Mathematical modelling of glob-driven tear film breakup.

Evaporation is a recognized contributor to tear film thinning and tear breakup (TBU). Recently, a different type of TBU is observed, where TBU happens under or around a thick area of lipid within a second after a blink. The thick lipid corresponds to a glob. Evaporation alone is too slow to offer a complete explanation of this breakup. It has been argued that the major reason of this rapid tear film thinning is divergent flow driven by a lower surface tension of the glob (via the Marangoni effect). We examine the glob-driven TBU hypothesis in a 1D streak model and axisymmetric spot model. In the model, the streak or spot glob has a localized high surfactant concentration, which is assumed to lower the tear/air surface tension and also to have a fixed size. Both streak and spot models show that the Marangoni effect can lead to strong tangential flow away from the glob and may cause TBU. The models predict that smaller globs or thinner films will decrease TBU time (TBUT). TBU is located underneath small globs, but may occur outside larger globs. In addition to tangential flow, evaporation can also contribute to TBU. This study provides insights about mechanism of rapid thinning and TBU which occurs very rapidly after a blink and how the properties of the globs affect the TBUT.

Dynamics of Fluorescent Imaging for Rapid Tear Thinning.

A previous mathematical model has successfully simulated the rapid tear thinning caused by glob (thicker lipid) in the lipid layer. It captured a fast spreading of polar lipid and a corresponding strong tangential flow in the aqueous layer. With the simulated strong tangential flow, we now extend the model by adding equations for conservation of solutes, for osmolarity and fluorescein, in order to study their dynamics. We then compare our computed results for the resulting intensity distribution with fluorescence experiments on the tear film. We conclude that in rapid thinning, the fluorescent intensity can linearly approximate the tear film thickness well, when the initial fluorescein concentration is small. Thus, a dilute fluorescein is recommended for visualizing the rapid tear thinning during fluorescent imaging.

Computed flow and fluorescence over the ocular surface.

Fluorescein is perhaps the most commonly used substance to visualize tear film thickness and dynamics; better understanding of this process aids understanding of dry eye syndrome which afflicts millions of people. We study a mathematical model for tear film flow, evaporation, solutal transport and fluorescence over the exposed ocular surface during the interblink. Transport of the fluorescein ion by fluid flow in the tear film affects the intensity of fluorescence via changes in concentration and tear film thickness. Evaporation causes increased osmolarity and potential irritation over the ocular surface; it also alters fluorescein concentration and thus fluorescence. Using thinning rates from in vivo measurements together with thin film equations for flow and transport of multiple solutes, we compute dynamic results for tear film quantities of interest. We compare our computed fluorescent intensity distributions with in vivo observations. A number of experimental features are recovered by the model.

Duplex Tear Film Evaporation Analysis.

Tear film thinning, hyperosmolarity, and breakup can cause irritation and damage to the human eye, and these form an area of active investigation for dry eye syndrome research. Recent research demonstrates that deficiencies in the lipid layer may cause locally increased evaporation, inducing conditions for breakup. In this paper, we explore the conditions for tear film breakup by considering a model for tear film dynamics with two mobile fluid layers, the aqueous and lipid layers. In addition, we include the effects of osmosis, evaporation as modified by the lipid, and the polar portion of the lipid layer. We solve the system numerically for reasonable parameter values and initial conditions and analyze how shifts in these cause changes to the system's dynamics.

Epilepsy and Pregnancy: For healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group.

Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy-related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene - Golden Moments of opportunities for improving outcomes -Which Key Groups have a role in making change -When - 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries.

Single best answer question-writing tips for clinicians.

Assessment is essential for progression in medical careers. Thus, an important aspect of developing as a clinical teacher is the ability to produce high-quality assessments for junior colleagues. The single best answer (SBA) question format is becoming ubiquitous in the assessment of the application of knowledge in clinical medicine; writing this style of examination question can be a challenge. This concise guide highlights key SBA question-writing tips, aiming to help aspiring clinical teachers set high-quality knowledge assessments.

Whole mount immunofluorescence analysis of placentas from normotensive versus preeclamptic pregnancies.

