Healthcare professionals' views of the use and administration of two salvage therapy drugs for acute ulcerative colitis:a nest qualitative study within the CONSTRUCT trial

OBJECTIVES: Insight into healthcare professionals’ views and experiences of the use of ciclosporin and infliximab as salvage therapies for acute ulcerative colitis (UC) and how this may affect participation in a comparison trial is lacking. The study aimed to capture views and opinions of healthcare professionals about the two drugs within the CONSTRUCT trial. DESIGN: An interview-based qualitative study using Framework Analysis embedded within an open-label, pragmatic randomised trial. SETTING: National Health Service Health Boards and Trusts, including large teaching and district hospitals in England, Scotland and Wales. PARTICIPANTS: Principal Investigators (PIs) for trial sites (who were all consultant gastroenterologists) and nurses responsible for administering and monitoring the salvage therapy drugs across trial sites. 15 PIs and 8 nurses recruited from a range of sites stratified by site recruitment rates were interviewed. RESULTS: Interviews revealed that professionals made judgements regarding the salvage therapies largely based on experience of giving the two drugs and perceptions of effectiveness and adverse side effects. A clear preference for infliximab among nurses was revealed, largely based on experiences of administration and drug handling, with some doctors strongly favouring infliximab based on experience of prescribing the drug as well as patient views and the existing evidence base. Most doctors were more equivocal, and all were prepared to suspend preferences and wait for evidence of effectiveness and safety from the CONSTRUCT trial. PIs also questioned guidelines around drug use and restrictions placed on personal autonomy in delivering best patient care. CONCLUSIONS: Findings highlight healthcare professionals’ preference for the salvage treatment, infliximab in treating steroid-resistant UC, largely based on resource intensive nursing requirements of intravenous administration of ciclosporin. Not all doctors expressed this preference, being more equivocal, and all professionals were content to suspend preferences within the CONSTRUCT trial and recognised the importance of establishing relative effectiveness and safety. TRIAL REGISTRATION NUMBER: ISRCTN 22663589

Exploring differentially expressed genes of Staphylococcus aureus exposed to human tonsillar cells using RNA sequencing

Background - The nose and the throat are the most predominant colonizing sites of Staphylococcus aureus, and colonization is a risk factor for infection. Nasal colonization is well described; however, we have limited knowledge about S. aureus throat colonization. The main objective of this study was to explore differentially expressed genes (DEGs) in S. aureus throat isolate TR145 exposed to human tonsil epithelial cells (HTEpiC) by using RNA sequencing (RNA-seq) and pathway analysis. DEGs in S. aureus at 1 or 3 hours (h) interaction with its host were explored. Results - S. aureus was co-cultured in absence and presence of tonsillar cells at 1 or 3 h. Over the 3 h time frame, the bacteria multiplied, but still caused only minor cytotoxicity. Upon exposure to tonsillar cell line, S. aureus changed its transcriptomic profile. A total of 508 DEGs were identified including unique (1 h, 160 DEGs and 3 h, 78 DEGs) and commonly shared genes (1 and 3 h, 270 DEGs). Among the DEGs, were genes encoding proteins involved in adhesion and immune evasion, as well as iron acquisition and transport. Reverse transcription qPCR was done on selected genes, and the results correlated with the RNA-seq data. Conclusion - We have shown the suitability of using HTEpiC as an in vitro model for investigating key determinants in S. aureus during co-incubation with host cells. Several DEGs were unique after 1 or 3 h exposure to host cells, while others were commonly expressed at both time points. As their expression is induced upon meeting with the host, they might be explored further for future targets for intervention to prevent either colonization or infection in the throat

Approaching the Dirac point in high mobility multi-layer epitaxial graphene

Multi-layer epitaxial graphene (MEG) is investigated using far infrared (FIR) transmission experiments in the different limits of low magnetic fields and high temperatures. The cyclotron-resonance like absorption is observed at low temperature in magnetic fields below 50 mT, allowing thus to probe the nearest vicinity of the Dirac point and to estimate the conductivity in nearly undoped graphene. The carrier mobility is found to exceed 250,000 cm$^2$/(V.s). In the limit of high temperatures, the well-defined Landau level (LL) quantization is observed up to room temperature at magnetic fields below 1 T, a phenomenon unique in solid state systems. A negligible increase in the width of the cyclotron resonance lines with increasing temperature indicates that no important scattering mechanism is thermally activated, supporting recent expectations of high room-temperature mobilities in graphene.Comment: 5 pages, 3 figure

