The Dirac-Maxwell Equations with Cylindrical Symmetry

A reduction of the Dirac-Maxwell equations in the case of static cylindrical symmetry is performed. The behaviour of the resulting system of o.d.e.'s is examined analytically and numerical solutions presented. There are two classes of solutions. The first type of solution is a Dirac field surrounding a charged "wire". The Dirac field is highly localised, concentrated in cylindrical shells about the wire. A comparison with the usual linearized theory demonstrates that this localization is entirely due to the non-linearities in the equations which result from the inclusion of the "self-field". The second class of solutions have the electrostatic potential finite along the axis of symmetry but unbounded at large distances from the axis.Comment: 17 pages, Latex, 5 figures, psfig, to be published in J. Maths Phy

Magnetic Monopoles, Electric Neutrality and the Static Maxwell-Dirac Equations

We study the full Maxwell-Dirac equations: Dirac field with minimally coupled electromagnetic field and Maxwell field with Dirac current as source. Our particular interest is the static case in which the Dirac current is purely time-like -- the "electron" is at rest in some Lorentz frame. In this case we prove two theorems under rather general assumptions. Firstly, that if the system is also stationary (time independent in some gauge) then the system as a whole must have vanishing total charge, i.e. it must be electrically neutral. In fact, the theorem only requires that the system be {\em asymptotically} stationary and static. Secondly, we show, in the axially symmetric case, that if there are external Coulomb fields then these must necessarily be magnetically charged -- all Coulomb external sources are electrically charged magnetic monopoles

Adults’ number-line estimation strategies: Evidence from eye movements

Although the development of number-line estimation ability is well documented, little is known of the processes underlying successful estimators’ mappings of numerical information onto spatial representations during these tasks. We tracked adults’ eye movements during a number-line estimation task to investigate the processes underlying number-to-space translation, with three main results. First, eye movements were strongly related to the target number’s location, and early processing measures directly predicted later estimation performance. Second, fixations and estimates were influenced by the size of the first number presented, indicating that adults calibrate their estimates online. Third, adults’ number-line estimates demonstrated patterns of error consistent with the predictions of psychophysical models of proportion estimation, and eye movement data predicted the specific error patterns we observed. These results support proportion-based accounts of number-line estimation and suggest that adults’ translation of numerical information into spatial representations is a rapid, online process

Overtreatment of COPD with Inhaled Corticosteroids - Implications for Safety and Costs: Cross-Sectional Observational Study

<div><p>Introduction</p><p>Combined inhaled long-acting beta-agonists and corticosteroids (LABA+ICS) are costly. They are recommended in severe or very severe chronic obstructive pulmonary disease (COPD). They should not be prescribed in mild or moderate disease. In COPD ICS are associated with side-effects including risk of pneumonia. We quantified appropriateness of prescribing and examined the risks and costs associated with overuse. </p> <p>Methods</p><p>Data were extracted from the electronic and paper records of 41 London general practices (population 310,775) including spirometry, medications and exacerbations. We classified severity, assessed appropriateness of prescribing using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for 2009, and performed a sensitivity analysis using the broader recommendations of the 2011 revision.</p> <p>Results</p><p>3537 patients had a diagnosis of COPD. Spirometry was recorded for 2458(69%). 709(29%) did not meet GOLD criteria. 1749(49%) with confirmed COPD were analysed: 8.6% under-treated, 38% over-treated. Over-prescription of ICS in GOLD stage I or II (n=403, 38%) and in GOLD III or IV without exacerbations (n=231, 33.6%) was common. An estimated 12 cases (95%CI 7-19) annually of serious pneumonia were likely among 897 inappropriately treated. 535 cases of overtreatment involved LABA+ICS with a mean per patient cost of £553.56/year (€650.03). Using the broader indications for ICS in the 2011 revised GOLD guideline 25% were still classified as over-treated. The estimated risk of 15 cases of pneumonia (95%CI 8-22) in 1074 patients currently receiving ICS would rise by 20% to 18 (95%CI 9.8-26.7) in 1305 patients prescribed ICS if all with GOLD grade 3 and 4 received LABA+ICS. </p> <p>Conclusion</p><p>Over-prescription of ICS in confirmed COPD was widespread with considerable potential for harm. In COPD where treatment is often escalated in the hope of easing the burden of disease clinicians should consider both the risks and benefits of treatment and the costs where the benefits are unproven. </p> </div

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

The ‘vicious cycle’ of personalised asthma action plan implementation in primary care: a qualitative study of patients and health professionals’ views

Background: Personal asthma action plans (PAAPs) have been guideline recommended for years, but consistentlyunder-issued by health professionals and under-utilised by patients. Previous studies have investigated sub-optimalPAAP implementation but more insight is needed into barriers to their use from the perspective of professionals,patients and primary care teams.Methods: A maximum variation sample of professional and patient participants were recruited from five demographicallydiverse general practices and another group of primary care professionals in one Scottish region. Interviews were digitallyrecorded and data thematically analysed using NVivo.Results: Twenty-nine semi-structured interviews were conducted (11 adults with asthma, seven general practitioners, tenpractice nurses, one hospital respiratory nurse). Three over-arching themes emerged: 1) patients generally do not valuePAAPs, 2) professionals do not fully value PAAPs and, 3) multiple barriers reduce the value of PAAPs in primary care. Sixpatients had a PAAP but these were outdated, not reflecting their needs and not used. Patients reported not wanting orneeding PAAPs, yet identified circumstances when these could be useful. Fifteen professionals had selectively issuedPAAPs with eight having reviewed one. Many professionals did not value PAAPs as they did not see patients using theseand lacked awareness of times when patients could have benefited from one. Multi-level compounding barriers emerged.Individual barriers included poor patient awareness and professionals not reinforcing PAAP use. Organisational barriersincluded professionals having difficulty accessing PAAP templates and fragmented processes including patients not beingasked to bring PAAPs to their asthma appointments.Conclusions: Primary care PAAP implementation is in a vicious cycle. Professionals infrequently review/update PAAPswith patients; patients with out-dated PAAPs do not value or use these; professionals observing patients’ lack of interestin PAAPs do not discuss these. Patients observing this do not refer to their plans and perceive them to be of little valuein asthma self-management. Twenty-five years after PAAPs were first recommended, primary care practices are still notready to support their implementation. Breaking this vicious cycle to create a healthcare context more conducive to PAAPimplementation requires a whole systems approach with multi-faceted interventions addressing patient, professional andorganisational barriers

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec