Evaluation of the Impact of Meibomian Gland Dysfunction Using a Novel Patient-Reported Outcome Instrument.

Purpose: This study was intended to characterize the impact of meibomian gland dysfunction (MGD) on patients' quality of life. Methods: In this prospective, multicenter, noninterventional clinical study (NCT01979887), eligible individuals (age ≥40 years; absence of uncontrolled ocular/systemic disease) were categorized, based on composite grading of ocular symptoms, Schirmer score, and meibum quality, into (1) non-MGD, (2) mild/moderate MGD, or (3) severe MGD cohorts. The MGD Impact Questionnaire (MGD IQ), a 10-item patient-reported outcome measure, was self-administered at clinic visit on day 1, and readministered on day 22 to assess intervisit agreement regarding MGD IQ responses. Results: In total, 75 subjects were assigned to the study cohorts (25 per cohort). Across cohorts, MGD IQ item scores rose incrementally with increasing MGD severity. The severe MGD cohort experienced greater difficulty with reading and performance of leisure activities, greater time on eye care, and greater bother with eye care and eye appearance than the mild/moderate MGD cohort (all P < 0.05). Compared with the non-MGD cohort, the mild/moderate MGD cohort had greater difficulty working on computer, whereas the severe MGD cohort had greater difficulty reading, driving, and performing leisure activities, more frequent difficulty with outdoor activities, more time on eye care, and greater bother with eye care (all P < 0.05). Intervisit agreement between MGD IQ responses was fair to moderate (weighted kappa statistic 0.33‒0.58). Conclusions: Vision-related activities are negatively impacted by increasing severity of MGD. The MGD IQ instrument can help characterize disease severity and amplify the patient's voice in patient-centric clinical research. ClinicalTrials.gov NCT01979887.

The Phase 3 INVIGORATE Trial of Reproxalap in Patients with Seasonal Allergic Conjunctivitis.

Purpose: There is an unmet need for new treatments for allergic conjunctivitis. Objective: To assess the activity of reproxalap, a novel reactive aldehyde species modulator, in a real-world model of seasonal allergen exposure. Methods: The INVIGORATE Trial, a prospective, quadruple-masked, vehicle-controlled, crossover, sequence-randomized Phase 3 trial, tested the efficacy of reproxalap in adults with a history of moderate to severe allergic conjunctivitis, ragweed pollen allergy, and allergen chamber-induced ocular itching and redness. Patients were randomly assigned (1:1) to receive 0.25% reproxalap ophthalmic solution or vehicle, followed by a 2-week washout period before crossing over to the other test article. The primary endpoint was ocular itching from 110 to 210 minutes after chamber entry; the key secondary endpoint was ocular redness over the chamber duration (0-4 scales for both endpoints). Results: Of the 95 randomly assigned patients, 89 completed all visits (reproxalap to vehicle: n = 46; vehicle to reproxalap: n = 43). Primary and key secondary endpoints were met: reproxalap significantly reduced ocular itching (mean [SE]: -0.50 [0.03], p < 0.001) and redness (-0.14 [0.01], p < 0.001) relative to vehicle. Responder analyses confirmed the clinical relevance of both end points. Reproxalap was safe and well tolerated. No clinically significant changes in safety assessments were observed. No serious or severe treatment-emergent adverse events (TEAEs) were reported. The most commonly reported TEAE was mild and transient installation site irritation after reproxalap versus vehicle administration. Conclusion: In this well-controlled allergen chamber trial, reproxalap was statistically superior to vehicle across typical symptoms and signs of allergic conjunctivitis. Trial Registration: NCT04207736.

Geographic Atrophy Management Consensus (GA-MAC): a Delphi panel study on identification, diagnosis and treatment.

