A land-use transport-interaction framework for large scale strategic urban modeling

We introduce a family of land use transportation interaction (LUTI) models which enable future employment, population and flows or trips between these activities to be explained and predicted. We begin by focusing on the generic spatial interaction model, noting the ways in which its components reflect demand and supply at different locations measured in terms of employment and working population. This suggests an equilibrium structure which is our starting point in developing a simplified version of the model which we extend to deal with four different activity sectors – housing, retail activities, schools, and health facilities. We use this generic structure to develop four related versions of the generic LUTI model equations for residential populations, retailing, education and hospitals which are all driven by employment in terms of where people live and work. This constitutes our integrated framework that we use in calibrating, that is fine-tuning the model to three urban areas (cities) in Europe: to Oxford and its county, Turin and its region, and Athens in its hinterland of Attica reflecting population volumes from 700,000, 1.7 million and 3.8 million persons respectively. In each case, we use the models to predict the impact of different scenarios – new housing developments in Oxfordshire, new universities and metro lines in Turin, and economic development in the Athens region. We describe the details of these scenarios in Supplementary Information (SI) which shows the versatility of using the models to examine such impacts and we conclude with directions for improving the various models and nesting them at different scales within the land use-transport planning process

Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product

FDA Critical Path Initiatives: Opportunities for Generic Drug Development

FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs

Human Gastrointestinal Juices Intended for Use in In Vitro Digestion Models

The aim of this study was to characterise the individual human gastric and duodenal juices to be used in in vitro model digestion and to examine the storage stability of the enzymes. Gastroduodenal juices were aspirated, and individual variations in enzymatic activities as well as total volumes, pH, bile acids, protein and bilirubin concentrations were recorded. Individual pepsin activity in the gastric juice varied by a factor of 10, while individual total proteolytic activity in the duodenal juice varied by a factor of 5. The duodenal amylase activity varied from 0 to 52.6 U/ml, and the bile acid concentration varied from 0.9 to 4.5 mM. Pooled gastric and duodenal juices from 18 volunteers were characterised according to pepsin activity (26.7 U/ml), total proteolytic activity (14.8 U/ml), lipase activity (951.0 U/ml), amylase activity (26.8 U/ml) and bile acids (4.5 mM). Stability of the main enzymes in two frozen batches of either gastric or duodenal juice was studied for 6 months. Pepsin activity decreased rapidly and adjusting the pH of gastric juice to 4 did not protect the pepsin from degradation. Lipase activity remained stable for 4 months, however decreased rapidly thereafter even after the addition of protease inhibitors. Glycerol only marginally stabilised the survival of the enzymatic activities. These results of compositional variations in the individual gastrointestinal juices and the effect of storage conditions on enzyme activities are useful for the design of in vitro models enabling human digestive juices to simulate physiological digestion

A review of exposure assessment methods for epidemiological studies of health effects related to industrially contaminated sites

BACKGROUND: this paper is based upon work from COST Action ICSHNet. Health risks related to living close to industrially contaminated sites (ICSs) are a public concern. Toxicology-based risk assessment of single contaminants is the main approach to assess health risks, but epidemiological studies which investigate the relationships between exposure and health directly in the affected population have contributed important evidence. Limitations in exposure assessment have substantially contributed to uncertainty about associations found in epidemiological studies. OBJECTIVES: to examine exposure assessment methods that have been used in epidemiological studies on ICSs and to provide recommendations for improved exposure assessment in epidemiological studies by comparing exposure assessment methods in epidemiological studies and risk assessments. METHODS: after defining the multi-media framework of exposure related to ICSs, we discussed selected multi-media models applied in Europe. We provided an overview of exposure assessment in 54 epidemiological studies from a systematic review of hazardous waste sites; a systematic review of 41 epidemiological studies on incinerators and 52 additional studies on ICSs and health identified for this review. RESULTS: we identified 10 multi-media models used in Europe primarily for risk assessment. Recent models incorporated estimation of internal biomarker levels. Predictions of the models differ particularly for the routes ‘indoor air inhalation’ and ‘vegetable consumption’. Virtually all of the 54 hazardous waste studies used proximity indicators of exposure, based on municipality or zip code of residence (28 studies) or distance to a contaminated site (25 studies). One study used human biomonitoring. In virtually all epidemiological studies, actual land use was ignored. In the 52 additional studies on contaminated sites, proximity indicators were applied in 39 studies, air pollution dispersion modelling in 6 studies, and human biomonitoring in 9 studies. Exposure assessment in epidemiological studies on incinerators included indicators (presence of source in municipality and distance to the incinerator) and air dispersion modelling. Environmental multi-media modelling methods were not applied in any of the three groups of studies. CONCLUSIONS: recommendations for refined exposure assessment in epidemiological studies included the use of more sophisticated exposure metrics instead of simple proximity indicators where feasible, as distance from a source results in misclassification of exposure as it ignores key determinants of environmental fate and transport, source characteristics, land use, and human consumption behaviour. More validation studies using personal exposure or human biomonitoring are needed to assess misclassification of exposure. Exposure assessment should take more advantage of the detailed multi-media exposure assessment procedures developed for risk assessment. The use of indicators can be substantially improved by linking definition of zones of exposure to existing knowledge of extent of dispersion. Studies should incorporate more often land use and individual behaviour

Excitability and synaptic transmission in the enteric nervous system: Does diet play a role?

© Springer International Publishing Switzerland 2016. Changes in diet are a challenge to the gastrointestinal tract which needs to alter its processing mechanisms to continue to process nutrients and maintain health. In particular, the enteric nervous system (ENS) needs to adapt its motor and secretory programs to deal with changes in nutrient type and load in order to optimise nutrient absorption. The nerve circuits in the gut are complex, and the numbers and types of neurons make recordings of specific cell types difficult, time-consuming, and prone to sampling errors. Nonetheless, traditional research methods like intracellular electrophysiological approaches have provided the basis for our understanding of the ENS circuitry. In particular, animal models of intestinal inflammation have shown us that we can document changes to neuronal excitability and synaptic transmission. Recent studies examining diet-induced changes to ENS programming have opted to use fast imaging techniques to reveal changes in neuron function. Advances in imaging techniques using voltage- or calcium-sensitive dyes to record neuronal activity promise to overcome many limitations inherent to electrophysiological approaches. Imaging techniques allow access to a wide range of ENS phenotypes and to the changes they undergo during dietary challenges. These sorts of studies have shown that dietary variation or obesity can change how the ENS processes information-in effect reprogramming the ENS. In this review, the data gathered from intracellular recordings will be compared with measurements made using imaging techniques in an effort to determine if the lessons learnt from inflammatory changes are relevant to the understanding of diet-induced reprogramming

A retrospective study of PBDEs and PCBs in human milk from the Faroe Islands

BACKGROUND: Persistent organic pollutants (POPs) in wildlife and humans remain a cause of global concern, both in regard to traditional POPs, such as the polychlorinated biphenyls (PCBs), and emerging POPs, such as the polybrominated diphenyl ethers (PBDEs). To determine the time related concentrations, we analyzed human milk for these substances at three time points between 1987 and 1999. Polychlorobiphenylols (OH-PCBs), the dominating class of PCB metabolites, some of which are known to be strongly retained in human blood, were also included in the assessment. METHODS: We obtained milk from the Faroe Islands, where the population is exposed to POPs from their traditional diet (which may include pilot whale blubber). In addition to three pools, nine individual samples from the last time point were also analyzed. After cleanup, partitioning of neutral and acidic compounds, and separation of chemical classes, the analyses were carried out by gas chromatography and/or gas chromatography/mass spectrometry. RESULTS: Compared to other European populations, the human milk had high PCB concentrations, with pool concentrations of 2300 ng/g fat 1987, 1600 ng/g fat in 1994, and 1800 ng/g fat in 1999 (based on the sum of eleven major PCB congeners). The nine individual samples showed great variation in PCB concentrations. The OH-PCBs were present in trace amounts only, at levels of approximately 1% of the PCB concentrations. The PBDE concentrations showed a clear increase over time, and their concentrations in human milk from 1999 are among the highest reported so far from Europe, with results of individual samples ranging from 4.7 to 13 ng/g fat CONCLUSION: Although remote from pollution sources, the Faroe Islands show high concentrations of POPs in human milk, particularly PCBs, but also PBDEs. The PBDEs show increasing concentrations over time. The OH-PCB metabolites are poorly transferred to human milk, which likely is related to their acidic character

Acidic Digestion in a Teleost: Postprandial and Circadian Pattern of Gastric pH, Pepsin Activity, and Pepsinogen and Proton Pump mRNAs Expression

Two different modes for regulation of stomach acid secretion have been described in vertebrates. Some species exhibit a continuous acid secretion maintaining a low gastric pH during fasting. Others, as some teleosts, maintain a neutral gastric pH during fasting while the hydrochloric acid is released only after the ingestion of a meal. Those different patterns seem to be closely related to specific feeding habits. However, our recent observations suggest that this acidification pattern could be modified by changes in daily feeding frequency and time schedule. The aim of this study was to advance in understanding the regulation mechanisms of stomach digestion and pattern of acid secretion in teleost fish. We have examined the postprandial pattern of gastric pH, pepsin activity, and mRNA expression for pepsinogen and proton pump in white seabream juveniles maintained under a light/dark 12/12 hours cycle and receiving only one morning meal. The pepsin activity was analyzed according to the standard protocol buffering at pH 2 and using the actual pH measured in the stomach. The results show how the enzyme precursor is permanently available while the hydrochloric acid, which activates the zymogen fraction, is secreted just after the ingestion of food. Results also reveal that analytical protocol at pH 2 notably overestimates true pepsin activity in fish stomach. The expression of the mRNA encoding pepsinogen and proton pump exhibited almost parallel patterns, with notable increases during the darkness period and sharp decreases just before the morning meal. These results indicate that white seabream uses the resting hours for recovering the mRNA stock that will be quickly used during the feeding process. Our data clearly shows that both daily illumination pattern and feeding time are involved at different level in the regulation of the secretion of digestive juices

Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state

Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds