The Clinical Efficacy of Different Relaxation Exercises on Intraocular Pressure Reduction: A Meta-Analysis.

Objective: The aim of this study was to synthesize the available evidence on the clinical efficacy of different relaxation exercises on intraocular pressure (IOP) reduction. Methods: A systemic search of PubMed, Embase, Cochrane CENTRAL, and Web of Science was undertaken from the earliest record to 10 April 2024. Peer-reviewed studies that reported on healthy individuals and glaucoma patients engaging in relaxation exercises for at least three weeks were included. The primary outcome was changes in IOP levels from baseline, before the commencement of relaxation exercises, to post-exercise. Our statistical analysis employed a random-effects model, with effect sizes reported using Hedges' g. Results: Twelve studies were included, totaling 764 eyes (mean participant age ranging from 21.07 to 69.50 years). Relaxation exercises significantly reduced IOP, with Hedges' g being -1.276 (95% CI: -1.674 to -0.879) and I2 = 84.4%. Separate subgroup analyses showed that breathing exercises (Hedges' g = -0.860, p < 0.0001), mindfulness-based stress reduction (MBSR) (Hedges' g = -1.79, p < 0.0001), and ocular exercises (Hedges' g = -0.974, p < 0.0001) were associated with reduced IOP levels. The reduction in IOP following the relaxation exercises was found to be associated with baseline IOP either greater than (Hedges' g = -1.473, p < 0.0001) or less than 21 mmHg (Hedges' g = -1.22, p < 0.0001). Furthermore, this effect persisted with follow-up durations of less than (Hedges' g = -1.161, p < 0.0001) and more than one month (Hedges' g = -1.324, p < 0.0001). Conclusions: The current meta-analysis indicates that relaxation exercises can significantly reduce IOP levels. Relaxation exercises are a potential class of novel treatments for glaucoma patients that deserve further evaluation.

Assessing Uveitis Risk following Pediatric Down Syndrome Diagnosis: A TriNetX Database Study.

Background and Objectives: The risks of uveitis development among pediatric patients with Down syndrome (DS) remain unclear. Therefore, we aimed to determine the risk of uveitis following a diagnosis of DS. Materials and Methods: This multi-institutional retrospective cohort study utilized the TriNetX database to identify individuals aged 18 years and younger with and without a diagnosis of DS between 1 January 2000 and 31 December 2023. The non-DS cohort consisted of randomly selected control patients matched by selected variables. This included gender, age, ethnicity, and certain comorbidities. The main outcome is the incidence of new-onset uveitis. Statistical analysis of the uveitis risk was reported using hazard ratios (HRs) and 95% confidence intervals (CIs). Separate analyses of the uveitis risk among DS patients based on age groups and gender were also performed. Results: A total of 53,993 individuals with DS (46.83% female, 58.26% white, mean age at index 5.21 ± 5.76 years) and 53,993 non-DS individuals (45.56% female, 58.28% white, mean age at index 5.21 ± 5.76 years) were recruited from the TriNetX database. Our analysis also showed no overall increased risk of uveitis among DS patients (HR: 1.33 [CI: 0.89-1.99]) compared to the non-DS cohort across the 23-year study period. Subgroup analyses based on different age groups showed that those aged 0-1 year (HR: 1.36 [CI: 0.68-2.72]), 0-5 years (HR: 1.34 [CI: 0.75-2.39]), and 6-18 years (HR: 1.15 [CI: 0.67-1.96]) were found to have no association with uveitis risk compared to their respective non-DS comparators. There was also no increased risk of uveitis among females (HR: 1.49 [CI: 0.87-2.56]) or males (HR: 0.82 [CI: 0.48-1.41]) with DS compared to their respective non-DS comparators. Conclusions: Our study found no overall increased risk of uveitis following a diagnosis of DS compared to a matched control population.

The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.

Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/Cys192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1ß release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.

Prevalence of uveitis in syphilis patients in Taiwan.

Few population-based studies have looked at the risk of uveitis among syphilis patients. Our study addresses the knowledge gap by reporting on uveitis risk in syphilis patients through a retrospective cohort study. The Taiwan National Health Insurance database was used for this study, covering the period from January 1st, 2009, to December 31st, 2020. We created a 1:4 propensity score matched cohort between the syphilis patients and controls, which accounted for gender, age, and comorbidities. The primary endpoint was the incidence of newly recorded uveitis. The assessment of uveitis risk in syphilis patients included the use of the Kaplan-Meier method and multivariate Cox proportional hazard model. A total of 31,597 syphilis patients and 126,379 matched comparisons were recruited. The uveitis incidence rate from our syphilis patients was 1.25 per 1000 person-years. The uveitis incidence rate from our non-syphilis group was 0.8 per 1000 person-years. After matching, the syphilis group was found to have a higher risk of developing uveitis (adjusted hazard ratio (aHR) [95% CI]: 1.57 [1.36-1.81], P < .001). Among males and individuals aged 20-34 years, subgroup analysis showed an increased risk of uveitis in the presence of syphilis infection. The Kaplan-Meier survival curve showed a significant difference in uveitis incidence between syphilis and non-syphilis groups (log-rank test P < .001). In summary, our study revealed that Taiwanese syphilis patients were at a higher risk of developing uveitis. These results highlight the need for regular ocular monitoring and screening in individuals with syphilis.

The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study.

Reports on uveitis after COVID-19 have been limited. Our objective was to examine the risk of uveitis among COVID-19 patients. This was a retrospective cohort study based on the TriNetX platform. The exposure group was patients with positive laboratory test result for SARS-CoV-2 and the comparison group was those tested negative for COVID-19 throughout the study period. The endpoint is the new diagnoses of uveitis. This study composed of 2 105 424 patients diagnosed with COVID-19 (55.4% female; 62.5% white; mean age at index 40.7 years) and 2 105 424 patients (55.4% female; 62.4% white; mean age at index 40.7 years) who never had COVID-19. There was significantly increased risk of new diagnosis of uveitis since the first month after diagnosis of COVID-19 compared with matched controls (HR: 1.18, 95% CI: 1.03-1.34) up to 24 months (HR: 1.16, 95% CI: 1.09-1.22). Our findings strengthen those previously raised by case series with a larger and multicenter study. We found that uveitis was significantly associated with COVID-19 infection. Our findings reiterate the need for careful investigation as well as increased awareness from ophthalmologists in considering the possibility of COVID-19 in vulnerable patients with new presentation of uveitis.

Clinical Efficacy of Omidenepag Isopropyl for Primary Open-Angle Glaucoma, Normal Tension Glaucoma, or Ocular Hypertension: A Meta-Analysis.

Purpose: To investigate the clinical efficacy of omidenepag isopropyl (OMDI) among glaucoma patients in terms of increased intraocular pressure (IOP) changes through a meta-analysis. Methods: Studies investigating the clinical efficacy of OMDI toward glaucoma patients were systemically searched. Inclusion criteria include recruiting studies that consisted of glaucoma or normal tension glaucoma patients who received OMDI treatment at least 4 weeks in duration. The primary outcome was to compare changes in IOP levels at baseline before OMDI treatment and after OMDI treatment. Results: Six studies were included with a total of 358 eyes. Our results showed OMDI monotherapy resulted in significant decreased IOP among patients with ocular hypertension, with weighted mean difference post-OMDI treatment being -4.684 (95% confidence interval: -6.010 to -3.358) and I2 of 91.092%. Separate subgroup analyses also showed initial IOP greater than 21 mmHg and those within the age group greater than 65 years old to be correlated with significant reduction in IOP post-OMDI. Randomized control trial (RCTs) design was also found to be superior compared with non-RCT in terms of investigating IOP changes after OMDI. The country of origin of the recruited studies and OMDI dosage frequencies were also found to have no effect on overall IOP changes after OMDI treatment. Conclusions: The current meta-analysis indicates OMDI to be a clinically effective treatment for glaucoma patients in terms of lowering IOP levels.

NLRP3 is essential for neutrophil polarization and chemotaxis in response to leukotriene B4 gradient.

Neutrophil recruitment to sites of infection and inflammation is an essential process in the early innate immune response. Upon activation, a subset of neutrophils rapidly assembles the multiprotein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome forms at the microtubule organizing center, which promotes the formation of interleukin (IL)-1ß and IL-18, essential cytokines in the immune response. We recently showed that mice deficient in NLRP3 (NLRP3-/-) have reduced neutrophil recruitment to the peritoneum in a model of thioglycolate-induced peritonitis. Here, we tested the hypothesis that this diminished recruitment could be, in part, the result of defects in neutrophil chemotaxis. We find that NLRP3-/- neutrophils show loss of cell polarization, as well as reduced directionality and velocity of migration toward increasing concentrations of leukotriene B4 (LTB4) in a chemotaxis assay in vitro, which was confirmed through intravital microscopy of neutrophil migration toward a laser-induced burn injury of the liver. Furthermore, pharmacologically blocking NLRP3 inflammasome assembly with MCC950 in vitro reduced directionality but preserved nondirectional movement, indicating that inflammasome assembly is specifically required for polarization and directional chemotaxis, but not cell motility per se. In support of this, pharmacological breakdown of the microtubule cytoskeleton via nocodazole treatment induced cell polarization and restored nondirectional cell migration in NLRP3-deficient neutrophils in the LTB4 gradient. Therefore, NLRP3 inflammasome assembly is required for establishment of cell polarity to guide the directional chemotactic migration of neutrophils.

Tinnitus as a Potential Risk Factor for Uveitis: A 14-Year Nationwide Population-Based Cohort Study in Taiwan.

BACKGROUND: Tinnitus and uveitis have shared commonality in pathophysiology in terms of autoimmunity. However, no studies that have linked any association between the conditions of tinnitus and uveitis. METHODS: This is a retrospective study conducted from the Taiwan National Health Insurance database in order to investigate whether tinnitus patients are at increased risk of uveitis. Patients newly diagnosed with tinnitus between 2001 and 2014 were recruited and followed up until 2018. The endpoint of interest was a diagnosis of uveitis. RESULTS: A total of 31,034 tinnitus patients and 124,136 matched comparisons were analyzed. Tinnitus patients were found to have a significantly higher cumulative incidence for uveitis than those without the diagnosis of tinnitus with incidence rate of 1.68 (95% CI 1.55-1.82) per 10 000 person-months for tinnitus group and 1.48 (95% CI 1.42-1.54) per 10 000 person-months for non-tinnitus group. CONCLUSION: Tinnitus patients were found to have increased risk of developing uveitis.

Method for Visualization of Emergency Granulopoiesis in the Zebrafish Embryo.

Emergency granulopoiesis (EG) is a response to severe inflammation in which increased neutrophils are generated in the hematopoietic tissue. Photolabeling is utilized to distinguish newly developed neutrophils from existing neutrophils. However, this technique requires a strong laser line and labels subsets of the existing neutrophils. Here we create a transgenic zebrafish line that expresses a time-dependent switch from green fluorescent protein (GFP) to red fluorescent protein (RFP) in neutrophils, which allows quantification of EG using simple GFP/RFP ratiometric imaging.

Neutrophil Lifespan Extension with CLON-G and an In Vitro Spontaneous Death Assay.

The average lifespan of a neutrophil is less than 24 h, which limits basic research on neutrophils and the application of neutrophil studies. Our previous research indicated that multiple pathways could mediate the spontaneous death of neutrophils. A cocktail was developed by simultaneously targeting these pathways, caspases-lysosomal membrane permeabilization-oxidant-necroptosis inhibition plus granulocyte colony-stimulating factor (CLON-G), which prolonged the neutrophil lifespan to greater than 5 days without significantly compromising the neutrophil function. Concurrently, a reliable and stable protocol for assessing and evaluating neutrophil death was also developed. In this work, we show that CLON-G can prolong the neutrophil lifespan in vitro to more than 5 days, and we exhibit the lengthening of the neutrophil lifespan with FACS and confocal fluorescence microscopy. This report introduces procedures for the preparation of CLON-G and showcases an in vitro spontaneous death assay of neutrophils, which can be used for the study of neutrophils and for subsequently interrogating neutrophil death, thus providing a reliable resource for the neutrophil community.

Diagnosis and Treatment of Tubercular Uveitis in Taiwan - Consensus of Expert Panels.

