Accelerated in vivo proliferation of memory phenotype CD4+ T-cells in human HIV-1 infection irrespective of viral chemokine co-receptor tropism.

CD4(+) T-cell loss is the hallmark of HIV-1 infection. CD4 counts fall more rapidly in advanced disease when CCR5-tropic viral strains tend to be replaced by X4-tropic viruses. We hypothesized: (i) that the early dominance of CCR5-tropic viruses results from faster turnover rates of CCR5(+) cells, and (ii) that X4-tropic strains exert greater pathogenicity by preferentially increasing turnover rates within the CXCR4(+) compartment. To test these hypotheses we measured in vivo turnover rates of CD4(+) T-cell subpopulations sorted by chemokine receptor expression, using in vivo deuterium-glucose labeling. Deuterium enrichment was modeled to derive in vivo proliferation (p) and disappearance (d*) rates which were related to viral tropism data. 13 healthy controls and 13 treatment-naive HIV-1-infected subjects (CD4 143-569 cells/ul) participated. CCR5-expression defined a CD4(+) subpopulation of predominantly CD45R0(+) memory cells with accelerated in vivo proliferation (p = 2.50 vs 1.60%/d, CCR5(+) vs CCR5(-); healthy controls; P<0.01). Conversely, CXCR4 expression defined CD4(+) T-cells (predominantly CD45RA(+) naive cells) with low turnover rates. The dominant effect of HIV infection was accelerated turnover of CCR5(+)CD45R0(+)CD4(+) memory T-cells (p = 5.16 vs 2.50%/d, HIV vs controls; P<0.05), naïve cells being relatively unaffected. Similar patterns were observed whether the dominant circulating HIV-1 strain was R5-tropic (n = 9) or X4-tropic (n = 4). Although numbers were small, X4-tropic viruses did not appear to specifically drive turnover of CXCR4-expressing cells (p = 0.54 vs 0.72 vs 0.44%/d in control, R5-tropic, and X4-tropic groups respectively). Our data are most consistent with models in which CD4(+) T-cell loss is primarily driven by non-specific immune activation

Jay Forrester

Jay Wright Forrester was an American engineer and management thinker. He founded System Dynamics, an approach based on computer modelling which arguably has done more than any other method to provide a practical and realistic analysis of change processes in systems. System Dynamics (SD) has been taken up across the world, initially by Forrester’s students and colleagues, but increasingly by a much wider community. It has had profound and influential applications in a range of fields, most prominently organisational management, urban planning and environmental policy. Forrester summed up his concerns and his understanding of SD in an ‘elevator pitch’ (a statement short enough to be spoken in an elevator ride) on an email list: System dynamics deals with how things change through time, which includes most of what most people find important. It uses computer simulation to take the knowledge we already have about details in the world around us and to show why our social and physical systems behave the way they do. System dynamics demonstrates how most of our own decision-making policies are the cause of the problems that we usually blame on others, and how to identify policies we can follow to improve our situation. (Forrester JW. System dynamics in the elevator. System-dynamics email list. https://www.ventanasystems.co.uk/forum/viewtopic.php?t=1787#p1964. Accessed 25 Sept 2019, 1997

To GP or not to GP: a natural experiment in children triaged to see a GP in a tertiary paediatric emergency department (ED)

