General practitioners' use of risk prediction tools and their application to Barretts Oesophagus : a qualitative study

Background: Risk prediction tools are widely used for the early identification of disease and expediting referrals to medical specialists for further assessment. This study provides an understanding of general practitioners preferences for using some prediction tools over others. The recent development of a risk prediction model for Barrett’s oesophagus prompted our investigation of General Practitioners perspectives of the barriers and enablers to its use and screening tools per se. Method: Individual semi-structured interviews explored the use of risk prediction tools in the general practice setting. A case scenario was used to create a schema that described the risk assessment process for Barrett’s oesophagus. A content analysis of verbatim transcripts was coded for barriers and enablers to tool use and linked to explanatory themes. Results: Data was collected from five general practitioners and one gastroenterologist. Barriers to regular use of risk prediction tools were identified and grouped using five themes; time poverty, tool format style, remembering to use, relevance of questions, and reduced autonomy in clinical decision making. Five key reasons for regular use were also identified; simple to use, memory prompt, provides a clear guide, aids in keeping me focused, and easy to access. All participants acknowledged the need for identifying Barrett’s oesophagus, the precursor to oesophageal adenocarcinoma, and viewed our tool as a significant contribution to risk assessment of this condition. Conclusion: Identifying barriers and enablers is essential to wide implementation of risk prediction tools. Participants provided information crucial to the translation of our risk prediction model for Barrett’s oesophagus into clinical practice. They also confirmed that the developed model would be useful in the clinical setting

The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub-populations of rat trigeminal ganglion sensory neurons.

The recent discovery that mammalian nociceptors express Toll-like receptors (TLRs) has raised the possibility that these cells directly detect and respond to pathogens with implications for either direct nociceptor activation or sensitization. A range of neuronal TLRs have been identified, however a detailed description regarding the distribution of expression of these receptors within sub-populations of sensory neurons is lacking. There is also some debate as to the composition of the TLR4 receptor complex on sensory neurons. Here we use a range of techniques to quantify the expression of TLR4, TLR7 and some associated molecules within neurochemically-identified sub-populations of trigeminal (TG) and dorsal root (DRG) ganglion sensory neurons. We also detail the pattern of expression and co-expression of two isoforms of lysophosphatidylcholine acyltransferase (LPCAT), a phospholipid remodeling enzyme previously shown to be involved in the lipopolysaccharide-dependent TLR4 response in monocytes, within sensory ganglia. Immunohistochemistry shows that both TLR4 and TLR7 preferentially co-localize with transient receptor potential vallinoid 1 (TRPV1) and purinergic receptor P2X ligand-gated ion channel 3 (P2X3), markers of nociceptor populations, within both TG and DRG. A gene expression profile shows that TG sensory neurons express a range of TLR-associated molecules. LPCAT1 is expressed by a proportion of both nociceptors and non-nociceptive neurons. LPCAT2 immunostaining is absent from neuronal profiles within both TG and DRG and is confined to non-neuronal cell types under naïve conditions. Together, our results show that nociceptors express the molecular machinery required to directly respond to pathogenic challenge independently from the innate immune system

Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets

Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-γ, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Vα14Jα18 TCRα paired with unique Vβ7 or Vβ8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORγt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity

Discrete physiological effects of beetroot juice and potassium nitrate supplementation following 4-wk sprint interval training

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.The physiological and exercise performance adaptations to sprint interval training (SIT) may be modified by dietary nitrate (NO3) supplementation. However, it is possible that different types of NO3 supplementation evoke divergent physiological and performance adaptations to SIT. The purpose of this study was to compare the effects of 4-wk SIT with and without concurrent dietary NO3 supplementation administered as either NO3-rich beetroot juice (BR) or potassium NO3 (KNO3). Thirty recreationally active subjects completed a battery of exercise tests before and after a 4-wk intervention in which they were allocated to one of three groups: 1) SIT undertaken without dietary NO3 supplementation (SIT); 2) SIT accompanied by concurrent BR supplementation (SIT BR); or 3) SIT accompanied by concurrent KNO3 supplementation (SIT KNO3). During severe-intensity exercise, V O2peak and time to task failure were improved to a greater extent with SIT +BR than SIT and SIT KNO3 (P 0.05). There was also a greater reduction in the accumulation of muscle lactate at 3 min of severe-intensity exercise in SIT BR compared with SIT KNO3 (P <0.05). Plasma NO2 concentration fell to a greater extent during severe-intensity exercise in SIT BR compared with SIT and SIT KNO3 (P <0.05). There were no differences between groups in the reduction in the muscle phosphocreatine recovery time constant from pre- to postintervention (P <0.05). These findings indicate that 4-wk SIT with concurrent BR supplementation results in greater exercise capacity adaptations compared with SIT alone and SIT with concurrent KNO3 supplementation. This may be the result of greater NO-mediated signaling in SIT +BR compared with SIT+ KNO3. NEW & NOTEWORTHY We compared the influence of different forms of dietary nitrate supplementation on the physiological and performance adaptations to sprint interval training (SIT). Compared with SIT alone, supplementation with nitrate-rich beetroot juice, but not potassium NO3, enhanced some physiological adaptations to training

Familial adenomatous patients with desmoid tumours show increased expression of miR-34a in serum and high levels in tumours

Familial adenomatous polyposis (FAP) is rare affecting 1 in 10,000 people and a subset (10%) are at risk of myofibroblastic desmoid tumours (DTs) after colectomy to prevent cancer. DTs are a major cause of morbidity and mortality. The absence of markers to monitor progression and a lack of treatment options are significant limitations to clinical management. We investigated microRNAs (miRNA) levels in DTs and serum using expression array analysis on two independent cohorts of FAP patients (total, n=24). Each comprised equal numbers of patients who had formed DTs (cases) and those who had not (controls). All controls had absence of DTs confirmed by clinical and radiological assessment over at least three years post- colectomy. Technical qPCR validation was performed using an expanded cohort (29 FAP patients; 16 cases and 13 controls). The most significant elevated serum miRNA marker of DTs was miR-34a-5p and in-situ hybridisation (ISH) showed most DTs analysed (5/6) expressed miRNA-34a-5p. Exome sequencing of tumour and matched germline DNA did not detect mutations within the miR-34a-5p transcript sites or 3'-UTR of target genes that would alter functional miRNA activity. In conclusion, miR-34a-5p is a potential circulatory marker and therapy target. A large prospective world-wide multi-centre study is now warranted

Molecular dynamics simulations of oscillatory Couette flows with slip boundary conditions

The effect of interfacial slip on steady-state and time-periodic flows of monatomic liquids is investigated using non-equilibrium molecular dynamics simulations. The fluid phase is confined between atomically smooth rigid walls, and the fluid flows are induced by moving one of the walls. In steady shear flows, the slip length increases almost linearly with shear rate. We found that the velocity profiles in oscillatory flows are well described by the Stokes flow solution with the slip length that depends on the local shear rate. Interestingly, the rate dependence of the slip length obtained in steady shear flows is recovered when the slip length in oscillatory flows is plotted as a function of the local shear rate magnitude. For both types of flows, the friction coefficient at the liquid-solid interface correlates well with the structure of the first fluid layer near the solid wall.Comment: 31 pages, 11 figure

Uncovering the hidden costs of offshoring: The interplay of complexity, organizational design, and experience

This study investigates estimation errors due to hidden costs—the costs of implementation that are neglected in strategic decision-making processes—in the context of services offshoring. Based on data from the Offshoring Research Network, we find that decision makers are more likely to make cost-estimation errors given increasing configuration and task complexity in captive offshoring and offshore outsourcing, respectively. Moreover, we show that experience and a strong orientation toward organizational design in the offshoring strategy reduce the cost-estimation errors that follow from complexity. Our findings contribute to research on the effectiveness of sourcing and global strategies by stressing the importance of organizational design and experience in dealing with increasing complexity

On using visibility correlations to probe the HI distribution from the dark ages to the present epoch I: Formalism and the expected signal

Redshifted 21 cm radiation originating from the cosmological distribution of neutral hydrogen (HI) appears as a background radiation in low frequency radio observations. The angular and frequency domain fluctuations in this radiation carry information about cosmological structure formation. We propose that correlations between visibilities measured at different baselines and frequencies in radio-interferometric observations be used to quantify the statistical properties of these fluctuations. This has an inherent advantage over other statistical estimators in that it deals directly with the visibilities which are the primary quantities measured in radio-interferometric observations. Also, the visibility correlation has a very simple relation with power spectrum. We present estimates of the expected signal for nearly the entire post-recombination era, from the dark ages to the present epoch. The epoch of reionization, where the HI has a patchy distribution, has a distinct signature where the signal is determined by the size of the discrete ionized regions. The signal at other epochs, where the HI follows the dark matter, is determined largely by the power spectrum of dark matter fluctuations. The signal is strongest for baselines where the antenna separations are within a few hundred times the wavelength of observation, and an optimal strategy would preferentially sample these baselines. In the frequency domain, for most baselines the visibilities at two different frequencies are uncorrelated beyond \Delta \nu ~ 1 MHz, a signature which in principle would allow the HI signal to be easily distinguished from the continuum sources of contamination.Comment: 12 pages, 9 figures, Accepted to MNRAS; Replaced to match version accepted in MNRA

Cover to Volume 3

The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth