Efficacy of Azithromycin Eyedrops for Individuals With Meibomian Gland Dysfunction-Associated Posterior Blepharitis.

PURPOSE: To examine the safety and efficacy of azithromycin eyedrops in Japanese individuals with meibomian gland dysfunction (MGD)-associated posterior blepharitis. METHODS: Individuals with MGD-associated posterior blepharitis who visited the Itoh Clinic, Saitama, Japan, were randomly assigned to receive azithromycin (1%) eyedrops (AZM group, 16 eyes of 16 patients) or preservative-free artificial tears (control group, 20 eyes of 20 patients) for 2 weeks. All subjects also applied a warming eyelid compress twice per day. Subjective symptoms (Standardized Patient Evaluation of Eye Dryness [SPEED] score), lipid layer thickness (LLT) and interferometric pattern of the tear film, plugging and vascularity of the lid margin, noninvasive break-up time of the tear film (NIBUT) and fluorescein-based break-up time of the tear film (TBUT), corneal-conjunctival fluorescein staining score, tear meniscus height, meibum grade, meiboscore, tear osmolarity, and Schirmer test value were determined before and after treatment. Side effects of treatment were also recorded. RESULTS: In the AZM group, SPEED score, LLT, interferometric pattern, plugging and vascularity of the lid margin, NIBUT, TBUT, meibum grade, and tear osmolarity were significantly improved after treatment compared with baseline. The SPEED score, interferometric pattern, plugging, vascularity, meibum grade, and tear osmolarity were also significantly improved after treatment in the AZM group compared with the control group. Common side effects in the AZM group were transient eye irritation and blurred vision. CONCLUSION: Azithromycin eyedrops improved eyelid inflammation, the quality and quantity of the lipid layer of the tear film, and tear film stability. Such eyedrops thus seem to be a safe and effective treatment for MGD-associated posterior blepharitis.

New insights into the morphology and function of meibomian glands.

Meibomian glands secrete meibum, which gives rise to the lipid layer of the tear film and thereby prevents excessive evaporation of tear fluid. Meibomian gland dysfunction (MGD) is a major causative condition of evaporative dry eye, which is more common than the aqueous-deficient type of dry eye. Noninvasive meibography relies on infrared light and an infrared-sensitive camera to reveal the morphology of meibomian glands in both the upper and lower eyelids, whereas tear interferometry allows both qualitative and quantitative evaluation of the lipid layer of the tear film. These two techniques not only provide valuable clinical information related to dry eye but also allow clinical evaluation of MGD. Tear interferometry also has the potential to distinguish the condition of the tear film between normal individuals and dry eye patients. Furthermore, combined evaluation of the noninvasive breakup time of the tear film and the interferometric fringe pattern as determined by tear interferometry allows classification of the subtype of dry eye disease.

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions.

VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A-induced neuronal growth. VEGF-B-induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B-deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury.

New Insights Into the Lipid Layer of the Tear Film and Meibomian Glands.

Meibomian glands secrete lipids (meibum) that form the surface lipid layer of the tear film and thereby prevent excessive evaporation of tear fluid. Meibomian gland dysfunction is a major cause of evaporative dry eye, which is more prevalent than aqueous-deficient dry eye. Noninvasive meibography with infrared light and an infrared charge-coupled device camera can detect morphological changes of meibomian glands in both upper and lower eyelids, whereas tear interferometry allows qualitative and quantitative evaluations of the lipid layer of the tear film. Such assessment of meibomian gland morphology provides clinical information that contributes to the diagnosis of evaporative dry eye, whereas that of the lipid layer of the tear film allows the monitoring of meibomian gland function. In addition, the balance between the lipid and aqueous layers of the tear film revealed by tear interferometry has provided both support for the operation of a compensatory system that maintains tear film homeostasis as well as insight into the pathophysiology of dry eye.

Meibomian Gland Dysfunction and Contact Lens Discomfort.

Meibomian glands are located in the eyelids and secrete meibum, which gives rise to the lipid layer of the tear film. Changes to these glands can lead to the development of meibomian gland dysfunction (MGD), which is associated with various ocular symptoms such as fatigue, dryness, burning sensation, and heavy sensation. The diagnosis of MGD thus relies on evaluation of ocular symptoms, meibum condition, and lid margin abnormalities. The recent development of noninvasive meibography and tear interferometry has provided important insight into meibomian gland structure and function, respectively. Wearers of contact lenses complain of ocular symptoms that are thought to be attributable to a variety of causes, such as a diminished aqueous or mucin layer of the tear film, changes in tear protein concentration, and altered meibomian gland structure or function. Many studies have examined the relation between contact lens wear and meibomian gland changes. Such studies have found that lens wear is associated with adverse changes in meibomian gland morphology and in the condition of the lid margin and meibum, suggesting that contact lenses negatively affect meibomian glands. Meibomian gland dysfunction-like changes in meibomian glands induced by contact lens wear may thus be responsible for at least some of the ocular symptoms in lens wearers.

Vascular endothelial growth factor promotes anatomical and functional recovery of injured peripheral nerves in the avascular cornea.

Peripheral nerve injury is a major neurological disorder that can cause severe motor and sensory dysfunction. Neurogenic effects of vascular endothelial growth factor (VEGF) have been found in the central nervous system, and we examined whether VEGF could promote anatomical and functional recovery of peripheral nerves after injury using an avascular corneal nerve injury model. We found that VEGF enhanced neurite elongation in isolated trigeminal ganglion neurons in a dose-dependent manner. This effect was suppressed by neutralizing antibodies for VEGF receptor (VEGFR) 1 and 2 or neuropilin receptor 1 or by VEGFR2 inhibitors (SU 1498 and Ki 8751). In vivo, mice receiving sustained VEGF via implanted pellets showed increased corneal nerve regeneration after superficial injury compared with those receiving vehicle. VEGF injected subconjunctivally at the time of injury accelerated reinnervation, the recovery of mechanosensation, and epithelial wound healing. Endogenous VEGF expression was up-regulated in the corneal epithelium and stroma after wounding. Thus, VEGF can mediate peripheral neuron growth but requires the activation of multiple VEGF receptor types. In addition, VEGF can accelerate the return of sensory and trophic functions of damaged peripheral nerves. Wounding induces the expression of VEFG, which may modulate physiological nerve repair.

Safety and Efficacy of Photocatalytic Micro-Mist Desktop Humidifier for Dry Eye Caused by Digital Environment: A Randomized Controlled Trial.

Background/Objectives: Modern life is inconceivable without visual display terminal (VDT) work, including smartphones, computers, and games for both children and adults. VDT work under air conditioning and low humidity poses a high risk of dry eye and digital eye strain. Methods: Thirty-one participants were randomly divided into two groups using a desktop humidifier with photocatalytic technology, namely the "with mist" (humidifier) group and "without mist" (control) group. Participants performed VDT tasks using the humidifier with or without mist for 1 h. Ocular subjective symptoms and objective tear film parameters were assessed before, immediately after, and 1.5 h after the VDT task with or without mist. (Registry ID: UMIN000054379) Results: Ocular symptom scores improved significantly in the humidifier group immediately after the VDT task and up to 1.5 h later compared to before the task (p < 0.001, =0.006, respectively). Immediately after the VDT task, tear meniscus height was significantly higher and non-invasive breakup time was significantly longer in the humidifier group than in the control group (p < 0.001, =0.040, respectively). Plugging of the meibomian gland orifices was significantly reduced only in the humidifier group immediately after the VDT task compared to before the VDT task and remained significantly reduced up to 1.5 h later (p = 0.004, 0.016, respectively). Conclusions: The use of the photocatalytic desktop humidifier during VDT task resulted in significant improvements in the tear film parameters and subjective symptoms. The photocatalytic desktop humidifier could be effective in alleviating dry eye and eye strain in computer users in a modern office environment.

Comparison of Intense Pulsed Light Therapy on Patients with Meibomian Gland Dysfunction Using AQUA CEL and M22 Devices.

The purpose of this study was to compare the efficacy of Intense Pulsed Light (IPL) therapy for meibomian gland dysfunction (MGD) using the new AQUA CEL (AC, Jeisys) device and the traditional M22 (Lumenis) device. A total of 59 eyes of 59 patients with MGD (12 men and 47 women, mean age 49 ± 12 years) were enrolled. They randomly received four sessions of IPL therapy every three weeks either with AC (30 eyes) or M22 (29 eyes). Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire score, noninvasive breakup time (NIBUT), lid margin abnormalities, corneal and conjunctival fluorescein staining, fluorescein breakup time (FBUT), Schirmer's test, meiboscore and meibum grade were evaluated before treatment and one month after treatment. Before IPL, no significant differences were seen in age, gender, or measured parameters between the AC and M22 groups (p > 0.05, respectively). SPEED score, NIBUT, lid margin abnormalities, fluorescein staining, FBUT, and meibum grade improved significantly in both groups after IPL compared to before IPL (p < 0.001, respectively). There were no significant differences in measured parameters between the two groups after IPL (p > 0.05, respectively). IPL therapy with AC and M22 devices has been shown to be equally effective for the treatment of MGD.

Therapeutic Efficacy and Safety of Intense Pulsed Light for Refractive Multiple Recurrent Chalazia.

To evaluate the efficacy and safety of intense pulsed light (IPL) combined with meibomian gland expression (MGX) for the treatment of refractory multiple and recurrent chalazia without surgery or curettage. This was a retrospective controlled study. Patients with multiple and recurrent chalazia, who had performed the conventional treatment at least 2 months without any surgery or curettage, were enrolled in this study. Twenty-nine consecutive multiple recurrent chalazia (12 patients) were assigned to receive either the combination of IPL and MGX or MGX alone as a control. Each eye underwent one to four treatment sessions with 2-week intervals. Parameters were evaluated before and 1 month after the final treatment session. Clinical assessments included symptom, size of each chalazion, lid margin abnormalities, corneal and conjunctival fluorescein staining, meibum grade, the number of Demodex mites, the Schirmer value and meiboscore. All parameters except meiboscore and the Schirmer value were significantly improved with IPL-MGX therapy, whereas only meibum grade was significantly improved with MGX alone. There were no adverse events which occurred in either group. IPL-MGX was safe and effective for multiple and recurrent chalazia without surgery or curettage by reducing the size of chalazion and improving lid margin abnormalities and meibum grade.

Exploratory Search for Characteristic Symptoms to Distinguish Meibomian Gland Dysfunction from Dry Eye in a Population-Based Study in Japan.

Symptom overlap between meibomian gland dysfunction (MGD) and dry eye (DE) makes it difficult to distinguish between these two conditions on the basis of symptoms alone. We searched for characteristic symptoms that might help to distinguish MGD from DE on the basis of a population-based study. Subjects comprised 311 residents of Takushima island (18 to 96 years), including 117 individuals with MGD and 114 with DE. Responses to a symptom-related questionnaire (19 items) were subjected to factor analysis, and univariate regression analysis was performed to identify ocular surface parameters associated with characteristic symptoms of MGD. Factor analysis revealed aggregation of symptoms according to three factors: Factor 1 related to Symptom Score, Factor 2 to DE, and Factor 3 to MGD. Symptoms associated with DE included 11 items, whereas the only item related to MGD was tearing sensation. Pearson's correlation analysis revealed that tearing sensation was associated with tear meniscus height (TMH), noninvasive tear-film breakup time, fluorescein staining score, meiboscore, meibum grade, and Schirmer value. Subjects with MGD experienced significantly more tearing and had a larger TMH than did those without MGD (p = 0.0334). Tearing sensation may thus be a characteristic symptom of MGD. Physicians should suspect MGD who complain of tearing sensation.

Laser treatment of giant iris cyst with nanophthalmos.

We report a case of a giant iris cyst treated with neodymium-doped yttrium aluminum garnet laser cystotomy. A 33-year-old woman presented with nanophthalmos and ocular hypertension secondary to a giant iris cyst after congenital cataract surgery in the left eye. Examination with a rotating Scheimpflug camera and anterior-segment optical coherence tomography revealed a large iris cyst surrounding the pupillary region. She underwent laser iridocystotomy and irrigation of the anterior chamber. No recurrence of the iris cyst has been noted after 18 months and the IOP is normal. The cyst was treated successfully by laser cystotomy without other ocular tissue damage. Examination with a rotating Scheimpflug camera and anterior-segment optical coherence tomography proved to be simple and quick methods for assessing the iris cyst.

