LASIG II - Pulsed laser ion generator study Final report

Ion current produced by illuminating materials with focused output of pulsed ruby lase

Evaluating Matrix Circuits

The circuit evaluation problem (also known as the compressed word problem) for finitely generated linear groups is studied. The best upper bound for this problem is $\mathsf{coRP}$, which is shown by a reduction to polynomial identity testing. Conversely, the compressed word problem for the linear group $\mathsf{SL}_3(\mathbb{Z})$ is equivalent to polynomial identity testing. In the paper, it is shown that the compressed word problem for every finitely generated nilpotent group is in $\mathsf{DET} \subseteq \mathsf{NC}^2$. Within the larger class of polycyclic groups we find examples where the compressed word problem is at least as hard as polynomial identity testing for skew arithmetic circuits

Eigentheory of Cayley-Dickson algebras

We show how eigentheory clarifies many algebraic properties of Cayley-Dickson algebras. These notes are intended as background material for those who are studying this eigentheory more closely.Comment: 17 page

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Inherited thrombocytopenias are a heterogeneous group of disorders characterised by abnormally low platelet counts which can be associated with abnormal bleeding. Next generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease causing genes. However its full potential has not previously been utilised. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown aetiology with platelet counts varying from 11-186x109 /L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified “pathogenic” or “likely pathogenic” variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases which include novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia

Identifying Children with HEreditary Coagulation disorders (iCHEC): A protocol for a prospective cohort study

Introduction It is challenging to obtain a reliable bleeding history in children who are referred for a suspected inherited bleeding disorder. Bleeding symptoms may be subtle as children face fewer haemostatic challenges compared with adults. In order to standardise bleeding histories, questionnaires have been developed, called bleeding assessment tools (BATs). Although it has been shown that high bleeding scores are associated with the presence of a mucocutaneous bleeding disorder, these BATs lack sensitivity, efficiency and flexibility in the paediatric setting. We developed a new BAT (the iCHEC (identifying Children with HEreditary Coagulation disorders) BAT) to improve on these characteristics. We aim to evaluate the diagnostic accuracy of the iCHEC BAT as a screening tool for children who are suspected for having a bleeding disorder. Methods and analysis This is a prospective cohort study. Children (age 0-18 years) suspected for a bleeding disorder who present at tertiary haematology clinics, and/or their parents/guardians, will be asked to complete the iCHEC BAT. Sensitivity was increased by inclusion of paediatric-specific bleeding symptoms and novel qualitative questions per bleeding symptom. Efficiency was improved by developing a self-administered (online) version of the questionnaire. Flexibility for changes in the bleeding phenotype of developing children was improved by including questions that define when the bleeding symptoms occurred in the past. The diagnostic accuracy of the specific bleeding items will be evaluated by receiver operator characteristic curves, using classification based on the results from laboratory assessment as the reference standard. Analysis of the discriminative power of individual bleeding symptoms will be assessed. Ethics and dissemination The study has been approved by the medical ethics committees of all participating centres in the Netherlands, Canada and the UK. All paediatric subjects and/or their parents/guardians will provide written informed consent. Study results will be submitted for publication in peer-reviewed journals

Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months’ treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population

Medicinal cannabis users downplaying and shifting stigma: Articulations of the ‘natural’, of what is/is not a ‘drug’ and oppositions with ‘chemical’ substances

Whilst sympathy exists among the general public for chronically ill and/or disabled people who use cannabis medicinally, cannabis remains a prohibited substance in the UK. How do medicinal cannabis users negotiate this potential stigma when talking about their use of this substance? I reflect on the spoken discourses of 10 medicinal cannabis users (from a sample of 32), obtained by way of qualitative interviews, adopting a critical discourse analysis approach to the data. Specifically, I focus on their articulations around three related themes: cannabis as a ‘natural’ substance, discursive oppositions between cannabis and other substances and articulations about what is/is not a ‘drug’. I examine how participants articulated these themes in ways that attempted to negotiate the potential for stigma that talking about their substance use involved. I found they used rhetorical strategies that downplay their own deviance, attempt to shift the application of stigma to users of other substances or both. I argue that the more powerful the discursive resources that are articulated, the less rhetorical work an individual has to do to negotiate positive moral standing in an encounter. I also consider to what degree these articulations involved constructions emphasising individual self-control. I argue that in asserting that cannabis is a ‘natural’ substance (and therefore is less inherently risky to use than manufactured substances) the participants do emphasise their individual self-control

Reflected near-field blast pressure measurements using high speed video

Background: The design and analysis of protective systems requires a detailed understanding of, and the ability to accurately predict, the distribution of pressure loads acting on an obstacle following an explosive detonation. In particular, there is a pressing need for accurate characterisation of blast loads in the region very close to a detonation, where even small improvised devices can produce serious structural or material damage. Objective: Accurate experimental measurement of these near-field blast events, using intrusive methods, is demanding owing to the high magnitudes (> 100 MPa) and short durations (< 1 ms) of loading. The objective of this article is to develop a non-intrusive method for measuring reflected blast pressure distributions using image analysis. Methods: This article presents results from high speed video analysis of near-field spherical PE4 explosive blasts. The Canny edge detection algorithm is used to track the outer surface of the explosive fireball, with the results used to derive a velocity-radius relationship. Reflected pressure distributions are calculated using this velocity-radius relationship in conjunction with the Rankine-Hugoniot jump conditions. Results: The indirectly measured pressure distributions from high speed video are compared with directly measured pressure distributions and are shown to be in good qualitative agreement with respect to distribution of reflected pressures, and in good quantitative agreement with peak reflected pressures (within 10% of the maximum recorded value). Conclusions: The results indicate that it is possible to accurately measure blast loads in the order of 100s MPa using techniques which do not require sensitive recording equipment to be located close to the source of the explosion