Co-Processed Excipients for Dispersible Tablets–Part 1: Manufacturability

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr’s index ˂ 20), excellent tabletability (tensile strength > 3.0 MPa at 0.85 solid fraction), very low friability (< 1% after 15 min), rapid disintegration times (27–49 s) and produced dispersions of ideal fineness (< 250 μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients

Co-Processed Excipients for Dispersible Tablets—Part 2: Patient Acceptability

Palatability and patient acceptability are critical attributes of dispersible tablet formulation. Co-processed excipients could provide improved organoleptic profile due to rational choice of excipients and manufacturing techniques. The aim of this study was to identify the most suitable co-processed excipient to use within directly compressible dispersible tablet formulations. Nine excipients, selected based on successful manufacturability, were investigated in a randomised, preference and acceptability testing in 24 healthy adult volunteers. Excipients were classified in order of preference as follows (from most preferred): SmartEx QD100 > F-Melt Type C > F-Melt Type M > MicroceLac > Ludiflash > CombiLac > Pharmaburst 500 > Avicel HFE-102 > Avicel PH-102. Broad differences were identified in terms of acceptability, with SmartEx QD100 being ‘very acceptable’, F-Melt Type C, F-Melt Type M and MicroceLac being ‘acceptable’, Ludiflash, CombiLac and Pharmaburst 500 being ‘neutral’ and Avicel products being ‘very unacceptable’ based on ratings using 5-point hedonic scales. Organoleptic differences were ascribed to different composition and physical properties of excipients, resulting in dissimilar taste and mouth-feel. Excipients with particle size in water larger than 200-250 µm were considered poorly acceptable, which supports the use of this value as a threshold for maximum particle size of dispersible formulation. The most promising co-processed excipients for directly compressible dispersible tablets were successfully identified

No evidence for an association between the -36A>C phospholamban gene polymorphism and a worse prognosis in heart failure

Background: In Brazil, heart failure leads to approximately 25,000 deaths per year. Abnormal calcium handling is a hallmark of heart failure and changes in genes encoding for proteins involved in the re-uptake of calcium might harbor mutations leading to inherited cardiomyopathies. Phospholamban (PLN) plays a prime role in cardiac contractility and relaxation and mutations in the gene encoding PLN have been associated with dilated cardiomyopathy. In this study, our objective was to determine the presence of the -36A>C alteration in PLN gene in a Brazilian population of individuals with HF and to test whether this alteration is associated with heart failure or with a worse prognosis of patients with HF. Methods: We genotyped a cohort of 881 patients with HF and 1259 individuals from a cohort of individuals from the general population for the alteration -36A>C in the PLN gene. Allele and genotype frequencies were compared between groups (patients and control). In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotypic groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the -36A>C were compared regarding mortality incidence in HF patients. Results: No significant association was found between the study polymorphism and HF in our population. In addition, no association between PLN -36A>C polymorphism and demographic, clinical and functional characteristics and mortality incidence in this sample of HF patients was observed. Conclusion: Our data do not support a role for the PLN -36A>C alteration in modulating the heart failure phenotype, including its clinical course, in humans

A Survey on Continuous Time Computations

We provide an overview of theories of continuous time computation. These theories allow us to understand both the hardness of questions related to continuous time dynamical systems and the computational power of continuous time analog models. We survey the existing models, summarizing results, and point to relevant references in the literature

Career-Success Scale – A new instrument to assess young physicians' academic career steps

Background: Within the framework of a prospective cohort study of Swiss medical school graduates, a Career-Success Scale (CSS) was constructed in a sample of young physicians choosing different career paths in medicine. Furthermore the influence of personality factors, the participants' personal situation, and career related factors on their career success was investigated. Methods: 406 residents were assessed in terms of career aspired to, and their career progress. The Career-Success Scale, consisting of 7 items, was developed and validated, addressing objective criteria of academic career advancement. The influence of gender and career aspiration was investigated by a two-factorial analysis of variance, the relationships between personality factors, personal situation, career related factors and the Career-Success Scale by a multivariate linear regression analysis. Results: The unidimensional Career-Success Scale has an internal consistency of 0.76. It is significantly correlated at the bivariate level with gender, instrumentality, and all career related factors, particularly with academic career and received mentoring. In multiple regression, only gender, academic career, surgery as chosen specialty, and received mentoring are significant predictors. The highest values were observed in participants aspiring to an academic career, followed by those pursuing a hospital career and those wanting to run a private practice. Independent of the career aspired to, female residents have lower scores than their male colleagues. Conclusion: The Career-Success Scale proved to be a short, reliable and valid instrument to measure career achievements. As mentoring is an independent predictor of career success, mentoring programs could be an important instrument to specifically enhance careers of female physicians in academia

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients

[[abstract]]Background:Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients. Methods:Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m-2. The primary end point was disease-control rate (DCR). Results:Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5-43.1) and 7.3 (95% CI: 4.7-9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1-17.9) and 5.8 (95% CI: 1.4-10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1-2 local and/or allergic reactions. Conclusions:ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.British Journal of Cancer advance online publication, 31 August 2010; doi:10.1038/sj.bjc.6605856 www.bjcancer.com

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

The impact of gender and parenthood on physicians' careers - professional and personal situation seven years after graduation

BACKGROUND: The profile of the medical profession is changing in regard to feminization, attitudes towards the profession, and the lifestyle aspirations of young physicians. The issues addressed in this study are the careers of female and male physicians seven years after graduation and the impact of parenthood on career development. METHODS: Data reported originates from the fifth assessment (T5) of the prospective SwissMedCareer Study, beginning in 2001 (T1). At T5 in 2009, 579 residents (81.4% of the initial sample at T1) participated in the questionnaire survey. They were asked about occupational factors, career-related factors including specialty choice and workplace, work-life balance and life satisfaction. The impact of gender and parenthood on the continuous variables was investigated by means of multivariate and univariate analyses of variance; categorical variables were analyzed using Chi-square tests. RESULTS: Female physicians, especially those with children, have lower rates of employment and show lower values in terms of career success and career support experiences than male physicians. In addition, parenthood has a negative impact on these career factors. In terms of work-life balance aspired to, female doctors are less career-oriented and are more inclined to consider part-time work or to continue their professional career following a break to bring up a family. Parenthood means less career-orientation and more part-time orientation. As regards life satisfaction, females show higher levels of satisfaction overall, especially where friends, leisure activities, and income are concerned. Compared to their male colleagues, female physicians are less advanced in their specialty qualification, are less prone to choosing prestigious surgical fields, have a mentor less often, more often work at small hospitals or in private practice, aspire less often to senior hospital or academic positions and consider part-time work more often. Any negative impact on career path and advancement is exacerbated by parenthood, especially as far as women are concerned. CONCLUSION: The results of the present study reflect socially-rooted gender role stereotypes. Taking into account the feminization of medicine, special attention needs to be paid to female physicians, especially those with children. At an early stage of their career, they should be advised to be more proactive in seeking mentoring and career-planning opportunities. If gender equity in terms of career chances is to be achieved, special career-support measures will have to be provided, such as mentoring programs, role models, flexitime and flexible career structures

Critical Thinking in Nursing Education: Literature Review

The need for critical thinking in nursing has been accentuated in response to the rapidly changing health care environment. Nurses must think critically to provide effective care whilst coping with the expansion in role associated with the complexities of current health care systems. This literature review will present a history of inquiry into critical thinking and research to support the conclusion that critical thinking is necessary not only in the clinical practice setting, but also as an integral component of nursing education programs to promote the development of nurses’ critical thinking abilities. The aims of this paper are: (a) to review the literature on critical thinking; (b) to examine the dimensions of critical thinking; (c) to investigate the various critical thinking strategies for their appropriateness to enhance critical thinking in nurses, and; (d) to examine issues relating to evaluation of critical thinking skills in nursing.</ul