Markov chain Monte Carlo with Gaussian processes for fast parameter estimation and uncertainty quantification in a 1D fluid-dynamics model of the pulmonary circulation.

The past few decades have witnessed an explosive synergy between physics and the life sciences. In particular, physical modelling in medicine and physiology is a topical research area. The present work focuses on parameter inference and uncertainty quantification in a 1D fluid-dynamics model for quantitative physiology: the pulmonary blood circulation. The practical challenge is the estimation of the patient-specific biophysical model parameters, which cannot be measured directly. In principle this can be achieved based on a comparison between measured and predicted data. However, predicting data requires solving a system of partial differential equations (PDEs), which usually have no closed-form solution, and repeated numerical integrations as part of an adaptive estimation procedure are computationally expensive. In the present article, we demonstrate how fast parameter estimation combined with sound uncertainty quantification can be achieved by a combination of statistical emulation and Markov chain Monte Carlo (MCMC) sampling. We compare a range of state-of-the-art MCMC algorithms and emulation strategies, and assess their performance in terms of their accuracy and computational efficiency. The long-term goal is to develop a method for reliable disease prognostication in real time, and our work is an important step towards an automatic clinical decision support system.

Assessing model mismatch and model selection in a Bayesian uncertainty quantification analysis of a fluid-dynamics model of pulmonary blood circulation.

This study uses Bayesian inference to quantify the uncertainty of model parameters and haemodynamic predictions in a one-dimensional pulmonary circulation model based on an integration of mouse haemodynamic and micro-computed tomography imaging data. We emphasize an often neglected, though important source of uncertainty: in the mathematical model form due to the discrepancy between the model and the reality, and in the measurements due to the wrong noise model (jointly called 'model mismatch'). We demonstrate that minimizing the mean squared error between the measured and the predicted data (the conventional method) in the presence of model mismatch leads to biased and overly confident parameter estimates and haemodynamic predictions. We show that our proposed method allowing for model mismatch, which we represent with Gaussian processes, corrects the bias. Additionally, we compare a linear and a nonlinear wall model, as well as models with different vessel stiffness relations. We use formal model selection analysis based on the Watanabe Akaike information criterion to select the model that best predicts the pulmonary haemodynamics. Results show that the nonlinear pressure-area relationship with stiffness dependent on the unstressed radius predicts best the data measured in a control mouse.

Influence of image segmentation on one-dimensional fluid dynamics predictions in the mouse pulmonary arteries.

Computational fluid dynamics (CFD) models are emerging tools for assisting in diagnostic assessment of cardiovascular disease. Recent advances in image segmentation have made subject-specific modelling of the cardiovascular system a feasible task, which is particularly important in the case of pulmonary hypertension, requiring a combination of invasive and non-invasive procedures for diagnosis. Uncertainty in image segmentation propagates to CFD model predictions, making the quantification of segmentation-induced uncertainty crucial for subject-specific models. This study quantifies the variability of one-dimensional CFD predictions by propagating the uncertainty of network geometry and connectivity to blood pressure and flow predictions. We analyse multiple segmentations of a single, excised mouse lung using different pre-segmentation parameters. A custom algorithm extracts vessel length, vessel radii and network connectivity for each segmented pulmonary network. Probability density functions are computed for vessel radius and length and then sampled to propagate uncertainties to haemodynamic predictions in a fixed network. In addition, we compute the uncertainty of model predictions to changes in network size and connectivity. Results show that variation in network connectivity is a larger contributor to haemodynamic uncertainty than vessel radius and length.

Hemodynamic assessment of pulmonary hypertension in mice: a model-based analysis of the disease mechanism.

This study uses a one-dimensional fluid dynamics arterial network model to infer changes in hemodynamic quantities associated with pulmonary hypertension in mice. Data for this study include blood flow and pressure measurements from the main pulmonary artery for 7 control mice with normal pulmonary function and 5 mice with hypoxia-induced pulmonary hypertension. Arterial dimensions for a 21-vessel network are extracted from micro-CT images of lungs from a representative control and hypertensive mouse. Each vessel is represented by its length and radius. Fluid dynamic computations are done assuming that the flow is Newtonian, viscous, laminar, and has no swirl. The system of equations is closed by a constitutive equation relating pressure and area, using a linear model derived from stress-strain deformation in the circumferential direction assuming that the arterial walls are thin, and also an empirical nonlinear model. For each dataset, an inflow waveform is extracted from the data, and nominal parameters specifying the outflow boundary conditions are computed from mean values and characteristic timescales extracted from the data. The model is calibrated for each mouse by estimating parameters that minimize the least squares error between measured and computed waveforms. Optimized parameters are compared across the control and the hypertensive groups to characterize vascular remodeling with disease. Results show that pulmonary hypertension is associated with stiffer and less compliant proximal and distal vasculature with augmented wave reflections, and that elastic nonlinearities are insignificant in the hypertensive animal.

[Retroperitoneal pyogenic infections with uncertain etiopathogenesis. Diagnostic and therapeutic difficulties]. / Supuratiile retroperitoneale cu etiologie imprecisa. Dificultati diagnostice si terapeutice.