BACKGROUND/AIMS: With a paradigm shift in geographic atrophy (GA) treatments now available, establishing consensus on the identification and diagnosis of the disease along with considerations for management of patients with GA will assist eye care professionals (ECP) in their day-to-day practices, leading to improved patient outcomes. METHODS: A modified Delphi panel process (Geographic Atrophy Management Consensus) consisting of three total surveys and one virtual live meeting held between survey 2 and survey 3. Data were collected from July to October 2022. Participants included expert members of the eye care community that have demonstrated outstanding leadership among peers: a steering committee with three ECPs and a 15-member panel divided between five optometrists, five comprehensive ophthalmologists and five retina specialists. Consensus on statements related to the management of patients with GA was calculated using the RAND/UCLA Appropriateness Method. RESULTS: At the conclusion of the third survey, consensus was reached on 91% of the 77 statements. Critical consensus topics include: (1) optical coherence tomography as the favoured method to diagnose and monitor GA, (2) preferred practice patterns regarding referral of patients to retina specialists and (3) treatment criteria given the advent of emerging therapeutics for GA. CONCLUSIONS: Generating awareness of early signs of disease development, progression and identifying the best tools to evaluate GA establishes ideal management and referral strategies. Given the paradigm shift in GA management driven by approved therapies, coupled with the fact that the disease is progressive resulting in devastating vision loss, these strategies are critical to ensure best overall outcomes.

Addressing excessive evaporation: an unmet need in dry eye disease.

Dry eye disease (DED) is a common condition in which tear film abnormalities result in a damaging cycle of tear hyperosmolarity, desiccating stress, inflammation, and ocular surface injury. In a healthy tear film, meibum produced by the meibomian glands forms a lipid layer that stabilizes the tear film and protects against aqueous tear evaporation. Excessive tear evaporation due to a deficient lipid layer is believed to be the most common cause of DED, and most evaporative DED is associated with meibomian gland dysfunction (MGD); this highlights the pathophysiologic importance of the dysfunctional tear lipid layer. Current treatments for DED may be used to supplement hyperosmolar aqueous tears, lubricate the ocular surface, increase meibum flow, decrease inflammation, promote tear production, or otherwise decrease clinical signs of ocular surface damage and/or improve symptoms. Until now, no prescription eye drop has directly addressed the excessive evaporation that occurs in most patients with DED. Perfluorohexyloctane (PFHO) ophthalmic solution (MIEBO™; Bausch + Lomb) is a preservative-free eye drop that has demonstrated the ability to form a long-lasting barrier that inhibits evaporation in preclinical studies. FDA approval of PFHO was based on results from 2 pivotal clinical trials (GOBI [NCT04139798] and MOJAVE [NCT04567329]) in patients with DED and clinical signs of MGD which demonstrated consistent improvements in both signs and symptoms of disease, with a safety profile similar to that of saline eye drops. PFHO is the first and only FDA-approved eye drop that directly targets tear evaporation in patients with DED, thereby promoting ocular surface healing and providing symptomatic relief.

Exploring Signs and Symptoms Associated with Meibomian Gland Dysfunction for Use as Clinical Trial Endpoints.

Purpose: Dry eye disease is attributed to impaired tear production and/or evaporative dry eye. Evaporative dry eye is frequently associated with meibomian gland dysfunction (MGD). The objective of this study was to identify clinical study endpoints related to MGD. Methods: This 22-day, noninterventional, case-control clinical study involved three cohorts with increasing MGD severity: no MGD, mild/moderate MGD, and severe MGD. Symptoms were assessed with an ocular symptom questionnaire grading blurred vision, eye burning, eye dryness, eye pain, light sensitivity, eye itching, eye foreign body sensation, and overall ocular discomfort. Sign assessments included the maximum meibum quality score (MMQS), tear breakup time, Schirmer tear tests, biomicroscopy, and corneal staining. Signs and symptoms were compared between cohorts and study visits. Results: Seventy-five study participants were assigned to the cohorts (25 per cohort). MMQS scores increased with increasing MGD severity, reflecting the selection criteria for the cohorts. Between-visit scores showed a weighted kappa statistic of 0.72 indicating substantial agreement. Mean scores of all assessed symptoms increased with increasing MGD severity. Scores for symptoms showed moderate (κ = 0.41-0.60) to substantial (κ = 0.61-0.80) agreement between visits. Overall ocular discomfort demonstrated the strongest correlation with the MMQS. Conclusion: The MMQS was a reproducible sign of MGD showing good agreement with ocular symptoms. Overall ocular discomfort was well correlated with typical dry eye symptoms and could potentially be used as a single measure of MGD symptoms. The findings from this observational study may inform endpoints for future clinical trials. ClinicalTrials.gov NCT01979887.

