Comparative Effectiveness of Step-up Therapies in Children with Asthma Prescribed Inhaled Corticosteroids : A Historical Cohort Study

This work was supported by the Respiratory Effectiveness Group. Acknowledgments We thank the Respiratory Effectiveness Group for funding this work, Annie Burden for assistance with statistics, and Simon Van Rysewyk and Lisa Law for assistance with medical writing.Peer reviewedPostprin

Growth and form of the mound in Gale Crater, Mars: Slope wind enhanced erosion and transport

Ancient sediments provide archives of climate and habitability on Mars. Gale Crater, the landing site for the Mars Science Laboratory (MSL), hosts a 5-km-high sedimentary mound (Mount Sharp/Aeolis Mons). Hypotheses for mound formation include evaporitic, lacustrine, fluviodeltaic, and aeolian processes, but the origin and original extent of Gale’s mound is unknown. Here we show new measurements of sedimentary strata within the mound that indicate ∼3° outward dips oriented radially away from the mound center, inconsistent with the first three hypotheses. Moreover, although mounds are widely considered to be erosional remnants of a once crater-filling unit, we find that the Gale mound’s current form is close to its maximal extent. Instead we propose that the mound’s structure, stratigraphy, and current shape can be explained by growth in place near the center of the crater mediated by wind-topography feedbacks. Our model shows how sediment can initially accrete near the crater center far from crater-wall katabatic winds, until the increasing relief of the resulting mound generates mound-flank slope winds strong enough to erode the mound. The slope wind enhanced erosion and transport (SWEET) hypothesis indicates mound formation dominantly by aeolian deposition with limited organic carbon preservation potential, and a relatively limited role for lacustrine and fluvial activity. Morphodynamic feedbacks between wind and topography are widely applicable to a range of sedimentary and ice mounds across the Martian surface, and possibly other planets

Reported analgesic administration to rabbits undergoing experimental surgical procedures

<p>Abstract</p> <p>Background</p> <p>It has become widely accepted that whenever animals are used in scientific procedures, the 3Rs principle of replacement, reduction and refinement described by William Russell and Rex Burch should be adhered to. Animals should be replaced with non-sentient alternatives if possible, the number of animals used should be reduced and experimental procedures should be refined to minimise pain, suffering and distress. Administration of analgesic agents to animals undergoing surgical procedures is a refinement used to alleviate pain. In this study, a structured literature review was carried out to examine current trends in analgesic administration to rabbits undergoing experimental surgical procedures.</p> <p>Results</p> <p>128 papers from 51 peer-reviewed journals were selected for inclusion in this review. Reporting administration of systemic analgesia to rabbits in peer-reviewed scientific papers increased significantly from 16% to 50% between 1995-1997 and 2005-2007 (<it>P </it>< 0.001). Papers that reported ethical approval were more likely than papers that did not specify approval to report systemic analgesic administration (<it>P </it>< 0.001). When systemic analgesics were administered, buprenorphine was the most frequently used agent and non-steroidal anti-inflammatory drugs were used less frequently than opioids in both time periods.</p> <p>Conclusions</p> <p>Although this review provides evidence that systemic analgesic administration to rabbits undergoing surgical procedures is increasing, rabbits do not always receive analgesia when they undergo experimental surgery. Other practices in rabbit perioperative care that could be improved, highlighted by this survey include: 1) changing the timing of analgesic administration by giving systemic analgesics pre- or perioperatively rather than only postoperatively, 2) using multimodal analgesia when pain is likely to be moderate to severe and 3) increasing the use of non-steroidal anti-inflammatory drugs and use of other techniques such as epidural analgesia particularly for orthopaedic procedures.</p

Integrative multiomics analysis highlights immune-cell regulatory mechanisms and shared genetic architecture for 14 immune-associated diseases and cancer outcomes

Developing functional insight into the causal molecular drivers of immunological disease is a critical challenge in genomic medicine. Here, we systematically apply Mendelian randomization (MR), genetic colocalization, immune-cell-type enrichment, and phenome-wide association methods to investigate the effects of genetically predicted gene expression on ten immune-associated diseases and four cancer outcomes. Using whole blood-derived estimates for regulatory variants from the eQTLGen consortium (n = 31,684), we constructed genetic risk scores for 10,104 genes. Applying the inverse-variance-weighted MR method transcriptome wide while accounting for linkage disequilibrium structure identified 664 unique genes with evidence of a genetically predicted effect on at least one disease outcome (p < 4.81 × 10(−5)). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci by using gene expression data derived from 18 types of immune cells. This highlighted many cell-type-dependent effects, such as PRKCQ expression and asthma risk (posterior probability = 0.998), which was T cell specific. Phenome-wide analyses on 311 complex traits and endpoints allowed us to explore shared genetic architecture and prioritize key drivers of disease risk, such as CASP10, which provided evidence of an effect on seven cancer-related outcomes. Our atlas of results can be used to characterize known and novel loci in immune-associated disease and cancer susceptibility, both in terms of elucidating cell-type-dependent effects as well as dissecting shared disease pathways and pervasive pleiotropy. As an exemplar, we have highlighted several key findings in this study, although similar evaluations can be conducted via our interactive web platform

A cohort study of the recovery of health and wellbeing following colorectal cancer (CREW study): protocol paper

Background: the number of people surviving colorectal cancer has doubled in recent years. While much of the literature suggests that most people return to near pre-diagnosis status following surgery for colorectal cancer, this literature has largely focused on physical side effects. Longitudinal studies in colorectal cancer have either been small scale or taken a narrow focus on recovery after surgery. There is a need for a comprehensive, long-term study exploring all aspects of health and wellbeing in colorectal cancer patients. The aim of this study is to establish the natural history of health and wellbeing in people who have been treated for colorectal cancer. People have different dispositions, supports and resources, likely resulting in individual differences in restoration of health and wellbeing. The protocol described in this paper is of a study which will identify who is most at risk of problems, assess how quickly people return to a state of subjective health and wellbeing, and will measure factors which influence the course of recovery. Methods: this is a prospective, longitudinal cohort study following 1000 people with colorectal cancer over a period of two years, recruiting from 30 NHS cancer treatment centres across the UK. Questionnaires will be administered prior to surgery, and 3, 9, 15 and 24 months after surgery, with the potential to return to this cohort to explore on-going issues related to recovery after cancer. Discussion: outcomes will help inform health care providers about what helps or hinders rapid and effective recovery from cancer, and identify areas for intervention development to aid this process. Once established the cohort can be followed up for longer periods and be approached to participate in related projects as appropriate and subject to funding<br/

Life History Phenology and Sediment Size Association of the Dragonfly Cordulegaster dorsalis (Odonata: Cordulegastridae) in an Ephemeral Habitat in Southwestern British Columbia

The life cycle of the dragonfly Cordulegaster dorsalis was studied over one year by systematic sampling of larvae in three intermittent headwater streams in southwestern British Columbia. We determined that larvae normally take three years to reach maturity, emerging throughout July and August. There is limited evidence suggesting a split cohort development, with early emergence after two years. Additionally, we tested whether larval instars were distributed randomly or if they occupied different sediment microhabitats. Smaller animals tend to be associated with smaller grained organic sediments, although there was high variation between the streams

Investigating the role of the Caenorhabditis elegans unfolded protein response in immunity and development

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2012.Cataloged from PDF version of thesis.Includes bibliographical references.Proteins destined for the secretory pathway are folded, posttranslationally modified, and assembled into complexes in the endoplasmic reticulum (ER). To maintain ER proteostasis, the rate of nascent peptide influx into the ER must be matched with the rate of protein folding and export. An imbalance between peptide influx and ER folding capacity activates a conserved set of signal transduction pathways termed the ER Unfolded Protein Response (UPR), which function to restore ER proteostasis. In metazoans, the UPR is controlled by three signaling pathways, controlled by the ER localized transmembrane sensors IRE-1, PERK/PEK-1, and ATF6/ATF-6. The molecular mechanisms and output of the UPR have been defined largely by exogenously inhibiting ER protein folding, either chemically or through overexpression of unfoldable mutant ER proteins, while genetic studies have implicated essential functions for UPR signaling in normal development and in the pathogenesis of disease. This work defines an essential role for the UPR in Caenorhabditis elegans in protection against host immunity and maintenance of ER proteostasis during development. In Chapter Two, I show that the IRE-1 -XBP- 1 pathway is activated by infection with the bacterial pathogen Pseudomonas aeruginosa and is essential for larval development in the presence of pathogen. Through genetic analyses, I demonstrate that immune activation is necessary and sufficient to activate the IRE-1 -XBP- 1 pathway, and that the function of the IRE-1 -XBP- 1 pathway during infection is to protect against the host immune response. In Chapter Three, I present evidence suggesting that the IRE-1 and PEK- 1 negative feedback loops function constitutively to maintain ER proteostasis, even during growth under standard, "unstressed" conditions. Together, these studies highlight the integral role of UPR signaling in C. elegans physiology, and future work, described in Chapters Four and Five, will use genetic approaches to further define the molecular mechanisms underlying this requirement for UPR activity.by Claire E. Richardson.Ph.D

Starting an undergraduate degree amid the COVID-19 pandemic:A mixed-method egocentric network study on student loneliness

Students who began their undergraduate university studies in the midst of the COVID-19 pandemic (the 'COVID cohort'), may have been particularly at risk for experiencing increased loneliness. This study employed an exploratory egocentric network and mixed-methods approach to investigate the links between social networks and loneliness in the COVID cohort. Of sixty-one respondents meeting inclusion criteria for the study, fifty-eight first-year undergraduate students from the September 2020 intake at a large Scottish University provided egocentric network data via an online survey, as well as responses to three open-ended questions which were aimed at generating qualitative data about participants' experiences of starting university in the context of the COVID-19 pandemic. Bivariate analyses suggest that having a larger social network, and higher satisfaction with that network, was associated with reduced loneliness. We additionally explored these associations in subsamples of students living on-campus and living off-campus. Our qualitative data adds valuable insight into the impact that pandemic-related social-distancing restrictions had on limiting students' opportunities for meeting their peers and forging meaningful social connections at university. Limitations of this study include a small sample size and an exploratory approach requiring further investigation and replication. However, in the context of universities continuing to use hybrid teaching models, this study provides useful initial insights, highlighting potential avenues for institutions to support students in developing social connections in the transition to higher education.</p

Experiences of older people dying in nursing homes : a narrative systematic review of qualitative studies

Objectives To identify and synthesise qualitative research from 2001 investigating older people's (65+ years) experiences of dying in nursing and care homes. Methods and outcomes Eight electronic databases (AMED, ASSIA, CINAHL Plus, Embase, HMIC, Medline, PsychINFO and Scopus) from 2001 to July 2017 were searched. Studies were included if they were qualitative, primary research and described the experiences of dying in nursing or care homes from the perspectives of the older people themselves, their families or staff. Study quality assessment was undertaken to systematically assess methodological quality, but no studies were excluded as a result. Results 1305 articles were identified. Nine met the inclusion criteria. North American studies dominated. Most used a mixture of observations and interviews. All the included studies highlighted the physical discomfort of dying, with many older people experiencing potentially avoidable symptoms if care were to be improved. Negative psychosocial experiences such as loneliness and depression were also often described in addition to limited support with spiritual needs. Conclusions More qualitative research giving a holistic understanding of older people’s experiences of dying in residential care homes is needed. Undertaking research on this topic is challenging and requires great sensitivity, but the dearth of qualitative research from the perspectives of those most closely involved in older people’s deaths hampers service improvement