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Survey of Ophthalmology 2022The human tear film is at the interface between the ocular surface and the external environment. Although investigation has been hindered by its small volume,... (Review)
Review
The human tear film is at the interface between the ocular surface and the external environment. Although investigation has been hindered by its small volume, improvements in preanalytical and analytical methods have allowed the omics approach to represent an innovative biomarker search strategy. There is still a significant lack of standardization, representing a barrier for performing between-studies comparisons and transferring experimental findings into clinical use and trials. We summarize the preanalytical and analytical procedures, describe the biomarkers that can be found using the metabo-lipidomics approach, and provide our expert opinion for omics investigations in human tears. For this systematic review of 38 studies, we searched PubMed by combining Boolean operators with the following keywords: tear, metabolomic, lipidomic, -omics. The human tear metabo-lipidome has been well-characterized in normal individuals using high-resolution liquid chromatography coupled with mass spectrometry. Lipid and metabolite profiles were influenced by ocular (e.g., dry eye disorders; Meibomian gland dysfunction; contact lens wear; glaucoma; keratoconus; pterygium) and systemic conditions (e.g., multiple sclerosis). Investigating the tear metabo-lipidome could improve our understanding of the pathogenesis of both ocular and systemic diseases, but also provide diagnostic as well as prognostic biomarkers.
Topics: Biomarkers; Dry Eye Syndromes; Humans; Lipidomics; Meibomian Glands; Metabolomics; Tears
PubMed: 35093405
DOI: 10.1016/j.survophthal.2022.01.010 -
JAMA Ophthalmology Dec 2022Dry eye is a common clinical manifestation, a leading cause of eye clinic visits, and a significant societal and personal economic burden in the United States. Meibomian... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Dry eye is a common clinical manifestation, a leading cause of eye clinic visits, and a significant societal and personal economic burden in the United States. Meibomian gland dysfunction (MGD) is a major cause of evaporative dry eye.
OBJECTIVE
To conduct a systematic review and meta-analysis to obtain updated estimates of the prevalence and incidence of dry eye and MGD in the United States.
DATA SOURCES
Ovid MEDLINE and Embase.
STUDY SELECTION
A search conducted on August 16, 2021, identified studies published between January 1, 2010, and August 16, 2021, with no restrictions regarding participant age or language of publication. Case reports, case series, case-control studies, and interventional studies were excluded.
DATA EXTRACTION AND SYNTHESIS
The conduct of review followed a protocol registered on PROSPERO (CRD42021256934). PRISMA guidelines were followed for reporting. Joanna Briggs Institute and Newcastle Ottawa Scale tools were used to assess risk of bias. Data extraction was conducted by 1 reviewer and verified by another for accuracy. Prevalence of dry eye and MGD were combined in separate meta-analyses using random-effects models.
MAIN OUTCOMES AND MEASURES
Prevalence and incidence of dry eye and MGD in the United States. Summary estimates from meta-analysis of dry eye and MGD prevalence with 95% CI and 95% prediction intervals (95% PI).
RESULTS
Thirteen studies were included in the systematic review. Dry eye prevalence was reported by 10 studies, dry eye incidence by 2 studies, and MGD prevalence by 3 studies. Meta-analysis estimated a dry eye prevalence of 8.1% (95% CI, 4.9%-13.1%; 95% PI, 0%-98.9%; 3 studies; 9 808 758 participants) and MGD prevalence of 21.2% (95% CI, 7.2%-48.3%; 95% PI, 0%-100%; 3 studies; 19 648 participants). Dry eye incidence was 3.5% in a population 18 years and older and 7.8% in a population aged 68 years and older. No studies reported MGD incidence.
CONCLUSIONS AND RELEVANCE
This systematic review and meta-analysis demonstrated uncertainty about the prevalence and incidence of dry eye and MGD in the United States. Population-based epidemiological studies that use consistent and validated definitions of dry eye and MGD are needed for higher-certainty estimates of dry eye and MGD prevalence and incidence in the United States.
