Self-Supervised Learning-Based General Laboratory Progress Pretrained Model for Cardiovascular Event Detection.

OBJECTIVE: Leveraging patient data through machine learning techniques in disease care offers a multitude of substantial benefits. Nonetheless, the inherent nature of patient data poses several challenges. Prevalent cases amass substantial longitudinal data owing to their patient volume and consistent follow-ups, however, longitudinal laboratory data are renowned for their irregularity, temporality, absenteeism, and sparsity; In contrast, recruitment for rare or specific cases is often constrained due to their limited patient size and episodic observations. This study employed self-supervised learning (SSL) to pretrain a generalized laboratory progress (GLP) model that captures the overall progression of six common laboratory markers in prevalent cardiovascular cases, with the intention of transferring this knowledge to aid in the detection of specific cardiovascular event. METHODS AND PROCEDURES: GLP implemented a two-stage training approach, leveraging the information embedded within interpolated data and amplify the performance of SSL. After GLP pretraining, it is transferred for target vessel revascularization (TVR) detection. RESULTS: The proposed two-stage training improved the performance of pure SSL, and the transferability of GLP exhibited distinctiveness. After GLP processing, the classification exhibited a notable enhancement, with averaged accuracy rising from 0.63 to 0.90. All evaluated metrics demonstrated substantial superiority ([Formula: see text]) compared to prior GLP processing. CONCLUSION: Our study effectively engages in translational engineering by transferring patient progression of cardiovascular laboratory parameters from one patient group to another, transcending the limitations of data availability. The transferability of disease progression optimized the strategies of examinations and treatments, and improves patient prognosis while using commonly available laboratory parameters. The potential for expanding this approach to encompass other diseases holds great promise. CLINICAL IMPACT: Our study effectively transposes patient progression from one cohort to another, surpassing the constraints of episodic observation. The transferability of disease progression contributed to cardiovascular event assessment.

Molecular and Phenotypic Characterization of Ocular Methicillin-Resistant Staphylococcus epidermidis Isolates in Taiwan.

Purpose: Staphylococcus epidermidis, a commensal, has emerged as an important opportunistic pathogen, particularly methicillin-resistant S. epidermidis (MRSE). The mechanism behind this transformation remains unclear. This study aimed to investigate the molecular and phenotypic characteristics of MRSE isolated from healthy conjunctiva and ocular infections. Methods: We collected MRSE isolates from two groups: healthy conjunctiva from patients undergoing cataract surgeries and ocular infections at our hospital. Genotypic analysis included pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec), and biofilm-related genes (icaA, aap, and bhp). Additionally, phenotypic data on biofilm production and antibiotic susceptibility were recorded. Results: A total of 86 isolates, including 42 from healthy conjunctiva and 44 from ocular infections, were analyzed. MLST identified 21 sequence types (STs), with ST59 being the most frequent (n = 33, 39.5%), followed by ST130 (n = 10, 11.6%), ST57 (n = 6, 7.0%), and ST2 (n = 6, 7.0%). All isolates were categorized in 23 PFGE types, and SCCmec IV was the most prevalent SCCmec type (n = 52, 60.5%). The two sources of isolates exhibited overlapping molecular types and phenotypic traits, although the ocular infection isolates exhibited significantly higher multidrug resistance compared to healthy conjunctiva isolates (P = 0.032). When contrasting ST59 with non-ST59, ST59 displayed a significantly higher presence of aap (100%) and bhp (69.7%) while lacking icaA (0%). ST59 also showed lower susceptibility to fluoroquinolones compared to non-ST59 (42.4%-54.5% vs. 75.5%-83.0%; P < 0.01). Conclusions: MRSE isolates from healthy conjunctiva and ocular infections demonstrated a degree of resemblance. Specific strains, notably ST59, exhibited distinctive characterizations.

Ocular Manifestations and Outcomes in Children With Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Comparison With Adult Patients.

