Successful use of sirolimus for refractory atrial ectopic tachycardia in a child with cardiac rhabdomyoma

Cardiac rhabdomyomas are common in tuberous sclerosis. We report a child who developed rhabdomyoma related arrhythmia refractory to antiarrhythmic drug therapy. Reversion of the atrial ectopic tachycardia was achieved with mammalian target of rapamycin pathway (mTOR) inhibitor sirolimus. As per our knowledge, this is the first time that sirolimus has been successfully used in this setting.     

Clinical features of infection caused by non-tuberculous mycobacteria: 7 years’ experience

Introduction

Non-tuberculous mycobacteria (NTM) are ubiquitous organisms associated with various infections. The aim of the study was to determine the most relevant clinical characteristics of NTM during the 7-year period.

Methodology

A retrospective study of NTM infections was conducted between January 2009 and December 2016. The American Thoracic Society/Infectious Disease Society of America criteria were used to define cases of pulmonary or an extrapulmonary site.

Results

A total of 85 patients were included in the study. Pulmonary cases predominated 83/85 (98%), while extrapulmonary NTM were present in 2/95 (2%) patients. Overall, ten different NTM species were isolated. The most common organisms were slow-growing mycobacteria (SGM) presented in 70/85 (82.35%) patients. Isolated SGM strains were Mycobacterium avium complex (MAC) in 25/85 (29.41%) patients, M. xenopi in 20/85 (23.53%) patients, M. kansasii in 15/85 (17.65%) patients and M. peregrinum and M. gordonae in 5/85 (5.88%) patients each. Isolated rapid-growing mycobacteria (RGM) strains were M. abscessus in 8/85 (9.41%) patients, M. fortuitum in 4/85 (4.71%) patients and M. chelonae in 3/85 (3.53%) patients. Almost all patients (98%; 83/85) had comorbidities. Among 75 (88.24%) patients who completed follow-up, 59 (69.41%), 10 (11.76%) and 6 (7%), were cured, experienced relapse and died, respectively.

Conclusion

In the present study, pulmonary NTM infections were more frequent compared to extrapulmonary disease forms. SGM were most common isolates with MAC pulmonary disease the most frequently found. Comorbidities have an important role in NTM occurrence. Further investigation should focus on an NTM drug susceptibility testing.

     

The effect of alcohols as the third component on diffusion in mixtures of aromatics and ketones

With laboratory and numerical work, we demonstrate that one of the main diffusion coefficients and the smaller eigenvalue of the Fick diffusion matrix are invariant to the number of methylene groups of the alcohol in ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol). A critical analysis of the relationship between the kinetic and thermodynamic contributions to the diffusion coefficients allows us to explain this intriguing behaviour of this class of mixture. These findings are reflected by the diffusive behaviour of the according binary subsystems. Our approach provides a promising systematic framework for future investigations into the important and challenging problem of transport diffusion in multicomponent liquids.

The Fick diffusion coefficient matrix of three ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol) is investigated with laboratory and numerical work.

Multicomponent diffusion plays a crucial role in various natural and industrial processes involving mass transfer.^1–3 Liquids appearing in nature and technical applications are essentially multicomponent. However, only data on binary diffusion coefficients are relatively abundant because the diffusion behavior of ternary and higher mixtures is much more complex.^4,5 Describing the isothermal–isobaric diffusion of a ternary mixture by Fick’s law requires four different diffusion coefficients that are composition dependent. The presence of cross diffusion coefficients aggravates the interpretation and data processing in experimental work, resulting in large uncertainties.^6,7 Thus, efforts are being made to develop new methods for analysis of multicomponent diffusion explicitly addressing various degrees of complexity.^8–10 Predictive equations for multicomponent diffusion of liquids mostly rely on extensions of the Darken relation,^11–13 which is only valid for ideal mixtures.¹⁴ The underlying physical phenomena in non-ideal mixtures are not well understood and the lack of experimental data impedes the development and verification of new predictive equations.The objective of this study was not only to measure and predict the Fick diffusion coefficient matrix for a series of ternary liquid mixtures, rather, the emphasis lied on understanding common features and whether they can be related to the behavior of the pure components and binary subsystems. Three ternary mixtures that are composed of organic compounds were selected, i.e. an aromatic, a ketone and an alcohol. Throughout, the first two components were benzene (1) and acetone (2) and the third component was one of the alcohols, methanol, ethanol or 2-propanol. For each mixture, nine state points along a composition path with a constant content of benzene, x₁ = 0.33 mol mol⁻¹, were studied under ambient conditions (298.15 K and 0.1 MPa). Seven of the state points were ternary mixtures and two were binary subsystems. To obtain reliable results for the Fick diffusion coefficient matrix, two complementary approaches were used, i.e. experiments and predictive molecular simulations. This combination allows for a critical analysis and leads to a deeper understanding of the underlying phenomena.^14,15The Taylor dispersion technique was utilized for the experiments.^16,17 In this method, a small quantity of mixture with a slightly different composition is injected into a laminar stream. It disperses due to convection and diffusion while flowing through a capillary tube and the refractive index is measured at its end to sample the concentration distribution. We have used the same apparatus as in previous works.^6,7 The Fick diffusion matrix is obtained by fitting working equations to the measured signal, i.e. the Taylor peak. The mathematical model of the Taylor dispersion technique was originally developed on the basis of Fick’s law in the volume reference frame. In a ternary mixture, two molar fluxes J^v_i relative to a volume averaged velocity are related to gradients of molar concentration ∇C_i with four diffusion coefficients D^v_ij. Alternatively, fluxes expressed in the molar reference frame J_i are relative to a molar averaged velocity and the mole fraction gradients ∇x_i act as a driving force1with molar density ρ. The fluxes of all three components are constrained by ΣJ_i = 0. The main diffusion coefficients D₁₁ and D₂₂ relate the flux of one component to its own mole fraction gradient and the cross diffusion coefficients D₁₂ and D₂₁ describe the coupling of the flux of one component with the gradient of the other. The third component does not appear in eqn (1) explicitly, but in general it affects all four diffusion coefficients. The transformation of experimental data from the volume to the molar reference frame (D^v_ij to D_ij) could be done here on the basis of the pure component volumes (see the ESI^†).Equilibrium molecular dynamics (MD) simulations were employed in this work, allowing for examination at the microscopic scale. The underlying molecular models were rigid, non-polarizable force fields of united atom type, consisting of a varying number of Lennard–Jones, point charge, dipole and quadrupole sites (see the ESI^†). Note that the force field parameters were adjusted to pure fluid properties only so that all simulation results for the mixtures are strictly predictive. Diffusion coefficients were sampled with the Green–Kubo formalism, based on integrated correlation functions of net velocities of the contained species.^11,15 Thereby, phenomenological coefficients Δ_ij were obtained, associating the diffusive fluxes with the chemical potential gradients ∇μ_i2with gas constant R and temperature T. Fluxes J_i correspond to the molar reference frame as in eqn (1).The diffusion coefficients from experiment and simulation are related to different driving forces so that the chemical potential gradients have to be transformed to the mole fraction gradients for their comparison.¹⁸ This transformation is contained in the thermodynamic factor matrix Γ3with the activity coefficient of species i being γ_i, which expresses the non-ideality of a mixture with respect to the composition. This relationship shows that the Fick diffusion coefficients are actually the product of two contributions, a kinetic Δ_ij and a thermodynamic Γ_ij. The separate observation of these two contributions promotes understanding of the underlying physical phenomena. In the present study, the thermodynamic factor was calculated using the Wilson excess Gibbs energy (g^E) model, using parameters fitted to experimental vapor–liquid equilibrium data of the binary subsystems (see the ESI^†). This combination of MD simulation results with a g^E model was successfully used in previous work to predict Fick diffusion coefficients, including several binary subsystems of the ternary mixtures studied here.¹⁹The four elements of the Fick diffusion coefficient matrix were determined for the three ternary mixtures, benzene + acetone + methanol/ethanol/2-propanol, for nine different compositions, each at ambient temperature and pressure.Results for the first main element of the diffusion matrix D₁₁, which relates the flux of benzene to its own mole fraction gradient, are shown in Fig. 1(a). The experimental data agree quantitatively with the molecular simulation data. D₁₁ increases with the acetone content in the ternary mixture. Since mixtures with a constant mole fraction of benzene (x₁ = 0.33 mol mol⁻¹) were studied throughout, the left edge of Fig. 1(a) corresponds to the binary limit of benzene + alcohol, while the right edge corresponds to that of benzene + acetone. Analysis of the ternary diffusive fluxes implies the following asymptotic behavior of the diffusion coefficients towards the binary limits:⁷ (i) at the infinite dilution limit, x₂ → 0, the ternary coefficient D₁₁ tends to the binary Fick diffusion coefficient of benzene + alcohol; (ii) at the other limit, x₃ → 0, D₁₁ − D₁₂ = D₂₂ − D₂₁ → D_bin (benzene + acetone) should hold. The present experimental and simulation results for D₁₁ are consistent with these asymptotic limits.Open in a separate windowFig. 1Top: The main Fick diffusion coefficient (molar reference frame) of benzene D₁₁ in the three ternary mixtures benzene (1) + acetone (2) + alcohol (3) at a constant benzene mole fraction x₁ = 0.33 mol mol⁻¹ from experiment (triangles) and MD simulation combined with the Wilson g^E model (circles). Both data sets were sampled at the same compositions, but are slightly shifted in the plot for visibility reasons. The symbols at the edges of this plot are the binary diffusion coefficients of benzene + alcohol (x₂ → 0) and of benzene + acetone (x₃ → 0). Bottom: The binary Fick diffusion coefficient of the subsystems benzene + alcohol and benzene + acetone. Most of the binary experimental data were taken from the literature.^20–27An inspection of Fig. 1(a) provides an unexpected finding: the main element D₁₁ is almost identical for all three mixtures along the examined composition path, i.e. it is independent of the contained type of alcohol. To explain this intriguing behavior of D₁₁, the properties of the pure components are considered first (see

Peripheral bronchial identification on chest CT using unsupervised machine learning

Purpose

To automatically identify small- to medium-diameter bronchial segments distributed throughout the lungs.

Methods

We segment the peripheral pulmonary vascular tree and construct cross-sectional images perpendicular to the lung vasculature. The bronchi running with pulmonary arteries appear as concentric rings, and potential center points that lie within the bronchi are identified by looking for circles (using the circular Hough transform) and rings (using a novel variable ring filter). The number of candidate bronchial center points are further reduced by using agglomerative hierarchical clustering applied to the points represented with 18 features pertaining to their 3D position, orientation and appearance of the surrounding cross-sectional image. Resulting clusters corresponded to bronchial segments. Parameters of the algorithm are varied and applied to two experimental data sets to find the best values for bronchial identification. The optimized algorithm was then applied to a further 21 CT studies obtained using two different CT vendors.

Results

The parameters that result in the most number of true positive bronchial center points with > 95% precision are a tolerance of 0.15 for the hierarchical clustering algorithm and a threshold of 75 HU with 10 spokes for the ring filter. Overall, the performance on all 21 test data sets from CT scans from both vendors demonstrates a mean number of 563 bronchial points detected per CT study, with a mean precision of 96%. The detected points across this group of test data sets are relatively uniformly distributed spatially with respect to spherical coordinates with the origin at the center of the test imaging data sets.

Conclusion

We have constructed a robust algorithm for automatic detection of small- to medium-diameter bronchial segments throughout the lungs using a combination of knowledge-based approaches and unsupervised machine learning. It appears robust over two different CT vendors with similar acquisition parameters.

     

Prevention of hospital infections by intervention and training (PROHIBIT): results of a pan-European cluster-randomized multicentre study to reduce central venous catheter-related bloodstream infections

Purpose

To test the effectiveness of a central venous catheter (CVC) insertion strategy and a hand hygiene (HH) improvement strategy to prevent central venous catheter-related bloodstream infections (CRBSI) in European intensive care units (ICUs), measuring both process and outcome indicators.

Methods

Adult ICUs from 14 hospitals in 11 European countries participated in this stepped-wedge cluster randomised controlled multicentre intervention study. After a 6 month baseline, three hospitals were randomised to one of three interventions every quarter: (1) CVC insertion strategy (CVCi); (2) HH promotion strategy (HHi); and (3) both interventions combined (COMBi). Primary outcome was prospective CRBSI incidence density. Secondary outcomes were a CVC insertion score and HH compliance.

Results

Overall 25,348 patients with 35,831 CVCs were included. CRBSI incidence density decreased from 2.4/1000 CVC-days at baseline to 0.9/1000 (p < 0.0001). When adjusted for patient and CVC characteristics all three interventions significantly reduced CRBSI incidence density. When additionally adjusted for the baseline decreasing trend, the HHi and COMBi arms were still effective. CVC insertion scores and HH compliance increased significantly with all three interventions.

Conclusions

This study demonstrates that multimodal prevention strategies aiming at improving CVC insertion practice and HH reduce CRBSI in diverse European ICUs. Compliance explained CRBSI reduction and future quality improvement studies should encourage measuring process indicators.

     

Intracellular calcium levels as screening tool for nanoparticle toxicity

The use of engineered nano‐sized materials led to revolutionary developments in many industrial applications and in the medical field. These materials, however, also may cause cytotoxicity. In addition to size, surface properties and shape were identified as relevant parameters for cell damage. Cell damage may occur as disruption of membrane integrity, induction of apoptosis and by organelle damage. Generation of oxidative stress may serve as an indicator for cytotoxicity. Effects occurring upon short contact of particles with cells, for instance in the systemic blood circulation, could be identified according to increases of intracellular [Ca²⁺] levels, which are caused by variety of toxic stimuli. Negatively charged, neutral and positively charged polystyrene particles of different sizes were used to study the role of size and surface properties on viability, membrane disruption, apoptosis, lysosome function, intracellular [Ca²⁺] levels and generation of oxidative stress. Silica particles served to test this hypothesis. Twenty nm polystyrene particles as well as 12 nm and 40 nm silica particles caused membrane damage and apoptosis with no preference of the surface charge. Only 20 nm plain and amine functionalized polystyrene particles cause oxidative stress and only the plain particles lysosomal damage. A potential role of surface charge was identified for 200 nm polystyrene particles, where only the amidine particles caused lysosomal damage. Increases in intracellular [Ca²⁺] levels and cytotoxicity after 24 h was often linked but determination of intracellular [Ca²⁺] levels could serve to characterize further the type of membrane damage. © 2015 The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.