Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors.

Transforming growth factor beta-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, 'p001', showed significantly reduced overall survival (5-year overall survival 30.7% for p001/ p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year nonrelapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/ p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04-2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06-2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor beta-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor beta-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms

Long Term Prognostic Impact of Sex-specific Longitudinal Changes in Blood Pressure. The EPIC-Norfolk Prospective Population Cohort Study

AIMS: We aimed to determine the sex differences in longitudinal systolic and diastolic blood pressure (SBP and DBP) trajectories in mid-life and delineate the associations between these and mortality (all-cause, cardiovascular, and non-cardiovascular) and incident cardiovascular disease (CVD) in old age. METHODS AND RESULTS: Participants were selected from the European Prospective Investigation into Cancer, Norfolk (EPIC-Norfolk) cohort study. Sex-specific trajectories were determined using group-based trajectory models using three clinic BP measurements acquired between 1993 and 2012 (mean exposure ∼12.9 years). Multivariable Cox regressions determined the associations between trajectories and incident outcomes over the follow-up (median follow-up 9.4 years). A total of 2897 men (M) and 3819 women (F) were included. At baseline, women were younger (F-55.5, M-57.1), had a worse cardiometabolic profile and were less likely to receive primary CVD prevention including antihypertensive treatment (F-36.0%, M-42.0%). Over the exposure period, women had lower SBP trajectories while men exhibited more pronounced SBP decreases over this period. Over the follow-up period, women had lower mortality (F-11.9%, M-20.5%) and CVD incidence (F-19.8%, M-29.6%). Compared to optimal SBP (≤120 mmHg) and DBP (≤70 mmHg) trajectories, hypertensive trajectories were associated with increased mortality and incident CVD in both men and women during follow-up at univariable level. These associations were nevertheless not maintained upon extensive confounder adjustment including antihypertensive therapies. CONCLUSION: We report sex disparities in CVD prevention which may relate to worse cardiometabolic profiles and less pronounced longitudinal SBP decreases in women. Effective anti-hypertensivetherapy may offset the adverse outcomes associated with prolonged exposure to high blood pressure

Enhanced switching stability in Ta 2 O 5 resistive RAM by fluorine doping

The effect of fluorine doping on the switching stability of Ta2O5 resistive random access memory devices is investigated. It shows that the dopant serves to increase the memory window and improve the stability of the resistive states due to the neutralization of oxygen vacancies. The ability to alter the current in the low resistance state with set current compliance coupled with large memory window makes multilevel cell switching more favorable. The devices have set and reset voltages of <1V with improved stability due to the fluorine doping. Density functional modelling shows that the incorporation of fluorine dopant atoms at the two-fold O vacancy site in the oxide network removes the defect state in the mid bandgap, lowering the overall density of defects capable of forming conductive filaments. This reduces the probability of forming alternative conducting paths and hence improves the current stability in the low resistance states. The doped devices exhibit more stable resistive states in both dc and pulsed set and reset cycles. The retention failure time is estimated to be a minimum of 2 years for F-doped devices measured by temperature accelerated and stress voltage accelerated retention failure methods

The role of nitrogen doping in ALD Ta2O5 and its influence on multilevel cell switching in RRAM

The role of nitrogen doping on the stability and memory window of resistive state switching in N-doped Ta2O5 deposited by atomic layer deposition is elucidated. Nitrogen incorporation increases the stability of resistive memory states which is attributed to neutralization of electronic defect levels associated with oxygen vacancies. The density functional simulation with screened exchange hybrid functional approximation finds that the incorporation of nitrogen dopant atoms in the oxide network removes the O vacancy midgap defect states, thus nullifying excess defects and eliminating alternative conductive paths. By effectively reducing the density of vacancy-induced defect states through N doping, 3-bit multilevel cell switching is demonstrated, consisting of eight distinctive resistive memory states achieved by either controlling the set current compliance or the maximum voltage during reset. Nitrogen doping has a threefold effect; widening the switching memory window to accommodate more intermediate states, improving the stability of states, and providing gradual reset for multi-level cell switching during reset. The N-doped Ta2O5 devices have relatively small set and reset voltages (< 1 V) with reduced variability due to doping

Low estimated glomerular filtration rate and pneumonia in stroke patients: findings from a prospective stroke registry in the East of England

Priya Vart,1,2 Joao H Bettencourt-Silva,3,4 Anthony K Metcalf,3,4 Kristian M Bowles,3,4 John F Potter,3,4 Phyo K Myint1,3,4 1Ageing Clinical and Experimental Research, Institute of Applied Health Sciences, School of Medicine, Medical Sciences &amp; Nutrition, University of Aberdeen, Aberdeen, UK; 2Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands; 3Stroke Research Group, Norfolk and Norwich University Hospital, Norwich, UK; 4Norwich Medical School, University of East Anglia, Norwich, UK Purpose: Low estimated glomerular filtration rate (eGFR) (&lt;60 mL/min/1.73 m2) is a recognized risk factor for pneumonia in general population. While pneumonia is common after stroke, the association between levels of eGFR and pneumonia in stroke patient population has not yet been examined thoroughly. Patients and methods: Using data of 10,329 patients from the Norfolk and Norwich Stroke Registry between January 2003 and April 2015, we examined the association of poststroke pneumonia (in-hospital and after discharge) with low eGFR and when eGFR is divided into the complete spectrum of clinically relevant categories; (&ge;90) (ref.), 60&ndash;89, 45&ndash;59, 30&ndash;44, 15&ndash;30, and &lt;15 mL/min/1.73 m2). Results: In all, 1,519 (14.7%) developed in-hospital pneumonia and 1,037 (12.9%) developed pneumonia after hospital discharge. In age- and sex-adjusted model, low eGFR was associated with in-hospital pneumonia (subdistribution hazard ratio (sHR): 1.13; 95% CI: 1.01&ndash;1.25) and pneumonia after discharge (sHR: 1.20; 95% CI: 1.07&ndash;1.38). In fully adjusted model, association remained significant for pneumonia after hospital discharge. When eGFR was categorized in all clinically relevant categories, association with in-hospital pneumonia tended to be &ldquo;U&rdquo; shaped (eg, compared to eGFR &ge;90, sHR for 60&ndash;89 was 0.78; 95% CI: 0.62&ndash;0.99 and for &lt;15 was 1.06; 95% CI: 0.71&ndash;1.60) and association with pneumonia after discharge tended to increase with decline in eGFR level such that risk was almost two fold higher at eGFR &lt;15 (sHR: 1.85; 95% CI: 1.01&ndash;3.51). Association for in-hospital pneumonia was driven mainly by aspiration pneumonia, whereas association in stroke survivors was predominantly for nonaspiration pneumonia. Conclusion: In stroke patients, low eGFR at admission was associated with pneumonia, particularly severely reduced eGFR with nonaspiration pneumonia after hospital discharge. eGFR could form the basis for identifying patients at high risk of poststroke pneumonia. Keywords: stroke, eGFR, prognosis, epidemiolog

Reconstructing ‘the Alcoholic’: Recovering from Alcohol Addiction and the Stigma this Entails

Public perception of alcohol addiction is frequently negative, whilst an important part of recovery is the construction of a positive sense of self. In order to explore how this might be achieved, we investigated how those who self-identify as in recovery from alcohol problems view themselves and their difficulties with alcohol and how they make sense of others’ responses to their addiction. Semi-structured interviews with six individuals who had been in recovery between 5 and 35 years and in contact with Alcoholics Anonymous were analysed using Interpretative Phenomenological Analysis. The participants were acutely aware of stigmatising images of ‘alcoholics’ and described having struggled with a considerable dilemma in accepting this identity themselves. However, to some extent they were able to resist stigma by conceiving of an ‘aware alcoholic self’ which was divorced from their previously unaware self and formed the basis for a new more knowing and valued identity

What do evidence-based secondary journals tell us about the publication of clinically important articles in primary healthcare journals?

BACKGROUND: We conducted this analysis to determine i) which journals publish high-quality, clinically relevant studies in internal medicine, general/family practice, general practice nursing, and mental health; and ii) the proportion of clinically relevant articles in each journal. METHODS: We performed an analytic survey of a hand search of 170 general medicine, general healthcare, and specialty journals for 2000. Research staff assessed individual articles by using explicit criteria for scientific merit for healthcare application. Practitioners assessed the clinical importance of these articles. Outcome measures were the number of high-quality, clinically relevant studies published in the 170 journal titles and how many of these were published in each of four discipline-specific, secondary "evidence-based" journals (ACP Journal Club for internal medicine and its subspecialties; Evidence-Based Medicine for general/family practice; Evidence-Based Nursing for general practice nursing; and Evidence-Based Mental Health for all aspects of mental health). Original studies and review articles were classified for purpose: therapy and prevention, screening and diagnosis, prognosis, etiology and harm, economics and cost, clinical prediction guides, and qualitative studies. RESULTS: We evaluated 60,352 articles from 170 journal titles. The pass criteria of high-quality methods and clinically relevant material were met by 3059 original articles and 1073 review articles. For ACP Journal Club (internal medicine), four titles supplied 56.5% of the articles and 27 titles supplied the other 43.5%. For Evidence-Based Medicine (general/family practice), five titles supplied 50.7% of the articles and 40 titles supplied the remaining 49.3%. For Evidence-Based Nursing (general practice nursing), seven titles supplied 51.0% of the articles and 34 additional titles supplied 49.0%. For Evidence-Based Mental Health (mental health), nine titles supplied 53.2% of the articles and 34 additional titles supplied 46.8%. For the disciplines of internal medicine, general/family practice, and mental health (but not general practice nursing), the number of clinically important articles was correlated withScience Citation Index (SCI) Impact Factors. CONCLUSIONS: Although many clinical journals publish high-quality, clinically relevant and important original studies and systematic reviews, the articles for each discipline studied were concentrated in a small subset of journals. This subset varied according to healthcare discipline; however, many of the important articles for all disciplines in this study were published in broad-based healthcare journals rather than subspecialty or discipline-specific journals

Scalable Production and Purification of Adeno-Associated Viral Vectors (AAV).

Here we describe methods for the production of adeno-associated viral (AAV) vectors by transient transfection of HEK293 cells grown in serum-free medium in orbital shaken bioreactors and the subsequent purification of vector particles. The protocol for expression of AAV components is based on polyethyleneimine (PEI) mediated transfection of a 2-plasmid system and is specified for production in milliliter to liter scales. After PEI and plasmid DNA (pDNA) complex formation the diluted cell culture is transfected without a prior concentration step or medium exchange. Following a 3-day batch process, cell cultures are further processed using different methods for lysis and recovery. Methods for the purification of viral particles are described, including iodixanol gradient purification, immunoaffinity chromatography, and ultrafiltration, as well as quantitative PCR to quantify vector titer

Does age matter? The impact of rodent age on study outcomes

Rodent models produce data which underpin biomedical research and non-clinical drug trials, but translation from rodents into successful clinical outcomes is often lacking. There is a growing body of evidence showing that improving experimental design is key to improving the predictive nature of rodent studies and reducing the number of animals used in research. Age, one important factor in experimental design, is often poorly reported and can be overlooked. The authors conducted a survey to assess the age used for a range of models, and the reasoning for age choice. From 297 respondents providing 611 responses, researchers reported using rodents most often in the 6–20 week age range regardless of the biology being studied. The age referred to as ‘adult’ by respondents varied between six and 20 weeks. Practical reasons for the choice of rodent age were frequently given, with increased cost associated with using older animals and maintenance of historical data comparability being two important limiting factors. These results highlight that choice of age is inconsistent across the research community and often not based on the development or cellular ageing of the system being studied. This could potentially result in decreased scientific validity and increased experimental variability. In some cases the use of older animals may be beneficial. Increased scientific rigour in the choice of the age of rodent may increase the translation of rodent models to humans