Estimating dry biomass and plant nitrogen concentration in pre-Alpine grasslands with low-cost UAS-borne multispectral data – a comparison of sensors, algorithms, and predictor sets

Grasslands are an important part of pre-Alpine and Alpine landscapes. Despite the economic value and the significant role of grasslands in carbon and nitrogen (N) cycling, spatially explicit information on grassland biomass and quality is rarely available. Remotely sensed data from unmanned aircraft systems (UASs) and satellites might be an option to overcome this gap. Our study aims to investigate the potential of low-cost UAS-based multispectral sensors for estimating above-ground biomass (dry matter, DM) and plant N concentration. In our analysis, we compared two different sensors (Parrot Sequoia, SEQ; MicaSense RedEdge-M, REM), three statistical models (linear model; random forests, RFs; gradient-boosting machines, GBMs), and six predictor sets (i.e. different combinations of raw reflectance, vegetation indices, and canopy height). Canopy height information can be derived from UAS sensors but was not available in our study. Therefore, we tested the added value of this structural information with in situ measured bulk canopy height data. A combined field sampling and flight campaign was conducted in April 2018 at different grassland sites in southern Germany to obtain in situ and the corresponding spectral data. The hyper-parameters of the two machine learning (ML) approaches (RF, GBM) were optimized, and all model setups were run with a 6-fold cross-validation. Linear models were characterized by very low statistical performance measures, thus were not suitable to estimate DM and plant N concentration using UAS data. The non-linear ML algorithms showed an acceptable regression performance for all sensor–predictor set combinations with average (avg; cross-validated, cv) R2cv of 0.48, RMSEcv,avg of 53.0 g m2, and rRMSEcv,avg (relative) of 15.9 % for DM and with R2cv, avg of 0.40, RMSEcv,avg of 0.48 wt %, and rRMSEcv, avg of 15.2 % for plant N concentration estimation. The optimal combination of sensors, ML algorithms, and predictor sets notably improved the model performance. The best model performance for the estimation of DM (R2cv=0.67, RMSEcv=41.9 g m2, rRMSEcv=12.6 %) was achieved with an RF model that utilizes all possible predictors and REM sensor data. The best model for plant N concentration was a combination of an RF model with all predictors and SEQ sensor data (R2cv=0.47, RMSEcv=0.45 wt %, rRMSEcv=14.2 %). DM models with the spectral input of REM performed significantly better than those with SEQ data, while for N concentration models, it was the other way round. The choice of predictors was most influential on model performance, while the effect of the chosen ML algorithm was generally lower. The addition of canopy height to the spectral data in the predictor set significantly improved the DM models. In our study, calibrating the ML algorithm improved the model performance substantially, which shows the importance of this step

Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes

Significance: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging. Critical Issues: Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+ promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways. Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD+ precursors and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients\u27 NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases

'Recruitment, recruitment, recruitment' - the need for more focus on retention: a qualitative study of five trials

Abstract Background Loss to follow-up (attrition) is a frequent problem in clinical trials and can introduce bias or reduce power. So, understanding retention issues and strategies to address these are important. As part of a multi-method project, this qualitative study aimed to explore retention strategies used by trial teams and factors which may influence strategy adoption. Method A purposive sample of active trials was selected from the UK NIHR HTA portfolio of ongoing trials in 2014/2015. Semi-structured interviews with several trial team members from each trial and supplementary interviews with experienced trial managers explored strategies in collecting clinical outcome data and retaining participants. Interview data were analysed thematically using techniques of constant comparison. Results Twenty-two semi-structured interviews with trial team members including chief investigators, trial managers, nurses and research administrators revealed strategies used to enhance retention. Some were recognised methods and planned from trial outset whilst others were implemented more responsively. Interviewees placed great value on fostering positive relationships with trial participants to enhance retention. However, these strategies took time which was not always appreciated by the wider trial team or funding bodies. The national focus on recruitment targets in networks posed a challenge to staff and was deemed detrimental to retention. The ‘moral compass’ of individual researchers relied on their own beliefs and values and research experience and the factors affected their confidence to pursue participant data during follow-up. Conclusion The role of trial staff and their underlying behaviours influence retention practices and, combined with emphasis on recruitment targets, can be detrimental to motivation and retention activities. There is a need to consider how to train and support trial staff involved in retention practices and recognition of retention from funding bodies and oversight organisations

