Prediction of Infant Drug Exposure Through Breastfeeding: Population PK Modeling and Simulation of Fluoxetine Exposure.

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.

The impact of triathlon training and racing on athletes' general health.

Although the sport of triathlon provides an opportunity to research the effect of multi-disciplinary exercise on health across the lifespan, much remains to be done. The literature has failed to consistently or adequately report subject age group, sex, ability level, and/or event-distance specialization. The demands of training and racing are relatively unquantified. Multiple definitions and reporting methods for injury and illness have been implemented. In general, risk factors for maladaptation have not been well-described. The data thus far collected indicate that the sport of triathlon is relatively safe for the well-prepared, well-supplied athlete. Most injuries 'causing cessation or reduction of training or seeking of medical aid' are not serious. However, as the extent to which they recur may be high and is undocumented, injury outcome is unclear. The sudden death rate for competition is 1.5 (0.9-2.5) [mostly swim-related] occurrences for every 100,000 participations. The sudden death rate is unknown for training, although stroke risk may be increased, in the long-term, in genetically susceptible athletes. During heavy training and up to 5 days post-competition, host protection against pathogens may also be compromised. The incidence of illness seems low, but its outcome is unclear. More prospective investigation of the immunological, oxidative stress-related and cardiovascular effects of triathlon training and competition is warranted. Training diaries may prove to be a promising method of monitoring negative adaptation and its potential risk factors. More longitudinal, medical-tent-based studies of the aetiology and treatment demands of race-related injury and illness are needed.

Patients satisfaction in an academic walk-in centre: a new model of residents training achieved by family doctors.

BACKGROUND: Walk-in centres may improve access to healthcare for some patients, due to their convenient location and extensive opening hours, with no need for an appointment. Herein, we describe and assess a new model of walk-in centre, characterised by care provided by residents and supervision achieved by experienced family doctors. The main aim of the study was to assess patients' satisfaction about the care they received from residents and their supervision by family doctors. The secondary aim was to describe walk-in patients' demographic characteristics and to identify potential associations with satisfaction. METHODS: The study was conducted in the walk-in centre of Lausanne. Patients who consulted between 11th and 31st April were automatically included and received a questionnaire in French. We used a five-point Likert scale, ranging from "not at all satisfied" to "very satisfied", converted from values of 1 to 5. We focused on the satisfaction regarding residents' care and supervision by a family doctor. The former was divided in three categories: "Skills", "Treatment" and "Behaviour". A mean satisfaction score was calculated for each category and a multivariable logistic model was applied in order to identify associations with patients' demographics. RESULTS: The overall response rate was 47% [184/395]. Walk-in patients were more likely to be women (62%), young (median age 31), with a high education level (40% of University degree or equivalent). Patients were "very satisfied" with residents' care, with a median satisfaction score between 4.5 and 5, for each category. Over 90% of patients were "satisfied" or "very satisfied" that a family doctor was involved in the consultation. Age showed the greatest association with satisfaction. CONCLUSION: Patients were highly satisfied with care provided by residents and with the involvement of a family doctor in the consultation. Older age showed the greatest positive association with satisfaction with a positive impact. The high level satisfaction reported by walk-in patients supports this new model of walk-in centre.

Accurate and efficient simulation of multiphase flow in a heterogeneous reservoir by using error estimate and control in the multiscale finite-volume framework

The multiscale finite-volume (MSFV) method is designed to reduce the computational cost of elliptic and parabolic problems with highly heterogeneous anisotropic coefficients. The reduction is achieved by splitting the original global problem into a set of local problems (with approximate local boundary conditions) coupled by a coarse global problem. It has been shown recently that the numerical errors in MSFV results can be reduced systematically with an iterative procedure that provides a conservative velocity field after any iteration step. The iterative MSFV (i-MSFV) method can be obtained with an improved (smoothed) multiscale solution to enhance the localization conditions, with a Krylov subspace method [e.g., the generalized-minimal-residual (GMRES) algorithm] preconditioned by the MSFV system, or with a combination of both. In a multiphase-flow system, a balance between accuracy and computational efficiency should be achieved by finding a minimum number of i-MSFV iterations (on pressure), which is necessary to achieve the desired accuracy in the saturation solution. In this work, we extend the i-MSFV method to sequential implicit simulation of time-dependent problems. To control the error of the coupled saturation/pressure system, we analyze the transport error caused by an approximate velocity field. We then propose an error-control strategy on the basis of the residual of the pressure equation. At the beginning of simulation, the pressure solution is iterated until a specified accuracy is achieved. To minimize the number of iterations in a multiphase-flow problem, the solution at the previous timestep is used to improve the localization assumption at the current timestep. Additional iterations are used only when the residual becomes larger than a specified threshold value. Numerical results show that only a few iterations on average are necessary to improve the MSFV results significantly, even for very challenging problems. Therefore, the proposed adaptive strategy yields efficient and accurate simulation of multiphase flow in heterogeneous porous media.

Sustained antipsychotic effect of metacognitive training in psychosis: a randomized-controlled study.

Persistent psychotic symptoms represent a major challenge for psychiatric care. Basic research has shown that psychotic symptoms are associated with cognitive biases. Metacognitive training (MCT) aims at helping patients to become aware of these biases and to improve problem-solving. Fifty-two participants fulfilling diagnostic criteria of schizophrenia or schizoaffective disorders and persistent delusions and stabilized antipsychotic medication were enrolled in this study. Following baseline assessment patients were randomized either to treatment as usual (TAU) conditions or TAU+MCT. The intervention consisted of eight weekly 1-hour sessions (maximum: 8 hours). Participants were assessed at 8 weeks and 6-months later by blind assessors. Participants were assessed with the Psychotic Symptoms Rating Scales (PSYRATS) and the positive subscale of the PANSS. Between-group differences in post- and pre-test values were significant at a medium effect size in favor of the MCT for the PSYRATS delusion scale and the positive scale of the PANSS both at post and follow-up. The results of this study indicate that MCT training has a surplus antipsychotic effect for patients suffering from schizophrenia-related disorders who demonstrate only a partial response to antipsychotic treatment and that the effect of the intervention persists for at least 6 months after the intervention.

Magnetic microstructures from magnetic force microscopy and Monte Carlo simulation in CoFe-Ag-Cu granular films

CoFe-Ag-Cu granular films, prepared by rf sputtering, displayed magnetic domain microstructures for ferromagnetic concentrations above about 32% at, and below the percolation threshold. All samples have a fcc structure with an (111) texture perpendicular to the film plane. Magnetic force microscopy (MFM) showed a variety of magnetic domain microstructures, extremely sensitive to the magnetic history of the sample, which arise from the balance of the ferromagnetic exchange, the dipolar interactions and perpendicular magnetocrystalline anisotropy, MFM images indicate that in virgin samples, magnetic bubble domains with an out-of-plane component of the magnetization are surrounded by a quasicontinuous background of opposite magnetization domains. The application of a magnetic field in different geometries drastically modifies the microstructure of the system in the remanent state: i) for an in-plane field, the MFM images show that most of the magnetic moments are aligned along the film plane, ii) for an out-of-plane field, the MFM signal increases about one order of magnitude, and out-of-plane striped domains with alternating up and down magnetization are stabilized. Numerical simulations show that a variety of metastable domain structures (similar to those observed experimentally) can be reached, depending on magnetic history, in systems with competing perpendicular anisotropy, exchange and dipolar interactions.

Computer simulation study of liquid lithium at 470 and 843 K

Both structural and dynamical properties of 7Li at 470 and 843 K are studied by molecular dynamics simulation and the results are comapred with the available experimental data. Two effective interatomic potentials are used, i.e., a potential derived from the Ashcroft pseudopotential [Phys. Lett. 23, 48 (1966)] and a recently proposed potential deduced from the neutral pseudoatom method [J. Phys.: Condens. Matter 5, 4283 (1993)]. Although the shape of the two potential functions is very different, the majority of the properties calculated from them are very similar. The differences among the results using the two interaction models are carefully discussed.