There is currently a lack of guidelines with regard to tubercular uveitis (TBU) management in Taiwan. We therefore propose an evidence-based consensus on the management for TBU. The Taiwan Ocular Inflammation Society conducted a meeting that included nine ophthalmologist and one infection disease expert that focused on three broad areas of (1) nomenclature for TBU, (2) assessment and diagnosis for TBU, and (3) treatment of TBU. Brief literature review on TBU diagnosis and management was conducted that informed this panel meeting in order to make decisions on each consensus statements. In terms of our results, a consensus statements and recommendations for the diagnosis and management of TBU were developed. This consensus statement provides an algorithmic approach toward diagnosing and managing TBU. These statements are meant to enhance but not replace individual clinician-patient interactions and to facilitate real-world clinical practice improvement in terms of TBU patients care.

Palmitoylation of gasdermin D directs its membrane translocation and pore formation in pyroptosis.

Gasdermin D (GSDMD)-mediated macrophage pyroptosis plays a critical role in inflammation and host defense. Plasma membrane perforation elicited by caspase-cleaved GSDMD N-terminal domain (GSDMD-NT) triggers membrane rupture and subsequent pyroptotic cell death, resulting in release of pro-inflammatory IL-1ß and IL-18. However, the biological processes leading to its membrane translocation and pore formation are not fully understood. Here, using a proteomics approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner and demonstrated that post-translational palmitoylation of GSDMD at Cys191/Cys192 (human/mouse) led to membrane translocation of GSDMD-NT but not full-length GSDMD. GSDMD lipidation, mediated by palmitoyl acyltransferases ZDHHC5/9 and facilitated by LPS-induced reactive oxygen species (ROS), was essential for GSDMD pore-forming activity and pyroptosis. Inhibition of GSDMD palmitoylation with palmitate analog 2-bromopalmitate or a cell permeable GSDMD-specific competing peptide suppressed pyroptosis and IL-1ß release in macrophages, mitigated organ damage, and extended the survival of septic mice. Collectively, we establish GSDMD-NT palmitoylation as a key regulatory mechanism controlling GSDMD membrane localization and activation, providing a novel target for modulating immune activity in infectious and inflammatory diseases. One Sentence Summary: LPS-induced palmitoylation at Cys191/Cys192 is required for GSDMD membrane translocation and its pore-forming activity in macrophages.

Optical Coherence Tomography Biomarkers in Predicting Treatment Outcomes of Diabetic Macular Edema after Ranibizumab Injections.

Background and Objectives: The identification of possible biomarkers that can predict treatment response among DME eyes is important for the individualization of treatment plans. We investigated optical coherence tomography (OCT)-based biomarkers that may predict the one-year real-life outcomes among diabetic macular edema (DME) eyes following treatment by intravitreal ranibizumab (IVR) injections. Materials and Methods: A total of 65 eyes from 35 treatment-naïve patients with DME treated with ranibizumab injection were recruited. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), and OCT scans were retrospectively recorded at baseline before treatment and at 3 months, 6 months, and 12 months after treatment. The OCT scans were evaluated for biomarkers of interest, which included central retinal thickness (CRT), amount and locations of hyperreflective foci (HRF), subretinal fluid (SRF), intraretinal cysts (IRC), large outer nuclear layer cyst (LONLC), ellipsoid zone disruption (EZD), disorganization of retinal inner layers (DRIL), hard exudates (HE), epiretinal membrane (ERM), and vitreomacular interface (VMI). Correlations between these OCT biomarkers and outcome measures (visual and structural) were statistically analyzed. Results: A total of 65 eyes from 35 patients with DME were enrolled. The mean age was 64.2 ± 10.9 years old. Significant improvement in terms of mean BCVA (p < 0.005) and mean CRT was seen at final follow-up compared to baseline. The biomarkers of DRIL, LONLC, and SRF were found to be predictive for at least 50 µm CRT reduction after treatment (with odds ratio of 8.69, 8.5, and 17.58, respectively). The biomarkers of IRC, LONLC, and SRF were predictive for significant improvement in terms of BCVA and CRT after treatment. Finally, the number of HRF was predictive for both BCVA improvement and a CRT reduction of less than 100 µm after treatment. No serious complications were reported during the study. Conclusion: Our study demonstrated the utility of OCT biomarkers as therapeutic predictors of ranibizumab treatment among DME eyes.

Diabetic retinopathy as a potential risk factor for ptosis: A 13-year nationwide population-based cohort study in Taiwan.

