Diffusion about the mean drift location in a biased random walk

Random walks are used to model movement in a wide variety of contexts: from the movement of cells undergoing chemotaxis to the migration of animals. In a two- dimensional biased random walk, the diffusion about the mean drift position is entirely dependent on the moments of the angular distribution used to determine the movement direction at each step. Here we consider biased random walks using several different angular distributions and derive expressions for the diffusion coefficients in each direction based on either a fixed or variable movement speed, and we use these to generate a probability density function for the long-time spatial distribution. we demonstrate how diffusion is typically anisotropic around the mean drift position and illustrate these theoretical results using computer simulations. we relate these results to earlier studies of swimming microorganisms and explain how the results can be generalized to other types of animal movement. © 2010 by the Ecological Society of America

Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor

Background: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. Methods: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. Results: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. Conclusions: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc

How just and just how? A systematic review of social equity in conservation research

Background: Conservation decisions not only impact wildlife, habitat, and environmental health, but also human wellbeing and social justice. The inclusion of safeguards and equity considerations in the conservation field has increasingly garnered attention in international policy processes and amongst conservation practitioners. Yet, what constitutes an ‘equitable’ solution can take many forms, and how the concept is treated within conservation research is not standardized. This review explores how social equity is conceptualized and assessed in conservation research.Methods/Design: Using a structured search and screening process, we identified 138 peer-reviewed studies that addressed equity in relation to conservation actions. The authors developed a coding framework to guide the review process, focusing on the current state of, definitions used for, and means of assessing social equity in empirical conservation research.Review Results: Results show that empirical research on social equity in conservation is rapidly growing, with the majority of studies on the topic published only since 2009. Equity within conservation research is skewed toward distributional concerns and to a lesser extent procedural issues, with recognition and contextual equity receiving little attention. Studies are primarily situated in forested biomes of the Global South. Conservation interventions mostly resulted in mixed or negative impacts on equity.Synthesis and Discussion: Our results demonstrate the current limitations of research on equity in conservation, and raise challenging questions about the social impacts of conservation and how to ameliorate equity concerns. Framing of equity within conservation research would benefit from greater transparency of study motivation, more explicit definition of how equity is used within the study context, and consideration for how best to assess it.We recommend that the empirical conservation literature more deeply engage with different notions of equity when studying, planning, and implementing actions to address potential trade-offs among equity and conservation objectives and beneficiaries

School-based interventions to prevent anxiety, depression and conduct disorders in children and young people:a systematic review, network meta-analysis and economic evaluation

Background: Schools in the UK increasingly have to respond to anxiety, depression and conduct disorder as key causes of morbidity in children and young people. Objective: The objective was to assess the comparative effectiveness of educational setting-based interventions for the prevention of anxiety, depression and conduct disorder in children and young people. Design: This study comprised a systematic review, a network meta-analysis and an economic evaluation. Data sources: The databases MEDLINE, EMBASE™ (Elsevier, Amsterdam, the Netherlands), PsycInfo® (American Psychological Association, Washington, DC, USA) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to 4 April 2018, and the NHS Economic Evaluation Database (NHS EED) was searched on 22 May 2019 for economic evaluations. No language or date filters were applied. Main outcomes: The main outcomes were post-intervention self-reported anxiety, depression or conduct disorder symptoms. Review methods: Randomised/quasi-randomised trials of universal or targeted interventions for the prevention of anxiety, depression or conduct disorder in children and young people aged 4–18 years were included. Screening was conducted independently by two reviewers. Data extraction was conducted by one reviewer and checked by a second. Intervention- and component-level network meta-analyses were conducted in OpenBUGS. A review of the economic literature and a cost–consequence analysis were conducted. Results: A total of 142 studies were included in the review, and 109 contributed to the network meta-analysis. Of the 109 studies, 57 were rated as having an unclear risk of bias for random sequence generation and allocation concealment. Heterogeneity was moderate. In universal secondary school settings, mindfulness/relaxation interventions [standardised mean difference (SMD) –0.65, 95% credible interval (CrI) –1.14 to –0.19] and cognitive–behavioural interventions (SMD –0.15, 95% CrI –0.34 to 0.04) may be effective for anxiety. Cognitive–behavioural interventions incorporating a psychoeducation component may be effective (SMD –0.30, 95% CrI –0.59 to –0.01) at preventing anxiety immediately post intervention. There was evidence that exercise was effective in preventing anxiety in targeted secondary school settings (SMD –0.47, 95% CrI –0.86 to –0.09). There was weak evidence that cognitive–behavioural interventions may prevent anxiety in universal (SMD –0.07, 95% CrI –0.23 to 0.05) and targeted (SMD –0.38, 95% CrI –0.84 to 0.07) primary school settings. There was weak evidence that cognitive–behavioural (SMD –0.04, 95% CrI –0.16 to 0.07) and cognitive–behavioural + interpersonal therapy (SMD –0.18, 95% CrI –0.46 to 0.08) may be effective in preventing depression in universal secondary school settings. Third-wave (SMD –0.35, 95% CrI –0.70 to 0.00) and cognitive–behavioural interventions (SMD –0.11, 95% CrI –0.28 to 0.05) incorporating a psychoeducation component may be effective at preventing depression immediately post intervention. There was no evidence of intervention effectiveness in targeted secondary, targeted primary or universal primary school settings post intervention. The results for university settings were unreliable because of inconsistency in the network meta-analysis. A narrative summary was reported for five conduct disorder prevention studies, all in primary school settings. None reported the primary outcome at the primary post-intervention time point. The economic evidence review reported heterogeneous findings from six studies. Taking the perspective of a single school budget and based on cognitive–behavioural therapy intervention costs in universal secondary school settings, the cost–consequence analysis estimated an intervention cost of £43 per student. Limitations: The emphasis on disorder-specific prevention excluded broader mental health interventions and restricted the number of eligible conduct disorder prevention studies. Restricting the study to interventions delivered in the educational setting may have limited the number of eligible university-level interventions. Conclusions: There was weak evidence of the effectiveness of school-based, disorder-specific prevention interventions, although effects were modest and the evidence not robust. Cognitive–behavioural therapy-based interventions may be more effective if they include a psychoeducation component. Future work: Future trials for prevention of anxiety and depression should evaluate cognitive–behavioural interventions with and without a psychoeducation component, and include mindfulness/relaxation or exercise comparators, with sufficient follow-up. Cost implications must be adequately measured. Study registration: This study is registered as PROSPERO CRD42016048184. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information

Genomic epidemiology of syphilis in England: a population-based study.

BACKGROUND: Syphilis is a sexually transmitted bacterial infection caused by Treponema pallidum subspecies pallidum. Since 2012, syphilis rates have risen dramatically in many high-income countries, including England. Although this increase in syphilis prevalence is known to be associated with high-risk sexual activity in gay, bisexual, and other men who have sex with men (GBMSM), cases are rising in heterosexual men and women. The transmission dynamics within and between sexual networks of GBMSM and heterosexual people are not well understood. We aimed to investigate if whole genome sequencing could be used to supplement or enhance epidemiological insights around syphilis transmission. METHODS: We linked national patient demographic, geospatial, and behavioural metadata to whole T pallidum genome sequences previously generated from patient samples collected from across England between Jan 1, 2012, and Oct 31, 2018, and performed detailed phylogenomic analyses. FINDINGS: Of 497 English samples submitted for sequencing, we recovered 240 genomes (198 from the UK Health Security Agency reference laboratory and 42 from other laboratories). Three duplicate samples (same patient and collection date) were included in the main phylogenies, but removed from further analyses of English populations, leaving 237 genomes. 220 (92·8%) of 237 samples were from men, nine (3·8%) were from women, and eight (3·4%) were of unknown gender. Samples were mostly from London (n=118 [49·8%]), followed by southeast England (n=29 [12·2%]), northeast England (n=24 [10·1%]), and southwest England (n=15 [6·3%]). 180 (76·0%) of 237 genomes came from GBMSM, compared with 25 (10·5%) from those identifying as men who have sex with women, 15 (6·3%) from men with unrecorded sexual orientation, nine (3·8%) from those identifying as women who have sex with men, and eight (3·4%) from people of unknown gender and sexual orientation. Phylogenomic analysis and clustering revealed two dominant T pallidum sublineages in England. Sublineage 1 was found throughout England and across all patient groups, whereas sublineage 14 occurred predominantly in GBMSM older than 34 years and was absent from samples sequenced from the north of England. These different spatiotemporal trends, linked to demography or behaviour in the dominant sublineages, suggest they represent different sexual networks. By focusing on different regions of England we were able to distinguish a local heterosexual transmission cluster from a background of transmission in GBMSM. INTERPRETATION: These findings show that, despite extremely close genetic relationships between T pallidum genomes globally, genomics can still be used to identify putative transmission clusters for epidemiological follow-up. This could be of value for deconvoluting putative outbreaks and for informing public health interventions. FUNDING: Wellcome funding to the Sanger Institute, UK Research and Innovation, National Institute for Health and Care Research, European and Developing Countries Clinical Trials Partnership, and UK Health Security Agency

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme