Imaging tumour distribution of a polymeric drug delivery platformin vivoby PET-MRI

Background Over the past decade, molecular imaging has played a key role in the progression of drug delivery platforms from concept to commercialisation. Of the molecular imaging techniques commonly utilised, positron emission tomography (PET) can yield a breadth of information not easily accessible by other methodologies and when combined with other complementary imaging modalities, is a powerful tool for pre- and clinical development of therapeutics. However, very little research has focussed on the information available from complimentary imaging modalities. This paper reports on the data-rich methodologies of contrast enhanced PET/CT and PET/MRI for probing efficacy of polymer drug delivery platforms. Results The information available from an ExiTron nano 6000 contrast enhanced PET/CT and a gadolinium (Gd) enhanced PET/MRI image of a 64Cu labeled HBP in the same mouse was qualitatively compared. Conclusions Gd contrast enhanced PET/MRI offers a powerful methodology for investigating the distribution of polymer drug delivery platforms in vivo and throughout a tumour volume. Furthermore, information about depth of penetration away from primary blood vessels can be gleaned, potentially leading to development of more efficacious delivery vehicles for clinical use.

Measured and predicted total body water in children with myelomeningocele

Objective: Children with myelomeningocele (MMC) have an altered body composition and an atypical distribution of total body water (TBW). The aim of the present study was to determine the accuracy of current predictive equations, based on bioelectrical impedance analysis (BIA), in determining TBW when compared with measured TBW using deuterium dilution. Methods: Fourteen children with MMC were measured for whole body BIA and TBW (using deuterium dilution and the Plateau method). Total body water was predicted using equations based on the resistance and characteristic frequency from BIA measurements and heights of subjects. Results: The mean measured TBW was 15.46 ± 8.28 L and the mean predictions for TBW using equations based on the resistance and characteristic frequency from BIA measurements and heights of subjects were 18.29 ± 8.41 L, 17.72 ± 11.42 L and 12.51 ± 7.59 L, respectively. The best correlation was found using characteristic frequency. The limits of agreement between measured and predicted TBW values using Bland-Altman analysis were large. Conclusions: The present study suggests that the prediction of TBW in children with MMC can be made accurately using the equation of Cornish et al. based on BIA measurements of characteristic frequency.

Spatial distribution of aerosol black carbon over India during pre-monsoon season

Aerosol black carbon (BC) mass concentrations ([BC]), measured continuously during a multi-platform field experiment, Integrated Campaign for Aerosols gases and Radiation Budget (ICARB, March-May 2006), from a network of eight observatories spread over geographically distinct environments of India, (which included five mainland stations, one highland station, and two island stations (one each ill Arabian Sea and Bay of Bengal)) are examined for their spatio-temporal characteristics. During the period of study, [BC] showed large variations across the country, with values ranging from 27 mu g m(3) over industrial/urban locations to as low as 0.065 mu g m(-3) over the Arabian Sea. For all mainland stations, [BC] remained high compared to highland as well as island stations. Among the island stations, Port Blair (PBR) had higher concentration of BC, compared to Minicoy (MCY), implying more absorbing nature of Bay of Bengal aerosols than Arabian Sea. The highland station Nainital (NTL), in the central Himalayas, showed low values of [BC], comparable or even lower than that of the island station PBR, indicating the prevalence of cleaner environment over there. An examination of the changes in the mean temporal features, as the season advances from winter (December-February) to pre-monsoon (March-May), revealed that: (a) Diurnal variations were pronounced over all the mainland stations, with all afternoon low and a nighttime high: (b) At the islands, the diurnal variations, though resembled those over the mainlands, were less pronounced; and (c) In contrast to this, highland station showed an opposite pattern with an afternoon high and a late night or early morning low. The diurnal variations at all stations are mainly caused by the dynamics of local Atmospheric Boundary Layer (ABL), At the entire mainland as well as island stations (except HYD and DEL), [BC] showed a decreasing trend from January to May, This is attributed to the increased convective mixing and to the resulting enhanced vertical dispersal of species in the ABL. In addition, large short-period modulations were observed at DEL and HYD, which appeared to be episodic, An examination of this in the light of the MODIS-derived fire count data over India along with the back-trajectory analysis revealed that advection of BC from extensive forest fires and biomass-burning regions upwind were largely responsible for this episodic enhancement in BC at HYD and DEL.

Cardiovascular diseases and vulnerable plaques: data, modeling, predictions and clinical applications PREFACE

Introduction Two symposia on “cardiovascular diseases and vulnerable plaques” Cardiovascular disease (CVD) is the leading cause of death worldwide. Huge effort has been made in many disciplines including medical imaging, computational modeling, bio- mechanics, bioengineering, medical devices, animal and clinical studies, population studies as well as genomic, molecular, cellular and organ-level studies seeking improved methods for early detection, diagnosis, prevention and treatment of these diseases [1-14]. However, the mechanisms governing the initiation, progression and the occurrence of final acute clinical CVD events are still poorly understood. A large number of victims of these dis- eases who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs [8,9]. Most cardiovascular diseases are associated with vulnerable plaques. A grand challenge here is to develop new imaging techniques, predictive methods and patient screening tools to identify vulnerable plaques and patients who are more vulnerable to plaque rupture and associated clinical events such as stroke and heart attack, and recommend proper treatment plans to prevent those clinical events from happening. Articles in this special issue came from two symposia held recently focusing on “Cardio-vascular Diseases and Vulnerable Plaques: Data, Modeling, Predictions and Clinical Applications.” One was held at Worcester Polytechnic Institute (WPI), Worcester, MA, USA, July 13-14, 2014, right after the 7th World Congress of Biomechanics. This symposium was endorsed by the World Council of Biomechanics, and partially supported by a grant from NIH-National Institute of Biomedical Image and Bioengineering. The other was held at Southeast University (SEU), Nanjing, China, April 18-20, 2014.

Flow pattern analysis in a highly stenotic patient-specific carotid bifurcation model using a turbulence model

The aim of this study is to investigate the blood flow pattern in carotid bifurcation with a high degree of luminal stenosis, combining in vivo magnetic resonance imaging (MRI) and computational fluid dynamics (CFD). A newly developed two-equation transitional model was employed to evaluate wall shear stress (WSS) distribution and pressure drop across the stenosis, which are closely related to plaque vulnerability. A patient with an 80% left carotid stenosis was imaged using high resolution MRI, from which a patient-specific geometry was reconstructed and flow boundary conditions were acquired for CFD simulation. A transitional model was implemented to investigate the flow velocity and WSS distribution in the patient-specific model. The peak time-averaged WSS value of approximately 73Pa was predicted by the transitional flow model, and the regions of high WSS occurred at the throat of the stenosis. High oscillatory shear index values up to 0.50 were present in a helical flow pattern from the outer wall of the internal carotid artery immediately after the throat. This study shows the potential suitability of a transitional turbulent flow model in capturing the flow phenomena in severely stenosed carotid arteries using patient-specific MRI data and provides the basis for further investigation of the links between haemodynamic variables and plaque vulnerability. It may be useful in the future for risk assessment of patients with carotid disease.

Image-based midsole insert design and the material effects on heel plantar pressure distribution during simulated walking loads

The primary objective of this paper is to study the use of medical image-based finite element (FE) modelling in subjectspecific midsole design and optimisation for heel pressure reduction using a midsole plug under the calcaneus area (UCA). Plugs with different relative dimensions to the size of the calcaneus of the subject have been incorporated in the heel region of the midsole. The FE foot model was validated by comparing the numerically predicted plantar pressure with biomechanical tests conducted on the same subject. For each UCA midsole plug design, the effect of material properties and plug thicknesses on the plantar pressure distribution and peak pressure level during the heel strike phase of normal walking was systematically studied. The results showed that the UCA midsole insert could effectively modify the pressure distribution, and its effect is directly associated with the ratio of the plug dimension to the size of the calcaneus bone of the subject. A medium hardness plug with a size of 95% of the calcaneus has achieved the best performance for relieving the peak pressure in comparison with the pressure level for a solid midsole without a plug, whereas a smaller plug with a size of 65% of the calcaneus insert with a very soft material showed minimum beneficial effect for the pressure relief.

Correlation of macrophage location and plaque stress distribution using USPIO-enhanced MRI in a patient with symptomatic severe carotid stenosis: A new insight into risk stratification

High resolution, USPIO-enhanced MR imaging can be used to identify inflamed atherosclerotic plaque. We report a case of a 79-year-old man with a symptomatic carotid stenosis of 82%. The plaque was retrieved for histology and finite element analysis (FEA) based on the preoperative MR imaging was used to predict maximal Von Mises stress on the plaque. Macrophage location correlated with maximal predicted stresses on the plaque. This supports the hypothesis that macrophages thin the fibrous cap at points of highest stress, leading to an increased risk of plaque rupture and subsequent stroke.

Deriving optimal fishing effort for managing Australia's Moreton Bay multispecies trawl fishery with aggregated effort data

Deriving an estimate of optimal fishing effort or even an approximate estimate is very valuable for managing fisheries with multiple target species. The most challenging task associated with this is allocating effort to individual species when only the total effort is recorded. Spatial information on the distribution of each species within a fishery can be used to justify the allocations, but often such information is not available. To determine the long-term overall effort required to achieve maximum sustainable yield (MSY) and maximum economic yield (MEY), we consider three methods for allocating effort: (i) optimal allocation, which optimally allocates effort among target species; (ii) fixed proportions, which chooses proportions based on past catch data; and (iii) economic allocation, which splits effort based on the expected catch value of each species. Determining the overall fishing effort required to achieve these management objectives is a maximizing problem subject to constraints due to economic and social considerations. We illustrated the approaches using a case study of the Moreton Bay Prawn Trawl Fishery in Queensland (Australia). The results were consistent across the three methods. Importantly, our analysis demonstrated the optimal total effort was very sensitive to daily fishing costs-the effort ranged from 9500-11 500 to 6000-7000, 4000 and 2500 boat-days, using daily cost estimates of $0, $500, $750, and $950, respectively. The zero daily cost corresponds to the MSY, while a daily cost of $750 most closely represents the actual present fishing cost. Given the recent debate on which costs should be factored into the analyses for deriving MEY, our findings highlight the importance of including an appropriate cost function for practical management advice. The approaches developed here could be applied to other multispecies fisheries where only aggregated fishing effort data are recorded, as the literature on this type of modelling is sparse.

Intra-cluster correlation structure in longitudinal data analysis: Selection criteria and misspecification tests

Selection criteria and misspecification tests for the intra-cluster correlation structure (ICS) in longitudinal data analysis are considered. In particular, the asymptotical distribution of the correlation information criterion (CIC) is derived and a new method for selecting a working ICS is proposed by standardizing the selection criterion as the p-value. The CIC test is found to be powerful in detecting misspecification of the working ICS structures, while with respect to the working ICS selection, the standardized CIC test is also shown to have satisfactory performance. Some simulation studies and applications to two real longitudinal datasets are made to illustrate how these criteria and tests might be useful.

Investigating physical properties of solid dosage forms during pharmaceutical processing : Process analytical applications of vibrational spectroscopy

In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms

Optimal sign tests for data from ranked set samples

This paper considers the one-sample sign test for data obtained from general ranked set sampling when the number of observations for each rank are not necessarily the same, and proposes a weighted sign test because observations with different ranks are not identically distributed. The optimal weight for each observation is distribution free and only depends on its associated rank. It is shown analytically that (1) the weighted version always improves the Pitman efficiency for all distributions; and (2) the optimal design is to select the median from each ranked set.

Robust estimating functions and bias correction for longitudinal data analysis

Robust methods are useful in making reliable statistical inferences when there are small deviations from the model assumptions. The widely used method of the generalized estimating equations can be "robustified" by replacing the standardized residuals with the M-residuals. If the Pearson residuals are assumed to be unbiased from zero, parameter estimators from the robust approach are asymptotically biased when error distributions are not symmetric. We propose a distribution-free method for correcting this bias. Our extensive numerical studies show that the proposed method can reduce the bias substantially. Examples are given for illustration.

Maximum likelihood estimation of mortality and growth with individual variability from multiple length-frequency data

We consider estimation of mortality rates and growth parameters from length-frequency data of a fish stock and derive the underlying length distribution of the population and the catch when there is individual variability in the von Bertalanffy growth parameter L-infinity. The model is flexible enough to accommodate 1) any recruitment pattern as a function of both time and length, 2) length-specific selectivity, and 3) varying fishing effort over time. The maximum likelihood method gives consistent estimates, provided the underlying distribution for individual variation in growth is correctly specified. Simulation results indicate that our method is reasonably robust to violations in the assumptions. The method is applied to tiger prawn data (Penaeus semisulcatus) to obtain estimates of natural and fishing mortality.

Effects of fish density distribution and effort distribution on catchability

The effects of fish density distribution and effort distribution on the overall catchability coefficient are examined. Emphasis is also on how aggregation and effort distribution interact to affect overall catch rate [catch per unit effort (cpue)]. In particular, it is proposed to evaluate three indices, the catchability index, the knowledge parameter, and the aggregation index, to describe the effectiveness of targeting and the effects on overall catchability in the stock area. Analytical expressions are provided so that these indices can easily be calculated. The average of the cpue calculated from small units where fishing is random is a better index for measuring the stock abundance. The overall cpue, the ratio of lumped catch and effort, together with the average cpue, can be used to assess the effectiveness of targeting. The proposed methods are applied to the commercial catch and effort data from the Australian northern prawn fishery. The indices are obtained assuming a power law for the effort distribution as an approximation of targeting during the fishing operation. Targeting increased catchability in some areas by 10%, which may have important implications on management advice.

Geometry Of Proline And Hydroxyproline .1. An Analysis Of X-Ray Crystal-Structure Data

We have carried out an analysis of crystal structure data on prolyl and hydroxyprolyl moieties in small molecules. The flexibility of the pyrrolidine ring due to the pyramidal character of nitrogen has been defined in terms of two projection angles δ1 and δ2. The distribution of these parameters in the crystal structures is found to be consistent with results of the energy calculations carried out on prolyl moieties in our laboratory.