Purpose: To determine the risk of ptosis among diabetic retinopathy (DR) patients. Methods: This is a population-based, retrospective, matched-cohort study where DR patients were recruited from the Taiwan National Health Insurance Research Database (NHIRD) to investigate the risk of developing ptosis. Preexisting co-factors of interest included smoking status and medical comorbidities of hyperlipidemia and hypertension. Statistical analysis was performed using T-test, Cox-proportional hazard ratios adjusted for comorbidities (aHR), Wilcoxon rank sum test, Kaplan-Meier estimators, and log rank tests. Results: Follow-up data of 9,494 patients with DR and 37,976 matched control cohort (non-DR) from 2000 to 2012 were analyzed. DR patients were found to have significantly increased risk of developing ptosis (adjusted hazard ratio (HR) [95% CI]: 2.76 [1.74-4.38], p < 0.001) when compared to the control cohort. From analysis in different strata, adult age and non-smokers were shown to have higher risk for ptosis development among DR patients. Furthermore, DR patients was also found to have increased risk of developing ptosis when compared to matched controls, regardless of whether they had medical comorbidities of lipid metabolism disorders or hypertension. Conclusions: In this large-scale study using real-world data, our results showed that DR patients were found to have increased risk of developing ptosis. Female gender, adult age, and non-smokers were also shown to increase the risk of ptosis among DR patients. This has implications towards the care of diabetic patients, complications such as ptosis should be properly screened for when encountering such patients. Before ptosis surgery, the possibility of underlying diabetes or DR should be also scrutinized and treated properly to avoid undesirable postoperative dissension.

Association between immune checkpoint inhibitor medication and uveitis: a population-based cohort study utilizing TriNetX database.

Objective: To explore the associations between the use of immune checkpoint inhibitors (ICIs) and the risk of developing uveitis among cancer patients. Methods: Cancer patients who received ICI therapy and a comparison group of cancer patients who did not receive ICI therapy were retrospectively recruited from the TriNetX electronic heath-record registry. The outcome of interest was the development of new-onset uveitis. Propensity score matching based on a 1:1 ratio was conducted in order to reduce bias. Multi-variate cox proportional hazard models and Kaplan Meier method were also utilized to assess for the risk of uveitis among cancer patients who received ICI therapy. Results: 71931 cancer patients (54.7% male; 76.5% white; mean age at index 63.6 ± 12.2 years) who received ICI treatment (ICI group) and 71931 cancer patients (54.7% male; 77% white; mean age at index 63.5 ± 12.4 years) who never received ICI (comparison group) were recruited. Associated Kaplan-Meier curves showed significantly increased uveitis risk among the ICI group for all follow-up years (p<0.001). The risk of uveitis was also higher among the ICI group during the 144-month follow-up period with a hazard ratio (HR) of 2.39 (95% CI: 2.07-2.75). Increased risk for specific uveitis diseases, such as iridocyclitis, chorioretinal inflammation, retinal vasculitis, unspecified purulent endophthalmitis, pan-uveitis and sympathetic uveitis were found. Subgroup analysis demonstrated an elevated hazard ratio for the development of uveitis among ICI recipients, spanning individuals below the age of 65 as well as those aged 65 and older. The elevated hazard ratio for uveitis development among ICI recipients was also observed across all genders, among those of white and Asian ethnicities, those with smoking history, and those with comorbid conditions such as hypertension and dyslipidemia, in comparison to their non-ICI counterparts. An additional subgroup analysis on monotherapy versus combinatory ICI regimens was also conducted. Individuals who received monotherapy from the class of anti-PD-1 (HR:1.98 [CI: 1.65-2.37]) and anti-CTLA-4 (HR:5.86 [CI:1.99-17.24]) exhibited elevated hazard ratios for uveitis development compared to their non-ICI comparators. Those exposed to combinatory ICI regimens, specifically a combination of anti-PD-1 and anti-CTLA4 (HR: 5.04 [CI:3.55-7.16]), showed increased hazard ratios for uveitis development compared to their non-ICI comparators. In contrast, individuals exposed to a combination of anti-PD-1 and anti-PD-L1 (HR: 2.47 [CI:0.81-7.50]) did not demonstrate an increased risk for uveitis compared to their non-ICI comparators. Conclusion: A significantly increased risk for uveitis diseases was found among the ICI group from the first year of follow-up. Increased awareness should be promoted on the occurrence of uveitis among cancer patients receiving ICI therapy.