Risk of Recurrence in Acute Anterior Uveitis.

PURPOSE: To examine the frequency of recurrence and identify risk factors for recurrence in patients with acute anterior uveitis (AAU). DESIGN: Retrospective cohort study from a single tertiary ophthalmic clinical centre. PARTICIPANTS: All subjects with AAU identified from a database of Inflammatory Eye Disease presenting to Te Whatu Ora (Auckland, New Zealand) between 2008 and 2021. METHODS: Data was collected retrospectively from chart review and electronic patient records for all patients during the study period. Rates of recurrence were reported using Kaplan Meier estimator. Multivariate analysis of risk factors for recurrence were calculated using a marginal Cox regression model. MAIN OUTCOME MEASURES: The primary outcome measure was disease recurrence. Secondary outcome measure was moderate vision loss (≤20/50). RESULTS: 2763 eyes of 2092 subjects with AAU were studied, with a median follow up time of 8.9 years, and a total follow up of 19,794.9 eye-years. Recurrence occurred in the ipsilateral eye in 1258 eyes (45.5%) and in the contralateral eye in 522 eyes (27.3%). Rates of ipsilateral recurrence over ten years were 38.1% for idiopathic disease, 43.2% for HLAB27/inflammatory arthritis, and 44.9% for viral uveitis. On multivariate analysis the following were associated with increased risk of ipsilateral recurrence: older age (p<0.001); Maori ethnicity (p=0.006); Asian ethnicity (p<0.001); HLA-B27/inflammatory arthritis (p<0.001); viral uveitis (p=0.018). There was no association with gender, smoking, bilateral disease, or hypertensive uveitis. Rates of contralateral eye involvement were significantly lower than ipsilateral eye recurrence. Contralateral recurrence at ten years was 15.2% in idiopathic uveitis, 37.6% in HLAB27/inflammatory arthritis, and 2.0% in viral uveitis. Risk factors identified for contralateral eye involvement were Maori ethnicity (p=0.003), Pasifika (Pacific Islanders) ethnicity (p=0.021), HLAB27/inflammatory arthritis (p<0.001). Moderate vision loss (≤20/50) was present in 411 eyes (14.9%) at final follow up and was more common if time to first recurrence was shorter (p<0.001). CONCLUSIONS: Approximately half of patients with AAU will develop recurrence in the ipsilateral eye and a quarter will have recurrence in the contralateral eye. Patients with viral disease have the highest risk of ipsilateral recurrence and lowest risk of contralateral recurrence. Patients with risk factors for recurrence should be managed and counselled appropriately to minimise the risk of visual loss and complications of uveitis.

Effects of Core Size and Surfactant Choice on Fluid Saturation Development in Surfactant/Polymer Corefloods.

Surfactant/polymer flooding allows for a significant increase in oil recovered at both laboratory and field scales. Limitations in application at the reservoir scale are, however, present and can be associated with both the complexity of the underlying displacement process and the time-intensive nature of the up-scaling workflow. Pivotal to this workflow are corefloods which serve to both validate the extent of oil recovery and extract modeling parameters used in upscaling. To enhance the understanding of the evolution of the saturation distribution within the rock sample, we present the utilization of X-ray computed tomography to image six distinct surfactant/polymer corefloods. In doing so, we visualize the formation and propagation of an oil bank by reconstructing multidimensional saturation maps. We conduct experiments on three distinct core sizes and two different surfactants, an SBDS/isbutanol formulation and an L-145-10s 90 formulation, in order to decouple the effect of these two parameters on the flow behavior observed in situ. We note that the oil production post oil bank breakthrough is primarily influenced by the surfactant choice, with the SDBS/isobutanol formulation displaying longer tailing production of a low oil cut. On the other hand, the core size dominated the extent of self-similarity of the saturation profiles with smaller cores showing less overlap in the self-similarity profiles. Consequently, we highlight the difference in applicability of a fractional flow approach to larger and smaller cores for upscaling parameter extraction and thus provide guidance for corefloods where direct imaging is not available.

Ophthalmic artery stenosis on three-dimensional rotational angiography: Interrater agreement, prevalence, and risk factors.