Relationship Between Human Meibum Lipid Composition and the Severity of Meibomian Gland Dysfunction: A Spectroscopic Analysis.

Purpose: Information on the relationship between meibum lipid composition and severity of meibomian gland dysfunction (MGD) is limited. The purpose of this study was to analyze the molecular components of meibum collected from individuals with no MGD, mild-to-moderate MGD, and severe MGD. Methods: Adults with and without MGD were enrolled in a prospective, multicenter, exploratory clinical trial (ClinicalTrials.gov Identifier: NCT01979887). Molar ratios of cholesteryl ester to wax ester (RCE/WE) and aldehyde to wax ester (Rald/WE) in meibum samples were measured with 1H-NMR spectroscopy. Results were evaluated for participants grouped by MGD disease status and severity (non-MGD, mild-to-moderate MGD, and severe MGD), as defined by maximum meibum quality scores, Schirmer test results, and Subject Ocular Symptom Questionnaire responses. Results: Sixty-nine meibum samples from 69 individuals were included in the analysis: 24 non-MGD, 24 mild-to-moderate MGD, and 21 severe MGD. Mean RCE/WE was 0.29 in non-MGD, 0.14 in mild-to-moderate MGD (P = 0.038 vs. non-MGD, 51% lower), and 0.07 in severe MGD (P = 0.16 vs. mild-to-moderate MGD, 52% lower; P = 0.002 vs. non-MGD, 76% lower). Mean Rald/WE was 0.00022 in non-MGD, 0.00083 in mild-to-moderate MGD (P = 0.07 vs. non-MGD, 277% higher), and 0.0024 in severe MGD (P = 0.003 vs. mild-to-moderate MGD, 190% higher; P < 0.001 vs. non-MGD, 992% higher). Conclusions: RCE/WE was lowest and Rald/WE was highest in the severe MGD cohort, suggesting that these meibum constituent molar ratios may result from the pathophysiology associated with MGD and can impact ocular surface lipid and tear film homeostasis. These findings may potentially help identify targets for MGD treatment.

Demodex Blepharitis: A Comprehensive Review of the Disease, Current Management, and Emerging Therapies.

ABSTRACT: Demodex blepharitis is a common disease of the eyelid, affecting approximately 25 million Americans. This article reviews what is known about the mechanisms and impact of Demodex blepharitis, risk factors, signs and symptoms, diagnostic techniques, current management options, and emerging treatments. Demodex mites contribute to blepharitis in several ways: direct mechanical damage, as a vector for bacteria, and by inducing hypersensitivity and inflammation. Risk factors for Demodex blepharitis include increasing age, rosacea, and diabetes. The costs, symptom burden, and psychosocial effects of Demodex blepharitis are considerable. The presence of collarettes is pathognomonic for Demodex blepharitis. Redness, dryness, discomfort, foreign body sensation, lash anomalies, and itching are also hallmarks of the disease. Although a number of oral, topical, eyelid hygiene and device-based options have been used clinically and evaluated in studies for the management of Demodex blepharitis, none have been FDA approved to treat the disease. Recent randomized controlled clinical trials suggest that lotilaner ophthalmic solution, 0.25%, is a topical treatment with the potential to eradicate Demodex mites and eliminate collarettes and eyelid redness for an extended period.

TFOS Lifestyle: Impact of lifestyle challenges on the ocular surface.

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.

Delphi Panel Consensus Regarding Current Clinical Practice Management Options for Demodex blepharitis.

