The EuroPrevall outpatient clinic study on food allergy: background and methodology.

BACKGROUND: The EuroPrevall project aimed to develop effective management strategies in food allergy through a suite of interconnected studies and a multidisciplinary integrated approach. To address some of the gaps in food allergy diagnosis, allergen risk management and socio-economic impact and to complement the EuroPrevall population-based surveys, a cross-sectional study in 12 outpatient clinics across Europe was conducted. We describe the study protocol. METHODS: Patients referred for immediate food adverse reactions underwent a consistent and standardized allergy work-up that comprised collection of medical history; assessment of sensitization to 24 foods, 14 inhalant allergens and 55 allergenic molecules; and confirmation of clinical reactivity and food thresholds by standardized double-blind placebo-controlled food challenges (DBPCFCs) to milk, egg, fish, shrimp, peanut, hazelnut, celeriac, apple and peach. RESULTS: A standardized methodology for a comprehensive evaluation of food allergy was developed and implemented in 12 outpatient clinics across Europe. A total of 2121 patients (22.6% <14 years) reporting 8257 reactions to foods were studied, and 516 DBPCFCs were performed. CONCLUSIONS: This is the largest multicentre European case series in food allergy, in which subjects underwent a comprehensive, uniform and standardized evaluation including DBPCFC, by a methodology which is made available for further studies in food allergy. The analysis of this population will provide information on the different phenotypes of food allergy across Europe, will allow to validate novel in vitro diagnostic tests, to establish threshold values for major allergenic foods and to analyse the socio-economic impact of food allergy.

Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria.

OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis.

BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ. METHODS: We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals. RESULTS: Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (-9.1%, 90%CI -22.8 to +7.1; P = 0.19) or on BDQ and M2 clearance (+12.2%, 90%CI -13.7 to +38; P = 0.32). CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects.

Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations.

BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. AIMS: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. SOURCES: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. CONTENT: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens. IMPLICATIONS: Semi-mechanistic PKPD models allow for integration of knowledge on the interaction between antibiotics for various PK and PD profiles, and can account for associated variability within the population as well as parameter uncertainty. Decisions on suitable combination regimens can thereby be facilitated. We find the application of semi-mechanistic PKPD models to be essential for efficient development of antibiotic combination regimens that optimize bacterial killing and/or suppress resistance development.

Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients.

This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P < 0.01). Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.

Riemann tensor of motion vision revisited.

This note shows that the Riemann-space interpretation of motion vision developed by Barth and Watson is neither necessary for their results, nor sufficient to handle an intrinsic coordinate problem. Recasting the Barth-Watson framework as a classical velocity-solver (as in computer vision) solves these problems.

Probability of conduction deficit as related to fiber length in random-distribution models of peripheral neuropathies.

This paper presents a set of probabilistic models which reproduce the proximodistal gradient of sensory deficit in peripheral neuropathies, on the basis of the occurrence of axonal dysfunction as a result of randomly distributed abnormalities. The models, which are based on conduction block, loss of temporal coherence, and weak interactions between nerve fibers, demonstrate that randomly distributed axonal dysfunction provides a sufficient condition for distal sensory deficit. The models predict a marked reduction in the length for normal sensory conduction with small increases in the probability of axomal dysfunction, providing a possible correlate for the rapid clinical progression of some neuropathies. The hypothesis that weak interactions between fibers result in paresthesiae in peripheral neuropathies is also discussed.

Application of 24-hour burst TENS in a back school.

The Back School program consists of exercises and education designed to reduce back pain. Sixty-six percent of the patients had too much back pain to participate. The purpose of this clinical report is to describe how 24-hour burst transcutaneous electrical nerve stimulation (TENS) treatment enabled these patients with severe back pain to participate in the Back School. Patients recovering from a laminectomy, chemonucleolysis, or scoliosis surgery were used to determine that 24-hour burst TENS was the most effective TENS protocol for reducing pain. Twenty-four-hour burst TENS was then prescribed for 129 patients with severe back pain to enable them to complete the Back School program. Eighty percent of these patients returned to their usual activities within 12 months. The Back School program has been shown to be an effective and safe treatment for back pain, and 24-hour burst TENS treatment allows patients with severe back pain to participate in it.

Decomposition of Cohen's matrix R into simpler color invariants.

Matrix R of linear-group tristimulus invariants, presented by Cohen and Friden (1976) and Cohen and Kappauf (1982), was decomposed into functions of simpler tristimulus volume ratios (also linear-group invariants). Such volume ratios were applied to the dual problems of color constancy and illuminant-invariant object-color recognition by an artificial trichromatic photosensor. The proof of the decomposition theorem relies on a lemma used in previous work elucidating the conditions for illuminant-invariance of clockwise/counterclockwise ordering of triads of object colors in chromaticity space.

Image segmentation by object color: a unifying framework and connection to color constancy.

A unifying framework is presented for algorithms that use the bands of a multispectral image to segment the image at material (i.e., reflectance) boundaries while ignoring spatial inhomogeneities incurred by accidents of lighting and viewing geometry. The framework assumes that the visual stimulus (image field) from a uniformly colored object is the sum of a small number of terms, each term being the product of a spatial and a spectral part. Based on this assumption, several quantities depending on the reflected light can be computed that are spatially invariant within object boundaries. For an image field either from two light sources on a matte surface or from a single light source on a dielectric surface with highlights, the invariants are the components of the unit normal to the plane in color space spanned by the pixels from the object. In some limited cases the normal to the plane can be used to estimate spectral-reflectance parameters of the object. However, in general the connection of color-constancy theories with image segmentation by object color is a difficult problem. The concomitant constraints on segmentation and color-constancy algorithms are discussed in light of this fact.

Mesopic color matching: some theoretical issues.

In this paper I address some theoretical issues concerning the additivity laws of Grassmann as they might apply to color matches in mesopic vision (in which light intensities are such that both rods and cones are active). It is first shown that rods and cones have linearly independent spectral responses, and hence rod and cone spectral responses span a four-dimensional matching space. Next, the iterative tetrachromatic-matching experiment of Trezona [Vision Res. 13, 9 (1973)] is examined for consistency with a four-dimensional Grassmann structure; convergence conditions for the technique are derived and shown to be consistent with the actual conditions of the experiment. Finally, a discussion is presented of the conditions under which mesopic color matching would require only three primaries, even when color matching obeys four-dimensional (but not three-dimensional) Grassmann laws. A two-dimensional rod-cone diagram gives significant but not complete insight into the conditions for trichromacy in a four-dimensional color-matching space.

Heuristic analysis of von Kries color constancy.

The properties of constancy models based on the proportionality rule of von Kries are examined in a series of simplified examples. It is found that the breadth of receptor-sensitivity functions causes metamerism, thwarting color constancy. Overlap of these functions limits the accuracy of von Kries adaptation for a more subtle reason: it causes nonzero off-diagonal elements in the transformation matrix relating object reflectance to receptor stimulations. Such off-diagonal elements make von Kries adaptation an inexact color-constancy scheme, even when the illuminant is restricted to prevent metamerism.

Necessary and sufficient conditions for Von Kries chromatic adaptation to give color constancy.

Necessary and sufficient spectral conditions are presented for Von Kries chromatic adaptation to give color constancy. Von-Kries-invariant reflectance spectra are computed for illuminant spectral power distributions that are arbitrary linear combinations of the first three daylight phases. Experiments are suggested to test models of color constancy using computed spectra (either exact or approximate) within the illuminant-invariant framework.

Conduction through demyelinated plaques in multiple sclerosis: computer simulations of facilitation by short internodes.