Topics: Humans; Meibomian Gland Dysfunction; Incidence; Prevalence; Dry Eye Syndromes; Case-Control Studies; Meibomian Glands
PubMed: 36301551
DOI: 10.1001/jamaophthalmol.2022.4394 -
The Ocular Surface Apr 2023Many factors in the domains of mental, physical, and social health have been associated with various ocular surface diseases, with most of the focus centered on aspects... (Meta-Analysis)
Meta-Analysis
Many factors in the domains of mental, physical, and social health have been associated with various ocular surface diseases, with most of the focus centered on aspects of dry eye disease (DED). Regarding mental health factors, several cross-sectional studies have noted associations between depression and anxiety, and medications used to treat these disorders, and DED symptoms. Sleep disorders (both involving quality and quantity of sleep) have also been associated with DED symptoms. Under the domain of physical health, several factors have been linked to meibomian gland abnormalities, including obesity and face mask wear. Cross-sectional studies have also linked chronic pain conditions, specifically migraine, chronic pain syndrome and fibromyalgia, to DED, principally focusing on DED symptoms. A systematic review and meta-analysis reviewed available data and concluded that various chronic pain conditions increased the risk of DED (variably defined), with odds ratios ranging from 1.60 to 2.16. However, heterogeneity was noted, highlighting the need for additional studies examining the impact of chronic pain on DED signs and subtype (evaporative versus aqueous deficient). With respect to societal factors, tobacco use has been most closely linked to tear instability, cocaine to decreased corneal sensitivity, and alcohol to tear film disturbances and DED symptoms.
Topics: Humans; Chronic Pain; Cross-Sectional Studies; Dry Eye Syndromes; Life Style; Tears; Meibomian Glands
PubMed: 37054911
DOI: 10.1016/j.jtos.2023.04.008 -
Optometry and Vision Science : Official... Mar 2023This study aimed to use meta-analysis to estimate the association between dyslipidemia and meibomian gland dysfunction. (Meta-Analysis)
Meta-Analysis
PURPOSE
This study aimed to use meta-analysis to estimate the association between dyslipidemia and meibomian gland dysfunction.
METHODS
The following databases were searched: PubMed, Google Scholar, and Scopus. Case-control and cohort studies assessing the association between dyslipidemia and meibomian gland dysfunction were included. The association was assessed using odds ratios. Heterogeneity between studies was assessed with the χ2 statistic and degree of inconsistency. The quality of studies was assessed using the Newcastle-Ottawa Scale. The systematic review was registered on PROSPERO (ID: CRD42022347982).
RESULTS
The systematic review included three case-control and two cohort studies. The odds of hypercholesterolemia and hypertriglyceridemia in meibomian gland dysfunction were 5.45 (95% confidence interval [CI], 1.65 to 17.95) and 3.28 (95% CI, 1.25 to 8.62), respectively. The odds of elevated serum low-density lipoprotein and reduced high-density lipoprotein in meibomian gland dysfunction were 2.72 (95% CI, 1.24 to 5.98) and 1.15 (95% CI, 0.74 to 1.79), respectively. The current study's limitation is that the effects of sex, age, and meibomian gland dysfunction severity on the association between dyslipidemia and meibomian gland dysfunction were not assessed.
CONCLUSIONS
The current study suggests a significant association between dyslipidemia and meibomian gland dysfunction. This finding suggests that meibomian gland dysfunction diagnosis may call for dyslipidemia screening.
Topics: Humans; Meibomian Gland Dysfunction; Meibomian Glands; Eyelid Diseases; Dyslipidemias; Cohort Studies; Tears
PubMed: 36722777
DOI: 10.1097/OPX.0000000000001994 -
The Cochrane Database of Systematic... May 2016Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids which can affect children and adults. BKC involves changes of the... (Review)
Review
BACKGROUND
Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids which can affect children and adults. BKC involves changes of the eyelids, dysfunction of the meibomian glands, and inflammation of the conjunctiva and cornea. Chronic inflammation of the cornea can lead to scarring, vascularisation and opacity. BKC in children can cause significant symptoms which include irritation, watering, photophobia and loss of vision. Loss of vision in children with BKC may be due to corneal opacity, refractive error or amblyopia.BKC treatment is directed towards the obstruction of meibomian gland openings, the bacterial flora of lid margin and conjunctiva, and ocular surface inflammation. Dietary modifications that involve increased intake in essential fatty acids (EFAs) may also be beneficial. Both topical and systemic treatments are used; this Cochrane review focuses on systemic treatments.
OBJECTIVES
To assess and compare data on the efficacy and safety of systemic treatments (including antibiotics, nutritional supplements and immunosuppressants), alone or in combination, for BKC in children aged between zero to 16 years.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2016), EMBASE (January 1980 to April 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 April 2016.
SELECTION CRITERIA
We searched for randomised controlled trials that involved systemic treatments in children aged between zero to 16 years with a clinical diagnosis of BKC. We planned to include studies that evaluated a single systemic medication versus placebo, and studies that compared two or multiple active treatments. We planned to include studies in which participants receive additional treatments, such as topical antibiotics, anti-inflammatories and lubricants, warm lid compresses and lid margin cleaning.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the literature search results (titles and abstracts) to identify studies that possibly met the inclusion criteria of the review. We divided studies into 'definitely include', 'definitely exclude' and 'possibly include' categories. We made a final judgement as to the inclusion or exclusion of studies in the 'possibly include' category after we obtained the full text of each article.
MAIN RESULTS
No report or trial met the inclusion criteria of this Cochrane review; no randomised controlled trials have been carried out on this topic. There is a lack of standardised outcome measures.
AUTHORS' CONCLUSIONS
There is currently no evidence from clinical trials regarding the safety and efficacy of systemic treatments for BKC. Trials are required to test efficacy and safety of current and future treatments. Outcome measures need to be developed which can capture both objective clinical and patient-reported aspects of the condition and treatments.
Topics: Adolescent; Blepharitis; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Keratoconjunctivitis
PubMed: 27236587
DOI: 10.1002/14651858.CD011750.pub2 -
Eye (London, England) Oct 2020To systematically review studies of managing meibomian gland dysfunction (MGD) with azithromycin and pool clinical outcomes to show its effectiveness. Eligible studies... (Meta-Analysis)
Meta-Analysis Review
To systematically review studies of managing meibomian gland dysfunction (MGD) with azithromycin and pool clinical outcomes to show its effectiveness. Eligible studies were retrieved from five main electronic databases. Symptom score was the primary outcome, while clinical signs and objective measurements were secondary outcomes. Pooled rates for adverse events were also calculated. Improvements in each outcome after administering either oral azithromycin (OA) or topical azithromycin (TA) were pooled and measured by standard mean difference (SMD) to show the overall effectiveness. Then the effectiveness was sub-grouped by TA and OA. In addition, pooled outcomes after administering TA and oral doxycycline (OD) were compared with assess their effectiveness. Finally, 18 eligible studies were included. The overall pooled symptom scores were significantly reduced after administering both TA and OA [P < 0.0001; SMD = 1.54 (95% CI: 1.15-1.92)]. Similarly, the overall combined eyelid signs, plugging of the meibomian gland, meibum quality, and tear secretion were also distinctly improved. However, significant improvements for tear break-up time (TBUT) and corneal staining (CS) were achieved by TA (TBUT: P = 0.02; CS: P = 0.02) but not by OA (TBUT: P = 0.08; CS: P = 0.14). The pooled adverse event rates for TA and OA were 25% and 7%, respectively. Moreover, TA was comparable to OD to treat MGD regarding symptom score, TBUT and tear secretion. This study showed that MGD could be treated effectively with oral or topical azithromycin by improving symptoms, clinical signs, and stabilization of tear film. Topical azithromycin seemed to be superior over oral azithromycin or doxycycline in improving the quality of tear film in the short term.
