Real-World Efficacy and Safety of Tafluprost in Primary Open-Angle Glaucoma Patients with Corneal Disorders: A Taiwan Experience.

Purpose: To investigate the efficacy and safety of switching to 0.0015% tafluprost ophthalmic solution with reduced benzalkonium chloride (BAK) on primary open-angle glaucoma (POAG) patients with corneal disorders under 0.005% latanoprost treatment. Material and Methods. This was a single-arm, open-label, switching study on adult POAG patients treated with latanoprost 0.005% for more than 3 months, with corneal disorders but no dry eye therapy. All patients were switched to tafluprost 0.0015% and followed up for 3 months. The primary outcome was the change in fluorescein staining score (National Eye Institute/Industry [NEI] score) at the end of the study. Secondary outcomes included changes in intraocular pressure (IOP), tear break-up time (TBUT), hyperemia score, and other ocular and nonocular adverse events. Results: Of the 20 patients initially enrolled, 17 patients, all with POAG, completed the study. At the end of the study, the mean NEI score significantly decreased by 1.8 ± 2.2 (p < 0.01). No significant changes in IOP were observed (12.8 ± 4.6 mmHg at baseline vs. 12.3 ± 4.0 mmHg on visit 2; p=0.470). TBUT increased by 1.2 ± 1.7 seconds (p < 0.05). The proportions of patients with no sign of hyperemia on the bulbar and palpebral conjunctiva increased from 58.5% to 64.7% at baseline (before switching to tafluprost treatment) to 94.1% and 94.1%, respectively, after switching to tafluprost treatment. Dry eye sensation scores were significantly reduced (p < 0.05), while other ocular symptom scores did not change significantly. Conclusion: Switching to tafluprost 0.0015% significantly improved fluorescein staining score, TBUT, and conjunctival hyperemia while maintaining IOP control among POAG patients with corneal disorders.

A Pooled Assessment of Ocular Surface Disease After Switching from Preserved Prostaglandins to Tafluprost Across Six Countries in Asia.

Background: Preserved prostaglandin analogs (PGAs) have been linked to ocular surface disease (OSD). While the benefits of preservative-low (PL) or -free (PF) Tafluprost (Santen Inc., Japan) were reported in real-world studies in Western countries, this is the first study in Asia to assess the effectiveness and safety of switching from preserved PGA to PL or PF-Tafluprost. Methods: We conducted a meta-analysis on studies that included adults (>18 years of age) with a Corneal Fluorescein Staining Score (CFS) >1. These individuals had switched to PL or PF-tafluprost after using a preserved PGA therapy for at least 3 months for glaucoma and were identified from Santen's tafluprost study database. A total of six studies from South Korea, Philippines, Malaysia, Singapore, Thailand, Taiwan were pooled for analysis. Results: An intraocular pressure (IOP) reduction of 5.9% (0.91 mmHg) was seen in 265 patients. However, this result was not statistically significant (95% CI: -3.64, 1.81; Figure 1). Among 132 patients, a 47.9% reduction in the CFS (95% CI: -3.65, -1.91) was seen. Tear film break-up (n=183) significantly increased by 1.06 seconds (95% CI: 0.65, 1.47). In 88 patients, the bulbar conjunctiva score decreased by -0.46 (95% CI: -0.81, -0.10) and palpebral conjunctiva score decreased by -0.42 (95% CI: -0.67-0.17). One or more new adverse reactions were reported in 3% of the individuals after switching. Conclusion: Tafluprost IOP reduction is comparable to other PGAs, with significant improvements in the ocular surface and minimal adverse reactions which were already previously reported.

Novel Mutations in the TMPRSS3 Gene may Contribute to Taiwanese Patients with Nonsyndromic Hearing Loss.

A previous study indicated that mutations in the transmembrane protease serine 3 (TMPRSS3) gene, which encodes a transmembrane serine protease, cause nonsyndromic hearing loss (NSHL). This was the first description of a serine protease involved in hearing loss (HL). In Taiwan, however, data on the TMPRSS3 gene's association with NSHL is still insufficient. In this study, we described 10 mutations of TMPRSS3 genes found in 14 patients after screening 230 children with NSHL. The prevalence of the TMPRSS3 mutation appeared to be 6.09% (14/230). Of the 10 mutations, three were missense mutations: c.239G>A (p.R80H), c.551T>C (p.L184S), and 1253C>T (p.A418V); three were silent mutations, and four were mutations in introns. To determine the functional importance of TMPRSS3 mutations, we constructed plasmids carrying TMPRSS3 mutations of p.R80H, p.L184S, and p.A418V. TMPRSS3 function can be examined by secretory genetic assay for site-specific proteolysis (sGASP) and Xenopus oocyte expression system. Our results showed that p.R80H, p.L184S, and p.A418V TMPRSS3 mutations gave ratios of 19.4%, 13.2%, and 27.6%, respectively, via the sGASP system. Moreover, these three TMPRSS3 mutations failed to activate the epithelial sodium channel (ENaC) in the Xenopus oocyte expression system. These results indicate that the p.R80H, p.L184S, and p.A418V missense mutations of TMPRSS3 resulted in greatly diminishing the proteolytic activity of TMPRSS3. Our study provides information for understanding the importance of TMPRSS3 in the NSHL of Taiwanese children and provides a novel molecular explanation for the role of TMPRSS3 in HL.

Evolutionary histories of coxsackievirus B5 and swine vesicular disease virus reconstructed by phylodynamic and sequence variation analyses.

Coxsackievirus (CV)-B5 is a common human enterovirus reported worldwide; swine vesicular disease virus (SVDV) is a porcine variant of CV-B5. To clarify the transmission dynamics and molecular basis of host switching between CV-B5 and SVDV, we analysed and compared the VP1 and partial 3Dpol gene regions of these two viruses. Spatiotemporal dynamics of viral transmission were estimated using a Bayesian statistical inference framework. The detected selection events were used to analyse the key molecules associated with host switching. Analyses of VP1 sequences revealed six CV-B5 genotypes (A1-A4 and B1-B2) and three SVDV genotypes (I-III). Analyses of partial 3Dpol revealed five clusters (A-E). The genotypes evolved sequentially over different periods, albeit with some overlap. The major hub of CV-B5 transmission was in China whereas the major hubs of SVDV transmission were in Italy. Network analysis based on deduced amino acid sequences showed a diverse extension of the VP1 structural protein, whereas most sequences were clustered into two haplotypes in the partial 3Dpol region. Residue 178 of VP1 showed four epistatic interactions with residues known to play essential roles in viral host tropism, cell entry, and viral decoating.

An Application of NGS for WDR36 Gene in Taiwanese Patients with Juvenile-Onset Open-Angle Glaucoma.

Primary open-angle glaucoma (POAG) is one of the most important disease in ophthalmology with high prevalence and risk of irreversible blindness. If diagnosed before the age of 35, it is usually categorized as juvenile open-angle glaucoma (JOAG). The WDR36 gene is reckoned as one of the major causative genes of POAG, and had been studied to be related to the pathogenesis of POAG in the literature. We have selected 61 JOAG patients and 61 JOAG-free individuals, and by next-generation sequencing method, the WDR36 gene of the subjects were analyzed. We identified 26 variations exclusively in JOAG group. Among these 26 variations, there were 3 noteworthy variations. First, a novel variation c.460-650A>G was found in our study which might cause premature termination of splicing of the conserved domain in WDR36; second, c.1494+1111G>T (rs13178997) had significantly different frequency in our JOAG patients compared to the reference frequency on NCBI; third, a variation c.710+30C>T (rs10038177) was found in our study, which had already been reported to be related to high-pressure glaucoma. We offer the profile of WDR36 in JOAG in Taiwan population, and we suggest that WDR36 gene is involved in the pathogenesis of JOAG as a subordinate modifier gene.