Clinical and laboratory observations both suggest that it may be possible for action potentials to traverse, in a continuous manner and without interruption, demyelinated zones along some axons. This continuous mode of conduction requires the presence of sufficient numbers of sodium channels in the demyelinated region. One of the factors which will tend to prevent such conduction is the impedance mismatch at sites of focal demyelination, which may result in a reduction in current density sufficient to cause conduction failure. As part of an effort to examine the conditions which would promote conduction into, and beyond, the demyelinated region, we examined, using computer simulations, the effects of reduction in length of the proximal internodes closest to the demyelinated region. Our results indicate that reduction in length of the two internodes closest to the demyelinated region. to approximately one-third of normal length or less, will facilitate conduction beyond the plaque. The results suggest that reductions in internode length, which have been histologically observed along some demyelinated fibres, may have functional significance in terms of facilitating conduction past focally demyelinated zones.

Remarks on signal-processing explanations of the trichromacy of vision.

We present criticism of signal-processing arguments recently used to explain the trichromacy of color vision. In particular, we note that illuminant spectral power distributions (SPD's) can be metameric even when the signal-processing arguments state that trichromatic vision represents such SPD's without ambiguity. Being statistical in nature, these arguments need not apply to each individual SPD; however, further use of the arguments calls for attributing them to some ensemble of SPD's and then testing whether the ensemble satisfies the underlying statistical assumptions.

Relationship between the degree of coronary artery disease and of left ventricular function and the duration of the QT-interval in ECG.

Advanced coronary artery disease (CAD), impaired left ventricular function and prolongation of the QT-interval are considered risk factors for sudden cardiac death in CAD-patients. So far, however, there are no studies investigating in detail whether there is a correlation between the QT-interval and changes in coronary anatomy or changes in left ventricular function. Therefore, coronary angiographic data were related to QT-intervals in 304 patients, who were catheterized because of suspected coronary artery disease. QT-intervals were expressed as QTc = QT/square root RR (Bazett's correction for heart rate), left ventricular function was assessed by the ejection fraction of the ventricular angiogram, and coronary angiograms were classified according to the Gensini score as well as into 1-, 2- and 3-vessel disease (stenoses greater than or equal to 50%). A multidimensional linear regression model was employed to eliminate the effects of varying mean rates still present after application of Bazett's formula. In patients with 1-, 2- and 3-vessel disease, significant changes of QTc were observed only in patients with impaired left ventricular function (EF less than 60%). In these patients the QTc-interval increased significantly from 1- to 3-vessel disease. If the critical degree of coronary stenosis was changed from greater than or equal to 50% to greater than or equal to 90% further prolongations of QTc were noted. In patients with 1-, 2- and 3-vessel disease the QTc-duration difference was further enhanced if either the proximal part of the descending branch of the left coronary artery (LAD) or the left main stem were affected (stenoses greater than or equal to 50%). The data reveal that prolongation in the duration of electrical systole correlates with known cardiac risk factors for sudden death, i.e. 3-vessel-disease, proximal LAD or left main stem stenosis and impaired left ventricular function. In the individual patient, however, the prognostic value of a single QTc-determination is limited because of a large interindividual variation of the data.

Analysis of human color mechanisms using sinusoidal spectral power distributions.

We examined the effects of probing human color mechanisms using sinusoidal spectral power distributions (SPD's) varying in frequency (i.e., from 0.1 to 5.0 cycles/300 nm for a constant starting phase) and phase (i.e., from 0 to 360 deg for a fixed frequency of 1 cycle/300 nm) through computer simulation using several color models. Predicted modulation sensitivity functions (MSF's) in spectral frequency and phase differ among the models and indicate that measurements of the minimum amplitudes necessary to detect sinusoidal SPD's would be useful for distinguishing among theories of color vision. MSF's obtained from similar analyses of dichromats' color mechanisms reveal characteristic patterns of modulation sensitivities and suggest that such measures could serve to distinguish type and degree of color-vision defect. Some implications based on sinusoidal approximations to illuminant and reflectance spectra are discussed along with more general considerations regarding sine-wave SPD's as a probe for mechanisms of color vision.