Publications by authors named "Saaeha Rauz"

75 Publications

Public perceptions of eye symptoms and hospital services during the first UK lockdown of the COVID-19 pandemic: a web survey study.

BMJ Open Ophthalmol 2021 13;6(1):e000854. Epub 2021 Oct 13.

Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Objective: This study aimed to explore the British public's healthcare-seeking beliefs concerning eye symptoms, and assess how the first COVID-19 lockdown influenced these.

Methods And Analysis: An anonymous web-based survey was disseminated through mailing lists and social media between June and August 2020. The survey sought participants' views on the severity and urgency of the need for medical review for four ophthalmic and two general medical scenarios on a five-point scale. Participants were asked to answer questions twice: once ignoring the COVID-19 pandemic, and once taking this into account, with additional questions asked to identify factors influencing the decision to seek medical attention and ward admission.

Results: A total of 402 participants completed the survey (mean age 61.6 years, 63.1% female and 87.7% of white ethnicity). Scores for symptom severity and urgency of medical review increased significantly with the severity of the clinical scenario (both p<0.001). However, participants gave significantly lower scores for the urgency of medical attention when accounting for the COVID-19 pandemic (compared with no pandemic) for all scenarios (all p<0.001). Younger age, greater deprivation and non-white ethnicity were correlated with a lower perception of seriousness and urgency of medical attention.

Conclusions: During the first UK lockdown of the COVID-19 pandemic, reduced urgency of medical review for ocular and systemic pathologies was reported in response to the pandemic, which represents a barrier to healthcare-seeking behaviour. This has the potential to critically delay medical review and timely management, negatively impacting patient outcomes.
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http://dx.doi.org/10.1136/bmjophth-2021-000854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520595PMC
October 2021

The impact of the COVID-19 pandemic on microbial keratitis presentation patterns.

PLoS One 2021 18;16(8):e0256240. Epub 2021 Aug 18.

Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.

Background: Microbial keratitis (MK) is the most common non-surgical ophthalmic emergency, and can rapidly progress, causing irreversible sight-loss. This study explored whether the COVID-19 (C19) national lockdown impacted upon the clinical presentation and outcomes of MK at a UK tertiary-care centre.

Methods: Medical records were retrospectively reviewed for all patients with presumed MK requiring corneal scrapes, presenting between 23rd March and 30th June in 2020 (Y2020), and the equivalent time windows in 2017, 2018 and 2019 (pre-C19).

Results: In total, 181 and 49 patients presented during the pre-C19 and Y2020 periods, respectively. In Y2020, concurrent ocular trauma (16.3% vs. 5.5%, p = 0.030) and immunosuppression use (12.2% vs 1.7%, p = 0.004) were more prevalent. Despite proportionately fewer ward admissions during the pandemic (8.2% vs 32.6%, p<0.001), no differences were observed in baseline demographics; presenting visual acuity (VA; median 0.6 vs 0.6 LogMAR, p = 0.785); ulcer area (4.0 vs 3.0mm2, p = 0.520); or final VA (0.30 vs 0.30 LogMAR, p = 0.990). Whilst the overall rates of culture positivity were similar in Y2020 and pre-C19 (49.0% vs. 54.7%, p = 0.520), there were differences in the cultures isolated, with a lower rate of poly-microbial cultures in Y2020 (8.3% vs. 31.3%, p = 0.022).

Conclusions: Patient characteristics, MK severity and final visual outcomes did not appear to be affected in the first UK lockdown, despite fewer patients being admitted for care. Concurrent trauma and systemic immunosuppression use were greater than in previous years. The difference in spectra of isolated organisms may relate to behavioural changes, such as increased hand hygiene.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256240PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372897PMC
August 2021

A systematic review assessing the quality of patient reported outcomes measures in dry eye diseases.

PLoS One 2021 9;16(8):e0253857. Epub 2021 Aug 9.

Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.

Background: Patient-reported outcome measures (PROMs) can provide valuable insights on the impact of a disease or treatment on a patient's health-related quality of life. In ophthalmology, particularly in dry eye disease (DED) and ocular surface disease (OSD), it is unclear whether the available PROMs were developed using comprehensive guidelines. To address this, we evaluated the methodological quality of studies assessing the psychometric properties of PROMs in DED and OSD [PROSPERO registration number CRD42019142328].

Methods: Four databases were searched; reference list and citation searching of included studies was also conducted. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was used to appraise the quality of the studies evaluating the psychometric properties of PROMs used in DED and OSD.

Results: The search strategy (S3 Table) retrieved 5,761 records, 573 duplicates were removed, 5,188 abstracts were screened and 127 full-text articles were retrieved for further review. Of these, 118 full-text articles did not meet the eligibility criteria and were excluded. Reference list and citation searching, identified an additional 8 articles bringing the total numbers of papers reviewed to 17. In general, psychometric properties such as content validity, measurement error and structural validity were not assessed by the studies included in this review. Studies reviewing The Impact of Dry Eye on Everyday Life (IDEEL) presented with the highest quality scores together with the Ocular Surface Disease Index (OSDI) questionnaire.

Conclusions: The quality of studies evaluating PROMs in DED and OSD was considered using the COSMIN standards. The majority of the studies evaluating PROMs included in this review did not meet the recommended COSMIN criteria and the quality of the PROMs evaluated is not assured. Further evaluation of their psychometric properties is required if these are going to be used in clinical practice or research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253857PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351938PMC
November 2021

Anxiety and depression in inflammatory eye disease: exploring the potential impact of topical treatment frequency as a putative psychometric item.

BMJ Open Ophthalmol 2021 6;6(1):e000649. Epub 2021 Jul 6.

Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Objective: To evaluate whether topical therapy is linked to scores related to anxiety, depression and quality of life (QoL) in inflammatory eye disease (IED).

Methods And Analysis: Patients with ocular surface disease (OSD, N=100) and Uveitis (N=100) completed self-administered validated questions on ocular symptoms and well-being, with supplemental questions on eye drop frequency.

Results: Forty (20%) patients had scores consistent with depression and 33 (17%) anxiety. Anxiety, depression, QoL and OSD index (OSDI) scores did not differ significantly between OSD and Uveitis groups. In those with anxiety or depression, QoL was significantly reduced in all WHO Quality Of Life-BREF domains (all p<0.001). Multivariable analysis considering demographic and disease-related factors found daily topical drop frequency to be independently associated with anxiety (p=0.009) but not depression (p=0.300).

Conclusion: A high proportion of patients with IED demonstrated scores indicative of anxiety and depression. Preliminary evidence suggests that the frequency of topical eye drops potentially plays a significant role in the psychological health status of patients with IED.
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http://dx.doi.org/10.1136/bmjophth-2020-000649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261890PMC
July 2021

Biological tissues and components, and synthetic substrates for conjunctival cell transplantation.

Ocul Surf 2021 Oct 11;22:15-26. Epub 2021 Jun 11.

Department of Eye and Vision Science, University of Liverpool, William Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK. Electronic address:

The conjunctiva is the largest component of the ocular surface. It can be damaged by various pathological processes leading to scarring, loss of tissue and dysfunction. Depending on the amount of damage, restoration of function may require a conjunctival graft. Numerous studies have investigated biological and synthetic substrates in the search for optimal conditions for the ex vivo culture of conjunctival epithelial cells that can be used as tissue grafts for transplantation. These substrates have advantages and disadvantages that are specific to the characteristics of each material; the development of an improved material remains a priority. This review is the second of a two-part review in The Ocular Surface. In the first review, the structure and function of the conjunctiva was evaluated with a focus on the extracellular matrix and the basement membrane, and biological and mechanical characteristics of the ideal substrate with recommendations for further studies. In this review the types of biological and synthetic substrates used for conjunctival transplantation are discussed including substrates based on the extracellular matrix. .
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http://dx.doi.org/10.1016/j.jtos.2021.06.003DOI Listing
October 2021

The conjunctival extracellular matrix, related disorders and development of substrates for conjunctival restoration.

Ocul Surf 2021 Jun 5. Epub 2021 Jun 5.

Department of Eye and Vision Science, University of Liverpool, William Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK. Electronic address:

The conjunctiva can be damaged by numerous diseases with scarring, loss of tissue and dysfunction. Depending on extent of damage, restoration of function may require a conjunctival graft. A wide variety of biological and synthetic substrates have been tested in the search for optimal conditions for ex vivo culture of conjunctival epithelial cells as a route toward tissue grafts. Each substrate has specific advantages but also disadvantages related to their unique physical and biological characteristics, and identification and development of an improved substrate remains a priority. To achieve the goal of mimicking and restoring a biological material, requires information from the material. Specifically, extracellular matrix (ECM) derived from conjunctival tissue. Knowledge of the composition and structure of native ECM and identifying contributions of individual components to its function would enable using or mimicking those components to develop improved biological substrates. ECM is comprised of two components: basement membrane secreted predominantly by epithelial cells containing laminins and type IV collagens, which directly support epithelial and goblet cell adhesion differentiation and growth and, interstitial matrix secreted by fibroblasts in lamina propria, which provides mechanical and structural support. This review presents current knowledge on anatomy, composition of conjunctival ECM and related conjunctival disorders. Requirements of potential substrates for conjunctival tissue engineering and transplantation are discussed. Biological and synthetic substrates and their components are described in an accompanying review.
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http://dx.doi.org/10.1016/j.jtos.2021.05.011DOI Listing
June 2021

Evaluation of full-length nanopore 16S sequencing for detection of pathogens in microbial keratitis.

PeerJ 2021 15;9:e10778. Epub 2021 Feb 15.

Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, West Midlands, UK.

Background: Microbial keratitis is a leading cause of preventable blindness worldwide. Conventional sampling and culture techniques are time-consuming, with over 40% of cases being culture-negative. Nanopore sequencing technology is portable and capable of generating long sequencing reads in real-time. The aim of this study is to evaluate the potential of nanopore sequencing directly from clinical samples for the diagnosis of bacterial microbial keratitis.

Methods: Using full-length 16S rRNA amplicon sequences from a defined mock microbial community, we evaluated and benchmarked our bioinformatics analysis pipeline for taxonomic assignment on three different 16S rRNA databases (NCBI 16S RefSeq, RDP and SILVA) with clustering at 97%, 99% and 100% similarities. Next, we optimised the sample collection using an ex vivo porcine model of microbial keratitis to compare DNA recovery rates of 12 different collection methods: 21-gauge needle, PTFE membrane (4 mm and 6 mm), Isohelix SK-2S, Sugi Eyespear, Cotton, Rayon, Dryswab, Hydraflock, Albumin-coated, Purflock, Purfoam and Polyester swabs. As a proof-of-concept study, we then used the sampling technique that provided the highest DNA recovery, along with the optimised bioinformatics pipeline, to prospectively collected samples from patients with suspected microbial keratitis. The resulting nanopore sequencing results were then compared to standard microbiology culture methods.

Results: We found that applying alignment filtering to nanopore sequencing reads and aligning to the NCBI 16S RefSeq database at 100% similarity provided the most accurate bacterial taxa assignment. DNA concentration recovery rates differed significantly between the collection methods ( < 0.001), with the Sugi Eyespear swab providing the highest mean rank of DNA concentration. Then, applying the optimised collection method and bioinformatics pipeline directly to samples from two patients with suspected microbial keratitis, sequencing results from Patient A were in agreement with culture results, whilst Patient B, with negative culture results and previous antibiotic use, showed agreement between nanopore and Illumina Miseq sequencing results.

Conclusion: We have optimised collection methods and demonstrated a novel workflow for identification of bacterial microbial keratitis using full-length 16S nanopore sequencing.
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http://dx.doi.org/10.7717/peerj.10778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891086PMC
February 2021

Human leukocyte antigen B*0702 is protective against ocular Stevens-Johnson syndrome/toxic epidermal necrolysis in the UK population.

Sci Rep 2021 02 3;11(1):2928. Epub 2021 Feb 3.

Academic Unit of Ophthalmology, Birmingham and Midland Eye Centre, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Dudley Road, Birmingham, B18 7QU, UK.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are part of a disease continuum of vesiculobullous mucocutaneous reactions affecting the skin and mucous membranes including the ocular surface. Manifestations of disease range from mild dry eye to progressive conjunctival cicatrisation, limbal epithelial stem cell failure and corneal blindness. In Far Eastern and South East Asian populations where SJS/TEN is prevalent, numerous human leukocyte antigen (HLA) gene variants at the A, B and C loci have been identified as risk factors for developing SJS/TEN with severe ocular complications (SOC). By contrast, the incidence of SJS/TEN with SOC in European countries is relatively low. To date, ocular SJS/TEN risk altering alleles have not been widely investigated in European populations. In this study, we analysed the association of HLA -A, -B and -C alleles with SJS/TEN in 33 patients residing in the UK with age matched controls. The data showed statistically significant novel negative allele association with HLA-B*0702 and a trend with HLA-C*0702 in the patient group, indicating these alleles are protective. Further characterisation of protective and risk alleles in other ethnic groups is required to fully elucidate the putative role of these alleles in the susceptibility of SJS/TEN with or without severe ocular complications in patients in the UK.
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http://dx.doi.org/10.1038/s41598-021-82400-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859395PMC
February 2021

What's new in ocular and oral aspects of Sjögren's syndrome and do new treatments work?

Rheumatology (Oxford) 2021 03;60(3):1034-1041

Institute of Dentistry, Queen Mary University of London, London, UK.

Primary SS (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands leading to glandular dysfunction, resulting in dryness of the eyes, mouth and other mucosal surfaces. Systemic manifestations also occur in the majority of patients. There has been increasing interest in recent years, with a number of publications regarding the classification criteria, diagnostic tools, disease activity, damage, impact and potential treatments. This article reviews recent advances in the diagnosis and treatment of ocular and oral involvement in pSS. Recent stand-out developments include measurement of tear osmolarity as a marker in dry eye disease diagnosis, new devices measuring tear constituents and meibomian gland structure and treatment of its dysfunction. Lip biopsy is still valuable despite emerging evidence of non-invasive diagnostic techniques, notably salivary gland ultrasound.
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http://dx.doi.org/10.1093/rheumatology/keaa854DOI Listing
March 2021

The management of Sjögren's syndrome: British Society for Rheumatology guideline scope.

Rheumatology (Oxford) 2021 05;60(5):2122-2127

Rheumatology Department, Selly Oak Hospital, University Hospital Birmingham, Birmingham, UK.

The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol [1]. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.
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http://dx.doi.org/10.1093/rheumatology/keaa870DOI Listing
May 2021

Calculating the economic burden of presumed microbial keratitis admissions at a tertiary referral centre in the UK.

Eye (Lond) 2021 08 7;35(8):2146-2154. Epub 2020 Dec 7.

Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.

Purpose: Microbial keratitis (MK) is the most common non-surgical ophthalmic emergency admission in the UK. However, few prospective health-economic studies of MK have been performed, and no specific healthcare resources group (HRG) code exists. This study is designed to determine the feasibility of a data collection tool derived from the microbiology ophthalmology group (MOG) clinical record form, to enable quantification of direct costs of inpatient care, as well as prospective capture of epidemiological data relating to outcomes of MK.

Methods: Clinical, demographic and economic data were collected retrospectively between January and December 2013 for 101 consecutive patients admitted with MK, using an adaption of the MOG toolset. The direct cost of admission (COA) was calculated using national reference costs and compared to actual income to generate profit/deficit profiles for individual patients. Indices of multiple deprivation were used to assess effect of deprivation on the COA.

Results: The total income generated through discharge coding was £252,116, compared to a COA of £357,075, yielding a deficit of £104,960 (median: £754 per patient). The cost deficit increased significantly with length of stay (LOS, p < 0.001), whilst patients with short LOS were income generators; cost neutrality occurred at 4.8 days. Greater socioeconomic deprivation was also associated with a significantly higher cost deficit.

Conclusion: LOS is the key driver for COA of care for MK admissions. Protocols should encourage discharge of patients who are able to self-administer treatment after the sterilisation phase. The MOG-derived data collection toolset captures pertinent clinical data for quantification of COA. Further development into a multiuser and multisite platform is required for robust prospective testing, together with expansion to capture indirect costs of disease burden, including impact of treatment, visual morbidity and quality of life.
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http://dx.doi.org/10.1038/s41433-020-01333-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302743PMC
August 2021

Mediterranean diet and risk of Sjögren's syndrome.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):216-221. Epub 2020 Oct 23.

Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, UK.

Objectives: Non-genetic risk factors for Sjögren's syndrome (SS) are poorly understood. Adherence to a Mediterranean diet has been associated with reduction in other autoimmune diseases. We examined the association of Mediterranean diet with SS.

Methods: New patients attending a single centre warranting investigation for primary SS (pSS) were recruited into the Optimising Assessment in Sjögren's Syndrome cohort established in Birmingham, UK (2014-2018). Participants were classified into pSS and non-SS sicca, considered as cases and non-cases, respectively, and asked to complete an optional food frequency questionnaire on their diet before onset of symptoms. A semi-quantitative Mediterranean diet score (MDS) was calculated (possible range=0 to 18). Using multivariate logistic regression, corrected for energy intake, body-mass index, sex, age, symptom duration, and smoking status, we examined the association of MDS with SS.

Results: Dietary data were available for 133/243 (55%) eligible patients (n=82 pSS and n=51 sicca). In the adjusted model, a higher total MDS (mean ± SD, 9.41±2.31 points) was associated with lower odds of pSS (OR 0.81, 95% CI 0.66-0.99; p=0.038) per one unit of MDS. Among MDS components, the strongest association was seen with fish with OR 0.44 (95% CI 0.24-0.83; p=0.01) in the comparison between <1 portion/week and 1 to 2.5 portions/week. Higher galactose, vitamin A-retinol-equivalents and vitamin C showed associations with lower odds of pSS in multivariate analysis, where the association of vitamin C was attenuated when adjusted for MDS.

Conclusions: When adjusted for potential confounders, adherence to the Mediterranean diet was associated with lower likelihood of having pSS.
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October 2020

Using the West Midlands CONCERT to characterise regional incidence of acute-onset post cataract surgery endophthalmitis.

Eye (Lond) 2021 Jun 1;35(6):1730-1740. Epub 2020 Sep 1.

Birmingham and Midland Eye Centre, Birmingham, UK.

Background: Whilst research and innovation is embedded within the UK's National Health Service (NHS) constitution, Doctors-in-training have little opportunity to contribute to designing, leading and recruiting into clinical trials or cohort studies. We formed the West Midlands Collaborative Ophthalmology Network for Clinical Effectiveness & Research by Trainees (The West Midlands CONCERT) and undertook a characterisation of post cataract surgery endophthalmitis as a proof-of-concept study to test the feasibility of the CONCERT model.

Methods: Doctors-in-training formed a collaborative working group to test the concept of delivering a pan-regional clinical effectiveness study across multiple hospital sites by performing retrospective analyses of post cataract endophthalmitis over a 6-year period.

Results: Overall, 157,653 cataract surgeries were performed by participating centres accredited to deliver the Royal College of Ophthalmologists training curriculum. Thirty-eight cases of post cataract endophthalmitis were identified, giving an incidence of 2.41 per 10,000 cases (0.0241%). A further 15 endophthalmitis cases presented who had surgery in non-training centres, giving a total of 53 cases. The most common organisms were S. epidermidis (14 (51.9%)) and P. aeruginosa (5 (18.5%)). Anterior-chamber and vitreous sampling yielded positive culture in 33.3% (6/18) and 50.9% (27/53), respectively. At 6 months follow-up, 19 (51.4%) patients achieved visual acuities of ≤0.5 LogMAR. Repeat intravitreal injections (11 (20.8%)) and vitrectomy (n = 22 (41.5%)) were not associated with better outcomes.

Conclusions: Using post cataract endophthalmitis as a pilot cohort, this study highlights the feasibility of using the CONCERT model for studies across multiple sites. A UK-CONCERT could provide a powerful infrastructure enabling characterisation of patient cohorts and a platform for high-quality interventional studies, improving patient care.
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http://dx.doi.org/10.1038/s41433-020-01158-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169918PMC
June 2021

Rapid assessment of ocular drug delivery in a novel ex vivo corneal model.

Sci Rep 2020 07 16;10(1):11754. Epub 2020 Jul 16.

Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Drug delivery by topical application has higher patient acceptance and lower morbidity than intraocular injection, but many ophthalmic treatments are unable to enter the eye or reach the posterior segment after topical application. The first stage towards posterior segment delivery after topical application is ocular surface penetration and existing models are in vivo or use large quantities of tissue. We therefore developed a novel ex vivo model using discs of porcine and human cornea and sclera (5 mm diameter) to assess penetration of a candidate neuroprotective siRNA. siRNA against caspase 2 or control solutions of known penetrance were applied to the corneal epithelial surface and trans-corneal penetration and corneal adsorbance measured at fixed time points. To demonstrate that leakage did not occur, we applied dextran blue, which should not penetrate the intact cornea and did not do so in our model. Fluorescein penetration (0.09%) was less than rhodamine B (6.98%) at 60 min. siCASP2 penetration was 0.01% by 60 min. When the applied siCASP2 was washed off after 2 min, (representing lacrimal drainage) 0.071% penetrated porcine cornea by 60 min and 0.0002% penetrated human cornea and 0.001% penetrated human sclera. Our ex vivo model rapidly and cost-effectively assesses transcorneal penetration of candidate topical therapies, allowing rates of trans-corneal penetration for potential therapies such as siRNA to be evaluated with small quantities of human or animal tissue.
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http://dx.doi.org/10.1038/s41598-020-68254-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366725PMC
July 2020

Comment on: "Controversies regarding mask usage in ophthalmic units in the United Kingdom during the COVID-19 pandemic".

Eye (Lond) 2021 07 28;35(7):2056-2057. Epub 2020 May 28.

Birmingham and Midland Eye Centre, Dudley Road, Birmingham, B18 7QH, UK.

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http://dx.doi.org/10.1038/s41433-020-0986-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225629PMC
July 2021

The neuroregenerative effects of topical decorin on the injured mouse cornea.

J Neuroinflammation 2020 May 4;17(1):142. Epub 2020 May 4.

Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, 3053, Australia.

Background: The cornea is innervated with a rich supply of sensory nerves that play important roles in ocular surface health. Any injury or pathology of the corneal nerves increases the risk of dry eye disease and infection. This study aims to evaluate the therapeutic potential of topical decorin to improve corneal nerve regeneration in a mouse model of sterile epithelial abrasion injury.

Methods: Bilateral central corneal epithelial abrasions (2-mm, Alger Brush) were performed on young C57BL/6 J mice to remove the corneal sensory nerves. Decorin, or vehicle, was applied topically, three times per day for 1 week or every 2 h for 6 h. Spectral-domain optical coherence tomography was performed to measure the abrasion area and corneal thickness. Wholemount immunofluorescence staining was used to assess sensory nerve regeneration (β-tubulin III) and immune cell density (CD45, Iba1, CD11c). To investigate the specific role of dendritic cells (DCs), Cx3cr1 mice, which spontaneously lack resident corneal epithelial DCs, were also investigated. The effect of prophylactic topical administration of recombinant human decorin (applied prior to the abrasion) was also investigated. Nerve tracing (NeuronJ software) was performed to compare recovery of basal nerve axons and superficial nerve terminals in the central and peripheral cornea.

Results: At 6 h after injury, topical decorin application was associated with greater intraepithelial DC recruitment but no change in re-epithelialisation or corneal thickness, compared to the vehicle control. One week after injury, sub-basal nerve plexus and superficial nerve terminal density were significantly higher in the central cornea in the decorin-treated eyes. The density of corneal stromal macrophages in the decorin-treated eyes and their contralateral eyes was significantly lower compared to saline-treated corneas. No significant improvement in corneal nerve regeneration was observed in Cx3cr1 mice treated with decorin.

Conclusions: Decorin promotes corneal epithelial nerve regeneration after injury. The neuroregenerative effect of topical decorin was associated with a higher corneal DC density during the acute phase, and fewer macrophages at the study endpoint. The corneal neuroregenerative effects of decorin were absent in mice lacking intraepithelial DCs. Together, these findings support a role for decorin in DC-mediated neuroregeneration following corneal abrasion injury.
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http://dx.doi.org/10.1186/s12974-020-01812-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199348PMC
May 2020

Effectiveness of pharmacological agents for the treatment of non-infectious scleritis: a systematic review protocol.

Syst Rev 2020 03 12;9(1):54. Epub 2020 Mar 12.

Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham and Midland Eye Centre, City Hospital, Dudley Road, Birmingham, B18 7QU, UK.

Background: Non-infectious scleritis is a potentially sight-threatening condition in which the sclera, the white outer layer of the eye, becomes inflamed. Whilst scleritis can be infective, the majority of cases are due to non-infectious causes, often occurring in association with an underlying systemic autoimmune or auto-inflammatory condition. Thorough systemic work-up is crucial to identify disease aetiology and exclude infection; however, a significant proportion of disease remains idiopathic with the underlying cause unknown. Non-infectious scleritis is normally managed with systemic corticosteroid and immunosuppression, yet there is no widely agreed consensus on the most appropriate therapy, and no national or international guidelines exist for treatment of non-infectious scleritis.

Methods: Standard systematic review methodology will be used to identify, select and extract data from comparative studies of pharmacological interventions used to treat patients with non-infectious scleritis. Searches of bibliographic databases (Cochrane Library, MEDLINE, CINAHL and EMBASE) and clinical trial registers will be employed. No restrictions will be placed on language or date of publication. Non-English articles will be translated where necessary. The primary outcome of interest will be disease activity measured by reduction in scleritis grading according to standardised grading systems. Secondary outcomes will include change in best corrected visual acuity, reduction in concurrent dose of systemic corticosteroid, time to treatment failure, adverse events and health-related quality of life. Risk of bias assessment will be conducted appropriate to each study design. Study selection, data extraction and risk of bias assessment will be completed by two reviewers independently. Data will be presented in a table and a narrative synthesis will be undertaken. Meta-analysis will be performed where methodological and clinical homogeneity exists. Subgroup and sensitivity analysis will be undertaken if appropriate.

Discussion: Many studies have investigated the effectiveness of pharmacological agents used in the management of non-infectious scleritis. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review will help guide ophthalmologists managing patients with non-infectious scleritis and may form the basis for evidence-based recommendations for future clinical practice and encourage standardisation of treatment protocols.

Systematic Review Registration: PROSPERO CRD42019125198.
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http://dx.doi.org/10.1186/s13643-020-01314-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068966PMC
March 2020

Triamcinolone acetonide loaded-cationic nano-lipoidal formulation for uveitis: Evidences of improved biopharmaceutical performance and anti-inflammatory activity.

Colloids Surf B Biointerfaces 2020 Jun 25;190:110902. Epub 2020 Feb 25.

University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India. Electronic address:

Topical administration of corticosteroids is the cornerstone treatment of anterior uveitis, but poor corneal penetration and retention cause hindrance in their therapeutic utility. The conventional eye drops are less valuable in conditions where inflammation reaches deeper regions of the eye. Therefore, there is a clear need for an effective drug delivery system, which can increase corticosteroid penetration after topical application. To address this, cationic nanostructured lipid carriers of the drug triamcinolone acetonide (cTA-NLC) were prepared. The cTA-NLC were prepared by a hot microemulsion method and evaluated for drug release, permeation, cell uptake, cytotoxicity, anti-inflammatory activity and ocular irritancy. The cTA-NLC are nanometric in size (< 200 nm), with a zeta potential of about +35 mv and % drug EE of 88 %. The nanocarriers exhibited slow and sustained release of around 84 % in 24 h and transcorneal drug permeation of 51 % in 8 h. The nanocarriers exhibited no cytotoxicity (% cell viability of>90 %). The cell uptake study showed that nanocarriers could retain inside the cells for 24 h. The developed formulation could significantly reduce the TNF-α level in LPS induced inflamed cells. The studies indicated that cTA-NLC could be a promising option for the topical treatment of uveitis.
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http://dx.doi.org/10.1016/j.colsurfb.2020.110902DOI Listing
June 2020

Adherence to Topical Medication in Patients with Inflammatory Eye Disease.

Ocul Immunol Inflamm 2020 Jan 16:1-6. Epub 2020 Jan 16.

Inflammatory Eye Disease Service, Birmingham & Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.

: To evaluate adherence to topical medication in patients with inflammatory eye disease.: Questionnaire survey of patients attending inflammatory eye disease clinics. Treatment regimen was validated against hospital-generated clinic letters.: There were 86 patients (52 uveitis and 34 ocular surface disease) with 30% (26/86) failing to identify one or more of the medications they were using, and 28% (24/86) unable to offer the correct indication for their treatment. A total of 64% (55/86) failed to use their medication as advised (27% on a daily basis); the commonest reason being forgetfulness. In patients using multiple eye drops, 26% left insufficient time intervals between successive eye drops, and 58% (50/86) reported not being given any instruction on drop instillation.: We highlight poor adherence to topical medication in patients with inflammatory eye disease. We recommend a dedicated practitioner providing a proactive approach to patient education to improve adherence.
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http://dx.doi.org/10.1080/09273948.2019.1699122DOI Listing
January 2020

Validation of a clinical assessment tool for cicatrising conjunctivitis.

Ocul Surf 2020 01 3;18(1):121-129. Epub 2019 Nov 3.

Corneal and External Diseases Department, Moorfields Eye Hospital NHS Foundation Trust, United Kingdom; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, United Kingdom.

Purpose: This study was designed to validate a semi-quantitative clinical assessment tool for cicatrising conjunctivitis (CC).

Methods: Fifty-five patients (109 eyes) with mucous membrane pemphigoid (MMP) and 31 patients (61 eyes) with Stevens-Johnson syndrome (SJS) were included. Three methods were used for validation: (1) comparison of inter- and intra-observer reproducibility for the components selected for the initial version of the tool, (2) quantitative measurement of the scarring component with a fornix depth measurer, compared with qualitative Tauber grading methodology, (3) the final version of the tool was compared with the published Sotozono SJS grading system. Main outcome measures included: inter- and intra-observer reproducibility, calculation of composite measures of scarring and morbidity, component redundancy, and correlation with other grading systems.

Results: Inter- and intra-observer agreement was moderate-to-excellent for graded components of conjunctival hyperaemia, upper and lower symblepharon, upper and lower fornix depth, corneal vascularisation, and corneal opacity. There was poor-to-good agreement for limitation of motility which was rejected from inclusion in the final tool. Composite scores for scarring components and morbidity components showed good-to-excellent agreement and distribution of ocular disease severity. Analysis of the composite components showed no redundancy - all components contributed independently. Comparison with both Tauber and Sotozono grading methodologies showed good concordance.

Conclusions: This study has developed the first validated assessment tool applicable to causes of CC. The tool is concise and discriminates patients with varying disease severity. It measures both disease activity and severity and is suitable for clinical and research applications.
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http://dx.doi.org/10.1016/j.jtos.2019.10.010DOI Listing
January 2020

Disease activity and patient reported outcome measures in Sjögren's - what are the best tools to evaluate?

Rheumatology (Oxford) 2019 Jun 24. Epub 2019 Jun 24.

Rheumatology Department, Milton Keynes University Hospital, Milton Keynes.

In primary SS (pSS), clinical features in SS can be divided into two facets: the patient perceived manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, with efforts made by an international collaboration, consensual clinical indexes were developed for assessing both facets: one patient reported outcome, the EULAR SS Patients Reported Index (ESSPRI), and one activity index for systemic manifestations, the EULAR SS Disease Activity Index (ESSDAI). In addition, objective measures were developed to quantify the importance and consequence of ocular and oral dryness, few being specific of pSS. Work is ongoing to develop indexes combining all these approaches. Recent changes in the assessment of pSS patients, and the emergence of new targeted therapies, have put a greater emphasis on the design of clinical trials in pSS, and led for the first time to a positive randomized clinical trial.
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http://dx.doi.org/10.1093/rheumatology/kez201DOI Listing
June 2019

A self-healing hydrogel eye drop for the sustained delivery of decorin to prevent corneal scarring.

Biomaterials 2019 07 20;210:41-50. Epub 2019 Apr 20.

School of Chemical Engineering, University of Birmingham, Birmingham, BI5 2TT, UK. Electronic address:

Scarring/Opacity on the surface of the eye and vascularisation following infectious diseases, inflammation and corneal trauma are often a leading cause of blindness. The 'gold standard' treatment to prevent corneal scarring is the application of amniotic membrane (AM) to the ocular surface in the acute stage of injury. Although clinically effective, the use of the AM is associated with biological variability and unpredictable responses. Potential health risks including disease transmission, significant ethical issues surrounding the tissue donation process and stringent regulations/storage conditions, preclude widespread use. Consequently, there is a demand for the development of a new, synthetic alternative, that is stable at room temperature, capable of protecting the wound and has the capacity to deliver anti-scarring and anti-inflammatory mediators. Here we have developed a micro-structured fluid gel eye drop, to deliver a potent anti-scarring molecule, decorin. We have compared the release of decorin from the formulated dressing to a typical gel film, demonstrating enhanced release for the fluid gel eye-drops. Therefore, we have investigated the effect of the fluid gel system in 2D human corneal fibroblast culture models, as well as shown the retention of the gellan fluid gel in an in vivo rat model. At the same time the efficacy of the fluid gel eye drop was studied in an organ culture model, whereby the fluid gel containing decorin, significantly (P < 0.05) increased re-epithelialisation within 4 days of treatment.
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http://dx.doi.org/10.1016/j.biomaterials.2019.04.013DOI Listing
July 2019

Sustained release of decorin to the surface of the eye enables scarless corneal regeneration.

NPJ Regen Med 2018 21;3:23. Epub 2018 Dec 21.

2School of Chemical Engineering, University of Birmingham, Birmingham, B15 2TT UK.

Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of , applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available.
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http://dx.doi.org/10.1038/s41536-018-0061-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303295PMC
December 2018

Dry Eye Disease: Time to Introduce Ocular Surface Stress Tests?

Authors:
Saaeha Rauz

Ophthalmology 2018 10;125(10):1506-1507

Birmingham, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2018.06.016DOI Listing
October 2018

Neurotrophic keratopathy.

Prog Retin Eye Res 2018 09 23;66:107-131. Epub 2018 Apr 23.

Department of Ophthalmology III, Quinze-Vingts Hospital, DHU Sight Restore, INSERM-DHOS CIC, and Vision Institute, INSERM, U968, Sorbonne Universités, Paris, France. Electronic address:

Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK.
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http://dx.doi.org/10.1016/j.preteyeres.2018.04.003DOI Listing
September 2018

Comparison of ESSDAI and ClinESSDAI in potential optimisation of trial outcomes in primary Sjögren's syndrome: examination of data from the UK Primary Sjögren's Syndrome Registry.

Swiss Med Wkly 2018 7;148:w14588. Epub 2018 Feb 7.

, UNITED KINGDOM.

Objectives: To assess the use of the Clinical EULAR Sjögren's Syndrome Disease Activity Index (ClinESSDAI), a version of the ESSDAI without the biological domain, for assessing potential eligibility and outcomes for clinical trials in patients with primary Sjögren's syndrome (pSS), according to the new ACR-EULAR classification criteria, from the UK Primary Sjögren's Syndrome Registry (UKPSSR).

Methods: A total of 665 patients from the UKPSSR cohort were analysed at their time of inclusion in the registry. ESSDAI and ClinESSDAI were calculated for each patient.

Results: For different disease activity index cut-off values, more potentially eligible participants were found when ClinESSDAI was used than with ESSDAI. The distribution of patients according to defined disease activity levels did not differ statistically (chi2 p = 0.57) between ESSDAI and ClinESSDAI for moderate disease activity (score ≥5 and <14; ESSDAI 36.4%; ClinESSDA 36.5%) or high disease activity (score ≥14; ESSDAI 5.4%; ClinESSDAI 6.8%). We did not find significant differences between the indexes in terms of activity levels for individual domains, with the exception of the articular domain. We found a good level of agreement between both indexes, and a positive correlation between lymphadenopathy and glandular domains with the use of either index and with different cut-off values. With the use of ClinESSDAI, the minimal clinically important improvement value was more often achievable with a one grade improvement of a single domain than with ESSDAI. We observed similar results when using the new ACR-EULAR classification criteria or the previously used American-European Consensus Group (AECG) classification criteria for pSS.

Conclusions: In the UKPSSR population, the use of ClinESSDAI instead of ESSDAI did not lead to significant changes in score distribution, potential eligibility or outcome measurement in trials, or in routine care when immunological tests are not available. These results need to be confirmed in other cohorts and with longitudinal data.
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http://dx.doi.org/10.4414/smw.2018.14588DOI Listing
October 2018

A qualitative exploration of physical, mental and ocular fatigue in patients with primary Sjögren's Syndrome.

PLoS One 2017 31;12(10):e0187272. Epub 2017 Oct 31.

Centre for Translational Inflammation Research, University of Birmingham, Birmingham, United Kingdom.

Introduction: Primary Sjögren's Syndrome (pSS) affects exocrine glands such as those producing the tear film, leading to dry and painful eyes, but is also associated with fatigue. The experience of fatigue in pSS, and its relationship with sicca symptoms, is poorly understood.

Methods: Twenty people diagnosed with pSS were recruited to participate in a semi-structured qualitative interview about their symptoms experience. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis.

Results: People with pSS described physical tiredness, mental fatigue and ocular fatigue. Mental fatigue was characterised by difficulties in attention, particularly, the ability to follow conversations and short-term memory problems. Participants linked their experience of fatigue to feeling of depression, frustration, irritation and anxiety, and therefore, fatigue was suggested to have had a large impact on their psychological well-being. People with pSS also described a range of ocular symptoms including pain, dryness, and itching, which were compounded by fatigue. For some, eye fatigue was pervasive, and daily activities involving the eyes such as reading, using the computer and driving were impaired. In some cases, the level of ocular discomfort was so severe it prevented sleep, which in turn impacted on general fatigue levels.

Conclusions: People with pSS experience fatigue in a range of ways; physical, mental and ocular fatigue were described. Fatigue was suggested to exacerbate other ocular symptoms, posed serious physical limitations and caused psychological distress. Further research into the nature of fatigue and ocular symptoms in pSS is required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663496PMC
November 2017
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