Self-dynamic structure factor of dense liquids: Theory and simulation

The self-intermediate dynamic structure factor Fs(k,t) of liquid lithium near the melting temperature is calculated by molecular dynamics. The results are compared with the predictions of several theoretical approaches, paying special attention to the Lovesey model and the Wahnstrm and Sjgren mode-coupling theory. To this end the results for the Fs(k,t) second memory function predicted by both models are compared with the ones calculated from the simulations.

Magnetic relaxation of a one-dimensional model for small particle systems with dipolar interactions: Monte Carlo simulation

Atribution as a function of the time are analyzed and this study leads to a deeper knowledge of the microscopic processes involved in the magnetic relaxation

Postmortem pump-driven reperfusion of the vascular system of porcine lungs: towards a new model for surgical training.

PURPOSE: The objective of this experiment is to establish a continuous postmortem circulation in the vascular system of porcine lungs and to evaluate the pulmonary distribution of the perfusate. This research is performed in the bigger scope of a revascularization project of Thiel embalmed specimens. This technique enables teaching anatomy, practicing surgical procedures and doing research under lifelike circumstances. METHODS: After cannulation of the pulmonary trunk and the left atrium, the vascular system was flushed with paraffinum perliquidum (PP) through a heart-lung machine. A continuous circulation was then established using red PP, during which perfusion parameters were measured. The distribution of contrast-containing PP in the pulmonary circulation was visualized on computed tomography. Finally, the amount of leak from the vascular system was calculated. RESULTS: A reperfusion of the vascular system was initiated for 37 min. The flow rate ranged between 80 and 130 ml/min throughout the experiment with acceptable perfusion pressures (range: 37-78 mm Hg). Computed tomography imaging and 3D reconstruction revealed a diffuse vascular distribution of PP and a decreasing vascularization ratio in cranial direction. A self-limiting leak (i.e. 66.8% of the circulating volume) towards the tracheobronchial tree due to vessel rupture was also measured. CONCLUSIONS: PP enables circulation in an isolated porcine lung model with an acceptable pressure-flow relationship resulting in an excellent recruitment of the vascular system. Despite these promising results, rupture of vessel walls may cause leaks. Further exploration of the perfusion capacities of PP in other organs is necessary. Eventually, this could lead to the development of reperfused Thiel embalmed human bodies, which have several applications.

Intraoperative training on the techniques of sentinel node biopsy in breast cancer

Principles: Surgeon's experience is crucial for proper application of sentinel node biopsy (SNB) in patients with breast cancer. A 20-30 cases learning curve of sentinel node (SN) and axillary lymph node dissection (ALND) was widely practiced. In order to speed up this learning curve, surgeons may be trained intraoperative by an experienced surgeon. The purpose of this report is to evaluate the results of this procedure. Methods: Patients with one primary invasive breast cancer (cT1-T2[<3 cm]cN0) underwent SNB based on lymphoscintigraphy using technetium Tc 99m colloid, intraoperative gamma probe detection, with or without blue dye mapping. This was followed by completion ALND when SN was positive or not found. SNB was performed by one experienced surgeon (teacher) or by 10 junior surgeons trained by the experienced surgeon (trainees). Four groups were defined: (i) SNB with immediate ALND for the teacher's learning curve, (ii) SNB by the teacher, (iii) SNB by the trainees under the teacher's supervision, and (iv) SNB by the trainees alone. Results: Between May 1999 and December 2007, a total of 808 évaluable patients underwent SNB. The SN identification rate was 98% in the teacher's group, and 99% in the trainees' group (p = 0.196). SN were positive in respectively 28% and 29% of patients (p = 0.196). The distribution of isolated tumor cells, micrometastases and metastases was not statistically different between the teacher's and the trainees' groups (p = 0.163). Conclusion: These comparable results confirm the success with which the SNB was taught. This strategy avoided the 20-30 SNB followed by immediate ALND early required per surgeon.