Topics: Azithromycin; Eyelid Diseases; Humans; Meibomian Gland Dysfunction; Meibomian Glands; Tears
PubMed: 32346111
DOI: 10.1038/s41433-020-0876-2 -
The Cochrane Database of Systematic... Feb 2017Hordeolum is an acute, purulent inflammation of the eyelid margin usually caused by obstructed orifices of the sebaceous glands of the eyelid. The condition, which... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hordeolum is an acute, purulent inflammation of the eyelid margin usually caused by obstructed orifices of the sebaceous glands of the eyelid. The condition, which affects sebaceous glands internally or externally, is common. When the meibomian gland in the tarsal plate is affected, internal hordeolum occurs, while when the glands of Zeis or Moll associated with eyelash follicles are affected, external hordeolum, or stye occurs. The onset of hordeolum is usually self limited, and may resolve in about a week with spontaneous drainage of the abscess. When the condition is severe, it can spread to adjacent glands and tissues. Recurrences are very common. As long as an internal hordeolum remains unresolved, it can develop into a chalazion or generalized eyelid cellulitis. Acupuncture is a traditional Chinese medical therapy aimed to treat disease by using fine needles to stimulate specific points on the body. However, it is unclear if acupuncture is an effective and safe treatment for acute hordeolum.
OBJECTIVES
The objective of this review was to investigate the effectiveness and safety of acupuncture to treat acute hordeolum compared with no treatment, sham acupuncture, or other active treatment. We also compared the effectiveness and safety of acupuncture plus another treatment with that treatment alone.
SEARCH METHODS
We searched CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, Embase, PubMed, Latin American and Caribbean Health Sciences Literature Database (LILACS), three major Chinese databases, as well as clinical trial registers all through 7 June 2016. We reviewed the reference lists from potentially eligible studies to identify additional randomised clinical trials (RCTs).
SELECTION CRITERIA
We included RCTs of people diagnosed with acute internal or external hordeola. We included RCTs comparing acupuncture with sham acupuncture or no treatment, other active treatments, or comparing acupuncture plus another treatment versus another treatment alone.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures used by Cochrane.
MAIN RESULTS
We included 6 RCTs with a total of 531 participants from China. The mean age of the participants ranged from 18 to 28 years. Four RCTs included participants diagnosed with initial acute hordeolum with a duration of less than seven days; one RCT included participants diagnosed with initial acute hordeolum without specifying the duration; and one RCT included participants with recurrent acute hordeolum with a mean duration of 24 days. About 55% (291/531) of participants were women. Three RCTs included participants with either external or internal hordeolum; one RCT included participants with only external hordeolum; and two RCTs did not specify the type of hordeolum. Follow-up was no more than seven days after treatment in all included RCTs; no data were available for long-term outcomes. Overall, the certainty of the evidence for all outcomes was low to very low, and we judged all RCTs to be at high or unclear risk of bias.Three RCTs compared acupuncture with conventional treatments. We did not pool the data from these RCTs because the conventional treatments were not similar among trials. Two trials showed that resolution of acute hordeolum was more likely in the acupuncture group when compared with topical antibiotics (1 RCT; 32 participants; risk ratio (RR) 3.60; 95% confidence interval (CI) 1.34 to 9.70; low-certainty of evidence) or oral antibiotics plus warm compresses (1 RCT; 120 participants; RR 1.45; 95% CI 1.18 to 1.78; low-certainty of evidence). In the third trial, little or no difference in resolution of hordeolum was observed when acupuncture was compared with topical antibiotics plus warm compresses (1 RCT; 109 participants; RR 1.00; 95% CI 0.96 to 1.04; low-certainty of evidence). One RCT mentioned adverse outcomes, stating that there was no adverse event associated with acupuncture.Three RCTs compared acupuncture plus conventional treatments (two RCTs used topical antibiotics and warm compresses, one RCT used topical antibiotics only) versus the conventional treatments alone. One of the three RCTs, with very low-certainty evidence, did not report the resolution of acute hordeolum; however, it reported that acute hordeolum relief might be higher when acupuncture was combined with conventional treatments than with conventional treatments alone group (60 participants; RR 1.80; 95% CI 1.00 to 3.23). Pooled analysis of the remaining two RCTs, with low-certainty evidence, estimated resolution of acute hordeolum was slightly higher in the combined treatment group compared with the conventional treatment alone group at 7-day follow-up (210 participants; RR 1.12; 95% CI 1.03 to 1.23; I = 0%). None of the three RCTs reported adverse outcomes. Among the included RCTs, four participants, two from the acupuncture plus conventional treatments group and two from the conventional treatments alone group, withdrew due to exacerbation of symptoms.
