Uncovering the dynamics and consequences of RNA isoform changes during neuronal differentiation.

Static gene expression programs have been extensively characterized in stem cells and mature human cells. However, the dynamics of RNA isoform changes upon cell-state-transitions during cell differentiation, the determinants and functional consequences have largely remained unclear. Here, we established an improved model for human neurogenesis in vitro that is amenable for systems-wide analyses of gene expression. Our multi-omics analysis reveals that the pronounced alterations in cell morphology correlate strongly with widespread changes in RNA isoform expression. Our approach identifies thousands of new RNA isoforms that are expressed at distinct differentiation stages. RNA isoforms mainly arise from exon skipping and the alternative usage of transcription start and polyadenylation sites during human neurogenesis. The transcript isoform changes can remodel the identity and functions of protein isoforms. Finally, our study identifies a set of RNA binding proteins as a potential determinant of differentiation stage-specific global isoform changes. This work supports the view of regulated isoform changes that underlie state-transitions during neurogenesis.

Contribution of systemic factors on macular vessel density: a sex-specific population-based study.

PURPOSE: To evaluate the influence of systemic factors on macular vessel density in quantitative Optical Coherence Tomography Angiography (OCTA) by sex. STUDY DESIGN: A cross-sectional study. METHODS: A total of 2018 adults were recruited in this study. Participants were excluded (n=964) due to missing data, eye-related problems, or low OCTA scan quality. Macular vessel densities were measured with OCTA using split-spectrum amplitude decorrelation angiography algorithm. Only the data from the right eyes were selected for analysis. Multivariable linear regression analysis was performed to determine the associations between macular vessel density and obesity-related systemic factors in each gender group. RESULTS: The right eyes of 1054 participants (59.6% women) were enrolled. Men had significantly higher obesity parameters and associated risk factors. In multivariable linear regression analysis in men, older age and type 2 diabetes mellitus were independently associated with lower superficial retinal vessel density (ß = -0.37, p = 0.002; ß = -1.22, p = 0.03) and deep retinal vessel density, respectively (ß = -0.66, p < 0.001; ß = -1.76, p = 0.02); positive association was also observed between body mass index (BMI) and superficial retinal vessel density (ß = 0.56, p = 0.02). In women, only higher systolic blood pressure was independently associated with a lower deep retinal vessel density (ß = -0.50, p = 0.003). CONCLUSIONS: This large cross-sectional study shows that older age and type 2 diabetes mellitus are associated with lower superficial and deep retinal capillary vessel density in men. This may help clinicians better understand how systemic factors influence retinal vessel density in different genders and future studies can ascertain more potential sex differences.

Rapid Generation of hPSC-Derived High Endothelial Venule Organoids with In Vivo Ectopic Lymphoid Tissue Capabilities.

Bioengineering strategies for the fabrication of implantable lymphoid structures mimicking lymph nodes (LNs) and tertiary lymphoid structures (TLS) could amplify the adaptive immune response for therapeutic applications such as cancer immunotherapy. No method to date has resulted in the consistent formation of high endothelial venules (HEVs), which is the specialized vasculature responsible for naïve T cell recruitment and education in both LNs and TLS. Here orthogonal induced differentiation of human pluripotent stem cells carrying a regulatable ETV2 allele is used to rapidly and efficiently induce endothelial differentiation. Assembly of embryoid bodies combining primitive inducible endothelial cells and primary human LN fibroblastic reticular cells results in the formation of HEV-like structures that can aggregate into 3D organoids (HEVOs). Upon transplantation into immunodeficient mice, HEVOs successfully engraft and form lymphatic structures that recruit both antigen-presenting cells and adoptively-transferred lymphocytes, therefore displaying basic TLS capabilities. The results further show that functionally, HEVOs can organize an immune response and promote anti-tumor activity by adoptively-transferred T lymphocytes. Collectively, the experimental approaches represent an innovative and scalable proof-of-concept strategy for the fabrication of bioengineered TLS that can be deployed in vivo to enhance adaptive immune responses.

Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Sector-Based Regression Strategies to Reduce Refractive Error-Associated Glaucoma Diagnostic Bias When Using OCT and OCT Angiography.