Purpose: To obtain consensus on Demodex blepharitis (DB) treatment using a modified Delphi panel process. Methods: Literature search identified gaps in knowledge surrounding treatment of DB. Twelve ocular surface disease experts comprised the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH). They completed a live roundtable discussion in addition to 3 surveys consisting of scaled, open-ended, true/false, and multiple-choice questions pertaining to the treatment of DB. Consensus for scaled questions using a 1 to 9 Likert scale was predefined as median scores of 7-9 and 1-3. For other question types, consensus was achieved when 8 of 12 panelists agreed. Results: The experts agreed that an effective therapeutic agent for treatment of DB would likely decrease the necessity of mechanical intervention, such as lid scrubs or blepharoexfoliation (Median = 8.5; Range 2-9). When treating DB, panelists believed that collarettes serve as a surrogate for mites, and that eliminating or reducing collarettes should be the main clinical goal of treatment (Median = 8; Range 7-9). The panelists would treat patients with at least 10 collarettes, regardless of other signs or symptoms and agreed that DB can be cured, but there is always the possibility for a reinfestation (n = 12). There was also consensus that collarettes, and therefore mites, are the primary treatment target and the way by which clinicians can monitor patient response to therapy (Median = 8; Range 7-9). Conclusion: Expert panelists achieved consensus on key facets of DB treatment. Specifically, there was consensus that collarettes are pathognomonic for DB, that DB patients with >10 collarettes should be treated even in the absence of symptoms, and that treatment efficacy can be tracked by collarette resolution. By increasing awareness about DB, understanding the goals of and monitoring treatment efficacy, patients will receive better care and, ultimately, better clinical outcomes.

Dry Eye Disease Associated with Meibomian Gland Dysfunction: Focus on Tear Film Characteristics and the Therapeutic Landscape.

Meibomian gland dysfunction (MGD) is highly prevalent and is the leading cause of evaporative dry eye disease (DED). MGD is characterized by a reduction in meibum secretion and/or a change in meibum composition that results in the disruption of the tear film lipid layer and an increase in the tear film evaporation rate. Excessive evaporation causes tear film instability, desiccation, tear hyperosmolarity, inflammation, and apoptosis of ocular surface cells, resulting in a continuous cycle of DED. The primary treatment goal for DED associated with MGD is to restore the tear film lipid layer and decrease evaporation, thereby reducing ocular signs and symptoms. The management of MGD includes home care options (eyelid hygiene, warming eye masks, ocular lubricants) and office-based treatments (manual expression, microblepharoexfoliation, thermal pulsation, intense pulsed light, intraductal probing). Topical ophthalmic prescription medications attempt to alter various factors that may contribute to DED (e.g., inflammation, bacterial growth, inadequate tear production). In this review, clinical evidence regarding available treatments and emerging therapies from randomized studies in patients with DED associated with MGD is summarized. Although some treatment modalities have been evaluated specifically for DED patients with MGD, large-scale randomized controlled trials are needed to confirm efficacy and safety in this patient population. Currently, there are no approved prescription pharmacologic treatments specifically indicated for DED associated with MGD, and those medications approved for the treatment of DED do not target the key driver of the disease (i.e., excessive evaporation). NOV03 (perfluorohexyloctane; under review with the US Food and Drug Administration) is the most advanced emerging therapy for DED associated with MGD and has demonstrated statistically significant improvements in both signs and symptoms in randomized controlled trials. Development of novel pharmacotherapies will improve therapeutic options and allow for a more individualized approach for patients with DED associated with MGD.

Clinical diagnosis and management of Demodex blepharitis: the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH).

BACKGROUND: Twelve ocular surface disease experts convened to achieve consensus about Demodex blepharitis (DB) using a modified Delphi panel process. METHODS: Online surveys were administered using scaled, open-ended, true/false, and multiple-choice questions. Consensus for questions using a 1 to 9 Likert scale was predefined as median scores of 7-9 and 1-3. For other question types, consensus was achieved when 8 of 12 panellists agreed. Questions were randomized, and results of each survey informed the following survey. RESULTS: Twelve practitioners comprised the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH). Following 3 surveys, experts agreed that DB is chronic (n = 11) and recurrent (n = 12) and is often misdiagnosed. Consensus was achieved regarding inflammation driving symptoms (median = 7; range 7-9), collarettes as the most common sign (n = 10) and pathognomonic for DB (median = 9; range 8-9), and itching as the most common symptom (n = 12). Panellists agreed that DB may be diagnosed based on collarettes, mites, and/or patient symptoms (n = 10) and felt that patients unresponsive to typical therapies should be evaluated for DB (n = 12). Consensus about the most effective currently available OTC treatment was not reached. CONCLUSIONS: The Delphi methodology proved effective in establishing consensus about DB, including signs, symptoms, and diagnosis. Consensus was not reached about the best treatment or how to grade severity. With increased awareness, eyecare practitioners can offer DB patients better clinical outcomes. A follow-up Delphi panel is planned to obtain further consensus surrounding DB treatment.

Dietary protein oscillation: effects on digestibility, nutrient balance and estimated microbial protein synthesis in lactating dairy cows.

Various studies with growing ruminants report increases in nitrogen use efficiency (NUE) when feeding oscillating (OS) dietary CP, whereas limited research with lactating dairy cows demonstrates a lack of improvement in NUE when feeding OS diets. We hypothesised that a total mixed ration (TMR) delivering OS CP (48-h phases of 134 and 171 g CP/kg DM, respectively) compared to a static CP TMR (ST; 152 g CP/kg DM) would result in similar or increased urinary purine derivative excretion (as a marker of microbial protein synthesis (MPS)) and greater urinary nitrogen excretion in lactating dairy cows. Responses in intake, production, apparent total tract digestibility (ATTD), nutrient balance, and estimated MPS were evaluated using faecal and urine collection in 12 multiparous cows (172 ± 39 d in milk) in a randomised complete block design, where total urinary output was estimated indirectly. All measurements were taken during d 8 (at 1700) to d 16 (at 1700) of the 16-d study that followed a 28-d period in which cows already received their respective treatments. Dry matter intake, yields of milk, protein, fat, lactose, and fat- and protein-corrected milk were similar for ST and OS. Milk composition, BW, and body condition score also did not differ between treatments, except for a tendency for increased milk urea concentration with OS (13.7 vs 12.4 mg/dL). Feed efficiency, NUE and ATTD of organic matter, NDF, CP and gross energy did not differ, but ATTD of crude fat (658 vs 627 g/kg) and starch (980 vs 975 g/kg) increased, and ATTD of DM (702 vs 691 g/kg) tended to increase with OS. Milk energy as a proportion of digested energy tended to decrease with OS (34.6 vs 37.1%), but other energy metabolism variables were not affected by treatment. Estimated urinary nitrogen excretion increased (165 vs 144 g/d), estimated urinary nitrogen as a proportion of nitrogen intake tended to increase (25.3 vs 22.7%), and milk nitrogen as a proportion of digested nitrogen decreased (47.3 vs 51.8%) in response to OS. Estimated urinary excretion of creatinine (184 vs 165 mmol/d), uric acid (29 vs 20 mmol/d) and urea (3.1 vs 2.5 mol/d) increased, but other nitrogen metabolism parameters were not affected by OS. Overall, oscillating dietary CP content did not affect lactational performance, milk NUE, or estimated MPS. However, ATTD of some nutrients increased, postabsorptive energy use for milk synthesis tended to decrease, and estimated urinary nitrogen losses increased with OS.

Evaluation of the effects of latanoprost and benzalkonium chloride on the cell viability and nonpolar lipid profile produced by human meibomian gland epithelial cells in culture.

Purpose: The purpose of this study was to explore the effects of a PGF2α analog, latanoprost, and its preservative, benzalkonium chloride (BAK), on the cell viability and lipidomic expression of immortalized human meibomian gland epithelial cells (HMGECs). Methods: Differentiated HMGECs were exposed to latanoprost (0.05 to 50 µg/ml), BAK (0.2 to 200 µg/ml), or combined latanoprost-BAK (0.05-0.2 to 50-200 µg/ml). EP- and FP-type receptors, the cognate receptors of PGE2 and PGF2α, were inhibited, thereby sparing and isolating the function of each receptor to one condition. Cell viability was assessed by ATP quantitation, and lipid extracts were analyzed by ESI-MSMSALL with a Triple TOF 5600 Mass Spectrometer (SCIEX, Framingham, MA) using SCIEX LipidView 1.3. Results: Latanoprost and BAK were found to be lethal to HMGECs at the highest concentrations (p < 0.001 for both). The cytotoxicity of latanoprost was mediated through FP- and EP-independent mechanisms. Both latanoprost and BAK significantly modulated the lipidomic expression of several cholesteryl esters (8% and 30%, respectively) and triacylglycerols (10% and 12%, respectively). The combined latanoprost-BAK agent appeared to be no more toxic and to only negligibly alter the lipid profile relative to its individual components. Conclusions: The use of latanoprost and BAK in glaucoma may alter the viability of the meibomian glands and their lipid expression in vivo. Sublethal concentrations of BAK appear to modulate meibum lipid expression, particularly in relation to sterol biosynthesis. Non-preserved latanoprost had less cytotoxicity at lower doses and fewer lipidomic effects compared to BAK, further strengthening the argument in favor of BAK-free pharmaceutical preparations.

Digestive and metabolic efficiency of energy and nitrogen during lactation and the dry period in dairy cows.

The objective of this study was to characterize total-tract nutrient digestibility, energy balance, and N balance in the critical dietary and metabolic transitions of the lactation cycle. Twelve dairy cows were housed in tiestalls from 10 wk before to 16 wk after parturition. After 2 wk of adaptation to the facility and diet, digestibility of organic matter (OM), neutral detergent fiber (NDF), starch, and N were measured, and energy and N balances determined at weekly intervals by total collection of feces, urine, and milk over 48 h. Cows were individually fed ad libitum a grass silage- and corn silage-based total mixed ration during lactation and a corn silage- and barley straw-based total mixed ration during the dry period. Effects of stage of lactation were evaluated by clustering week in 5 groups: late lactation (wk -8 to -7), dry period (wk -6 to -1), and 3 early lactation periods (wk 1 to 5, wk 6 to 10, and wk 11 to 16). In lactation, apparent total-tract digestibility of OM, NDF, and starch was lowest in the first 5 wk of lactation. From wk 2 to 16 after parturition, apparent nutrient digestibility of all nutrients increased linearly, but with a negative quadratic component for dry matter, OM, and NDF, to levels comparable to those reported in last 2 wk of the previous lactation. However, differences in digestibility across lactation stage were moderate, illustrated by the difference between OM digestibility in late lactation (last 2 wk, 74.8%) and early lactation (first 5 wk, 72.5%). Cows were in negative energy balance for the first 8 wk after calving, and in negative N balance for the first 4 wk after calving. Based on energy and N balance, we predicted that 36.5 kg of body fat and 3.5 kg of body protein were gained in the last 8 wk before calving, and that 47.5 kg of body fat and 7.6 kg of body protein were mobilized in the first weeks of lactation. These predicted changes in body mass, both the gain before calving and loss after calving, were greater by 37% and 10%, respectively, than fluctuations in measured body weight (corrected for predicted gut fill and fetus weights). At wk 1 and 2 postpartum, body N loss corresponded to 25 and 29%, respectively, of total N excretion in milk, and body energy loss corresponded to 64% and 44%, respectively, of the energy exported to milk, illustrating the important contribution of N and energy from body stores to milk production in early lactation. Metabolic N efficiency, measured as total N output (milk and body) over digestible N input (from diet and body), averaged 54.4% in the last 2 wk of lactation, increased to 65.9% 2 wk after calving, and decreased linearly as lactation advanced to 61.9% by wk 16. Short (48 h) but weekly repetition of total collection of feces and urine appears to be a suitable approach to evaluate temporal changes in nutrient digestibility, energy balance, and N balance across lactation and the dry period.

Nicotinic acetylcholine receptor stimulation: A new approach for stimulating tear secretion in dry eye disease.

Tear secretion is regulated by the lacrimal functional unit consisting of afferent and efferent nerve innervation. The afferent arm consists of trigeminal nociceptors on the ocular surface and nasal mucosa. When stimulated by agonists, nicotinic acetylcholine receptors on nerve endings in the nose initiate a reflex arc resulting in instantaneous tear secretion. Pharmacologic nasal neural stimulation to increase endogenous tear production is a novel approach to treating dry eye disease.

Reproxalap Activity and Estimation of Clinically Relevant Thresholds for Ocular Itching and Redness in a Randomized Allergic Conjunctivitis Field Trial.

INTRODUCTION: This clinical trial assessed the activity of reproxalap, a novel reactive aldehyde species modulator, and estimated clinically relevant thresholds for changes in ocular itching and redness in an allergic conjunctivitis field trial. METHODS: This was a randomized, double-masked, vehicle-controlled phase 2 trial. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days in an environmental setting with approximately four doses per day of either 0.25% reproxalap, 0.5% reproxalap, or vehicle. Patients recorded ocular itching, redness, tearing, and eyelid swelling scores (each with a 0-4 scale, except for a 0-3 scale for swelling), and completed the Allergic Conjunctivitis Quality of Life Questionnaire at the beginning and end of the trial. RESULTS: Mixed model of repeated measures analysis demonstrated statistically lower itching and tearing scores (pooled P = 0.026 and P < 0.001, respectively) and numerically lower redness and eyelid swelling scores than vehicle on days when pollen exceeded the 95th percentile value. Using three anchor-based and three distribution-based approaches, the meaningful within-patient change and the between-group meaningful difference for patient-reported ocular itching and redness was estimated to be approximately 0.5. The most common treatment-emergent adverse event associated with reproxalap was transient irritation upon instillation. CONCLUSION: In a field clinical trial, reproxalap was well tolerated and superior to vehicle in reducing ocular itching on high-pollen days. The clinical meaningfulness threshold estimates of 0.5 units are among the first such calculations generated for the standard ocular itching and redness scores, providing important context for the clinical interpretation of clinical trials in allergic conjunctivitis.

While allergic conjunctivitis affects millions of patients worldwide, treatments with new mechanisms have not been introduced in decades. Reproxalap, a medicine being investigated as a treatment for allergic conjunctivitis, works by regulating reactive aldehyde species­molecules that are increased in a variety of inflammatory diseases. This clinical trial assessed the activity of reproxalap and estimated what amount of change in ocular itching and redness should be considered clinically important. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days and were given one of three possible eye drops at approximately four doses per day: 0.25% reproxalap; 0.5% reproxalap; or vehicle, which was composed of the same ingredients but does not contain reproxalap. Patients recorded ocular itching, redness, tearing, and eyelid swelling (all scales ranged from 0 [none] to 4 [severe] except for eyelid swelling, which ranged from 0 to 3), and completed a quality-of-life questionnaire on allergic conjunctivitis at the beginning and end of the trial. The results indicated that reproxalap was significantly better than vehicle in reducing itching and tearing scores and was better than vehicle in reducing redness and eyelid swelling scores on days when pollen counts were high. The trial also suggested that a reduction in ocular itching and redness scores of approximately 0.5 or more (scale 0­4) is likely to be clinically important. Overall, reproxalap was well tolerated and no safety concerns were noted. The most common side effect was transient ocular discomfort after eye drop administration.

Reduction of Artificial Tears and Use of Adjunctive Dry Eye Therapies After Lifitegrast Treatment: Evidence from Clinical and Real-World Studies.

Purpose: To assess the frequency of patients reducing the use of artificial tears (ATs) among patients with dry eye disease (DED) following lifitegrast treatment. Patients and Methods: Two independent analyses were performed using the data from the 1-year, randomized, multicenter, Phase 3 SONATA trial and a noninterventional, real-world evidence (RWE) study conducted in patients with DED who were treated with lifitegrast in the United States and Canada. In SONATA, patients who had used ATs in the lifitegrast and placebo groups were included. The RWE study reviewed patients' electronic medical records, prescribing patterns, and practices of physicians throughout the survey. These data were then used to compare the proportion of patients using ATs in the 6-month pre-index period versus the 12-month post-index period. Results: Of 293 patients (lifitegrast, n=195; placebo, n=98) from SONATA, 107 (lifitegrast, n=64; placebo, n=43) used ATs during the on-therapy period while 186 (lifitegrast, n=131; placebo, n=55) did not. Of those not using ATs, the proportion of patients in the lifitegrast group at any time was higher (~67% [n=131]) versus placebo (~56% [n=55]); this was the case at all study time-points (Days 90, 180, 270, and 360). The RWE study included 600 patient charts (US, n=550; Canada, n=50); 75.5% (n=453) reported AT use. There was ~40% decrease in the proportion of patients using ATs as adjunct DED therapy to lifitegrast in the post-index period (n=273) versus those in the pre-index period (n=453). Conclusion: The findings show that the reliance on AT use can be gradually reduced with lifitegrast treatment, eventually leading to a reduction in disease burden.

Feeding hydrogenated palm fatty acids and rumen-protected protein to lactating Holstein-Friesian dairy cows modifies milk fat triacylglycerol composition and structure, and solid fat content.

The aim of this study was to analyze the effect of fat and protein supplementation to dairy cattle rations on milk fat triacylglycerol (TAG) composition, fatty acid (FA) positional distribution in the TAG structure, and milk solid fat content (SFC). Fifty-six lactating Holstein-Friesian cows were blocked into 14 groups of 4 cows and randomly assigned 1 of 4 dietary treatments fed for 28 d: (1) low protein, low fat, (2) high protein, low fat, (3) low protein, high fat, and (4) high protein, high fat. The high protein and high fat diets were obtained by isoenergetically supplementing the basal ration (low protein, low fat) with rumen-protected soybean meal and rumen-protected rapeseed meal, and hydrogenated palm FA (mainly C16:0 and C18:0), respectively. Fat supplementation modified milk TAG composition more extensively compared with protein supplementation. Fat supplementation resulted in decreased concentrations of the low molecular weight TAG carbon number (CN) 26 to CN34 and medium molecular weight TAG CN40, CN44, and CN46, and increased concentrations of CN38 and the high molecular weight TAG CN50 and CN52. Increased contents of C16:0, C18:0, and C18:1cis-9 in TAG in response to fat supplementation were related to increases in the relative concentrations of C16:0 and C18:0 at the sn-2 position and C18:0 and C18:1cis-9 at the sn-1(3) positions of the TAG structure. Increased concentrations of high molecular weight TAG species CN50 and CN52 in response to fat supplementation was associated with increased milk SFC at 20, 25, and 30°C. Our study shows that important alterations in milk TAG composition and structure occur when feeding hydrogenated palm FA to lactating dairy cattle, and that these alterations result in an increased SFC of milk fat. These changes in milk SFC and TAG composition and structure may improve absorption of both fat and minerals in milk-based products for infants and may affect processing of milk fat.

Preterm birth after recurrent pregnancy loss: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the impact of recurrent pregnancy loss (RPL) on the risk of preterm birth (PTB) in subsequent pregnancies. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Pregnant women with and without a history of RPL. INTERVENTION(S): PubMed, Embase, Google Scholar and Cochrane trial registry were used to identify relevant studies. MAIN OUTCOME MEASURE(S): The odds ratios (ORs) for the association between RPL and PTB across included studies were evaluated. Effect estimates were pooled using a DerSimonian and Laird random-effects meta-analysis model. RESULT(S): Eighteen studies met the inclusion criteria. A total of 58,766 women with a history of RPL and 2,949,222 women without a history of RPL were included. A pooled OR of 1.60 (95% confidence interval [CI], 1.45-1.78; 18 observational studies; I2 = 85.6%) was observed in our random-effects meta-analysis. A trend toward higher odds of PTB is observed with the increasing number of pregnancy losses: 2 RPLs (pooled OR, 1.31; 95% CI, 1.09-1.57; I2 = 88.9%); ≥2 RPLs (pooled OR, 1.58; 95% CI, 1.27-1.96; I2 = 71.7%); and ≥3 RPLs (pooled OR, 1.81; 95% CI, 1.58-2.07; I2 = 73.6%). The analysis of the risk of PTB for patients with unexplained RPL demonstrated a significantly heightened risk of PTB in this subgroup (pooled OR, 2.05; 95% CI, 1.46-2.89; I2 = 21.0%). Inconsistent adjustment for confounders and significant between-study heterogeneity were noted in this study. CONCLUSION(S): Despite significant heterogeneity among studies, we found that women with a history of RPL had significantly higher odds of delivering preterm infants in subsequent pregnancies. CLINICAL TRIAL REGISTRATION NUMBER: CRD 224763.