Showing papers by "Simon Jones published in 2013"

Anaesthesia and airway management in mucopolysaccharidosis

Abstract: This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can't intubate, can't ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support.

Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study.

Abstract: Background Serum phosphate is a known risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD), however data on the association of these outcomes with serum phosphate in the general population are scarce. We investigate this relationship in people with and without CKD in a large community-based population. Methods Three groups from an adult cohort of the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial (ISRCTN56023731) were followed over a period of 2.5 years: people with normal renal function (N = 24,184), people with CKD stages 1–2 (N = 20,356), and people with CKD stages 3–5 (N = 13,292). We used a multilevel logistic regression model to determine the association between serum phosphate, in these groups, and a composite outcome of all-cause mortality, cardiovascular events, and advanced coronary artery disease. We adjusted for known cardiovascular risk factors. Findings Higher phosphate levels were found to correlate with increased cardiovascular risk. In people with normal renal function and CKD stages 1–2, Phosphate levels between 1.25 and 1.50 mmol/l were associated with increased cardiovascular events; odds ratio (OR) 1.36 (95% CI 1.06–1.74; p = 0.016) in people with normal renal function and OR 1.40 (95% CI 1.09–1.81; p = 0.010) in people with CKD stages 1–2. Hypophosphatemia ( 1.50 mmol/l) was associated with increased cardiovascular risk; OR 2.34 (95% CI 1.64–3.32; p<0.001). Other phosphate ranges were not found to have a significant impact on cardiovascular events in people with CKD stages 3–5. Conclusions Serum phosphate is associated with cardiovascular events in people with and without CKD. Further research is required to determine the mechanisms underlying these associations.

Bringing computer science back into schools: lessons from the UK

Abstract: Computer science in UK schools is a subject in decline: the ratio of Computing to Maths A-Level students (i.e. ages 16--18) has fallen from 1:2 in 2003 to 1:20 in 2011 and in 2012. In 2011 and again in 2012, the ratio for female students was 1:100, with less than 300 female students taking Computing A-Level in the whole of the UK each year. Similar problems have been observed in the USA and other countries, despite the increased need for computer science skills caused by IT growth in industry and society. In the UK, the Computing At School (CAS) group was formed to try to improve the state of computer science in schools. Using a combination of grassroots teacher activities and policy lobbying at a national level, CAS has been able to rapidly gain traction in the fight for computer science in schools. We examine the reasons for this success, the challenges and dangers that lie ahead, and suggest how the experience of CAS in the UK can benefit other similar organisations, such as the CSTA in the USA.

HALO: haskell to logic through denotational semantics

Abstract: Even well-typed programs can go wrong in modern functional languages, by encountering a pattern-match failure, or simply returning the wrong answer. An increasingly-popular response is to allow programmers to write contracts that express semantic properties, such as crash-freedom or some useful post-condition. We study the static verification of such contracts. Our main contribution is a novel translation to first-order logic of both Haskell programs, and contracts written in Haskell, all justified by denotational semantics. This translation enables us to prove that functions satisfy their contracts using an off-the-shelf first-order logic theorem prover.

Parental social support, coping strategies, resilience factors, stress, anxiety and depression levels in parents of children with MPS III (Sanfilippo syndrome) or children with intellectual disabilities (ID)

Abstract: Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of four enzymes involved in the catabolism of the glycosaminoglycan heparan sulphate. It is a degenerative disorder, with a progressive decline in children's intellectual and physical functioning. There is currently no cure for the disorder. To date there is a paucity of research on how this disorder impacts parents psychological functioning. Specifically, research in the area has failed to employ adequate control groups to assess if the impact of this disorder on parents psychological functioning differs from parenting a child with intellectual disability (ID). The current study examined child behaviour and parental psychological functioning in 23 parents of children with MPS III and 23 parents of children with ID. Parents completed postal questionnaires about their child's behaviour and abilities and their own psychological functioning. Parents of children with MPS III reported fewer behavioural difficulties as their child aged, more severe level of intellectual disability, and similar levels of perceived social support, coping techniques, stress, anxiety and depression levels as parents of children with ID. Both groups of parents scored above the clinical cut off for anxiety and depression. Parents of children with MPS III rated themselves as significantly less future-orientated and goal directed than parents of children with ID. Services should develop support packages for parents of children with MPS III that incorporate an understanding of the unique stressors and current-difficulty approach of this population. Future research should examine gender differences between parental psychological functioning, using mixed qualitative and quantitative approaches, and utilise matched developmental level and typically developing control groups.

The Kynurenine Pathway in Stem Cell Biology

Abstract: The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.

Management of mucopolysaccharidosis type IH (Hurler’s syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution’s experience

Abstract: Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.

Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study.

Abstract: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7–17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6 % (CI −92.0 −85.2, p < 0.001), 54.1 % (CI −69.5- −38.7, p < 0,001), and 25.7 % (CI −44.3- −7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15 %, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI −8.9 −51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI −0.2-0.8, NS). These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.

Exploiting vector instructions with generalized stream fusio

Abstract: Stream fusion is a powerful technique for automatically transforming high-level sequence-processing functions into efficient implementations. It has been used to great effect in Haskell libraries for manipulating byte arrays, Unicode text, and unboxed vectors. However, some operations, like vector append, still do not perform well within the standard stream fusion framework. Others, like SIMD computation using the SSE and AVX instructions available on modern x86 chips, do not seem to fit in the framework at all. In this paper we introduce generalized stream fusion, which solves these issues. The key insight is to bundle together multiple stream representations, each tuned for a particular class of stream consumer. We also describe a stream representation suited for efficient computation with SSE instructions. Our ideas are implemented in modified versions of the GHC compiler and vector library. Benchmarks show that high-level Haskell code written using our compiler and libraries can produce code that is faster than both compiler- and hand-vectorized C.

Association of chronic kidney disease (CKD) and failure to monitor renal function with adverse outcomes in people with diabetes: a primary care cohort study

Abstract: Chronic kidney disease (CKD) is a known risk factor for cardiovascular events and all-cause mortality. We investigate the relationship between CKD stage, proteinuria, hypertension and these adverse outcomes in the people with diabetes. We also study the outcomes of people who did not have monitoring of renal function. A cohort of people with type 1 and 2 diabetes (N = 35,502) from the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial was followed up over 2.5 years. A composite of all-cause mortality, cardiovascular events, and end stage renal failure comprised the outcome measure. A multilevel logistic regression model was used to determine correlates with this outcome. Known cardiovascular and renal risk factors were adjusted for. Proteinuria and reduced estimated glomerular filtration rate (eGFR) were independently associated with adverse outcomes in people with diabetes. People with an eGFR <60 ml/min, proteinuria, and hypertension have the greatest odds ratio (OR) of adverse outcome; 1.58 (95% CI 1.36-1.83). Renal function was not monitored in 4460 (12.6%) people. Unmonitored renal function was associated with adverse events; OR 1.35 (95% CI 1.13-1.63) in people with hypertension and OR 1.32 (95% CI 1.07-1.64) in those without. Proteinuria, eGFR < 60 ml/min, and failure to monitor renal function are associated with cardiovascular and renal events and mortality in people with diabetes.

Computing at school in the UK: from guerrilla to gorilla

Abstract: This paper summarises the rapid and radical developments during 2012-2013 in the K-12 school computing curriculum in UK. We draw out lessons from our experience that may be useful to others.

The provision and impact of online patient access to their electronic health records (EHR) and transactional services on the quality and safety of health care: systematic review protocol.

Abstract: Background: Innovators have piloted improvements in communication, changed patterns of practice and patient empowerment from online access to electronic health records (EHR). International studies of online services, such as prescription ordering, online appointment booking and secure communications with primary care, show good uptake of email consultations, accessing test results and booking appointments; when technologies and business process are in place. Online access and transactional services are due to be rolled out across England by 2015; this review seeks to explore the impact of online access to health records and other online services on the quality and safety of primary health care. Objective: To assess the factors that may affect the provision of online patient access to their EHR and transactional services, and the impact of such access on the quality and safety of health care. Method: Two reviewers independently searched 11 international databases during the period 1999-2012. A range of papers including descriptive studies using qualitative or quantitative methods, hypothesis-testing studies and systematic reviews were included. A detailed eligibility criterion will be used to shape study inclusion. A team of experts will review these papers for eligibility, extract data using a customised extraction form and use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument to determine the quality of the evidence and the strengths of any recommendation. Data will then be descriptively summarised and thematically synthesised. Where feasible, we will perform a quantitative meta-analysis. Prospero (International Prospective Register of Systematic Reviews) registration number: crd42012003091.

The Evidence-base for Using Ontologies and Semantic Integration Methodologies to Support Integrated Chronic Disease Management in Primary and Ambulatory Care: Realist Review. Contribution of the IMIA Primary Health Care Informatics WG.

Abstract: Most chronic diseases are managed in primary and ambulatory care. The chronic care model (CCM) suggests a wide range of community, technological, team and patient factors contribute to effective chronic disease management. Ontologies have the capability to enable formalised linkage of heterogeneous data sources as might be found across the elements of the CCM.

Adaptive frame buffer compression

Abstract: Image data is subject to compression and decompression when it is respectively written to and read from a frame buffer. If a portion of the image data is identified as static (subject to less than a threshold amount of change for greater than a threshold time), then compression control parameters used for compression of that portion of the image are adjusted so as to increase the compression ratio achieved, hold the degree of lossiness substantially constant and increase the energy consumed while compressing that portion. The increased energy consumption during this high compression ratio compression is likely compensated for by a reduction in energy subsequently consumed when writing that frame-buffer image data to the frame buffer and reading that frame-buffer image data multiple times from the frame buffer. The compression characteristics varied may be to increase the block size used in the compression. Other variations in compression applied may be to change from single-pass compression to multi-pass compression, switch compression on and off altogether, or reorder the data when it has been compressed so as to match the order it will be read and so achieve support for longer read burst.

An assessment of “failure to rescue” derived from routine NHS data as a nursing sensitive patient safety indicator for surgical inpatient care

Abstract: Background: ‘Failure to rescue’ - death after a treatable complication - is used as a nursing sensitive quality indicator in the USA. It is associated with the size of the nursing workforce relative to patient load, for example patient to nurse ratio, although assessments of nurse sensitivity have not previously considered other staff groups. This study aims to assess the potential to derive failure to rescue and a proxy measure, based on long length of stay, from English hospital administrative data. By exploring change in coding practice over time and measuring associations between failure to rescue and factors including staffing, we assess whether these are useful nurse sensitive indicators. Design: Cross sectional observational study of routinely collected administrative data. Participants: Discharge data from 66,100,672 surgical admissions to 146 general acute hospital trusts in England (1997 to 2009). Results: Median percentage of surgical admissions with at least one secondary diagnosis recorded increased from 26% in 1997/8 to 40% in 2008/9. Regression analyses showed that mortality based failure to rescue was significantly associated (p Conclusion: Failure to rescue can be derived from English administrative data and may be a valid quality indicator. This is the first study to assess the association between failure to rescue and medical staffing. The suggestion that it is particularly sensitive to nursing is not clearly supported, nor is the suggestion that the number of patients with an extended hospital stay is a good proxy.

Evidence Normalization in System FC (Invited Talk)

Abstract: System FC is an explicitly typed language that serves as the target language for Haskell source programs. System FC is based on System F with the addition of erasable but explicit type equality proof witnesses. Equality proof witnesses are generated from type inference performed on source Haskell programs. Such witnesses may be very large objects, which causes performance degradation in later stages of compilation, and makes it hard to debug the results of type inference and subsequent program transformations. In this paper we present an equality proof simplification algorithm, implemented in GHC, which greatly reduces the size of the target System FC programs.

The computing at school working group

Abstract: The Computing at School (CAS) Working Group aims to promote the teaching of computer science at school. CAS was born out of our excitement with our discipline, combined with a serious concern that many students are being "turned off" computing by a combination of factors that have conspired to make the subject seem dull and pedestrian. Our goal is to put the excitement back into Computing at school.

Evidence normalization in System FC

Abstract: System FC is an explicitly typed language that serves as the target language for Haskell source programs. System FC is based on System F with the addition of erasable but explicit type equality proof witnesses. Equality proof witnesses are generated from type inference performed on source Haskell programs. Such witnesses may be very large objects, which causes performance degradation in later stages of compilation, and makes it hard to debug the results of type inference and subsequent program transformations. In this paper we present an equality proof simplification algorithm, implemented in GHC, which greatly reduces the size of the target System FC programs.

Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

Abstract: Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

Creating a large area landcover dataset for public land monitoring and reporting

Abstract: Enhanced up-to-date information on the extent and quality of woody vegetation systems is required to inform sustainable land management. Government and land management agencies require tools to generate consistent and scientifically robust large area (i.e. landscape level) woody vegetation spatial features – with which to conduct environmental monitoring and assessment, under a number of regulatory environmental monitoring frameworks (e.g. UN Framework Convention on Climate Change, State of the Forest reporting - Victoria, National Forest Inventory – Australia). This paper presents a method for the creation of a partial sample land cover baseline to complement existing on-ground forest monitoring plots and the total sample mapping using moderate-resolution remote sensing imagery. The land cover baseline was created via non-stereo, on-screen aerial photographic interpretation (API). Land cover maps were produced from 790 2x2 km digital (georectified) high-resolution (≤ 50 cm) colour aerial photographs (photoplots) located across a large area sampling grid (stratified by IBRA1 Bioregion), with an average of 72 photoplots in each Bioregion. Forest type and structural components (based on the National Vegetation Information System – NVIS) and land cover information in non-forest areas (based on the UN FAO Land Cover Classification System - LCCS) were derived using a semi-automated API (air photo interpretation) methodology. Initially, landscape elements (image objects) were delineated using automated segmentation algorithms and these were tuned to ensure resultant image objects approximated the land cover classes of interest given the stated minimum mapping unit (0.5 ha). Image objects were subsequently verified and classified, using operator knowledge, into hierarchical land cover categories (including dominant species, height, canopy cover, LCCS class - and where appropriate, whether the area had been fire affected). Modelling to a baseline year was required to account for landcover change events and non-synchronous image capture. Continuous improvement and validation of the dataset was built into the methodology so as to provide on-going feedback to the API team and report accuracy across all bioregions. This case study demonstrates the operational capability of semi-automated API to support large area (state-wide) environmental monitoring and assessment.

Closed Type Families with Overlapping Equations (extended version)

Abstract: Open, type-level functions are a recent innovation in Haskell that move Haskell towards the expressiveness of dependent types, while retaining the look and feel of a practical programming language. This paper shows how to increase expressiveness still further, by adding closed type functions whose equations may overlap, and may have non-linear patterns over an open type universe. Although practically useful and simple to implement, these features go beyond conventional dependent type theory in some respects, and have a subtle metatheory.