A new method for the reproducible generation of polymorphs: two forms of sulindac with very different solubilities

Polymorphism of drugs has been the subject of intense interest in the pharmaceutical industry for over forty years. Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, colour, filterability, density, flow properties, and many other properties. The difference in solubility is particularly important for pharmaceuticals, as it can affect drug efficacy, bioavailability and safety. Despite significant investment in processes to find all the possible polymorphs of active pharmaceutical ingredients (APIs), new polymorphs can suddenly appear without warning. Polymorphs tend to convert spontaneously from less stable to more stable forms, and, therefore, it is best to discover and characterize the stable form as early as possible. Ideally the most stable polymorph will be found while the drug candidate is still in the discovery process, so that this is the form used for subsequent testing. The most stable polymorph will be the least soluble and solubility may be a limiting factor in the efficacy of the API. Despite the huge importance of polymorphism in the properties of materials, however, there is no method that can produce all the stable polymorphs of a compound, or even one that can provide confidence that the most stable polymorph has been obtained. Here we describe a new method, `potentiometric cycling for polymorph creation (PC)2', which is able to generate the most stable polymorph in aqueous solution. This new method has been applied to sulindac, a non-steroidal anti-inflammatory drug, which also shows promise in anticancer treatment, producing two polymorphs of this API, including a new more stable one. By adjusting the conditions, this method is able to produce either polymorph exclusively.</jats:p

Multi-locus Test Conditional on Confirmed Effects Leads to Increased Power in Genome-wide Association Studies

Complex diseases or phenotypes may involve multiple genetic variants and interactions between genetic, environmental and other factors. Current genome-wide association studies (GWAS) mostly used single-locus analysis and had identified genetic effects with multiple confirmations. Such confirmed single-nucleotide polymorphism (SNP) effects were likely to be true genetic effects and ignoring this information in testing new effects of the same phenotype results in decreased statistical power due to increased residual variance that has a component of the omitted effects. In this study, a multi-locus association test (MLT) was proposed for GWAS analysis conditional on SNPs with confirmed effects to improve statistical power. Analytical formulae for statistical power were derived and were verified by simulation for MLT accounting for confirmed SNPs and for single-locus test (SLT) without accounting for confirmed SNPs. Statistical power of the two methods was compared by case studies with simulated and the Framingham Heart Study (FHS) GWAS data. Results showed that the MLT method had increased statistical power over SLT. In the GWAS case study on four cholesterol phenotypes and serum metabolites, the MLT method improved statistical power by 5% to 38% depending on the number and effect sizes of the conditional SNPs. For the analysis of HDL cholesterol (HDL-C) and total cholesterol (TC) of the FHS data, the MLT method conditional on confirmed SNPs from GWAS catalog and NCBI had considerably more significant results than SLT

Optimizing substitution matrix choice and gap parameters for sequence alignment

<p>Abstract</p> <p>Background</p> <p>While substitution matrices can readily be computed from reference alignments, it is challenging to compute optimal or approximately optimal gap penalties. It is also not well understood which substitution matrices are the most effective when alignment accuracy is the goal rather than homolog recognition. Here a new parameter optimization procedure, POP, is described and applied to the problems of optimizing gap penalties and selecting substitution matrices for pair-wise global protein alignments.</p> <p>Results</p> <p>POP is compared to a recent method due to Kim and Kececioglu and found to achieve from 0.2% to 1.3% higher accuracies on pair-wise benchmarks extracted from BALIBASE. The VTML matrix series is shown to be the most accurate on several global pair-wise alignment benchmarks, with VTML200 giving best or close to the best performance in all tests. BLOSUM matrices are found to be slightly inferior, even with the marginal improvements in the bug-fixed RBLOSUM series. The PAM series is significantly worse, giving accuracies typically 2% less than VTML. Integer rounding is found to cause slight degradations in accuracy. No evidence is found that selecting a matrix based on sequence divergence improves accuracy, suggesting that the use of this heuristic in CLUSTALW may be ineffective. Using VTML200 is found to improve the accuracy of CLUSTALW by 8% on BALIBASE and 5% on PREFAB.</p> <p>Conclusion</p> <p>The hypothesis that more accurate alignments of distantly related sequences may be achieved using low-identity matrices is shown to be false for commonly used matrix types. Source code and test data is freely available from the author's web site at <url>http://www.drive5.com/pop</url>.</p

Observed Reductions in Schistosoma mansoni Transmission from Large-Scale Administration of Praziquantel in Uganda: A Mathematical Modelling Study

To date schistosomiasis control programmes based on chemotherapy have largely aimed at controlling morbidity in treated individuals rather than at suppressing transmission. In this study, a mathematical modelling approach was used to estimate reductions in the rate of Schistosoma mansoni reinfection following annual mass drug administration (MDA) with praziquantel in Uganda over four years (2003-2006). In doing this we aim to elucidate the benefits of MDA in reducing community transmission.Age-structured models were fitted to a longitudinal cohort followed up across successive rounds of annual treatment for four years (Baseline: 2003, TREATMENT: 2004-2006; n = 1,764). Instead of modelling contamination, infection and immunity processes separately, these functions were combined in order to estimate a composite force of infection (FOI), i.e., the rate of parasite acquisition by hosts.MDA achieved substantial and statistically significant reductions in the FOI following one round of treatment in areas of low baseline infection intensity, and following two rounds in areas with high and medium intensities. In all areas, the FOI remained suppressed following a third round of treatment.This study represents one of the first attempts to monitor reductions in the FOI within a large-scale MDA schistosomiasis morbidity control programme in sub-Saharan Africa. The results indicate that the Schistosomiasis Control Initiative, as a model for other MDA programmes, is likely exerting a significant ancillary impact on reducing transmission within the community, and may provide health benefits to those who do not receive treatment. The results obtained will have implications for evaluating the cost-effectiveness of schistosomiasis control programmes and the design of monitoring and evaluation approaches in general

Disparities in self-reported postpartum depression among Asian, Hawaiian, and Pacific Islander women in Hawai‘i: Pregnancy, Risk, Assessment, and Monitoring System (PRAMS), 2004-2007

Postpartum depression affects 10–20% of women and causes significant morbidity and mortality among mothers, children, families, and society, but little is known about postpartum depression among the individual Asian and Pacific Islander racial/ethnic groups. This study sought to identify the prevalence of postpartum depression among common Asian and Pacific Islander racial/ethnic groups. Data from the Hawaii Pregnancy Risk Assessment and Monitoring System (PRAMS), a population-based surveillance system on maternal behaviors and experiences before, during, and after the birth of a live infant, were analyzed from 2004 through 2007 and included 7,154 women. Questions on mood and interest in activities since giving birth were combined to create a measure of Self-reported Postpartum Depressive Symptoms (SRPDS). A series of generalized logit models with maternal race or ethnicity adjusted for other sociodemographic characteristics evaluated associations between SRPDS and an intermediate level of symptoms as possible indicators of possible SRPDS. Of all women in Hawaii with a recent live birth, 14.5% had SRPDS, and 30.1% had possible SRPDS. The following Asian and Pacific Islander racial or ethnic groups were studied and found to have higher odds of SRPDS compared with white women: Korean (adjusted odds ratio [AOR] = 2.8;95% confidence interval [CI]: 2.0–4.0), Filipino (AOR = 2.2;95% CI: 1.7–2.8), Chinese (AOR = 2.0;95% CI: 1.5–2.7), Samoan (AOR = 1.9;95% CI: 1.2–3.2), Japanese (AOR = 1.6;95% CI: 1.2–2.2), Hawaiian (AOR = 1.7;95% CI: 1.3–2.1), other Asian (AOR = 3.3;95% CI: 1.9–5.9), other Pacific Islander (AOR = 2.2;95% CI: 1.5–3.4), and Hispanic (AOR = 1.9;95% CI: 1.1–3.4). Women who had unintended pregnancies (AOR = 1.4;95% CI: 1.2–1.6), experienced intimate partner violence (AOR = 3.7;95% CI: 2.6–5.5), smoked (AOR = 1.5;95% CI: 1.2–2.0), used illicit drugs (AOR = 1.9;95% CI: 1.3–3.9), or received Women, Infant, and Children (WIC) benefits during pregnancy (AOR = 1.4;95% CI: 1.2–2.6) were more likely to have SRPDS. Several groups also were at increased risk for possible SRPDS, although this risk was not as prominent as seen with the risk for SRPDS. One in seven women reported SRPDS, and close to a third reported possible SRPDS. Messages about postpartum depression should be incorporated into current programs to improve screening, treatment, and prevention of SRPDS for women at risk

Greenland ice sheet surface mass loss: recent developments in observation and modeling

Surface processes currently dominate Greenland ice sheet (GrIS) mass loss. We review recent developments in the observation and modelling of GrIS surface mass balance (SMB), published after the July 2012 deadline for the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5). Since IPCC AR5 our understanding of GrIS SMB has further improved, but new observational and model studies have also revealed that temporal and spatial variability of many processes are still poorly quantified and understood, e.g. bio-albedo, the formation of ice lenses and their impact on lateral meltwater transport, heterogeneous vertical meltwater transport (‘piping’), the impact of atmospheric circulation changes and mixed-phase clouds on the surface energy balance and the magnitude of turbulent heat exchange over rough ice surfaces. As a result, these processes are only schematically or not at all included in models that are currently used to assess and predict future GrIS surface mass loss

An Integrated Approach for the Analysis of Biological Pathways using Mixed Models

Gene class, ontology, or pathway testing analysis has become increasingly popular in microarray data analysis. Such approaches allow the integration of gene annotation databases, such as Gene Ontology and KEGG Pathway, to formally test for subtle but coordinated changes at a system level. Higher power in gene class testing is gained by combining weak signals from a number of individual genes in each pathway. We propose an alternative approach for gene-class testing based on mixed models, a class of statistical models that

Conformism in the food processing techniques of white-faced capuchin monkeys (Cebus capucinus)

Researchers of “culture” have long been interested in the role of social learning in establishing patterns of behavioral variation in wild animals, but very few studies examine this issue using a developmental approach. This 7-year study examines the acquisition of techniques used to process Luehea candida fruits in a wild population of white-faced capuchin monkeys, Cebus capucinus, residing in and near Lomas Barbudal Biological Reserve, Costa Rica. The two techniques for extracting seeds (pounding or scrubbing) were approximately equal in efficiency, and subjects experimented with both techniques before settling on one technique—typically the one they most frequently observed. In a sample of 106 subjects that had already settled on a preferred technique, the females adopted the maternal technique significantly more often than expected by chance, but the males did not. Using a longitudinal approach, I examined the acquisition of Luehea processing techniques during the first 5 years of life. Regression analysis revealed that the technique most frequently observed (measured as proportion of Luehea processing bouts observed that used pounding as opposed to scrubbing) significantly predicted the technique adopted by female observers, particularly in the second year of life; the amount of impact of the observed technique on the practiced technique was somewhat less significant for male observers. These results held true for (a) observations of maternal technique only, (b) observations of technique used by all individuals other than the mother, and (c) observations of maternal and non-maternal techniques combined

How is the New Public Management applied in the occupational health care system? - decision-makers' and OH personnel's views in Finland

<p>Abstract</p> <p>Background</p> <p>In many countries occupational health care system is in change. Occupational health studies are mainly focused on occupational health substance and content. This study offers new perspectives on municipal OHS and its operations from management perspective.</p> <p>Aim</p> <p>The aim of this study is to analyse how New Public Management (NPM) doctrines are applied in the Finnish occupational health care system (OHS). The main focus is to describe and compare the views of decision-makers' and OH workers within the framework of NPM.</p> <p>Methods</p> <p>The data were collected by semi-structured interviews from 17 municipal decision-makers' and 26 municipal OH workers. Data was analyzed by examining coded data in a theory-driven way according to Hood's doctrine of NPM.</p> <p>Results</p> <p>The doctrines were not as compatible with the OH personnel view as with the decision-makers' view. Decision-makers and OH personnel highlighted the strict criteria required for operation evaluation. Moreover, decision-makers strongly accentuated professional management in the public sector and the reorganization of public sector units. These were not equally relevant in OH personnel views. In OH personnel views, other doctrines (more attention to performance and accomplishments, emphasizing and augmentation of the competition and better control of public expense and means test) were not similarly in evidence, only weak evidence was observed when their importance viewed as medium by decision-makers. Neither of the respondents group kept the doctrine of management models of the private sector relevant.</p> <p>Conclusions</p> <p>The NPM and Hoods doctrine fitted well with OH research. The doctrine brought out view differences and similarities between decision-makers and OH personnel. For example, policymakers highlighted more strongly the structural change by emphasizing professional management compared to OH personnel. The need for reorganization of municipal OH, regardless of different operational preconditions, was obvious for both decision-makers and OH personnel. The adaptation of more clarify management to a municipal context is not trouble-free. The municipality systemic structure, complex operational environment, and reconciliation of political and officer authority set challenges to management of municipalities.</p

Protection of Melanized Cryptococcus neoformans from Lethal Dose Gamma Irradiation Involves Changes in Melanin's Chemical Structure and Paramagnetism

Certain fungi thrive in highly radioactive environments including the defunct Chernobyl nuclear reactor. Cryptococcus neoformans (C. neoformans), which uses L-3,4-dihydroxyphenylalanine (L-DOPA) to produce melanin, was used here to investigate how gamma radiation under aqueous aerobic conditions affects the properties of melanin, with the aim of gaining insight into its radioprotective role. Exposure of melanized fungal cell in aqueous suspensions to doses of γ-radiation capable of killing 50 to 80% of the cells did not lead to a detectable loss of melanin integrity according to EPR spectra of melanin radicals. Moreover, upon UV-visible (Xe-lamp) illumination of melanized cells, the increase in radical population was unchanged after γ-irradiation. Gamma-irradiation of frozen cell suspensions and storage of samples for several days at 77 K however, produced melanin modification noted by a reduced radical population and reduced photoresponse. More direct evidence for structural modification of melanin came from the detection of soluble products with absorbance maxima near 260 nm in supernatants collected after γ-irradiation of cells and cell-free melanin. These products, which include thiobarbituric acid (TBA)-reactive aldehydes, were also generated by Fenton reagent treatment of cells and cell-free melanin. In an assay of melanin integrity based on the metal (Bi+3) binding capacity of cells, no detectable loss in binding was detected after γ-irradiation. Our results show that melanin in C. neoformans cells is susceptible to some damage by hydroxyl radical formed in lethal radioactive aqueous environments and serves a protective role in melanized fungi that involves sacrificial breakdown