Modification of Risk for All-cause and Cardiovascular Disease-related Mortality with Changes in the Body Mass Index in Older Individuals: A Population-based Cohort Study.

INTRODUCTION: Existing evidence evaluating the impact of change in body mass index (BMI) on the risk of all-cause and cardiovascular disease (CVD)-related mortality in older people is limited and inconsistent. This population-based cohort study evaluated the association of changes in BMI over time with all-cause and CVD-related mortality in older adults. METHODS: We recruited 55,351 adults aged over 65 years between 2006-2011 from Taipei Elderly Health Examination Program who underwent repeated annual health examinations at 3.2 year-intervals and were followed-up for mortality over 5.5 years. Cox proportional hazard and Fine-Gray sub-distribution hazard models with death from non-CVD causes as the competing risk were used to determine the impact of changes in BMI status on the risk of all-cause or CVD-related mortality, respectively. RESULTS: Over 227,967 person-years of follow-up, 4,054 participants died, including 940 (23.2%) CVD-related deaths. After adjusting for other covariates, >10% decrease of BMI was significantly associated with a higher risk of all-cause (adjusted hazard ratio [AHR]= 1.93; 95% confidence interval [CI]: 1.74-2.13) and CVD-related mortality (AHR= 1.96; 95%CI: 1.60-2.40), compared with stable BMI. Sensitivity analysis showed that a >10% decrease in BMI was significantly associated with a high risk of all-cause and CVD-related mortality in participants with normal weight, underweight, overweight, or obesity at baseline. DISCUSSION/CONCLUSION: Older adults with >10% decrease in BMI are at high risk of all-cause and CVD-related mortality. Our findings suggest that older individuals experiencing a substantial reduction in BMI should undergo a thorough evaluation to minimize the risks associated with mortality.

Diagnostic ability of macular nerve fiber layer thickness measured by swept-source optical coherence tomography in preperimetric glaucoma.

BACKGROUND: We evaluated the diagnostic ability of macula retinal nerve fiber layer (mRNFL) thickness in preperimetric glaucoma (PPG) patients. METHODS: This prospective study included 83 patients with PPG and 83 age- and refractive error-matched normal control subjects. PPG was defined as a localized RNFL defect corresponding to glaucomatous optic disc changes with a normal visual field test. We used spectral-domain (SD) optical coherence tomography (OCT) to measure the circumpapillary RNFL (cpRNFL) thickness and macular ganglion cell-inner plexiform layer (GCIPL) thickness. Swept-source (SS) OCT was used to measure cpRNFL thickness, macular ganglion cell layer + inner plexiform layer (IPL) thickness (GCL+), and macular ganglion cell layer + IPL+ mRNFL thickness (GCL++). The mRNFL thickness was defined as GCL++ minus GCL+. To evaluate the diagnostic power of each parameter, the area under the receiver operating characteristics curve (AUROC) was analyzed to differentiate PPG from the normal groups. RESULTS: Using SD-OCT, all GCIPL parameters and most cpRNFL parameters, except at the nasal and temporal quadrant, were significantly lower in PPG versus normal controls. PPG eyes had significantly smaller values than normal controls for all cpRNFL and GCL parameters measured by SS-OCT, except mRNFL at the superonasal area. The inferotemporal GCL++ had the largest AUROC value (0.904), followed by inferotemporal GCL+ (0.882), inferotemporal GCIPL thickness (0.871), inferior GCL++ (0.866), inferior cpRNFL thickness by SS-OCT (0.846), inferior cpRNFL thickness by SD-OCT (0.841), and inferotemporal mRNFL thickness (0.840). The diagnostic performance was comparable between inferotemporal mRNFL thickness and the best measures of GCL (inferotemporal GCL++, p = 0.098) and cpRNFL (inferior cpRNFL thickness by SS-OCT, p = 0.546). CONCLUSION: The diagnostic ability of mRNFL thickness was comparable to that of the best measures of cpRNFL and GCL analysis for eyes with PPG. Therefore, mRNFL thickness could be a new parameter to detect early structural changes in PPG.

ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.

AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII. ARID1A depletion resulted in enhanced accumulation of micronuclei, activation of cGAS-STING pathway, and an increased expression of immunomodulatory cytokines upon ionizing radiation. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and estimates the levels of tumor-infiltrating immune cells, which can predict the response to the combination of radio- and immunotherapy.

New-onset Glaucoma Following Moderna COVID-19 Vaccination.

Aim: To report a case of new-onset glaucoma following administration of the Moderna (mRNA-1273) vaccine. Background: Previous studies have reported a low incidence of ocular adverse events induced by the coronavirus disease 2019 (COVID-19) vaccine. The literature on open-angle glaucoma associated with COVID-19 vaccination is limited. Case description: The patient complained of blurred vision 2 days following the administration of the second dose of the Moderna vaccine in July 2021. At presentation, the ophthalmic examination showed elevated intraocular pressure (IOP) of 30 mm Hg in her right eye (OD) and 18 mm Hg in her left eye (OS). There were no signs of intraocular inflammation or glaucomatous optic neuropathy at the initial presentation. She was treated with a topical ß-blocker first. In addition, 1 month later, her IOPs were 28 mm Hg OD and 26 mm Hg OS. Although treated with multiple antiglaucoma medications, her optic cup-to-disc ratios were increased in both eyes (OU) compared to May 2019. She developed a glaucomatous visual field (VF) defect OD in October 2021. Optical coherence tomography (OCT) revealed progressive retinal nerve fiber layer (RNFL) thinning in OU. Conclusion: Glaucoma may be a rare but severe ocular adverse event of the Moderna vaccines. The ophthalmologist should pay attention to the risk of increased IOP following COVID-19 vaccination. Clinical significance: We reported a case of new-onset open-angle glaucoma presumably associated with COVID-19 vaccination. How to cite this article: Su Y, Yeh S, Chen M. New-onset Glaucoma Following Moderna COVID-19 Vaccination. J Curr Glaucoma Pract 2023;17(2):106-109.

Effects of safety attitude on factors related to burnout among nurses working at a dedicated infectious disease control hospital during the COVID-19 pandemic.

AIM: Repeated occupational exposure and increased stress and fatigue levels contribute to a high risk of coronavirus disease 2019 (COVID-19) infection among frontline nurses. This study aimed to explore the relationships among teamwork, work environment and resources, work-life balance, stress perception and burnout among nurses working at a dedicated infectious disease control hospital. METHODS: The participants were 389 nurses at a dedicated infectious disease control hospital in Taipei City, Taiwan. This study adopted survey design with a questionnaire using the Safety Attitude Questionnaire. RESULTS: The work-life balance among nurses at the dedicated hospital significantly mediated the effects of teamwork and work environment and resources on burnout. In addition, stress perception had interaction effects on work-life balance and burnout. CONCLUSION: This study's results provide important recommendations for managing teamwork, work environment and resources, work-life balance, stress perception and burnout prevention in nurses to help them better prepare and cope with emergencies. Findings can serve as a reference for developing relevant hospital management policies.

Urban-Rural Disparity in Birth Cohort Effects on Breast Cancer Incidence.

Breast cancer is the most commonly diagnosed cancer among women worldwide. Studies have reported minimal birth cohort effects on the incidence rates of breast cancer in Western countries but have reported notable birth cohort effects in some Asian countries. The risks of breast cancer may also vary within a country. In the present study, we abstracted female invasive breast cancer data from the Taiwan Cancer Registry for the period 1997-2016. We used the age-period-cohort model to compare birth cohort effects on breast cancer incidence rates between urban and rural regions in Taiwan. We identified a notable urban-rural disparity in birth cohort effects on breast cancer incidence rates in women in Taiwan. The incidence rates in the urban regions were higher than those in the rural regions across all cohorts. However, the incidence rates rose faster in the rural regions than in the urban regions across the cohorts. The risks of breast cancer observed for women born in 1992 were approximately 22 and 11 times than those observed for women born in 1917 in rural and urban regions, respectively. The observed gap in breast cancer incidence rates between the urban and rural regions gradually disappeared across the cohorts. Accordingly, we speculate that urbanization and westernization in Taiwan may be the drivers of female breast cancer incidence rates across birth cohorts.

Tumor-intrinsic SIRPA promotes sensitivity to checkpoint inhibition immunotherapy in melanoma.

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture system. Mice bearing SIRPA-deficient melanoma tumors show no response to anti-PD-L1 treatment, whereas melanoma-specific SIRPA overexpression significantly enhances immunotherapy response. Mechanistically, SIRPA is regulated by its pseudogene, SIRPAP1. Our results suggest a complicated role of SIRPA in the tumor ecosystem, highlighting cell-type-dependent antagonistic effects of the same target on immunotherapy.

