Input estimation for extended-release formulations exemplified with exenatide

Estimating the in vivo absorption profile of a drug is essential when developing extended-release medications. Such estimates can be obtained by measuring plasma concentrations over time and inferring the absorption from a model of the drug’s pharmacokinetics. Of particular interest is to predict the bioavailability—the fraction of the drug that is absorbed and enters the systemic circulation. This paper presents a framework for addressing this class of estimation problems and gives advice on the choice of method. In parametric methods, a model is constructed for the absorption process, which can be difficult when the absorption has a complicated profile. Here, we place emphasis on non-parametric methods that avoid making strong assumptions about the absorption. A modern estimation method that can address very general input-estimation problems has previously been presented. In this method, the absorption profile is modeled as a stochastic process, which is estimated using Markov chain Monte Carlo techniques. The applicability of this method for extended-release formulation development is evaluated by analyzing a dataset of Bydureon, an injectable extended-release suspension formulation of exenatide, a GLP-1 receptor agonist for treating diabetes. This drug is known to have non-linear pharmacokinetics. Its plasma concentration profile exhibits multiple peaks, something that can make parametric modeling challenging, but poses no major difficulties for non-parametric methods. The method is also validated on synthetic data, exploring the effects of sampling and noise on the accuracy of the estimates

Network information and connected correlations

Entropy and information provide natural measures of correlation among elements in a network. We construct here the information theoretic analog of connected correlation functions: irreducible $N$--point correlation is measured by a decrease in entropy for the joint distribution of $N$ variables relative to the maximum entropy allowed by all the observed $N-1$ variable distributions. We calculate the ``connected information'' terms for several examples, and show that it also enables the decomposition of the information that is carried by a population of elements about an outside source.Comment: 4 pages, 3 figure

Etiology, risk factors and sex differences in ischemic stroke in the Ludwigshafen stroke study, a population-based stroke registry

Background: Stroke etiology in ischemic stroke guides preventive measures and etiological stroke subgroups may show considerable differences between both sexes. In a population-based stroke registry we analyzed etiological subgroups of ischemic stroke and calculated sex-specific incidence and mortality rates. Methods: The Ludwigshafen Stroke Study is a prospective ongoing population-based stroke registry. Multiple overlapping methods of case ascertainment were used to identify all patients with incident stroke or transient ischemic attack. Modified TOAST ( Trial of Org 10172 in Acute Stroke Treatment) criteria were applied for subgroup analysis in ischemic stroke. Results: Out of 626 patients with first-ever ischemic stroke in 2006 and 2007, women (n = 327) were older (73.5 8 12.6 years) than men (n = 299; 69.7 8 11.5 years; p < 0.001). The age-adjusted incidence rate of ischemic stroke was significantly higher in men (1.37; 95% CI 1.20–1.56) than in women (1.12; 95% CI 0.97–1.29; p = 0.04). Cardioembolism (n = 219; 35.0%), smallartery occlusion (n = 164; 26.2%), large-artery atherosclerosis (n = 98; 15.7%) and ‘probable atherothrombotic stroke’ (n = 84; 13.4%) were common subgroups of ischemic stroke. Stroke due to large-artery atherosclerosis (p = 0.025), current smoking (p = 0.008), history of smoking (p 85 years) was detected. Conclusions: Cardioembolism is the main source for ischemic stroke in our population. Etiology of ischemic stroke differs between sexes, with large-artery atherosclerotic stroke and associated diseases (coronary artery disease and peripheral artery disease) being more common in men

Protein phosphatase 2A plays a crucial role in Giardia lamblia differentiation

Author Posting. © The Authors, 2006. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Molecular and Biochemical Parasitology 152 (2007): 80-89, doi:10.1016/j.molbiopara.2006.12.001.The ability of Giardia lamblia to undergo two distinct differentiations in response to physiologic stimuli is central to its pathogenesis. The giardial cytoskeleton changes drastically during encystation and excystation. However, the signal transduction pathways mediating these transformations are poorly understood. We tested the hypothesis that PP2A, a highly conserved serine/threonine protein phosphatase, might be important in giardial differentiation. We found that in vegetatively growing trophozoites, gPP2A-C protein localizes to basal bodies/centrosomes, and to cytoskeletal structures unique to Giardia: the ventral disk, and the dense rods of the anterior, posterior-lateral, and caudal flagella. During encystation, gPP2A-C protein disappears from only the anterior flagellar dense rods. During excystation, gPP2A-C localizes to the cyst wall in excysting cysts but is not found in the wall of cysts with emerging excyzoites. Transcriptome and immunoblot analyses indicated that gPP2A-C mRNA and protein are upregulated in mature cysts and during the early stage of excystation that models passage through the host stomach. Stable expression of gPP2A-C antisense RNA did not affect vegetative growth, but strongly inhibited the formation of encystation secretory vesicles (ESV) and water-resistant cysts. Moreover, the few cysts that formed were highly defective in excystation. Thus, gPP2A-C localizes to universal cytoskeletal structures and to structures unique to Giardia. It is also important for encystation and excystation, crucial giardial transformations that entail entry into and exit from dormancy.This work was funded by NIH grants GM61896, AI51687, AI42488, and DK35108. Dr. A.G. McArthur was supported by NIH grant AI51089 and the Marine Biological Laboratory’s Program in Global Infectious Diseases, funded by the Ellison Medical Foundation

A new measurement for posterior tilt predicts reoperation in undisplaced femoral neck fractures: 113 consecutive patients treated by internal fixation and followed for 1 year

Background and purpose Preoperative posterior tilt in undisplaced (Garden I–II) femoral neck fractures is thought to influence rates of reoperation. However, an exact method for its measurement has not yet been presented. We designed a new measurement for posterior tilt on preoperative lateral radiographs and investigated its association with later reoperation

Interferences on aerosol acidity quantification due to gas-phase ammonia uptake onto acidic sulfate filter samples

Measurements of the mass concentration and chemical speciation of aerosols are important to investigate their chemical and physical processing from near emission sources to the most remote regions of the atmosphere. A common method to analyze aerosols is to collect them onto filters and analyze the filters offline; however, biases in some chemical components are possible due to changes in the accumulated particles during the handling of the samples. Any biases would impact the measured chemical composition, which in turn affects our understanding of numerous physicochemical processes and aerosol radiative properties. We show, using filters collected onboard the NASA DC-8 and NSF C-130 during six different aircraft campaigns, a consistent, substantial difference in ammonium mass concentration and ammonium-to-anion ratios when comparing the aerosols collected on filters versus an Aerodyne aerosol mass spectrometer (AMS). Another online measurement is consistent with the AMS in showing that the aerosol has lower ammonium-to-anion ratios than obtained by the filters. Using a gas uptake model with literature values for accommodation coefficients, we show that for ambient ammonia mixing ratios greater than 10 ppbv, the timescale for ammonia reacting with acidic aerosol on filter substrates is less than 30 s (typical filter handling time in the aircraft) for typical aerosol volume distributions. Measurements of gas-phase ammonia inside the cabin of the DC-8 show ammonia mixing ratios of 45±20 ppbv, consistent with mixing ratios observed in other indoor environments. This analysis enables guidelines for filter handling to reduce ammonia uptake. Finally, a more meaningful limit of detection for University of New Hampshire Soluble Acidic Gases and Aerosol (SAGA) filters collected during airborne campaigns is ∼0.2 µg sm−3 of ammonium, which is substantially higher than the limit of detection of ion chromatography. A similar analysis should be conducted for filters that collect inorganic aerosol and do not have ammonia scrubbers and/or are handled in the presence of human ammonia emissions

Transcriptome analyses of the Giardia lamblia life cycle

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Molecular and Biochemical Parasitology 174 (2010): 62-65, doi:10.1016/j.molbiopara.2010.05.010.We quantified mRNA abundance from 10 stages in the Giardia lamblia life cycle in vitro using Serial Analysis of Gene Expression (SAGE). 163 abundant transcripts were expressed constitutively. 71 transcripts were upregulated specifically during excystation and 42 during encystation. Nonetheless, the transcriptomes of cysts and trophozoites showed major differences. SAGE detected co-expressed clusters of 284 transcripts differentially expressed in cysts and excyzoites and 287 transcripts in vegetative trophozoites and encysting cells. All clusters included known genes and pathways as well as proteins unique to Giardia or diplomonads. SAGE analysis of the Giardia life cycle identified a number of kinases, phosphatases, and DNA replication proteins involved in excystation and encystation, which could be important for examining the roles of cell signaling in giardial differentiation. Overall, these data pave the way for directed gene discovery and a better understanding of the biology of Giardia lamblia.BJD, DSR, and FDG were supported by NIH grants AI42488, GM61896, DK35108, and AI051687. DP and SGS were supported by grants from the Swedish Natural Science Research Council, the Swedish Medical Research Council, and the Karolinska Institutet. AGM, SRB, SPP, and MJC were supported by NIH grant AI51089 and by the Marine Biological Laboratory’s Program in Global Infectious Diseases, funded by the Ellison Medical Foundation

Simultaneous identification of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis ‒ multicenter evaluation of the Alinity m STI assay

Abstract Objectives Accurate and rapid diagnosis of sexually transmitted infections (STIs) is essential for timely administration of appropriate treatment and reducing the spread of the disease. We examined the performance of the new Alinity m STI assay, a qualitative real-time multiplex PCR test for simultaneous identification of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), and Trichomonas vaginalis (TV) run on the fully automated Alinity m platform. Methods This international, multicenter study evaluated the accuracy, reproducibility, and clinical performance of the Alinity m STI assay compared to commonly used STI assays in a large series of patient samples encountered in clinical practice. Results The Alinity m STI assay identified accurately and precisely single and mixed pathogens from an analytical panel of specimens. The Alinity m STI assay demonstrated high overall agreement rates with comparator STI assays (99.6% for CT [n=2,127], 99.2% for NG [n=2,160], 97.1% for MG [n=491], and 99.4% for TV [n=313]). Conclusions The newly developed Alinity m STI assay accurately detects the 4 sexually transmitted target pathogens in various collection devices across clinically relevant specimen types, regardless of single or mixed infection status

Improved molecular laboratory productivity by consolidation of testing on the new random-access analyzer Alinity m

Abstract Objectives Automated molecular analyzers have accelerated diagnosis, allowing earlier intervention and better patient follow-up. A recently developed completely automated molecular analyzer, Alinity™ m (Abbott), offers consolidated, continuous, and random-access testing that may improve molecular laboratory workflow. Methods An international, multicenter study compared laboratory workflow metrics across various routine analyzers and Alinity m utilizing assays for human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV), hepatitis B virus (HBV), high-risk human papillomavirus (HR HPV), and sexually transmitted infection (STI) (Chlamydia trachomatis [CT]/Neisseria gonorrhoeae [NG]/Trichomonas vaginalis [TV]/Mycoplasma genitalium [MG]). Three turnaround times (TATs) were assessed: total TAT (sample arrival to result), sample onboard TAT (sample loading and test starting to result), and processing TAT (sample aspiration to result). Results Total TAT was reduced from days with routine analyzers to hours with Alinity m, independent of requested assays. Sample onboard TATs for standard workflow using routine analyzers ranged from 7 to 32.5 h compared to 2.75–6 h for Alinity m. The mean sample onboard TAT for STAT samples on Alinity m was 2.36 h (±0.19 h). Processing TATs for Alinity m were independent of the combination of assays, with 100% of results reported within 117 min. Conclusions The consolidated, continuous, random-access workflow of Alinity m reduces TATs across various assays and is expected to improve both laboratory operational efficiency and patient care