitting distributions using maximum likelihood: methods and packages.

The most powerful tests of response time (RT) models often involve the whole shape of the RT distribution, thus avoiding mimicking that can occur at the level of RT means and variances. Nonparametric distribution estimation is, in principle, the most appropriate approach, but such estimators are sometimes difficult to obtain. On the other hand, distribution fitting, given an algebraic function, is both easy and compact. We review the general approach to performing distribution fitting with maximum likelihood (ML) and a method based on quantiles (quantile maximum probability, QMP). We show that QMP has both small bias and good efficiency when used with common distribution functions (the ex-Gaussian, Gumbel, lognormal, Wald, and Weibull distributions). In addition, we review some software packages performing ML (PASTIS, QMPE, DISFIT, and MATHEMATICA) and compare their results. In general, the differences between packages have little influence on the optimal solution found, but the form of the distribution function has: Both the lognormal and the Wald distributions have non-linear dependencies between the parameter estimates that tend to increase the overall bias in parameter recovery and to decrease efficiency. We conclude by laying out a few pointers on how to relate descriptive models of RT to cognitive models of RT. A program that generated the random deviates used in our studies may be downloaded from www.psychonomic.org/archive/.

Humans↗
PubMed2003

Coarse-grained sequences for protein folding and design.

We present the results of sequence design on our off-lattice minimalist model in which no specification of native-state tertiary contacts is needed. We start with a sequence that adopts a target topology and build on it through sequence mutation to produce new sequences that comprise distinct members within a target fold class. In this work, we use the alpha/beta ubiquitin fold class and design two new sequences that, when characterized through folding simulations, reproduce the differences in folding mechanism seen experimentally for proteins L and G. The primary implication of this work is that patterning of hydrophobic and hydrophilic residues is the physical origin for the success of relative contact-order descriptions of folding, and that these physics-based potentials provide a predictive connection between free energy landscapes and amino acid sequence (the original protein folding problem). We present results of the sequence mapping from a 20- to the three-letter code for determining a sequence that folds into the WW domain topology to illustrate future extensions to protein design.

Amino Acid Sequence↗
PubMed2003

Cool walking: a new Markov chain Monte Carlo sampling method.

Effective relaxation processes for difficult systems like proteins or spin glasses require special simulation techniques that permit barrier crossing to ensure ergodic sampling. Numerous adaptations of the venerable Metropolis Monte Carlo (MMC) algorithm have been proposed to improve its sampling efficiency, including various hybrid Monte Carlo (HMC) schemes, and methods designed specifically for overcoming quasi-ergodicity problems such as Jump Walking (J-Walking), Smart Walking (S-Walking), Smart Darting, and Parallel Tempering. We present an alternative to these approaches that we call Cool Walking, or C-Walking. In C-Walking two Markov chains are propagated in tandem, one at a high (ergodic) temperature and the other at a low temperature. Nonlocal trial moves for the low temperature walker are generated by first sampling from the high-temperature distribution, then performing a statistical quenching process on the sampled configuration to generate a C-Walking jump move. C-Walking needs only one high-temperature walker, satisfies detailed balance, and offers the important practical advantage that the high and low-temperature walkers can be run in tandem with minimal degradation of sampling due to the presence of correlations. To make the C-Walking approach more suitable to real problems we decrease the required number of cooling steps by attempting to jump at intermediate temperatures during cooling. We further reduce the number of cooling steps by utilizing "windows" of states when jumping, which improves acceptance ratios and lowers the average number of cooling steps. We present C-Walking results with comparisons to J-Walking, S-Walking, Smart Darting, and Parallel Tempering on a one-dimensional rugged potential energy surface in which the exact normalized probability distribution is known. C-Walking shows superior sampling as judged by two ergodic measures.

Journal Article↗