Investigating Rare Events by Transition Interface Sampling

We briefly review simulation schemes for the investigation of rare transitions and we resume the recently introduced Transition Interface Sampling, a method in which the computation of rate constants is recast into the computation of fluxes through interfaces dividing the reactant and product state.Comment: 12 pages, 1 figure, contributed paper to the proceedings of NEXT 2003, Second Sardinian International Conference on News and Expectations in Thermostatistics, 21-28 Sep 2003, Cagliari (Italy

A Novel Path Sampling Method for the Calculation of Rate Constants

We derive a novel efficient scheme to measure the rate constant of transitions between stable states separated by high free energy barriers in a complex environment within the framework of transition path sampling. The method is based on directly and simultaneously measuring the fluxes through many phase space interfaces and increases the efficiency with at least a factor of two with respect to existing transition path sampling rate constant algorithms. The new algorithm is illustrated on the isomerization of a diatomic molecule immersed in a simple fluid.Comment: 14 pages, including 13 figures, RevTeX

Rate constants for diffusive processes by partial path sampling

We introduce a path sampling method for the computation of rate constants for systems with a highly diffusive character. Based on the recently developed algorithm of transition interface sampling (TIS) this procedure increases the efficiency by sampling only parts of complete transition trajectories confined within a certain region. The algorithm assumes the loss of memory for highly diffusive progression along the reaction coordinate. We compare the new technique to the TIS method for a simple diatomic system and show that the computation time of the new method scales linearly, instead of quadraticaly, with the length of the diffusive barrier. The validity of the memory loss assumption is also discussed.Comment: 12 pages, including 8 figures, RevTeX

Elaborating Transition Interface Sampling Methods

We review two recently developed efficient methods for calculating rate constants of processes dominated by rare events in high-dimensional complex systems. The first is transition interface sampling (TIS), based on the measurement of effective fluxes through hypersurfaces in phase space. TIS improves efficiency with respect to standard transition path sampling (TPS) rate constant techniques, because it allows a variable path length and is less sensitive to recrossings. The second method is the partial path version of TIS. Developed for diffusive processes, it exploits the loss of long time correlation. We discuss the relation between the new techniques and the standard reactive flux methods in detail. Path sampling algorithms can suffer from ergodicity problems, and we introduce several new techniques to alleviate these problems, notably path swapping, stochastic configurational bias Monte Carlo shooting moves and order-parameter free path sampling. In addition, we give algorithms to calculate other interesting properties from path ensembles besides rate constants, such as activation energies and reaction mechanisms.Comment: 36 pages, 5 figure

Assessment of eating rate and food intake in spoon versus fork users in a laboratory setting

Accumulating evidence show positive relationships between eating rate and body weight. Acute food intake is affected by eating rate, bite size, and palatability. The objective was to assess differences between participants who chose to use a spoon vs. fork in eating rate and food intake of four meals that differ in palatability (low vs. high salt) and in energy density (low vs. high fat). Forty-eight healthy adults (16 males, 18-54 y, BMI: 17.8-34.4 kg/m2) were recruited. Participants attended four lunch time sessions after a standardised breakfast. Meals were either (1) low-fat/low-salt, (2) low-fat/high-salt, (3) high-fat/low-salt, or (4) high-fat/high-salt. Nineteen participants (6 males) consistently used a fork and 21 (8 males) used a spoon, 8 participants were inconsistent in cutlery use and excluded from analyses. Spoon users had on average a higher BMI than fork users (p=0.006). Effects of cutlery use, BMI status (BMI<25 vs. BMI>25), salt, and fat, and their interactions were assessed in a General Linear Model. Spoon users consumed faster (fork: 53±2.8g/min; spoon: 62±2.1g/min, p=0.022) and tended to consume more (p=0.09), whereas the duration of the meals were similar (fork: 6.9±0.3min; spoon: 6:7±0.2min, p=0.55). BMI status affected both eating rate and food intake (p=0.005). There were no significant two-way or three-way interactions between salt, fat, and cutlery use on eating rate or food intake. In conclusion, participants who chose to consume with forks ate slower compared to spoon users

Efficient path sampling on multiple reaction channels

Due to the time scale problem, rare events are not accessible by straight forward molecular dynamics. The presence of multiple reaction channels complicates the problem even further. The feasibility of the standard free energy based methods relies strongly on the success in finding a proper reaction coordinate. This can be very difficult task in high-dimensional complex systems and even more if several distinct reaction channels exist. Moreover, even if a proper reaction coordinate can be found, ergodic sampling will be a challenge. In this article, we discuss the recent advancements of path sampling methods to tackle this problem. We argue why the path sampling methods, via the transition interface sampling technique, is less sensitive to the choice of reaction coordinate. Moreover, we review a new algorithm, parallel path swapping, that can dramatically improve the ergodic sampling of trajectories for the multiple reaction channel systems.Comment: 7 pages, 4 figures. Article submitted for the proceedings of the Conference on Computational Physics, Brussels 200

Role of therapeutic drug monitoring in pulmonary infections : use and potential for expanded use of dried blood spot samples

Respiratory tract infections are among the most common infections in men. We reviewed literature to document their pharmacological treatments, and the extent to which therapeutic drug monitoring (TDM) is needed during treatment. We subsequently examined potential use of dried blood spots as sample procedure for TDM. TDM was found to be an important component of clinical care for many (but not all) pulmonary infections. For gentamicin, linezolid, voriconazole and posaconazole dried blood spot methods and their use in TDM were already evident in literature. For glycopeptides, beta-lactam antibiotics and fluoroquinolones it was determined that development of a dried blood spot (DBS) method could be useful. This review identifies specific antibiotics for which development of DBS methods could support the optimization of treatment of pulmonary infections

The Asakura-Oosawa model in the protein limit: the role of many-body interactions

We study the Asakura-Oosawa model in the "protein limit", where the penetrable sphere radius $R_{AO}$ is much greater than the hard sphere radius $R_c$. The phase behaviour and structure calculated with a full many-body treatment show important qualitative differences when compared to a description based on pair potentials alone. The overall effect of the many-body interactions is repulsive.Comment: 9 pages and 11 figures, submitted to J. Phys.: Condensed Matter, special issue "Effective many-body interactions and correlations in soft matter

Density functional theory and demixing of binary hard rod-polymer mixtures

A density functional theory for a mixture of hard rods and polymers modeled as chains built of hard tangent spheres is proposed by combining the functional due to Yu and Wu for the polymer mixtures [J. Chem. Phys. {\bf 117}, 2368 (2002)] with the Schmidt's functional [Phys. Rev. E {\bf 63}, 50201 (2001)] for rod-sphere mixtures. As a simple application of the functional, the demixing transition into polymer-rich and rod-rich phases is examined. When the chain length increases, the phase boundary broadens and the critical packing fraction decreases. The shift of the critical point of a demixing transition is most noticeable for short chains.Comment: 4 pages,2 figures, in press, PR

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis

BACKGROUND Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.)