Phylodynamic Characterization of an Ocular-Tropism Coxsackievirus A24 Variant.

Recent phylodynamic studies have focused on using tree topology patterns to elucidate interactions among the epidemiological, evolutionary, and demographic characteristics of infectious agents. However, because studies of viral phylodynamics tend to focus on epidemic outbreaks, tree topology signatures of tissue-tropism pathogens might not be clearly identified. Therefore, this study used a novel Bayesian evolutionary approach to analyze the A24 variant of coxsackievirus (CV-A24v), an ocular-tropism agent of acute hemorrhagic conjunctivitis. Analyses of the 915-nucleotide VP1 and 690-nt 3Dpol regions of 21 strains isolated in Taiwan and worldwide during 1985-2010 revealed a clear chronological trend in both the VP1 and 3Dpol phylogenetic trees: the emergence of a single dominant cluster in each outbreak. The VP1 sequences included three genotypes: GI (prototype), GIII (isolated 1985-1999), and GIV (isolated after 2000); no VP1 sequences from GII strains have been deposited in GenBank. Another five genotypes identified in the 3Dpol region had support values >0.9. Geographic and demographic transitions among CV-A24v clusters were clearly identified by Bayes algorithm. The transmission route was mapped from India to China and then to Taiwan, and each prevalent viral population declined before new clusters emerged. Notably, the VP1 and 3Dpol genes had high nucleotide sequence similarities (94.1% and 95.2%, respectively). The lack of co-circulating lineages and narrow tissue tropism affected the CV-A24v gene pool.

RISK OF RETINAL VEIN OCCLUSION IN PATIENTS WITH PSORIASIS: A Population-Based Cohort Study.

PURPOSE: To investigate the risk of developing retinal vein occlusion (RVO) in patients with psoriasis. METHODS: In this retrospective population-based cohort study, 30,198 patients with psoriasis (Psoriasis((+)) group) and 30,198 controls without psoriasis (Psoriasis((−)) group) between 2001 and 2006 from the Taiwan National Health Insurance Research Database were selected. RESULTS: The incidence of RVO was 1.46 times higher in the Psoriasis((+)) group than in the Psoriasis((−)) group (3.61 vs. 2.47/10,000 person-years) (adjusted hazard ratio = 1.50; 95% confidence interval = 1.07-2.10) calculated using Cox proportional hazard regression. Age was an independent risk factor for RVO (adjusted hazard ratio: 11.9 for patients 65 years or older vs. 1.00 for those 0-49 years old). In the 65 years or older Psoriasis((+)) group, the incidence of developing RVO was 1.97 times higher (95% confidence interval = 1.19-3.26) than in the 65 years or older Psoriasis((−)) group. In Psoriasis((+)) women, the incidence of developing RVO was 1.82 times higher (95% = 1.05-3.14) than in Psoriasis((−)) women. For the subgroup with comorbid hypertension, the incidence of developing RVO was 2.07 times higher (95% confidence interval = 1.22-3.50) in the Psoriasis((+)) group than in the Psoriasis((−)) group. CONCLUSION: Psoriasis was significantly associated with a higher risk of developing RVO.

Higher risk of developing sudden sensorineural hearing loss in patients with chronic otitis media.

IMPORTANCE: Several sources have suggested an association between chronic sensory hearing impairment and chronic otitis media (COM). However, to our knowledge, no studies have evaluated the risk of sudden sensorineural hearing loss (SSNHL) in patients with COM (COM-positive). OBJECTIVE: To examine the risk of developing SSNHL in COM-positive patients. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study; we compared 10 248 patients with newly diagnosed COM from January 1, 2001, through December 31, 2008, with 30 744 age- and sex-matched controls using data from Taiwan's National Health Insurance Research Database. METHODS: We followed each patient and evaluated the incidence of SSNHL. MAIN OUTCOMES AND MEASURES: The incidence of SSNHL at the end of 2011. RESULTS: The incidence of SSNHL was 3 times higher in the COM-positive cohort than in the COM-negative cohort (14.47 vs 4.83 per 10 000 person-years). Cox proportional hazard regressions showed that the adjusted hazard ratio (AHR) was 3.02 (95% CI, 2.30-3.98). A stratified analysis showed that the highest risk of developing SSNHL was in the first follow-up year (incidence rate ratio [IRR], 3.87; 95% CI, 1.93-7.79). Thereafter, the risk declined during years 1 to 5 and then peaked (IRR, 3.01; 95% CI, 1.89-4.79). Patients who needed surgery had a higher incidence of SSNHL (AHR, 2.69; 95% CI, 1.62-4.48) compared with patients who needed only medication and observation. CONCLUSIONS AND RELEVANCE: Chronic otitis media was significantly associated with a higher risk of developing SSNHL.

Risk of sudden sensorineural hearing loss in patients with psoriasis: a retrospective cohort study.

SIGNIFICANCE: Psoriasis, a common immune-mediated disease, affects approximately 2% of the population worldwide. Sudden sensorineural hearing loss (SSNHL) might be a manifestation of systemic vascular involvement in autoimmune disease. However, to the best of our knowledge, there is no systematic English-language examination of the risk of SSNHL in patients with psoriasis. OBJECTIVES: We tested the hypothesis that psoriasis is a risk factor for developing SSNHL. METHODS: Using Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study to compare patients diagnosed with psoriasis from January 1, 2001 through December 31, 2006 (n=28,817) with gender-, age-, and comorbidities-matched controls (n=28,817). We followed each patient until the end of 2011 and evaluated the incidence of SSNHL for at least 6 years after the initial psoriasis diagnosis. RESULTS: The incidence of SSNHL was 1.51 times higher in the psoriasis cohort than in the control cohort (7.12 vs 4.73 per 10,000 person-years). Using Cox proportional hazard regressions, the adjusted hazard ratio (AHR) was 1.51 (95% confidence interval [CI] 1.18-1.93). Comorbid hypertension was an independent risk factor for SSNHL (AHR 1.49; 95% CI 1.05-2.13). However, the incidence rate ratios (IRRs) for each comorbidity subgroup in the psoriasis and control cohorts were not significantly different. CONCLUSIONS AND RELEVANCE: Psoriasis was significantly associated with a higher risk of developing SSNHL. We suggest that physicians advise patients with psoriasis to seek medical attention if they have hearing impairments, because they may also have a higher risk of developing SSNHL.

Effect of metformin on the incidence of head and neck cancer in diabetics.

BACKGROUND: The purpose of this study was to examine the effect of metformin on head and neck cancer in patients with diabetes. METHODS: We compared 66,600 patients, all with diabetes and all newly diagnosed with head and neck cancer in 2002. Half were being treated with metformin for diabetes (Met(+) ) and half were not (Met(-) : controls). All were matched for comorbidities (obesity, coronary artery disease, hyperlipidemia, and hypertension), sex, and age. The risk of head and neck cancer at the end of 2011 was determined. RESULTS: The incidence of head and neck cancer was 34% lower in the Met(+) cohort than in the Met(-) cohort (adjusted hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.55-0.79). The risks for oropharyngeal cancer (adjusted HR = 0.66; 95% CI = 0.17-0.74) and nasopharyngeal carcinoma (NPC; adjusted HR = 0.50; 95% CI = 0.31-0.80) were significantly lower in the Met(+) cohort than in the Met(-) cohort. CONCLUSION: Metformin is associated with a lower risk of developing head and neck cancer in patients with diabetes.

The connexin 30.3 of zebrafish homologue of human connexin 26 may play similar role in the inner ear.