Bleb-related infection after primary trabeculectomy: medical chart reviews from 1993 to 2021.

BACKGROUND: To investigate the incidence of and risk factors for bleb-related infection (BRI) in patients who underwent mitomycin C-augmented primary trabeculectomy. METHODS: We reviewed the medical charts of consecutive patients who had received primary trabeculectomy in Taipei Veterans General Hospital. We recorded the demographic and clinical characteristics of patients before, during and after surgery. Furthermore, we recorded the time interval between surgery and infection onset, clinical manifestations and visual outcomes of patients with BRI. The cumulative incidence of BRI was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to explore factors associated with BRI. RESULTS: In total, 1663 eyes were postoperatively followed up for 94.57±65.23 months. The cumulative incidence of BRI was 1.86 per 1000 person-years during the 28-year follow-up period: 24 (1.44%) patients developed BRI and 6 (0.36%) patients additionally developed endophthalmitis. A multivariate analysis revealed a significant association of BRI with wound manipulation, high myopia and hyperlipidaemia. Patients younger than 60 years were more likely to receive wound manipulation than their elderly counterparts (<0.001). One year after BRI, the best corrected visual acuity of the eyes with blebitis did not change significantly, whereas that of the eyes with endophthalmitis worsened significantly. CONCLUSION: Risk factors for BRI after trabeculectomy include wound manipulation, high myopia and hyperlipidaemia. Considering myopia is highly prevalent throughout the world and is a risk factor for glaucoma, the lifelong risk of BRI after trabeculectomy in eyes with high myopia warrants the attention of ophthalmologists.

Proteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets.

Primary liver cancer is a heterogeneous disease in terms of its etiology, histology, and therapeutic response. Concurrent proteomic and genomic characterization of a large set of clinical liver cancer samples can help elucidate the molecular basis of heterogeneity and thus serve as a valuable resource for personalized liver cancer treatment. In this study, we perform proteomic profiling of ~300 proteins on 259 primary liver cancer tissues with reverse-phase protein arrays, mutational analysis using whole genome sequencing and transcriptional analysis with RNA-Seq. Patients are of Japanese ethnic background and mainly HBV or HCV positive, providing insight into this important liver cancer subtype. Unsupervised classification of tumors based on protein expression profiles reveal three proteomic subclasses R1, R2, and R3. The R1 subclass is immunologically hot and demonstrated a good prognosis. R2 contains advanced proliferative tumor with TP53 mutations, high expression of VEGF receptor 2 and the worst prognosis. R3 is enriched with CTNNB1 mutations and elevated mTOR signaling pathway activity. Twenty-two proteins, including CDK1 and CDKN2A, are identified as potential prognostic markers. The proteomic classification presented in this study can help guide therapeutic decision making for liver cancer treatment.

Risk factors for ocular neovascularization after central retinal artery occlusion.

BACKGROUND: To report the incidence and risk factors associated with ocular neovascularization (NV) in patients with central retinal artery occlusion (CRAO). METHODS: This retrospective study included patients diagnosed with acute CRAO in a single tertiary center. Medical charts were reviewed for ocular NV occurrences. We analyzed systemic and ocular conditions on first visit and demographic data. RESULTS: Eighty-seven eyes were eligible for this study. Among these, 13 eyes had ocular NV after CRAO, with an incidence of 15%. The prevalences of hypertension, diabetes mellitus, history of stroke, chronic kidney disease (CKD), and age at first visit were higher among patients with ocular NV than among patients without ocular NV after CRAO. Moreover, most patients with CKD in the ocular NV group had undergone dialysis. A multivariate regression analysis revealed that CKD (hazard ratio [HR]: 9.27, 95% CI, 1.87-46.05, p = 0.006) and glaucoma history (HR: 7.52, 95% CI, 1.14-49.46, p = 0.036) were significant risk factors for developing ocular NV among patients with CRAO. CONCLUSION: CKD and glaucoma history were significant risk factors for developing ocular NV after CRAO, particularly among patients that underwent dialysis.

A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis.

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Transcriptome profiling reveals the developmental regulation of NaCl-treated Forcipomyia taiwana eggs.

BACKGROUND: The biting midge, Forcipomyia taiwana, is one of the most annoying blood-sucking pests in Taiwan. Current chemical control methods only target the adult, not the immature stages (egg to pupa), of F. taiwana. Discovering new or alternative tactics to enhance or replace existing methods are urgently needed to improve the effectiveness of F. taiwana control. The egg is the least understood life stage in this pest species but may offer a novel point of control as addition of NaCl to the egg environment inhibits development. Thus, the objective of this study was to use RNA profiling to better understand the developmental differences between wild-type melanized (black) and NaCl-induced un-melanized (pink), infertile F. taiwana eggs. RESULTS: After de novo assembly with Trinity, 87,415 non-redundant transcripts (Ft-nr) with an N50 of 1099 were obtained. Of these, 26,247 (30%) transcripts were predicted to have long open reading frames (ORFs, defined here as ≥300 nt) and 15,270 (17.5%) transcripts have at least one predicted functional domain. A comparison between two biological replicates each of black and pink egg samples, although limited in sample size, revealed 5898 differentially expressed genes (DEGs; 40.9% of the transcripts with long ORFs) with ≥2-fold difference. Of these, 2030 were annotated to a Gene Ontology biological process and along with gene expression patterns can be separated into 5 clusters. KEGG pathway analysis revealed that 1589 transcripts could be assigned to 18 significantly enriched pathways in 2 main categories (metabolism and environmental information processing). As expected, most (88.32%) of these DEGs were down-regulated in the pink eggs. Surprisingly, the majority of genes associated with the pigmentation GO term were up-regulated in the pink egg samples. However, the two key terminal genes of the melanin synthesis pathway, laccase2 and DCE/yellow, were significantly down-regulated, and further verified by qRT-PCR. CONCLUSION: We have assembled and annotated the first egg transcriptome for F. taiwana, a biting midge. Our results suggest that down-regulation of the laccase2 and DCE/yellow genes might be the mechanism responsible for the NaCl-induced inhibition of melanization of F. taiwana eggs.

Genome-Wide Polygenic Risk Score for Predicting High Risk Glaucoma Individuals of Han Chinese Ancestry.

Glaucoma is a progressive and irreversible blindness-causing disease. However, the underlying genetic factors and molecular mechanisms remain poorly understood. Previous genome-wide association studies (GWAS) have made tremendous progress on the SNP-based disease association and characterization. However, most of them were conducted for Europeans. Since differential genetic characteristics among ethnic groups were evident in glaucoma, it is worthwhile to complete its genetic landscape from the larger cohorts of Asian individuals. Here, we present a GWAS based on the Taiwan Biobank. Among 1013 glaucoma patients and 36,562 controls, we identified a total of 138 independent glaucoma-associated SNPs at the significance level of p < 1 × 10-5. After clumping genetically linked SNPs (LD clumping), 134 independent SNPs with p < 10-4 were recruited to construct a Polygenic Risk Score (PRS). The model achieved an area under the receiver operating characteristic curve (AUC) of 0.8387 (95% CI = [0.8269-0.8506]), and those within the top PRS quantile had a 45.48-fold increased risk of glaucoma compared with those within the lowest quantile. The PRS model was validated with an independent cohort that achieved an AUC of 0.7283, thereby showing the effectiveness of our polygenic risk score in predicting individuals in the Han Chinese population with higher glaucoma risks.

A four-gene signature predicts survival and anti-CTLA4 immunotherapeutic responses based on immune classification of melanoma.

Cutaneous melanoma is the most malignant skin cancer. Biomarkers for stratifying patients at initial diagnosis and informing clinical decisions are highly sought after. Here we classified melanoma patients into three immune subtypes by single-sample gene-set enrichment analysis. We further identified a four-gene tumor immune-relevant (TIR) signature that was significantly associated with the overall survival of melanoma patients in The Cancer Genome Atlas cohort and in an independent validation cohort. Moreover, when applied to melanoma patients treated with the CTLA4 antibody, ipilimumab, the TIR signature could predict the response to ipilimumab and the survival. Notably, the predictive power of the TIR signature was higher than that of other biomarkers. The genes in this signature, SEL1L3, HAPLN3, BST2, and IFITM1, may be functionally involved in melanoma progression and immune response. These findings suggest that this four-gene signature has potential use in prognosis, risk assessment, and prediction of anti-CTLA4 response in melanoma patients.