Purpose: This cross-sectional study aimed to investigate the sectoral variance of optical coherence tomography (OCT) and OCT angiography (OCTA) glaucoma diagnostic parameters across eyes with varying degrees of refractive error. Methods: Healthy participants, including individuals with axial ametropia, enrolled in the Hong Kong FAMILY cohort were imaged using the Avanti/AngioVue OCT/OCTA system. The OCT and OCTA parameters obtained include peripapillary nerve fiber layer thickness (NFLT), peripapillary nerve fiber layer plexus capillary density (NFLP-CD), and macular ganglion cell complex thickness (GCCT). Sectoral measurements of NFLT, NFLP-CD, and GCCT were based on sectors and hemispheres. Results: A total of 1339 eyes from 791 participants were stratified based on spherical equivalent refraction: high myopia (<-6 D), low myopia (-6 D to -1 D), emmetropia (-1 D to 1 D), and hyperopia (>1 D). Multivariable broken stick regression models, accounting for age, sex, and signal strength, showed that all NFLT sectors except temporally, the inferior GCCT hemisphere, and half of the NFLP-CD sectors were more affected by ametropia-related covariates than the corresponding global parameters. As expected, the false-positive rates in those sectors were elevated. Finally, sector-specific axial length (AL) and spherical equivalent (SE) adjustments helped reduce the elevated false-positive rates. Conclusions: The effect of optical magnification is even more prominent among sectors than the global parameters. AL- and SE-based adjustments should be individualized to each sector to mitigate this magnification bias effectively. Translational Relevance: Identifying sectoral differences among diagnostic parameters and adopting these sector-based adjustments into commercial OCT systems will hopefully reduce false-positive rates related to refractive error.

A qualitative study of Canadian resident experiences with Competency-Based Medical Education.

Background: Competency-based medical education (CBME) is an outcomes-based curricular paradigm focused on ensuring that graduates are competent to meet the needs of patients. Although resident engagement is key to CBME's success, few studies have explored how trainees have experienced CBME implementation. We explored the experiences of residents in Canadian training programs that had implemented CBME. Methods: We conducted semi-structured interviews with 16 residents in seven Canadian postgraduate training programs, exploring their experiences with CBME. Participants were equally divided between family medicine and specialty programs. Themes were identified using principles of constructivist grounded theory. Results: Residents were receptive to the goals of CBME, but in practice, described several drawbacks primarily related to assessment and feedback. For many residents, the significant administrative burden and focus on assessment led to performance anxiety. At times, residents felt that assessments lacked meaning as supervisors focused on "checking-boxes" or provided overly broad, non-specific comments. Furthermore, they commonly expressed frustration with the perceived subjectivity and inconsistency of judgments on assessments, especially if assessments were used to delay progression to greater independence, contributing to attempts to "game the system." Faculty engagement and support improved resident experiences with CBME. Conclusion: Although residents value the potential for CBME to improve the quality of education, assessment and feedback, the current operationalization of CBME may not be consistently achieving these objectives. The authors suggest several initiatives to improve how residents experience assessment and feedback processes in CBME.

Contexte: La formation médicale axée sur les compétences (FMFC) est un paradigme d'apprentissage axé sur les résultats et visant à garantir que les diplômés aient les compétences nécessaires pour répondre aux besoins des patients. Bien que l'engagement des résidents soit la clé du succès de la FMFC, peu d'études ont exploré comment ils vivent son introduction. Nous nous sommes penchés sur l'expérience des résidents dans les programmes de formation canadiens qui ont mis en œuvre la FMFC. Méthodes: Nous avons mené des entrevues semi-structurées avec 16 résidents de sept programmes de formation postdoctorale canadiens, afin de sonder leur expérience de la FMFC. Les participants provenaient de façon égale de la médecine familiale et de programmes de spécialité. Les thèmes ont été dégagés en appliquant les principes de la théorie enracinée constructiviste. Résultats: Bien que réceptifs aux objectifs de la FMFC, les résidents décrivent des inconvénients de sa mise en pratique, notamment sur le plan de l'évaluation et de la rétroaction. Pour beaucoup d'entre eux, la focalisation sur l'évaluation et le fardeau administratif qui y est lié ont été une source d'anxiété de performance. Les résidents ont l'impression que les évaluations manquent parfois de pertinence, car les superviseurs, se sentant contraints de « cocher des cases ¼, font des commentaires trop généraux et peu ciblés. De plus, un sentiment de frustration a été fréquemment exprimé face à la subjectivité et à l'incohérence perçues des jugements dans les évaluations, surtout lorsque ces dernières sont utilisées pour retarder le cheminement vers une plus grande indépendance, ce qui contribue à des tentatives de « déjouer le système ¼. L'implication et le soutien du corps professoral ont aidé à bonifier l'expérience des résidents. Conclusion: Bien que les résidents apprécient le potentiel de la FMFC pour rehausser la qualité de la formation, de l'évaluation et de la rétroaction, son opérationnalisation actuelle ne permet pas d'atteindre ces objectifs de façon systématique. Les auteurs proposent quelques initiatives pour améliorer la façon dont les résidents vivent les processus d'évaluation et de rétroaction dans le cadre de la FMFC.