INTRODUCTION: Defects in placental angiogenesis and spiral artery remodeling have been proposed to play essential roles in the development of preeclampsia. However, the specific molecular mechanism(s) responsible for aberrant placental angiogenesis in preeclampsia are incompletely understood. The vascular endothelial growth factor receptors (VEGFR1, R2, R3) and STAT3 have critical functions in normal blood vessel development, but their potential roles in preeclampsia are currently unclear. In this study, we utilized a novel whole mount immunofluorescence (WMIF) method to compare expression of VEGFR1, R2, R3 and activated, phosphorylated STAT3 (pSTAT3) in placentas of preeclamptic (PE) versus normotensive (NT) pregnancies. METHODS: Placental biopsies collected from NT and PE pregnant women were fixed and stained with fluorochrome-conjugated antibodies to identify specific cell populations as follows: CD31 for blood vessel endothelial cells, cytokeratin-7 for trophoblast cells, and CD45 for immune cells. Expression of the VEGFRs and pSTAT3 were subsequently characterized by WMIF in conjunction with confocal microscopy. RESULTS: A total of 18 PE and 18 NT placentas were evaluated. No significant differences in the cell type-specific expression patterns or expression levels of VEGFR1, VEGFR2 or VEGFR3 were detected between NT and PE placentas. In contrast, statistically significant increases in pSTAT3 staining were detected in endothelial cells of PE placentas versus NT controls. DISCUSSION: Our study demonstrates that increased pSTAT3 expression in placental endothelial cells is associated with PE. We speculate that elevated pSTAT3 expression in the blood vessels of PE placentas may be due to aberrant angiogenesis, increased pro-inflammatory cytokine expression, and/or placental stress.

Shared decision-making in epilepsy management.

Policy makers, clinicians, and patients increasingly recognize the need for greater patient involvement in clinical decision-making. Shared decision-making helps address these concerns by providing a framework for clinicians and patients to make decisions together using the best evidence. Shared decision-making is applicable to situations where several acceptable options exist (clinical equipoise). Such situations occur commonly in epilepsy, for example, in decisions regarding the choice of medication, treatment in pregnancy, and medication withdrawal. A talk model is a way of implementing shared decision-making during consultations, and decision aids are useful tools to assist in the process. Although there is limited evidence available for shared decision-making in epilepsy, there are several benefits of shared decision-making in general including improved decision quality, more informed choices, and better treatment concordance.

Dynamics and function of the tear film in relation to the blink cycle.

Great strides have recently been made in quantitative measurements of tear film thickness and thinning, mathematical modeling thereof and linking these to sensory perception. This paper summarizes recent progress in these areas and reports on new results. The complete blink cycle is used as a framework that attempts to unify the results that are currently available. Understanding of tear film dynamics is aided by combining information from different imaging methods, including fluorescence, retroillumination and a new high-speed stroboscopic imaging system developed for studying the tear film during the blink cycle. During the downstroke of the blink, lipid is compressed as a thick layer just under the upper lid which is often released as a narrow thick band of lipid at the beginning of the upstroke. "Rippling" of the tear film/air interface due to motion of the tear film over the corneal surface, somewhat like the flow of water in a shallow stream over a rocky streambed, was observed during lid motion and treated theoretically here. New mathematical predictions of tear film osmolarity over the exposed ocular surface and in tear breakup are presented; the latter is closely linked to new in vivo observations. Models include the effects of evaporation, osmotic flow through the cornea and conjunctiva, quenching of fluorescence, tangential flow of aqueous tears and diffusion of tear solutes and fluorescein. These and other combinations of experiment and theory increase our understanding of the fluid dynamics of the tear film and its potential impact on the ocular surface.

Tear film dynamics with evaporation, wetting, and time-dependent flux boundary condition on an eye-shaped domain.

We study tear film dynamics with evaporation on a wettable eye-shaped ocular surface using a lubrication model. The mathematical model has a time-dependent flux boundary condition that models the cycles of tear fluid supply and drainage; it mimics blinks on a stationary eye-shaped domain. We generate computational grids and solve the nonlinear governing equations using the OVERTURE computational framework. In vivo experimental results using fluorescent imaging are used to visualize the influx and redistribution of tears for an open eye. Results from the numerical simulations are compared with the experiment. The model captures the flow around the meniscus and other dynamic features of human tear film observed in vivo.

A MODEL FOR THE TEAR FILM AND OCULAR SURFACE TEMPERATURE FOR PARTIAL BLINKS.

