Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids.

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

A singlicate immunogenicity method to detect anti-polyethylene glycol antibodies: pre- and post-dose of PEGylated therapies.

Aim: Preexisting anti-polyethylene glycol (PEG) antibodies (APAs) may affect the efficacy and safety of PEGylated compounds. Omontys® and Krystexxa® withdrawal and SARS-CoV-2 RNA vaccine anaphylaxis have all been linked to APAs. This project aimed to develop and validate a method to detect total antibodies against PEG, pre- and post-dose. Materials & methods: The repetitive, linear PEG structure prevented the use of a bridging homogenous format, hence the requirement to use a solid-phase extraction and acid dissociation assay coupled with the Meso Scale Discovery® platform. Results & conclusion: Using singlicate analysis, the method was validated to successfully detect APA pre- and post-dose, with a crucial aspect of the method being the preparation of an appropriate negative control.

Comparing Half-Dose Photodynamic Therapy with Subthreshold Micropulse Laser for the Treatment of Central Serous Chorioretinopathy.

PURPOSE: To compare the anatomic and functional outcomes of half-dose photodynamic therapy (PDT) and yellow 577-nm subthreshold micropulse laser (SMLT) in treating patients with chronic central serous chorioretinopathy (CSCR). DESIGN: Prospective, double-masked, randomized, controlled clinical trial. PARTICIPANTS: Patients with chronic CSCR confirmed by clinical features and multimodal imaging. METHODS: Eligible patients were randomized (1:1) to receive half-dose PDT or SMLT. The same treatment was repeated if persistent subretinal fluid (SRF) was observed. Treatment responses were evaluated 1 month after treatment and every 3 months until the end point at 12 months. MAIN OUTCOME MEASURES: The primary outcome measure was the complete resolution of SRF on OCT scan at month 12. Secondary outcomes included the changes in best-corrected visual acuity (BCVA), central macular thickness (CMT) as measured by OCT, retinal sensitivity as measured by microperimetry, and vision-related quality of life using the National Eye Institute 25-Item Visual Function Questionnaire. RESULTS: Between April 2017 and October 2020, 68 patients were recruited. At 1 month after treatment, SRF resolved in 8 (24.2%) of 33 patients receiving SMLT and in 20 (58.8%) of 34 patients receiving half-dose PDT. This increased to 23 (82.1%) of 28 patients in the SMLT group and 30 (90.9%) of 33 patients in the half-dose PDT group at 12 months of follow-up. Kaplan-Meier survival curves showed significantly faster resolution of SRF in the half-dose PDT group than the SMLT group (P = 0.016). Both groups showed significant improvement in BCVA (-0.12 ± 0.21, P = 0.005 for SMLT; -0.13 ± 0.12, P < 0.001 for half-dose PDT), CMT (-154.2 ± 105.6, P < 0.001 for SMLT; -140.8 ± 94.0, P < 0.001 for half-dose PDT), and retinal sensitivity (5.70 ± 5.02, P < 0.001 for SMLT; 6.05 ± 3.83, P < 0.001 for half-dose PDT) at 12 months compared with baseline. There was no significant difference between the 2 treatment groups at each time point in all investigations except BCVA at 3 months (P = 0.03). CONCLUSIONS: When comparing half-dose PDT to subthreshold SMLT, this study has shown both treatments to be viable options, with half-dose PDT achieving faster anatomic success and functional improvement. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A novel in-situ Raman spectroscopic cell for aqueous geochemistry at the solid-liquid interface.

In-situ Raman spectroscopy has the potential to be a powerful technique for monitoring geochemical reactions at a solid-liquid interface in real time. In this article, we present the development and testing of an in-situ Raman spectroscopic cell, which can be used for reaction systems at moderate temperatures and pressure [<1000 psi (6.89 MPa), <100 °C, relevant to subsurface geologic systems] and can hold samples large enough for chemical mapping of heterogeneous rock surfaces. The system is validated by measuring the temperature-dependent conversion of gypsum to calcite over time. Near total conversion of gypsum to calcite on the mineral surface took 29 hours at room temperature and 150 minutes at 100 °C, corresponding to an 11.6-fold increase in the conversion rate. We anticipate that this cell can be an important tool in quantifying the rates of carbon mineralization relevant to geologic carbon sequestration, particularly for the elevated rates recently observed in mafic/ultramafic rocks.

Early effects of very early cochlear implant activation on tinnitus.