Retinal image quality in myopic children undergoing orthokeratology alone or combined with 0.01% atropine.

BACKGROUND: The retinal image quality derived from lower-order (LOA) and higher-order aberrations (HOA) for fixed 3-mm and photopic pupil diameters, in children undergoing combined 0.01% atropine and orthokeratology (AOK) versus those receiving orthokeratology alone (OK) over two years was evaluated. METHODS: The visual Strehl ratio based on the optical transfer function (VSOTF), derived from 2nd- to 4th-order terms (LOA and HOA combined), 2nd-order terms (LOA only), and 3rd- to 4th-order terms (HOA only) for fixed 3-mm and natural photopic pupil diameters, was compared between the two treatment groups. The individual Zernike coefficients for a fixed 3-mm pupil size of 2nd- to 4th-orders, root mean square (RMS) of LOA ([Formula: see text], [Formula: see text], and [Formula: see text] combined), HOA (3rd to 4th orders inclusive), and Coma ([Formula: see text] combined) were also compared between the two groups. RESULTS: Right eye data of 33 AOK and 35 OK participants were analysed. Under photopic conditions, significantly lower VSOTF based on HOA only was observed in the AOK group compared with that in the OK group at all post-treatment visits (all P < 0.05); however, interactions between HOA and LOA resulted in comparable overall retinal image quality (i.e., VSOTF based on LOA and HOA combined) between the two groups at all visits (all P > 0.05). For a fixed 3-mm pupil size, the VSOTF based on HOA only, LOA only, or HOA and LOA combined, were not different between the two groups (all P > 0.05). AOK participants had slower axial elongation (mean ± SD, 0.17 ± 0.19 mm vs. 0.35 ± 0.20 mm, P < 0.001), a larger photopic pupil size (4.05 ± 0.61 mm vs. 3.43 ± 0.41 mm, P < 0.001) than OK participants, over two years. CONCLUSIONS: HOA profile related to an enlarged pupil size may provide visual signal influencing eye growth in the AOK group.

Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes.

OBJECTIVE: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (ß ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3). CONCLUSIONS: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

The association between altered intestinal microbiome, impaired systemic and ocular surface immunity, and impaired wound healing response after corneal alkaline-chemical injury in diabetic mice.

Purpose: We aim to investigate the effect of sustained hyperglycemia on corneal epithelial wound healing, ocular surface and systemic immune response, and microbiome indices in diabetic mice compared to controls after alkaline chemical injury of the eye. Methods: Corneal alkaline injury was induced in the right eye of Ins2Akita (Akita) mice and wild-type mice. The groups were observed at baseline and subsequently days 0, 3, and 7 after injury. Corneal re-epithelialization was observed under slit lamp with fluorescein staining using a cobalt blue light filter. Enucleated cornea specimens were compared at baseline and after injury for changes in cornea thickness under hematoxylin and eosin staining. Tear cytokine and growth factor levels were measured using protein microarray assay and compared between groups and time points. Flow cytometry was conducted on peripheral blood and ocular surface samples to determine CD3+CD4+ cell count. Fecal samples were collected, and gut microbiota composition and diversity pattern were measured using shotgun sequencing. Results: Akita mice had significantly delayed corneal wound healing compared to controls. This was associated with a reduction in tear levels of vascular endothelial growth factor A, angiopoietin 2, and insulin growth factor 1 on days 0, 3, and 7 after injury. Furthermore, there was a distinct lack of upregulation of peripheral blood and ocular surface CD3+CD4+ cell counts in response to injury in Akita mice compared to controls. This was associated with a reduction in intestinal microbiome diversity indices in Akita mice compared to controls after injury. Specifically, there was a lower abundance of Firmicutes bacterium M10-2 in Akita mice compared to controls after injury. Conclusion: In diabetic mice, impaired cornea wound healing was associated with an inability to mount systemic and local immune response to ocular chemical injury. Baseline and post-injury differences in intestinal microbial diversity and abundance patterns between diabetic mice and controls may potentially play a role in this altered response.

Nanotechnology-augmented sonodynamic therapy and associated immune-mediated effects for the treatment of pancreatic ductal adenocarcinoma.

PURPOSE: Sonodynamic therapy (SDT) is emerging as a cancer treatment alternative with significant advantages over conventional therapies, including its minimally invasive and site-specific nature, its radical antitumour efficacy with minimal side effects, and its capacity to raise an antitumour immune response. The study explores the efficacy of SDT in combination with nanotechnology against pancreatic ductal adenocarcinoma. METHODS: A nanoparticulate formulation (HPNP) based on a cathepsin B-degradable glutamate-tyrosine co-polymer that carries hematoporphyrin was used in this study for the SDT-based treatment of PDAC. Cathepsin B levels in BxPC-3 and PANC-1 cells were correlated to cellular uptake of HPNP. The HPNP efficiency to induce a sonodynamic effect at varying ultrasound parameters, and at different oxygenation and pH conditions, was investigated. The biodistribution, tumour accumulation profile, and antitumour efficacy of HPNP in SDT were examined in immunocompetent mice carrying bilateral ectopic murine pancreatic tumours. The immune response profile of excised tumour tissues was also examined. RESULTS: The HPNP formulation significantly improved cellular uptake of hematoporphyrin for both BxPC-3 and PANC-1 cells, while increase of cellular uptake was positively correlated in PANC-1 cells. There was a clear SDT-induced cytotoxicity at the ultrasound conditions tested, and the treatment impaired the capacity of both BxPC-3 and PANC-1 cells to form colonies. The overall acoustic energy and pulse length, rather than the power density, were key in eliciting the effects observed in vitro. The SDT treatment in combination with HPNP resulted in 21% and 27% reduction of the target and off-target tumour volumes, respectively, within 24 h. A single SDT treatment elicited an antitumour effect that was characterized by an SDT-induced decrease in immunosuppressive T cell phenotypes. CONCLUSION: SDT has significant potential to serve as a monotherapy or adjunctive treatment for inoperable or borderline resectable PDAC.

A Survey of Transcription Factors in Cell Fate Control.

Transcription factors (TFs) play a cardinal role in the development and maintenance of human physiology by acting as mediators of gene expression and cell state control. Recent advancements have broadened our knowledge on the potency of TFs in governing cell physiology and have deepened our understanding of the mechanisms through which they exert this control. The ability of TFs to program cell fates has gathered significant interest in recent decades, and high-throughput technologies now allow for the systematic discovery of forward programming factors to convert pluripotent stem cells into numerous differentiated cell types. The next generation of these technologies has the potential to improve our understanding and control of cell fates and states and provide advanced therapeutic modalities to address many medical conditions.

Combined 0.01% atropine with orthokeratology in childhood myopia control (AOK) study: A 2-year randomized clinical trial.

BACKGROUND: To investigate whether combining 0.01% atropine with orthokeratology (AOK) has a better effect in retarding axial elongation, compared with orthokeratology alone (OK) over two years. METHODS: A total of 96 Chinese children aged six to < 11 years with myopia (1.00 - 4.00 D, inclusive) were randomized into either the AOK or OK group in a 1:1 ratio. Axial length (the primary outcome), and secondary outcomes (e.g. pupil size and choroidal thickness) were measured at 1-month and at 6-monthly intervals after commencement of treatment. RESULTS: Both intention-to-treat and per-protocol analyses showed significantly slower axial elongation in the AOK group than OK group over two years (P = 0.008, P < 0.001, respectively). AOK subjects had statistically slower axial elongation (adjusted mean [standard error], 0.17 [0.03] mm vs 0.34 [0.03] mm, P < 0.001), larger increase in mesopic (0.70 [0.09] mm vs 0.31 [0.09] mm, P = 0.003) and photopic pupil size (0.78 [0.07] mm vs 0.23 [0.07] mm, P < 0.001), and greater thickening of the choroid (22.6 [3.5] µm vs -9.0 [3.5] µm, P < 0.001) than OK subjects over two years. Except for a higher incidence of photophobia in the AOK group (P = 0.006), there were no differences in the incidence of any other symptom or adverse events between the two groups. Slower axial elongation was associated with a larger increase in the photopic pupil size and a greater thickening in the choroid in the AOK group. CONCLUSIONS: Slower axial elongation following 2-year AOK treatment may result from increased pupil dilation and a thickening in the choroid observed in the AOK group.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Use of the Cancer and Aging Research Group Predictive Model for Chemotherapy-Related Toxic Effects in a Multiethnic, Older Adult Asian Population.

Importance: The Cancer and Aging Research Group (CARG) prediction model for chemotherapy-related toxic effects has been developed but not yet validated in older Asian adults. In view of differences in drug metabolism and toxic effect reporting in the Asian population, the ability of this tool to guide the cancer treatment decision-making process in older Asian adults needs to be assessed. Objective: To examine the validity of the CARG predictive model in a multiethnic Asian cohort of older adults. Design, Setting, and Participants: In this prognostic study, patients of various Asian ethnicities 70 years or older with a solid tumor diagnosis receiving chemotherapy at the National University Cancer Institute, Singapore, were accrued from June 1, 2017, to January 1, 2019. Their risks of chemotherapy-related toxic effects were calculated using the CARG tool. A geriatric assessment was performed, and the treating oncologist (blinded to the CARG scores) was asked to give an estimated likelihood of toxic effects (low, medium, or high). Chemotherapy-related toxic effects were recorded during each clinic visit. Validation of the prediction model was performed by calculating the area under the receiver operating characteristic curve. Multivariate analyses were performed to identify variables in other domains in the geriatric assessment predicting for severe toxic effects. Main Outcomes and Measures: Grade 3 to 5 toxic effects and hospitalization. Results: The study included 200 patients (median age, 74 years [range, 70-89 years]; 110 [55.0%] male; 177 [88.5%] Chinese, 17 [8.5%] Malay, 4 [2.0%] Indian, and 2 [1.0%] other ethnicities [according to Singapore's national system of race classification]). A total of 137 patients (68.5%) experienced grade 3 to 5 toxic effects, and 131 (65.5%) required hospitalization. The area under the receiver operating characteristic curve for the CARG chemotoxicity prediction model was 0.74 (95% CI, 0.67-0.82), retaining good discrimination in the study population. Conclusions and Relevance: This prognostic study conducted in a multiethnic Asian cohort of older adults supports the validity of the CARG predictive model in this population, predicting which older adults are at risk of chemotherapy-related toxic effects.

Regression-Based Strategies to Reduce Refractive Error-Associated Glaucoma Diagnostic Bias When Using OCT and OCT Angiography.

Purpose: The purpose of this study was to correct refractive error-associated bias in optical coherence tomography (OCT) and OCT angiography (OCTA) glaucoma diagnostic parameters. Methods: OCT and OCTA imaging were obtained from participants in the Hong Kong FAMILY cohort. The Avanti/AngioVue OCT/OCTA system was used to measure the peripapillary nerve fiber layer thickness (NFLT), peripapillary nerve fiber layer plexus capillary density (NFLP-CD), macular ganglion cell complex thickness (GCCT), and macular superficial vascular complex vascular density (SVC-VD). Healthy eyes, including ones with axial ametropia, were enrolled for analysis. Results: A total of 1346 eyes from 792 participants were divided into 4 subgroups: high myopia (<-6D), low myopia (-6D to -1D), emmetropia (-1D to 1D), and hyperopia (>1D). After accounting for age, sex, and signal strength, multivariable regression showed strong dependence in most models for NFLT, GCCT, and NFLP-CD on axial eye length (AL), spherical equivalent (SE) refraction, and apparent optic disc diameter (DD). Optical analysis indicated that AL-related transverse optical magnification variations predominated over anatomic variations and were responsible for these trends. Compared to the emmetropic group, the false positive rates were significantly (Chi-square test P < 0.003) elevated in both myopia groups for NFLT, NFLP-CD, and GCCT. Regression-based adjustment of these diagnostic parameters with AL or SE significantly (McNemar test P < 0.03) reduced the elevated false positive rates. Conclusions: Myopic eyes are biased to have lower NFLT, GCCT, and NFLP-CD measurements. AL- and SE-based adjustments were effective in mitigating this bias. Translational Relevance: Adoption of these adjustments into commercial OCT systems may reduce false positive rates related to refractive error.