Comparison of the iCare, Tono-Pen, non-contact airpuff, and Goldmann applanation tonometers in eyes with corneal edema after penetrating keratoplasty.

BACKGROUND: To compare the utility of the iCare, Tono-Pen, and non-contact airpuff (NCT) tonometers with the Goldmann applanation tonometer (GAT) for measuring intraocular pressure (IOP) in patients with corneal edema after penetrating keratoplasty (PKP) and to assess the effects of central corneal thickness (CCT) and corneal curvature (CC) on IOP measurements. METHODS: Thirty-two eyes of 27 patients with corneal edema after PKP due to corneal abnormalities and 43 control eyes of 30 patients with normal corneas were recruited. Before IOP measurements, all patients underwent a baseline examination, including auto-refraction, keratometry, slit lamp biomicroscopy, and CCT measurement. IOP was measured using the devices in the same order: first the NCT, followed by the iCare, Tono-Pen, and GAT. The differences between the iCare, Tono-Pen, NCT, and GAT were calculated with repeated-measures analysis of variance. The Bland-Altman method was used to assess the agreement between the iCare, Tono-Pen, and NCT versus the GAT. The influences of CCT and CC on IOP measurement were evaluated by correlation analysis using Pearson's correlation coefficient. RESULTS: Mean IOP measurements were significantly higher with the NCT and Tono-Pen than with the GAT in the PKP and control groups. When compared with GAT, iCare showed significantly higher IOP readings in the control group, but the IOP readings did not differ between the iCare and GAT in the PKP group. Poor agreement was noted between the NCT and GAT in both groups. The Tono-Pen showed clinically acceptable agreement with GAT in control eyes and poor agreement in PKP eyes. The agreement between the iCare and GAT appeared to be clinically acceptable in both groups. Correlation analysis of the results from control eyes showed that the IOP measurements with the GAT and NCT were weakly related to CCT and moderately correlated with CC. The iCare IOP readings were weakly correlated with CCT and CC. CONCLUSION: In the PKP group, the NCT and Tono-Pen significantly overestimated IOP, whereas the iCare IOP readings were similar to those obtained using the GAT. Poor agreement was noted between the NCT and GAT as well as between the Tono-Pen and GAT, but the iCare showed clinically acceptable agreement with GAT. In normal corneas, the GAT, NCT, and iCare were affected by CCT and CC. The iCare tonometer was less affected by corneal edema than were the NCT and the Tono-Pen. The iCare appears to be a useful device for IOP measurement in eyes with corneal edema after PKP.

XEN45 Gel Stent implantation in eyes with primary open angle glaucoma: A study from a single hospital in Taiwan.

BACKGROUND: To evaluate the effectiveness and safety of the XEN45 Gel Stent in East Asian patients with primary open angle glaucoma (POAG). METHODS: We retrospectively reviewed 37 medically uncontrolled POAG patients who received XEN45 Gel Stent. The primary outcomes were reduction in intraocular pressure (IOP) and in the number of glaucoma medications 12 months after surgery. The secondary outcomes were requirement for intervention and further glaucoma surgery. The adverse intraoperative and postoperative events were investigated. RESULTS: At the 12-month postoperative follow-up, the mean IOP was significantly reduced from the preoperative value of 21.7 ± 7.7 mmHg to 15.0 ± 2.0 mmHg (p = 0.001). The mean number of glaucoma medications decreased from 3.4 ± 0.9 to 1.3 ± 1.5 (p < 0.001). Seventeen patients (45.9%) required postoperative interventions. Four patients (10.8%) received additional glaucoma surgery. Postoperative IOP at month 1 was significantly associated with outcomes at the 12-month follow-up and the need for subsequent intervention and additional glaucoma surgery. CONCLUSION: The XEN45 Gel Stent effectively reduced the IOP values and number of glaucoma medications in East Asian patients with POAG. No major complications were observed, but almost half of the eyes in the study required intervention for wound healing modification. Postoperative IOP at month 1 was a predictor of surgical success at 12 months after surgery.

Next-Generation Analytics for Omics Data.

The increasing omics data present a daunting informatics challenge. DrBioRight, a natural language-oriented and artificial intelligence-driven analytics platform, enables the broad research community to perform analysis in an intuitive, efficient, transparent, and collaborative way. The emerging next-generation analytics will maximize the utility of omics data and lead to a new paradigm for biomedical research.

Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.

Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications.