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SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star) 1-3 . Two jets of ionized matter with a bulk velocity of approximately 0.26c (where c is the speed of light in vacuum) extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets 2,4-8 . SS 433 differs from other microquasars (small-scale versions of quasars that are present within our own Galaxy) in that the accretion is believed to be super-Eddington 9-11 , and the luminosity of the system is about 10 40 ergs per second 2,9,12,13 . The lobes of W50 in which the jets terminate, about 40 parsecs from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed 14-16 . At higher energies (greater than 100 gigaelectronvolts), the particle fluxes of γ-rays from X-ray hotspots around SS 433 have been reported as flux upper limits 6,17-20 . In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons that are interacting with the ambient gas. Here we report teraelectronvolt γ-ray observations of the SS 433/W50 system that spatially resolve the lobes. The teraelectronvolt emission is localized to structures in the lobes, far from the centre of the system where the jets are formed. We have measured photon energies of at least 25 teraelectronvolts, and these are certainly not Doppler-boosted, because of the viewing geometry. We conclude that the emission-from radio to teraelectronvolt energies-is consistent with a single population of electrons with energies extending to at least hundreds of teraelectronvolts in a magnetic field of about 16 microgauss.

To date, experimental investigations to determine the droplet size distribution (DSD) of subsea oil spills were mostly conducted at surface conditions, i.e. at atmospheric pressure, and with dead, i.e. purely liquid, oils. To investigate the influence of high hydrostatic pressure and of gases dissolved in the oil on the DSD, experiments with a downscaled blowout are conducted in a high-pressure autoclave at 150 bar hydrostatic pressure. Jets of "live", i.e. methane-saturated, crude oil and n-decane are compared to jets of "dead" hydrocarbon liquids in artificial seawater. Experiments show that methane dissolved in the liquid oil increases the volume median droplet diameter significantly by up to 97%. These results are not in good accordance with state-of-the-art drop formation models, which are based on oil-only experiments at atmospheric pressure, and therefore show the need for a modification of such models which incorporates effects of hydrostatic pressure and dissolved gases for the modeling of deep-sea oil spills and blowouts.

Background: Consensus guidelines from the European Crohns and Colitis Organisation conclude that optimizing quality of care in inflammatory bowel disease [IBD] involves information and education. However, there is no standardized patient education programme in IBD and education varies from centre to centre., Aim: To assess patients' education needs in IBD to facilitate design of a patient education programme., Methods: We created focus groups of 12 patients with IBD and used qualitative analysis to generate hypotheses. We then developed a quantitative questionnaire which was disseminated to 327 IBD patients attending three different centres. Five patients declined to participate and thus 322 patients (159 [49%] male, 180 [58%] Crohn's disease, median age 38 years and disease duration 7 years) were included., Results: Patients were most keen to receive education on medications, 'what to expect in future', living with IBD and diet. They wanted to receive this information from specialist doctors or nurses and believed it could improve their quality of life. Though the internet was the preferred source of general information [i.e. planning holidays], it was the least preferred source of IBD education. While there was a trend for females to prefer peer education, family history of IBD was the only statistically significant factor associated with information preferences., Conclusion: This is a patient-centred, mixed methodology study on patient education in IBD. Patients' preferences for education include components such as what to expect and diet and patients seem to distrust the internet as an IBD information source. International validation would be valuable to create a consensus education programme.

Background: The aim of this study is to determine whether the American Academy of Orthopaedic Surgeons' (AAOS) Appropriate Use Criteria (AUC) for distal radius fractures correlates with actual treatment by orthopedic hand surgeons at a level I trauma center., Methods: ICD-9 codes were used to retrospectively identify patients who presented with wrist fractures over 1 year. Patients with isolated distal radius fractures were evaluated using the AAOS AUC application for distal radius fractures. Actual treatment was then compared with treatment recommended by the AUC., Results: Of the 112 patients, 64 (57%) received treatment that matched the AAOS AUC recommendation as an "appropriate treatment." Actual management matched the AUC recommendation 100%, 7%, and 50% of the time, for Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) type A, B, and C fractures, respectively. Surgery was performed for type A, B, and C fractures 30%, 7%, and 50% of the time, respectively. For type B fractures, only the 2 cases that were managed operatively were in agreement with the AUC. For type C fractures, increased patient age (57 years and older) was significantly associated with nonoperative treatment decisions. Surgeon decisions for nonoperative treatment were in agreement with the AUC recommendations 40% of the time, whereas surgeon decisions for surgery matched the AUC recommendations 97% of the time., Conclusions: We found low agreement between actual treatment decisions and the AUC-recommended "appropriate" treatments, especially for the type B and C fractures that were managed nonoperatively. The AUC favors surgery for all intra-articular fractures, while we emphasized age and fracture displacement in our decision-making process.

The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross pathology and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a 'One Health' approach to inform human TB biomarker development and post-exposure vaccine development.

Background: Sequelae of venous thromboembolism (VTE) in children include recurrence, development of post thrombotic syndrome (PTS) when venous return from a limb is affected and chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Identification of laboratory-based risk factors may be useful for individualized risk assessment for VTE sequelae. Coagulation activation and inflammation may contribute to their pathophysiology. We performed a systematic review to investigate the association between biomarkers of coagulation activation, inflammation and fibrinolysis and adverse VTE outcomes in children and young adults., Methods: A systematic search of electronic databases, PubMed (NIH), EMBASE (Ovid), Web of Science (Thompson Reuters), and SCOPUS (Elsevier) for studies published through November 2016 was conducted using "VTE" including MeSH terms for "coagulation activation," "inflammation" and "fibrinolysis," with no limit on publication date. A study was eligible for inclusion when it evaluated patients (< 21years) with VTE and biomarkers of coagulation activation, inflammation, and fibrinolysis and assessed for their association with development of adverse thrombotic outcomes. A modified Newcastle Ottawa Scale was applied to examine the quality of included studies., Results: Our search strategy yielded 200 references. A total of 3 cohort studies representing 220 patients with VTE were included. Two authors independently assessed all references for inclusion. Three studies (2 prospective cohort and one mixed cohort study) were identified that reported on biomarkers of coagulation activation, inflammation and fibrinolysis, checked at least once after VTE diagnosis and assessed association with primary outcomes of recurrent VTE, PTS and CTEPH. Studies varied with regards to definition of outcomes, the type of biomarkers measured and time point of measurement. We were unable to meta-analyze results due to marked clinical heterogeneity and <3 studies available for each biomarker. Descriptively, a significant association was found for elevated plasma levels of FVIII and D-dimer for a compound outcome of PTS, recurrence and progression in one study, and positive lupus anticoagulant at DVT diagnosis and subsequent PTS by another study. No studies were found for CTEPH., Conclusions: Elevated D-dimer, FVIII and lupus anticoagulant show promise for predicting recurrent VTE and PTS in children and young adults. Further research is needed to elucidate whether these markers might be useful to predict development of adverse outcomes after VTE in children., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The unexpectedly high flux of cosmic-ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the High-Altitude Water Cherenkov Observatory (HAWC), of extended tera-electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera-electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin., (Copyright © 2017, American Association for the Advancement of Science.)

Purpose: Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor., Methods: We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods., Results: No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association., Conclusion: Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

Pneumococcal vaccination rates among children receiving a kidney transplant remain suboptimal. Current practice guidelines in the United States recommend giving the PPSV23 after priming with the PCV13. We conducted a QI initiative to increase pneumococcal vaccine rates in our kidney transplant recipients by developing an age-based vaccine algorithm, obtaining vaccine records, and generating reminders for patients and clinicians. A monthly report from the EHR tracked outcomes. The process metric was missed vaccine opportunities, and the overall objective was to improve coverage with both the PCV13 and PPSV23. Over the first six months, we increased the percentage of visits where the vaccine was given from a baseline of 4% to 33%. However, by the end of the 12-month period, the percentage of eligible visits where the vaccine was given decreased to 8.7%. Nevertheless, over the 12-month observation period, we were able to increase the percentage of transplant patients receiving the PCV13 and PPSV23 from 6% to 52%. Utilizing an age-based algorithm and the electronic medical record, vaccine champions can track both missed visit opportunities and the number of vaccinated patients to improve pneumococcal immunization coverage for these high-risk patients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The discovery of novel antigens is an essential requirement in devising new diagnostics or vaccines for use in control programmes against human tuberculosis (TB) and bovine tuberculosis (bTB). Identification of potential epitopes recognised by CD4 + T cells requires prediction of peptide binding to MHC class-II, an obligatory prerequisite for T cell recognition. To comprehensively prioritise potential MHC-II-binding epitopes from Mycobacterium bovis , the agent of bTB and zoonotic TB in humans, we integrated three binding prediction methods with the M. bovis proteome using a subset of human HLA alleles to approximate the binding of epitope-containing peptides to the bovine MHC class II molecule BoLA-DRB3. Two parallel strategies were then applied to filter the resulting set of binders: identification of the top-scoring binders or clusters of binders. Our approach was tested experimentally by assessing the capacity of predicted promiscuous peptides to drive interferon-γ secretion from T cells of M. bovis infected cattle. Thus, 376 20-mer peptides, were synthesised (270 predicted epitopes, 94 random peptides with low predictive scores and 12 positive controls of known epitopes). The results of this validation demonstrated significant enrichment (>24 %) of promiscuously recognised peptides predicted in our selection strategies, compared with randomly selected peptides with low prediction scores. Our strategy offers a general approach to the identification of promiscuous epitopes tailored to target populations where there is limited knowledge of MHC allelic diversity.

Spending on psychotropic medications has grown rapidly in recent decades. Using national data on drug expenditures, patent expirations, future drug development and expert interviews, we project that spending will grow more slowly over the period 2012-2020. The average annual increase is projected to be just 3.0 % per year, continuing the steady deceleration in recent years. The main drivers of this expected deceleration include slower development of new drugs, upcoming patent expirations which will lower prices, and payers' growing ability to manage utilization and promote generic use. The slowdown will relieve some cost pressures on payers, particularly Medicare and Medicaid.

Purpose: To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS)., Patients and Methods: We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT., Results: Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort., Conclusion: The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS., (© 2016 by American Society of Clinical Oncology.)

Background and Aims: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity., Methods: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls., Results: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients., Conclusions: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Prezi is a presentation software allowing lecturers to develop ideas and produce mind maps as they might do on an old-style blackboard. This study examines students' experience of lectures presented using Prezi to identify the strengths and weaknesses of this new teaching medium., Methods: Prezi was used to present mental health lectures to final-year medical and physiotherapy students. These lectures were also available online. This cross-sectional study used a questionnaire to assess students' experience of the software., Results: Of students approached, 75.5 % (74/98) took part in the study. A majority, 98.6 % (73/74), found Prezi to be a more engaging experience than other styles of lecture delivery. The overview or "mind map" provided by Prezi was found to be helpful by 89.2 % (66/74). Problems arose when students used Prezi in their personal study, with 31.1 % (23/74) reporting some difficulties, mostly of a technical nature., Conclusion: This study highlights the potential of Prezi for providing students with an engaging and stimulating educational experience. For Prezi to be effective, however, the lecturer has to understand and be familiar with the software and its appropriate use.

Reports suggest an association between internet use and the elevated risk of suicide and self harm. This study examined the resources a suicidal person might find when searching the internet 'front page' for help. Voluntary suicide help websites accounted for 7/12 front page hits. The National Suicide Research Foundation (NSRF) and the National Office for Suicide Prevention (NOSP), a blog and a newspaper article made up the remainder. Sites were difficult to navigate and highly variable in content. Phone credit was required in many cases in order to contact helplines; opening hours and locations were limited. Most statutory websites referred help-seekers to the voluntary sector, mainly the Samaritans. Information on fundraising and volunteering competed with other sources of help. Of concern, the front page also included links to methods to complete suicide. Irish professional medical bodies offered very limited advice. Our findings suggest that online information is variable and potentially harmful. There is an opportunity for all agencies and providers to generate a co-ordinated internet front page tailored for at-risk groups.

