Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models

The use of in silico tools within the drug development process to predict a wide range of properties including absorption, distribution, metabolism, elimination and toxicity has become increasingly important due to changes in legislation and both ethical and economic drivers to reduce animal testing. Whilst in silico tools have been used for decades there remains reluctance to accept predictions based on these methods particularly in regulatory settings. This apprehension arises in part due to lack of confidence in the reliability, robustness and applicability of the models. To address this issue we propose a scheme for the verification of in silico models that enables end users and modellers to assess the scientific validity of models in accordance with the principles of good computer modelling practice. We report here the implementation of the scheme within the Innovative Medicines Initiative project “eTOX” (electronic toxicity) and its application to the in silico models developed within the frame of this project

Factors associated with alcohol reduction in harmful and hazardous drinkers following alcohol brief intervention in Scotland: a qualitative enquiry

Background: Alcohol Brief Intervention (ABI) uses a motivational counselling approach to support individuals to reduce excessive alcohol consumption. There is growing evidence on ABI’s use within various health care settings, although how they work and which components enhance success is largely unknown. This paper reports on the qualitative part of a mixed methods study. It explores enablers and barriers associated with alcohol reduction following an ABI. It focuses on alcohol’s place within participants’ lives and their personal perspectives on reducing consumption. There are a number of randomised controlled trials in this field though few ABI studies have addressed the experiences of hazardous/harmful drinkers. This study examines factors associated with alcohol reduction in harmful/hazardous drinkers following ABI. Methods: This qualitative study was underpinned by a realist evaluation approach and involved semistructured interviews with ten harmful or hazardous alcohol drinkers. Participants (n = 10) were from the intervention arm of a randomised controlled trial (n = 124). All had received ABI, a 20 min motivational counselling interview, six months previously, and had reduced their alcohol consumption. Interviews were recorded, transcribed verbatim and thematically analysed. Results: Participants described their views on alcohol, its’ place in their lives, their personal perspectives on reducing their consumption and future aspirations. Conclusions: The findings provide an insight into participants’ views on alcohol, ABI, and the barriers and enablers to change. Participants described a cost benefit analysis, with some conscious consideration of the advantages and disadvantages of reducing intake or abstaining from alcohol. Findings suggest that, whilst hospital admission can act as a catalyst, encouraging individuals to reflect on their alcohol consumption through ABI may consolidate this, turning this reflective moment into action. Sustainability may be enhanced by the presence of a ‘significant other’ who encourages and experiences benefit. In addition having a purpose or structure with activities linked to employment and/or social and leisure pursuits offers the potential to enhance and sustain reduced alcohol consumption. Trial registration: Trial registration number TRN NCT00982306 September 22nd 200

Multidimensional sexual perfectionism and female sexual function: A longitudinal investigation

Research on multidimensional sexual perfectionism differentiates four forms of sexual perfectionism: self-oriented, partner-oriented, partner-prescribed, and socially prescribed. Self-oriented sexual perfectionism reflects perfectionistic standards people apply to themselves as sexual partners; partner-oriented sexual perfectionism reflects perfectionistic standards people apply to their sexual partner; partner-prescribed sexual perfectionism reflects people’s beliefs that their sexual partner imposes perfectionistic standards on them; and socially prescribed sexual perfectionism reflects people’s beliefs that society imposes such standards on them. Previous studies found partner-prescribed and socially prescribed sexual perfectionism to be maladaptive forms of sexual perfectionism associated with a negative sexual self-concept and problematic sexual behaviors, but only examined cross-sectional relationships. The present article presents the first longitudinal study examining whether multidimensional sexual perfectionism predicts changes in sexual self-concept and sexual function over time. A total of 366 women aged 17-69 years completed measures of multidimensional sexual perfectionism, sexual esteem, sexual anxiety, sexual problem self-blame, and female sexual function (cross-sectional data). Three to six months later, 164 of the women completed the same measures again (longitudinal data). Across analyses, partner-prescribed sexual perfectionism emerged as the most maladaptive form of sexual perfectionism. In the cross-sectional data, partner-prescribed sexual perfectionism showed positive relationships with sexual anxiety, sexual problem self-blame, and intercourse pain and negative relationships with sexual esteem, desire, arousal, lubrication, and orgasmic function. In the longitudinal data, partner-prescribed sexual perfectionism predicted increases in sexual anxiety and decreases in sexual esteem, arousal, and lubrication over time. The findings suggest that partner-prescribed sexual perfectionism contributes to women’s negative sexual self-concept and female sexual dysfunction

The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease

DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis

RATIONALE: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge of epigenetics of AMs in IPF are limited. METHODS: We undertook DNA methylation profiling using Illumina EPIC (850k) arrays in sorted AMs from Healthy (n=14) and IPF (n=30) donors. Cell-type deconvolution was performed using reference myeloid-cell DNA methylomes. MEASUREMENTS AND MAIN RESULTS: Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF-AMs. DNAm 'clock' analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKFB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. CONCLUSIONS: Collectively, our data identify that changes in the epigenome are associated with development and function of AMs in the IPF lung

Morbidity, life style and psychosocial situation in cancer survivors aged 60-69 years: results from The Nord-Trøndelag Health Study (The HUNT-II Study)

<p>Abstract</p> <p>Background</p> <p>Due to considerable health status differences in the elderly population, research limited to narrow age-spans might be an advantage. In this population-based controlled study we compare short-term (<5 years) (STS) and long-term (≥5 years) (LTS) cancer survivors and cancer-free controls aged 60-69 years from two Norwegian health registers; the Health Survey of North-Trøndelag County (HUNT-2 study) and the Cancer Registry of Norway (CRN). We examined possible factors associated with being cancer survivor.</p> <p>Methods</p> <p>Among 9,089 individuals aged 60-69 who participated in HUNT-2, 334 had been diagnosed with invasive primary cancer from 1 month to 42 years before HUNT-2 according to CRN and self-report. An overall random sample of controls without cancer five times larger than the sample of cases (N = 1,670) were drawn from the parent cohort.</p> <p>Results</p> <p>The cancer sample comprised 128 STS and 206 LTS. For most variables no significant differences were observed between LTS and STS. LTS were significantly more women, and cases with gynaecological cancer, with physical impairment and more thyroid diseases compared to STS. When comparing all the survivors with controls, the survivors showed significantly higher rate of pensioning, decreased self-rated health, more physical impairment and thyroid diseases, daily use of medication and psychotropics and higher level of anxiety and Framingham Risk score. Multivariate logistic regression analysis showed that increasing age, being female, physical impairment and thyroid diseases all were significantly associated with being survivor versus controls.</p> <p>Conclusion</p> <p>STS and LTS showed mostly similar situation. Compared to controls, the survivors reported somewhat poorer physical and mental health, but these differences were of doubtful clinical significance.</p

A Self-Consistent Model for Positronium Formation from Helium Atoms

The differential and total cross sections for electron capture by positrons from helium atoms are calculated using a first-order distorted wave theory satisfying the Coulomb boundary conditions. In this formalism a parametric potential is used to describe the electron screening in a consistent and realistic manner. The present procedure is self consistent because (i) it satisfies the correct boundary conditions and post-prior symmetry, and (ii) the potential and the electron binding energies appearing in the transition amplitude are consistent with the wave functions describing the collision system. The results are compared with the other theories and with the available experimental measurements. At the considered range of collision energies, the results agree reasonably well with recent experiments and theories. [Note: This paper will be published on volume 42 of the Brazilian Journal of Physics

The molecular characterisation of Escherichia coli K1 isolated from neonatal nasogastric feeding tubes

Background: The most common cause of Gram-negative bacterial neonatal meningitis is E. coli K1. It has a mortality rate of 10–15%, and neurological sequelae in 30– 50% of cases. Infections can be attributable to nosocomial sources, however the pre-colonisation of enteral feeding tubes has not been considered as a specific risk factor. Methods: Thirty E. coli strains, which had been isolated in an earlier study, from the residual lumen liquid and biofilms of neonatal nasogastric feeding tubes were genotyped using pulsed-field gel electrophoresis, and 7-loci multilocus sequence typing. Potential pathogenicity and biofilm associated traits were determined using specific PCR probes, genome analysis, and in vitro tissue culture assays. Results: The E. coli strains clustered into five pulsotypes, which were genotyped as sequence types (ST) 95, 73, 127, 394 and 2076 (Achman scheme). The extra-intestinal pathogenic E. coli (ExPEC) phylogenetic group B2 ST95 serotype O1:K1:NM strains had been isolated over a 2 week period from 11 neonates who were on different feeding regimes. The E. coli K1 ST95 strains encoded for various virulence traits associated with neonatal meningitis and extracellular matrix formation. These strains attached and invaded intestinal, and both human and rat brain cell lines, and persisted for 48 h in U937 macrophages. E. coli STs 73, 394 and 2076 also persisted in macrophages and invaded Caco-2 and human brain cells, but only ST394 invaded rat brain cells. E. coli ST127 was notable as it did not invade any cell lines. Conclusions: Routes by which E. coli K1 can be disseminated within a neonatal intensive care unit are uncertain, however the colonisation of neonatal enteral feeding tubes may be one reservoir source which could constitute a serious health risk to neonates following ingestion