Interventions to increase access to or uptake of physical health screening in people with severe mental illness: a realist review

Objectives: To identify and evaluate interventions aimed at increasing uptake of, or access to, physical health screening by adults with severe mental illness; to examine why interventions might work. Design: Realist review. Setting: Primary, secondary and tertiary care. Results: A systematic search identified 1448 studies, of which 22 met the inclusion criteria. Studies were from Australia (n=3), Canada (n=1), Hong Kong (n=1), UK (n=11) and USA (n=6). The studies focused on breast cancer screening, infection preventive services and metabolic syndrome (MS) screening by targeting MSrelated risk factors. The interventions could be divided into those focusing on (1) health service delivery changes (12 studies), using quality improvement, randomised controlled trial, cluster randomised feasibility trial, retrospective audit, cross-sectional study and satisfaction survey designs and (2) tests of tools designed to facilitate screening (10 studies) using consecutive case series, quality improvement, retrospective evaluation and pre–post audit study designs. All studies reported improved uptake of screening, or that patients had received screening they would not have had without the intervention. No estimation of overall effect size was possible due to heterogeneity in study design and quality. The following factors may contribute to intervention success: staff and stakeholder involvement in screening, staff flexibility when taking physical measurements (eg, using adapted equipment), strong links with primary care and having a pharmacist on the ward. Conclusions: A range of interventions may be effective, but better quality research is needed to determine any effect size. Researchers should consider how interventions may work when designing and testing them in order to target better the specific needs of this population in the most appropriate setting. Behaviour-change interventions to reduce identified barriers of patient and health professional resistance to screening this population are required. Resource constraints, clarity over professional roles and better coordination with primary care need to be addresse

Relating increasing hantavirus incidences to the changing climate: the mast connection

<p>Abstract</p> <p>Background</p> <p>Nephropathia epidemica (NE), an emerging rodent-borne viral disease, has become the most important cause of infectious acute renal failure in Belgium, with sharp increases in incidence occurring for more than a decade. Bank voles are the rodent reservoir of the responsible hantavirus and are known to display cyclic population peaks. We tried to relate these peaks to the cyclic NE outbreaks observed since 1993. Our hypothesis was that the ecological causal connection was the staple food source for voles, being seeds of deciduous broad-leaf trees, commonly called "mast". We also examined whether past temperature and precipitation preceding "mast years" were statistically linked to these NE outbreaks.</p> <p>Results</p> <p>Since 1993, each NE peak is immediately preceded by a mast year, resulting in significantly higher NE case numbers during these peaks (Spearman R = -0.82; P = 0.034). NE peaks are significantly related to warmer autumns the year before (R = 0.51; P < 0.001), hotter summers two years before (R = 0.32; P < 0.001), but also to colder (R = -0.25; P < 0.01) and more moist summers (R = 0.39; P < 0.001) three years before. Summer correlations were even more pronounced, when only July was singled out as the most representative summer month.</p> <p>Conclusion</p> <p>NE peaks in year 0 are induced by abundant mast formation in year-1, facilitating bank vole survival during winter, thus putting the local human population at risk from the spring onwards of year 0. This bank vole survival is further promoted by higher autumn temperatures in year-1, whereas mast formation itself is primed by higher summer temperatures in year-2. Both summer and autumn temperatures have been rising to significantly higher levels during recent years, explaining the virtually continuous epidemic state since 2005 of a zoonosis, considered rare until recently. Moreover, in 2007 a NE peak and an abundant mast formation occurred for the first time within the same year, thus forecasting yet another record NE incidence for 2008. We therefore predict that with the anticipated climate changes due to global warming, NE might become a highly endemic disease in Belgium and surrounding countries.</p