Efficient Parameter Estimation in Preclinical Animal Pharmacokinetic Studies

An estimation of the average value of pharmacokinetic parameters in a group of animals provides limited information if there is no good measure of the variability of each of the parameters. The traditional approach used in the analysis of animal pharmacokinetic data obtained from studies involving the use of small laboratory animals (rats or mice) in which each animal supplies only one concentration - time point does not provide this, nor can it assess the influence of physiology (or pathology) on pharmacokinetics. The consideration of variability within the same species during interspecies scaling has been advocated (Vocci & Farber, 1988). Thus, provision should be made for the estimation of variability inherent in an animal population in analysing data obtained by "destructive sampling". The NONMEM approach does, however, provide estimates of both average values of pharmacokinetic parameters and their statistical distribution within the population. In this thesis data were generated by simulation (assuming no covariance), and analysed using the NONMEM program. The efficiency of this approach is the focus of this thesis. Experimental error, number of samples taken, and the arrangement of samples in time are factors which must be taken into account in designing experiments for efficient parameter estimation. In addition, appropriate methods of data analysis must be used to extract the required information from the data. Simulated data sets were used to investigate the effect of various design features on the efficiency of parameter estimation using the one observation per animal design. In addition, the efficiency with which parameters could be estimated given a range of parameter values and variability was investigated. Several methods were used to determine the efficiency of parameter estimation. Prediction error (bias and precision) was useful in assessing the efficiency with which individual parameters were estimated. In addition, the 99% individual and joint confidence intervals containing the true parameter 95% of the time for all parameters were introduced as aids to judging the efficiency of estimation of individual and all parameters of a model, considered as a set. Confidence interval tables were constructed to reveal the influence of bias and standard error on parameter estimation. Also, the design number, a new statistic which combines the contributions of bias and precision in judging the efficiency of parameter estimation, was introduced to complement bias and precision, and confidence intervals methods of analysis. The design number also allowed the efficiency with which all parameters of a model were estimated as a set to be judged. The incidence of high pairwise correlations of parameter estimates was also taken into account in assessing the acceptability of estimates and the adequacy of model parameterization. Assuming IV bolus injection with the monoexponential pharmacokinetic model, simulation studies were carried out to investigate the influence of interanimal variability on the estimation of population pharmacokinetic parameters and their variances. The range of variability investigated was similar to that expected in real studies, and sampling was done at set times. The efficiency of estimation of the structural model parameters (Cl and V) was good, on average, irrespective of the variability in Cl and V. However, the estimation of these parameters was associated with negative bias which was attributed to the nature of the NONMEM program (i. e. estimation error since negative bias was also observed in subsequent studies in which dE was set to 0%). The variance parameters were mostly inefficiently estimated in this study and all other studies using the one observation per animal design. This was attributable to the lack of information in the data set about dE. When the effect of the arrangement of concentrations in time on parameter estimation was studied with the two sample point design, efficient parameter estimates were obtained when the first sample was obtained as early as possible (5 min. ) and the second sample was located at > 1.4 times the simulated t1/2 (84min. ) of the drug. When three or four sample points were used the exact location of the third or fourth sample was not critical to efficient parameter estimation. The efficiency of parameter estimation was investigated given a range of parameter values, concentration measurement error, and sampling schedules with the two compartment model parameterized as A, a, B, B and assuming IV bolus injection with animals sampled at set times. The parameters, considered as a set, were efficiently estimated when a was in the range of 2.0 to 4.0 h-1 and the A:B ratio in the range of 2.5 to 30.0. These results were attributed to the distribution of data points between the distribution and elimination phases of the plasma concentration - time profile. Concentration measurement error greater than 10% yielded variance parameter estimates with a greater degree of bias and imprecision

Valoració de la culminació del procés de transferències i model universitari

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Tuberculosis Prevalence- A Contemporary Public Health Challenge and the Instituted Barriers in Presbyterian Joint Hospital Uburu, Ohaozara L. G. A. Ebonyi State, Nigeria

A prevalence study is crucial in assessing the extent of occurrence with regard to an outbreak of a disease. High prevalence of tuberculosis (TB) has been reported in Nigeria. The study aimed at investigating the prevalence of tuberculosis reported cases from 2009-2013 and tuberculosis instituted barriers in Presbyterian Joint Hospital Uburu (PJHU) in Ohaozara Local Government Area, Ebonyi State of Nigeria. Ex-post-facto research design was used for the study. The study population consisted of 675 tuberculosis reported cases from 2009-2013 in PJHU. The same number (675) was the sample size for the study. Data were collected using the researcher’s Template which was filled with information from the hospital’s records. The template consisted of four items viz: year case was reported, number of cases, gender and TB instituted barriers in PJHU. Analysis of the data showed that the prevalence of tuberculosis reported cases in 2009 was 196 (29.0%), 152 (22.5%), in 2010; 138 (20.4%) in 2011; 110 (16.3%) in 2012 and 79 (11.7%) in 2013. The results showed that the highest prevalence rate 29.0% was recorded in 2009 while the lowest prevalence rate of 11.7% was recorded in 2013. Tuberculosis instituted barriers in PJHU included isolation, safe disposal of sputum, personal hygiene and others as presented in Table 2. The Chi-square analysis of no significant difference in the prevalence of tuberculosis by gender was accepted (X2 Cal 2.376 < X2 Tab.3.841, df 1, P= .05). From the findings of the study males were found to be as susceptible to tuberculosis as females. It was recommended among others that teaching of tuberculosis control practices by health workers should be integrated into a wider scheme for health care education and family planning services as well as establishing Directly Observed Home Treatment Short Course (DOHTS) in order to take TB services to the door steps of TB patients. Keywords: Tuberculosis, Prevalence, Control practices, and gender

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Effective pressure interface law for transport phenomena between an unconfined fluid and a porous medium using homogenization

We present modeling of the incompressible viscous flows in the domain containing an unconfined fluid and a porous medium. For such setting a rigorous derivation of the Beavers-Joseph-Saffman interface condition was undertaken by J\"ager and Mikeli\'c [SIAM J. Appl. Math. \rm 60 (2000), p. 1111-1127] using the homogenization method. So far the interface law for the pressure was conceived and confirmed only numerically. In this article we justify rigorously the pressure jump condition using the corresponding boundary layer

Lead-induced Oxidative Stress and Chemoprotective Role of Dietary Supplements on Wistar Albino Rats

The heavy metal lead (Pb) is a common environmental pollutant with widespread distribution, and oxidative stress has been implicated in the pathogenesis of its toxicity. The ameliorative effect of nutritional contents of palm oil and cod liver oil (dietary supplements) following exposure to sublethal concentration of Pb on adult Wistar albino rats was studied. Toxicity was induced by administering intraperitoneally, 30 mg/kg body weight of lead acetate at alternate days for 21 days. Groups treated with supplements received daily oral dose of 2.5 ml palm oil or cod liver oil or 1.25 ml palm oil and 1.25 ml cod liver oil (synergy). Increased activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, decreased activities of superoxide dismutase, catalase, glutathione peroxidase and increased concentrations of total bilirubin and lipid peroxidation product were observed in Pb exposed rats without nutritional supplement treatment. However, these negative oxidative states were ameliorated in rats by the concomitant administration of nutritional supplements, singly and in combination. Furthermore, non-significant changes were observed in the haematological parameters determined. These observations indicate potential therapeutic benefits in the use of palm oil and cod liver oil in the management of lead-induced toxicity

A criterion for separating process calculi

We introduce a new criterion, replacement freeness, to discern the relative expressiveness of process calculi. Intuitively, a calculus is strongly replacement free if replacing, within an enclosing context, a process that cannot perform any visible action by an arbitrary process never inhibits the capability of the resulting process to perform a visible action. We prove that there exists no compositional and interaction sensitive encoding of a not strongly replacement free calculus into any strongly replacement free one. We then define a weaker version of replacement freeness, by only considering replacement of closed processes, and prove that, if we additionally require the encoding to preserve name independence, it is not even possible to encode a non replacement free calculus into a weakly replacement free one. As a consequence of our encodability results, we get that many calculi equipped with priority are not replacement free and hence are not encodable into mainstream calculi like CCS and pi-calculus, that instead are strongly replacement free. We also prove that variants of pi-calculus with match among names, pattern matching or polyadic synchronization are only weakly replacement free, hence they are separated both from process calculi with priority and from mainstream calculi.Comment: In Proceedings EXPRESS'10, arXiv:1011.601

Selfing revealed potential for higher yield performance than backcrossing among tomato segregating populations of Solanum lycopersicum × S. pimpinellifolium crosses under tropical humid climate

The objectives of this study were to assess and identify new source of phenotypic variability among F3 and BC1F2 tomato populations, and apply genotype by yield*trait (GYT) biplots for population and line selection based on multiple traits. Four diverse cultivated parents (‘CLN2498D’ [D] and ‘CLN2417H’ [H] from Ethiopia; ‘UC Dan INDIA’ [U] and ‘Tima’ [T] from Nigeria), and wild parent ‘LA2093’ [W] were used to generate 276 potential breeding lines. The lines were categorized into eight populations (‘pop_1_W/H1’, ‘pop_2_W/H2’, ‘pop_3_W/D1’, ‘pop_4_W/D2’, ‘pop_5_W/T1’, ‘pop_6_W/T2’, ‘pop_7_W/U1’, and ‘pop_8_W/U2’), and evaluated twice in the field using 19 × 15 alpha-lattice design with two replicates. Significant differences were observed among lines and populations for all yield enhancing traits. ‘Pop_1_W/H1’, ‘pop_4_W/D2’ and ‘pop_6_W/T2’ expressed the highest genetic divergence for plant height, number of leaves, total flower and fruit number, and fruit weight. GYT biplots revealed that all yield*trait interactions had a positive correlation with each other. F3 populations, ‘pop_5_W/T1’ and ‘pop_1_W/H1’ exhibited the best performance for majority of the yield*trait combinations. Hierarchical clustering on principal components (HCPC) revealed overlapping lines (70.58% of Cluster D lines) and (54.05% of Cluster U lines) from the two F3 populations. In BC1F2 population, 32.35% of the 34 original lines of Cluster D and 48.48% of Cluster T lines overlapped between Clusters D and T, while 18.18% of Cluster T lines and 8.82% of Cluster H lines were transgressive between Clusters T and H. Transgressive segregants ‘0210U1’, ‘0211U1’, and ‘0171T1’ of selfed population using multivariate analysis were believed to represent potential sources of novel genetic variation for future tomato breeding