PURPOSE: To compare the clinical features and visual outcomes in children and adults with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). DESIGN: Retrospective comparative case series. METHODS: This retrospective study included 280 eyes of 140 patients (35 children and 105 adults) with SJS/TEN treated between 2010 and 2020. The primary outcome measures were the final best-corrected visual acuity (BCVA) and severity of dry eye. The secondary outcome measure was the medical and surgical therapies used. RESULTS: Among 64 eyes of children recruited in the study, acute ocular involvement was found in 58 eyes (90.6%). The chronic score in pediatric patients was significantly higher than that in adult patients (P = .004). The use of antibiotics/nonsteroidal anti-inflammatory drugs (NSAIDs) and Mycoplasma infection were the more common etiologies in children. In all, 75% of eyes in children maintained a visual acuity of 20/40 or better at a mean follow-up time of 4.3 years. The severity of dryness was comparable between the child and adult groups. The proportion of eyes undergoing amniotic membrane and oral mucosa transplantation was significantly higher in children than in adults in the chronic stage, reflecting that children exhibit much more severe complications. CONCLUSIONS: Although pediatric SJS/TEN patients have more severe ocular complications than adults, most children maintain long-term good vision. Early intervention and aggressive treatment help to preserve vision.

Methicillin-Resistant Staphylococcus aureus Ocular Infection in Taiwan: Potential Role of Panton-Valentine Leukocidin Gene.

Purpose: The relationship between Panton-Valentine leucocidin (PVL), a major virulence factor of Staphylococcus aureus, and disease severity and clinical outcomes remains unclear. We investigated the molecular characteristics and role of the PVL gene in methicillin-resistant S. aureus (MRSA) ocular infection in Taiwan. Methods: Patients with culture-proven S. aureus ocular infection in Chang Gung Memorial Hospital from 2010 to 2017 were included. The presence of the PVL gene was detected for all S. aureus isolates. MRSA isolates were characterized through pulsed-field gel electrophoresis (PFGE), staphylococcal multilocus sequence type, and staphylococcal cassette chromosome mec (SCCmec) typing. Drug susceptibility was examined using disk diffusion method and E-test. Patients' demographics, diagnoses, and outcomes were collected. Results: There were 112 methicillin-sensitive S. aureus and 103 MRSA isolates. Among 50 PVL(+) S. aureus isolates, 43 were MRSA. CC59/PFGE type D/SCCmec IV, VT (38 of 43 isolates, 88%), and CC59/PFGE type C/SCCmec IV (27 of 60 isolates, 45%) were the predominant clones in the PVL(+) and PVL(-) MRSA isolates, respectively. When we compared the two CC59 strains, the patients with PVL(+)/CC59 MSRA infection were significantly younger than those with PVL(-)/CC59 MSRA (39.3 vs. 61.7 years; P = 0.001). PVL(+)/CC59 MSRA caused significantly more eyelid disorders (36.8% vs. 3.7%; P = 0.002) but less keratitis (23.7% vs. 51.9%; P = 0.034). The antibiograms of the two strains were similar. Conclusions: PVL(+) MRSA is significantly associated with eyelid infection, especially in young patients. Translational Relevance: PVL gene plays a role in clinical features of MRSA ocular infections.

Production of Modified Autologous Conditioned Serum and Ex Vivo Assessment of Its Healing Potential in Murine Corneal Epithelium.

Human blood-derived topical therapies have been a boon to clinicians in recent decades. Autologous serum (AS) and platelet-rich plasma (PRP) are enriched in epitheliotropic growth factors that are essential in corneal wound healing. Unlike AS, PRP is based on a differential centrifugation system, yielding more platelet-derived growth factors. Autologous conditioned serum (ACS) not only preserves the preparation of AS and PRP, but also focuses on immune-modulating properties, which are important in inflammatory diseases. The lack of standardized protocols and high preparation costs are limitations for the clinical application of ACS. This video experiment demonstrates a standard operating procedure for preparing modified autologous conditioned serum (mACS) eye drops. First, glycerol was added into heparin syringes as the blood cell stabilizer during hypoxic incubation. To activate the blood cells, a 4 h incubation at 37 °C was initiated. Then, the blood samples were centrifuged at 3,500 × g for 10 min at room temperature. After filtration of the supernatant through a 0.22 µm filter, the mACS eye drops were fully prepared. A tentative try-out of the therapeutic effect of mACS showed that it may have competitive advantages over conventional AS in the corneal wound healing in ex vivo mouse eyes. The AS used in this study was prepared according to published studies and the clinical practice in our hospital. Therefore, the efficacy of mACS on ocular surface diseases could be evaluated in future research through in vivo animal studies and clinical trials.

Application of a deep learning system in glaucoma screening and further classification with colour fundus photographs: a case control study.

BACKGROUND: To verify efficacy of automatic screening and classification of glaucoma with deep learning system. METHODS: A cross-sectional, retrospective study in a tertiary referral hospital. Patients with healthy optic disc, high-tension, or normal-tension glaucoma were enrolled. Complicated non-glaucomatous optic neuropathy was excluded. Colour and red-free fundus images were collected for development of DLS and comparison of their efficacy. The convolutional neural network with the pre-trained EfficientNet-b0 model was selected for machine learning. Glaucoma screening (Binary) and ternary classification with or without additional demographics (age, gender, high myopia) were evaluated, followed by creating confusion matrix and heatmaps. Area under receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and F1 score were viewed as main outcome measures. RESULTS: Two hundred and twenty-two cases (421 eyes) were enrolled, with 1851 images in total (1207 normal and 644 glaucomatous disc). Train set and test set were comprised of 1539 and 312 images, respectively. If demographics were not provided, AUC, accuracy, precision, sensitivity, F1 score, and specificity of our deep learning system in eye-based glaucoma screening were 0.98, 0.91, 0.86, 0.86, 0.86, and 0.94 in test set. Same outcome measures in eye-based ternary classification without demographic data were 0.94, 0.87, 0.87, 0.87, 0.87, and 0.94 in our test set, respectively. Adding demographics has no significant impact on efficacy, but establishing a linkage between eyes and images is helpful for a better performance. Confusion matrix and heatmaps suggested that retinal lesions and quality of photographs could affect classification. Colour fundus images play a major role in glaucoma classification, compared to red-free fundus images. CONCLUSIONS: Promising results with high AUC and specificity were shown in distinguishing normal optic nerve from glaucomatous fundus images and doing further classification.

Staphylococcus aureus Keratitis in Taiwan: Genotyping, Antibiotic Susceptibility, and Clinical Features.

Staphylococcus aureus is an important pathogen for keratitis, a vision-threatening disease. We aimed to investigate the genotyping, antibiotic susceptibility, and clinical features of S. aureus keratitis, and to explore the possible role of Panton-Valentine leucocidin (PVL), a major virulence factor of S. aureus. We recruited 49 patients with culture-proven S. aureus keratitis between 2013 and 2017 at Chang Gung Memorial Hospital, Taiwan. PVL gene, multilocus sequence type (MLST), staphylococcal cassette chromosome mec (SCCmec), and pulsed-field gel electrophoresis (PFGE) were performed. Antibiotic susceptibility was verified using disk diffusion/E test. There were 49 patients with S. aureus keratitis; 17 (34.7%) were caused by methicillin-resistant S. aureus (MRSA) and 9 (18.4%) isolates had PVL genes. The predominant genotyping of MRSA isolates was CC59/PFGE type D/SCCmec VT/PVL (+). All methicillin-sensitive S. aureus (MSSA) and approximately 60% MRSA were susceptible to fluoroquinolones. No significant differences in clinical features, treatments, and visual outcomes were observed between MRSA/MSSA or PVL(+)/PVL(-) groups. In Taiwan, approximately one third of S. aureus keratitis was caused by MRSA, mainly community-associated MRSA. Although MRSA isolates were more resistant than MSSA, clinical characteristics were similar between two groups. Fluoroquinolones could be good empiric antibiotics for S. aureus keratitis.

Fusarium Keratitis in Taiwan: Molecular Identification, Antifungal Susceptibilities, and Clinical Features.