In this paper, we investigate the dynamics of tear film and the associated temperature variation for partial blinks. We investigate the mechanism of fluid supply during partial blink cycles, and compare the film thickness with observation in vivo. We find that varying the thickness of the fluid layer beneath the moving upper lid improves the agreement for the in vivo measurement of tear film thickness after a half blink. By examining the flux of the fluid, we provide an explanation of this assumption. We also investigate the temperature dynamics both at the ocular surface and inside the simulated anterior chamber. Our simulation results suggest that the ocular surface temperature readjusts rapidly to normal temperature distribution after partial blinks.

Management of suspected viral encephalitis in adults--Association of British Neurologists and British Infection Association National Guidelines.

In the 1980s the outcome of patients with herpes simplex encephalitis was shown to be dramatically improved with aciclovir treatment. Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis. Several comprehensive reviews of the investigation and management of encephalitis have been published. However, their impact on day-to day clinical practice appears to be limited. The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines. In February 2008 a group of clinicians met in Liverpool to begin the development process for clinical care guidelines based around a similar simple algorithm, supported by an evidence base, whose implementation is hoped would improve the management of patients with suspected encephalitis.

Genetic epilepsy with febrile seizures plus: definite and borderline phenotypes.

Generalised epilepsy with febrile seizures plus (GEFS+) is the most studied familial epilepsy syndrome. However, characteristics of UK families have not previously been reported. Among the first 80 families recruited to our families study, four broad subphenotypes were identified: families with classical GEFS+; families with borderline GEFS+; families with unclassified epilepsy; and families with an alternative syndromal diagnosis. Borderline GEFS+ families shared many characteristics of classical GEFS+ families-such as prominent febrile seizures plus and early onset febrile seizures-but included more adults with focal epilepsies (rather than the idiopathic generalised epilepsies predominating in GEFS+) and double the prevalence of migraine. Thus the authors believe that a novel and robust familial epilepsy phenotype has been identified. Subcategorising families with epilepsy is helpful in targeting both clinical and research resources. Most families with GEFS+ have no identified causal mutation, and so predicting genetic homogeneity by identifying endophenotypes becomes more important.

Identifying and prioritising epilepsy treatment uncertainties.

OBJECTIVE: To identify and prioritise uncertainties regarding epilepsy treatment from people with epilepsy, their carers and epilepsy clinicians. BACKGROUND: Failure to acknowledge and address genuine treatment uncertainties has caused unnecessary iatrogenic harm. The authors define an uncertainty as a question that cannot be sufficiently answered by a systematic review of the literature. The database of the uncertainties of the effects of treatment (DUETs) is a collection of 'known unknowns' that enables patient-prioritised research. DESIGN AND PARTICIPANTS: The authors organised five separate focus groups (two consisting of clinicians, three of patients and carers) to garner questions on epilepsy treatment uncertainties; these yielded 398 potential research questions. Participants were asked to rank the questions in terms of importance. The authors then performed a thematic analysis. RESULTS: Patients rated questions concerning cognitive drug side effects, managing the consequences of side effects and improving public awareness about the treatment of epilepsy through improved services as most important. For clinicians, the most important themes were treatment programmes for non-epileptic attack disorder (NEAD), concerns about side effects in utero and uncertainties regarding prescribing in pregnancy. CONCLUSIONS: Patient uncertainties were often focussed on very practical considerations-how to take prescribed medication, access to services and how to minimise drug side effects. Clinicians' questions were also practical but clustered around 'the challenging consultation'-for example, NEAD, sudden unexplained death in epilepsy and prescribing in pregnancy. The authors have published the research questions on NHS Evidence and are working with them to identify those questions which represent genuine uncertainties. The authors encourage other clinicians to seek patient and carers' priorities in order to shape their research agenda.

Awake seizures after pure sleep-related epilepsy: a systematic review and implications for driving law.

Who with sleep seizures is safe to drive? Driving law is controversial; ineligibility varies between individual US states and EU countries. Current UK driving law is strongly influenced by a single-centre study from 1974 where most participants were not taking antiepileptic drugs (AEDs). However, pure sleep-related epilepsy is often fully controlled on medication, and its withdrawal can provoke awake seizures. This systematic review asked, 'What is the risk of awake seizures in pure sleep-related epilepsy?' 9885 titles were identified; 2312 were excluded (not human or adult); 40 full texts were reviewed; six papers met our inclusion criteria; each of these six studies had a different pure sleep-related epilepsy definition. Using the largest prospective study, we were able to calculate next year's awake seizure chance (treated with antiepileptic medication). This was maximal in the second year: 5.7% (95% CI 3.0 to 10.4%). European licensing bodies including the UK's Driver and Vehicle Licensing Agency broadly accept a risk of less than 20% for Group 1 licensing. However, this study excluded patients with frontal-lobe epilepsies. Furthermore, follow-up (n=160) varied from 2 to 6 years, yet new awake seizures may occur even after 10-20 years of pure sleep-related epilepsy A paucity of evidence underpins present licensing law; current rulings would be difficult to defend if legally challenged. The law may be penalising people with pure sleep-related epilepsy without increased risk of awake seizures, while failing to identify subgroups at unacceptable risk of an awake seizure at the wheel.

Epilepsy genetics: clinical beginnings and social consequences.

The approach to epilepsy care has transformed in the last 30 years, with more and better anti-epileptic medications, improved cerebral imaging and increased surgical options. Alongside this, developments in neuroscience and molecular genetics have furthered the understanding of epileptogenesis. Future developments in pharmacogenomics hold the promise of antiepileptic drugs matched to specific genotypes. Despite this rapid progress, one-third of epilepsy patients remain refractory to medication, with their seizures impacting upon day-to-day activity, social well-being, independence, economic output and quality of life. International genome collaborations, such as HapMap and the Welcome Trust Case-Control Consortium single nucleotide polymorphism (SNP) mapping project have identified common genetic variations in diseases of major public health importance. Such genetic signposts should help to identify at-risk populations with a view to producing more effective pharmaceutical treatments. Neurological disorders, despite comprising one-fifth of UK acute medical hospital admissions, are surprisingly under-represented in these projects. Epilepsy is the commonest serious neurological disorder worldwide. Although physically, psychologically, socially and financially disabling, it rarely receives deserved attention from physicians, scientists and governmental bodies. As outlined in this article, research into epilepsy genetics presents unique challenges. These help to explain why the identification of its complex genetic traits has lagged well behind other disciplines, particularly the efforts made in neuropsychiatric disorders. Clinical beginnings must underpin any genetic understanding in epilepsy. Success in identifying genetic traits in other disorders does not make the automatic case for genome-wide screening in epilepsy, but such is a desired goal. The essential clinical approach of accurately phenotyping, diagnosing and interpreting the dynamic nature of epilepsy remains fundamental to harvesting its potential translational outcomes.

Goya's deafness.

Francisco Goya (1746-1828), a major Spanish artist, became profoundly deaf aged 46 years, following an acute illness. Despite this, his success continued and he eventually died aged 82 years. His illness is sketchily documented in letters written during his convalescence, describing headache, deafness, tinnitus, unsteadiness and visual disturbance with recovery (apart from deafness) over three months. There was a milder similar illness two years before, suggesting a relapsing condition. Vogt-Koyanagi-Harada syndrome, although previously accepted as Goya's diagnosis, is not supported by the limited evidence. Susac's syndrome or Cogan's syndrome, although both rare, are more likely explanations.

An overset grid method for the study of reflex tearing.

We present an overset grid method to simulate the evolution of human tear film thickness subject to reflex tearing. The free-surface evolution is governed by a single fourth-order non-linear equation derived from lubrication theory with specified film thickness and volume flux at each end. The model arises from considering the limiting case where the surfactant is strongly affecting the surface tension. In numerical simulations, the overset grid is composed of fine boundary grids near the upper and lower eyelids to capture localized capillary thinning referred to as 'black lines' and a Cartesian grid covers the remaining domain. Numerical studies are performed on a non-linear test problem to confirm the accuracy and convergence of the scheme. The computations on the tear film model show qualitative agreement with in vivo tear film thickness measurements. Furthermore, the role of the black lines in the presence of tear supply from the lid margins, reflex tearing, was found to be more subtle than a barrier to tear fluid flow between the anterior of the eye and the meniscus at the lid margin. During reflex tearing, tears may flow through the region normally containing the black line and drift down over the cornea under the influence of gravity.