Analysis of Iterative Methods for the Linear Boltzmann Transport Equation

In this article we consider the iterative solution of the linear system of equations arising from the discretisation of the poly-energetic linear Boltzmann transport equation using a discontinuous Galerkin finite element approximation in space, angle, and energy. In particular, we develop preconditioned Richardson iterations which may be understood as generalisations of source iteration in the mono-energetic setting, and derive computable a posteriori bounds for the solver error incurred due to inexact linear algebra, measured in a relevant problem-specific norm. We prove that the convergence of the resulting schemes and a posteriori solver error estimates are independent of the discretisation parameters. We also discuss how the poly-energetic Richardson iteration may be employed as a preconditioner for the generalised minimal residual (GMRES) method. Furthermore, we show that standard implementations of GMRES based on minimising the Euclidean norm of the residual vector can be utilized to yield computable a posteriori solver error estimates at each iteration, through judicious selections of left- and right-preconditioners for the original linear system. The effectiveness of poly-energetic source iteration and preconditioned GMRES, as well as their respective a posteriori solver error estimates, is demonstrated through numerical examples arising in the modelling of photon transport.Comment: 27 pages, 8 figure

Efficient High-Order Space-Angle-Energy Polytopic Discontinuous Galerkin Finite Element Methods for Linear Boltzmann Transport

We introduce an $hp$-version discontinuous Galerkin finite element method (DGFEM) for the linear Boltzmann transport problem. A key feature of this new method is that, while offering arbitrary order convergence rates, it may be implemented in an almost identical form to standard multigroup discrete ordinates methods, meaning that solutions can be computed efficiently with high accuracy and in parallel within existing software. This method provides a unified discretisation of the space, angle, and energy domains of the underlying integro-differential equation and naturally incorporates both local mesh and local polynomial degree variation within each of these computational domains. Moreover, general polytopic elements can be handled by the method, enabling efficient discretisations of problems posed on complicated spatial geometries. We study the stability and $hp$-version a priori error analysis of the proposed method, by deriving suitable $hp$-approximation estimates together with a novel inf-sup bound. Numerical experiments highlighting the performance of the method for both polyenergetic and monoenergetic problems are presented.Comment: 27 pages, 2 figure

Thrombocytogenesis by megakaryocyte; Interpretation by protoplatelet hypothesis

Serial transmission electron microscopy of human megakaryocytes (MKs) revealed their polyploidization and gradual maturation through consecutive transition in characteristics of various organelles and others. At the beginning of differentiation, MK with ploidy 32N, e.g., has 16 centrosomes in the cell center surrounded by 32N nucleus. Each bundle of microtubules (MTs) emanated from the respective centrosome supports and organizes 16 equally volumed cytoplasmic compartments which together compose one single 32N MK. During the differentiation, single centriole separated from the centriole pair, i.e., centrosome, migrates to the most periphery of the cell through MT bundle, corresponding to a half of the interphase array originated from one centrosome, supporting one “putative cytoplasmic compartment” (PCC). Platelet demarcation membrane (DM) is constructed on the boundary surface between neighbouring PCCs. Matured PCC, composing of a tandem array of platelet territories covered by a sheet of DM is designated as protoplatelet. Eventually, the rupture of MK results in release of platelets from protoplatelets

Healthcare providers' views on the acceptability of financial incentives for breastfeeding:a qualitative study

BACKGROUND: Despite a gradual increase in breastfeeding rates, overall in the UK there are wide variations, with a trend towards breastfeeding rates at 6–8 weeks remaining below 40% in less affluent areas. While financial incentives have been used with varying success to encourage positive health related behaviour change, there is little research on their use in encouraging breastfeeding. In this paper, we report on healthcare providers’ views around whether using financial incentives in areas with low breastfeeding rates would be acceptable in principle. This research was part of a larger project looking at the development and feasibility testing of a financial incentive scheme for breastfeeding in preparation for a cluster randomised controlled trial. METHODS: Fifty–three healthcare providers were interviewed about their views on financial incentives for breastfeeding. Participants were purposively sampled to include a wide range of experience and roles associated with supporting mothers with infant feeding. Semi-structured individual and group interviews were conducted. Data were analysed thematically drawing on the principles of Framework Analysis. RESULTS: The key theme emerging from healthcare providers’ views on the acceptability of financial incentives for breastfeeding was their possible impact on ‘facilitating or impeding relationships’. Within this theme several additional aspects were discussed: the mother’s relationship with her healthcare provider and services, with her baby and her family, and with the wider community. In addition, a key priority for healthcare providers was that an incentive scheme should not impact negatively on their professional integrity and responsibility towards women. CONCLUSION: Healthcare providers believe that financial incentives could have both positive and negative impacts on a mother’s relationship with her family, baby and healthcare provider. When designing a financial incentive scheme we must take care to minimise the potential negative impacts that have been highlighted, while at the same time recognising the potential positive impacts for women in areas where breastfeeding rates are low

Sarcolemma-localized nNOS is required to maintain activity after mild exercise

Many neuromuscular conditions are characterized by an exaggerated exercise- induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients(1), and some patients experience severe fatigue without any demonstrable somatic disease(2). Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown(2). With no treatment available, this form of inactivity is a major determinant of disability(3). Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase ( nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS- null mice do not have muscle pathology and have no loss of muscle- specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction- induced signalling from sarcolemma- localized nNOS, which decreases cGMP- mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise- induced signalling.Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant ; University of Iowa Cardiovascular Interdisciplinary Research ; National Research Service Award ; National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Institutes of Health ; Senator Paul D. Wellstone Fellowship ; Muscular Dystrophy Association Development Grant ; Howard Hughes Medical InstituteWe thank M. Anderson and M. Henry for comments, and M. M. Kilburg, K. Uppal, B. J. Steinmann and S. Watkins and members of the Campbell laboratory for scientific contributions. This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant. Y.M.K. was supported by grants from the University of Iowa Cardiovascular Interdisciplinary Research/ National Research Service Award (NRSA) Fellowship, from an individual NRSA Fellowship from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, from the National Institutes of Health (NIH), and from a Senator Paul D. Wellstone Fellowship. E.P.R. was supported by a Muscular Dystrophy Association Development Grant. R.M.W. was supported by the NIH. K.P.C. is an investigator of the Howard Hughes Medical Institute.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62850/1/nature07414.pd

Hemangiopericytomas of the spine: case report and review of the literature

We describe a rare case of a primary intracranial meningeal hemangiopericytoma (HPC) with late metastasis to the cervical spine. A 36-year-old woman had a left occipital lesion that was histopathologically identified as HPC. Fourteen years after resection, the tumor recurred and was treated with radiotherapy. Three years later, CT imaging showed a large mass in the liver consistent with metastatic HPC, and MRI of the cervical spine showed an extensive lesion of the C3 vertebral body. The patient underwent C3 corpectomy with en-bloc tumor removal and follow-up radiation with no local recurrence or other spinal metastasis for the following 4 years. Regardless of the subtype of spinal HPC, complete surgical removal and radiotherapy appear to be treatment of choice

Climate Science Special Report: Fourth National Climate Assessment (NCA4), Volume I

New observations and new research have increased our understanding of past, current, and future climate change since the Third U.S. National Climate Assessment (NCA3) was published in May 2014. This Climate Science Special Report (CSSR) is designed to capture that new information and build on the existing body of science in order to summarize the current state of knowledge and provide the scientific foundation for the Fourth National Climate Assessment (NCA4)

Impact of Dendritic Size and Dendritic Topology on Burst Firing in Pyramidal Cells

Neurons display a wide range of intrinsic firing patterns. A particularly relevant pattern for neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of action potentials with short interspike intervals. Besides ion-channel composition, dendritic morphology appears to be an important factor modulating firing pattern. However, the underlying mechanisms are poorly understood, and the impact of morphology on burst firing remains insufficiently known. Dendritic morphology is not fixed but can undergo significant changes in many pathological conditions. Using computational models of neocortical pyramidal cells, we here show that not only the total length of the apical dendrite but also the topological structure of its branching pattern markedly influences inter- and intraburst spike intervals and even determines whether or not a cell exhibits burst firing. We found that there is only a range of dendritic sizes that supports burst firing, and that this range is modulated by dendritic topology. Either reducing or enlarging the dendritic tree, or merely modifying its topological structure without changing total dendritic length, can transform a cell's firing pattern from bursting to tonic firing. Interestingly, the results are largely independent of whether the cells are stimulated by current injection at the soma or by synapses distributed over the dendritic tree. By means of a novel measure called mean electrotonic path length, we show that the influence of dendritic morphology on burst firing is attributable to the effect both dendritic size and dendritic topology have, not on somatic input conductance, but on the average spatial extent of the dendritic tree and the spatiotemporal dynamics of the dendritic membrane potential. Our results suggest that alterations in size or topology of pyramidal cell morphology, such as observed in Alzheimer's disease, mental retardation, epilepsy, and chronic stress, could change neuronal burst firing and thus ultimately affect information processing and cognition

Final analysis of a 14-year long-term follow-up study of the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in women from four nordic countries

Publisher's version (útgefin grein)Background: The quadrivalent human papillomavirus (qHPV) vaccine prevented vaccine HPV type-related infection and disease in young women in the 4-year FUTURE II efficacy study (NCT00092534). We report long-term effectiveness and immunogenicity at the end of 14 years of follow-up after enrollment in FUTURE II. Methods: Young women (16–23 years of age) from Denmark, Iceland, Norway, and Sweden who received three qHPV vaccine doses during the randomized, double-blind, placebo-controlled FUTURE II base study were followed for effectiveness for an additional ≥10 years through national registries. Tissue samples including but not limited to those collected during organized cervical cancer screening programs were obtained from regional biobanks to be adjudicated for histopathology diagnosis and tested for HPV DNA. The observed incidence of HPV16/18-related high-grade cervical dysplasia (primary outcome) was compared with recent historical background incidence rates in an unvaccinated population. Serum was collected at years 9 and 14 to assess antibody responses. Findings: No cases of HPV16/18-related high-grade cervical dysplasia were observed in the per-protocol effectiveness population (N = 2121; 24,099·0 person-years of follow-up) during the entire study. Vaccine effectiveness of 100% (95% CI 94·7–100) was demonstrated for ≥12 years, with a trend toward continued protection through 14 years post-vaccination. Seropositivity rates at study conclusion were >90% (HPV6/11/16) and 52% (HPV18) using competitive Luminex immunoassay, and >90% (all four HPV types) using the more sensitive IgG Luminex immunoassay. Interpretation: Vaccination of young women with qHPV vaccine offers durable protection against HPV16/18-related high-grade cervical dysplasia for ≥12 years, with a trend toward continued protection through 14 years post-vaccination, and induces sustained HPV6/11/16/18 antibody responses for up to 14 years post-vaccination. There was no evidence of waning immunity, suggesting no need for a booster dose during that period.Funding for this research was provided by Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ,USA (MSD).The authors would like to thank the study participants and base-study investigators. In particular, the authors are grateful to SuzanneCampbell, Ragnhild Flingtorp, and Bo Terning Hansen for contribu-tions to the study; Sara Nordqvist Kleppe for data management; andJette Junge for contributions serving on the pathology panel. Chris-tine Shields of MSD provided clinical scientist support to thefinalanalysis and contributed to the clinical study report. Roshonda Flor-ence of ExecuPharm provided operational leadership and coordi-nated with the pathology panel and central laboratories; this wasfunded by MSD.Medical writing support, under the direction of the authors, wasprovided by Erin Bekes, PhD, of CMC AFFINITY, McCann Health Medi-cal Communications, and was funded by MSD, in accordance withGood Publication Practice (GPP3) guidelines.Peer Reviewe

Configuration of vascular services: a multiple methods research programme

Background Vascular services is changing rapidly, having emerged as a new specialty with its own training and specialised techniques. This has resulted in the need for reconfiguration of services to provide adequate specialist provision and accessible and equitable services. Objectives To identify the effects of service configuration on practice, resource use and outcomes. To model potential changes in configuration. To identify and/or develop electronic data collection tools for collecting patient-reported outcome measures and other clinical information. To evaluate patient preferences for aspects of services other than health-related quality of life. Design This was a multiple methods study comprising multiple systematic literature reviews; the development of a new outcome measure for users of vascular services (the electronic Personal Assessment Questionnaire – Vascular) based on the reviews, qualitative studies and psychometric evaluation; a trade-off exercise to measure process utilities; Hospital Episode Statistics analysis; and the development of individual disease models and a metamodel of service configuration. Setting Specialist vascular inpatient services in England. Data sources Modelling and Hospital Episode Statistics analysis for all vascular inpatients in England from 2006 to 2018. Qualitative studies and electronic Personal Assessment Questionnaire – Vascular evaluation with vascular patients from the Sheffield area. The trade-off studies were based on a societal sample from across England. Interventions The data analysis, preference studies and modelling explored the effect of different potential arrangements for service provision on the resource use, workload and outcomes for all interventions in the three main areas of inpatient vascular treatment: peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease. The electronic Personal Assessment Questionnaire – Vascular was evaluated as a potential tool for clinical data collection and outcome monitoring. Main outcome measures Systematic reviews assessed quality and psychometric properties of published outcome measures for vascular disease and the relationship between volume and outcome in vascular services. The electronic Personal Assessment Questionnaire – Vascular development considered face and construct validity, test–retest reliability and responsiveness. Models were validated using case studies from previous reconfigurations and comparisons with Hospital Episode Statistics data. Preference studies resulted in estimates of process utilities for aneurysm treatment and for travelling distances to access services. Results Systematic reviews provided evidence of an association between increasing volume of activity and improved outcomes for peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease. Reviews of existing patient-reported outcome measures did not identify suitable condition-specific tools for incorporation in the electronic Personal Assessment Questionnaire – Vascular. Reviews of qualitative evidence, primary qualitative studies and a Delphi exercise identified the issues to be incorporated into the electronic Personal Assessment Questionnaire – Vascular, resulting in a questionnaire with one generic and three disease-specific domains. After initial item reduction, the final version has 55 items in eight scales and has acceptable psychometric properties. The preference studies showed strong preference for endovascular abdominal aortic aneurysm treatment (willingness to trade up to 0.135 quality-adjusted life-years) and for local services (up to 0.631 quality-adjusted life-years). A simulation model with a web-based interface was developed, incorporating disease-specific models for abdominal aortic aneurysm, peripheral arterial disease and carotid artery disease. This predicts the effects of specified reconfigurations on workload, resource use, outcomes and cost-effectiveness. Initial exploration suggested that further reconfiguration of services in England to accomplish high-volume centres would result in improved outcomes, within the bounds of cost-effectiveness usually considered acceptable in the NHS. Limitations The major source of evidence to populate the models was Hospital Episode Statistics data, which have limitations owing to the complexity of the data, deficiencies in the coding systems and variations in coding practice. The studies were not able to address all of the potential barriers to change where vascular services are not compliant with current NHS recommendations. Conclusions There is evidence of potential for improvement in the clinical effectiveness and cost-effectiveness of vascular services through further centralisation of sites where major vascular procedures are undertaken. Preferences for local services are strong, and this may be addressed through more integrated services, with a range of services being provided more locally. The use of a web-based tool for the collection of clinical data and patient-reported outcome measures is feasible and can provide outcome data for clinical use and service evaluation. Future work Further evaluation of the economic models in real-world situations where local vascular service reconfiguration is under consideration and of the barriers to change where vascular services do not meet NHS recommendations for service configuration is needed. Further work on the electronic Personal Assessment Questionnaire – Vascular is required to assess its acceptability and usefulness in clinical practice and to develop appropriate report formats for clinical use and service evaluation. Further studies to assess the implications of including non-health-related preferences for care processes, and location of services, in calculations of cost-effectiveness are required. Study registration This study is registered as PROSPERO CRD42016042570, CRD42016042573, CRD42016042574, CRD42016042576, CRD42016042575, CRD42014014850, CRD42015023877 and CRD42015024820. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 5. See the NIHR Journals Library website for further project information