Tear film and ocular surface neuropeptides: Characteristics, synthesis, signaling and implications for ocular surface and systemic diseases.

Ocular surface neuropeptides are vital molecules primarily involved in maintaining ocular surface integrity and homeostasis. They also serve as communication channels between the nervous system and the immune system, maintaining the homeostasis of the ocular surface. Tear film and ocular surface neuropeptides have a role in disease often due to abnormalities in their synthesis (either high or low production), signaling through defective receptors, or both. This creates imbalances in otherwise normal physiological processes. They have been observed to be altered in many ocular surface and systemic diseases including dry eye disease, ocular allergy, keratoconus, LASIK-induced dry eye, pterygium, neurotrophic keratitis, corneal graft rejection, microbial keratitis, headaches and diabetes. This review examines the characteristics of neuropeptides, their synthesis and their signaling through G-protein coupled receptors. The review also explores the types of neuropeptides within the tears and ocular surface, and how they change in ocular and systemic diseases.

A new portable digital meniscometer.

PURPOSE: The aims of this study were (i) to develop a new portable slit-lamp mounted digital meniscometer (PDM) and (ii) to test its accuracy and repeatability compared to the existing Yokoi et al. videomeniscometer (VM). METHODS: We developed a novel application for an iPod or iPhone, which created an illuminated target of parallel black and white bands. This was used as a portable device with which to perform reflective meniscometry. The medians of three consecutive measurements on five glass capillaries (internal radii, 0.100 to 0.505 mm) were compared between VM and PDM at two different sessions. Also, the central lower tear meniscus radius (TMR) in 20 normal subjects (10 males and 10 females; mean [SD] age, 32.3 [9.3] years) was measured using both techniques. Correlations between the instruments were analyzed using the Pearson coefficient. Differences between sessions and instruments were analyzed using Bland-Altman plots, coefficient of repeatability, and paired t-tests. RESULTS: The PDM and VM were accurate in vitro (95% confidence interval [CI] of difference: PDM -0.0134 to +0.0074 mm, p = 0.468; VM -0.0282 to + 0.0226 mm; p = 0.775) and reproducible between sessions (95% coefficient of repeatability, 0.019 and 0.018, respectively). The mean difference between the PDM and VM in vitro was 0.0002 mm (95% CI, -0.0252 to + 0.0256; p = 0.984). In human subjects, mean (SD) TMR measured with the PDM (0.34 [0.10] mm) and VM (0.36 [0.11] mm) was significantly correlated (r = 0.940; p < 0.001), and there was no statistically significant difference between the measured TMR of the instruments (p = 0.124). CONCLUSIONS: This new slit-lamp mounted digital meniscometer produces accurate and reliable measurements and provides similar values for tear meniscus radius, in human studies, to the existing VM. The instrument is suitable for use in both research and clinical practice.

Improving awareness, identification, and management of meibomian gland dysfunction.

Ocular surface disorder--and dry eye, in particular--is a leading reason for visits to eye care professionals. It has been generally accepted that meibomian gland dysfunction (MGD) is a leading cause of evaporative dry eye, as well as being associated with aqueous-deficient dry eye. Yet, researchers and clinicians have lacked a global consensus on the definition of MGD, its epidemiology, pathophysiology, and management. Various systemic diseases and medications have been associated with the progression of both dry eye and MGD, as have several ocular disorders beyond those directly affecting the surface. It is in the best interest of patients for clinicians to be able to better identify and diagnose MGD, differentiating it from other ocular surface disorders, and to recognize the effects of MGD on the ocular surface, and thus initiate appropriate therapy. This CME activity provides expert insight into the Tear Film and Ocular Surface Society's International Workshop on MGD consensus report, offering practical application of its findings to better manage MGD patient care, particularly for those patients facing or undergoing ocular surgery.

An explanation for the central to peripheral thickness variation in the mouse cornea.

BACKGROUND: The mouse corneal stroma varies in thickness across its diameter. The purpose of the present study was to explain this variation and to advance our understanding of stromal lamellar architecture in the mammalian cornea. METHODS: Eight C57BL/6 mice were killed, eyes enucleated, immersed in 2% glutaraldehyde fixative, processed and sectioned transversely for light and transmission electron microscopy. Transmission electron micrographs were assembled into montages and printed at 5000× magnification and used for lamellar counts and thickness assessments. RESULTS: The mouse cornea had an average of 49.8±2.4 lamellae centrally averaging 2.1µm in thickness versus 35.5±3.0 lamellae, averaging 1.9µm in thickness peripherally. The central to peripheral decrease in number lamellae and lamellar thickness measured utilizing the transmission electron microscope was statistically significant (P<0.005). CONCLUSIONS: This study demonstrated that the thickness difference between the thicker central and thinner peripheral mouse cornea is explained primarily by the number of lamellae present and that the peripheral lamellar dropout occurred in the anterior 2/3 of stroma. The decreased lamellar count towards the periphery suggested that not all lamellae cross the cornea limbus to limbus. These findings may be relevant to the thickness variation of the human cornea.

A solute gradient in the tear meniscus. I. A hypothesis to explain Marx's line.

Marx's line is a line of mucosal staining behind the mucocutaneous junction. It can be demonstrated throughout life in all normal lids by staining with lissamine green and related dyes. Of all the body orifices, only the mucosae of the eye and mouth are directly exposed to the atmosphere. In this paper, we suggest that for the eye, this exposure leads to the formation of Marx's line. The tear meniscus thins progressively toward its apex, where it is pinned at the mucocutaneous junction of the lid. It also thins toward the black line, which segregates the meniscus from the tear film after the blink. We predict that, because of the geometry of the tear meniscus, evaporation generates a solute gradient across the meniscus profile in the anteroposterior plane, which peaks at the meniscus apices at the end of the interblink. One outcome would be to amplify the level of tear molarity at these sites so that they reach hyperosmolar proportions. Preliminary mathematical modeling suggests that dilution of this effect by advection and diffusion of solute away from the meniscus apex at the mucocutaneous junction will be restricted by spatial constraints, the presence of tear and surface mucins at this site, and limited fluid flow. We conclude that evaporative water loss from the tear meniscus may result in a physiological zone of hyperosmolar and related stresses to the occlusal conjunctiva, directly behind the mucocutaneous junction. We hypothesize that this stimulates a high epithelial cell turnover at this site, incomplete epithelial maturation, and a failure to express key molecules such as MUC 16 and galectin-3, which, with the tight junctions between surface epithelial cells, are necessary to seal the ocular surface and prevent penetration of dyes and other molecules into the epithelium. This is proposed as the basis for Marx's line. In Part II of this paper (also published in this issue of The Ocular Surface), we address additional pathophysiological consequences of this mechanism, affecting lid margins.

A solute gradient in the tear meniscus. II. Implications for lid margin disease, including meibomian gland dysfunction.

We have hypothesized previously that evaporation from the tears generates a solute gradient across the tear meniscus, which delivers hyperosmolar stress to the mucocutaneous junction (MCJ) of the lid margin. This is proposed as the basis for Marx's line, a line of staining with topically applied dyes that lies directly behind the MCJ. In this article, we consider the implications of this hypothesis for progressive damage to the lid margin as an age-related phenomenon, its amplification in dry eye states, and its possible role in the etiology of meibomian gland dysfunction (MGD). It is suggested that a hyperosmolar or related stimulus, acting behind the MCJ over a lifetime, promotes the anterior migration of the MCJ, which is a feature of the aging lid margin. This mechanism would be amplified in dry eye states, not only by reason of increased tear molarity at the meniscus apex but also by raising the concentration of inflammatory peptides at this site. This could explain the increased width and irregularity of Marx's line in dry eye. While the presence of stem cells at the lid margin may equip this region to respond to such stress, their depletion could be the basis of irreversible lid margin damage. It is further proposed, given the proximity of the MCJ to the meibomian gland orifices, that the solute gradient mechanism could play a role in the initiation of MGD by delivering hyperosmolar and inflammatory stresses to the terminal ducts and orifices of the glands. By the same token, the presence of a zone of increased epithelial permeability in this region may provide a back door route for the delivery of drugs in the treatment of MGD.

Tear Osmolarity in the Diagnosis of Systemic Dehydration and Dry Eye Disease.

Systemic dehydration due to inadequate water intake or excessive water loss, is common in the elderly and results in a high morbidity and significant mortality. Diagnosis is often overlooked and there is a need for a simple, bedside diagnostic test in at-risk populations. Body hydration is highly regulated with plasma osmolality (pOsm) being tightly controlled over a wide range of physiological conditions. By contrast, normal tear osmolarity (tOsm) is more variable since the tear film is exposed to evaporation from the open eye. While plasma hyperosmolality is a diagnostic feature of systemic dehydration, tear hyperosmolality, with other clinical features, is diagnostic of dry eye. Studies in young adults subjected to exercise and water-deprivation, have shown that tOsm may provide an index of pOsm, with the inference that it may provide a simple measure to diagnose systemic dehydration. However, since the prevalence of both dry eye and systemic dehydration increases with age, the finding of a raised tOsm in the elderly could imply the presence of either condition. This diagnostic difficulty can be overcome by measuring tear osmolality after a period of evaporative suppression (e.g., a 45 min period of lid closure) which drives tOsm osmolality down to a basal level, close to that of the pOsm. The arguments supporting the use of this basal tear osmolarity (BTO) in the diagnosis of systemic dehydration are reviewed here. Further studies are needed to confirm that the BTO can act as a surrogate for pOsm in both normally hydrated subjects and in patients with systemic dehydration and to determine the minimum period of lid closure required for a simple, "point-of-care" test.

Attitudes towards diagnostic tests and therapies for dry eye disease.

AIM: The purpose of this study was to survey the attitudes of optometrists and ophthalmologists, located in a number of different countries, towards diagnostic tests and therapies for dry eye disease. METHODS: A web-based questionnaire was used to survey attitudes using forced-choice questions and Likert scales. RESULTS: Sixty-one respondents (23 ophthalmologists and 38 optometrists) reported a wide range of patient dry eye symptoms. A large variation in use of diagnostic tests was noted. Patient symptoms and fluorescein staining were reported to be significantly more valuable and more frequently performed than any other test. Artificial tear supplements and improved lid hygiene were the preferred therapeutic options selected by the entire group. The results demonstrated a wide variation in attitudes in relation to satisfaction with the range of available diagnostic and therapeutic options. CONCLUSIONS: This study indicates that the interest for the issue of dry eye is relatively limited amongst eye professionals, as demonstrated by the poor participation in the questionnaire.

Predicted phenotypes of dry eye: proposed consequences of its natural history.

This paper reviews current knowledge of the pathophysiology of dry eye and predicts that the clinical picture in late disease differs in both severity and quality from that in early disease. It is hypothesized that hybrid forms evolve, in which aqueous-deficient dry eye (ADDE) takes on features of evaporative dry eye (EDE) and vice versa. As a consequence, early and late forms may require different diagnostic criteria and respond to different therapeutic regimes. Tear hyperosmolarity plays a key role in the damage mechanism of dry eye, and ADDE is recognized to be a low-volume, hyperosmolar state. As ADDE advances, a progressive decrease in lacrimal secretion occurs, exacerbated by loss of the corneal reflex. This causes a decrease in tear volume, thinning of the aqueous tear film, and retarded spreading of the tear film lipid layer. The latter is hypothesized to cause an increase in evaporative water loss and an added evaporative component to the dry eye. Thus, in advanced disease, the hybrid state would be an organic ADDE, accompanied by a functional EDE in the absence of meibomian gland dysfunction. This functional EDE would respond to agents that expand the tear volume, restore corneal sensitivity, or provide an artificial tear film lipid layer.

Classification and diagnosis of dry eye.

BACKGROUND: Dry eye, or keratoconjunctivitis sicca (KCS), is divided into two subgroups, tear-deficient and evaporative. Each form calls for a different therapeutic approach and it is therefore essential to apply a combination of diagnostic tests in order to establish the exact diagnosis. MATERIAL AND METHODS: The diagnosis of KCS is based in part on the patient's history and symptoms and in part on the application of specific tests. Several non-invasive tests exist (e.g. slit-lamp examination, meniscometry, interferometry). Mildly invasive tests are the fluorescein tests, staining with lissamine green, meibometry and meibography. Markedly invasive tests include the Schirmer test and staining with rose bengal. Additional histological procedures are the ocular ferning test and impression cytology. RESULTS: A combination of diagnostic tests leads to one of the two forms of KCS. Its severity is calculated according to grading systems, which exist for several tests. The longitudinal observation of the dry eye patient is provided on the basis of this same grading system, although limited reproducibility is reported for some tests. CONCLUSION: The diagnostic steps for dry eye patients can be efficiently arranged. In most of the cases, non-invasive or mildly invasive tests provide an accurate diagnosis.

Career choices for ophthalmology made by newly qualified doctors in the United Kingdom, 1974-2005.

BACKGROUND: The paper aims to report trends in career choices for ophthalmology among UK medical graduates. METHODS: Postal questionnaire surveys were undertaken of qualifiers from all UK medical schools in nine qualification years since 1974. Data were analysed by univariate cross-tabulation. The significance of comparisons between groups of doctors were calculated by the use of chi-squared tests and adjusted residuals. RESULTS: Ophthalmology was the first choice of long term career for 2.3% of men and 1.5% of women one year after qualification; 2.0% of men and 1.4% of women three years after; and 1.8% of men and 1.2% of women at five years. Comparing early choices with eventual destinations, 64% who chose ophthalmology in year one, 84% in year three, and 92% in year five eventually practised in the specialty. The concordance between year one choice and eventual destination was higher for ophthalmology than for most other specialties. 'Enthusiasm for and commitment to the specialty' was the most important single factor in influencing career choice. The prospect of good working hours and conditions was also an important influence: it influenced career choice a great deal for a higher percentage of those who chose ophthalmology (66% in the third year) than those who made other surgical choices (23%). CONCLUSION: Those choosing ophthalmology show a high level of commitment to it. Their commitment is strengthened by the prospect of attractive hours and working conditions. Many doctors who become ophthalmologists have already made their choice by the end of their first post-qualification year.

Estimating basal tear osmolarity in normal and dry eye subjects.

PURPOSE: Tear osmolarity (tOsm) is used as a measure of severity in dry eye disease (DED) and has been proposed as an index of body hydration. In DED the level of tear hyperosmolarity is compared with that of a control population. It is proposed here that a better index of body hydration and a more valid reference point in DED can be acquired by measuring the tOsm after a period of evaporative suppression. METHOD: 8 normal and DED subjects were recruited, their tOsm measured in uncontrolled environmental 'clinic conditions'. Then in experiment 1 they entered a controlled environment chamber and had tOsm measured after 45 minutes of eye closure and then, with the eyes open, at 15 minute intervals for a further 45 minutes, at a relative humidity (RH) of 45%. Alternatively, in experiment 2, they had tOsm measured every 15 minutes for 45 minutes during exposure to 70% RH, as a separate measure to suppress evaporation. RESULTS: A significant decrease in tOsm occurred in both normal and DED subjects after lid closure in experiment 1 (normal RE p=0.015; normal LE p=0.006; DED RE p=0.0002; DED LE p=0.01). The tOsm also fell slightly after exposure to 70% RH in experiment 2 significant in the LE of normal group only (normal LE p=0.045). CONCLUSIONS: Suppression of tear evaporation resulted in a fall in tOsm, close to that of plasma osmolarity (285-295mOsm/L). It is proposed that this new measure, termed Basal Tear Osmolarity (BTO), could provide a valuable index of plasma osmolarity and hence of body hydration and in DED, a personal baseline against which to gauge the severity of tear hyperosmolarity.

The influence of visible light exposure on cultured RGC-5 cells.

PURPOSE: To determine the effects of visible light on normal or metabolically compromised cultured rat RGC-5 cells. METHODS: Cultured RGC-5 cells were exposed to different durations as well as intensities of optical radiation, filtered to exclude wavelengths below 400 nm. Some cells were also subjected to metabolic compromise by depriving them of serum (serum deprivation; SD). Treated cells were assayed for cell viability using the 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay, for DNA breakdown by terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP-linked nick end labeling (TUNEL), apoptotic protein activation by immunoblotting, and the production of reactive oxygen species (ROS) with dihydroethidium. A subset of cells was treated with 100 pM rotenone as an alternative means to induce metabolic stress; this was to determine that the influence of light on compromised cells was not specific to serum-deprivation alone. RESULTS: Exposure to the light for 48 h activated both caspase-3 and Bcl-associated X-protein (Bax) in cultured RGC-5 cells. Furthermore, light (1000 or 4000 lux), SD, and rotenone caused minor but significant decreases in cellular MTT reduction. SD and light also led to cellular DNA breakdown, although only light caused ROS production. Light (48 h) significantly exacerbated the effect of SD on MTT reduction and DNA cleavage. Furthermore, the antioxidant, trolox, significantly blunted the detrimental influence of light on cell viability, increase in TUNEL-positive cells, and the generation of ROS. CONCLUSIONS: Exposure to light was slightly, but significantly, harmful to healthy RGC-5 cells alone, but was much more toxic to those cells that were energetically compromised. Continuous light exposure can therefore detrimentally affect metabolically stressed RGC-5 cells. This may have implications for some ocular retinopathies such as glaucoma.

Morphologic and volumetric studies of the meibomian glands in elderly human eyelids.

PURPOSE: To study the microscopic structure of postmortem human Meibomian glands (MGs) in the elderly. METHODS: Human MG samples from left lower eyelids were obtained at autopsy from 5 men and 4 women with a mean age of 63.1 +/- 7.67 years. The tissues were fixed and embedded in paraffin. Serial transverse sections 5 mum thick were stained with hematoxylin and eosin (H&E), van Gieson, and Masson blue stains. Computer-assisted 3-dimensional reconstructions of MGs were performed, and morphologic and volumetric data were analyzed. RESULTS: The average length of human MGs in the nasal, central, and temporal areas was 1.551 +/- 0.43, 1.654 +/- 0.47, and 1.594 +/- 0.57 mm, respectively. The average surface area of the glands in the nasal, central, and temporal areas was 0.029 +/- 0.03, 0.033 +/- 0.01, and 0.056 +/- 0.03 mm, respectively. The average volume of glands in the nasal, central, and temporal areas was 0.054 +/- 00.4, 0.056 +/- 0.03, and 0.053 +/- 0.03 mm, respectively. A circular, floral arrangement of acini, surrounding the terminal duct just deep to the skin, is probably responsible for the circular arrangement seen clinically around each healthy orifice. We confirmed that most glands are embedded within a cylindrical, connective tissue matrix. CONCLUSIONS: We report the dimensions of normal Meibomian acini in an older population. Some structural features observed may explain normal physiologic landmarks or contribute to glandular pathophysiology.

Central Connections of the Lacrimal Functional Unit.

PURPOSE: To study the contribution of each eye to the reflex tear response, after unilateral and bilateral topical anesthesia. METHOD: A closed-eye, modified Schirmer test was performed bilaterally in 8 normal subjects, in a controlled environment chamber set to 23°C, 45% relative humidity, and 0.08 m/s airflow. Eye drops were instilled into each eye 10 minutes before the Schirmer test. Experiments were as follows: 1) bilateral saline (control), 2) unilateral anesthesia (ipsilateral anesthetic; contralateral saline), and 3) bilateral anesthesia. RESULTS: There was no difference in between-eye wetting lengths in the saline control eyes (P = 0.394) or the bilaterally anesthetized eyes (P = 0.171). The wetting length was reduced in both eyes after bilateral anesthesia compared with saline controls (P = 0.001; P ≤ 0.0005). After unilateral anesthesia, the wetting length was reduced in the anesthetized eye compared with its saline control by 51.4% (P ≤ 0.0005) and compared with its fellow, unanesthetized eye (P = 0.005). The fellow eye value was also reduced compared with its saline control (P = 0.06). CONCLUSIONS: The wetting length was reduced by topical anesthesia, when instilled bilaterally and ipsilaterally. The latter response implies an ipsilateral, reflex sensory drive to lacrimal secretion. In the unanesthetized fellow eye, the reduction compared with its saline control was not quite significant. This implies a relative lack of central, sensory, reflex cross-innervation, although the possibility cannot entirely be ruled out. These results are relevant to the possibility of reflex lacrimal compensation from a normal fellow eye, in cases of unilateral corneal anesthesia.

Rasch analysis of three dry eye questionnaires and correlates with objective clinical tests.

PURPOSE: To assess the psychometric properties of Chinese versions of the Ocular Comfort Index (OCI), Ocular Surface Disease Index (OSDI) and McMonnies questionnaires. Further, to assess the correlation between questionnaire scores and objective dry eye disease (DED) clinical tests. METHODS: Translated versions of the OCI, OSDI and McMonnies questionnaires were completed in a random order by 238 participants with DED. Objective clinical tests included visual acuity (VA), fluorescein tear film break-up time (TBUT), corneal fluorescein staining, Schirmer I testing and meibomian gland grading. Rasch analysis was used to assess questionnaire psychometrics and spearman rank for correlations. RESULTS: For the OCI, the person separation was 2.31, item infit and outfit statistics ranged from 0.74-1.14 and 0.75-1.32, respectively, and targeting 1.54 logits. For the OSDI, person separation was 0.94. None of the three subscales provided valid measurements based on Rasch analysis. For the McMonnies questionnaire, person separation was 1.17, item infit and outfit statistics ranged from 0.7 to 1.21 and 0.51-3.49, respectively. There were weak correlations between questionnaire scores and clinical tests. There were weak correlations between OSDI scores and VA, fluorescein TBUT, Schirmer I testing and corneal fluorescein staining. There were weak correlations between McMonnies scores and VA, fluorescein TBUT, Schirmer I testing, and corneal fluorescein staining and meibomian gland grading. CONCLUSIONS: The OCI questionnaire was the only questionnaire that provided valid measurement on the basis of Rasch analysis, although slight multidimensionality was found. There were weak correlations between OCI scores and fluorescein TBUT, Schirmer I testing, and corneal fluorescein staining. Due to this paradoxical disconnect between symptoms and signs and the repeatability of tests, the use of both subjective and objective markers in the clinical management of patients or as endpoints in clinical trials would appear prudent.

Defining Ocular Surface Disease Activity and Damage Indices by an International Delphi Consultation.

PURPOSE: Unifying terminology for the description of ocular surface disease (OSD) is vital for determining treatment responses and ensuring robust clinical trial outcomes. To date, there are no agreed parameters describing 'activity' and 'damage' phases of disease. METHODS: A working group of international experts in OSD, oculoplastics, and uveitis from a range of backgrounds (university, teaching, district general and private hospitals) participated in a modified Delphi consensus-building exercise (October 31, 2011 to March 20, 2015). Two steering group meetings took place in which factors based upon published literature were discussed and supplemented with anonymous web-based questionnaires to refine clinical indices according to 'activity' (reversible changes resulting directly from the inflammatory process) and/or 'damage' (persistent, >6 months duration) changes resulting from previously active disease that are cumulative and irreversible). RESULTS: The recommended set of clinical parameters for the assessment of OSD encompasses 68 clinical indices and 22 ancillary grading tools (in parenthesis) subdivided by anatomical domain as follows: 4(4) tear-film, eyelid 21(3), 17(3) conjunctiva, 15(10) cornea and 11(2) Anterior Chamber/Sclera. Of these; 17(2) were considered as measures of clinical activity, 27(3) as damage, 1(8) as measures of both activity and damage. Twenty-three clinical descriptors and 9 tools did not reach the threshold for inclusion into the main standard set. These were defined as 'second tier' parameters for use in special clinical settings. CONCLUSION: These core parameters provide the first description of 'activity' and 'damage' relevant to OSD and provide a platform for the future development of scoring scales for each parameter.

TFOS DEWS II pathophysiology report.

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

TFOS DEWS II Report Executive Summary.

This article presents an Executive Summary of the conclusions and recommendations of the 10-chapter TFOS DEWS II report. The entire TFOS DEWS II report was published in the July 2017 issue of The Ocular Surface. A downloadable version of the document and additional material, including videos of diagnostic and management techniques, are available on the TFOS website: www.TearFilm.org.