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Purpose To determine the effects of prolonged cryopreservation at subzero-degree temperatures on corneal transparency and histology after treatment with preservation medium containing the phosphodiester glycerylphosphorylcholine (GPC). Methods Rabbit corneas (n = 30) were immersed for 3 hours in K-Sol preservation medium containing 30 mM GPC. Three groups with 6 corneas each were refrigerated at -8°C for 2 weeks and liquid nitrogen temperature for 2 and 6 weeks, respectively. Two groups with 6 corneas each immersed in K-Sol preservation medium only were refrigerated at -8°C for 2 weeks and liquid nitrogen temperature for 6 weeks, respectively. Postthawing corneal transparency was measured on a grading scale after which corneas were prepared for and analyzed by light and transmission electron microscopy. Results All 3 groups of corneas preserved with GPC maintained a greater degree of corneal transparency compared with corneas preserved without GPC. The number of corneas retaining epithelial and endothelial layers increased in all groups where corneas were preserved in medium containing GPC, in contrast to corneas preserved in medium without GPC. Cytoplasmic vacuolization or nuclear damage was greater in corneas preserved without GPC. Similar findings were found in corneas stored at -8°C and liquid nitrogen temperatures. Conclusions This study demonstrates a cryoprotective effect of corneas preserved in K-Sol containing the phosphodiester GPC at subzero-degree temperatures. In corneas immersed in preservation medium containing GPC, a higher degree of transparency is maintained and a lesser degree of histopathologic changes is observed with storage at both -8°C and in liquid nitrogen.

Protecting nurses in healthcare facilities from SARS-CoV-2 infection is essential for maintaining an adequate nursing force. Foundational guidelines, consistently utilized, protect the nursing staff from infection. This article describes guidelines designed to reduce acute infection and associated morbidity and mortality among nursing staff and improve compliance with infection prevention protocols.

Protection of nurses in healthcare facilities from SARS-CoV-2 infection is essential for maintaining an adequate nursing force. Foundational guidelines consistently utilized, will protect the nursing staff from infection. This article provides guidelines that, when followed by frontline nursing staff, can reasonably be expected to reduce acute infection, associated morbidity, and mortality.

This document establishes safety guidelines for physicians, nurses, and allied health care and facility staff who may be exposed to patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a health care facility. SARS-CoV-2 infection is highly contagious and places health care workers at risk for infection resulting in coronavirus disease (COVID-19). Physicians, nurses, and allied health care and facility staff in all frontline environments must be provided and utilize necessary personal protective equipment (PPE). It is important that health care staff adopt a universal set of guidelines in which to conduct themselves in order to minimize infection with the SARS-CoV-2 contagion. The establishment of these guidelines is necessary in this viral pandemic since such directives can create a standard of safety that is universally accepted. These guidelines establish a framework to provide consistency among health care facilities and staff from the time the staff member arrives at the health care facility until they return home. These guidelines provide a practical description of the minimum necessary protection for physicians, nurses, and allied health care and facility staff against SARS-CoV-2 infection.

Purpose The aim of this study was to compare the efficacy of two lipid-based lubricant eye drops in patients with lipid-deficient dry eye. Methods This Phase IV, multicenter, prospective, double-masked study enrolled adults (aged ≥18 years) who had a tear film breakup time (TFBUT) of ≤15 seconds(s), and unanesthetized Schirmer I test of ≥3 mm to ≤12 mm in at least one eye, at both screening and baseline visits. Eligible patients (n=231) were randomized (1:1) and received either Systane® Balance (SYSB; n=117) or Refresh® Optive Advanced (RFO-Ad, n=114), four-times a day, for 35 days. The primary endpoint was non-inferiority for change from baseline in TFBUT at Day 35 (non-inferiority was established if the lower limit of the 95% confidence interval (CI) for the difference between the treatment groups was > –1.0 s); secondary endpoints (test of superiority) were change in TFBUT and global ocular discomfort visual analog scale (VAS) score at Day 35. Other endpoints included the impact of dry eye on everyday life (IDEEL) treatment satisfaction scores (inconvenience and effectiveness) and safety. Results At Day 35, the mean change from baseline in TFBUT was 0.998 s in the SYSB and 0.868 s in the RFO-Ad groups with a treatment difference: 0.130 s; (95% CI −0.34, 0.60; P0.05 for treatment difference). Both treatments were well tolerated. Conclusion SYSB lubricant eye drops were non-inferior to RFO-Ad for improvement in TFBUT in patients with lipid-deficient dry eye. Both lubricant eye drops improved TFBUT and ocular discomfort scores in patients with lipid-deficient dry eye.

Purpose To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis. Design Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). Participants Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus. Methods Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression. Main Outcome Measures The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign. Results Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non–adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age. Conclusions A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non–adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome.

This study documents the absorption of glycerylphosphorylcholine (GPC) into corneas ex vivo. Corneas in quadruplicate were incubated in preservation medium containing 30 mM GPC, which is used as a reference marker. The GPC reference marker is used to calibrate 31P nuclear magnetic resonance (NMR) spectral chemical-shift positions for identification of phosphatic metabolites and to calculate intracorneal pH in intact tissues ex vivo. Following baseline NMR ex vivo analysis, corneas were stored in eye bank chambers in preservation medium containing 30 mM GPC at 4 °C overnight for 8 h. After returning to room temperature, NMR analysis was repeated on the same corneas in fresh GPC-free preservation medium. NMR analysis also was performed on the 30 mM GPC preservation medium alone from the eye bank chambers for detection of the GPC signal. The elevated GPC signal unexpectedly persisted in corneas incubated at 4 °C overnight even though GPC was not present in the fresh GPC-free preservation medium. In fact, the concentration of GPC in the intact cornea was many times higher than that found in the cornea endogenously. The levels of phosphatic metabolites and the energy modulus, after subtracting the spectral contribution of the 30 mM exogenous GPC, as well as the intracorneal pH remained unchanged from pre-refrigeration analyses. Corneas also retained transparency through the time-course of this study irrespective of temperature or change in temperature. The GPC signal in the NMR analysis of the preservation medium from the eye bank chambers was nearly undetectable. GPC was unexpectedly absorbed into the corneal tissue without detectable metabolic or physical toxicity. The intracorneal uptake of GPC at reduced temperatures parallels the increase in GPC that occurs naturally in muscle tissue in animals during wintering periods and the very high concentration of GPC in sperm, a cryogenically compatible cell, suggestive of a potential role for GPC in cryopreservation.

We report results from a multicenter, randomized clinical trial (N=535) of the effect of ω-3 supplementation, relative to placebo, on exploratory and minimally invasive outcome measures for moderate to severe dry eye disease.

Purpose The present study examined the long-term (3 years) effects of a single (12 min) thermal pulsation system (TPS) treatment on symptomatic patients with evaporative dry eye disease (DED) secondary to meibomian gland dysfunction (MGD). Methods In this prospective, cohort, observational, single-center study design, signs (meibomian gland secretion [MGS] scores and tear film breakup time [TBUT]) and symptoms (Ocular Surface Disease Index [OSDI] and Standard Patient Evaluation of Eye Dryness [SPEED] questionnaires) were determined in 20 patients (40 eyes) with MGD and dry eye symptoms at baseline (BL), 1 month, and 3 years post-TPS treatment using LipiFlow. Results Meibomian gland secretion scores increased from BL (4.5±0.8) to 1 month (12.0±1.1, P≤0.001). Improvement persisted at 3 years (18.4±1.4) relative to BL (P≤0.001). Meibomian gland secretion scores in all regions of the lower eyelid were improved over BL at 1 month (nasal [P≤0.001], central [P≤0.001], temporal [P≤0.01]) and 3 years (nasal [P≤0.001], central [P≤0.001], temporal [P≤0.001]). TBUT increased from BL (4.1±0.4) to 1 month (7.9±1.4, P≤0.05) but was not significantly different than BL at 3 years (4.5±0.6, P>0.05). The OSDI scores decreased from BL (26.0±4.6) to 1 month (14.7±4.3, P≤0.001) but returned to BL levels at 3 years (22.5±5.4, P>0.05). The SPEED scores decreased from BL (13.4±1.0) to 1 month (6.5±1.3, P≤0.001), and this improvement persisted at 3 years (9.5±1.6, P≤0.001). Conclusions Thermal pulsation may be a uniquely efficacious treatment option for DED secondary to MGD in that a single 12-min procedure is associated with significant improvement in MGS and SPEED scores for up to 3 years.

The hypothesis proposed herein is presented to explain the unexpectedly high concentration of ATP and provide evidence to support its hydrotropic function in the crystalline lens determined using 31P NMR. The lens, historically considered to be a metabolically quiescent organ, has the requisite machinery to synthesize ATP, such that the homeostatic level is maintained at about 3 mM. This relatively high concentration of ATP has been found to be consistent among multiple mammalian species including humans. This millimolar quantity is many times greater than the micromolar amounts required for the other known functions of ATP. The recent postulation that ATP at millimolar concentrations functions as a hydrotrope in various cell/tissue homogenates preventing protein aggregation coupled with observations presented herein, provide support for extending the hypothesis that ATP functions as a hydrotrope not only in homogenates but in an intact functioning organ, the crystalline lens. Concentrations of ATP of this magnitude are hypothesized to be required to maintain protein solubility and effectively prevent protein aggregation. This concept is important considering protein aggregation is the etiology for age-related cataractogenesis. ATP is a common ubiquitous intracellular molecule possessing the requisite hydrotropic properties for maintaining intracellular proteins in a fluid, non-aggregated state. It is proposed that the amphiphilic ATP molecule shields the hydrophobic regions on intralenticular fiber cell protein molecules and provides a hydrophilic interfacial surface comprised of the ATP negatively charged triphosphate side chain. Evidence is presented that this side chain is exposed to and has been reported to organize intracellular interstitial water to form an interfacial rheologically dynamic water layer. Such organization of water is substantiated with the effect of deuterium oxide (heavy water) on ATP line widths of the side chain phosphates measured ex vivo by 31P NMR. A novel model is presented to propose how this water layer separates adjacent lens fiber cell proteins, keeping them from aggregating. This hypothesis proposes that ATP can prevent protein aggregation in normal intact lenses, and with declining concentrations can be related to the disease process in age-related cataractogenesis, an affliction that affects every older human being.

Purpose To determine the 1-year post-treatment dry eye status of subjects with meibomian gland dysfunction and dry eye symptoms after receiving a single LipiFlow Thermal Pulsation System treatment. Design Single-centre, prospective, observational, open-label, 1-month-registered clinical trial with a 1-year follow-up examination. Participants Patients with evaporative dry eye disease with meibomian gland dysfunction and dry eye symptoms who had participated in the registered 1-month clinical trial. Methods Eighteen of 30 subjects initially enrolled were able to return for a 1-year follow-up. Both eyes of all patients were treated with a single 12-min treatment using the LipiFlow Thermal Pulsation System. Meibomian gland function, tear break-up time and dry eye symptoms were measured. Data are presented for pretreatment (baseline), and 1-month and 1-year post-treatment. Main Outcome Measures Meibomian gland secretion scores, and tear break-up time and dry eye symptoms. Results Significant improvement in meibomian gland secretion scores from baseline measurements (4.0 ± 3.4) to 1-month post-treatment (11.3 ± 4.7; P

To evaluate the effect of a single treatment with the LipiFlow(®) Thermal Pulsation System on signs of meibomian gland dysfunction (MGD) and dry eye symptoms over a 9-month period.Patients (n = 42 eyes, 21 subjects) diagnosed with MGD and dry eye symptoms were recruited for a non-significant risk, prospective, open-label, 1-month clinical trial. Patients received a single 12-minute treatment using the LipiFlow(®) Thermal Pulsation System on each eye. The LipiFlow(®) device applies heat to the conjunctival surfaces of the upper and lower inner eyelids while simultaneously applying pulsatile pressure to the outer eyelid surfaces to express the meibomian glands. Patient symptoms were evaluated using the Ocular Surface Disease Index (OSDI) and Standard Patient Evaluation for Eye Dryness (SPEED) dry eye questionnaires; tear break-up time was measured with the dry eye test (DET™); and meibomian gland function was evaluated using a standardized diagnostic expression technique. Data are presented for patient's pre-treatment (baseline) and at 1-month and 9-month post-treatment.Meibomian gland secretion scores improved significantly from baseline (4.4 ± 4.0) to 1-month post-treatment (11.3 ± 6.2; p0.0001) and this improvement was maintained with no significant regression at 9 months (11.7 ± 5.9). Similarly, baseline tear break-up time (4.8 ± 3.2) was significantly increased at 1 month (9.6 ± 7.6; p0.001) and this increase was maintained with no significant regression at 9 months (7.1 ± 5.6). Symptom scores on both OSDI and SPEED questionnaires improved significantly at 1 month (p0.0001) and this improvement was maintained at 9 months.With such prolonged improvement in signs and symptoms of dry eye disease, the LipiFlow(®) Thermal Pulsation System offers a technological advancement for the treatment of dry eye disease secondary to meibomian gland dysfunction. A single 12-minute LipiFlow(®) treatment results in up to 9 months of sustained improvement of meibomian gland function, tear break-up time and dry eye symptoms that are unparalleled with current dry eye treatments.

The inner border of the eyelid margin is critically important for ocular surface integrity because it guarantees the thin spread of the tear film. Its exact morphology in the human is still insufficiently known. The histology in serial sections of upper and lower lid margins in whole-mount specimens from 10 human body donors was compared to in vivo confocal microscopy of eight eyes with a Heidelberg retina-tomograph (HRT II) and attached Rostock cornea module. Behind the posterior margin of the Meibomian orifices, the cornified epidermis stopped abruptly and was replaced by a continuous layer of para-keratinized (pk) cells followed by discontinuous pk cells. The pk cells covered the muco-cutaneous junction (MCJ), the surface of which corresponded to the line of Marx (0.2-0.3 mm wide). Then a stratified epithelium with a conjunctival structure of cuboidal cells, some pk cells, and goblet cells formed an epithelial elevation of typically about 100 μm initial thickness (lid wiper). This continued for 0.3-1.5 mm and formed a slope. The MCJ and lid wiper extended all along the lid margin from nasal to temporal positions in the upper and lower lids. Details of the epithelium and connective tissue were also detectable using the Rostock cornea module. The human inner lid border has distinct zones. Due to its location and morphology, the epithelial lip of the lid wiper appears a suitable structure to spread the tear film and is distinct from the MCJ/line of Marx. Better knowledge of the lid margin appears important for understanding dry eye disease and its morphology can be analysed clinically by in vivo confocal microscopy.

The cat, albeit an expensive animal to breed and maintain, affords a relatively large eye ideal for studies on the embryonic retina. This study reports on the efficacy of serial removal of feline foetuses for studies on the histogenesis of the retina. Single feline foetuses were serially removed from the uterus of pregnant cats to determine if there were histologic changes in the foetal retina of the remaining foetuses during subsequent development. The retinas of neonates from mothers that had undergone hysterotomies were compared by light and transmission electron microscopy to those from animals whose mother's had not had hysterotomies. No histologic differences in the retinas were detected between the 2 groups. The duration of gestation was unaffected. This study indicates that it is possible to obtain embryonic retinal tissue at more than one stage of development from the same pregnant female without inducing histologically observable anomalies.

Olopatadine 0.2% (Pataday, Alcon Laboratories Inc., Fort Worth, Texas, USA) and epinastine 0.05% (Elestat, Inspire Pharmaceuticals, Inc., Durham, NC, USA) are topical ocular anti-allergic agents. Both are H(1) antihistamine/mast cell stabilizers indicated for the treatment of ocular itching associated with allergic conjunctivitis.To compare the efficacy and comfort of olopatadine 0.2% with epinastine 0.05%, in the prevention of ocular itching associated with allergic conjunctivitis following conjunctival allergen challenge (CAC).This was a 7 week, four visit, double-masked, randomized, placebo-controlled CAC study. Visit 1 screened subjects for positive ocular allergic responses and Visit 2 confirmed those responses. At Visit 3, 92 subjects were randomized into one of four treatment groups to receive one drop of study medication in each eye: (1) olopatadine 0.2%/placebo, (2) epinastine 0.05%/placebo, (3) olopatadine 0.2%/epinastine 0.05%, (4) placebo/placebo. Subjects were challenged 12 h after drop instillation to evaluate duration of action. At Visit 4, subjects were challenged 5 min after drop instillation to evaluate onset of action. Drop comfort was assessed at Visit 4. MAIN OUTCOME MEASURES;This article focuses on the results of the onset-of-action challenge (Visit 4). At Visit 4, ocular itching was assessed at 3, 5, and 7 min and redness was assessed at 7, 15, and 20 min post-challenge. Drop comfort was assessed upon instillation, at 30s, and at 1, 2, and 5 min post-instillation. Olopatadine 0.2%-treated eyes exhibited significantly lower mean ocular itching scores versus epinastine 0.05%-treated eyes at 5 (p = 0.024) and 7 min (p = 0.003) post-challenge. Olopatadine 0.2%-treated eyes exhibited significantly lower mean redness scores versus epinastine 0.05%-treated eyes at all time points post-challenge (ciliary: por = 0.013, conjunctival: por = 0.015, episcleral: por = 0.006). Olopatadine 0.2% was rated as significantly more comfortable than epinastine 0.05% at 1 min post-drop instillation (p = 0.003). All adverse events were non-serious and unrelated to study medication. Although the CAC model reproduces allergic responses that are not environmentally-induced, patients experience varying severities of responses as are seen in real-world situations.Olopatadine 0.2% was superior to epinastine 0.05% in preventing ocular itching and redness at onset when induced by the CAC model.

Objectives. The lid wiper is defined as that portion of the marginal conjunctiva of the upper eyelid that wipes the ocular surface during blinking. The purpose of this study was to investigate whether lid wiper epitheliopathy occurred with patients who reported dry eye symptoms, yet had normal fluorescein breakup time (FBUT) and Schirmer test values and an absence of fluorescein corneal staining. Methods. One hundred patients were divided into two groups based on the presence or absence of dry eye symptoms, as determined with the Standard Patient Evaluation of Eye Dryness questionnaire. Other criteria for admission to both groups were FBUT of 10 seconds or more, Schirmer test value of 10 mm or more, and absence of fluorescein corneal staining. After instillation of fluorescein and rose bengal dyes, the lid wipers of 50 asymptomatic and 50 symptomatic patients were graded for staining from grade 0 (absent) to grade 3 (severe). Results. Of the symptomatic patients, 76% had staining of the lid wiper: 44%, grade 1; 22%, grade 2; and 10%, grade 3. Of the asymptomatic patients, 12% had staining; 8%, grade 1; 4%, grade 2; and 0%, grade 3. The difference in prevalence of lid wiper staining between the symptomatic and asymptomatic groups was significant (P0.0001). Conclusions. Lid wiper epitheliopathy, diagnosed by staining with fluorescein and rose bengal dyes, is a frequent finding when symptoms of dry eye are experienced in the absence of routine clinical dry eye findings.

Purpose To assess the clinical characteristics, incidence, and pathologic correlation of corneal epithelial adhesion abnormalities encountered during LASIK. Design Prospective noncomparative interventional case series. Participants Five hundred consecutive eyes of 268 patients undergoing primary LASIK procedures by one surgeon utilizing the Moria LSK One microkeratome and VISX Star S-2 excimer laser. Methods Corneal epithelial adhesion was assessed immediately preoperatively using a cellulose surgical sponge (adhesion test), and the incidence, extent, and location of epithelial defects occurring during the microkeratome incision of the corneal flap were recorded. Epithelial specimens from 7 corneas requiring debridement of dysadhesive epithelium were examined by transmission electron microscopy. Main outcome measures The characteristics of the study population (age, gender, contact lens use, relevant ocular surface or systemic disease, refractive error, keratometry, pachymetry) and the microkeratome-related variables (head selection and vacuum level) were compared with the results of the preoperative epithelial adhesion test, the development of intraoperative epithelial effects (size and location), and the postoperative outcome. Results Epithelial defects were sustained by 51 corneas (10.2%), and among these, 31 (6.2%) were microdefects and 20 (4.0%) were macrodefects. The adhesion test was positive (indicative of compromised adhesion of epithelium to stroma) in 20 (64.5%) corneas with microdefects, but false negatives (epithelial defect despite negative adhesion test) occurred in 11 cases (35.4%). The adhesion test was positive in 16 (80%) of corneas having macrodefects, with 4 (20%) false negatives. Thus, the overall positive predictive value of the adhesion test was 59%, and the percentage of positive prediction was 92% (Bayes' theorem). Among all other outcome measures assessed, only corneal flap thickness seemed a potential risk factor, as 40 (78.4%) epithelial defects were associated with the creation of a 180-μm-thick flap, whereas 10 (19.6%) were associated with a 160-μm-thick flap and only 1 (2%) occurred with a 130-μm flap. These trends were not, however, statistically significant ( P = 0.15, Fisher exact test). Transmission electron microscopy of all epithelial debridement specimens disclosed consistent abnormality of the basement membrane adhesion complex, as thickened and multilaminated basement membrane remained adherent to the intact epithelial sheet. Conclusions: Corneal epithelial dysadhesion and defects occurring in the course of LASIK surgery may be associated with an intrinsic compromise of the basement membrane adhesion complex, as evidenced clinically by the adhesion test and demonstrated pathologically by duplicated basement membrane.

To determine the duration of action of ketotifen 0.025% eye drops vs placebo taken as single or multiple doses in an allergen challenge model.Two randomized, multicenter, double-masked, contralateral placebo-controlled studies, one a single-dose and one a multiple-dose study.Two conjunctival provocation tests (CPTs) were initially conducted to confirm reproducibility of subject responses in both studies. Subjects in study 1 (n = 87) received single doses of ketotifen in one eye and placebo in the other 15 minutes, 6 hours, and 8 hours before CPT. Subjects in study 2 (n = 85) received ketotifen or placebo once 8 hours before CPT. Single-dose efficacy results were used to further qualify a subject as a responder. Responders were re-randomized to a 4-week twice daily dosing regimen with a CPT 8 hours after the final dose. In both studies, ocular symptoms were assessed at three time points 3 to 15 minutes after challenge. There were no significant differences in adverse events between groups.For both studies, ocular itching and vascular injection were significantly reduced (P.003) at all time points after instillation of ketotifen, with a maximum reduction at 7 minutes postchallenge. In study 2, chemosis, tearing, and lid swelling were also assessed and were significantly reduced (P.008) after instillation of ketotifen.Ketotifen 0.025% eye drops were safe and statistically effective in preventing ocular itching, injection, and other signs and symptoms of allergic conjunctivitis at 15 minutes, 6 hours, and 8 hours after a single dose and at 8 hours after the final dose of a 4-week twice daily regimen.

Ketotifen fumarate 0.025% ophthalmic solution and nedocromil sodium 2.0% ophthalmic solution are 2 topical antiallergic medications with different modes of action and efficacy profiles. Both solutions are indicated for ocular itching associated with allergic conjunctivitis.This study compared the efficacy, safety, and comfort of ketotifen fumarate 0.025% ophthalmic solution and nedocromil sodium 2.0% ophthalmic solution for the prevention of ocular itching, using the conjunctival allergen challenge (CAC) model.This was a single-center, double-masked, contralateral, randomized, placebo- and active-controlled CAC clinical trial. Subjects aged10 years with a history of allergic hypersensitivity who responded to the CAC at screening visits 1 and 2 qualified for randomization at visit 3. At visit 3 (day 21) and visit 4 (day 35), subjects received 1 of 3 treatments: ketotifen, nedocromil, or placebo (artificial tears), randomized by eye. Allergen challenges were conducted at 5 minutes posttreatment dose (visit 3) and 12 hours posttreatment dose (visit 4). At each visit, subjects evaluated their ocular itching every 30 seconds for 20 minutes. At visit 4, subjects evaluated the comfort of the medication immediately after instillation, at 30 seconds after instillation, and at l, 2, 5, and 10 minutes after instillation. The subjects were also queried about overall eyedrop comfort by choosing from descriptive terms and about overall eyedrop preference based on comfort and perceived efficacy.Eighty-five subjects were screened for this study. Fifty-nine (28 males, 31 females; mean age, 38.7 years) qualified and were randomized to receive study medications. Ketotifen-treated eyes experienced significantly less ocular itching induced by CAC than nedocromil-treated eyes and those that received placebo at both the 5-minute and 12-hour posttreatment allergen challenges (all P0.05). Nedocromil-treated eyes showed no statistical or clinical differences from placebo at any time point. Ketotifen-treated eyes showed no differences in comfort from those that received placebo but were significantly more comfortable than nedocromil-treated eyes at 1, 2, 5, and 10 minutes after instillation (all P0.05). On the basis of comfort and subjective efficacy, 60% of subjects preferred ketotifen, 21% preferred nedocromil, and 19% preferred placebo.Ketotifen was significantly more effective and comfortable than nedocromil at both 5 minutes and 12 hours after administration in this CAC model.

This single-masked, contralateral-eye, active-controlled allergen-challenge study compared ketotifen fumarate .025% and cromolyn sodium 4% ophthalmic solutions in the prevention of ocular itching, tearing, and redness induced by allergen challenge. After a confirmatory conjunctival provocation test (CPT), 56 patients randomly received masked study medication (placebo in one eye, cromolyn in the other eye) four times daily for 2 weeks. At visit 3, patients received one drop of ketotifen in the eye previously treated with placebo and cromolyn in the other eye. Ocular comfort was assessed 30 seconds postinstillation, and a CPT was conducted 15 minutes and 4 hours postinstillation to evaluate ocular itching, tearing, and redness. Forty-seven patients were analyzed for efficacy. At the 15-minute and 4-hour challenges, ketotifen was superior to cromolyn in preventing itching (P.001) at all assessments and redness (ciliary, conjunctival, and episcleral) (Por = .001) at most assessments. Tearing scores were higher in cromolyn-treated eyes than in ketotifen-treated eyes. Patients reported greater comfort in the ketotifen-treated than in the cromolyn-treated eye (P = .066). The most common adverse event was burning/stinging with cromolyn. A single dose of ketotifen was superior to a 2-week four-times-daily regimen of cromolyn in alleviating symptoms of allergic conjunctivitis in the conjunctival allergen-challenge model.

The most common form of dry eye disease is evaporative dry eye resulting from meibomian gland dysfunction (MGD) based on obstructed MG. A prospective, randomized, crossover, multicenter clinical study employed a single treatment with the automated computer controlled LipiFlow thermal pulsation system (LTPS). Improvement in signs & symptoms and its duration in patients with evaporative dry eye secondary to MGD was investigated over several time points. Initial results verified significant improvement of MG secretion at 2 & 4 weeks compared to conventional warm compress method. This was based on evaluation of tear film break up time (TF-BUT), ocular surface staining, patient symptoms (OSDI & SPEED test). The secretion score improved significantly from baseline (4.4 ± 4.0) to 1-month post-treatment (11.3 ± 6.2; p < 0.0001) and this improvement was maintained with no significant regression at 9 months (11.7 ± 5.9) and even at 3-years (18.4±6.2) after therapy. Treatment with the Lipiflow device is a technological advance that exceeds any known form of dry eye therapy in duration and efficacy, since it is efficacious even for extended durations (9-mos, 1-, 2- and 3-years) following a single 12-minute treatment.

The phospholipids of the skin are difficult to quantify because they represent only a small fraction of the skin tissue. In this study, 31 P nuclear magnetic resonance, which permits precise profiling of these phospholipids, was used to compare the phospholipids of upper eyelid epidermal and dermal lipid extracts (n = 13 profiles). Phospholipid profiles included alkylacylphosphatidylcholine (AAPC), dihydrosphingomyelin (DHSM), diphosphatidylglycerol (cardiolipin), ethanolamine plasmalogen (EPLAS), lysophosphatidylcholine, phosphatidic acid, phosphatidylcholine (PC), phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyelin, and uncharacterized phospholipids (U1 and U2, particularly enriched in the epidermis). The computed phospholipid metabolic index (n = 86 indexes) findings can be summarized as follows: a lower content of the enol and ether phospholipids in the epidermis relative to the dermis, internal compensation among the component phospholipids so as to maintain the choline functional group ratio, and a greater concentration of hydroxyl-containing functional groups in the epidermis. A membrane index (f mem ) value of -0.37 for the epidermis deviated considerably from the value of -0.06 characteristic of living membranes and the dermis. The production of the reduced phosphatides, EPLAS and AAPC, indicates the use of alternative pathways between the two tissues. Relative to the dermis, increased PC in the epidermis coupled with decreased DHSM, EPLAS, and AAPC are factors enabling the epidermis of eyelid tissue to be an effective water barrier.

The purpose of this study was to determine the relationship between the tear film and humidity by examining whether alterations in periocular humidity influence the thickness of the tear film lipid layer. Thirteen dry eye subjects presenting with a baseline lipid layer thickness of < or = 60 nm were fitted with modified swim goggles in which the right eye (OD) was exposed to conditions of high humidity and the left eye (OS) remained exposed to ambient room conditions. The lipid layer was monitored over a 60-min time course with goggles on and for an additional 60 min following goggle removal. The OD lipid layer increased significantly in thickness within 5 min of exposure to conditions of high humidity (p < 0.0001), reaching a maximum increase of 66.4 nm after 15 min of goggle wear (p < 0.0001). This maximum increase to a lipid layer thickness of 120.5 nm was maintained at the 30- and 60-min goggle time points. No significant change was detected OS. Following goggle removal, OD values declined but remained significantly elevated over the OS lipid layer thickness throughout the 60-min postgoggle period. Moderate to total relief of dry eye symptoms was reported during goggle wear and generally persisted at a reduced level for 1-3 h following goggle removal. Increased periocular humidity results in an increase in tear film lipid layer thickness, possibly by providing an environment that is more conducive to the spreading of meibomian lipid and its incorporation into the tear film.

The content of the meibomian gland lipid exprimate is known, but little is known about the phospholipids that comprise the glandular cells. The purpose of the present study is to identify and quantitate the phospholipid complement of the meibomian gland cells that produce the lipid secretion of meibomian oil and which is vital to tear film stability. Eyelids (n = 50) were excised from rabbits, and after surgical removal of surrounding tissues, the tarsal plates with and without expressing meibomian oil were extracted and phospholipids of the plates quantified by 31P nuclear magnetic resonance (NMR). Seventeen phospholipids were quantified from tarsal plates expressed of oil and tarsal plates containing meibomian oil: alkylacylphosphatidylcholine (AAPC), dihydrosphingomyelin (DHSM), dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin), ethanolamine plasmalogen (EPLAS), lysoethanolamine plasmalogen, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, phosphatidic acid, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sphingomyelin (SM), sphingosylphosphorylcholine. The six zwitterionic and neutral phospholipids, DHSM, EPLAS, PE, SM, AAPC, and PC together comprise 79.5% of the total meibomian gland phospholipid profile (in meibomian oil this value is 84.2%). The zwitterionic and neutral phospholipids dominate meibomian gland phospholipid profiles. Since the meibomian gland cells undergo holocrine secretion and form the meibomian glad secretion, such a composition is consistent with the hypothesis that a chemically stable lamellar surfactant layer phospholipids bind non-polar meibomian oil to the aqueous layer of the tear film.

Since the uveal tract becomes involved in inflammatory disorders, which are known to affect lipid metabolism, we studied normal membrane phospholipids (PLs) in order to (1) determine baseline PL profiles of the iris, ciliary body, and choroid, and (2) compare and contrast PL profiles of the uveal tissues.Iris, ciliary body and choroid tissues were isolated from rabbit eyes (n = 30) and extracted with chloroform-methanol using a modified Folch procedure. Quantitative tissue PL profiles were obtained using 31P nuclear magnetic resonance.Fourteen PLs were detected and quantitated in all three uveal tissues among which was one unidentified PL at -0.17 ppm. The five major PLs in the iris, ciliary body and choroid, respectively, have the following PL composition (mole percent of total phosphorus): ethanolamine plasmalogen 14.58, 15.07, 16.52; phosphatidylethanolamine 13.10, 12.40, 9.23; phosphatidylserine 11.24, 10.27, 12.13; sphingomyelin (SM) 11.10, 11.97, 18.21; and phosphatidylcholine (PC) 36.61, 36.70, 29.88. Additionally, lysophosphatidic acid, phosphatidic acid, lysophosphatidylcholine, phosphatidylinositol, and PC plasmalogen or alkacyl PC were detected in all tissues. Sphingosylphosphorylcholine also was detected in the ciliary body and choroid. Lysophosphatidylethanolamine was detected in the choroid. In addition, 42 PL metabolic indexes were calculated from these data, which permitted pathway-specific lipid analyses.This study establishes baseline PL profiles of the uveal tract tissues and will permit comparisons with tissues from eyes with inflammatory disorders. The PL concentrations in conjunction with the indexes demonstrate that overall the choroid has membranes that are less permeable to ion translocation than either the iris or the ciliary body, although there are compensatory concentration changes between the SM and PC components among these three tissues.

To evaluate the safety and effectiveness of the LipiFlow System compared to the iHeat Warm Compress (WC) for adults with meibomian gland dysfunction (MGD).This was a non-significant risk, prospective, open-label, randomized, crossover multicenter clinical trial. One hundred thirty-nine subjects were randomized between LipiFlow (n=69) and WC control (n=70). Subjects in the LipiFlow group received a 12-minute LipiFlow treatment and were reexamined at 1 day, 2 weeks and 4 weeks. Control subjects received a 5-minute iHeat treatment with instructions to perform the same treatment daily for 2 weeks. At 2 weeks, they crossed over (LipiFlow Crossover) and received the LipiFlow treatment. Effectiveness parameters: meibomian gland (MG) assessment, tear break-up time (TBUT) and dry eye symptoms. Safety parameters: adverse events, ocular health exam, ocular surface staining, intraocular pressure, visual acuity and discomfort.LipiFlow resulted in significant improvement (P0.05) in MG secretion at 2 and 4 weeks (mean ± standard deviation at baseline = 6.3 ± 3.5; 2 weeks = 14.3 ± 8.7; 4 weeks = 16.7 ± 8.7); and TBUT at 2 and 4 weeks: (at baseline = 5.5 ± 2.9; 2 weeks = 6.9 ± 5.0; 4 weeks = 7.4 ± 5.5). There was no significant change in MG secretion or TBUT in the control group. LipiFlow resulted in a greater significant reduction in dry eye symptoms than the iHeat WC. The crossover group demonstrated similar significant improvement 2 weeks post-treatment with the LipiFlow. There was no significant difference between groups in the incidence of non-serious, device-related adverse events.The LipiFlow System was significantly more effective than iHeat WC. These results support its safety and effectiveness in the treatment of MGD and dry eye symptoms.

Phospholipids of optic nerve (n = 30) from 5.6-kg rabbits were analyzed by 31P nuclear magnetic resonance (NMR) spectroscopy. Phospholipid metabolites detected were as follows (mol %): phos

This study establishes the metabolic similarities and differences of intact abattoir corneas and the human cornea ex vivo, using 31P nuclear magnetic resonance spectroscopy. Phosphorylated sugars (SP), inorganic orthophosphate (Pi), phosphodiesters, ATP, ADP, and the nucleoside diphosphosugars and dinucleotides (NS&DN) were quantitated. The intracorneal pH also was determined. In addition, metabolic indices ATP/Pi, ATP/ADP, ATP/ (ADP + Pi), SP/Pi, the phosphorylation potential, and the 31P energy modulus were calculated. Significant differences were observed between the abattoir and human corneas in phosphorylated sugars, NS&DN, and intracorneal pH, as well as in the indices ATP/ADP and SP/Pi. The overall energy status as measured by the 31P energy modulus was significantly higher in the bovine cornea when compared to the porcine and human corneas, suggestive of a very high energy reserve in the bovine cornea.

The purpose of this study was to investigate the prevalence of lid wiper epitheliopathy (LWE) in patients diagnosed with dry eye disease (DED).Patients were recruited for two groups. Inclusion criteria for the DED group (n = 50) was: a score greater than 10 with the Standard Patient Evaluation of Eye Dryness questionnaire, fluorescein break-up time 5 seconds or less, corneal and conjunctival staining with fluorescein, lissamine green Grade 1 or greater (scale 0-3), and Schirmer test with anesthesia 5 mm or less. For the asymptomatic group (n = 50), inclusion criteria were: no dry eye symptoms, fluorescein break-up time 10 seconds or greater, no corneal or conjunctival staining, and Schirmer test 10 mm or greater. Sequential instillations (n = 2, 5 minutes apart) of a mixture of 2% fluorescein and 1% lissamine green solution were used to stain the lid wipers of all patients. LWE was graded (scale 0-3) using the horizontal lid length and the average sagittal lid widths of the stained wiper.In symptomatic patients, 88% had LWE, of which 22% was Grade 1, 46% Grade 2, and 20% Grade 3. In asymptomatic patients, 16% had LWE, of which 14% was Grade 1, 2% was Grade 2, and 0% Grade 3. The difference in prevalence of lid wiper staining between groups was significant (P0.0001).The prevalence of LWE was six times greater for the DED group and the prevalence of LWE Grade 2 or greater was 16 times greater for the DED group than for the control group. These data further establish LWE as a diagnostic sign of dry eye disease.

(1) To investigate the relationship between dry eye symptoms and lipid layer thickness (LLT) in patients presenting for routine eye examination and (2) to consider the practicality of interferometry in a clinical practice.Patients presenting consecutively for routine eye examinations were recruited (n = 137, age range = 18-60 years, mean = 41.7 +/- 15.5 years, 102 females and 35 males). Patients were required to complete the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire after which their LLT was evaluated using a new interferometer (Ocular Surface Interferometer). Patients were assigned to 1 of 3 symptom categories: no symptoms (SPEED = 0), mild to moderate symptoms (SPEED = 1-9), and severe symptoms (SPEEDor = 10). Categorical analysis (contingency table) and linear regression were performed on the data.For patients with severe dry eye symptoms, 74% had an LLTor =60 nm. Conversely, 72% of patients with no dry eye symptoms had an LLT ofor =75 nm (contingency table, chi = 12.63, df = 2, p = 0.0018). Furthermore, a linear regression of LLT and SPEED score reveal a significant linear relationship (as LLT increases, SPEED score decreases; p = 0.0014).(1) The data indicate that approximately 3 of 4 patients reporting severe symptoms have relatively thin lipid layers of 60 nm or less, whereas approximately 3 of 4 patients without symptoms have relatively thick lipid layers of 75 nm or more. Thus, the presence of dry eye symptoms significantly increases the likelihood of a relatively thin lipid layer. LLT seems to correlate better to symptoms, especially severe symptoms, than other reported correlations with objective clinical tests for dry eye disease. (2) Interferometry has the potential to be a practical and useful addition to clinical practice.

From three groups of patients with corneal edema, the degree of edema was clinically quantified prior to penetrating keratoplasty. Corneas from patients with failed grafts (n = 16) had the greatest edema (mean score 3.8 +/- 0.6 SE), corneas with Fuchs' endothelial dystrophy (n = 12) had the least edema (1.4 +/- 0.4), and corneas with aphakic and pseudophakic bullous keratopathy (n = 40) had intermediate edema (2.7 +/- 0.5). Phosphorus-31 nuclear magnetic resonance spectroscopy was used to quantitate five high-energy phosphates and nine low-energy phosphates and calculate 12 metabolic indices from the specimens of these three edematous groups. Corneas with aphakic and pseudophakic bullous keratopathy had lower alpha-glycerophosphate (alpha-GP) and glycerol 3-phosphorylethanolamine and glycerol 3-phosphorylcholine (GPE & GPC), and higher phosphocreatine (PCr), adenosine diphosphate (ADP), monoesters/diesters, PCr/Pi (phosphocreatine/inorganic orthophosphate), and PCr/ATP (phosphocreatine/adenosine triphosphate) than corneas with Fuchs' endothelial dystrophy (p less than 0.05). Corneas from failed grafts had lower alpha-GP, ethanolamine phosphate (EP), ethanolamine phosphate and choline phosphate (EP&CP), monoesters/Pi, ATP/Pi, and energy modulus, no detectable GPE and GPC, and higher Pi, phosphorylglycans (PG), PCr, ADP, diesters, PCr/Pi, and PCr/ATP than those with Fuchs' endothelial dystrophy (p less than 0.05). Corneas from failed grafts had lower ATP, monoesters/Pi, ATP/Pi, PCr/Pi, and energy modulus and higher Pi, PG, ADP, diesters, and PCr/ATP than corneas with aphakic and pseudophakic bullous keratopathy (p less than 0.05). In summary, there was increasing decline in the high-energy metabolites and energy status with increasing edema.

This study compares porcine scleral and corneal phosphorylated intermediate metabolites determined using 31P NMR. These tissues comprise the tunica fibrosa (outer coat) of the eye. Since the sclera does not possess epithelia as does the cornea, comparative analysis of these tissues included examination of the cornea with and without its epithelia. The phosphorylated intermediates detected include: dihydroxyacetone phosphate, hexose 6-phosphates, alpha-glycerol phosphate, beta-glycerol phosphate, ethanolamine and choline phosphates, nucleoside mono-, di-, and tri-phosphates, inorganic orthophosphate, glycerol 3-phosphoryl-ethanolamine and -choline, phosphoglycans, phosphocreatine, nucleoside diphosphosugars, dinucleotides, and four uncharacterized (unknown) signals. Metabolic indices, comprised of individual or grouped metabolites, were calculated to further compare and contrast metabolites and to provide more pathway specific metabolic interrelations for phosphorylated metabolites. Significant differences exist between the corneal stroma and the sclera in 16 of the 22 phosphorylated metabolites determined, whereas differences exist between the whole cornea and the sclera in six of the 22 phosphorylated metabolites. Considering all metabolite levels and metabolic indices in aggregate, the sclera is most similar to the whole cornea and least similar to the corneal stroma.

Ocular humors (aqueous humor and vitreous body) were obtained from porcine eyes. Perchloric acid extracts were prepared from aqueous and vitreous aspirates, and phosphorus-31 nuclear magnetic resonance spectroscopy 31P-NMR performed. Resonance signals from four high-energy phosphate groups (phosphocreatine, adenosine tri- and diphosphate and the dinucleotides) and nine low-energy phosphate groups [dihydroxyacetone phosphate, hexose-6-phosphate, alpha-glycerophosphate, fructose-1,6-diphosphate, ethanolamine phosphate, choline phosphate, inorganic orthophosphate (Pi), glycerol-3-phosphorylethanolamine and glycerol-3-phosphorylcholine] were present in the aqueous humor and/or vitreous body. Vitreous body phosphates significantly elevated relative to that of the aqueous humor were: DHAP, Hex 6-P, alpha-GP, Fru 1,6-diP, CP, GPE, PCr, ATP, ADP, and the dinucleotides; only Pi was significantly lower. Six metabolic indices (monoesters, diesters, monoesters/diesters, monoesters/Pi, ATP/Pi, energy modulus) were determined; all vitreous body indices were significantly higher than those of the aqueous humor. In particular, the energy modulus, a measure of overall metabolic energy status, was higher in the vitreous body (0.121 +/- 0.047) than in the aqueous humor (0.05 +/- 0.021).