Publications by authors named "C Allan"

431 Publications

Clinical outcomes and the impact of prior oral anticoagulant use in patients with coronavirus disease 2019 admitted to hospitals in the UK - a multicentre observational study.

Br J Haematol 2021 Sep 9. Epub 2021 Sep 9.

Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, UK.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93-1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58-1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37-2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.
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http://dx.doi.org/10.1111/bjh.17787DOI Listing
September 2021

Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex.

J Biol Chem 2021 Aug 20;297(4):101102. Epub 2021 Aug 20.

Pfizer, Inc, La Jolla, California, USA. Electronic address:

CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction.
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http://dx.doi.org/10.1016/j.jbc.2021.101102DOI Listing
August 2021

Systems-Level Change to Alleviate Barriers to Cancer Clinical Trial Access for Adolescents and Young Adults in Australia.

J Adolesc Young Adult Oncol 2021 Jul 22. Epub 2021 Jul 22.

ONTrac at PeterMac, Victorian Adolescent and Young Adult Cancer Service, Peter MacCallum Cancer Centre, Melbourne, Australia.

International data demonstrate association between clinical trial participation and reduced cancer mortality. Adolescents and young adults (AYA) have low clinical trial enrollment rates. We established a program to understand local barriers and develop targeted solutions that lead to greater AYA clinical trial participation. A steering committee (SC) with expertise in adult and pediatric oncology, research ethics, and consumer representation was formed. The SC mapped barriers related to AYA trial access and established working groups (WGs) around three themes. The Regulatory Awareness WG identified a lack of understanding of processes that support protocol approval for clinical trials across the AYA age range. A guideline to raise awareness was developed. The Access WG identified challenges for young adults (18-25 years) to access a pediatric hospital to enroll in a pediatric trial. A procedure was developed to streamline applications for access. The first six applications using this procedure have been successful. The Availability WG identified lack of pediatric-adult oncology reciprocal relationships as a barrier to awareness of open trials, and future collaboration. An AYA Craft Group Framework was established to grow relationships within tumor streams across institutions; two craft groups are now operating locally. An additional achievement was a successful request to the Therapeutic Goods Administration for Australian adoption of the Food and Drug Administration Guidance on Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. This multipronged approach to improving AYA clinical trial access has relevance for other health environments. Our knowledge products are available as an online toolkit.
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http://dx.doi.org/10.1089/jayao.2021.0026DOI Listing
July 2021

Using optogenetics to link myosin patterns to contractile cell behaviors during convergent extension.

Biophys J 2021 Jul 20. Epub 2021 Jul 20.

Department of Mechanical Engineering, Columbia University, New York, New York. Electronic address:

Distinct patterns of actomyosin contractility are often associated with particular epithelial tissue shape changes during development. For example, a planar-polarized pattern of myosin II localization regulated by Rho1 signaling during Drosophila body axis elongation is thought to drive cell behaviors that contribute to convergent extension. However, it is not well understood how specific aspects of a myosin pattern influence the multiple cell behaviors, including cell intercalation, cell shape changes, and apical cell area fluctuations, that simultaneously occur during morphogenesis. Here, we developed two optogenetic tools, optoGEF and optoGAP, to activate or deactivate Rho1 signaling, respectively. We used these tools to manipulate myosin patterns at the apical side of the germband epithelium during Drosophila axis elongation and analyzed the effects on contractile cell behaviors. We show that uniform activation or inactivation of Rho1 signaling across the apical surface of the germband is sufficient to disrupt the planar-polarized pattern of myosin at cell junctions on the timescale of 3-5 min, leading to distinct changes in junctional and medial myosin patterns in optoGEF and optoGAP embryos. These two perturbations to Rho1 activity both disrupt axis elongation and cell intercalation but have distinct effects on cell area fluctuations and cell packings that are linked with changes in the medial and junctional myosin pools. These studies demonstrate that acute optogenetic perturbations to Rho1 activity are sufficient to rapidly override the endogenous planar-polarized myosin pattern in the germband during axis elongation. Moreover, our results reveal that the levels of Rho1 activity and the balance between medial and junctional myosin play key roles not only in organizing the cell rearrangements that are known to directly contribute to axis elongation but also in regulating cell area fluctuations and cell packings, which have been proposed to be important factors influencing the mechanics of tissue deformation and flow.
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http://dx.doi.org/10.1016/j.bpj.2021.06.041DOI Listing
July 2021

Accidental Injuries in Preschoolers: Are We Missing an Opportunity for Early Assessment and Intervention?

J Pediatr Psychol 2021 Aug;46(7):835-843

Department of Applied Psychology, Steinhardt School of Culture, Education and Human Development, New York University.

Objective: Children with attention-deficit/hyperactivity disorder (ADHD) are at risk for accidental injuries, but little is known about age-related changes in early childhood. We predicted that ADHD would be associated with greater frequency and volume of accidental injuries. We explored associations between ADHD and injury types and examined age-related changes within the preschool period.

Methods: Retrospective chart review data of 21,520 preschool children with accidental injury visits within a large pediatric hospital network were examined. We compared children with ADHD (n = 524) and without ADHD (n = 20,996) on number of injury visits by age, total number of injury visits, injury volume, and injury type.

Results: Children with ADHD averaged fewer injury visits at age 3 and 90% more visits at age 6. Children with ADHD had injury visits in more years during the 3-6 age. There were no differences in injury volumes. Among patients with an injury visit at age 3, children with ADHD had 6 times the probability of a subsequent visit at age 6. At age 3, children with ADHD were estimated to have 50% fewer injury visits than children without ADHD, but by age 6, children with ADHD had an estimated 74% more injury visits than children without ADHD. Risk for several injury types for children with ADHD exceeded that for patients without ADHD by at least 50%.

Conclusions: Early identification and treatment of preschool ADHD following accidental injury may prevent subsequent injuries. Clinical implications and future directions are discussed with emphasis on the maintenance of parental monitoring into the older preschool years.
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http://dx.doi.org/10.1093/jpepsy/jsab044DOI Listing
August 2021
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