Background: Formal thought disorder (FTD) is a core feature of psychosis, however there are gaps in our knowledge about its prevalence and factor structure. We had two aims: first, to establish the factor structure of FTD; second, to explore the clinical utility of dimensions of FTD in order to further the understanding of its nosology., Methods: A cross-validation study was undertaken to establish the factor structure of FTD in first episode psychosis (FEP). The relative utility of FTD categories vs. dimensions across diagnostic categories was investigated., Results: The prevalence of clinically significant FTD in this FEP sample was 21%, although 41% showed evidence of disorganised speech, 20% displayed verbosity and 24% displayed impoverished speech. A 3-factor model was identified as the best fit for FTD, with disorganisation, poverty and verbosity dimensions (GFI=0.99, RMR=0.07). These dimensions of FTD accurately distinguished affective from non-affective diagnostic categories. A categorical approach to FTD assessment was useful in identifying markers of clinical acuteness, as identified by short duration of untreated psychosis (OR=2.94, P<0.01) and inpatient treatment status (OR=3.98, P<0.01)., Conclusion: FTD is moderately prevalent and multi-dimensional in FEP. Employing both a dimensional and categorical assessment of FTD gives valuable clinical information, however there may be a need to revise our conceptualisation of the nosology of FTD. The prognostic value of FTD, as well as its neural basis, requires elucidation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Negative symptoms are included in diagnostic manuals as part of criteria for schizophrenia spectrum psychoses only, however some studies have found their presence in other diagnoses. This study sought to clarify negative symptom domain prevalence across diagnostic categories, while investigating whether negative symptoms predicted diagnostic shift over time. Scale for the Assessment of Negative Symptoms (SANS) data were collected at first presentation in 197 individuals presenting with first episode psychosis and again at one year follow-up assessment. Negative symptoms were highest among individuals with schizophrenia and among those whose diagnosis shifted from non-schizophrenia spectrum at baseline to schizophrenia spectrum at follow-up. In a non-schizophrenia spectrum group negative symptoms at baseline were not a significant predictor of diagnostic shift to schizophrenia spectrum diagnoses. The study suggests negative symptoms can present among individuals with non-schizophrenia spectrum diagnoses, although this is most relevant for individuals following diagnostic shift from non-schizophrenia spectrum to schizophrenia spectrum diagnoses. The findings support introduction of a negative symptom dimension when describing a range of psychotic illnesses, and indicate that further research investigating the evolution of negative symptoms in non-schizophrenia diagnoses is needed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To compare the effectiveness of virtual reality-based balance exercises to conventional balance exercises during vestibular rehabilitation in patients with unilateral peripheral vestibular loss (UVL)., Design: Assessor-blind, randomized controlled trial., Setting: Two acute care university teaching hospitals., Participants: Patients with UVL (N=71) who had dizziness/vertigo, and gait and balance impairment., Interventions: Patients with UVL were randomly assigned to receive 6 weeks of either conventional (n=36) or virtual reality-based (n=35) balance exercises during vestibular rehabilitation. The virtual reality-based group received an off-the-shelf virtual reality gaming system for home exercise, and the conventional group received a foam balance mat. Treatment comprised weekly visits to a physiotherapist and a daily home exercise program., Main Outcome Measures: The primary outcome was self-preferred gait speed. Secondary outcomes included other gait parameters and tasks, Sensory Organization Test (SOT), dynamic visual acuity, Hospital Anxiety and Depression Scale, Vestibular Rehabilitation Benefits Questionnaire, and Activities Balance Confidence Questionnaire. The subjective experience of vestibular rehabilitation was measured with a questionnaire., Results: Both groups improved, but there were no significant differences in gait speed between the groups postintervention (mean difference, -.03m/s; 95% confidence interval [CI], -.09 to .02m/s). There were also no significant differences between the groups in SOT scores (mean difference, .82%; 95% CI, -5.00% to 6.63%) or on any of the other secondary outcomes (P>.05). In both groups, adherence to exercise was high (∼77%), but the virtual reality-based group reported significantly more enjoyment (P=.001), less difficulty with (P=.009) and less tiredness after (P=.03) balance exercises. At 6 months, there were no significant between-group differences in physical outcomes., Conclusions: Virtual reality-based balance exercises performed during vestibular rehabilitation were not superior to conventional balance exercises during vestibular rehabilitation but may provide a more enjoyable method of retraining balance after unilateral peripheral vestibular loss., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Approximately 25 million individuals are projected to gain insurance as a result of the Affordable Care Act (ACA). This study estimated the prevalence of behavioral health conditions and their treatment among individuals likely to gain coverage., Methods: Pooled 2008-2011 National Survey on Drug Use and Health data for adults (ages 18-64) were used. Estimates were created for all adults, current Medicaid beneficiaries, and uninsured adults with incomes that might make them eligible for the Medicaid expansion or tax credits for use in the health insurance marketplace., Results: Individuals who may gain insurance under the ACA had lower rates of serious mental illnesses (5.4%, Medicaid expansion; 4.7%, marketplace) compared with current Medicaid beneficiaries (9.6%). They had higher rates of substance use disorders (13.6%, Medicaid expansion; 14.3%, marketplace) compared with Medicaid recipients (11.9%)., Conclusions: There is significant need for behavioral health treatment among individuals who may gain insurance under the ACA.

Objectives: Anxiety is associated with elevated levels of the inflammatory cytokine interleukin-6 (IL-6) and an increased risk for diseases with an inflammatory aetiology. In cancer, higher levels of IL-6 have been associated with increased expression of the epigenetic enzymes DNMT1 and Enhancer of Zeste Homolog 2 (EZH2). However, the relationship between IL-6 and DNA methyltransferases (DNMTs) and EZH2 expression has not previously been examined in anxious individuals., Methods: Global DNA methylation levels were measured using the Methylflash Methylated DNA Quantification Kit and gene expression levels of the DNMT and EZH2 genes in anxious (n=25) and nonanxious individuals (n=22) were compared using quantitative real-time PCR. Specifically, we investigated whether global DNA methylation or aberrant expression of these genes was correlated with IL-6 mRNA and protein serum levels in anxious individuals., Results: Anxious participants had significantly higher levels of global DNA methylation compared with controls (P=0.001). There were no differences in the mean mRNA expression levels of the DNMT1/3A/3B, EZH2 and IL-6 genes in anxious individuals compared with controls. However, the expression of DNMT1/3A, EZH2 and IL-6 genes increases with increasing Hospital Anxiety and Depression Scale-Anxiety scores in the anxious cohort only. Interestingly, IL-6 gene expression was correlated strongly with DNMT1/3A/3B and EZH2 expression, highlighting a potential relationship between IL-6 and important epigenetic regulatory enzymes., Conclusion: This study provides novel insight into the relationship between anxiety, epigenetics and IL-6. Moreover, our findings support the hypothesis that changes in DNA methylation profiles may contribute to the biology of anxiety.