Retroperitoneal pyogenic collections can appear in most distinct pathological situations. Establishing the topography and pathogenic route are essential steps in developing the therapeutic attitude. Diagnosis of suppurative retroperitoneal process complicating a previously attested disease is less difficult. The challenges appears in that cases with atypical, clinical picture, which presents associated pathological states (diabetes mellitus, chronic alcoholism, behavioral disturbances), as well as in primary retroperitoneal infections (psoas abscess, infected retroperitoneal tumors) or in that situations in which the patient presents toxico-septic shock on admission. A retrospective study on the patients with retroperitoneal infections admitted in our Clinic between 1996 - 2006 was carried out. We selected the cases in which preoperative etiopathogenic diagnosis was uncertain (in some situations the exact etiopathogenic route remaining unknown even postoperatively). The aim of this study is to evaluate the factors contributing to this, and how therapeutic attitude was influenced.

Clinical manifestations in the West Nile virus outbreak.

During the summer of 1996 an unusual clustering of meningoencephalitis cases was recorded in the Capital City, Bucharest, and in some areas from South-East Romania. After an initial suspicion of an enteroviral etiology was discarded, the West Nile etiology was confirmed by specific antibodies demonstration through hemagglutination-inhibition and ELISA tests. This study included 251 patients with the diagnoses of West Nile acute encephalitis (166 cases), acute meningitis (57 cases) and acute febrile disease (33 cases). The patients' age ranged from 1 to 89 years (mean 51.1 years). The most frequent clinical manifestations were: fever (95.7% of cases), cephalalgia (92.6%), stiffness of the neck (89.1%), vomiting (62.5%), marked asthenia (46.5%), myalgia (28.9%). In addition, patients with encephalitis exhibited: alteration of consciousness (89.2% of cases), tremor of extremities (40.4%), ataxia (44%), paralysis (15.1%). The fatality rate was 15.1% in acute encephalitis, 1.8% in acute meningitis and 0% in the acute febrile disease.

Evidence for tuberculous infection in Romanian HIV-positive children by enzyme-linked immunosorbent assay.

The pandemic spread of tuberculosis (TB) and human immunodeficiency virus (HIV) represents a serious world problem. The diagnosis of TB in developing countries remains difficult, particularly in patients with concomitant HIV infection. Anergia to tuberculin frequently occurs in HIV-positive patients with pulmonary or extrapulmonary disease, and radiographic images are atypical or nondiagnostic. Children are often in an even more unfavorable situation: they cannot expectorate, and the biological samples required for bacteriological examination and culture are more difficult to obtain. We present in this work the correlation between the presence of serum antimycobacterial antibodies [as demonstrated by an in-house enzyme-linked immunosorbent assay (ELISA)] in 41 out of 279 HIV-infected children, and clinical, bacteriological, radiological, and pathological data that support the diagnosis of TB in these children. The prevalence of antimycobacterial antibodies in our group of HIV-positive children was 23.3%. In only 4 of the total cases investigated could the diagnosis of TB not be supported by the results of standard tests for TB. The control group showed an insignificant interference from bacillus Calmette-Guerin (BCG) vaccination.

Virological investigations in adults with acute pneumonia.

Virological investigations (immunofluorescence reactions and isolation attempts with pharyngeal exudate specimens, as well as serological tests) were performed in 110 adult patients with pneumonia. Viral or inframicrobial agents were involved in 70 (63.7%) of the cases, either alone (27 cases) or in association with bacteria (43 cases). Parainfluenza and adenoviruses were most frequently encountered both in the cases with mixed (viral + bacterial) and in those with strictly viral pneumonia. Mycoplasma pneumoniae accounted for 11% of the cases; the role of chlamydial and rickettsial germs was insignificant.

Detection by immunofluorescence of possible viral implications in "idiopathic" peripheral facial paralysis.

The presence of viral antigens was detected by the indirect immunofluorescence technique in exfoliated cells occurring in the pharyngeal exudate of 18 out of 29 patients with peripheral facial paralysis. The most frequently encountered antigens were: Coxsackie A and B virus (33.3%), adenovirus (16.7%), and the association Coxsackie B virus + adenovirus (16.7%). The possibility that some of the so-called "idiopathic" peripheral facial paralyses may have a viral etiology is discussed.

Isolation of parainfluenza virus type 3 from an infant with meningoencephalitis.

A parainfluenza virus type 3 strain was isolated from the cerebrospinal fluid of an infant with a clinical diagnosis of meningoencephalitis. Specific HAI antibodies to parainfluenza virus type 3, ranging in titer from 1/80 to 1/160 could be detected in the infant's serum. A 2-fold rise in the level of complement fixing serum antibodies-from 1/16 at the first to 1/32 at the second collection-was recorded.

Extrarespiratory localizations of parainfluenza viruses.

Two hemagglutinating and hemadsorbant agents-serologically identified as parainfluenza viruses type 3-were isolated from the cerebrospinal fluid of a 10-month-old infant with meningoencephalitis and from the urethral secretion of a male patient with nonbacterial urethritis. Parainfluenza virus antigens types 1, 2, and 3 were detected by indirect immunofluorescence reactions in cells exfoliated in the vagina of women with genital neoplasia or common gynecopathies.

Amoxycillin for parenteral use: a pharmacological and clinical evaluation.

Pharmacological studies with intramuscular amoxycillin and intramuscular ampicillin were carried out in ten patients. Serum, urine levels, urinary recovery and renal clearance of intramuscular amoxycillin were similar to intramuscular ampicillin and to oral amoxycillin. The time to peak serum concentration was later for amoxycillin. Sputum levels were higher for amoxycillin. Amoxycillin intramuscularly was more painful than ampicillin in eleven out of thirty patients. The clinical response, evaluated in twenty-five patients was good and similar to ampicillin in our experience.