AUTHORS' CONCLUSIONS
Low-certainty evidence suggests that acupuncture with or without conventional treatments may provide short-term benefits for treating acute hordeolum when compared with conventional treatments alone. The certainty of the evidence was low to very low mainly due to small sample sizes, inadequate allocation concealment, lack of masking of the outcome assessors, inadequate or unclear randomization method, and a high or unreported number of dropouts. All RCTs were conducted in China, which may limit their generalizability to non-Chinese populations.Because no RCTs included a valid sham acupuncture control, we cannot rule out a potential expectation/placebo effect associated with acupuncture. As resolution is based on clinical observation, the outcome could be influenced by the observer's knowledge of the assigned treatment. Adverse effects of acupuncture were reported sparsely in the included RCTs, and, when reported, were rare. RCTs with better methodology, longer follow-up, and which are conducted among other populations are warranted to provide more general evidence regarding the benefit of acupuncture to treat acute hordeolum.
Topics: Acupuncture Therapy; Acute Disease; Adult; Anti-Bacterial Agents; Female; Hordeolum; Humans; Hyperthermia, Induced; Male; Randomized Controlled Trials as Topic; Recurrence; Young Adult
PubMed: 28181687
DOI: 10.1002/14651858.CD011075.pub2 -
Graefe's Archive For Clinical and... Jan 2021Intense pulsed light therapy (IPL) is a new method being used to treat meibomian gland dysfunction (MGD) globally. With an increasing number of studies being published,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intense pulsed light therapy (IPL) is a new method being used to treat meibomian gland dysfunction (MGD) globally. With an increasing number of studies being published, it is necessary to consider additional factors related to treatment. This review aims to investigate the efficacy and safety of IPL for the treatment of MGD.
METHODS
The PubMed, EMBASE, Web of Science, Cochrane Library, Google Scholar, China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and SinoMed databases were searched through February 24, 2020. Randomized clinical trials and cohort studies comparing IPL+ meibomian gland expression (MGX) or IPL alone with control groups were included. The weighted mean difference (WMD) was calculated to analyze the Ocular Surface Disease Index (OSDI) score and Standard Patient Evaluation of Eye Dryness (SPEED) score, and the standard mean difference (SMD) was calculated to analyze the tear breakup time (TBUT). Heterogeneity was quantified by the I statistic ranging from 0 to 100%, and a random effects model was used in this meta-analysis. All analyses were performed by RevMan 5.3. All p values were calculated by the t test, and p values were regarded as statistically significant at p < 0.05. The Cochrane Collaboration's tool for assessing risk of bias was used to identify and evaluate bias in the literature.
RESULTS
Nine studies with a total of 539 patients were included. Eight studies examined TBUT, six examined OSDI scores, and four examined SPEED scores. IPL combined with MGX showed superiority regarding the TBUT (SMD 2.33, 95% CI 1.04-3.61), and OSDI scores (WMD 11.93, 95% CI - 17.10 to - 6.77), with high heterogeneity. The SPEED scores were not significantly different.
CONCLUSIONS
IPL combined with MGX may be an effective and safe treatment for MGD, but it cannot improve all symptoms. IPL alone is not superior to MGX. The efficacy is also affected by the number and average frequency of treatments. The efficacy of IPL may decrease within 6 months after the last treatment, so it should be considered a long-term adjuvant therapy combined with MGX. When patients receive 3 or 4 treatments (once every 3-4 weeks), a return visit at 6 months after the last treatment is required.
Topics: Dry Eye Syndromes; Humans; Intense Pulsed Light Therapy; Meibomian Gland Dysfunction; Meibomian Glands; Tears
PubMed: 32725403
DOI: 10.1007/s00417-020-04834-1 -
International Ophthalmology Aug 2018To perform a systematic review of the literature examining the association between meibomian gland dysfunction (MGD) and dyslipidemia. (Review)
Review
PURPOSE
To perform a systematic review of the literature examining the association between meibomian gland dysfunction (MGD) and dyslipidemia.
METHODS
A systematic literature search was performed using the Medline database. A total of four studies directly relevant to our search are reviewed here.
RESULTS
In a series of four studies, all but one found that the prevalence of dyslipidemia was significantly higher in those with MGD compared to those without. Factors such as age, total cholesterol, LDL, HDL, and triglycerides demonstrated a significant association whereas sex, BMI, serum creatinine, and serum glucose did not. Various subsets within the MGD group, such as males between the ages of 24-64, were found to have higher total cholesterol levels compared to controls, highlighting the association of dyslipidemia with sex and age.
CONCLUSION
While each study carried its own limitations preventing a causal relationship from being established, it is evident that a strong positive correlation exists between dyslipidemia and MGD. As such, eye care practitioners, through the detection of MGD, may be identifying patients with dyslipidemia who were previously believed to have normal serum lipid profiles. This may imply that eye care providers have a role in detecting a well-known risk factor for cardiovascular disease. Additionally, if prospective studies can demonstrate a temporal relationship with MGD preceding dyslipidemia, clinicians could consider lipid-lowering agents as management for both conditions.
Topics: Dyslipidemias; Eyelid Diseases; Humans; Meibomian Glands; Prevalence
PubMed: 28688025
DOI: 10.1007/s10792-017-0633-0 -
Graefe's Archive For Clinical and... Jan 2022To investigate the efficacy and safety of a vectored thermal pulsation system (Lipiflow®) in the treatment of dry eye disease resulting from meibomian gland dysfunction... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To investigate the efficacy and safety of a vectored thermal pulsation system (Lipiflow®) in the treatment of dry eye disease resulting from meibomian gland dysfunction (MGD).
METHODS
We searched for randomized clinical trials (RCTs) in Embase, MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, and ClinicalTrials.gov up to 4 January 2021. The subjective symptoms, objective tests of dry eye, meibomian gland function, and the incidence of adverse events were evaluated.
RESULTS
Ten qualified RCTs incorporating 761 patients were analyzed. In the comparison of Lipiflow® treatment and lid hygiene, the subgroup with inconsistent units of randomization and analysis showed that the Lipiflow® treatment brought slight improvement in corneal fluorescein staining (mean difference (MD), - 0.42; 95% CI, - 0.75 to - 0.1), significant improvements in ocular surface disease index (OSDI) score (MD, - 7.4; 95% CI, - 11.06 to - 3.74), Standard Patient Evaluation of Eye Dryness (SPEED) score (MD, - 2.7; 95% CI, - 3.95 to - 1.45), meibomian glands yielding liquid secretion (MGYLS) (MD, 1.3; 95% CI, 0.78 to 1.82), and meibomian glands yielding secretion score (MGYSS) (MD, 4.09; 95% CI, 1.18 to 6.99). Meanwhile, significant improvements were detected in OSDI score, SPEED score, MGYLS, and MGYSS with patients who received Lipiflow® treatment compared with those who received nontreatment. The adverse events were comparable in the two control groups.
CONCLUSIONS
Lipiflow® treatment can improve the subjective and objective outcomes of MGD and does not increase the incidence of adverse events. The improper choice of units of analysis may be the leading cause of heterogeneity, which should be noted in the design of future ophthalmology research. Additional well-designed, large-scale RCTs are required to reach a firmer conclusion.
Topics: Dry Eye Syndromes; Humans; Hyperthermia, Induced; Meibomian Gland Dysfunction; Meibomian Glands; Tears; Treatment Outcome
PubMed: 34374808
DOI: 10.1007/s00417-021-05363-1