Unlabelled: Puberty is an important developmental stage wherein hormonal shifts mediate the physical and physiological changes that lead to menarche, but until now, the bacterial composition of vaginal microbiota during this period has been poorly characterized. We performed a prospective longitudinal study of perimenarcheal girls to gain insight into the timing and sequence of changes that occur in the vaginal and vulvar microbiota during puberty. The study enrolled 31 healthy, premenarcheal girls between the ages of 10 and 12 years and collected vaginal and vulvar swabs quarterly for up to 3 years. Bacterial composition was characterized by Roche 454 pyrosequencing and classification of regions V1 to V3 of 16S rRNA genes. Contrary to expectations, lactic acid bacteria, primarily Lactobacillus spp., were dominant in the microbiota of most girls well before the onset of menarche in the early to middle stages of puberty. Gardnerella vaginalis was detected at appreciable levels in approximately one-third of subjects, a notable finding considering that this organism is commonly associated with bacterial vaginosis in adults. Vulvar microbiota closely resembled vaginal microbiota but often exhibited additional taxa typically associated with skin microbiota. Our findings suggest that the vaginal microbiota of girls begin to resemble those of adults well before the onset of menarche., Importance: This study addresses longitudinal changes in vaginal and vulvar microbial communities prior to and immediately following menarche. The research is significant because microbial ecology of the vagina is an integral aspect of health, including resistance to infections. The physiologic changes of puberty and initiation of cyclic menstruation are likely to have profound effects on vaginal microbiota, but almost nothing is known about changes that normally occur during this time. Our understanding has been especially hampered by the lack of thorough characterization of microbial communities using techniques that do not rely on the cultivation of fastidious bacteria, as well as a dearth of studies on girls in the early to middle stages of puberty. This study improves our understanding of the normal development of vaginal microbiota during puberty and onset of menarche and may better inform clinical approaches to vulvovaginal care of adolescent girls., (Copyright © 2015 Hickey et al.)

The potential for young men in crisis to be supported by their lay networks is an important issue for suicide prevention, due to the under-utilisation of healthcare services by this population. Central to the provision of lay support is the capability of social networks to recognise and respond effectively to young men's psychological distress and suicide risk. The aim of this qualitative study was to explore young men's narratives of peer suicide, in order to identify how they interpreted and responded to behavioural changes and indications of distress from their friend before suicide. In-depth qualitative interviews were conducted during 2009/10 with 15 Irish males (aged 19-30 years) who had experienced the death by suicide of a male friend in the preceding 5 years. The data were analysed using a thematic approach. Through the analysis of the participants' stories and experiences, we identified several features of young male friendships and social interactions that could be addressed to strengthen the support available to young men in crisis. These included the reluctance of young men to discuss emotional or personal issues within male friendships; the tendency to reveal worries and emotion only within the context of alcohol consumption; the tendency of friends to respond in a dismissive or disapproving way to communication of suicidal thoughts; the difficulty of knowing how to interpret a friend's inconsistent or ambiguous behaviour prior to suicide; and beliefs about the sort of person who takes their own life. Community-based suicide prevention initiatives must enhance the potential of young male social networks to support young men in crisis, through specific provisions for developing openness in communication and responsiveness, and improved education about suicide risk., (© 2014 John Wiley & Sons Ltd.)

Background: Body image refers to a person's sense of their physical appearance and body function. A negative body image self-evaluation may result in psychosocial dysfunction. Crohn's disease and ulcerative colitis are associated with disabling features, and body image dissatisfaction is a concern for many patients with inflammatory bowel disease (IBD). However, no study has assessed body image and its comorbidities in patients with IBD using validated instruments. Our aim was to explore body image dissatisfaction in patients with IBD and assess its relationship with biological and psychosocial variables., Methods: We studied 330 patients (median age, 36 yr; range, 18-83; 169 men) using quantitative and qualitative methods. Patients completed a self-administered questionnaire that included a modified Hopwood Body Image Scale, the Cash Body Image Disturbance Questionnaire, and other validated instruments. Clinical and disease activity data were also collected., Results: Body image dissatisfaction was associated with disease activity (P < 0.001) and steroid treatment (P = 0.03) but not with immunotherapy (P = 0.57) or biological (P = 0.55) therapy. Body image dissatisfaction was also associated with low levels of general (P < 0.001) and IBD-specific (P < 0.001) quality of life, self-esteem (P < 0.001), and sexual satisfaction (P < 0.001), and with high levels of anxiety (P < 0.001) and depression (P < 0.001). Qualitative analysis indicated that patients were concerned about both physical and psychosocial consequences of body image dissatisfaction, including steroid side effects and impaired work and social activities., Conclusions: Body image dissatisfaction is common in patients with IBD, relates to specific clinical variables and is associated with significant psychological dysfunction. Its measurement is warranted as part of a comprehensive patient-centered IBD assessment.

Mental health problems are disproportionately represented in the community corrections system with limited information on the epidemiology of mental health and correlated factors such as suicide among probationers. This study recruited 2,077 probationers who completed screeners for mental health and substance disorders and suicide risk. Results found 13% of probationers were at high risk of suicide. Those who screened positive for a mental health condition were between 2 and 8 times more likely to screen positive for suicide risk. Allocation of additional resources to mental health in the criminal justice system and to effectively coordinate existing mental health services is needed.

Background: Recurrence rates following radiotherapy for prostate cancer in the post-operative adjuvant or salvage setting remain substantial. Previous work from our institution demonstrated that published prostate bed CTV guidelines frequently do not cover the pre-operative MRI defined prostate. Inadequate target delineation may contribute to the high recurrence rates, but increasing target volumes may increase dose to organs at risk., Methods: We propose guidelines for delineating post-prostatectomy target volumes based upon an individual's co-registered pre-operative MRI. MRI-based CTVs and PTVs were compared to those created using the RTOG guidelines in 30 patients. Contours were analysed in terms of absolute volume, intersection volume (Jaccard Index) and the ability to meet the RADICALS and QUANTEC rectal and bladder constraints (tomotherapy IMRT plans with PTV coverage of V98% ≥98%)., Results: CTV MRI was a mean of 18.6% larger than CTV RTOG: CTV MRI mean 138 cc (range 72.3 - 222.2 cc), CTV RTOG mean 116.3 cc (range 62.1 - 176.6 cc), (p < 0.0001). The difference in mean PTV was only 4.6%: PTV MRI mean 386.9 cc (range 254.4 - 551.2), PTV RTOG mean 370 cc (range 232.3 - 501.6) (p = 0.05). The mean Jaccard Index representing intersection volume between CTVs was 0.72 and 0.84 for PTVs. Both criteria had a similar ability to meet rectal and bladder constraints. Rectal DVH: 77% of CTV RTOG cases passed all RADICALS criteria and 37% all QUANTEC criteria; versus 73% and 40% for CTV MRI (p = 1.0 for both). Bladder DVH; 47% of CTV RTOG cases passed all RADICALS criteria and 67% all QUANTEC criteria, versus 57% and 60% for CTV MRI (p = 0.61for RADICALS, p = 0.79 for QUANTEC). CTV MRI spares more of the lower anterior bladder wall than CTV RTOG but increases coverage of the superior lateral bladder walls., Conclusion: CTV contours based upon the patient's co-registered pre-operative MRI in the post-prostatectomy setting may improve coverage of the individual's prostate bed without substantially increasing the PTV size or dose to bladder/ rectum compared to RTOG CTV guidelines. Further evaluation of whether the use of pre-operative MRI improves local control rates is warranted.