We performed molecular identification and antifungal susceptibilities of pathogens and investigated clinical features of 43 culture-proven Fusarium keratitis cases from 2015-2020 in Taiwan. The pathogens were identified by sequencing of their internal transcribed spacer regions of ribosomal DNA and translation elongation factor 1α gene; their antifungal susceptibilities (to seven agents) were determined by broth microdilution method. We also collected clinical data to compare the drug susceptibilities and clinical features of Fusarium solani species complex (FSSC) isolates with those of other Fusarium species complexes (non-FSSC). The FSSC accounted for 76.7% pathogens, among which F. falciforme (32.6%) and F. keratoplasticum (27.9%) were the most common species. Among clinically used antifungal agents, amphotericin B registered the lowest minimal inhibitory concentration (MIC), and the new azoles efinaconazole, lanoconazole and luliconazole, demonstrated even lower MICs against Fusarium species. The MICs of natamycin, voriconazole, chlorhexidine, lanoconazole, and luliconazole were higher for the FSSC than the non-FSSC, but no significant differences were noted in clinical outcomes, including corneal perforation and final visual acuity. In Taiwan, the FSSC was the most common complex in Fusarium keratitis; its MICs for five tested antifungal agents were higher than those of non-FSSC, but the clinical outcomes did not differ significantly.

Application of a Deep Learning System in Pterygium Grading and Further Prediction of Recurrence with Slit Lamp Photographs.

BACKGROUND: The aim of this study was to evaluate the efficacy of a deep learning system in pterygium grading and recurrence prediction. METHODS: This was a single center, retrospective study. Slit-lamp photographs, from patients with or without pterygium, were collected to develop an algorithm. Demographic data, including age, gender, laterality, grading, and pterygium area, recurrence, and surgical methods were recorded. Complex ocular surface diseases and pseudopterygium were excluded. Performance of the algorithm was evaluated by sensitivity, specificity, F1 score, accuracy, and area under the receiver operating characteristic curve. Confusion matrices and heatmaps were created to help explain the results. RESULTS: A total of 237 eyes were enrolled, of which 176 eyes had pterygium and 61 were non-pterygium eyes. The training set and testing set were comprised of 189 and 48 photographs, respectively. In pterygium grading, sensitivity, specificity, F1 score, and accuracy were 80% to 91.67%, 91.67% to 100%, 81.82% to 94.34%, and 86.67% to 91.67%, respectively. In the prediction model, our results showed sensitivity, specificity, positive predictive value, and negative predictive values were 66.67%, 81.82%, 33.33%, and 94.74%, respectively. CONCLUSIONS: Deep learning systems can be useful in pterygium grading based on slit lamp photographs. When clinical parameters involved in the prediction of pterygium recurrence were included, the algorithm showed higher specificity and negative predictive value in prediction.

Ex Vivo and In Vivo Animal Models for Mechanical and Chemical Injuries of Corneal Epithelium.

Corneal injury to the ocular surface, including chemical burn and trauma, may cause severe scarring, symblepharon, corneal limbal stem cells deficiency, and result in a large, persistent corneal epithelial defect. Epithelial defect with the following corneal opacity and peripheral neovascularization result in irreversible visual impairment and hinder future management, especially keratoplasty. Since the animal model can be used as an effective drug development platform, models of corneal injury to the mouse and alkali burn to rabbit corneal epithelium are developed here. New Zealand white rabbit is used in the alkali burn model. Different concentrations of sodium hydroxide can be applied onto the central circular area of the cornea for 30 s under intramuscular and topical anesthesia. After copious isotonic normal saline irrigation, residual loose corneal epithelium was removed with corneal burr deep down to the Bowman's layer within this circular area. Wound healing was documented by fluorescein staining under Cobalt blue light. C57BL/6 mice were used in the traumatic model of murine corneal epithelium. The murine central cornea was marked using a skin punch, 2 mm in diameter, and then debrided by a corneal rust ring remover with a 0.5 mm burr under a stereomicroscope. These models can be prospectively used to validate the therapeutic effect of eye drops or mixed agents such as stem cells, which potentially facilitate corneal epithelial regeneration. By observing corneal opacity, peripheral neovascularization, and conjunctival congestion with stereomicroscope and imaging software, therapeutic effects in these animal models can be monitored.

Clinical Features and Molecular Characteristics of Methicillin-Susceptible Staphylococcus aureus Ocular Infection in Taiwan.

This study analyzed the clinical features and molecular characteristics of methicillin-susceptible Staphylococcus aureus (MSSA) ocular infections in Taiwan and compared them between community-associated (CA) and health-care-associated (HA) infections. We collected S. aureus ocular isolates from patients at Chang Gung Memorial Hospital between 2010 and 2017. The infections were classified as CA or HA using epidemiological criteria, and the isolates were molecularly characterized using pulsed-field gel electrophoresis, multilocus sequence typing, and Panton-Valentine leukocidin (PVL) gene detection. Antibiotic susceptibility was evaluated using disk diffusion and an E test. A total of 104 MSSA ocular isolates were identified; 46 (44.2%) were CA-MSSA and 58 (55.8%) were HA-MSSA. Compared with HA-MSSA strains, CA-MSSA strains caused a significantly higher rate of keratitis, but a lower rate of conjunctivitis. We identified 14 pulsotypes. ST 7/pulsotype BA was frequently identified in both CA-MSSA (28.3%) and HA-MSSA (37.9%) cases. PVL genes were identified in seven isolates (6.7%). Both CA-MSSA and HA-MSSA isolates were highly susceptible to vancomycin, teicoplanin, tigecycline, sulfamethoxazole-trimethoprim, and fluoroquinolones. The most common ocular manifestations were keratitis and conjunctivitis for CA-MSSA and HA-MSSA, respectively. The MSSA ocular isolates had diverse molecular characteristics; no specific genotype differentiated CA-MSSA from HA-MSSA. Both strains exhibited similar antibiotic susceptibility.

Clinical characteristics and topographic findings of corneal ectasia in patients with symptomatic Demodex blepharitis.

PURPOSE: The purpose of this study is to present characteristics and topographic findings of patients with corneal ectasia and symptomatic ocular demodicosis. MATERIALS AND METHODS: A retrospective, noncomparative study. Twenty-one patients with symptomatic ocular demodicosis and corneal ectasia since 2017 to 2019 were enrolled. Patients with dry eye syndrome and meibomian gland dysfunction were identified and treated. Demographic data, topography, and clinical data were collected. All patients underwent lash sampling to confirm Demodex mite infestation by direct visualization under the microscope. RESULTS: Twenty-one ectasia patients (36 eyes) were enrolled with male preponderance (M:F =18:3). Mean age (years) was 28.6 ± 8.12. Of the 21 cases reviewed, the average number of topography taken was 6.8 within 43.8 months of follow-up. Corneal ectasia was characterized by focal thinning area beside central cornea, with corresponding mean thickness of 487.1 µm and 518 µm, respectively. All ectasia patients were combined with Demodex blepharitis and associated symptoms, proven by direct microscopic examination. After treatment with eyelid cleanser (OCuSOFT® Lid Scrub® PLUS), warm compress, and improved daily hygiene, ocular demodicosis and topographic changes were controlled and even reversed. CONCLUSION: Our results indicated that ocular demodicosis may be potentially associated with corneal ectasia. Demodex blepharitis still remains an overlooked differential diagnosis in clinic; however, it may be one of the risk factors triggering eye rubbing. Comorbidity of lid infestation with eye rubbing may lead to corneal ectasia, even in elder patients with thick cornea. Therefore, meticulous examination and intensive treatment were highly recommended in this group of patients.

Potential Role and Significance of Ocular Demodicosis in Patients with Concomitant Refractory Herpetic Keratitis.

PURPOSE: To evaluate the role of Demodex infestation of the eyelids in patients with recurrent herpetic keratitis. PATIENTS AND METHODS: This is a retrospective and noncomparative case series. Twenty-seven patients with ocular demodicosis and recurrent herpetic keratitis under conventional treatments were enrolled. Demographic data and clinical photographs were collected. Ocular demodicosis was confirmed by eyelash examination under a microscope. Eyelid scrub was initiated in these patients after proving Demodex infestation. Response after treatment was reviewed. RESULTS: Herpetic keratitis was characterized by epithelial defect, including dendritic lesions (seven eyes, 25.9%), geographic ulcer (three eyes, 11.1%), and neurotrophic ulcer (two eyes, 7.4%), associated with stromal involvement in 12 cases. Six cases with stromal reactivation, including disciform keratitis (two eyes, 7.4%), immune ring (three eyes, 11.1%), and ghost vessel (one eye, 3.7%), presented no epithelial defect. Active anterior uveitis with keratic precipitates was found in 15 cases. Demodex blepharitis was diagnosed with cylindrical dandruff along their lashes in all patients. Other ocular findings include meibomian gland dysfunction (15 eyes, 55.6%), mal-aligned lashes (eight eyes, 29.6%), telangiectasia (14 eyes, 51.9%), conjunctivitis (18 eyes, 66.7%), and ocular rosacea (three eyes, 11.1%). Initial unstable clinical presentations showed deterioration of corneal melting into descemetocele, corneal perforation, recalcitrant stromal infiltration/uveitis, and uncontrollable IOP, despite antiherpetic medication. After treatment of Demodex blepharitis, infestation was under control, followed by subjective improvement of ocular symptoms and a stable clinical outcome. CONCLUSION: Ocular demodicosis should be considered in patients with unstable recurrent herpetic keratitis. A prompt diagnosis and appropriate treatment may curb the progression of herpetic corneal infection.

Clinical appearance and pathological findings of conjunctival myxoma: Case report and literature review.

PURPOSE: To describe a case with a growing erythematous conjunctival mass in the left eye, diagnosed as conjunctival myxoma. OBSERVATIONS: A 31-year-old lady had corrected visual acuity of 6/7.5 and normal intraocular pressure in both eyes. Congested left bulbar conjunctiva with one slightly elevated nodule at nasal area was noted for one year. Excisional biopsy was performed after failed treatment with topical eye drops. Pathology showed conjunctival myxoma with spindle- and stellate-shaped cells, which was a rare ocular surface neoplasia. There was no combined systemic disease found. CONCLUSIONS AND IMPORTANCE: We described the clinical and pathological features of conjunctival myxoma. Systemic evaluation should be considered before and after surgical excision.

Liposomal dexamethasone-moxifloxacin nanoparticle combinations with collagen/gelatin/alginate hydrogel for corneal infection treatment and wound healing.

Infectious keratitis is still one of the major causes of visual impairment and blindness, often affecting developing countries. Eye-drop therapy to reduce disease progression is the first line of treatment for infectious keratitis. The current limitations in controlling ophthalmic infections include rapid precorneal drug loss and the inability to provide long-term extraocular drug delivery. The aim of the present study was to develop a novel ophthalmic formulation to treat corneal infection. The formulation was prepared by constructing moxifloxacin (MFX) and dexamethasone (DEX)-loaded nanostructured lipid carriers (Lipo-MFX/DEX) mixed with a collagen/gelatin/alginate (CGA) biodegradable material (CGA-Lipo-MFX/DEX) for prolonged ocular application. The characteristics of the prepared Lipo-MFX/DEX nanoparticles were as follows: average size, 132.1 ± 73.58 nm; zeta potential, -6.27 ± 4.95 mV; entrapment efficiency, 91.5 ± 3.5%; drug content, 18.1 ± 1.7%. Our results indicated that CGA-Lipo-MFX/DEX could release an effective working concentration in 60 min and sustain the drug release for at least 12 h. CGA-Lipo-MFX/DEX did not produce significant toxicities, but it increased cell numbers when co-cultured with ocular epithelial cells. An animal study also confirmed that CGA-Lipo-MFX/DEX could inhibit pathogen microorganism growth and improve corneal wound healing. Our results suggest that CGA-Lipo-MFX/DEX could be a useful anti-inflammatory formulation for ophthalmological disease treatment.

Clinical demographics of pterygium excision and prevalence of conjunctival intraepithelial neoplasia: a 15-year review.

PURPOSE: To find clinical demographics of pterygium surgery and prevalence of conjunctival intraepithelial neoplasia (CIN) in pterygium specimen. METHODS: This is a retrospective, institutional study. The records of patients who had received pterygium excision from 2000 to 2014 were reviewed. Patients after complete ophthalmic "examinations", surgical procedures, and pathological reports were enrolled. Surgical procedures, pathology, external eye photography, prevalence of CIN in specimen, and demographic data were described. RESULTS: Of 1787 pterygium cases, 928 were male and 859 were female. The mean age was 65.19 ± 14.21 years. Of these 1787 cases, 1435 (80.3%) cases had primary pterygium excision, while the others (n = 352; 19.7%) had pterygium excision for recurrence. Four cases presented CIN within pterygium tissue (0.22%). The mean age of pterygium patients with CIN was 57.75 ± 7.80 years. In stratified data, our patients who received primary and secondary pterygium excision were found prevalent in the eighth (28.2%) and seventh (26.1%) decade, respectively. Twelve percent of patients who underwent secondary pterygium excision had a recurrence and required another surgery. Patients requiring amniotic membrane transplantation (AMT) during primary pterygium excision were significantly younger (median, 58 years) than those (median, 67 years) without the assistance of AMT (p < 0.001). Similarly, AMT was utilized in younger patients (median, 56 years) during secondary pterygium excision, compared to those without AMT (median, 64 years) (p = 0.001). CONCLUSION: CIN combined with pterygium is very rare. However, the possibility of the development of ocular surface squamous neoplasia in pterygium tissue should not be ignored. Meticulous pathological investigation of the surgical samples is important.

HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27-mediated spliced X-box-binding protein 1 (sXBP1)/retinoic acid receptor-ß (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27-mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.

Blimp-1 Contributes to the Development and Function of Regulatory B Cells.

Regulatory B cells (Bregs) are a B cell subset that plays a suppressive role in immune responses. The CD19+CD1dhiCD5+ Bregs that can execute regulatory functions via secreting IL-10 are defined as B10 cells. Bregs suppress autoimmune and inflammatory diseases, whereas they exacerbate infectious diseases caused by bacteria, viruses, or parasites. Notably, the molecular mechanisms regulating the development and functions of Bregs are still largely unknown. Furthermore, the biological impact of Bregs in fungal infection has not yet been demonstrated. Here, we compared the gene expression profiles of IL-10-producing and -non-producing mouse splenic B cells stimulated with lipopolysaccharide (LPS) or anti-CD40 antibody. Blimp-1, a transcription factor known to be critical for plasma cell differentiation, was found to be enriched in the IL-10-producing B cells. The frequency of Blimp-1+ B10 cells was increased in LPS-treated mice and in isolated B10 cells that were stimulated with LPS. Surprisingly, B cell-specific Blimp-1 knockout (Cko) mice, generated by CD19 promoter driven Cre recombinase-dependent deletion of Prdm1 (gene encoding Blimp-1), showed higher frequencies of B10 cells both in the steady state and following injection with LPS, as compared with control littermates. However, B10 cells lacking Blimp-1 failed to efficiently suppress the proliferation of naïve CD4+ T cells primed with anti-CD3 and anti-CD28 antibodies. B10 cells can be stimulated for further differentiation into plasmablasts, and a subset of plasmablasts express IL-10. We found that B10 cells from Cko mice failed to generate both IL-10-non-producing and IL-10-producing plasmablasts. Mechanistically, we found that Blimp-1 can directly suppress Il-10, whereas, in the presence of activated STAT3, Blimp-1 works together with activated STAT3 to upregulate Il-10. Moreover, we also found that B10 cells improve the clearance of Candida albicans infection but worsen the infection mortality. Notably, a lack of Blimp-1 in B10 cells did not change these effects of adoptively transferred B10 cells on fungal infections. Together, our data show that Blimp-1 regulates the generation, differentiation, and IL-10 production of Bregs.

Regulatory mechanisms of B cell responses and the implication in B cell-related diseases.

Terminally differentiated B cell, the plasma cell, is the sole cell type capable of producing antibodies in our body. Over the past 30 years, the identification of many key molecules controlling B cell activation and differentiation has elucidated the molecular pathways for generating antibody-producing plasma cells. Several types of regulation modulating the functions of the important key molecules in B cell activation and differentiation add other layers of complexity in shaping B cell responses following antigen exposure in the absence or presence of T cell help. Further understanding of the mechanisms contributing to the proper activation and differentiation of B cells into antibody-secreting plasma cells may enable us to develop new strategies for managing antibody humoral responses during health and disease. Herein, we reviewed the effect of different types of regulation, including transcriptional regulation, post-transcriptional regulation and epigenetic regulation, on B cell activation, and on mounting memory B cell and antibody responses. We also discussed the link between the dysregulation of the abovementioned regulatory mechanisms and B cell-related disorders.

The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells.

T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.