Enhanced Monofocal Versus Conventional Monofocal Intraocular Lens in Cataract Surgery: A Meta-analysis.

PURPOSE: To compare different outcomes of an enhanced monofocal intraocular lens (IOL) versus a conventional monofocal IOL implantation after cataract surgery. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline was used for abstracting data and assessing quality. Comparative studies between enhanced monofocal versus conventional monofocal IOL implantations reporting outcomes in monocular and binocular visual acuities at various distances, spectacle independence, contrast sensitivity, optical quality, and adverse effects were identified from three databases. Meta-analysis, sensitivity analysis, and subgroup analysis were performed. RESULTS: A total of 680 eyes implanted with an enhanced monofocal IOL (Tecnis Eyhance ICB00; Johnson & Johnson) and 647 eyes with a conventional monofocal IOL from 3 randomized controlled trials and 9 comparative studies were included. The enhanced monofocal IOL showed better monocular uncorrected intermediate visual acuity (UIVA) (mean difference [MD]: -0.11 logMAR; 95% CI: -0.12 to -0.09), binocular UIVA (MD: -0.17 logMAR; 95% CI: -0.23 to -0.11), and binocular uncorrected near visual acuity performance (MD: -0.17 logMAR; 95% CI: -0.29 to -0.04) than the conventional monofocal IOL. More patients were spectacle free at intermediate distance with the enhanced monofocal IOL (odds ratio: 12.9; 95% CI: 6.2 to 27.0). Both monocular (MD: -0.002 logMAR; 95% CI: -0.01 to 0.01) and binocular (MD: 0.01 logMAR; 95% CI: -0.02 to 0.03) uncorrected distance visual acuity revealed non-significant differences between the IOL designs. Contrast sensitivity, photic phenomenon, and adverse effects were comparable. CONCLUSIONS: Enhanced monofocal IOLs effectively improved unaided intermediate vision with similar distance performance relative to conventional monofocal IOLs. This was achieved without compromising the contrast sensitivity or inducing photic phenomena. [J Refract Surg. 2022;38(8):538-546.].

Integrated electro-coagulation and gravity driven ceramic membrane bioreactor for roofing rainwater purification: Flux improvement and extreme operating case.

The collected roofing rainwater with high water quality and large water volume, can alleviate the crisis of water resources and fit the Low-Impact Development (LID) concept. In this work, a novel water purification technology, Electro-Coagulation coupled with Gravity-Driven Ceramic Membrane Bio-Reactor (EC-GDCMBR) was developed for the roofing rainwater purification under long-term operation (136 days). EC-GDCMBR system not only exhibited the better effluent quality, but also obtained the greater flux (~32 LMH). The reason contributed to the high permeability of ceramic membrane and large porosity of biofilm formed by floc growth (~36 µm) during the EC process, which was also proved by SEM image. The coagulation, adsorption, biodegradation, and coprecipitation of EC-GDCMBR was able to synergistically remove the particulate matter, ammonia nitrogen (NH3-N), Total Phosphorus (TP), organic substances, and heavy metal (i.e., Cr, Zn, and Cu). In particular, via the analysis of bacterial abundance, Extracellular Polymeric Substances (EPS), Assimilable Organic Carbon (AOC), Adenosine Tri-Phosphate (ATP) and Confocal Laser Scanning Microscopy (CLSM), EC could sweep most free bacteria on the ceramic membrane surface, enhancing the biological purification efficiency. Furthermore, a large amount of Pseudomonas (12.4 %-66.7 %) and Nitrospira (1.46 %-3.16 %) in the aggregates formed the biofilms, improved the NH3-N removal. During the long-term operation, there are some unavoidable problems, such as the thick and ripened biofilm of EC-GDCMBR would crack and fall off. Based on this, the current work also studied the reliability of GDCMBR under "extreme operating case", and the results showed that neither the biofilm detachment nor the biofilm breakup had a significant impact on the effluent quality. Overall, the findings of this study suggest the reliability of EC-GDCMBR for the sustainable operation of roofing rainwater purification and improve the application value of decentralized rainwater harvest device.