Intravital imaging of the human cornea reveals the differential effects of season on innate and adaptive immune cell morphodynamics.

PURPOSE: While the external environment has been shown to shape the systemic human immune landscape, defining the in vivo immune status of peripheral tissues has remained a technical challenge. We recently developed functional in vivo confocal microscopy (Fun-IVCM) for dynamic, longitudinal imaging of corneal immune cells in living humans. This study investigated the effect of seasonal-driven environmental factors on the density, morphology and dynamic behavior of human corneal immune cell subsets. DESIGN: Longitudinal, observational clinical study. PARTICIPANTS: Sixteen healthy participants (18-40 years) attended two visits in distinct seasons in Melbourne, Australia (Visit 1: Spring/Summer: November-December 2021; Visit 2: Autumn/Winter: April-June 2022). METHODS: Environmental data were collected over each period. Participants underwent ocular surface examinations and corneal Fun-IVCM (Heidelberg HRT-3, Rostock Corneal Module). Volume scans (80µm) were acquired at 5.5±1.5 minute intervals, for up to five timepoints. Time-lapse videos were created to analyze corneal immune cells, comprising epithelial T cells and dendritic cells (DCs), and stromal macrophages. Tear cytokines were analyzed using multiplex bead-based immunoassay. MAIN OUTCOME MEASURES: Difference in the density, morphological and dynamic parameters of corneal immune cell subsets over the study periods. RESULTS: Visit 1 was characterized by higher temperature, lower humidity, and higher air particulate and pollen levels than Visit 2. Clinical ocular surface parameters, and the density of immune cell subsets were similar across visits. At Visit 1 (Spring/Summer), corneal epithelial DCs were larger and more elongated, with a lower dendrite probing speed (0.38±0.21 vs 0.68±0.33µm/min, p<0.001) relative to Visit 2; stromal macrophages were more circular and had less dynamic activity (Visit 1: 7.2±1.9 vs Visit 2: 10.3±3.7 'dancing index', p<0.001). T cell morphology and dynamics were unchanged across periods. Basal tear levels of IL-2 and CXCL10 were lower during Spring/Summer. CONCLUSION: This novel study shows that the in vivo morphodynamics of innate corneal immune cells (DCs, macrophages) are modified by environmental factors, but such effects are not evident for adaptive immune cells (T cells). The cornea is a potential non-invasive, in vivo 'window' to season-dependent changes to the human immune system, with capacity to yield new insight into environmental influences on immune regulation.

Evaluating the efficacy and safety of therapeutic interventions for corneal neuropathy: A systematic review.

Corneal neuropathy involves corneal nerve damage that disrupts ocular surface integrity, negatively impacting quality-of-life from pain and impaired vision. Any ocular or systemic condition that damages the trigeminal nerve can lead to corneal neuropathy. However, the condition currently does not have standardized diagnostic criteria or treatment protocols. The primary aim of this systematic review was to evaluate the efficacy and safety of interventions for treating corneal neuropathy. Randomized controlled trials (RCTs) that investigated corneal neuropathy treatments were eligible if the intervention(s) was compared to a placebo or active comparator. Comprehensive searches were conducted in Ovid MEDLINE, Ovid Embase and clinical trial registries from inception to July 2022. The Cochrane Risk-of-Bias 2 tool was used to assess study methodological quality. Certainty of the body of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Overall, 20 RCTs were included. Evaluated interventions comprised regenerative therapies (n=6 studies), dietary supplements (n=4), anti-glycemic agents (n=3), combination therapy (n=3), supportive therapies (n=2) and systemic pain pharmacotherapies (n=2). Nine RCTs were judged at high risk of bias for most outcomes. Definitions for corneal neuropathy in the populations varied substantially across studies, consistent with lack of consensus on diagnostic criteria. A diverse range of outcomes were quantified, likely reflecting absence of an agreed core outcome. There was insufficient evidence to draw definitive conclusions on the efficacy or safety of any intervention. There was low or very low certainty evidence for several neuroregenerative agents and dietary supplements for improving corneal nerve fiber length in corneal neuropathy due to dry eye disease and diabetes. Low or very low certainty evidence was found for neuroregenerative therapies and dietary supplements not altering corneal immune cell density. This review identifies a need to standardize the clinical definition of corneal neuropathy and define a minimum set of core outcome measures. Together, this will provide a foundation for improved phenotyping of clinical populations in studies, and improve capacity to synthesize data to inform evidence-based based care. Protocol registration: PROSPERO ID: CRD42022348475.

Use of chemotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There are few data on international variation in chemotherapy use, despite it being a key treatment type for some patients with cancer. Here, we aimed to examine the presence and size of such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), eight Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring from within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in chemotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 893 461 patients with a new diagnosis of one of the studied cancers, 111 569 (12·5%) did not meet the inclusion criteria, and 781 892 were included in the analysis. There was large interjurisdictional variation in chemotherapy use for all studied cancers, with wide 95% PIs: 47·5 to 81·2 (pooled estimate 66·4%) for ovarian cancer, 34·9 to 59·8 (47·2%) for oesophageal cancer, 22·3 to 62·3 (40·8%) for rectal cancer, 25·7 to 55·5 (39·6%) for stomach cancer, 17·2 to 56·3 (34·1%) for pancreatic cancer, 17·9 to 49·0 (31·4%) for lung cancer, 18·6 to 43·8 (29·7%) for colon cancer, and 3·5 to 50·7 (16·1%) for liver cancer. For patients with stage 3 colon cancer, the interjurisdictional variation was greater than that for all patients with colon cancer (95% PI 38·5 to 78·4; 60·1%). Patients aged 85-99 years had 20-times lower odds of chemotherapy use than those aged 65-74 years, with very large interjurisdictional variation in this age difference (odds ratio 0·05; 95% PI 0·01 to 0·19). There was large variation in median time to first chemotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation, particularly for rectal cancer (95% PI -15·5 to 193·9 days; pooled estimate 89·2 days). Patients aged 85-99 years had slightly shorter median time to first chemotherapy compared with those aged 65-74 years, consistently between jurisdictions (-3·7 days, 95% PI -7·6 to 0·1). INTERPRETATION: Large variation in use and time to chemotherapy initiation were observed between the participating jurisdictions, alongside large and variable age group differences in chemotherapy use. To guide efforts to improve patient outcomes, the underlying reasons for these patterns need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

Use of radiotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There is little evidence on variation in radiotherapy use in different countries, although it is a key treatment modality for some patients with cancer. Here we aimed to examine such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), nine Canadian provinces (Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in radiotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data, or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 902 312 patients with a new diagnosis of one of the studied cancers, 115 357 (12·8%) did not meet inclusion criteria, and 786,955 were included in the analysis. There was large interjurisdictional variation in radiotherapy use, with wide 95% PIs: 17·8 to 82·4 (pooled estimate 50·2%) for oesophageal cancer, 35·5 to 55·2 (45·2%) for rectal cancer, 28·6 to 54·0 (40·6%) for lung cancer, and 4·6 to 53·6 (19·0%) for stomach cancer. For patients with stage 2-3 rectal cancer, interjurisdictional variation was greater than that for all patients with rectal cancer (95% PI 37·0 to 84·6; pooled estimate 64·2%). Radiotherapy use was infrequent but variable in patients with pancreatic (95% PI 1·7 to 16·5%), liver (1·8 to 11·2%), colon (1·6 to 5·0%), and ovarian (0·8 to 7·6%) cancer. Patients aged 85-99 years had three-times lower odds of radiotherapy use than those aged 65-74 years, with substantial interjurisdictional variation in this age difference (odds ratio [OR] 0·38; 95% PI 0·20-0·73). Women had slightly lower odds of radiotherapy use than men (OR 0·88, 95% PI 0·77-1·01). There was large variation in median time to first radiotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation (eg, oesophageal 95% PI 11·3 days to 112·8 days; pooled estimate 62·0 days; rectal 95% PI 34·7 days to 77·3 days; pooled estimate 56·0 days). Older patients had shorter median time to radiotherapy with appreciable interjurisdictional variation (-9·5 days in patients aged 85-99 years vs 65-74 years, 95% PI -26·4 to 7·4). INTERPRETATION: Large interjurisdictional variation in both use and time to radiotherapy initiation were observed, alongside large and variable age differences. To guide efforts to improve patient outcomes, underlying reasons for these differences need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

Retrospective observational study analysing the trends in ventilation tube insertion in children in Scotland between 2001 and 2018.

OBJECTIVES: Otitis media with effusion (OME) is common, affecting up to 90% of children. Around 25% will have a persistent effusion with conductive hearing loss which can impact their development. Ventilation tubes (VTs) can improve their hearing in the short term. This study aims to analyse the trends in VT insertion rates across Scotland. DESIGN: Retrospective observational study. SETTING: All mainland Scottish health boards. PARTICIPANTS: All children aged 0-16 who underwent a VT insertion procedure from 2001 to 2018 were included. MAIN OUTCOME MEASURES: Data were provided by the Scottish Public Health Observatory, using Scottish Morbidity Records. Mid-year population estimates were obtained from the National Records Office of Scotland. Socioeconomic deprivation was estimated based on area of residence using the Scottish Index of Multiple Deprivation. VT insertion rates were calculated and trends analysed. RESULTS: A total of 35 878 VT procedures were performed in total with a mean rate of 2.02 per 1000 children per year. The highest insertion rates were observed in children aged 4-6. VT insertion rates reduced during the study period (R = -0.729, p = .001). Variability in VT insertion rates between health boards reduced. There was a significant association between socioeconomic deprivation and VT insertion rate, with the most deprived children having the highest rate (p < .001). CONCLUSIONS: VT insertion rates and the variability between Scottish health boards have reduced over the past two decades, suggesting a more equitable system. Our data intimates that the decision to perform VT insertion is based upon disease prevalence rather than clinician preference.

Systematic review and appraisal of quality, definitions and treatment recommendations of clinical guidelines for glaucoma suspects.

BACKGROUND: To appraise the quality of clinical practice guidelines for glaucoma suspects, and to assess their consistency for how a 'glaucoma suspect' is defined and their recommendations for treatment initiation for such individuals. METHODS: This study included all documents that self-identified as a 'guideline' and provided recommendation(s) for the clinical care of glaucoma suspects. The quality of eligible guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. RESULTS: From 1196 records retrieved from comprehensive searches and two records manually included, 20 clinical practice guidelines were deemed eligible. Based on an appraisal using the AGREE II instrument, 16 (80%) guidelines had ≤2 domains with scores >66%. Overall, the lowest scoring domains were for applicability, editorial independence and stakeholder involvement. There was relatively poor agreement across the guidelines for what defines a 'glaucoma suspect' or 'primary open angle glaucoma [POAG] suspect', as well as the recommendations and criteria for treatment initiation in these populations. There was better agreement for the definition and recommendations for treatment initiation for 'primary angle closure suspects'. CONCLUSIONS: There is substantial room to improve the methodological quality of most current international clinical guidelines for glaucoma suspects. Clinicians should consider this finding when using such guidelines to inform their care of glaucoma suspects. Substantial variation in the definition of a POAG suspect and recommendations for treatment initiation underscores important gaps in the current evidence for the accurate prediction of glaucoma development and treatment effectiveness in these individuals.

Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections.

Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19-recovered vaccinees (recovered, vaccinated), and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19-recovered vaccinees displayed improved antibody-neutralizing activity, Fcγ receptor (FcγR) engagement, and IgA levels compared with COVID-19-uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma; however, these rises only negatively correlated with FcγR engagement in plasma. IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain. Salivary antibodies delayed initiation following breakthrough COVID-19 infection, especially Omicron BA.2, but rose rapidly thereafter. Importantly, salivary antibody FcγR engagements were enhanced following breakthrough infections. Our data highlight how preexisting immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.

Mucosal antibody responses following Vaxzevria vaccination.

Mucosal antibodies play a key role in protection against breakthrough COVID-19 infections and emerging viral variants. Intramuscular adenovirus-based vaccination (Vaxzevria) only weakly induces nasal IgG and IgA responses, unless vaccinees have been previously infected. However, little is known about how Vaxzevria vaccination impacts the ability of mucosal antibodies to induce Fc responses, particularly against SARS-CoV-2 variants of concern (VoCs). Here, we profiled paired mucosal (saliva, tears) and plasma antibodies from COVID-19 vaccinated only vaccinees (uninfected, vaccinated) and COVID-19 recovered vaccinees (COVID-19 recovered, vaccinated) who both received Vaxzevria vaccines. SARS-CoV-2 ancestral-specific IgG antibodies capable of engaging FcγR3a were significantly higher in the mucosal samples of COVID-19 recovered Vaxzevria vaccinees in comparison with vaccinated only vaccinees. However, when IgG and FcγR3a engaging antibodies were tested against a panel of SARS-CoV-2 VoCs, the responses were ancestral-centric with weaker recognition of Omicron strains observed. In contrast, salivary IgA, but not plasma IgA, from Vaxzevria vaccinees displayed broad cross-reactivity across all SARS-CoV-2 VoCs tested. Our data highlight that while intramuscular Vaxzevria vaccination can enhance mucosal antibodies responses in COVID-19 recovered vaccinees, restrictions by ancestral-centric bias may have implications for COVID-19 protection. However, highly cross-reactive mucosal IgA could be key in addressing these gaps in mucosal immunity and may be an important focus of future SARS-CoV-2 vaccine development.

TFOS Lifestyle Report Executive Summary: A Lifestyle Epidemic - Ocular Surface Disease.

The Tear Film & Ocular Surface Society (TFOS) Workshop entitled 'A Lifestyle Epidemic: Ocular Surface Disease' was a global initiative undertaken to establish the direct and indirect impacts of everyday lifestyle choices and challenges on ocular surface health. This article presents an executive summary of the evidence-based conclusions and recommendations of the 10-part TFOS Lifestyle Workshop report. Lifestyle factors described within the report include contact lenses, cosmetics, digital environment, elective medications and procedures, environmental conditions, lifestyle challenges, nutrition, and societal challenges. For each topic area, the current literature was summarized and appraised in a narrative-style review and the answer to a key topic-specific question was sought using systematic review methodology. The TFOS Lifestyle Workshop report was published in its entirety in the April 2023 and July 2023 issues of The Ocular Surface journal. Links to downloadable versions of the document and supplementary material, including report translations, are available on the TFOS website: http://www.TearFilm.org.

Blue-light filtering spectacle lenses for visual performance, sleep, and macular health in adults.

BACKGROUND: 'Blue-light filtering', or 'blue-light blocking', spectacle lenses filter ultraviolet radiation and varying portions of short-wavelength visible light from reaching the eye. Various blue-light filtering lenses are commercially available. Some claims exist that they can improve visual performance with digital device use, provide retinal protection, and promote sleep quality. We investigated clinical trial evidence for these suggested effects, and considered any potential adverse effects. OBJECTIVES: To assess the effects of blue-light filtering lenses compared with non-blue-light filtering lenses, for improving visual performance, providing macular protection, and improving sleep quality in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; containing the Cochrane Eyes and Vision Trials Register; 2022, Issue 3); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and WHO ICTRP, with no date or language restrictions. We last searched the electronic databases on 22 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs), involving adult participants, where blue-light filtering spectacle lenses were compared with non-blue-light filtering spectacle lenses. DATA COLLECTION AND ANALYSIS: Primary outcomes were the change in visual fatigue score and critical flicker-fusion frequency (CFF), as continuous outcomes, between baseline and one month of follow-up. Secondary outcomes included best-corrected visual acuity (BCVA), contrast sensitivity, discomfort glare, proportion of eyes with a pathological macular finding, colour discrimination, proportion of participants with reduced daytime alertness, serum melatonin levels, subjective sleep quality, and patient satisfaction with their visual performance. We evaluated findings related to ocular and systemic adverse effects. We followed standard Cochrane methods for data extraction and assessed risk of bias using the Cochrane Risk of Bias 1 (RoB 1) tool. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 17 RCTs, with sample sizes ranging from five to 156 participants, and intervention follow-up periods from less than one day to five weeks. About half of included trials used a parallel-arm design; the rest adopted a cross-over design. A variety of participant characteristics was represented across the studies, ranging from healthy adults to individuals with mental health and sleep disorders. None of the studies had a low risk of bias in all seven Cochrane RoB 1 domains. We judged 65% of studies to have a high risk of bias due to outcome assessors not being masked (detection bias) and 59% to be at high risk of bias of performance bias as participants and personnel were not masked. Thirty-five per cent of studies were pre-registered on a trial registry. We did not perform meta-analyses for any of the outcome measures, due to lack of available quantitative data, heterogenous study populations, and differences in intervention follow-up periods. There may be no difference in subjective visual fatigue scores with blue-light filtering lenses compared to non-blue-light filtering lenses, at less than one week of follow-up (low-certainty evidence). One RCT reported no difference between intervention arms (mean difference (MD) 9.76 units (indicating worse symptoms), 95% confidence interval (CI) -33.95 to 53.47; 120 participants). Further, two studies (46 participants, combined) that measured visual fatigue scores reported no significant difference between intervention arms. There may be little to no difference in CFF with blue-light filtering lenses compared to non-blue-light filtering lenses, measured at less than one day of follow-up (low-certainty evidence). One study reported no significant difference between intervention arms (MD - 1.13 Hz lower (indicating poorer performance), 95% CI - 3.00 to 0.74; 120 participants). Another study reported a less negative change in CFF (indicating less visual fatigue) with high- compared to low-blue-light filtering and no blue-light filtering lenses. Compared to non-blue-light filtering lenses, there is probably little or no effect with blue-light filtering lenses on visual performance (BCVA) (MD 0.00 logMAR units, 95% CI -0.02 to 0.02; 1 study, 156 participants; moderate-certainty evidence), and unknown effects on daytime alertness (2 RCTs, 42 participants; very low-certainty evidence); uncertainty in these effects was due to lack of available data and the small number of studies reporting these outcomes. We do not know if blue-light filtering spectacle lenses are equivalent or superior to non-blue-light filtering spectacle lenses with respect to sleep quality (very low-certainty evidence). Inconsistent findings were evident across six RCTs (148 participants); three studies reported a significant improvement in sleep scores with blue-light filtering lenses compared to non-blue-light filtering lenses, and the other three studies reported no significant difference between intervention arms. We noted differences in the populations across studies and a lack of quantitative data. Device-related adverse effects were not consistently reported (9 RCTs, 333 participants; low-certainty evidence). Nine studies reported on adverse events related to study interventions; three studies described the occurrence of such events. Reported adverse events related to blue-light filtering lenses were infrequent, but included increased depressive symptoms, headache, discomfort wearing the glasses, and lower mood. Adverse events associated with non-blue-light filtering lenses were occasional hyperthymia, and discomfort wearing the spectacles. We were unable to determine whether blue-light filtering lenses affect contrast sensitivity, colour discrimination, discomfort glare, macular health, serum melatonin levels or overall patient visual satisfaction, compared to non-blue-light filtering lenses, as none of the studies evaluated these outcomes. AUTHORS' CONCLUSIONS: This systematic review found that blue-light filtering spectacle lenses may not attenuate symptoms of eye strain with computer use, over a short-term follow-up period, compared to non-blue-light filtering lenses. Further, this review found no clinically meaningful difference in changes to CFF with blue-light filtering lenses compared to non-blue-light filtering lenses. Based on the current best available evidence, there is probably little or no effect of blue-light filtering lenses on BCVA compared with non-blue-light filtering lenses. Potential effects on sleep quality were also indeterminate, with included trials reporting mixed outcomes among heterogeneous study populations. There was no evidence from RCT publications relating to the outcomes of contrast sensitivity, colour discrimination, discomfort glare, macular health, serum melatonin levels, or overall patient visual satisfaction. Future high-quality randomised trials are required to define more clearly the effects of blue-light filtering lenses on visual performance, macular health and sleep, in adult populations.

Redefining the human corneal immune compartment using dynamic intravital imaging.

The healthy human cornea is a uniquely transparent sensory tissue where immune responses are tightly controlled to preserve vision. The cornea contains immune cells that are widely presumed to be intraepithelial dendritic cells (DCs). Corneal immune cells have diverse cellular morphologies and morphological alterations are used as a marker of inflammation and injury. Based on our imaging of corneal T cells in mice, we hypothesized that many human corneal immune cells commonly defined as DCs are intraepithelial lymphocytes (IELs). To investigate this, we developed functional in vivo confocal microscopy (Fun-IVCM) to investigate cell dynamics in the human corneal epithelium and stroma. We show that many immune cells resident in the healthy human cornea are T cells. These corneal IELs are characterized by rapid, persistent motility and interact with corneal DCs and sensory nerves. Imaging deeper into the corneal stroma, we show that crawling macrophages and rare motile T cells patrol the tissue. Furthermore, we identify altered immune cell behaviors in response to short-term contact lens wear (acute inflammatory stimulus), as well as in individuals with allergy (chronic inflammatory stimulus) that was modulated by therapeutic intervention. These findings redefine current understanding of immune cell subsets in the human cornea and reveal how resident corneal immune cells respond and adapt to chronic and acute stimuli.

TFOS Lifestyle: Impact of contact lenses on the ocular surface.

Several lifestyle choices made by contact lens wearers can have adverse consequences on ocular health. These include being non-adherent to contact lens care, sleeping in lenses, ill-advised purchasing options, not seeing an eyecare professional for regular aftercare visits, wearing lenses when feeling unwell, wearing lenses too soon after various forms of ophthalmic surgery, and wearing lenses when engaged in risky behaviors (e.g., when using tobacco, alcohol or recreational drugs). Those with a pre-existing compromised ocular surface may find that contact lens wear exacerbates ocular disease morbidity. Conversely, contact lenses may have various therapeutic benefits. The coronavirus disease-2019 (COVID-19) pandemic impinged upon the lifestyle of contact lens wearers, introducing challenges such as mask-associated dry eye, contact lens discomfort with increased use of digital devices, inadvertent exposure to hand sanitizers, and reduced use of lenses. Wearing contact lenses in challenging environments, such as in the presence of dust and noxious chemicals, or where there is the possibility of ocular trauma (e.g., sport or working with tools) can be problematic, although in some instances lenses can be protective. Contact lenses can be worn for sport, theatre, at high altitude, driving at night, in the military and in space, and special considerations are required when prescribing in such situations to ensure successful outcomes. A systematic review and meta-analysis, incorporated within the review, identified that the influence of lifestyle factors on soft contact lens dropout remains poorly understood, and is an area in need of further research. Overall, this report investigated lifestyle-related choices made by clinicians and contact lens wearers and discovered that when appropriate lifestyle choices are made, contact lens wear can enhance the quality of life of wearers.

TFOS Lifestyle: Impact of the digital environment on the ocular surface.

Eye strain when performing tasks reliant on a digital environment can cause discomfort, affecting productivity and quality of life. Digital eye strain (the preferred terminology) was defined as "the development or exacerbation of recurrent ocular symptoms and/or signs related specifically to digital device screen viewing". Digital eye strain prevalence of up to 97% has been reported, due to no previously agreed definition/diagnostic criteria and limitations of current questionnaires which fail to differentiate such symptoms from those arising from non-digital tasks. Objective signs such as blink rate or critical flicker frequency changes are not 'diagnostic' of digital eye strain nor validated as sensitive. The mechanisms attributed to ocular surface disease exacerbation are mainly reduced blink rate and completeness, partial/uncorrected refractive error and/or underlying binocular vision anomalies, together with the cognitive demand of the task and differences in position, size, brightness and glare compared to an equivalent non-digital task. In general, interventions are not well established; patients experiencing digital eye strain should be provided with a full refractive correction for the appropriate working distances. Improving blinking, optimizing the work environment and encouraging regular breaks may help. Based on current, best evidence, blue-light blocking interventions do not appear to be an effective management strategy. More and larger clinical trials are needed to assess artificial tear effectiveness for relieving digital eye strain, particularly comparing different constituents; a systematic review within the report identified use of secretagogues and warm compress/humidity goggles/ambient humidifiers as promising strategies, along with nutritional supplementation (such as omega-3 fatty acid supplementation and berry extracts).

TFOS Lifestyle: Impact of nutrition on the ocular surface.

Nutrients, required by human bodies to perform life-sustaining functions, are obtained from the diet. They are broadly classified into macronutrients (carbohydrates, lipids, and proteins), micronutrients (vitamins and minerals) and water. All nutrients serve as a source of energy, provide structural support to the body and/or regulate the chemical processes of the body. Food and drinks also consist of non-nutrients that may be beneficial (e.g., antioxidants) or harmful (e.g., dyes or preservatives added to processed foods) to the body and the ocular surface. There is also a complex interplay between systemic disorders and an individual's nutritional status. Changes in the gut microbiome may lead to alterations at the ocular surface. Poor nutrition may exacerbate select systemic conditions. Similarly, certain systemic conditions may affect the uptake, processing and distribution of nutrients by the body. These disorders may lead to deficiencies in micro- and macro-nutrients that are important in maintaining ocular surface health. Medications used to treat these conditions may also cause ocular surface changes. The prevalence of nutrition-related chronic diseases is climbing worldwide. This report sought to review the evidence supporting the impact of nutrition on the ocular surface, either directly or as a consequence of the chronic diseases that result. To address a key question, a systematic review investigated the effects of intentional food restriction on ocular surface health; of the 25 included studies, most investigated Ramadan fasting (56%), followed by bariatric surgery (16%), anorexia nervosa (16%), but none were judged to be of high quality, with no randomized-controlled trials.

TFOS Lifestyle - Evidence quality report: Advancing the evaluation and synthesis of research evidence.

Evidence-based practice is a dominant paradigm in healthcare that emphasizes the importance of ensuring the translation of the best available, relevant research evidence into practice. An Evidence Quality Subcommittee was established to provide specialized methodological support and expertise to promote rigorous and evidence-based approaches for the Tear Film and Ocular Surface Society (TFOS) Lifestyle Epidemic reports. The present report describes the purpose, scope, and activity of the Evidence Quality Subcommittee in the undertaking of high-quality narrative-style literature reviews, and leading prospectively registered, reliable systematic reviews of high priority research questions, using standardized methods for each topic area report. Identification of predominantly low or very low certainty evidence across the eight systematic reviews highlights a need for further research to define the efficacy and/or safety of specific lifestyle interventions on the ocular surface, and to clarify relationships between certain lifestyle factors and ocular surface disease. To support the citation of reliable systematic review evidence in the narrative review sections of each report, the Evidence Quality Subcommittee curated topic-specific systematic review databases and relevant systematic reviews underwent standardized reliability assessment. Inconsistent methodological rigor was noted in the published systematic review literature, emphasizing the importance of internal validity assessment. Based on the experience of implementing the Evidence Quality Subcommittee, this report makes suggestions for incorporation of such initiatives in future international taskforces and working groups. Content areas broadly relevant to the activity of the Evidence Quality Subcommittee, including the critical appraisal of research, clinical evidence hierarchies (levels of evidence), and risk of bias assessment, are also outlined.

Topical Decorin Reduces Corneal Inflammation and Imparts Neuroprotection in a Mouse Model of Benzalkonium Chloride-induced Corneal Neuropathy.

Purpose: We evaluated the neuroprotective and immunomodulatory effects of topical decorin in a murine model of benzalkonium chloride (BAK)-induced corneal neuropathy. Methods: Topical BAK (0.1%) was administered daily to both eyes of female C57BL/6J mice (n = 14) for 7 days. One group of mice received topical decorin (1.07 mg/mL) eye drops to one eye and saline (0.9%) to the contralateral eye; the other group received saline eye drops to both eyes. All eye drops were given three times daily over the experimental period. A control group (n = 8) received daily topical saline only, instead of BAK. Optical coherence tomography imaging was performed before (at day 0) and after (day 7) treatment to evaluate the central corneal thickness. Whole-mount immunofluorescence staining was performed to evaluate the density of corneal intraepithelial nerves and immune cells. Results: BAK-exposed eyes showed corneal epithelial thinning, infiltration of inflammatory macrophages and neutrophils, and a lower density of intraepithelial nerves. No change to the corneal stromal thickness or dendritic cell density was observed. After BAK exposure, decorin-treated eyes had a lower density of macrophages and less neutrophil infiltration and a higher nerve density than the saline-treated group. Contralateral eyes from the decorin-treated animals showed fewer macrophages and neutrophils relative to saline-treated animals. A negative correlation was found between corneal nerve density and macrophage or neutrophil density. Conclusions: Topical decorin provides neuroprotective and anti-inflammatory effects in a chemical model of BAK-induced corneal neuropathy. The attenuation of corneal inflammation by decorin may contribute to decreasing corneal nerve degeneration induced by BAK.