Patient-centred pharmaceutical design to improve acceptability of medicines : similarities and differences in paediatric and geriatric populations

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populationsPeer reviewedFinal Published versio

Is the squeezing of relic gravitational waves produced by inflation detectable?

Grishchuk has shown that the stochastic background of gravitational waves produced by an inflationary phase in the early Universe has an unusual property: it is not a stationary Gaussian random process. Due to squeezing, the phases of the different waves are correlated in a deterministic way, arising from the process of parametric amplification that created them. The resulting random process is Gaussian but non-stationary. This provides a unique signature that could in principle distinguish a background created by inflation from stationary stochastic backgrounds created by other types of processes. We address the question: could this signature be observed with a gravitational wave detector? Sadly, the answer appears to be "no": an experiment which could distinguish the non-stationary behavior would have to last approximately the age of the Universe at the time of measurement. This rules out direct detection by ground and space based gravitational wave detectors, but not indirect detections via the electromagnetic Cosmic Microwave Background Radiation (CMBR).Comment: 17 pages, 4 Postscript figures, uses revtex, psfig, to be submitted to PRD, minor revisions - appendix B clarified, corrected typos, added reference

Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. Objectives: To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods: Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 µmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. Conclusion: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations

Facilitators and Barriers to Prescribing PreExposure Prophylaxis (PrEP) for the Prevention of HIV

Background: What is PrEP and who gets it? PrEP is the use of medication by individuals to prevent HIV contraction, approved in 2012 after demonstrating safety and efficacy in the iPrEx study and Partners PrEP2 trials. HIV infection risk is 92% lower in patients using PrEP. Truvada®, a combination of tenofovir and emtricitabine taken orally daily, is the only approved PrEP regimen and is intended to compliment other prevention strategies such as condoms. HIV negative-individuals at risk for exposure to HIV have been identified as men who have sex with men (MSM), IV drug users, heterosexuals who have unprotected sex with partners of unknown HIV status, and those in serodiscordant relationships. Barriers to PrEP Implementation PrEP is effective when patients adhere; however, both the medical community and some high-risk populations have been slow to adopt it as an HIV prevention strategy. Surveys have shown clinicians perceived barriers to PrEP such as adverse side effects, viral drug resistance, increased high-risk behavior, cost, and training. HIV in Vermont New diagnoses of HIV among Vermont residents has remained relatively stable over the last twenty years. Vermont CARES, a non-profit, offers free and anonymous HIV tests and in-person risk-reduction counseling. Clients are increasingly asking about PrEP as a prevention strategy, but the response from the medical community is difficult to ascertain.https://scholarworks.uvm.edu/comphp_gallery/1235/thumbnail.jp

Abstract Interpretation with Unfoldings

We present and evaluate a technique for computing path-sensitive interference conditions during abstract interpretation of concurrent programs. In lieu of fixed point computation, we use prime event structures to compactly represent causal dependence and interference between sequences of transformers. Our main contribution is an unfolding algorithm that uses a new notion of independence to avoid redundant transformer application, thread-local fixed points to reduce the size of the unfolding, and a novel cutoff criterion based on subsumption to guarantee termination of the analysis. Our experiments show that the abstract unfolding produces an order of magnitude fewer false alarms than a mature abstract interpreter, while being several orders of magnitude faster than solver-based tools that have the same precision.Comment: Extended version of the paper (with the same title and authors) to appear at CAV 201

Measuring gravitational waves from binary black hole coalescences: II. the waves' information and its extraction, with and without templates

We discuss the extraction of information from detected binary black hole (BBH) coalescence gravitational waves, focusing on the merger phase that occurs after the gradual inspiral and before the ringdown. Our results are: (1) If numerical relativity simulations have not produced template merger waveforms before BBH detections by LIGO/VIRGO, one can band-pass filter the merger waves. For BBHs smaller than about 40 solar masses detected via their inspiral waves, the band pass filtering signal to noise ratio indicates that the merger waves should typically be just barely visible in the noise for initial and advanced LIGO interferometers. (2) We derive an optimized (maximum likelihood) method for extracting a best-fit merger waveform from the noisy detector output; one "perpendicularly projects" this output onto a function space (specified using wavelets) that incorporates our prior knowledge of the waveforms. An extension of the method allows one to extract the BBH's two independent waveforms from outputs of several interferometers. (3) If numerical relativists produce codes for generating merger templates but running the codes is too expensive to allow an extensive survey of the merger parameter space, then a coarse survey of this parameter space, to determine the ranges of the several key parameters and to explore several qualitative issues which we describe, would be useful for data analysis purposes. (4) A complete set of templates could be used to test the nonlinear dynamics of general relativity and to measure some of the binary parameters. We estimate the number of bits of information obtainable from the merger waves (about 10 to 60 for LIGO/VIRGO, up to 200 for LISA), estimate the information loss due to template numerical errors or sparseness in the template grid, and infer approximate requirements on template accuracy and spacing.Comment: 33 pages, Rextex 3.1 macros, no figures, submitted to Phys Rev

Stochastic Background Search Correlating ALLEGRO with LIGO Engineering Data

We describe the role of correlation measurements between the LIGO interferometer in Livingston, LA, and the ALLEGRO resonant bar detector in Baton Rouge, LA, in searches for a stochastic background of gravitational waves. Such measurements provide a valuable complement to correlations between interferometers at the two LIGO sites, since they are sensitive in a different, higher, frequency band. Additionally, the variable orientation of the ALLEGRO detector provides a means to distinguish gravitational wave correlations from correlated environmental noise. We describe the analysis underway to set a limit on the strength of a stochastic background at frequencies near 900 Hz using ALLEGRO data and data from LIGO's E7 Engineering Run.Comment: 8 pages, 2 encapsulated PostScript figures, uses IOP class files, submitted to the proceedings of the 7th Gravitational Wave Data Analysis Workshop (which will be published in Classical and Quantum Gravity