BACKGROUND: Cochlear implantation (CI) has long been the standard of care for patients with severe-to-profound hearing impairment. Yet the benefits of CI extend far beyond speech understanding, with mounting recent literature supporting its role in tinnitus abatement. However, those studies have uniformly analyzed the effects of tinnitus after the traditional 3-4 weeks waiting period between CI surgery and device activation. As many clinics are shifting these waiting intervals to become shorter (in some cases within 24 hours, little is known about tinnitus abatement very early in the postoperative period. The aim of this study was to compare preoperative and postoperative tinnitus handicaps in this unique but growing population of very early-activated patients. METHODS: Twenty-seven adults with severe-to-profound hearing impairment with chronic tinnitus (>6 months) were included. Patients with concomitant psychiatric disorders were excluded. All patients were implanted with the same array and were switched on within 24 hours after the surgery. Tinnitus Handicap Inventory (THI) was recorded preoperatively, immediately after activation at 24 hours postoperatively, at 1 week, 2 weeks, and I month after activation. Wilcoxon signed-rank test was used to compare values between preoperative assessment and respective fitting sessions. RESULTS: Mean THI 24 hours after implantation increased in comparison to that assessed preoperatively (77.6 vs 72.5, p = 0.001). By 1 week after surgery, the THI had decreased to 54.9 ( p < 0.001). This trend continued and was statistically significant at 2 weeks (36.0, p < 0.001) and 1 month (28.5, p < 0.001). CONCLUSION: On average, most patients with tinnitus will note a significant improvement in their tinnitus handicap when activated within 24 hours of CI. However, tinnitus does increase between surgery and 24 hours, most likely reflecting not only intracochlear changes, but modulation of the entire auditory pathway. Following this early rise, the tinnitus continues to abate over the following month. Patients with tinnitus may benefit from early activation, although should be counseled that they may experience an exacerbation during the very early postoperative period.

Investigation of Characteristic Motion Patterns of the Knee Joint During a Weightbearing Flexion.

This study aimed to develop and validate a novel flexion axis concept by calculating the points on femoral condyles that could maintain constant heights during knee flexion. Twenty-two knees of 22 healthy subjects were investigated when performing a weightbearing single leg lunge. The knee positions were captured using a validated dual fluoroscopic image system. The points on sagittal planes of the femoral condyles that had minimal changes in heights from the tibial plane along the flexion path were calculated. It was found that the points do formulate a medial-lateral flexion axis that was defined as the iso-height axis (IHA). The six degrees of freedom (6DOF) kinematics data calculated using the IHA were compared with those calculated using the conventional transepicondylar axis and geometrical center axis. The IHA measured minimal changes in proximal-distal translations and varus-valgus rotations along the flexion path, indicating that the IHA may have interesting clinical implications. Therefore, identifying the IHA could provide an alternative physiological reference for improvement of contemporary knee surgeries, such as ligament reconstruction and knee replacement surgeries that are aimed to reproduce normal knee kinematics and medial/lateral soft tissue tensions during knee flexion.

The impact of underrepresented minority or marginalized identity status on training outcomes of MD-PhD students.

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence. Our literature review identified four generalizable barriers that can impact the training outcomes of students from these marginalized and/or underrepresented groups: 1) discrimination and bias, 2) impostor syndrome and stereotype threat, 3) lack of identity-similar mentors, and 4) suboptimal institutional policies and procedures. We propose goal-oriented interventions that may begin to ameliorate the disparities present in MD-PhD program training environments that affect students from marginalized and/or underrepresented groups in academic medicine.

Intraocular inflammation following COVID-19 vaccination: the clinical presentations.

PURPOSE: The purpose of the study was to describe the cases of intraocular inflammation following COVID-19 vaccination (Comirnaty mRNA vaccine and CoronaVac vaccine) in Hong Kong. METHODS: This was a retrospective case series. RESULTS: This series includes 16 eyes among 10 female patients, with a mean age of 49.4 ± 17.4 years. Eight patients (80%) received the Pfizer-BioNTech mRNA vaccination. Anterior uveitis was the most common presentation of postvaccination uveitis (50%) observed in our series, followed by intermediate uveitis (30%) and posterior uveitis (20%), respectively. A case of retinal vasculitis in the form of frosted branch angiitis, previously only reported following COVID-19 infection, was observed following COVID-19 vaccination. The median time from vaccination to uveitis onset was 15.2 days (range: 0-6 weeks). Inflammation in 11 out 16 eyes (68.75%) was completely resolved with topical steroids. CONCLUSION: Anterior uveitis was the predominant presentations of uveitis flare-ups following COVID-19 in our case series, followed by intermediate uveitis. Aligning with the current global literature concerning this issue, most of the uveitis attacks presented as anterior uveitis and were completely resolved with topical steroids. Consequently, the risk of uveitis flare-ups should not deter the public from receiving COVID-19 vaccines.

COMPARING FUNCTIONAL AND VASCULAR LAYER OUTCOMES OF LASER PHOTOCOAGULATION VERSUS SUBTHRESHOLD MICROPULSE LASER FOR DIABETIC MACULAR EDEMA: An OCT-Angiography Study.

PURPOSE: To compare the efficacy of conventional laser and subthreshold micropulse laser (SML) in treating diabetic macular edema in terms of functional outcomes and changes in quantitative metrics for the retinal capillary and choriocapillary vascular layers. METHODS: Fifty-two eyes from 52 patients with treatment-naive, clinically significant macular edema were randomly assigned to the conventional laser group or SML group in a 1:1 ratio. Best-corrected visual acuity, central macular thickness (CMT), and optical coherence tomography angiography scans were measured at baseline, 1, 3, and 6 months after treatment. RESULTS: The SML group showed rapid visual recovery, improving from baseline of 0.320 ± 0.31 logarithm of the minimum angle of resolution (20/42 Snellen) to 0.270 ± 0.22 logarithm of the minimum angle of resolution (20/37 Snellen) at 1 month ( P = 0.038) and had significant improvements in CMT at 6-month post-treatment (353.88-301.00 µ m, P = 0.005). Statistically significant changes were detected across all optical coherence tomography angiography metrics, including vessel density, vessel length density, vessel diameter index, and fractal dimension, at 6 months for both groups in the deep capillary plexus and choriocapillary plexus. CONCLUSION: Subthreshold micropulse laser resulted in early visual recovery and sustained macular thickness improvement in the treatment of diabetic macular edema. Microvascular perfusion parameters, including vessel density, vessel length density, and fractal dimension, improved in the deep capillary plexus and choriocapillary plexus for both treatment groups at 6 months post-treatment.

Differential compensatory role of internal astigmatism in school children and adults: The Hong Kong Children Eye Study.

BACKGROUND: To compare the prevalence of refractive (RA), corneal (CA), and internal astigmatism (IA) in Hong Kong children and adults and evaluate the role of IA in compensating for total astigmatism and its relations to myopic traits. METHODS: The Hong Kong Children Eye Study is a population-based cross-sectional study. Totally 3704 school children (mean age 7.5 ± 1.0 years) and 5577 adults (mean age 41.1 ± 7.5 years), who were their parents, were recruited. Cycloplegic and non-cycloplegic refractive cylinders were obtained from children and adults, respectively. Spearman correlation was applied to detect associations between astigmatism, ocular biometrics, refraction, and lens power. Astigmatism compensation factor (CF) was derived from the power vector analysis J0 and J45. RESULTS: The prevalence of RA (≤-1.0 D), CA (≥+1.0 D) and IA (≥+1.0 D) was 21.9%, 63.9%, and 9.9% in children, and 30.9%, 39.5%, and 23.7% in adults respectively. The mean RA, CA and IA values in children and adults were -0.69 ± 0.66 D, +1.14 ± 0.61 D, +0.62 ± 0.32 D, and -0.80 ± 0.74 D, +0.97 ± 0.69 D, and +0.76 ± 0.43 D, respectively. In adults and children, IA was negatively correlated with axial length (p < 0.0001), but positively correlated with spherical values and equivalent (p < 0.0001), suggesting an association of astigmatism with myopic traits. A greater proportion of children exhibited compensation by IA than adults in J0 (86.6% vs. 66.0%, p < 0.0001) and J45 components (55.5% vs. 41.7%, p < 0.0001). CONCLUSIONS: Chinese children in Hong Kong exhibit a higher prevalence of RA and CA than in other cities. Children displayed a greater compensation by IA than adults, suggesting an age-related attenuation of IA compensation. IA is associated with myopic traits.

Physiological Axial Tibial Rotation of the Knee During a Weightbearing Flexion.

Axial tibial rotation is a characteristic motion of the knee, but how it occurs with knee flexion is controversial. We investigated the mechanisms of tibial rotations by analyzing in vivo tibiofemoral articulations. Twenty knees of 20 living human subjects were investigated during a weightbearing flexion from full extension to maximal flexion using a dual fluoroscopic imaging system. Tibiofemoral articular contact motions on medial and lateral femoral condyles and tibial surfaces were measured at flexion intervals of 15 deg from 0 deg to 120 deg. Axial tibial rotations due to the femoral and tibial articular motions were compared. Articular contact distances were longer on femoral condyles than on tibial surfaces at all flexion intervals (p < 0.05). The articular distance on medial femoral condyle is longer than on lateral side during flexion up to 60 deg. The internal tibial rotation was 6.8 ± 4.5 deg (Mean ± SD) at the flexion interval of 0-15 deg, where 6.1 ± 2.6 deg was due to articulations on femoral condyles and 0.7 ± 5.1 deg due to articulations on tibial surfaces (p < 0.05). The axial tibial rotations due to articulations on femoral condyles are significantly larger than those on tibial surfaces until 60 deg of flexion (p < 0.05). Minimal additional axial tibial rotations were observed beyond 60 deg of flexion. The axial tibial rotations were mainly attributed to uneven articulations on medial and lateral femoral condyles. These data can provide new insights into the understanding of mechanisms of axial tibial rotations and serve as baseline knowledge for improvement of knee surgeries.

Receipt of COVID-19 and seasonal influenza vaccines in California (USA) during the 2021-2022 influenza season.

BACKGROUND: Despite lower circulation of influenza virus throughout 2020-2022 during the COVID-19 pandemic, seasonal influenza vaccination has remained a primary tool to reduce influenza-associated illness and death. The relationship between the decision to receive a COVID-19 vaccine and/or an influenza vaccine is not well understood. METHODS: We assessed predictors of receipt of 2021-2022 influenza vaccine in a secondary analysis of data from a case-control study enrolling individuals who received SARS-CoV-2 testing. We used mixed effects logistic regression to estimate factors associated with receipt of seasonal influenza vaccine. We also constructed multinomial adjusted marginal probability models of being vaccinated for COVID-19 only, seasonal influenza only, or both as compared with receipt of neither vaccination. RESULTS: Among 1261 eligible participants recruited between 22 October 2021-22 June 2022, 43% (545) were vaccinated with both seasonal influenza vaccine and >1 dose of a COVID-19 vaccine, 34% (426) received >1 dose of a COVID-19 vaccine only, 4% (49) received seasonal influenza vaccine only, and 19% (241) received neither vaccine. Receipt of >1 COVID-19 vaccine dose was associated with seasonal influenza vaccination (adjusted odds ratio [aOR]: 3.72; 95% confidence interval [CI]: 2.15-6.43); this association was stronger among participants receiving >1 COVID-19 booster dose (aOR = 16.50 [10.10-26.97]). Compared with participants testing negative for SARS- CoV-2 infection, participants testing positive had lower odds of receipt of 2021-2022 seasonal influenza vaccine (aOR = 0.64 [0.50-0.82]). CONCLUSIONS: Recipients of a COVID-19 vaccine were more likely to receive seasonal influenza vaccine during the 2021-2022 season. Factors associated with individuals' likelihood of receiving COVID-19 and seasonal influenza vaccines will be important to account for in future studies of vaccine effectiveness against both conditions. Participants who tested positive for SARS-CoV-2 in our sample were less likely to have received seasonal influenza vaccine, suggesting an opportunity to offer influenza vaccination before or after a COVID-19 diagnosis.

Recruitment and Retention in Remote Research: Learnings From a Large, Decentralized Real-world Study.

BACKGROUND: Smartphones are increasingly used in health research. They provide a continuous connection between participants and researchers to monitor long-term health trajectories of large populations at a fraction of the cost of traditional research studies. However, despite the potential of using smartphones in remote research, there is an urgent need to develop effective strategies to reach, recruit, and retain the target populations in a representative and equitable manner. OBJECTIVE: We aimed to investigate the impact of combining different recruitment and incentive distribution approaches used in remote research on cohort characteristics and long-term retention. The real-world factors significantly impacting active and passive data collection were also evaluated. METHODS: We conducted a secondary data analysis of participant recruitment and retention using data from a large remote observation study aimed at understanding real-world factors linked to cold, influenza, and the impact of traumatic brain injury on daily functioning. We conducted recruitment in 2 phases between March 15, 2020, and January 4, 2022. Over 10,000 smartphone owners in the United States were recruited to provide 12 weeks of daily surveys and smartphone-based passive-sensing data. Using multivariate statistics, we investigated the potential impact of different recruitment and incentive distribution approaches on cohort characteristics. Survival analysis was used to assess the effects of sociodemographic characteristics on participant retention across the 2 recruitment phases. Associations between passive data-sharing patterns and demographic characteristics of the cohort were evaluated using logistic regression. RESULTS: We analyzed over 330,000 days of engagement data collected from 10,000 participants. Our key findings are as follows: first, the overall characteristics of participants recruited using digital advertisements on social media and news media differed significantly from those of participants recruited using crowdsourcing platforms (Prolific and Amazon Mechanical Turk; P<.001). Second, participant retention in the study varied significantly across study phases, recruitment sources, and socioeconomic and demographic factors (P<.001). Third, notable differences in passive data collection were associated with device type (Android vs iOS) and participants' sociodemographic characteristics. Black or African American participants were significantly less likely to share passive sensor data streams than non-Hispanic White participants (odds ratio 0.44-0.49, 95% CI 0.35-0.61; P<.001). Fourth, participants were more likely to adhere to baseline surveys if the surveys were administered immediately after enrollment. Fifth, technical glitches could significantly impact real-world data collection in remote settings, which can severely impact generation of reliable evidence. CONCLUSIONS: Our findings highlight several factors, such as recruitment platforms, incentive distribution frequency, the timing of baseline surveys, device heterogeneity, and technical glitches in data collection infrastructure, that could impact remote long-term data collection. Combined together, these empirical findings could help inform best practices for monitoring anomalies during real-world data collection and for recruiting and retaining target populations in a representative and equitable manner.

Global and gene-specific translational regulation in Escherichia coli across different conditions.

How well mRNA transcript levels represent protein abundances has been a controversial issue. Particularly across different environments, correlations between mRNA and protein exhibit remarkable variability from gene to gene. Translational regulation is likely to be one of the key factors contributing to mismatches between mRNA level and protein abundance in bacteria. Here, we quantified genome-wide transcriptome and relative translation efficiency (RTE) under 12 different conditions in Escherichia coli. By quantifying the mRNA-RTE correlation both across genes and across conditions, we uncovered a diversity of gene-specific translational regulations, cooperating with transcriptional regulations, in response to carbon (C), nitrogen (N), and phosphate (P) limitations. Intriguingly, we found that many genes regulating translation are themselves subject to translational regulation, suggesting possible feedbacks. Furthermore, a random forest model suggests that codon usage partially predicts a gene's cross-condition variability in translation efficiency; such cross-condition variability tends to be an inherent quality of a gene, independent of the specific nutrient limitations. These findings broaden the understanding of translational regulation under different environments and provide novel strategies for the control of translation in synthetic biology. In addition, our data offers a resource for future multi-omics studies.

Predictors of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Following High-Risk Exposure.

BACKGROUND: Non-pharmaceutical interventions (NPIs) are recommended for COVID-19 prevention. However, the effectiveness of NPIs in preventing SARS-CoV-2 transmission remains poorly quantified. METHODS: We conducted a test-negative design case-control study enrolling cases (testing positive for SARS-CoV-2) and controls (testing negative) with molecular SARS-CoV-2 diagnostic test results reported to California Department of Public Health between 24 February-12 November, 2021. We used conditional logistic regression to estimate adjusted odds ratios (aORs) of case status among participants who reported contact with an individual known or suspected to have been infected with SARS-CoV-2 ("high-risk exposure") ≤14 days before testing. RESULTS: 751 of 1448 cases (52%) and 255 of 1443 controls (18%) reported high-risk exposures ≤14 days before testing. Adjusted odds of case status were 3.02-fold (95% confidence interval: 1.75-5.22) higher when high-risk exposures occurred with household members (vs. other contacts), 2.10-fold (1.05-4.21) higher when exposures occurred indoors (vs. outdoors only), and 2.15-fold (1.27-3.67) higher when exposures lasted ≥3 hours (vs. shorter durations) among unvaccinated and partially-vaccinated individuals; excess risk associated with such exposures was mitigated among fully-vaccinated individuals. Cases were less likely than controls to report mask usage during high-risk exposures (aOR = 0.50 [0.29-0.85]). The adjusted odds of case status was lower for fully-vaccinated (aOR = 0.25 [0.15-0.43]) participants compared to unvaccinated participants. Benefits of mask usage were greatest among unvaccinated and partially-vaccinated participants, and in interactions involving non-household contacts or interactions occurring without physical contact. CONCLUSIONS: NPIs reduced the likelihood of SARS-CoV-2 infection following high-risk exposure. Vaccine effectiveness was substantial for partially and fully vaccinated persons.

GCN2 adapts protein synthesis to scavenging-dependent growth.

Pancreatic cancer cells with limited access to free amino acids can grow by scavenging extracellular protein. In a murine model of pancreatic cancer, we performed a genome-wide CRISPR screen for genes required for scavenging-dependent growth. The screen identified key mediators of macropinocytosis, peripheral lysosome positioning, endosome-lysosome fusion, lysosomal protein catabolism, and translational control. The top hit was GCN2, a kinase that suppresses translation initiation upon amino acid depletion. Using isotope tracers, we show that GCN2 is not required for protein scavenging. Instead, GCN2 prevents ribosome stalling but without slowing protein synthesis; cells still use all of the limiting amino acids as they emerge from lysosomes. GCN2 also adapts gene expression to the nutrient-poor environment, reorienting protein synthesis away from ribosomes and toward lysosomal hydrolases, such as cathepsin L. GCN2, cathepsin L, and the other genes identified in the screen are potential therapeutic targets in pancreatic cancer.

Randomised assessor-masked trial evaluating topical manuka honey (Optimel) in treatment of meibomian gland dysfunction.

PURPOSE: To evaluate the effects of manuka honey eye-drops in the treatment of meibomian gland dysfunction. METHODS: This is an assessor-masked (single-blind), randomised controlled trial comparing conventional treatment group with interventional group using Optimel 16% manuka honey topical eye-drops. 59 patients were recruited to the study and randomised into two groups: one given regular lubricants and the other given Optimel 16% manuka honey eye-drops. The Standard Patient Evaluation of Eye Dryness (SPEED) score was measured at baseline and on follow-up. 4 patients were lost to follow-up. Multiple ocular surface parameters were graded from slit lamp examination by a masked assessor. Results were compared from baseline to follow-up date 3 weeks later. RESULTS: Patients in the conventional treatment group demonstrated minimal difference in SPEED score at 3-week follow-up (mean difference 1.087, p=0.183), which was not statistically significant. However, measurements of tear film break-up time, corneal surface stain (Oxford), lid margin, conjunctival redness, as well as meibum quality and expressibility showed significant improvements at 3 weeks (p<0.01). Patients in the manuka honey eye-drops group showed significant difference after 3 weeks in SPEED score (mean difference 2.53, p=0.006), as well as in lid margin redness, conjunctival redness, corneal surface stain (Oxford), and meibum quality and expressibility (p=0.000). CONCLUSIONS: Optimel 16% manuka honey eye-drops showed significant improvement in symptoms and objective signs in meibomian gland dysfunction and are an effective alternative treatment for meibomian gland dysfunction. TRIAL REGISTRATION NUMBER: NCT04457648.

Intraocular Pressure Control Predicts Retinal Nerve Fiber Layer Thinning in Primary Angle Closure Disease: The CUPAL Study.

PURPOSE: To determine the relationship of intraocular pressure (IOP) control with subsequent retinal nerve fiber layer (RNFL) thinning in patients with primary angle closure disease (PACD). DESIGN: Prospective cohort study. METHODS: The study monitored 517 treated PACD eyes from 280 Chinese patients at least 24 months. IOP was measured every 3 months using Goldmann applanation tonometry, and RNFLs were measured by spectral-domain optical coherence tomography (Spectralis, Heidelberg Engineering) every 6 months. IOP mean and fluctuation were calculated as the average and the coefficient of variation of IOP measurements during the first 18 months of the study period. The relationship between IOP and subsequent RNFL changes over time were examined using multivariable linear mixed models. Intraclass correlations at the patient and eye levels were also controlled using nested random intercepts in the models. RESULTS: IOP mean (ß = -1.20 µm/y per 1 mm Hg, P < .001) and IOP fluctuation (ß = -3.10 µm/y per 10% unit change in the coefficient of variation, P < .001) were independently negatively associated with subsequent progressive global RNFL changes, after adjustment for age, sex, and baseline RNFL thickness. In the sectoral analysis, both higher mean IOP and IOP fluctuation predicted progressive RNFL thinning in the inferotemporal, superotemporal, superonasal, and temporal sectors in the order of strength of association. In the subgroup analysis by disease category, IOP fluctuation showed greater association with global RNFL thinning in eyes with primary angle closure glaucoma (P = .010) than in eyes without glaucomatous changes (P = .07). CONCLUSIONS: In treated PACD eyes, large IOP fluctuation is an independent predictor for subsequent progressive RNFL thinning in addition to high mean IOP during follow-up.