Context: The creation of 3-dimensional prostate cancer maps could assist with surgical intervention, radiotherapy treatment planning and for correlative pathology-imaging research., Objectives: To develop methodology for creating detailed, 3-dimensional, prostate cancer maps (3DPCM) of tumor location, extra prostatic extension sites, and positive margins and to assess the adequacy of current clinical target volumes for postoperative radiotherapy to the prostate using 3DPCM coregistered with preoperative magnetic resonance imaging., Design: Parallel slices of prostatectomy specimens were created with ProCUT, and 2-dimensional cancer maps were generated as line diagrams after microscopic examination of each slice. The 2-dimensional cancer maps were aligned and stacked to create a 3DPCM, which was coregistered with the preoperative magnetic resonance imaging scan. The map was exported to the radiotherapy planning system and was used to determine the areas at greater risk, which were then compared against the current Radiation Therapy Oncology Group guidelines for contouring postoperative clinical target volumes to assess the adequacy of coverage., Results: Twenty-eight patients with a mean age of 66 years (range, 52-73) underwent radical prostatectomy and postoperative radiotherapy. Seventeen patients (61%) received adjuvant radiotherapy for pT3 disease and/or positive margins, and the rest underwent salvage radiotherapy. Thirty-nine percent (11 of 28) of the patients had Gleason scores of 8 or 9. The contours based on the Radiation Therapy Oncology Group guidelines for postoperative radiotherapy resulted in inadequate coverage of extraprostatic extensions in 79% (22 of 28) and positive margins in 64% (18 of 28) of the cases., Conclusions: We have developed a methodology for creation of 3DPCM. Modification of the radiotherapy contours, based on the 3DPCM coregistered with pretreatment magnetic resonance imaging, covers the areas at high risk of recurrence. The 3DPCM could become an important clinical and research tool for urologists, pathologists, radiologists, and oncologists.

Background: Although variation exists in the classification and practice of managing clinical findings in research, emerging views suggest that researchers bear some responsibility in the management of incidental findings. This study contributes to the documentation of the population characteristics and prevalence of medical findings incidental to research participation, specifically findings related to coronary calcium scores and computed tomography (CT) scans that investigated cardiovascular disparities in an asymptomatic population., Methods: A total of 571 asymptomatic adult participants were recruited in the North Texas Healthy Heart Study. Participants completed a 16-slice CT scan of the heart and abdomen. Findings of radiology reports and 3 years of follow-up documentation were reviewed., Results: A total of 246 clinically apparent findings were identified in 169 asymptomatic participants (32.9% of participants who completed a CT scan). Another 245 participants (48%) had findings of unknown significance, a total of 307 findings. At least 4 cases in this study led to a clinically significant intervention., Conclusion: Although CT scans were completed for research purposes, study procedures resulted in the diagnosis and treatment of individuals who were previously asymptomatic. Potential clinical benefits in imaging research are moderated by considerations regarding possible harm and costs resulting from uncertain findings and the use of CT scans for nonclinical purposes. The continued development of protocols for the handling of incidental findings in research and the establishment of guidelines are needed to ensure that research procedures mirror the best interests of participants.

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.

Background: Negative symptoms have been previously reported during the psychosis prodrome, however our understanding of their relationship with treatment-phase negative symptoms remains unclear., Objectives: We report the prevalence of psychosis prodrome onset negative symptoms (PONS) and ascertain whether these predict negative symptoms at first presentation for treatment., Methods: Presence of expressivity or experiential negative symptom domains was established at first presentation for treatment using the Scale for Assessment of Negative Symptoms (SANS) in 373 individuals with a first episode psychosis. PONS were established using the Beiser Scale. The relationship between PONS and negative symptoms at first presentation was ascertained and regression analyses determined the relationship independent of confounding., Results: PONS prevalence was 50.3% in the schizophrenia spectrum group (n=155) and 31.2% in the non-schizophrenia spectrum group (n=218). In the schizophrenia spectrum group, PONS had a significant unadjusted (χ(2)=10.41, P<0.001) and adjusted (OR=2.40, 95% CI=1.11-5.22, P=0.027) association with first presentation experiential symptoms, however this relationship was not evident in the non-schizophrenia spectrum group. PONS did not predict expressivity symptoms in either diagnostic group., Conclusion: PONS are common in schizophrenia spectrum diagnoses, and predict experiential symptoms at first presentation. Further prospective research is needed to examine whether negative symptoms commence during the psychosis prodrome., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Body image refers to a persons' sense of their own physical appearance. This can be negatively influenced by a number of factors including disease states and treatments. Inflammatory bowel disease (IBD) carries a distinct psychosocial and a physical burden, but body image has not been formally assessed in patients with IBD, nor is there a validated body image questionnaire. Our aim was to assess and validate a body image questionnaire for patients with IBD., Methods: Three hundred thirty-eight ambulatory patients (median age, 36; 174 male) completed a questionnaire that included the Hopwood body image scale adapted from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Study Group. Data from another scale, the Cash Body Image Disturbance Questionnaire, were also collected in addition to demographic and clinical data., Results: Factor analysis resulted in a single factor solution explaining 65% of the variance. Internal consistency of the body image scale was demonstrated with a Cronbach alpha of 0.93. Convergent validity was established with a correlation coefficient of 0.64 (P < 0.001) with the Cash Body Image Disturbance Questionnaire. Females (P < 0.001) and those who had undergone either stoma or nonstoma forming surgery experienced more body image dissatisfaction (P = 0.002), indicating predictive validity. Reliability was confirmed with a test-retest correlation of 0.82 (P < 0.001)., Conclusions: The modified body image scale is a valid tool for assessing body image in patients with IBD.

Previous studies in schizophrenia samples suggest negative symptoms can be categorized as expressivity or experiential. This study examines the structure of the Scale for the Assessment of Negative Symptoms (SANS) at two separate interviews in a first episode psychosis (FEP) sample. SANS structure was determined with principal components analysis in a schizophrenia spectrum (SSD, N=191) and non-schizophrenia spectrum (NSSD, N=246) sample at first presentation. Confirmatory factor analysis (CFA) was conducted in the entire FEP sample (N=197) at a follow-up assessment. A three factor model solution was extracted in both SSD and NSSD at first presentation. The three components, consisting of expressivity, experiential and alogia/inattention components, explained 26.1%, 16.6% and 13.6% of the variance respectively in SSD. In NSSD the same three components explained 24.2%, 17.9% and 13.1% of the variance respectively. CFA at follow-up showed similar model fit for both the original SANS five factor and for a three factor model solution. The results indicate that either a three or five factor SANS model solution may be appropriate in a psychosis sample inclusive of both SSD and NSSD. The findings also provide initial support for expressivity and experiential domain research in NSSD., (© 2013 Published by Elsevier Ireland Ltd.)

Background: A positive attitude to patients with mental illness is important in all branches of medicine, as it can impact on the quality of care patients receive from doctors. Attitudes of preclinical medical students is an under researched area., Aims: This study aims to (1) assess the attitudes of preclinical and clinical medical students to patients with mental illness and (2) assess the effect of two modules taught using different teaching methods on students' attitudes to patients with mental illness., Methods: During the same academic year all students (N = 394) completing the year 3 preclinical psychiatry module and the final year psychiatry module completed an attitudinal questionnaire at the beginning and following completion of the module. Seventy-two percent of students completed both pre- and post-module questionnaires in full (n = 285)., Results: There was no significant difference in attitudes displayed by preclinical and clinical medical students prior to starting their respective modules. An association was found between female gender and more tolerant attitudes (r = 0.20, p = 0.02). Students who knew someone with experience of mental illness were associated with more tolerant attitudes (r = 0.32, p < 0.001). Final year students who completed the clinical module demonstrated a positive attitudinal shift (p < 0.001), and the attitudes of third and final year male students improved significantly following the module (p < 0.05)., Conclusions: Given the high rates of physical illness in patients with mental health problems, specific educational initiatives to address medical student's attitudes to patients with mental health problems should be an educational priority in medical school.

Purpose: In order to evaluate fluorescent in situ hybridization (FISH) as a method for predicting radiosensitivity, this study examined the incidence of translocations, after exposure to in vitro radiation, in both normally responding patients and those exhibiting severe late effects after radiotherapy treatment., Materials and Methods: Patients were selected from a randomized trial for intermediate-risk prostate cancer. Of the patients entered on trial with mature follow-up, 3% developed grade 3 late proctitis. Blood samples were taken from this radiosensitive cohort along with matched control patients with no late proctitis. Whole blood samples were exposed to 0 or 4 Gy and cultured according to the International Atomic Energy Agency (IAEA) recommended methods. Colour junctions were evaluated in the resulting metaphases and scored according to the Protocol for Aberration Identification and Nomenclature Terminology (PAINT) system., Results: Both groups were statistically similar at 0 Gy. After 4 Gy in vitro radiation, the radiosensitive group had significantly higher rates of chromosome damage in the number of colour junctions per cell (p = 0.002), the number of deletions per cell (p = 0.01) and the number of dicentrics per cell (p = 0.005)., Conclusions: These results indicate that the analysis of translocations using FISH after in vitro irradiation correlates with clinical response to radiation. This cytogenetic assay should be considered as a potential predictor of radiosensitivity.

Objectives: We studied housing retention and its predictors in the single-site Housing First model., Methods: Participants (n = 111) were chronically homeless people with severe alcohol problems who lived in a single-site Housing First program and participated in a larger nonrandomized controlled trial (2005-2008) conducted in Seattle, Washington. At baseline, participants responded to self-report questionnaires assessing demographic, illness burden, alcohol and other drug use, and psychiatric variables. Housing status was recorded over 2 years., Results: Participants were interested in housing, although a sizable minority did not believe they would be able to maintain abstinence-based housing. Only 23% of participants returned to homelessness during the 2-year follow-up. Commonly cited risk factors--alcohol and other drug use, illness burden, psychiatric symptoms, and homelessness history--did not predict resumed homelessness. Active drinkers were more likely to stay in this housing project than nondrinkers., Conclusions: We found that single-site Housing First programming fills a gap in housing options for chronically homeless people with severe alcohol problems.

The skeletal anatomy of the hand is composed of phalanges, metacarpal bones, and carpal bones. Its function is a product of the complex interactions between the power provided by the intrinsic and extrinsic musculature, the stability provided by the ligaments, and the structure provided by the bones, which serve as insertion and attachment sites for the muscles and ligaments. This article provides a detailed description of the skeletal anatomy of the human hand., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The 2007-09 recession had a dramatic effect on behavioral health spending, with the effect most prominent for private, state, and local payers. During the recession behavioral health spending increased at a 4.6 percent average annual rate, down from 6.1 percent in 2004-07. Average annual growth in private behavioral health spending during the recession slowed to 2.7 percent from 7.2 percent in 2004-07. State and local behavioral health spending showed negative average annual growth, -1.2 percent, during the recession, compared with 3.7 percent increases in 2004-07. In contrast, federal behavioral health spending growth accelerated to 11.1 percent during the recession, up from 7.2 percent in 2004-07. These behavioral health spending trends were driven largely by increased federal spending in Medicaid, declining private insurance enrollment, and severe state budget constraints. An increased federal Medicaid match reduced the state share of Medicaid spending, which prevented more drastic cuts in state-funded behavioral health programs during the recession. Federal Medicaid served as a critical safety net for people with behavioral health treatment needs during the recession.

Background and Purpose. This project examined the in vitro   γ H2AX response in lymphocytes of prostate cancer patients who had a radiosensitive response after receiving radiotherapy. The goal of this project was to determine whether the γ H2AX response, as measured by flow cytometry, could be used as a marker of individual patient radiosensitivity. Materials and Methods. Patients were selected from a randomized clinical trial evaluating the optimal timing of Dose Escalated Radiation and short-course Androgen Deprivation Therapy. Of 438 patients, 3% developed Grade 3 late radiation proctitis and were considered to be radiosensitive. Blood was drawn from 10 of these patients along with 20 matched samples from patients with Grade 0 proctitis. Dose response curves up to 10 Gy along with time response curves after 2 Gy (0-24 h) were generated for each sample. The γ H2AX response in lymphocytes and lymphocyte subsets was analyzed by flow cytometry. Results. There were no significant differences between the radiosensitive and control samples for either the dose course or the time course. Conclusions. Although γ H2AX response has previously been demonstrated to be an indicator of individual patient radiosensitivity, flow cytometry lacks the sensitivity necessary to distinguish any differences between samples from control and radiosensitive patients.

Purpose: In vitro irradiated blood samples from prostate cancer patients showing late normal tissue damage were examined for lymphocyte response by measuring chromosomal aberrations and proliferation rate., Methods and Materials: Patients were selected from a randomized trial evaluating the optimal timing of dose-escalated radiation and short-course androgen deprivation therapy. Of 438 patients, 3% experienced grade 3 late radiation proctitis and were considered to be radiosensitive. Blood samples were taken from 10 of these patients along with 20 matched samples from patients with grade 0 proctitis. The samples were irradiated at 6 Gy and, along with control samples, were analyzed for dicentric chromosomes and excess fragments per cell. Cells in first and second metaphase were also enumerated to determine the lymphocyte proliferation rate., Results: At 6 Gy, there were statistically significant differences between the radiosensitive and control cohorts for 3 endpoints: the mean number of dicentric chromosomes per cell (3.26 ± 0.31, 2.91 ± 0.32; P=.0258), the mean number of excess fragments per cell (2.27 ± 0.23, 1.43 ± 0.37; P<.0001), and the proportion of cells in second metaphase (0.27 ± 0.10, 0.46 ± 0.09; P=.0007)., Conclusions: These results may be a valuable indicator for identifying radiosensitive patients and for tailoring radiation therapy., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Purpose: Many studies suggest increased body mass index (BMI) is associated with worse breast cancer outcomes, but few account for variability in screening, access to treatment, and tumor differences. We examined the association between BMI and risk of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, and evaluated whether tumor characteristics differ by BMI among a mammographically screened population with access to treatment., Methods: Using a retrospective cohort study design, we followed 485 women aged ≥40 years diagnosed with stage I/II breast cancer within 24 months of a screening mammogram occurring between 1988 and 1993 for 10-year outcomes. BMI before diagnosis was categorized as normal (<25 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (≥30 kg/m(2)). Tumor marker expression was assessed via immunohistochemistry using tissue collected before adjuvant treatment. Medical records were abstracted to identify treatment, recurrence, and mortality. We used Cox proportional hazards to separately model the hazard ratios (HR) of our three outcomes by BMI while adjusting for age, stage, and tamoxifen use., Results: Relative to normal-weight women, obese women experienced increased risk of recurrence (HR 2.43; 95 % CI 1.34-4.41) and breast cancer death (HR 2.41; 95 % CI 1.00-5.81) within 10 years of diagnosis. There was no association between BMI and all-cause mortality. Obese women had significantly faster growing tumors, as measured by Ki-67., Conclusions: Our findings add to the growing evidence that obesity may contribute to poorer breast cancer outcomes, and also suggest that increased tumor proliferation among obese women is a pathway that explains part of their excess risk of adverse outcomes.

Background: Family-based cardiac screening programmes for persons at risk for genetic cardiac diseases are now recommended. However, the psychological wellbeing and health related quality of life (QoL) of such screened patients is poorly understood, especially in younger patients. We sought to examine wellbeing and QoL in a representative group of adults aged 16 and over in a dedicated family cardiac screening clinic., Methods: Prospective survey of consecutive consenting patients attending a cardiac screening clinic, over a 12 month period. Data were collected using two health measurement tools: the Short Form 12 (version 2) and the Hospital Anxiety and Depression Scale (HADS), along with baseline demographic and screening visit-related data. The HADS and SF-12v.2 outcomes were compared by age group. Associations with a higher HADS score were examined using logistic regression, with multi-level modelling used to account for the family-based structure of the data., Results: There was a study response rate of 86.6%, with n=334 patients providing valid HADS data (valid response rate 79.5%), and data on n=316 retained for analysis. One-fifth of patients were aged under 25 (n=61). Younger patients were less likely than older to describe significant depression on their HADS scale (p<0.0001), although there were overall no difference between the prevalence of a significant HADS score between the younger and older age groups (18.0% vs 20.0%, p=0.73). Significant positive associates of a higher HADS score were having lower educational attainment, being single or separated, and being closely related to the family proband. Between-family variance in anxiety and depression scores was greater than within-family variance., Conclusions: High levels of anxiety were seen amongst patients attending a family-based cardiac screening clinic.Younger patients also had high rates of clinically significant anxiety. Higher levels of anxiety and depression tends to run in families, and this has implications for family screening and intervention programmes.

Purpose: Despite the benefits of adjuvant radiotherapy after radical prostatectomy, approximately one-half of patients relapse. Four consensus guidelines have been published (European Organization for Research and Treatment of Cancer, Faculty of Radiation Oncology Genito-Urinary Group, Princess Margaret Hospital, Radiation Therapy Oncology Group) with the aim of standardizing the clinical target volume (CTV) delineation and improve outcomes. To date, no attempt has been made to compare these guidelines in terms of treatment volumes or organ at risk (OAR) irradiation. The extent to which the guideline-derived plans meet the dosimetric constraints of present trials or of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) trial is also unknown. Our study also explored the dosimetric benefits of intensity-modulated radiotherapy (IMRT)., Methods and Materials: A total of 20 patients treated with postoperative RT were included. The three-dimensional conformal radiotherapy (3D-CRT) plans were applied to cover the guideline-generated planning target volumes (66 Gy in 33 fractions). Dose-volume histograms (DVHs) were analyzed for CTV/planning target volume coverage and to evaluate OAR irradiation. The OAR DVHs were compared with the constraints proposed in the QUANTEC and Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trials. 3D-CRT plans were compared with the tomotherapy plans for the Radiation Therapy Oncology Group planning target volume to evaluate the advantages of IMRT., Results: The CTV differed significantly between guidelines (p < 0.001). The European Organization for Research and Treatment of Cancer-CTVs were significantly smaller than the other CTVs (p < 0.001). Differences in prostate bed coverage superiorly accounted for the major volumetric differences between the guidelines. Using 3D-CRT, the DVHs rarely met the QUANTEC or RADICALS rectal constraints, independent of the guideline used. The RADICALS bladder constraints were met most often by the European Organization for Research and Treatment of Cancer consensus guideline (14 of 20). The tomotherapy IMRT plans resulted in significant OAR sparing compared with the 3D-CRT plans; however, the RADICALS and QUANTEC criteria were still missed in a large percentage of cases., Conclusion: Treatment volumes using the current consensus guidelines differ significantly. For the four CTV guidelines, the rectal and bladder DVH constraints proposed in the QUANTEC and RADICALS trials are rarely met with 3D-CRT. IMRT results in significant OAR sparing; however, the RADICALS dose constraints are still missed for a large percentage of cases. The rectal and bladder constraints of RADICALS should be modified to avoid a reduction in the CTVs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Intracranial germ cell tumours (GCTs) are a rare and diverse group of tumours. Histology determines the type of treatment, natural history and prognosis. Germinoma GCTs account for the majority and are very radiosensitive. Conversely, non-germinoma GCTs (NGGCTs) are heterogeneous, relatively radioresistant and have a high risk of relapse despite multimodality therapy. Treatment of recurrence in these patients remains a therapeutic challenge. In this report we review the current literature for treatment of recurrent NGGCTs and present a case of recurrent NGGCT who relapsed despite autologous stem cell transplant (ASCT). The patient was successfully cured using multimodality therapy, consisting of repeat ASCT, intensity modulated radiation therapy and stereotactic radiosurgery.

Rapid expansion in scientific knowledge, changes in medical practice, and greater demands from patients and society necessitate reform of the medical curriculum. In recognition of this, medical educators across the world have recommended the adoption of competence-based education. This is intended to increase the rigour and relevance of the curriculum, move students beyond a focus on the memorisation and regurgitation of scientific facts, and better enable them to understand scientific principles and apply them to the practice of medicine. Experience from 40 years' use of competence-based curricula across the world suggests that the uncritical application of this approach to the medical curriculum may not achieve its intended aims. There are valuable lessons to be learnt from the history of competence-based education. By taking on board these lessons, confronting the pitfalls of this approach, and devising new and creative solutions to the problems inherent in this methodology, medical educators can better achieve their aim of providing a strong foundation for the practice of medicine in the twenty-first century. It is only through such a strategy-rather than the uncritical adoption of this educational approach-that we will have real movement and progress both in competence-based education in general, and in its applications to medicine in particular.

Background: Unilateral peripheral vestibular loss results in gait and balance impairment, dizziness and oscillopsia. Vestibular rehabilitation benefits patients but optimal treatment remains unknown. Virtual reality is an emerging tool in rehabilitation and provides opportunities to improve both outcomes and patient satisfaction with treatment. The Nintendo Wii Fit Plus® (NWFP) is a low cost virtual reality system that challenges balance and provides visual and auditory feedback. It may augment the motor learning that is required to improve balance and gait, but no trials to date have investigated efficacy., Methods/design: In a single (assessor) blind, two centre randomised controlled superiority trial, 80 patients with unilateral peripheral vestibular loss will be randomised to either conventional or virtual reality based (NWFP) vestibular rehabilitation for 6 weeks. The primary outcome measure is gait speed (measured with three dimensional gait analysis). Secondary outcomes include computerised posturography, dynamic visual acuity, and validated questionnaires on dizziness, confidence and anxiety/depression. Outcome will be assessed post treatment (8 weeks) and at 6 months., Discussion: Advances in the gaming industry have allowed mass production of highly sophisticated low cost virtual reality systems that incorporate technology previously not accessible to most therapists and patients. Importantly, they are not confined to rehabilitation departments, can be used at home and provide an accurate record of adherence to exercise. The benefits of providing augmented feedback, increasing intensity of exercise and accurately measuring adherence may improve conventional vestibular rehabilitation but efficacy must first be demonstrated., Trial Registration: Clinical trials.gov identifier: NCT01442623.

Objective: We implement an opt-out routine screening program in a high-volume, urban emergency department (ED), using conventional (nonrapid) technology as an alternative to rapid HIV tests., Methods: We performed a retrospective cohort study. Since October 2008, all patients who visited Ben Taub General Hospital ED and had blood drawn were considered eligible for routine opt-out HIV screening. The hospital is a large, publicly funded, urban, academic hospital in Houston, TX. The ED treats approximately 8,000 patients monthly. Screening was performed with standard chemiluminescence technology, batched hourly. Patients with positive screening test results were informed of their likely status, counseled by a service linkage worker, and offered follow-up care at an HIV primary care clinic. Confirmatory Western blot assays were automatically performed on all new HIV-positive samples., Results: Between October 1, 2008, and April 30, 2009, 14,093 HIV tests were performed and 39 patients (0.3%) opted out. Two hundred sixty-two (1.9%) HIV test results were positive and 80 new diagnoses were made, for an incidence of new diagnoses of 0.6%. There were 22 false-positive chemiluminescence results and 7 indeterminate Western blot results. Nearly half the patients who received a new diagnosis were not successfully linked to HIV care in our system., Conclusion: Opt-out screening using standard nonrapid technology, rather than rapid testing, is feasible in a busy urban ED. This method of HIV screening has cost benefits and a low false-positivity rate, but aggressive follow-up and referral of patients with new diagnoses for linkage to care is required., (Copyright © 2011. Published by Mosby, Inc.)

Background: Leishmania species are parasitic protozoa that have a tightly controlled cell cycle, regulated by cyclin-dependent kinases (CDKs). Cdc2-related kinase 3 (CRK3), an essential CDK in Leishmania and functional orthologue of human CDK1, can form an active protein kinase complex with Leishmania cyclins CYCA and CYC6. Here we describe the identification and synthesis of specific small molecule inhibitors of bacterially expressed Leishmania CRK3:CYC6 using a high throughput screening assay and iterative chemistry. We also describe the biological activity of the molecules against Leishmania parasites., Methodology/principal Findings: In order to obtain an active Leishmania CRK3:CYC6 protein kinase complex, we developed a co-expression and co-purification system for Leishmania CRK3 and CYC6 proteins. This active enzyme was used in a high throughput screening (HTS) platform, utilising an IMAP fluorescence polarisation assay. We carried out two chemical library screens and identified specific inhibitors of CRK3:CYC6 that were inactive against the human cyclin-dependent kinase CDK2:CycA. Subsequently, the best inhibitors were tested against 11 other mammalian protein kinases. Twelve of the most potent hits had an azapurine core with structure activity relationship (SAR) analysis identifying the functional groups on the 2 and 9 positions as essential for CRK3:CYC6 inhibition and specificity against CDK2:CycA. Iterative chemistry allowed synthesis of a number of azapurine derivatives with one, compound 17, demonstrating anti-parasitic activity against both promastigote and amastigote forms of L. major. Following the second HTS, 11 compounds with a thiazole core (active towards CRK3:CYC6 and inactive against CDK2:CycA) were tested. Ten of these hits demonstrated anti-parasitic activity against promastigote L. major., Conclusions/significance: The pharmacophores identified from the high throughput screens, and the derivatives synthesised, selectively target the parasite enzyme and represent compounds for future hit-to-lead synthesis programs to develop therapeutics against Leishmania species. Challenges remain in identifying specific CDK inhibitors with both target selectivity and potency against the parasite.