Education’s not black and white, it’s vibrant grey

This paper offers a learner’s eye-view of a journey through education, written in an auto-narrative style. Sarah’s story spans from Secondary School to College and through University finishing at the point of Graduation. Revealed in this open and honest account is an insight to coping with home life whilst navigating the trials of the Education system. Sarah makes criticisms of her peers at every level reminding us how competitive some students have to be to get on and achieve success in their education. Critical judgements are also made about Sarah’s School teachers and University lecturers, which are at times as rewarding as they are uncomfortable, but always truthful. Consequently, there is much to learn by both academics and students from this sensitive and vulnerable personal revelation. Sarah’s evidence in turn points to some fundamental questions about the genuine outcomes of the Educational system, e.g. what are we actually teaching young people to be like? And do we like the product in terms of their values, beliefs and motives? A concluding message from Sarah’s perspective is that greater independence in learning, freedom in thinking and equipping people to reason, judge and make decisions in whatever realm, may be defining steps towards becoming educated

Exploring the Pathogenic and Drug Resistance Mechanisms of Staphylococcus aureus

We have previously identified σS, an ECF sigma factor that is important in the virulence and stress response of S. aureus. Transcriptional profiling of sigS revealed that it is differentially regulated in a variety of laboratory and clinical strains of S. aureus, suggesting that there exists a regulatory network that modulates its expression. In order to identify direct regulators of sigS expression, we performed a biotin pull down assay in tandem with mass spectrometry. We identified CymR as a direct regulator and observed that sigS expression is increased in cells lacking cymR. In addition, transposon mutagenesis was performed to identify regulators of sigS expression. We identified insertions in genes that are transcriptional regulators, and elements involved in amino acid biosynthesis and DNA replication, recombination and repair as influencing sigS expression. Finally, methyl nitro-nitrosoguanidine mutagenesis in conjunction with whole genome sequencing was employed and revealed mutations in the lactose repressor, lacR, and the membrane sensor histidine kinase, kdpD, as negatively effecting sigS expression. EMSAs revealed that LacR is an indirect regulator of sigS expression, while the response regulator KdpE is a direct repressor. These results indicate that a complex regulatory network is in place for sigS that modulates its expression. In a continuation of studies on σS regulation, we next explored interplay with the products of genes conserved within the sigS locus. We determined that this region is conserved amongst all the sequenced staphylococci, and includes four genes: SAUSA300_1721 (a conserved hypothetical protein), as well as sigS, ecfX, and ecfY. In order to investigate the relationship between EcfX and σS we performed protein pull down assays and observed that these two protein interact. Further to this, transcriptional analysis of sigS in an ecfX mutant reveal that expression of sigS is decreased, indicating that it is an activator. Architectural analysis of the sigS locus via RNAseq revealed that the majority of transcription in this region comes from ecfY, a gene that is downstream and divergent to sigS. We demonstrate that inactivation of ecfY leads to a significant increase in sigS expression, and that ecfY null strains are more resistant to DNA damaging agents such as UV, H2O2, MMS, and ethidium bromide, which we have previously demonstrated that a sigS mutant is highly sensitive to. Our studies also revealed that an ecfY null strain is better able to survive intracellularly following phagocytosis by RAW 264.7 cell and demonstrates increased survival in whole-human blood, which is again opposed to that previously observed for sigS deficient strains. Because the ecfY null strain overexpresses sigS, we investigated the regulon of this sigma factor using this mutant in conjunction with RNAseq analysis. We identified that genes putatively under the control of σS are involved in DNA damage and repair, virulence, amino acid starvation and nucleic acid biosynthesis. Collectively, our results indicate that σS is regulated via a unique mechanism: positively through an apparent need for an activator protein (EcfX) and negatively via RNA-RNA interaction (the 3’ UTR of ecfY). We suggest that the evidence presented here greatly adds not only to our understanding of the regulatory circuits extant within S. aureus, but also to alternative sigma factor biology in general. Finally, we evaluated the efficacy of a novel library of quinazoline-based compounds against a highly drug resistant strain of S. aureus. We performed structure activity and structure property relationship assays in order to identify lead compounds. These methods lead to the identification of N2,N4-disubstituted quinazoline-2,4-diamines that had low minimum inhibitory concentrations, along with favorable physiochemical properties. Evaluation of their biological activity demonstrated limited potential for resistance of to our quinazoline based compounds, low toxicity to human epithelial cells, and strong efficacy in vivo. Taken together, our findings support the use of quinazoline derivatives as potential new antimicrobials against multidrug resistant S. aureus

Tracer concentration profiles measured in central London as part of the REPARTEE campaign

There have been relatively few tracer experiments carried out that have looked at vertical plume spread in urban areas. In this paper we present results from two tracer (cyclic perfluorocarbon) experiments carried out in 2006 and 2007 in central London centred on the BT Tower as part of the REPARTEE (Regent’s Park and Tower Environmental Experiment) campaign. The height of the tower gives a unique opportunity to study vertical dispersion profiles and transport times in central London. Vertical gradients are contrasted with the relevant Pasquill stability classes. Estimation of lateral advection and vertical mixing times are made and compared with previous measurements. Data are then compared with a simple operational dispersion model and contrasted with data taken in central London as part of the DAPPLE campaign. This correlates dosage with non-dimensionalised distance from source. Such analyses illustrate the feasibility of the use of these empirical correlations over these prescribed distances in central London

Extending periodic eddy covariance latent heat fluxes through tree sap-flow measurements to estimate long-term total evaporation in a peat swamp forest

A combination of measurement and modelling was used to find a pragmatic solution to estimate the annual total evaporation from the rare and indigenous Nkazana Peat Swamp Forest (PSF) on the east coast of Southern Africa to improve the water balance estimates within the area. Actual total evaporation (ETa) was measured during three window periods (between 7 and 9 days each) using an eddy covariance (EC) system on a telescopic mast above the forest canopy. Sap flows of an understory tree and an emergent tree were measured using a low-maintenance heat pulse velocity system for an entire hydrological year (October 2009 to September 2010). An empirical model was derived, describing the relationship between ETa from the Nkazana PSF and sap-flow measurements. These overlapped during two of the window periods (R2 = 0.92 and 0.90), providing hourly estimates of ETa from the Nkazana PSF for a year, totalling 1125 mm (while rainfall was 650 mm). In building the empirical model, it was found that to include the understory tree sap flow provided no benefit to the model performance. In addition, the relationship between the emergent tree sap flow with ETa between the two field campaigns was consistent and could be represented by a single empirical model (R2 = 0.90; RMSE = 0.08 mm h−1). During the window periods of EC measurement, no single meteorological variable was found to describe the Nkazana PSF ETa satisfactorily. However, in terms of evaporation models, the hourly FAO Penman–Monteith reference evaporation (ETo) best described ETa during the August 2009 (R2 = 0.75), November 2009 (R2 = 0.85) and March 2010 (R2 = 0.76) field campaigns, compared to the Priestley–Taylor potential evaporation (ETp) model (R2 = 0.54, 0.74 and 0.62 during the respective field campaigns). From the extended record of ETa (derived in this study from sap flow) and ETo, a monthly crop factor (Kc) was derived for the Nkazana PSF, providing a method of estimating long-term swamp forest water-use from meteorological data. The monthly Kc indicated two distinct periods. From February to May, it was between 1.2 and 1.4 compared with June to January, when the crop factor was 0.8 to 1.0. The derived monthly Kc values were verified as accurate (to one significant digit) using historical data measured at the same site, also using EC, from a previous study. The measurements provided insights into the microclimate within a subtropical peat swamp forest and the contrasting sap flow of emergent and understory trees. They showed that expensive, high-maintenance equipment can be used during manageable window periods in conjunction with low-maintenance systems, dedicated to individual trees, to derive a model to estimate long-term ETa over remote heterogeneous forests. In addition, the contrast in annual ETa and rainfall emphasised the reliance of the Nkazana PSF on groundwater

Automated psychological therapy using immersive virtual reality for treatment of fear of heights: A single-blind, parallel-group, randomised controlled trial

Background Engaging, interactive, and automated virtual reality (VR) treatments might help solve the unmet needs of individuals with mental health disorders. We tested the efficacy of an automated cognitive intervention for fear of heights guided by an avatar virtual coach (animated using motion and voice capture of an actor) in VR and delivered with the latest consumer equipment. Methods We did a randomised trial of automated VR versus usual care. We recruited adults aged older than 18 years with a fear of heights by radio advertisements in Oxfordshire, UK. We diagnosed fear of heights if participants scored more than 29 on the Heights Interpretation Questionnaire (HIQ). We randomly allocated participants by computer in a 1:1 ratio to either automated VR delivered in roughly six 30-min sessions administered about two to three times a week over a 2-week period (intervention group) or to usual care (control group). Randomisation was stratified by severity of fear of heights. The research team, who were unaware of the random allocation, administered three fear-of-height assessments, at baseline (0 weeks), at the end of treatment (2 weeks), and at follow-up (4 weeks). The primary outcome measure was HIQ score (range 16–80, with higher scores indicating greater severity). This trial is registered with the ISRCTN registry, number ISRCTN11898283. Findings Between Nov 25, 2017, and Feb 27, 2018, 100 individuals were enrolled and underwent randomisation, of whom 49 were assigned to the VR treatment group and 51 to the control group. All participants completed the 4-week follow-up. The mean total treatment time in VR was 124·43 min (SD 34·23). Compared with participants in the control group, the VR treatment reduced fear of heights at the end of treatment (mean change score −24·5 [SD 13·1] in the VR group vs −1·2 [7·3] in the control group; adjusted difference −24·0, 95% CI −27·7 to −20·3; Cohen's d=2·0; p<0·0001). The benefit was maintained at follow-up (mean change score −25·1 [SD 13·9] in the VR group vs −1·5 [7·8] in the control group; adjusted difference −24·3, 95% CI −27·9 to −20·6; Cohen's d=2·0; p<0·0001). The number needed to treat to at least halve the fear of heights was 1·3. No adverse events were reported. Interpretation Psychological therapy delivered automatically by a VR coach can produce large clinical benefits. Evidence-based VR treatments have the potential to greatly increase treatment provision for mental health disorders

Doctor Referral of Overweight People to a Low-Energy Treatment (DROPLET) in primary care using total diet replacement products:A protocol for a randomised controlled trial

Introduction The global prevalence of obesity has risen significantly in recent decades. There is a pressing need to identify effective interventions to treat established obesity that can be delivered at scale. The aim of the Doctor Referral of Overweight People to a Low-Energy Treatment (DROPLET) study is to determine the clinical effectiveness, feasibility and acceptability of referral to a low-energy total diet replacement programme compared with usual weight management interventions in primary care. Methods and analysis The DROPLET trial is a randomised controlled trial comparing a low-energy total diet replacement programme with usual weight management interventions delivered in primary care. Eligible patients will be recruited through primary care registers and randomised to receive a behavioural support programme delivered by their practice nurse or a referral to a commercial provider offering an initial 810 kcal/d low-energy total diet replacement programme for 8 weeks, followed by gradual food reintroduction, along with weekly behavioural support for 24 weeks. The primary outcome is weight change at 12 months. The secondary outcomes are weight change at 3 and 6 months, the proportion of participants achieving 5% and 10% weight loss at 12 months, and change in fat mass, haemoglobin A1c, low-density lipoprotein cholesterol and systolic and diastolic blood pressure at 12 months. Data will be analysed on the basis of intention to treat. Qualitative interviews on a subsample of patients and healthcare providers will assess their experiences of the weight loss programmes and identify factors affecting acceptability and adherence. Ethics and dissemination This study has been reviewed and approved by the National Health ServiceHealth Research Authority (HRA)Research Ethics Committee (Ref: SC/15/0337). The trial findings will be disseminated to academic and health professionals through presentations at meetings and peer-reviewed journals and to the public through the media. If the intervention is effective, the results will be communicated to policymakers and commissioners of weight management services.</p

The equity impact of brief opportunistic interventions to promote weight loss in primary care:secondary analysis of the BWeL randomised trial

BACKGROUND:Guidelines recommend that clinicians should make brief opportunistic behavioural interventions to patients who are obese to increase the uptake of effective weight loss programmes. The objective was to assess the effect of this policy on socioeconomic equity. METHODS:One thousand eight hundred eighty-two consecutively attending patients with obesity and who were not seeking support for weight loss from their GP were enrolled in a trial. Towards the end of each consultation, GPs randomly assigned participants to one of two 30-s interventions. In the active intervention (support arm), the GP offered referral to a weight management group. In the control intervention (advice arm), the GP advised the patient that their health would benefit from weight loss. Agreement to attend a behavioural weight loss programme, attendance at the programme and weight loss at 12 months were analysed by socioeconomic status, measured by postcode using the Index of Multiple Deprivation (IMD). RESULTS:Mean weight loss was 2.43 kg (sd 6.49) in the support group and 1.04 kg (sd 5.50) for the advice only group, but these effects were moderated by IMD (p = 0.039 for the interaction). In the support arm, weight loss was greater in higher socioeconomic groups. Participants from lower socioeconomic backgrounds were more likely to accept the offer and equally likely to attend a weight loss referral but attended fewer sessions. Adjusting for these sequentially reduced the gradient for the association of socioeconomic status with weight loss from + 0.035 to - 0.001 kg/IMD point. In the advice only arm, 10% took effective action to promote weight loss. The decision to seek support for weight loss outside of the trial did not differ by socioeconomic status, but weight loss among deprived participants who used external support was greater than among more affluent participants (p = 0.025). CONCLUSION:Participants' responses to GPs' brief opportunistic interventions to promote weight loss differed by socioeconomic status and trial arm. In the support arm, more deprived people lost less weight because they attended fewer sessions at the programme. In the advice arm, more deprived people who sought and paid for support for weight loss themselves lost more weight than more affluent people who sought support. TRIAL REGISTRATION:This trial is registered with the ISRCTN registry, number ISRCTN26563137 . Date of registration: January 3, 2013; date of first participant recruited: June 4, 2014

Sleep duration and psychotic experiences in patients at risk of psychosis: A secondary analysis of the EDIE-2 trial

Sleep disturbance is common among individuals at risk of psychosis, yet few studies have investigated the relationship between sleep disturbance and clinical trajectory. The Early Detection and Intervention Evaluation (EDIE-2) trial provides longitudinal data on sleep duration and individual psychotic experiences from a cohort of individuals at risk of psychosis, which this study utilises in an opportunistic secondary analysis. Shorter and more variable sleep was hypothesised to be associated with more severe psychotic experiences and lower psychological wellbeing. Mixed effect models were used to test sleep duration and range as predictors of individual psychotic experiences and psychological wellbeing over the 12-24 months (with assessments every 3 months) in 160 participants. Shorter sleep duration was associated with more severe delusional ideas and hallucinations cross-sectionally and longitudinally. The longitudinal relationships did not remain significant after conservative controls were added for the previous severity of psychotic experiences. No significant relationships were found between the sleep variables and other psychotic experiences (e.g. cognitive disorganisation), or psychological wellbeing. The results support a relationship between shorter sleep duration and delusional ideas and hallucinations. Future studies should focus on improving sleep disturbance measurement, and test whether treating sleep improves clinical trajectory in the at-risk group

RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation

Interleukin 7 (IL-7) promotes pre–B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre–B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre–B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 does not drive proliferation. Rather, Pim2 has antiproliferative functions that prevent the transit of pre–B cells harboring RAG DSBs from G1 into S phase, where these DNA breaks could be aberrantly repaired. Thus, signals from IL-7 and RAG DSBs activate distinct Pim kinase family members that have context-dependent activities in regulating pre–B cell proliferation and survival

Automated psychological therapy using immersive virtual reality for treatment of fear of heights:a single-blind, parallel-group, randomised controlled trial

Background: Engaging, interactive, and automated virtual reality (VR) treatments might help solve the unmet needs of individuals with mental health disorders. We tested the efficacy of an automated cognitive intervention for fear of heights guided by an avatar virtual coach (animated using motion and voice capture of an actor) in VR and delivered with the latest consumer equipment. Methods: We did a randomised trial of automated VR versus usual care. We recruited adults aged older than 18 years with a fear of heights by radio advertisements in Oxfordshire, UK. We diagnosed fear of heights if participants scored more than 29 on the Heights Interpretation Questionnaire (HIQ). We randomly allocated participants by computer in a 1:1 ratio to either automated VR delivered in roughly six 30-min sessions administered about two to three times a week over a 2-week period (intervention group) or to usual care (control group). Randomisation was stratified by severity of fear of heights. The research team, who were unaware of the random allocation, administered three fear-of-height assessments, at baseline (0 weeks), at the end of treatment (2 weeks), and at follow-up (4 weeks). The primary outcome measure was HIQ score (range 16–80, with higher scores indicating greater severity). This trial is registered with the ISRCTN registry, number ISRCTN11898283. Findings: Between Nov 25, 2017, and Feb 27, 2018, 100 individuals were enrolled and underwent randomisation, of whom 49 were assigned to the VR treatment group and 51 to the control group. All participants completed the 4-week follow-up. The mean total treatment time in VR was 124·43 min (SD 34·23). Compared with participants in the control group, the VR treatment reduced fear of heights at the end of treatment (mean change score −24·5 [SD 13·1] in the VR group vs −1·2 [7·3] in the control group; adjusted difference −24·0, 95% CI −27·7 to −20·3; Cohen's d=2·0; p&lt;0·0001). The benefit was maintained at follow-up (mean change score −25·1 [SD 13·9] in the VR group vs −1·5 [7·8] in the control group; adjusted difference −24·3, 95% CI −27·9 to −20·6; Cohen's d=2·0; p&lt;0·0001). The number needed to treat to at least halve the fear of heights was 1·3. No adverse events were reported. Interpretation: Psychological therapy delivered automatically by a VR coach can produce large clinical benefits. Evidence-based VR treatments have the potential to greatly increase treatment provision for mental health disorders.</p