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

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

Transdermal fluorescence detection of a dual fluorophore system for noninvasive point-of-care gastrointestinal permeability measurement

The intestinal mucosal barrier prevents macromolecules and pathogens from entering the circulatory stream. Tight junctions in this barrier are compromised in inflammatory bowel diseases, environmental enteropathy, and enteric dysfunction. Dual sugar absorption tests are a standard method for measuring gastrointestinal integrity, however, these are not clinically amenable. Herein, we report on a dual fluorophore system and fluorescence detection instrumentation for which gastrointestinal permeability is determined in a rat small bowel disease model from the longitudinal measured transdermal fluorescence of each fluorophore. This fluorophore technology enables a specimen-free, noninvasive, point-of-care gastrointestinal permeability measurement which should be translatable to human clinical studies

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

RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals

DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre–B cell receptor (pre–BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre–BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre–B cells. Here, we show that RAG DSBs inhibit pre–BCR signals through the ATM- and NF-κB2–dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre–BCR signaling. This regulatory circuit prevents the pre–BCR from inducing additional Igl chain gene rearrangements and driving pre–B cells with RAG DSBs into cycle. We propose that pre–B cells toggle between pre–BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes

Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines

Background and Aim Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. To improve outcomes for these patients, we need to develop new treatment strategies. Personalized cancer medicine, where patients are treated based on the characteristics of their own tumor, has gained significant interest for its promise to improve outcomes and reduce unnecessary side effects. The purpose of this study was to examine the potential utility of patient-derived colorectal cancer organoids (PDCOs) in a personalized cancer medicine setting. Methods Patient-derived colorectal cancer organoids were derived from tissue obtained from treatment-naïve patients undergoing surgical resection for the treatment of CRC. We examined the recapitulation of key histopathological, molecular, and phenotypic characteristics of the primary tumor. Results We created a bio-resource of PDCOs from primary and metastatic CRCs. Key histopathological features were retained in PDCOs when compared with the primary tumor. Additionally, a cohort of 12 PDCOs, and their corresponding primary tumors and normal sample, were characterized through whole exome sequencing and somatic variant calling. These PDCOs exhibited a high level of concordance in key driver mutations when compared with the primary tumor. Conclusions Patient-derived colorectal cancer organoids recapitulate characteristics of the tissue from which they are derived and are a powerful tool for cancer research. Further research will determine their utility for predicting patient outcomes in a personalized cancer medicine setting

Late Pleistocene sediments, landforms and events in Scotland: a review of the terrestrial stratigraphic record

Lithostratigraphical studies coupled with the development of new dating methods has led to significant progress in understanding the Late Pleistocene terrestrial record in Scotland. Systematic analysis and re-evaluation of key localities have provided new insights into the complexity of the event stratigraphy in some regions and the timing of Late Pleistocene environmental changes, but few additional critical sites have been described in the past 25 years. The terrestrial stratigraphic record remains important for understanding the timing, sequence and patterns of glaciation and deglaciation during the last glacial/interglacial cycle. Former interpretations of ice-free areas in peripheral areas during the Last Glacial Maximum (LGM) are inconsistent with current stratigraphic and dating evidence. Significant challenges remain to determine events and patterns of glaciation during the Early and Middle Devensian, particularly in the context of offshore evidence and ice sheet modelling that indicate significant build-up of ice throughout much of the period. The terrestrial evidence broadly supports recent reconstructions of a highly dynamic and climate-sensitive British–Irish Ice Sheet (BIIS), which apparently reached its greatest thickness in Scotland between 30 and 27ka, before the global LGM. A thick (relative to topography) integrated ice sheet reaching the shelf edge with a simple ice-divide structure was replaced after the LGM by a much thinner one comprising multiple dispersion centres and a more complex flow structure

A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR

Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by diff

Efficacy of self-monitored blood pressure, with or without telemonitoring, for titration of antihypertensive medication (TASMINH4): an unmasked randomised controlled trial.

BACKGROUND: Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care. METHODS: This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self-monitor their blood pressure. Patients were randomly assigned (1:1:1) to self-monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care (clinic blood pressure; usual care group). Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366. FINDINGS: 1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137·0 [SD 16·7] mm Hg and telemonitoring, 136·0 [16·1] mm Hg vs usual care, 140·4 [16·5]; adjusted mean differences vs usual care: self-monitoring alone, -3·5 mm Hg [95% CI -5·8 to -1·2]; telemonitoring, -4·7 mm Hg [-7·0 to -2·4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference -1·2 mm Hg [95% CI -3·5 to 1·2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups. INTERPRETATION: Self-monitoring, with or without telemonitoring, when used by general practitioners to titrate antihypertensive medication in individuals with poorly controlled blood pressure, leads to significantly lower blood pressure than titration guided by clinic readings. With most general practitioners and many patients using self-monitoring, it could become the cornerstone of hypertension management in primary care. FUNDING: National Institute for Health Research via Programme Grant for Applied Health Research (RP-PG-1209-10051), Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK

Benchmarking of viral bronchiolitis management by general practitioners in the United Kingdom

Viral bronchiolitis is the leading cause of hospitalization in infants in the United Kingdom (UK) with wide variation in rates of hospitalization in different geographical regions of the UK. A potential cause of these differences is variation in primary care management and referral to hospital. This study aimed to prospectively survey general practitioners (GPs) in the UK to provide a benchmark of practice against which future practice can be assessed. An electronic, structured questionnaire was sent to 1,001 geographically representative GPs in primary care centers in the UK, through the market research company MedeConnect, to assess their management of infants with viral bronchiolitis. We measured practice before the 2015 National Institute for Health and Care Excellence (NICE) bronchiolitis guideline against the guideline, to obtain a benchmark of practice. We also used a multivariate analysis to assess GP factors associated with variation in management. Thirty-nine percent of GPs did not refer to any guideline to manage infants with bronchiolitis, 33% did not routinely measure oxygen saturations, 48% prescribed an “inappropriate” (evidence of no benefit) medication, and 62% did not give written guidance to parents. GP factors influencing management included the year the GP qualified, sex, region of practice, and working at a dispensing practice. Up to 75% of GPs' management did not conform to the newly published 2015 NICE bronchiolitis guideline before its publication. There was wide variation in the management of infants with viral bronchiolitis by UK GPs. Most infants with viral bronchiolitis are not managed optimally by GPs and multiple GP factors influenced this management