Filtration‐histogram based magnetic resonance texture analysis (Mrta) for the distinction of primary central nervous system lymphoma and glioblastoma

Primary central nervous system lymphoma (PCNSL) has variable imaging appearances, which overlap with those of glioblastoma (GBM), thereby necessitating invasive tissue diagnosis. We aimed to investigate whether a rapid filtration histogram analysis of clinical MRI data supports the distinction of PCNSL from GBM. Ninety tumours (PCNSL n = 48, GBM n = 42) were analysed using pre‐treatment MRI sequences (T1‐weighted contrast‐enhanced (T1CE), T2‐weighted (T2), and apparent diffusion coefficient maps (ADC)). The segmentations were completed with proprietary texture analysis software (TexRAD version 3.3). Filtered (five filter sizes SSF = 2–6 mm) and unfil-tered (SSF = 0) histogram parameters were compared using Mann‐Whitney U non‐parametric test-ing, with receiver operating characteristic (ROC) derived area under the curve (AUC) analysis for significant results. Across all (n = 90) tumours, the optimal algorithm performance was achieved using an unfiltered ADC mean and the mean of positive pixels (MPP), with a sensitivity of 83.8%, specificity of 8.9%, and AUC of 0.88. For subgroup analysis with >1/3 necrosis masses, ADC permit-ted the identification of PCNSL with a sensitivity of 96.9% and specificity of 100%. For T1CE‐derived regions, the distinction was less accurate, with a sensitivity of 71.4%, specificity of 77.1%, and AUC of 0.779. A role may exist for cross‐sectional texture analysis without complex machine learning models to differentiate PCNSL from GBM. ADC appears the most suitable sequence, especially for necrotic lesion distinction

HPV16 oncogene expression levels during early cervical carcinogenesis are determined by the balance of epigenetic chromatin modifications at the integrated virus genome.

In cervical squamous cell carcinomas, high-risk human papillomavirus (HRHPV) DNA is usually integrated into host chromosomes. Multiple integration events are thought to be present within the cells of a polyclonal premalignant lesion and the features that underpin clonal selection of one particular integrant remain poorly understood. We previously used the W12 model system to generate a panel of cervical keratinocyte clones, derived from cells of a low-grade premalignant lesion naturally infected with the major HRHPV type, HPV16. The cells were isolated regardless of their selective advantage and differed only by the site of HPV16 integration into the host genome. We used this resource to test the hypothesis that levels of HPV16 E6/E7 oncogene expression in premalignant cells are regulated epigenetically. We performed a comprehensive analysis of the epigenetic landscape of the integrated HPV16 DNA in selected clones, in which levels of virus oncogene expression per DNA template varied ~6.6-fold. Across the cells examined, higher levels of virus expression per template were associated with more open chromatin at the HPV16 long control region, together with greater loading of chromatin remodelling enzymes and lower nucleosome occupancy. There were higher levels of histone post-translational modification hallmarks of transcriptionally active chromatin and lower levels of repressive hallmarks. There was greater abundance of the active/elongating form of the RNA polymerase-II enzyme (RNAPII-Ser2P), together with CDK9, the component of positive transcription elongation factor b complex responsible for Ser2 phosphorylation. The changes observed were functionally significant, as cells with higher HPV16 expression per template showed greater sensitivity to depletion and/or inhibition of histone acetyltransferases and CDK9 and less sensitivity to histone deacetylase inhibition. We conclude that virus gene expression per template following HPV16 integration is determined through multiple layers of epigenetic regulation, which are likely to contribute to selection of individual cells during cervical carcinogenesis.This work was supported by Cancer Research UK (Programme Grant A13080); the Medical Research Council; The Pathological Society of Great Britain and Ireland (E.L.A.K.); and the Agency for Science, Technology and Research, Singapore (Q.Y.A).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/onc.2016.

Consumers as tutors – legitimate teachers?

BACKGROUND: The aim of this study was to research the feasibility of training mental health consumers as tutors for 4(th )year medical students in psychiatry. METHODS: A partnership between a consumer network and an academic unit in Psychological Medicine was formed to jointly develop a training package for consumer tutors and a curriculum in interviewing skills for medical students. Student attitudes to mental health consumers were measured pre and post the program. All tutorial evaluation data was analysed using univariate statistics. Both tutors and students evaluated the teaching program using a 4 point rating scale. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test. RESULTS: Consumer tutors were successfully trained and accredited as tutors and able to sustain delivery of tutorials over a 4 year period. The study found that whilst the medical students started with positive attitudes towards consumers prior to the program, there was a general trend towards improved attitude across all measures. Other outcomes for tutors and students (both positive and negative) are described. CONCLUSIONS: Consumer tutors along with professional tutors have a place in the education of medical students, are an untapped resource and deliver largely positive outcomes for students and themselves. Further possible developments are described

Is Incarceration a Contributor to Health Disparities? Access to Care of Formerly Incarcerated Adults

Despite the disproportionate prevalence of incarceration in communities of color, few studies have examined its contribution to health disparities. We examined whether a lifetime history of incarceration is associated with recent access to medical and dental care. We performed a secondary data analysis of the 2007 Los Angeles County Health Survey, a population-based random-digit-dialing telephone survey of county households. Any history of incarceration in a prison/jail/detention center as an adult was assessed for a random subsample. Bivariate and multivariate logistic regression analyses examined whether incarceration history was associated with access to care, controlling for other characteristics. Ten percent of our study population reported a history of incarceration. While persons with an incarceration history were similar to their peers with regard to health and insurance status, their access to medical and dental care was worse. Incarceration history was independently associated with disparities in access to care. Interventions to improve the health of communities affected by high rates of incarceration could include efforts that enable access to care for formerly incarcerated adults

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Profiling strugglers in a graduate-entry medicine course at Nottingham: a retrospective case study

Background 10-15% of students struggle at some point in their medicine course. Risk factors include weaker academic qualifications, male gender, mental illness, UK ethnic minority status, and poor study skills. Recent research on an undergraduate medicine course provided a toolkit to aid early identification of students likely to struggle, who can be targeted by established support and study interventions. The present study sought to extend this work by investigating the number and characteristics of strugglers on a graduate-entry medicine (GEM) programme. Methods A retrospective study of four GEM entry cohorts (2003–6) was carried out. All students who had demonstrated unsatisfactory progress or left prematurely were included. Any information about academic, administrative, personal, or social difficulties, were extracted from their course progress files into a customised database and examined. Results 362 students were admitted to the course, and 53 (14.6%) were identified for the study, of whom 15 (4.1%) did not complete the course. Students in the study group differed from the others in having a higher proportion of 2ii first degrees, and scoring less well on GAMSAT, an aptitude test used for admission. Within the study group, it proved possible to categorise students into the same groups previously reported (struggler throughout, pre-clinical struggler, clinical struggler, health-related struggler, borderline struggler) and to identify the majority using a number of flags for early difficulties. These flags included: missed attendance, unsatisfactory attitude or behaviour, health problems, social/family problems, failure to complete immunity status checks, and attendance at academic progress committee. Conclusions Problems encountered in a graduate-entry medicine course were comparable to those reported in a corresponding undergraduate programme. A toolkit of academic and non-academic flags of difficulty can be used for early identification of many who will struggle, and could be used to target appropriate support and interventions

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Resilience of the Eastern African electricity sector to climate driven changes in hydropower generation

Notwithstanding current heavy dependence on gas-fired electricity generation in the Eastern African Power Pool (EAPP), hydropower is expected to play an essential role in improving electricity access in the region. Expansion planning of electricity infrastructure is critical to support investment and maintaining balanced consumer electricity prices. Variations in water availability due to a changing climate could leave hydro infrastructure stranded or result in underutilization of available resources. In this study, we develop a framework consisting of long-term models for electricity supply and water systems management, to assess the vulnerability of potential expansion plans to the effects of climate change. We find that the most resilient EAPP rollout strategy corresponds to a plan optimised for a slightly wetter climate compared to historical trends. This study demonstrates that failing to climate-proof infrastructure investments can result in significant electricity price fluctuations in selected countries (Uganda & Tanzania) while others, such as Egypt, are less vulnerable