Interventional radiology virtual simulator for liver biopsy.

PURPOSE: Training in Interventional Radiology currently uses the apprenticeship model, where clinical and technical skills of invasive procedures are learnt during practice in patients. This apprenticeship training method is increasingly limited by regulatory restrictions on working hours, concerns over patient risk through trainees' inexperience and the variable exposure to case mix and emergencies during training. To address this, we have developed a computer-based simulation of visceral needle puncture procedures. METHODS: A real-time framework has been built that includes: segmentation, physically based modelling, haptics rendering, pseudo-ultrasound generation and the concept of a physical mannequin. It is the result of a close collaboration between different universities, involving computer scientists, clinicians, clinical engineers and occupational psychologists. RESULTS: The technical implementation of the framework is a robust and real-time simulation environment combining a physical platform and an immersive computerized virtual environment. The face, content and construct validation have been previously assessed, showing the reliability and effectiveness of this framework, as well as its potential for teaching visceral needle puncture. CONCLUSION: A simulator for ultrasound-guided liver biopsy has been developed. It includes functionalities and metrics extracted from cognitive task analysis. This framework can be useful during training, particularly given the known difficulties in gaining significant practice of core skills in patients.

Unsupervised content classification based nonrigid registration of differently stained histology images.

Registration of histopathology images of consecutive tissue sections stained with different histochemical or immunohistochemical stains is an important step in a number of application areas, such as the investigation of the pathology of a disease, validation of MRI sequences against tissue images, multiscale physical modeling, etc. In each case, information from each stain needs to be spatially aligned and combined to ascertain physical or functional properties of the tissue. However, in addition to the gigabyte-size images and nonrigid distortions present in the tissue, a major challenge for registering differently stained histology image pairs is the dissimilar structural appearance due to different stains highlighting different substances in tissues. In this paper, we address this challenge by developing an unsupervised content classification method that generates multichannel probability images from a roughly aligned image pair. Each channel corresponds to one automatically identified content class. The probability images enhance the structural similarity between image pairs. By integrating the classification method into a multiresolution-block-matching-based nonrigid registration scheme (N. Roberts, D. Magee, Y. Song, K. Brabazon, M. Shires, D. Crellin, N. Orsi, P. Quirke, and D. Treanor, "Toward routine use of 3D histopathology as a research tool," Amer. J. Pathology, vol. 180, no. 5, 2012.), we improve the performance of registering multistained histology images. Evaluation was conducted on 77 histological image pairs taken from three liver specimens and one intervertebral disc specimen. In total, six types of histochemical stains were tested. We evaluated our method against the same registration method implemented without applying the classification algorithm (intensity-based registration) and the state-of-the-art mutual information based registration. Superior results are obtained with the proposed method.

ImaGiNe Seldinger: first simulator for Seldinger technique and angiography training.

In vascular interventional radiology, procedures generally start with the Seldinger technique to access the vasculature, using a needle through which a guidewire is inserted, followed by navigation of catheters within the vessels. Visual and tactile skills are learnt in a patient apprenticeship which is expensive and risky for patients. We propose a training alternative through a new virtual simulator supporting the Seldinger technique: ImaGiNe (imaging guided interventional needle) Seldinger. It is composed of two workstations: (1) a simulated pulse is palpated, in an immersive environment, to guide needle puncture and (2) two haptic devices provide a novel interface where a needle can direct a guidewire and catheter within the vessel lumen, using virtual fluoroscopy. Different complexities are provided by 28 real patient datasets. The feel of the simulation is enhanced by replicating, with the haptics, real force and flexibility measurements. A preliminary validation study has demonstrated training effectiveness for skills transfer.

Combining the interactome and deleterious SNP predictions to improve disease gene identification.

A method has been developed for the prediction of proteins involved in genetic disorders. This involved combining deleterious SNP prediction with a system based on protein interactions and phenotype distances; this is the first time that deleterious SNP prediction has been used to make predictions across linkage-intervals. At each step we tested and selected the best procedure, revealing that the computationally expensive method of assigning medical meta-terms to create a phenotype distance matrix was outperformed by a simple word counting technique. We carried out in-depth benchmarking with increasingly stringent data sets, reaching precision values of up to 75% (19% recall) for 10-Mb linkage-intervals (averaging 100 genes). For the most stringent (worst-case) data we attained an overall recall of 6%, yet still achieved precision values of up to 90% (4% recall). At all levels of stringency and precision the addition of predicted deleterious SNPs was shown to increase recall.

Physics-based virtual environment for training core skills in vascular interventional radiological procedures.

Recent years have seen a significant increase in the use of Interventional Radiology (IR) as an alternative to open surgery. A large number of IR procedures commences with needle puncture of a vessel to insert guidewires and catheters: these clinical skills are acquired by all radiologists during training on patients, associated with some discomfort and occasionally, complications. While some visual skills can be acquired using models such as the ones used in surgery, these have limitations for IR which relies heavily on a sense of touch. Both patients and trainees would benefit from a virtual environment (VE) conveying touch sensation to realistically mimic procedures. The authors are developing a high fidelity VE providing a validated alternative to the traditional apprenticeship model used for teaching the core skills. The current version of the CRaIVE simulator combines home made software, haptic devices and commercial equipments.

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.

Population pharmacokinetics of ethionamide in patients with tuberculosis.

SETTING: Three US referral hospitals. OBJECTIVE: Determine the population pharmacokinetic (PK) parameters of ethionamide (ETA) following multiple oral doses. DESIGN: Fifty-five patients with tuberculosis (TB) participated. Patients received multiple oral doses of ETA as part of their treatment. They also received other anti-tuberculosis medications based upon in vitro susceptibility data. Serum samples were collected over 12 h post-dose, and concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: ETA areas under the concentration-versus-time curve (AUCs) increased linearly with increasing oral doses from 250 to 1000 mg. Compared to the population pattern, delayed absorption was seen at least once in 15% of patients. ETA PK parameter estimates were independent of age, weight, height, gender, and creatinine clearance. TB patients appeared to have larger volumes of distribution (3.22 l/kg) and clearance values (1.88 l/h/kg) compared to previously studied healthy volunteers. This resulted in lower AUC values (3.95 mcg h/ml) in the TB patients. ETA displayed a short elimination half-life (1.94 h). The effect of different dosing strategies on calculated pharmacodynamic parameters was explored. Simulated doses of 250 mg BID to TID failed to achieve serum concentrations above the MIC. CONCLUSION: ETA PK parameters differed between TB patients and healthy volunteers, possibly due to differences in the completeness of absorption. Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical ETA MIC. Additional research is needed to determine the optimal dosing of ETA.

Ofloxacin population pharmacokinetics in patients with tuberculosis.

SETTING: Two tuberculosis hospitals in the United States. OBJECTIVE: To determine the population pharmacokinetic (PK) parameters of ofloxacin following multiple oral doses. DESIGN: A total of 73 patients with tuberculosis (TB) participated in the study. Subjects received multiple doses of ofloxacin as part of their treatment. They also received concurrent medications based on in vitro susceptibility data. Serum samples were collected over 10 h and assayed by a validated high performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: Ofloxacin concentrations increased linearly with increasing oral doses. Delayed absorption was seen at least once in 29% of patients. Ofloxacin elimination decreased with declining renal function and increasing age. Higher daily doses were well tolerated, and appeared to maximize the peak concentration to minimal inhibitory concentration ratio (Cmax:MIC). CONCLUSION: Ofloxacin PK parameters were comparable to those previously published for other patient populations. Higher daily doses may offer pharmacodynamic advantages for the treatment of TB.

AI-based algorithms for protein surface comparisons.

Many current methods for protein analysis depend on the detection of similarity in either the primary sequence, or the overall tertiary structure (the Calpha atoms of the protein backbone). These common sequences or structures may imply similar functional characteristics or active properties. Active sites and ligand binding sites usually occur on or near the surface of the protein; so similarly shaped surface regions could imply similar functions. We investigate various methods for describing the shape properties of protein surfaces and for comparing them. Our current work uses algorithms from computer vision to describe the protein surfaces, and methods from graph theory to compare the surface regions. Early results indicate that we can successfully match a family of related ligand binding sites, and find their similarly shaped surface regions. This method of surface analysis could be extended to help identify unknown surface regions for possible ligand binding or active sites.

Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.

Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible.

Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA). DESIGN: Randomized, four-period, crossover phase I study. SUBJECTS: Fourteen healthy men and women volunteers. INTERVENTIONS: Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminum-magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. MEASUREMENTS AND MAIN RESULTS: Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4+/-10.4 microg/ml, Tmax 1.43+/-1.06 hours, and AUC(0-infinity) 673+/-79.7 microg x hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6+/-9.0 microg/ml, Tmax of 1.43+/-1.23 hours, and AUC(0-infinity) of 628+/-88.4 microg x hr/ml. In the presence of the high-fat meal, mean Cmax was 45.6+/-9.44 pg/ml, Tmax 3.09+/-1.74 hours, and AUC(0-infinity) 687+/-116 microg x hr/ml. CONCLUSIONS: These small changes in Cmax, Tmax, and AUC(0-infinity) can be avoided by giving PZA on an empty stomach whenever possible.

Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide.

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied as part of a randomized cross-over phase I study of two dosage forms. Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high-performance liquid chromatography. The data were analyzed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modeling methods. Fast and slow acetylators of INH had median peak concentrations in plasma (C[max]) of 2.44 and 3.64 microg/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentrations of drugs in plasma [T(max)]), with median elimination half-lives (t1/2) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produced a median C(max) of 11.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 3.4 h. PZA produced a median C(max) of 28.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.