Objective: To evaluate the impact of integrating a general practitioner (GP) into a tertiary paediatric emergency department (ED) on admissions, waiting times and antibiotic prescriptions. Design: Retrospective cohort study. Setting: Alder Hey Children’s NHS Foundation Trust, a tertiary paediatric hospital in Liverpool, UK. Participants: From October 2014, a GP was colocated within the ED, from 14:00 to 22:00 hours, 7 days a week. Children triaged green on the Manchester Triage System without any comorbidities were classed as ‘GP appropriate’. The natural experiment compared patients triaged as ‘GP appropriate’ and able to be seen by a GP between 14:00 and 22:00 hours (GP group) to patients triaged as ‘GP appropriate’ seen outside of the hours when a GP was available (ED group). Intention-to-treat (ITT) analysis was used to assess the main outcomes. Results: 5223 patients were designated as ‘GP appropriate’—18.2% of the total attendances to the ED over the study period. There were 2821 (54%) in the GP group and 2402 (46%) in the ED group. The median duration of stay in the ED was 94 min (IQR 63–141) for the GP group compared with 113 min (IQR 70–167) for the ED group (p<0.0005). Using the ITT analysis equivalent, we demonstrated that the GP group were less likely to: be admitted to hospital (2.2% vs 6.5%, OR 0.32, 95% CI 0.24 to 0.44), wait longer than 4 hours (2.3% vs 5.1%, OR 0.45, 95% CI 0.33 to 0.61) or leave before being seen (3.1% vs 5.7%, OR 0.53, 95% CI 0.41 to 0.70), but more likely to receive antibiotics (26.1% vs 20.5%, OR 1.37, 95% CI 1.10 to 1.56). Sensitivity analyses yielded similar results. Conclusions: Introducing a GP to a paediatric ED service can significantly reduce waiting times and admissions, but may lead to more antibiotic prescribing. This study demonstrates a novel, potentially more efficient ED care pathway in the current context of rising demand for children’s emergency services

BARCRAWL and BARTAB: software tools for the design and implementation of barcoded primers for highly multiplexed DNA sequencing

<p>Abstract</p> <p>Background</p> <p>Advances in automated DNA sequencing technology have greatly increased the scale of genomic and metagenomic studies. An increasingly popular means of increasing project throughput is by multiplexing samples during the sequencing phase. This can be achieved by covalently linking short, unique "barcode" DNA segments to genomic DNA samples, for instance through incorporation of barcode sequences in PCR primers. Although several strategies have been described to insure that barcode sequences are unique and robust to sequencing errors, these have not been integrated into the overall primer design process, thus potentially introducing bias into PCR amplification and/or sequencing steps.</p> <p>Results</p> <p><it>Barcrawl </it>is a software program that facilitates the design of barcoded primers, for multiplexed high-throughput sequencing. The program <it>bartab </it>can be used to deconvolute DNA sequence datasets produced by the use of multiple barcoded primers. This paper describes the functions implemented by <it>barcrawl </it>and <it>bartab </it>and presents a proof-of-concept case study of both programs in which barcoded rRNA primers were designed and validated by high-throughput sequencing.</p> <p>Conclusion</p> <p><it>Barcrawl </it>and <it>bartab </it>can benefit researchers who are engaged in metagenomic projects that employ multiplexed specimen processing. The source code is released under the GNU general public license and can be accessed at <url>http://www.phyloware.com</url>.</p

Australian Sphingidae – DNA Barcodes Challenge Current Species Boundaries and Distributions

© 2014 Rougerie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

Mercury in Nelson's Sparrow Subspecies at Breeding Sites

Background: Mercury is a persistent, biomagnifying contaminant that can cause negative effects on ecosystems. Marshes are often areas of relatively high mercury methylation and bioaccumulation. Nelson’s Sparrows (Ammodramus nelsoni) use marsh habitats year-round and have been documented to exhibit tissue mercury concentrations that exceed negative effects thresholds. We sought to further characterize the potential risk of Nelson’s Sparrows to mercury exposure by sampling individuals from sites within the range of each of its subspecies

The ‘new normality’ in research? What message are we conveying our medical students?

The impact of COVID-19 on medical education has been mainly viewed from the perspective of the imposed transition from face-to- face to online delivery of information and the inforced stopping of practical teaching in hospitals.1-5 However, unfortunately, the deleterious effects of COVID-19 on how research findings are obtained, communicated and valued needs also careful consideration. Whilst teaching students that it is a genuinely exciting and unique time to be in medicine, as teachers of a subject entitled ‘Introduction to Research’ to second-year medical students, we feel particularly worried about what the handling of the pandemia is transmitting our future physicians. Now, more than ever before, scholars need to reaffirm the importance on how research findings are obtained and communicated