BACKGROUND: There is emerging interest in ophthalmic artery (OA) stenosis angioplasty for the treatment of age-related macular degeneration. Three-dimensional rotational angiography (3DRA) could be used during conventional angiography to determine the presence and severity of OA stenosis. In patients who had undergone 3DRA of the internal carotid artery, we aimed to assess the interrater agreement, prevalence, and risk factors for OA stenosis. METHODS: Consecutive patients from two centers who had undergone conventional angiography with 3DRA of the internal carotid arteries were enrolled in this study. 3DRAs were independently double read for the presence of OA stenosis, as defined as narrowing of the proximal OA of at least 50% when compared to the more distal "normal" OA. Interrater agreement for the evaluation of OA stenosis was assessed with the Cohen's kappa coefficient. Univariate and multivariable logistic regression were used to identify potential predictors of OA stenosis. RESULTS: Three hundred and two patients (97 men; mean ± SD 57.6 ± 13.4 years) were included in the analysis. Cohen's kappa coefficient (95% CI) was 0.877 (0.798-0.956). OA stenosis was present in 45 patients (14.9%). Multiple logistic regression demonstrated that female sex (odds ratio [OR] = 2.70, 95% confidence interval [CI] 1.18-6.09, p = 0.02) and smoking (OR = 2.11, 95% CI 1.10-4.06, p = 0.03) were significant risk factors for OA stenosis. Age, hypertension, diabetes, coronary artery disease, and subarachnoid hemorrhage were not associated with OA stenosis. CONCLUSION: The evaluation of OA stenosis on 3DRA had excellent interrater agreement. OA stenosis was common and was associated with smoking and female sex.

Is diabetic retinopathy screening worthwhile among people first diagnosed with diabetes at older ages? A cohort study of Norfolk diabetic retinopathy screening programme.

AIMS: England's Diabetic Eye Disease Screening Programme offers screening to every resident over age 12 with diabetes, starting as soon as possible after diagnosis and repeated annually. People first diagnosed with diabetes at older ages have shorter life expectancy and therefore may be less likely to benefit from screening and treatment. To inform decisions about whether diabetic eye screening policy should be stratified by age, we investigated the probability of receiving treatment according to age at first screening episode. METHODS: This was a cohort study of participants in the Norfolk Diabetic Retinopathy Screening Programme from 2006 to 2017, with individuals' programme data linked to hospital treatment and death data recorded up to 2021. We estimated and compared the probability, annual incidence and screening costs of receiving retinal laser photocoagulation or intravitreal injection and of death, in age groups defined by age at first screening episode. RESULTS: The probability of death increased with increasing age at diagnosis, while the probability of receiving either treatment decreased with increasing age. The estimated cost of screening per person who received either or both treatments was £18,608 among all participants, increasing with age up to £21,721 in those aged 70-79 and £26,214 in those aged 80-89. CONCLUSIONS: Diabetic retinopathy screening is less effective and less cost-effective with increasing age at diagnosis of diabetes, because of the increasing probability of death before participants develop sight-threatening diabetic retinopathy and can benefit from treatment. Upper age limits on entry into screening programmes or risk stratification in older age groups may, therefore, be justifiable.

COVID-19-associated mixed cilioretinal artery occlusion and central venous occlusion in a fit and healthy young patient.

Retinal artery occlusion is an unusual phenomenon in younger patients without background of diseases leading to hypercoagulable states. COVID-19 infection is increasingly recognised as being associated with thrombotic conditions. We present a case of a young female who is otherwise fit and well apart from recent COVID-19 infection, who presented with a mixed cilioretinal artery and venous occlusion.

Topical prostaglandin analogue use and cystoid macular oedema following uneventful cataract surgery: a randomised control trial.