The intercellular gap junction channels formed by connexins (CXs) are important for recycling potassium ions in the inner ear. CXs are encoded by a family of the CX gene, such as GJB2, and the mechanism leading to mutant connexin-associated diseases, including hearing loss, remains to be elucidated. In this study, using bioinformatics, we found that two zebrafish cx genes, cx27.5 and cx30.3, are likely homologous to human and mouse GJB2. During embryogenesis, zebrafish cx27.5 was rarely expressed at 1.5-3 h post-fertilization (hpf), but a relatively high level of cx27.5 expression was detected from 6 to 96 hpf. However, zebrafish cx30.3 transcripts were hardly detected until 9 hpf. The temporal experiment was conducted in whole larvae. Both cx27.5 and cx30.3 transcripts were revealed significantly in the inner ear by reverse transcription polymerase chain reaction (RT-PCR) and whole-mount in situ hybridization (WISH). In the HeLa cell model, we found that zebrafish Cx27.5 was distributed intracellularly in the cytoplasm, whereas Cx30.3 was localized in the plasma membrane of HeLa cells stably expressing Cx proteins. The expression pattern of zebrafish Cx30.3 in HeLa cells was more similar to that of cells expressing human CX26 than Cx27.5. In addition, we found that Cx30.3 was localized in the cell membrane of hair cells within the inner ear by immunohistochemistry (IHC), suggesting that zebrafish cx30.3 might play an essential role in the development of the inner ear, in the same manner as human GJB2. We then performed morpholino knockdown studies in zebrafish embryos to elucidate the physiological functions of Cx30.3. The zebrafish cx30.3 morphants exhibited wild-type-like and heart edema phenotypes with smaller inner ears at 72 hpf. Based on these results, we suggest that the zebrafish Cx30.3 and mammalian CX26 may play alike roles in the inner ear. Thus, zebrafish can potentially serve as a model for studying hearing loss disorders that result from human CX26 mutations.

Risk of retinal vein occlusion in patients with systemic lupus erythematosus: a population-based cohort study.

BACKGROUND/AIMS: To investigate the risk of developing retinal vein occlusion (RVO) in patients with systemic lupus erythematosus (SLE). METHODS: In this retrospective population-based cohort study, 6756 patients with SLE and 40 536 controls without SLE (1:6) were selected from the Taiwan National Health Insurance Research Database claims from 2001 to 2006. RESULTS: The incidence of RVO was 3.46-times higher in the SLE group than in controls (5.61 vs 1.62 per 10 000 person-years) (adjusted HR=3.883, 95% CI 2.299 to 6.558) calculated using Cox proportional hazard regression. Age was an independent risk factor for RVO, with adjusted HRs of 4.842 for individuals aged ≥50 years compared with those 0-49 years. For each age subgroup, the risk of RVO was significantly higher only in the 0-49-year-old SLE group than in controls. In the 0-49-year-old SLE group the incidence of developing RVO was 7.92 times higher (95% CI 3.60 to 17.45) in the SLE group than in the 0-49-year-old controls. In women with SLE, the incidence of developing RVO was 3.33-times higher (95% CI 1.88 to 5.90) than in female controls. CONCLUSIONS: SLE was significantly associated with an increased risk of developing RVO.

Mechanism of two novel human GJC3 missense mutations in causing non-syndromic hearing loss.

Connexins (CXs), as a component of gap junction channel, are homologous four transmembrane-domain proteins, with numerous studies confirming their auditory functions. Among a cohort of patients having incurred non-syndromic hearing loss, we identified two novel missense mutations, p.R15G and p.L23H, in the GJC3 gene encoding CX30.2/CX31.3, as causally related to hearing loss in previous study. However, the functional alteration of CX30.2/CX31.3 caused by the mutant GJC3 gene remains unknown. In this study, we compared the intracellular distribution of mutant CX30.2/CX31.3 (p.R15G and p.L23H) with the wild-type (WT) protein in HeLa cells and the effect of the mutant protein had on those cells. Analytical results indicated that p.R15G and p.L23H mutant exhibited continuous staining along apposed cell membranes in the fluorescent localization assay, which is the same with the WT. Moreover, ATP release (hemichannel function) is less in HeLa cells carrying mutant GJC3 genes than those of WT expressing cells. We believe that although p.R15G and p.L23H mutants do not decrease the trafficking of CX proteins, mutations in GJC3 genes result in a loss of hemichannel function of CX30.2/CX31.3 protein, possibly causing hearing loss. Results of this study provide a novel molecular explanation for the role of GJC3 in hearing loss.

Absence of optineurin (OPTN) gene mutations in Taiwanese patients with juvenile-onset open-angle glaucoma.

PURPOSE: To investigate sequence variants in the optineurin (OPTN) gene in patients with juvenile-onset open-angle glaucoma (JOAG) in Taiwan. METHODS: We analyzed the sequence variants of OPTN in 51 unrelated Taiwanese probands with JOAG and in 51 control group subjects who did not have JOAG. Genomic DNA was extracted from the individuals and subjected to polymerase chain reaction (PCR) to amplify all 16 exons and flanking introns of OPTN. The amplified products were then screened for base variants by autosequence. Data from the two study groups were then compared using Fisher's exact test and Armitage's trend test. RESULTS: Fifteen variants of OPTN were found in the 51 JOAG patients and 51 unrelated normal controls. Two were missense variants (M98K and K322E), one was a synonymous codon change (T34T), and 12 were changes in the noncoding sequences. Seven of the variants have been reported and eight were novel. All of the sequence changes were found in patients with JOAG and in the normal controls except for variant c.-233+25C>G, which was found only in the control group. Allelic frequencies of these sequence changes did not differ significantly between patients and controls (p>0.05) except for the variant c.-233+25C>G (p<0.001). Genotype frequencies of c.-233+25C>G was shown to be significant between the two groups using Fisher's two-tailed exact test (p<0.001) and Armitage's trend test (p=6.815e(-06)). CONCLUSIONS: Our data indicate that none of the mutations in OPTN are associated with JOAG. The variant M98K is not a risk factor and the variant c.-233+25C>G may be protective against glaucoma in Taiwanese.

Identification of mutations in the myocilin (MYOC) gene in Taiwanese patients with juvenile-onset open-angle glaucoma.

PURPOSE: To investigate mutations in the promoter and coding regions of the myocilin (MYOC) gene in Taiwanese patients suffering from juvenile-onset open-angle glaucoma (JOAG). METHODS: MYOC was analyzed for mutations in 48 unrelated Taiwanese probands with JOAG and in 100 healthy control subjects. Genomic DNA was extracted from peripheral blood leukocytes and then subjected to PCR to amplify exons, flanking introns and promoter regions of the MYOC gene. The amplified products were screened for base mutations by autosequence. Data from the two groups were then compared using the chi(2) test. Finally, the levels of MYOC transcripts were predicted by a neural network prediction system to study whether the intron mutations have any effect on the level of mRNA expression. RESULTS: The analysis revealed four MYOC mutations and six polymorphisms. The prevalence of MYOC gene mutations in this study was 12.5% (6/48). The mutations included one nonsense mutation (Arg46Stop; 3/6), one missense mutation (Val56Ala; 1/6), one intron mutation (c.604+228A>T; 1/6) as well as one mutation in the 3'-untranslated region (c.1515+73G>C; 1/6). In addition, although c.604+228A>T is an intron mutation and does not alter the content of the amino acid residue, the neural network prediction system revealed that it can potentially create a novel accept splice site during transcription. This mutation might affect the protein structure and consequently the normal function of myocilin. CONCLUSIONS: Our results indicate that the c.136C>T (Arg46Stop), c.158T>C (Val56Ala), c.604+228A>T, and c.1515+73G>C mutations of MYOC may be associated with JOAG. In addition, we suggest that the c.136C>T (Arg46Stop) mutation of MYOC is a hot spot in Taiwanese patients with JOAG.