Relation of Dietary Fatty Acids and Vitamin D to the Prevalence of Meibomian Gland Dysfunction in Japanese Adults: The Hirado-Takushima Study.

Intervention studies have shown that n-3 polyunsaturated fatty acid (PUFA) supplementation is effective for the treatment of meibomian gland dysfunction (MGD). Ointment containing an analog of vitamin D has also been found to improve symptoms and signs of MGD. We have now evaluated the relation of MGD prevalence to dietary intake of fatty acids (FAs) and vitamin D among a Japanese population. Subjects comprised 300 adults aged 20 to 92 years residing on Takushima Island. MGD was diagnosed on the basis of subjective symptoms, lid margin abnormalities, and meibomian gland obstruction. Dietary FA and vitamin D intake was estimated with a brief-type self-administered diet history questionnaire. MGD prevalence was 35.3%. Multivariate adjusted odds ratios (95% confidence intervals) between extreme quintiles of intake for MGD prevalence were 0.40 (0.16-0.97) for total fat, 0.40 (0.17-0.97) for saturated FAs, 0.40 (0.17-0.97) for oleic acid, 0.52 (0.23-1.18) for n-3 PUFAs, 0.63 (0.27-1.49) for n-6 PUFAs, 1.32 (0.59-2.95) for the n-6/n-3 PUFA ratio, and 0.38 (0.17-0.87) for vitamin D. Total fat, saturated FA, oleic acid, and vitamin D intake may thus be negatively associated with MGD prevalence in the Japanese.

Location and extent of subconjunctival hemorrhage.

PURPOSE: Subconjunctival hemorrhage (SCH) is a relatively frequent disease; however, there have been no reports about its location and extent. We examined its location and extent. METHODS: A total of 151 patients with SCH aged 2-94 years were studied. The conjunctiva was divided into 8 equal areas. The age, gender, medical history, ocular history and site of hemorrhage were determined for all subjects. RESULTS: The number of areas involved by SCH showed an age-related increase. Traumatic SCH had a smaller extent compared with SCH related to hypertension, diabetes and hyperlipidemia, or idiopathic SCH. Overall, SCH was significantly more common in the inferior areas than the superior areas (55.3% vs. 25.0%, p < 0.000001). In patients with SCH secondary to trauma or diabetes, however, the temporal areas were affected more often than the nasal areas (61.5% vs. 30.8% and 73.3% vs. 20.0%, respectively). CONCLUSION: SCH showed an age-related increase in extent and was predominant in the inferior areas. However, traumatic SCH was usually detected as localized hemorrhage in the temporal areas.

Non-pharmaceutical treatment options for meibomian gland dysfunction.

This review examines currently available non-pharmaceutical treatment modalities for meibomian gland dysfunction. A detailed search of the PubMed and MEDLINE databases was performed to identify original articles in English that have evaluated such nonpharmaceutical therapies in patients with this condition. Conventional therapies such as application of a warming compress, the practice of lid hygiene, and manual expression of meibomian glands as well as more technologically advanced approaches such as intraductal probing, thermal pulsation, and intense pulsed light therapy are included in the review. These non-pharmaceutical treatment options may each have a role to play in the management of meibomian gland dysfunction, but more studies are necessary to compare treatments directly under identical experimental conditions in order to determine their relative efficacy. Additional large-scale, randomised, controlled trials are also required to provide more information such as the specific indications best suited to each treatment modality, the efficacy of such approaches in combination with pharmaceutical-based therapy, and the mechanisms of action of some of the more technologically advanced systems.

Proposed Algorithm for Management of Meibomian Gland Dysfunction Based on Noninvasive Meibography.

Although the pathophysiology of meibomian gland dysfunction (MGD) remains incompletely understood, many treatment options have recently become available. According to an international workshop report, treatment selection for MGD should be based on a comprehensive stage classification dependent on ocular symptoms, lid margin abnormalities, meibum grade, and ocular surface staining. However, it is often difficult to evaluate all parameters required for such classification in routine clinical practice. We have now retrospectively evaluated therapeutic efficacy in MGD patients who received five types of treatment in the clinic setting: (1) meibocare (application of a warm compress and practice of lid hygiene), (2) meibum expression plus meibocare, (3) azithromycin eyedrops plus meibocare, (4) thermal pulsation therapy plus meibocare, or (5) intense pulsed light (IPL) therapy plus meibocare. Patients in each treatment group were classified into three subsets according to the meiboscore determined by noncontact meibography at baseline. Eyes in the IPL group showed improvement even if the meiboscore was high (5 or 6), whereas meibocare tended to be effective only if the meiboscore was low (1 or 2). The meiboscore may thus serve to guide selection of the most appropriate treatment in MGD patients. Prospective studies are warranted to confirm these outcomes.

Multicenter Study of Intense Pulsed Light for Patients with Refractory Aqueous-Deficient Dry Eye Accompanied by Mild Meibomian Gland Dysfunction.

Aqueous-deficient dry eye (ADDE) and meibomian gland dysfunction (MGD) can be refractory to therapy. Intense pulsed light (IPL) was recently introduced as an effective treatment for MGD. We here evaluated the efficacy of IPL combined with MG expression (MGX) compared with MGX alone (n = 23 and 20, respectively) for patients with refractory ADDE with mild MGD at three sites. Symptom score, visual acuity (VA), noninvasive breakup time (NIBUT) and lipid layer thickness (LLT) of the tear film, lid margin abnormalities, fluorescein BUT (FBUT), fluorescein staining, tear meniscus height (TMH), meibum grade, meiboscore, and Schirmer's test value were assessed at baseline and 1 and 3 months after treatment. LLT, plugging, vascularity, FBUT and NIBUT were improved only in the IPL-MGX group at three months compared with baseline. All parameters with the exception of VA, meiboscore, TMH, Schirmer's test value were also improved in the IPL-MGX group compared with the control group at three months, as was VA in patients with central corneal epitheliopathy. Although IPL-MGX does not affect aqueous layer, the induced improvement in quality and quantity of the lipid layer may increase tear film stability and ameliorate symptoms not only for evaporative dry eye but for ADDE.

Subconjunctival hemorrhage and conjunctivochalasis.

OBJECTIVE: Subconjunctival hemorrhage (SCH) is a relatively common disease, but there have been no reports concerning the relationship between SCH and conjunctivochalasis (CCh). We compared the grade of CCh between patients with SCH and control patients. DESIGN: Prospective, nonrandomized study. PARTICIPANTS: A total of 104 patients with SCH aged 41 to 94 years and 120 age- and gender-matched controls aged 41 to 94 years were enrolled. METHODS: The conjunctiva was divided into the following 8 equal areas: superior, superior/nasal, nasal, inferior/nasal, inferior, inferior/temporal, temporal, and superior/temporal. The age, gender, medical history, ocular history, site of hemorrhage, grade of CCh at 3 locations (nasal, middle, and temporal), and other parameters of CCh were determined in all subjects. MAIN OUTCOME MEASURES: Grade of each CCh parameter and location of SCH. RESULTS: The mean grade of CCh was higher in patients with SCH than in control patients at the nasal (P<0.00001), middle (P<0.00001), and temporal areas (P<0.00001). The downward gaze- or digital pressure-dependent changes of CCh and the frequency of superficial punctate keratitis were all increased in SCH patients compared with control patients (P<0.00001, P<0.00001, and P = 0.00106, respectively). The number of areas involved by SCH and the presence of SCH in each area were positively correlated with the grade of each CCh-related parameter (P<0.05). CONCLUSIONS: This was the first assessment of the grade of CCh in a large series of consecutive patients with SCH. Our results strongly suggest that CCh may have an important role in the pathogenesis of SCH.

Proposed diagnostic criteria for obstructive meibomian gland dysfunction.

PURPOSE: To compare clinical findings between patients with obstructive meibomian gland dysfunction (MGD) and normal controls and to propose diagnostic criteria for obstructive MGD. DESIGN: Cross-sectional, observational case series. PARTICIPANTS: Fifty-three eyes of 53 patients (18 men, 35 women; age [mean +/- standard deviation] 71.4 +/- 10.0 years) who were diagnosed with obstructive MGD and 60 eyes of 60 healthy volunteers (22 men, 38 women; 71.0 +/- 9.3 years) as a control group. METHODS: Ocular symptoms were scored from 0 to 14 according to the number of existing symptoms. Lid margin abnormality was scored from 0 to 4 depending on the number of existing abnormalities. Meibomian gland changes were scored from 0 to 6 based on noncontact meibography (meibo-score). Superficial punctuate keratopathy (SPK) was scored from 0 to 3. Meibum was graded from 0 to 3 depending on the volume and quality. Tear film production was evaluated by Schirmer's test. Receiver operating characteristic curves with calculations of area under the curve (AUC) were used to describe the accuracy of each parameter to differentiate obstructive MGD from normal eyes. MAIN OUTCOME MEASURES: Ocular symptom score, lid margin abnormality score, meibo-score, meibum score, SPK score, tear film breakup time (BUT), and the Schirmer value. RESULTS: Ocular symptom score, lid margin abnormality score, meibo-score, meibum score, and SPK score were significantly higher in the obstructive MGD group than in the control group (P<0.0001 for all scores). The BUT was significantly shorter in the obstructive MGD group than in the control group (P<0.0001). The AUC values indicated that the ocular symptom score had the highest diagnostic power as a single parameter, followed by the lid margin abnormality score, meibo-score, and BUT. CONCLUSIONS: Based on these findings, we recommend that physicians use the ocular symptom score, lid margin abnormality score, and meibo-score to diagnose MGD. Obstructive MGD should be suspected when any 2 of the 3 scores are abnormal. Obstructive MGD is very likely when all 3 scores are abnormal.

Severe hyperopic shift and irregular astigmatism after radial keratotomy.

OBJECTIVES: To report a case of acute high hyperopia occurring after radial keratotomy and evaluate the extent of corneal wavefront aberration with a Hartmann-Shack aberrometer. METHODS: A 45-year-old man had undergone bilateral radial keratotomy with four incisions for myopia 15 years earlier. The patient developed significant hyperopia and irregular corneal astigmatism in the left eye after the operation, reducing his best-corrected visual acuity. RESULTS: The best-corrected visual acuity was 20/20 (with refraction of +0.25-1.50 diopters [D] x 169) in the right eye and 10/20 (with refraction of +9.5D-3.00D x 50) in the left eye. Topography showed marked flattening of the left cornea, and simulated retinal images of Landolt C circles were distorted in the left eye. CONCLUSIONS: This is a rare case in which radial keratotomy induced severe hyperopic shift. Wavefront analysis with a Hartmann-Shack aberrometer revealed severe irregular astigmatism with small clear zones.

Tear film lipid layer increase after diquafosol instillation in dry eye patients with meibomian gland dysfunction: a randomized clinical study.

Diquafosol promotes secretion of tear fluid and mucin at the ocular surface and is administered for treatment of dry eye (DE). Tear film lipid layer is secreted from meibomian glands and stabilizes the tear film. We recently showed that diquafosol administration increased lipid layer thickness (LLT) for up to 60 min in normal human eyes. We here evaluated tear film lipid layer in DE patients (n = 47) with meibomian gland dysfunction (MGD) before as well as 30, 60, and 90 min after diquafosol administration. One drop of artificial tears or one drop of diquafosol was applied randomly to the eyes of each patient. Diquafosol significantly increased LLT at 30 (P < 0.001) and 60 (P = 0.042) min and noninvasive tear film breakup time for at least 90 min (P < 0.001 at each assessment point). Artificial tears had no such effect. Diquafosol significantly improved the tear interferometric pattern compared with artificial tears (P < 0.001 at each assessment point). A single topical administration of diquafosol thus improved LLT and tear film stability in DE patients with MGD, suggesting that diquafosol is a potential treatment not only for aqueous-deficient DE but also for evaporative DE associated with MGD.