BACKGROUND/AIMS: The association between the development of cystoid macular oedema (CMO) following uneventful cataract surgery and prostaglandin analogue (PGA) therapy has not been fully determined. The study aim was to investigate whether discontinuation of PGA therapy following uneventful cataract surgery affected the incidence of postoperative CMO. METHODS: A prospective randomised controlled trial of 62 eyes of 62 participants with ocular hypertension (OH) or primary open angle glaucoma (POAG) treated with PGAs prior to cataract surgery. Participants were randomised to continue with PGA therapy after cataract surgery (CPGA) (n=31) or to discontinue PGA therapy (n=31). The primary outcome measure was the development of CMO at 1-month postoperatively, determined by a masked observer assessment of optical coherence tomography scans. The secondary outcome measure was change from baseline intraocular pressure (IOP). RESULTS: The incidence of CMO was identical in both groups at 12.9% (4 of 31 eyes) at the 1-month postoperative visit (OR 1.000; 95% CI 0.227 to 4.415). At 1-month postoperatively, the IOP was significantly lower in the CPGA group compared with baseline IOP. CONCLUSION: Continuation of PGA therapy following uneventful cataract surgery in eyes with normal macular morphology did not increase the incidence of CMO. Continuation of PGA therapy significantly reduced IOP at 1-month postoperatively suggesting that, when indicated, it might be beneficial to continue PGA therapy in patients with POAG or OH after uneventful cataract surgery in the absence of other risk factors for developing CMO.

Erdheim-Chester Disease: Two cases from an ophthalmic perspective.

PURPOSE: We report two patients who presented initially to ophthalmology clinics with symptoms and signs of orbital inflammation that led to a diagnosis of Erdheim-Chester Disease (ECD). OBSERVATIONS: ECD is a rare form of non-Langerhans cell histiocytosis (LCH) which is characterised by multi-system organ involvement and poor prognosis with standard therapies. Both patients were positive for the BRAF V600E mutation on genetic testing and were treated with the BRAF inhibitors Vemurafenib and Dabrafenib respectively. These cases highlight the variable clinical presentation and course of ECD, the classical radiological and histopathological findings, and the high degree of clinical suspicion necessary to reach this diagnosis. CONCLUSIONS AND IMPORTANCE: The combination of xanthelasma and bilateral, diffuse intraconal orbital masses must suggest to the clinician the possibility of ECD; and consideration to arrange further investigation with a full body CT or FDG PET/CT scan should be given, even in the absence of wider systemic symptoms or signs. With the advent of targeted therapies such as BRAF inhibitors, it is of even more importance that a diagnosis of ECD is established in a timely manner in order to give these patients the best chance of reduced morbidity and increased survival.

Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model.

Cannabidiol (CBD), a non-euphorigenic compound derived from Cannabis, shows promise for improving recovery following cerebral ischemia and has recently been shown effective for the treatment of childhood seizures caused by Dravet and Lennox-Gastaut syndromes. Given evidence for activity to mitigate effects of CNS insult and dysfunction, we considered the possibility that CBD may also protect and improve functional recovery of a complex learned behavior. To test this hypothesis, we have applied a songbird, the adult male zebra finch, as a novel pre-clinical animal model. Their learned vocalizations were temporarily disrupted with bilateral microlesions of HVC (used as a proper name) a pre-vocal motor cortical-like brain region that drives song. These microlesions destroy about 10% of HVC, and temporarily impair song production, syntax and phonology for about seven days. Recovery requires sensorimotor learning as it depends upon auditory feedback. Four CBD doses (0, 1, 10 and 100 mg/kg) within three surgery conditions (microlesion, no-microlesion, sham-microlesion) were evaluated (n = 5-6). Birds were recorded over 20 days: three baseline; six pre-microlesion drug treatment days and; 11 post-microlesion treatment and recovery days. Results indicate 10 and 100 mg/kg CBD effectively reduced the time required to recover vocal phonology and syntax. In the case of phonology, the magnitude of microlesion-related disruptions were also reduced. These results suggest CBD holds promise to improve functional recovery of complex learned behaviors following brain injury, and represent establishment of an important new animal model to screen drugs for efficacy to improve vocal recovery.

Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male Mecp2 mutant mice.

BACKGROUND: Recent evidence suggests that 2-week treatment with the non-psychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of Rett syndrome (RTT). AIM: The aim of this study was to provide further insights into the efficacy of CBDV in Mecp2-null mice using a lifelong treatment schedule (from 4 to 9 weeks of age) to evaluate its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression. METHODS: CBDV 0.2, 2, 20 and 200 mg/kg/day was administered to Mecp2-null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wild-type and knockout mice to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system. RESULTS: CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in Mecp2 mutant mice at an advanced stage of the disease. Mecp2 deletion upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment. CONCLUSIONS: CBDV administration exerts an enduring rescue of memory deficits in Mecp2 mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.

Polypharmacology Shakes Hands with Complex Aetiopathology.

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex(®)), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the 'therapeutic handshake', to predict efficacy/safety of compound combinations of either natural or synthetic origin.

A case of episcleral tattooing--an emerging body modification trend.

BACKGROUND: In 2007 an article was published describing the first forays into the practice of episcleral tattooing. Currently only a handful of people worldwide have undergone this procedure, whereby a needle is used to inject dye under the bulbar conjunctiva. To date there have been no previous reports of the risks and complications of this emerging practice in the medical literature. We present a case involving a complication that arose in one of the few people in Britain to have undergone episcleral tattooing for cosmetic purposes. CASE PRESENTATION: A 43-year-old Caucasian man presented to the eye casualty clinic with red, lumpy conjunctivae bilaterally, having undergone episcleral tattooing 7 weeks previously. On examination there were 3 distinct areas of conjunctival swelling in each eye, representing a total of 6 injection sites. No other gross abnormalities were identified. The clinical picture remained unchanged 6 months on, apart from a degree of fading of the conjunctival dye. He will remain under our care to ensure that any further complications such as granulomatous inflammation are managed and documented. CONCLUSION: Episcleral tattooing is carried out by individuals with no medical training. The short-term complications reported so far include: headaches, severe photophobia, persistent foreign body sensation, and migration of ink staining. More serious short-term risks such as infection, globe penetration, and peri-ocular haemorrhage could occur. For now we can only speculate as to the long-term consequences, but these may include carcinogenic change or granulomatous inflammation. We feel that the potential risks of the procedure should be communicated more widely to those body modification practitioners undertaking it. This practice could result in more serious presentations to acute eye services in the future.

Evaluation of a neurosurgical robotic system to make accurate burr holes.

INTRODUCTION: Neurosurgery has been driven forward by the latest breakthroughs in technology that combine science and engineering. Neurosurgical robotic systems are a good example of such a breakthrough that has several potential advantages over existing techniques. This study sought to evaluate the Pathfinder robotic system in order to establish whether it is capable of carrying out burr hole procedures in specific locations in human skull replicas, along predetermined trajectories and for precise depths. METHODS: Three different registration fiducial configurations (A, B and C) were used on three different skull replicas of patients obtained from CT scan reconstructions. The skull replicas were scanned and the PathFinder robotic arm was used to place burr holes along specific trajectories. Target registration accuracies for surface targets and burr hole placements were measured, and the burr hole depths and trajectories were assessed. RESULTS: Overall registration errors, surface target registration accuracies, and burr hole target registration accuracies were submillimetric in all three registration fiducial configurations. However, the accuracies recorded in configurations B and C were significantly better than those in configuration A. CONCLUSION: Results demonstrated that the robotic system can approach surface and burr hole targets accurately. The accuracy was altered significantly by the configuration of registration fiducials and the robot was a useful tool to steady the surgical drill to place burr holes in specific locations and depth along the programmed trajectory.

Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle.

Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle. The propensity to undertake voluntary exercise or indulge in spontaneous physical exercise, which might be termed "exercise salience", is drawing increased scientific attention. Despite its genetic aspects, this complex behaviour is clearly modulated by the environment and influenced by physiological states. Inflammation is often overlooked as one of these conditions even though it is known to induce a state of reduced mobility. Chronic subclinical inflammation is associated with the metabolic syndrome; a largely lifestyle-induced disease which can lead to decreased exercise salience. The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity. One general consequence of hormesis is upregulation of mitochondrial function and resistance to oxidative stress. Examples of hormetic factors include calorie restriction, extreme environmental temperatures, physical activity and polyphenols. The hormetic modulation of inflammation, and thus, exercise salience, may help to explain the highly heterogeneous expression of voluntary exercise behaviour and therefore body composition phenotypes of humans living in similar obesogenic environments.

myGRN: a database and visualisation system for the storage and analysis of developmental genetic regulatory networks.

BACKGROUND: Biological processes are regulated by complex interactions between transcription factors and signalling molecules, collectively described as Genetic Regulatory Networks (GRNs). The characterisation of these networks to reveal regulatory mechanisms is a long-term goal of many laboratories. However compiling, visualising and interacting with such networks is non-trivial. Current tools and databases typically focus on GRNs within simple, single celled organisms. However, data is available within the literature describing regulatory interactions in multi-cellular organisms, although not in any systematic form. This is particularly true within the field of developmental biology, where regulatory interactions should also be tagged with information about the time and anatomical location of development in which they occur. DESCRIPTION: We have developed myGRN (http://www.myGRN.org), a web application for storing and interrogating interaction data, with an emphasis on developmental processes. Users can submit interaction and gene expression data, either curated from published sources or derived from their own unpublished data. All interactions associated with publications are publicly visible, and unpublished interactions can only be shared between collaborating labs prior to publication. Users can group interactions into discrete networks based on specific biological processes. Various filters allow dynamic production of network diagrams based on a range of information including tissue location, developmental stage or basic topology. Individual networks can be viewed using myGRV, a tool focused on displaying developmental networks, or exported in a range of formats compatible with third party tools. Networks can also be analysed for the presence of common network motifs. We demonstrate the capabilities of myGRN using a network of zebrafish interactions integrated with expression data from the zebrafish database, ZFIN. CONCLUSION: Here we are launching myGRN as a community-based repository for interaction networks, with a specific focus on developmental networks. We plan to extend its functionality, as well as use it to study networks involved in embryonic development in the future.

Bioartificial kidney in the treatment of acute renal failure associated with sepsis.

Acute renal failure (ARF) associated with sepsis has a high rate of mortality. It is not merely a surrogate marker for severity of disease but also an independent predictor of mortality and a separate pathogenic entity, even when nearly physiological doses of fluid and small-molecule clearance are maintained with currently available renal replacement therapies (RRT). The techniques to remove cytokines, including high-volume haemofiltration, haemodialysis using high-cut-off haemofilters, and absorptive techniques, lead to some improvement in outcome but are still insufficient to reverse the complicated biological dysregulation resulting from ARF associated with sepsis. The novel and exciting technique of cell therapy, which is based on the principle of using functional cells to replace a greater range of renal functions, may add significant benefit to current RRT in dealing with this disease process. Because renal tubule cells appear to play critical roles in immunoregulation, renal tubule cell therapy during ARF associated with sepsis should alter the detrimental multiple-organ consequences of sepsis. The development of a bioartificial kidney consisting of a conventional haemofiltration cartridge in series with a renal tubule assist device containing renal proximal tubule cells represents a new therapeutic approach to this clinical disorder. The results to date of large animal studies and recent Phase I/II and Phase II clinical trials show that such a device replaces multiple kidney functions and modifies the sepsis condition to improve survival in ARF.

Stem cell approaches for the treatment of renal failure.

The inadequacy of current treatment modalities and insufficiency of donor organs for cadaveric transplantation have driven a search for improved methods of dealing with renal failure. The rising concept of cell-based therapeutics has provided a framework around which new approaches are being generated, and its combination with advances in stem cell research stands to bring both fields to clinical fruition. This budding partnership is presently in its very early stages, but an examination of the cell-based therapies currently under development clearly shows the magnitude of the role that stem cells will ultimately play. The issue over reports of unexpected plasticity in adult stem cell differentiation remains a focus of debate, and evidence for bone marrow-derived stem cell contributions to renal repair has been challenged. The search for adult renal stem cells, which could have a considerable impact on much of the work discussed here, appears to be narrowing. The use of embryonic tissue in research continues to provide valuable insights but will be the subject of intense societal scrutiny and debate before it reaches the stage of clinical application. Embryonic stem (ES) cells, with their ability to generate all, or nearly all, of the cell types in the adult body and a possible source of cells genetically identical to the donor, hold great promise but face ethical and political hurdles for human use. Immunoisolation of heterologous cells by encapsulation creates opportunities for their safe use as a component of implanted or ex vivo devices.